Fight Aging!

A couple of interesting papers are doing the rounds, in which researchers report on a fivefold extension of yeast chronological life span through what they look on as an exercise in forced microevolution. They subjected yeast strains to an environment containing lithocholic acid, which is actually pretty unpleasant if you're a yeast cell, and allowed the yeast to adapt through generations. Few survived, and those that did survived through the acquisition of mutations that helped them resist the damaging effects of lithocholic acid. As it turns out, there is considerable overlap between mutations that help resist lithocholic acid and mutations that help resist the forms of damage that cause aging in yeast. As a result a number of the mutant lineages are stable and long-lived once the lithocholic acid is no longer present.

This is all quite interesting as a potential path to ranking the relevance of various repair and stress resistance mechanisms in cell aging, and as a way to obtain mutant lineages in which these mechanisms are enabled in potentially novel ways. Yeast are only somewhat multicellular, however, and thus one has to be careful in extrapolating information obtained on aging from yeast to animals. Since enhanced longevity through calorie restriction and cellular housekeeping mechanisms evolved very early on in the history of life, and since the underlying biological machinery is surprisingly similar in yeast and animals, yeast studies have proven very useful in understanding the ways in which cellular behavior changes in order to resist stress. There is no direct connection between cell life span and species life span, however, and when talking about yeast chronological age, it is the life span of a single cell that is under consideration.

Where the researchers overreach, I think, is in claiming that the observed outcome in microevolution argues strongly for programmed aging in macroevolution, in which aging is the result of a genetic program rather than an accumulation of biological wear and tear. It is perfectly possibly, however, to argue that their observations are in line with non-programmed aging theories in which aging is the result of damage accumulation; they have, after all, provided a way for cells to resist and repair damage to a greater degree than is usually possible through greater use of existing mechanisms. Further I'd say that the results at present are not necessarily at all relevant to the operation of macroevolution in the wild over longer periods of time, and again, the situation for single cells doesn't map directly to the situation for multicellular life.

As I understand it, there are views of the evolution of aging in which immortal species with unfettered reproduction are perfectly viable in and of themselves, but they will always be outcompeted in a changing environment by an aging species. Given the small number of mutations to produce yeast that lives five times longer than usual, why do we not see this yeast in the wild? We do not see immortals because they cannot exist, rather we do not see them because they are almost always quickly buried by their aging competitors whenever they do arise. Yet that apparently immortal animals can exist finds evidence in the absence of distinguishable aging in hydra, to pick the best known example. Even the negligible senescence observed in some species is somewhat challenging for the idea that long-lived organisms must necessarily grow more slowly and reproduce less efficiently than short-lived species.

Yeast mutants unlock the secrets of aging

The researchers exposed yeast to lithocholic acid, an aging-delaying natural molecule discovered in a previous study. In so doing, they created long-lived yeast mutants that they dubbed "yeast centenarians." These yeast mutants lived five times longer than their normal counterparts because their mitochondria - the part of the cell responsible for respiration and energy production - consumed more oxygen and produced more energy than in normal yeast. The centenarians were also much more resistant to oxidative damage, which is another process that causes aging. "This confirms that lithocholic acid, which occurs naturally in the environment, can not only delay yeast aging but can also force the evolution of exceptionally long-lived yeast."

The next step? Using yeast centenarians to test two types of aging theories: Programmed aging theories claim that organisms are genetically programmed to have a limited lifespan because aging serves some evolutionary purpose. That would mean that there are active mechanisms that cause aging and limit lifespan. Non-programmed aging theories contend that aging doesn't serve an evolutionary purpose. Therefore, an evolved mechanism whose main goal is to cause aging or limit lifespan simply cannot exist. What's more, non-programmed aging theories posit that any exceptionally long-lived organism must grow slower and reproduce less efficiently than an organism whose lifespan is limited at a certain age.

By producing long-lived yeast mutants and culturing them separately from normal yeast, the researchers were able to show that the centenarians grow and reproduce just as efficiently as the non-centenarians - thereby confirming programmed aging theories. "By confirming that there are active mechanisms limiting the longevity of any organism, we provided the first experimental evidence that such lifespan-limiting active mechanisms exist and can be manipulated by natural molecules to delay aging and improve health."

Empirical Validation of a Hypothesis of the Hormetic Selective Forces Driving the Evolution of Longevity Regulation Mechanisms

Exogenously added lithocholic bile acid and some other bile acids slow down yeast chronological aging by eliciting a hormetic stress response and altering mitochondrial functionality. Unlike animals, yeast cells do not synthesize bile acids. We therefore hypothesized that bile acids released into an ecosystem by animals may act as interspecies chemical signals that generate selective pressure for the evolution of longevity regulation mechanisms in yeast within this ecosystem. To empirically verify our hypothesis, in this study we carried out a three-step process for the selection of long-lived yeast species by a long-term exposure to exogenous lithocholic bile acid. Such experimental evolution yielded 20 long-lived mutants, three of which were capable of sustaining their considerably prolonged chronological lifespans after numerous passages in medium without lithocholic acid. The extended longevity of each of the three long-lived yeast species was a dominant polygenic trait caused by mutations in more than two nuclear genes. Each of the three mutants displayed considerable alterations to the age-related chronology of mitochondrial respiration and showed enhanced resistance to chronic oxidative, thermal, and osmotic stresses.

Our hypothesis posits the following: (1) only yeast exposed to exogenous bile acids can develop mechanisms of protection against cellular damage caused by these external stress agents and hormetic stimuli; (2) some of these mechanisms developed against bile acid-induced cellular damage can also protect yeast against damage and stress accumulated purely with age; (3) only those yeast species that have developed (due to exposure to exogenous bile acids) the most protective mechanisms against bile acid-induced cellular damage can also develop protective mechanisms against damage and stress accumulated with age; and (4) these yeast species are therefore expected to live longer. In this hypothesis, the presence of exogenous bile acids creates hormetic selective force that drives the evolution of not only protective mechanisms against bile acid-induced cellular damage but also longevity regulation mechanisms that protect against damage and stress accumulated with age. Moreover, this hypothesis suggests that yeast cells that are not exposed to exogenous bile acids cannot develop mechanisms of protection against cellular damage caused by these mildly toxic molecules. Thus, these yeast cells are unable to develop mechanisms of protection against damage and stress accumulated purely with age.

Empirical verification of evolutionary theories of aging

We recently selected 3 long-lived mutant strains of Saccharomyces cerevisiae by a lasting exposure to exogenous lithocholic acid. Each mutant strain can maintain the extended chronological lifespan after numerous passages in medium without lithocholic acid. In this study, we used these long-lived yeast mutants for empirical verification of evolutionary theories of aging. We provide evidence that the dominant polygenic trait extending longevity of each of these mutants 1) does not affect such key features of early-life fitness as the exponential growth rate, efficacy of post-exponential growth and fecundity; and 2) enhances such features of early-life fitness as susceptibility to chronic exogenous stresses, and the resistance to apoptotic and liponecrotic forms of programmed cell death.

These findings validate evolutionary theories of programmed aging. We also demonstrate that under laboratory conditions that imitate the process of natural selection within an ecosystem, each of these long-lived mutant strains is forced out of the ecosystem by the parental wild-type strain exhibiting shorter lifespan. We therefore concluded that yeast cells have evolved some mechanisms for limiting their lifespan upon reaching a certain chronological age. These mechanisms drive the evolution of yeast longevity towards maintaining a finite yeast chronological lifespan within ecosystems.

Researchers here investigate dysfunction of the class of cells known as pericytes that surround small blood vessels. These cells regulate blood flow, and in the brain support the blood-brain barrier, among other activities. Like all aspects of our cellular machinery, pericytes suffer damage, reduced function, and greater levels of cell death with advancing age. The open question, as is usually the case, is where this fits in the lengthy chain of of cause and consequence that leads from fundamental cellular damage and waste accumulation of the types outlined in the SENS rejuvenation research materials to specific age-related disease and disability.

A new study is the first to use a pericyte-deficient mouse model to test how blood flow is regulated in the brain. The goal was to identify whether pericytes could be an important new therapeutic target for treating neuron deterioration. "Pericyte degeneration may be ground zero for neurodegenerative disorders like Alzheimer's disease, ALS and possibly others. A glitch with gatekeeper cells that surround capillaries may restrict blood and oxygen supply to active areas of the brain, gradually causing neuron loss that might have important implications for Alzheimer's disease. Vascular problems increase the risk of cognitive impairment in many types of dementia, including Alzheimer's disease. Pericytes play an important part in keeping your brain healthy."

To test the theory, researchers stimulated the hind limb of young mice deficient in gatekeeper cells and monitored the global and individual responses of brain capillaries, the smallest blood vessels in the brain. The global cerebral blood flow response to an electric stimulus was reduced by about 30 percent compared to normal mice, denoting a weakened system. Relative to the control group, the capillaries of pericyte-deficient mice took 6.5 seconds longer to dilate. Slower capillary widening and a slower flow of red blood cells carrying oxygen through capillaries means it takes longer for the brain to get its fuel. As the mice turned 6 to 8 months old, global cerebral blood flow responses to stimuli progressively worsened. Blood flow responses for the experimental group were 58 percent lower than that of their age-matched peers. In short, with age, the brain's malfunctioning vascular system exponentially worsens.

"We now understand the function of blood vessel gatekeeper cells is to ensure adequate oxygen and energy supply to brain cells. Prior to our study, scientists knew patients with Alzheimer's disease, ALS and other neurodegenerative disorders experience changes to the blood flow and oxygen being supplied to the brain and that pericytes die. Our study adds a new piece of information: Loss of these gatekeeper cells leads to impaired blood flow and insufficient oxygen delivery to the brain. The big mystery now is: What kills pericytes in Alzheimer's disease?" Scientists are already working to further this line of research, scanning the brains of people who are genetically at risk for Alzheimer's. They are also collecting cerebral spinal fluid and blood for analysis of vascular damage, including injury to pericytes.

Link: http://news.usc.edu/115566/a-glitch-in-gatekeeper-cells-slowly-suffocates-the-brain/

Fibrosis is the inappropriate formation of scar-like tissue, and it is an important component in the pathology of a range of age-related diseases. Fibrosis causes loss of function where it disrupts the normal tissue structure of organs, and at present there is little in the medical toolkit that can be used to help. Better known examples of conditions in which fibrosis is significant include the progression of chronic kidney disease and damage to aged heart tissue. Here researchers note the possibility for an intervention that slows down the progression of fibrosis in mice, and may form the basis for a human therapy:

The wear and tear of life takes a cumulative toll on our bodies. Our organs gradually stiffen through fibrosis, which is a process that deposits tough collagen in our body tissue. Fibrosis happens little by little, each time we experience illness or injury. Eventually, this causes our health to decline. Ironically, fibrosis can stem from our own immune system's attempt to defend us during injury, stress-related illness, environmental factors and even common infections. But a team of scientists thinks preventative therapies could be on the horizon. "We've documented in mice how deletion of a single gene, PAD4, has a drastic effect on curbing the complex process of fibrosis." Looking to the future, they envision that the development of a once-daily pill, capable of inhibiting PAD4, could one day be used as a preventative measure.

The PAD4 gene controls an enzyme of the same name. In times of infection or bodily stress, the PAD4 enzyme activates a strange, primitive immune defense that ends up doing more harm than good. White blood cells, called neutrophils, self-combust and eject their own DNA strands outward like javelins. Sacrificing themselves, the exploded neutrophils and their outreaching DNA tentacles form so-called neutrophil extracellular traps (NETs), which nature perhaps intended to use as webs for catching foreign invaders and plugging up injury-related bleeding. Even though NETs try to help us, they counteractively set off a chain reaction that deposits an insidious type of collagen amidst our organs' hard-working cells. This collagen-laced fibrosis keeps piling up each time our body's immune system releases NETs. Over a lifetime, cumulative fibrosis is a far more important factor in health than any possible benefits imparted by NET release.

Whereas young hearts in mice and humans contain thin layers of connective tissue, older hearts typically have too much connective collagen built up between heart muscle cells. This reduces the heart's ability to pump blood efficiently. To investigate PAD4's effects on age-related cardiac fibrosis, researchers compared heart tissue of normal mice with another group of mice that had the PAD4 gene deleted. They observed that old mice without PAD4 had much less fibrosis than the normal mice. In fact, these mice had heart tissue that looked strikingly similar to heart tissue of young mice, and they kept up remarkably "young" levels of systolic and diastolic heart function as they aged. Researchers then looked at collagen deposition in mouse lungs. They found that deleting the PAD4 gene also significantly reduced lung fibrosis as mice aged. The researchers believe these observations show that deleting the PAD4 gene in mice protected their organs from age-related fibrosis and dysfunction. "If we could inhibit PAD4 or otherwise stop NET release in humans, we might be able to greatly reduce age-related fibrosis and improve our quality of life."

Link: https://www.eurekalert.org/pub_releases/2017-01/bch-faf012717.php

A fair few good scientific papers on the role of cellular senescence in the progression of osteoarthritis have emerged in the last year. Given that UNITY Biotechnology aims to initially trial senolytic therapies to clear senescent cells as a treatment for inflammatory joint diseases, a list in which osteoarthritis features prominently, and that the UNITY principals now have quite a lot of funding to work with, I expect that we'll be hearing a lot more on this topic over the course of the next few years. There is nothing quite like the existence of a funded company in a field to spur a great deal more investment in related research from all sources. The rate at which reviews of the relevant science are published tends to increase as well, with the paper linked below as an example of the type.

Senescent cells accumulate in tissues with age, and that accumulation is thought to be one of the causes of degenerative aging. While the immune system tends to destroy most of the senescence cells that fail to destroy themselves, its declining effectiveness in later life helps to ensure that the count of senescent cells keeps rising. In small numbers these cells are harmless; they have a role in wound healing, senescence followed by destruction is the normal end state for all somatic cells that reach the Hayflick limit, and senescence in response to damage or toxic stress helps to prevent cancer by removing those cells most at risk. Senescent cells secrete a potent mix of signal molecules, however, and when present in larger numbers this senescence-associated secretory phenotype (SASP) produces considerable harm. In the case of conditions driven by inflammation, or with strong inflammatory components, such as osteoarthritis, perhaps the most relevant aspect of cellular senescence is that the SASP includes pro-inflammatory signals. Senescent cells generate greater local inflammation, and more of all the consequences that follow on from that.

That rising inflammation has such an important role in the progression of many age-related conditions, and that senescent cells are a notable source of inflammation, are reasons to think that targeted removal of senescent cells should be broadly beneficial for human patients. The sooner that senolytic therapies can be brought to the clinic, the better. Currently the near term prospects seem quite hopeful, since the initial brace of senolytic drug candidates are forms of chemotherapeutic, already well characterized for human use as a result of cancer treatment trials, and their mechanisms of action comparatively well understood. If they can be used at lower dosages, at which the serious side-effects of cancer chemotherapy can be avoided, then we may well see responsible medical tourism for senescent cell clearance a couple of years from now. For those who want to wait for treatments with few to no side-effects, there is always the work being undertaken by Oisin Biotechnologies, which will likely follow on to clinics a few years thereafter.

Cellular senescence in osteoarthritis pathology

Osteoarthritis (OA) is the most prevalent disease of synovial joints (around 4.7% of global population for knee and hip OA alone), afflicting many millions worldwide with pain and disability, and thus represents an enormous healthcare and socioeconomic burden. Advancing age is a major risk factor, thus the burden of OA is set to increase dramatically as populations continue to age. A joint affected by OA exhibits progressive degeneration of the articular cartilage, formation of bony peripheral outgrowths (osteophytes), changes in subchondral bone and thickening of both the synovium and ligaments, and in many cases synovial inflammation (synovitis), which is thought to be an important driver of early pathology. Pathologic roles for multiple tissues in deteriorating joint function therefore define OA as a whole joint disease, driven by various biomechanical and inflammatory factors. There are currently no treatments available to effectively prevent or reverse progressive joint damage; therefore, new and innovative treatments are urgently required to improve treatment options. This will require continued improvements in our understanding of the molecular mechanisms underlying OA pathology.

Senescent cells secrete a variety of inflammatory cytokines, growth factors and many more soluble and insoluble factors known as the senescence-associated secretory phenotype (SASP). These factors are secreted into the cell microenvironment, with cytokines such as IL-6 and IL-8 enforcing the stable growth arrest of senescent cells. Various features of senescent cells, such as the SASP, can cause damage to surrounding tissue. SASP secreted by senescent cells can alter the tissue microenvironment, while the senescence of stem or progenitor cells can impair tissue regeneration. Over the past decade, many studies have linked cellular senescence to aging and age-related pathologies, thus leading to an overlap in research between the fields of disease processes and gerontology.

Although there are multiple joint tissues and cell types involved in OA pathology, chondrocytes have been the focus of the vast majority of studies to date that address a role for senescence. Chondrocytes are the only cell type present in articular cartilage, a highly specialized avascular and aneural tissue whose structural and mechanical properties are largely defined by the two predominant extracellular matrix (ECM) components, type II collagen, and aggrecan. Chondrocytes are responsible for producing and maintaining this ECM and receive nutrients and external chemical signals from the synovial fluid via secretions of fibroblast-like synoviocytes of the intimal synovial layer.

It is thought that cellular senescence may play a significant role in the pathology of OA, with OA chondrocytes exhibiting a variety of senescent-associated phenotypes. Despite recent traction for views of OA as a whole joint disease rather than merely dysfunctional cartilage, chondrocytes remain regarded as key players in OA pathology and are understood to exhibit during disease a perturbation of the normal balance between synthesis and degradation of extracellular matrix (ECM) components. This involves upregulating the production of matrix-degrading metalloproteinases such as MMP-13, exogenous activity of which was sufficient to recapitulate key OA features in mice. Senescence of chondrocytes would be expected to lead similarly to shifting of the balance between ECM synthesis and degradation, through metalloproteinase components of the SASP response.

Senotherapeutic agents are used to target specific properties of cellular senescence; more specifically, senolytics are used to target anti-apoptotic mechanisms and induce cell death within senescent cells. Senolytic drugs may therefore also be potentially used to provide an innovative therapeutic approach to treatment of various conditions. Dasatinib is currently used in the treatment of cancer. It is widely accepted that cancer cells and senescent cells share common anti-apoptotic characteristics, and the combination treatment of dasatinib and quercetin has already been observed to reduce the burden of senescent cells, as well as enhance cardiovascular function, in aged mice. We have reviewed a body of work that, taken together, strongly suggests that senescence could play a significant role in the pathogenesis of OA. Therefore, if dasatinib/quercetin combination therapy is effective in eliminating senescent cells, it could provide an extremely appealing therapeutic target for OA.

A spread in the longevity of similar individuals is a feature of any collection of demographic data. Are these variations simply random, a matter of luck and happenstance, or do they reflect underlying genetic or environment differences that are presently only poorly understood, absent in the data recorded for each individual? In other words, how much of natural variation in human longevity has been explained by the research community, and its causes identified, at least to a first approximation? Are there significant differences between individuals yet to be understood? It is possible to use statistical techniques to identify the relative contributions of distinct classes of influence on these variations in longevity, and here, researchers replicate past findings by showing that hidden differences between individuals likely account for little of the observed variation in human longevity. This suggests that there are probably no very large surprises ahead of us when it comes to understanding influences on aging in our species.

Individual variance, especially in fitness components, plays a key role in demography, ecology, and evolutionary biology. From an evolutionary perspective, variance in fitness components is potential material on which natural selection can operate. Longevity (age at death) is a fitness component that varies widely among individuals. This variance arises as a result of two different underlying causes: individual stochasticity and heterogeneity.

Individual stochasticity is variance due to random outcomes of probabilistic demographic processes (living or dying, reproducing or not, making or not making a life cycle transition). Even in a completely homogeneous population, in which every individual experienced exactly the same (age-specific) mortality rates, variance due to individual stochasticity would exist. Any calculation of the variance in longevity from an ordinary life table implicitly assumes that every individual is subject to the (age-specific) mortality rates in that life table, and hence that the variance is only due to individual stochasticity.

Variance in longevity can also result from unobserved, or latent, heterogeneity in the properties of individuals. For example, individuals of the same age may differ in their mortality rates due to genetic, environmental, or maternal effects. Such differences are often referred to as heterogeneity in individual frailty. Because more frail individuals are more at risk than others, heterogeneity in frailty leads to changes in cohort composition with age, due to within-cohort selection. As a cohort ages, the representation of less frail individuals increases, and the average mortality rate in an old cohort will be lower than one would expect based on extrapolation of mortality rates at younger ages. This selection effect has been suggested as an explanation for the mortality plateaus often observed at very old ages.

The effects of unobserved heterogeneity in survival analysis can be estimated using frailty models. In frailty models, a baseline mortality schedule is modified by a term representing individual frailty. The variance in longevity in a frailty model is a result of both stochasticity and heterogeneity. Little is known about the relative contribution of each to the total variance in longevity, and how those contributions may depend on species, sex, environmental conditions, etc. Other researchers have presented an ad hoc approach to this problem: the relative contributions of heterogeneity and stochasticity were estimated by reducing the initial variance in frailty to zero and attributing the remaining longevity variance to stochasticity. In an analysis of Swedish females, the fraction of variance due to heterogeneity was estimated to be only 0.071. Applying the same approach to a model for women from Turin resulted in an even lower estimate of 0.012.

Here, we present a more rigorous model. The variance due to individual stochasticity can be calculated from a Markov chain description of the life cycle. The variance due to heterogeneity can be calculated from a multistate model that incorporates the heterogeneity. We show how to use this approach to decompose the variance in longevity into contributions from stochasticity and heterogeneous frailty for male and female cohorts from Sweden (1751-1899), France (1816-1903), and Italy (1872-1899), and also for a selection of period data for the same countries. The results were consistent between countries and sexes: most of this variance in remaining longevity is due to stochasticity. Only a small fraction is attributable to heterogeneity. This fraction increases with starting age, because stochasticity-induced variance decreases faster with age than does heterogeneity-induced variance. However, even conditioning on survival to a starting age of 70 years, the average fraction due to heterogeneity is less than 0.10 (for cohort mortality) or 0.15 (for period mortality). Although data quality is, for obvious reasons, better for later cohorts and periods than for earlier ones, we found no clear temporal patterns in the fraction of variance due to heterogeneity.

Link: http://dx.doi.org/10.1016/j.tpb.2017.01.001

Members of the Spanish longevity science and cryonics communities have organized a conference to be held later this year in Barcelona, Madrid, and Seville. Good for them; it is always pleasant to see the various regional groups of our broader community growing in sophistication and reach. Advocacy and publicity for the cause of radical life extension moves forward one modest step at a time. The more that we talk to the public and the more that we work to build larger networks of supporters, the closer we move towards the realization of technologies that can extend healthy life spans. Further, the cryonics industry remains small enough at this time to benefit considerably from greater efforts to draw together the groups of supporters that exist in numerous countries around the world. We can hope that such an initiative will lead in time to the successful foundation of new cryonics service and support companies outside the US, an evolution of the industry that is long overdue.

Spain will host the first International Longevity and Cryopreservation Summit during May 26-28, 2017. Fundacion VidaPlus will be the main organizer of this world congress, with the help of other leading associations and organizations working on longevity, indefinite lifespans, cryopreservation, and other biomedical areas. Longevity extension has been one of the dreams of humanity since the beginning of recorded history. Even starting the 20th Century average lifespans were just about 40 years in the first industrial nations, and starting the 21st Century average lifespans have doubled again to around 80 years in the most advanced countries. The possibility of doubling again lifespans is increasing rapidly again thanks to exponential technologies and new medical research and development. On a parallel front, cryonics has also advanced considerably since the first spermatozoids were frozen and successfully reanimated about half a century ago. Then followed eggs, embryos, many tissues and complete organs, in different kinds of animals, including some small mammals. What will the future bring? Science and technology should lead the way!

Several institutions have been advancing research on longevity extension, from governments to private companies. Institutions like the Life Extension Foundation and the SENS Research Foundation, to name just two, have been pioneers in promoting investigations and applications on human longevity extension. Additionally, the two major US cryonics institutions, Alcor Life Extension Foundation and Cryonics Institute, have been holding successful regular meetings for their members and other insterested audiences during the last four decades. In Europe, there was an initial regional meeting in Goslar (Germany) in 2010, followed by Dresden (Germany) in 2014, Utrecht (Netherlands) in 2015, and then Basel (Switzerland) in 2016. KrioRus has also been promoting cryonics in Russia and other countries.

Now we are planning to host in Spain the first International Longevity and Cryonics Summit open to people from all continents, with participants coming from the United States to the United Kingdom, from Argentina to Australia, from Africa to China, from Russia to Venezuela. The topics considered will be very broad, ranging from recent medical advances to human cryopreservation. Spain will become the meeting point for this first summit, where there are plans to create an International Cryonics Society to gather and accredit the different groups working around the world. The first part of the May events will be the international congress in English during the weekend of May 27-28 in Madrid, followed by national events in Spanish on May 29 in Madrid, May 30 in Barcelona, and May 31 in Seville. The objective is to combine the international reunions with local audiences and to help promote longevity and cryonics research and development in Spain.

Link: http://longevitycryopreservationsummit.com/

As I opened the week with a reprint of the Million Year Life Span, it seems fitting to end the week with a short article that focuses on one important aspect of much the same topic. After aging is conquered, the pursuit of exceptional longevity will require us to move beyond biology. Given present accident rates, ageless humans will only live for a few thousand years. Even with vastly reduced accident rates, sooner or later the vulnerable human physiology will succumb to misfortune. To live for very much longer, for tens and hundreds of thousands of years, we must transcend our biological origins in some way. The operation of our minds must move to a far more robust and easily maintained machine infrastructure, each neuron a device. But as those who favor uploading and emulation of the mind in software would point out, physical existence based on machines taking the place of neurons is only one of the many options for transcendence that will open up with progress in technology. To my eyes, the vital, the only question to ask at each stage of the process of becoming greater and vaster than before is whether you will still be you afterwards: is your continuity as an individual preserved?

Becoming Immortal: The Future of Brain Augmentation and Uploaded Consciousness

Let's say you replace a single neuron in your brain with one that functions thousands of times faster than its biological counterpart. Are you still you? You'd probably argue that you are, and even a significant speed bump in a single neuron is likely to go largely unnoticed by your conscious mind. Now, you replace a second neuron. Are you still you? Again, yes. You still feel like yourself. You still have the continuity of experience that typically defines individuality. You probably still don't notice a thing, and indeed, with only a couple of overachieving neurons, there wouldn't be much to notice. So, let's ramp it up. You replace a million neurons in your brain with these new, speedy versions, gradually over the course of several months. Sounds like a bunch, right? Not really; you've still only replaced 0.001% of your brain's natural neurons by most estimates. Are you still you?

You may find you're reading books a teensy bit faster now, and comprehending them more easily. An abstract math concept that once confused you now begins to make some sense. You're still very much human, though. But why stop there? You're feeling pretty good. You feel the tug of something greater calling you. Is it the curiosity, the siren call of improving one's own intelligence? You embark on a neurological enhancement regimen of two billion fancy new neurons every month for a year. After this time, you've got on the order of 24 billion artificial neurons in your head, or about a quarter of your brain.

Are you still you? Your feelings and emotions are still intact, as the new neurons don't somehow erase them; they just process them faster. Or they don't, depending upon your preference. About half-way through this year, you began noticing profound perceptual changes. You've developed a partially eidetic memory. Your head is awash in curiosity and wonder about the world, and you auto-didactically devour articles at a rapid clip. Within weeks you've attained a PhD-level knowledge of twenty subjects, effortlessly. All art becomes not just a moving experience, but an experience embedded in a transcendental web of associations with other, far-removed concepts. Synesthesia doesn't begin to cover what you're experiencing. But here's the thing; it's not overwhelming, not to your enhanced, composite brain and supercharged mind.

You reason (extraordinarily quickly at this point), that since you don't seem to have lost any of your internal experience, you should seek the limit or its limitlessness, and replace the rest of it. After all, at this point, everyone else is, too. It's getting harder to find work for someone who's only a quarter-upgraded. Over the next three years you continually add new digital neurons as your biological ones age, change, and die out. Are you still you? Following this, you are a genius by all traditional measures. Only the most advanced frontiers of mathematics and philosophy give you pause. Everything you've ever experienced, every thought that was ever recorded in your brain (biological or otherwise) is available for easy access in an instant.

Years pass. The same medical technology that allowed your neurons to be seamlessly replaced, aided and accelerated by a planet full of supersavants, has replaced much of your biological body as well. You're virtually immortal. Only virtually, of course, because speeding toward Earth at a ludicrous velocity is a comet the size of Greenland. There is general displeasure that the Earth will be destroyed (and just after we got smart and finally cleaned her up!), but there's a distinct lack of existential terror. Everyone will be safe, because they are leaving. How does a civilization, even a very clever one, evacuate billions of people from a planet in the space of years? It builds some very large machines that circle the Sun, and it uploads everyone to these machines. Uploads? People? Why sure, by now everyone has 100% electronic minds. These minds are simply software; in fact, they always were. Only now, they're imminently accessible, and more importantly, duplicable.

Billions of bits of minds of people are beamed across the solar system to where the computers and their enormous solar panels float, awaiting their guests. Of course, just as with your neuronal replacements all those years ago, this is a gradual process. As neurons are transferred, their counterparts in your skull are disabled. The only difference you feel is a significant lag, sometimes on the order of minutes, due to the millions of miles of distance between one half of your consciousness and the other. Eventually, the transfer is complete, and you wake up in a place looking very familiar. Are you still you?

What is the difference between a process of gradual replacement that resembles the neurogenesis and cell death that already happens in the brain and a process that kills you in order to create a duplicate? Where does the Ship of Theseus, in which it seems sensible to argue it is the same ship if a single plank is replaced, become the grandfather's ax, where we start to have doubts about continuity when replacing the head or handle? Further, how fast and transformative a replacement of neurons can take place before we call it death rather than transcendence? The essential nature of slow replacement that argues for continuity is that (a) the new replacement is a small part of the whole, and (b) the replacement comes to equilibrium with the existing structure before the next replacement takes place. The neuron integrates into neural circuits, the plank is taken voyaging. Large replacements and rapid replacement are both problematic. Few people would be comfortable swapping out a quarter of the brain at once, or running a process of neuron by neuron replacement for the entire brain in an hour. Nor should they be. What use is it if a pattern survives when you, yourself, do not?

In the decades ahead, it will become possible to copy and dramatically alter the mind, as well as to replace neurons with machinery. That doesn't mean that every such implementation is a sound path to exceptional longevity, a continuity of the self far beyond the limits of biological human agelessness. Many of them will be expensive ways to achieve a subtle form of suicide. A copy of you is not you, and for that matter it is far from clear that an emulated mind running in software is in fact a discrete and continuous entity rather than an ongoing flicker of partial, immediately destroyed shades. That depends entirely on the computational architecture. Unless data is tied to physical structure in the same way as occurs in neurons and the human mind, it is hard to argue for an emulation to be alive, a discrete individual in the way we are. No mainstream computational architecture is heading in that direction, and it seems likely that the first emulations will run many layers of abstraction removed from questions of physical storage models. This is a horrible tragedy, but those who disagree with my metaphysics will no doubt go ahead and do it anyway.

I believe that an important existential challenge will arise in the next phase of human longevity, after aging is cured, driven by the economics of mind emulation and other neurotechnologies yet to be developed. Emulations, and other people willing to break continuity of the self by altering the data of the mind in similar drastic ways, such as by running multiple copies with periodic reintegration through overwriting data, will have a considerable economic advantage over those who strive to be certain in retaining continuity of identify. They can change themselves to circumstances, and undertake far more activities per unit time. If present opinions and trends are any guide, there is the risk of humanity dwindling to only a handful of long-lived entities, lost amidst a sea of transient and ever-changing ghosts that pretend to continuous existence but in fact destroy themselves over and over, more rapidly than they form thoughts. It will be the death of identity, and the death of all of those who once lived, but then chose to transform themselves into the basis for such a computational wilderness, where there is only oblivion writ large and repeated, not life as we understand it.

Stem cell therapies produce benefits, but for most of the presently available treatments this appears to be the result of changes in the signaling environment rather than any other activity on the part of the transplanted cells. The newly introduced stem cells fail to integrate with local tissues and typically don't last long after transplantation. So what exactly produces the observed beneficial changes in cellular behavior, level of inflammation, and degree of regeneration? There are no doubt many distinct mechanisms, as nothing is ever simple when it comes to cell biology, but of late researchers have focused on a role for exosomes. These are membrane-wrapped packages that cells pass between one another, and they appear to be involved in many cellular processes, though at present are only very partially cataloged and understood. If it turns out that they are a primary mechanism by which transplanted stem cells alter the behavior of local cells, then it should be possible to build therapies that deliver only exosomes:

Exosomes are tiny membrane-enclosed packages that form inside of cells before getting expelled. Long thought of as part of a cellular disposal system, scientists have more recently discovered that exosomes are packed with proteins, lipids and gene-regulating RNA. Studies have shown that exosomes from one cell can be taken up by another by fusing with the target cell's membrane, spurring it to make new proteins. Exosomes also facilitate cell-to-cell interactions and play a signaling role, prompting research into their potential therapeutic effect.

A new study in rats shows that exosomes appear to protect cells in the retina, the light-sensitive tissue in the back of the eye. Researchers investigated the role of stem cell exosomes on retinal ganglion cells, a type of retinal cell that forms the optic nerve that carries visual information from the eye to the brain. The death of retinal ganglion cells leads to vision loss in glaucoma and other optic neuropathies. Stem cells have been the focus of therapeutic attempts to replace or repair tissues because of their ability to morph into any type of cell in the body. However, from a practical standpoint, using exosomes isolated from stem cells presents some key advantages over transplanting whole stem cells. Exosomes can be purified, stored and precisely dosed in ways that stem cells cannot.

Another important advantage of exosomes is they lack the risks associated with transplanting live stem cells into the eye, which can potentially lead to complications such as immune rejection and unwanted cell growth. In a rat glaucoma model, researchers studied the effects of exosomes isolated from bone marrow stem cells on retinal ganglion cells. Exosomes were injected weekly into the rats' vitreous, the fluid within the center of the eye. Prior to injection, the exosomes were fluorescently labelled allowing the researchers to track the delivery of the exosome cargo into the retinal ganglion cells. Exosome-treated rats lost about a third of their retinal ganglion cells following optic nerve injury, compared with a 90-percent loss among untreated rats. Stem cell exosome-treated retinal ganglion cells also maintained function, according to electroretinography, which measures electrical activity of retinal cells. The researchers determined that the protective effects of exosomes are mediated by microRNA, molecules that interfere with or silence gene expression. Further research is needed to understand more about the specific contents of the exosomes.

Link: https://www.eurekalert.org/pub_releases/2017-01/nei-scs012517.php

This article is a profile of one of the research groups working on decellularization and reconstruction of the heart. As is more often the case in this field these days, those involved are willing to talk about timelines for putting this research into practice. Decellularization is a promising shortcut to the creation of patient-matched organs for transplantation. A donor organ is stripped of cells until only the extracellular matrix structure and its chemical guides and signals is left. That is then populated with the patient's cells, which grow into place and rebuild the tissues. Once the technical challenges have been solved, and the methodologies made reliable, this can potentially expand the pool of donor organs to include a sizable fraction of those that at present are discarded as unsuitable due to tissue damage. It should also be possible to use animal organs as well, such as from pigs, as the decellularization process removes near all of the sources of incompatibility.

Th first thing visitors to the Texas Heart Institute's Regenerative Medicine Research labs see is a pair of large photographs. In one, a lined hand of Denton Cooley, founder of the institute, who died last November, holds a mechanical heart much like the one that he was the first to implant into a human in 1969. In the other, Doris Taylor's gloved hand holds a pig's heart so stark-white, it matches her lab coat. It is a Ghost Heart, scrubbed clean of all cells, leaving only collagen, fibronectin and laminin, which provide a protein scaffold on which to build a new human heart very nearly from scratch. One day, it will cure far more patients with bum tickers than Cooley's earlier invention ever did.

Taylor and her 25-person multidisciplinary team decellularize seven or eight hearts, mostly from rats, a week, then inject the DNA-free scaffolds with stem cells. Because muscular heart cells do not divide, they cannot regenerate on their own like, say, the bladder, an organ which has been regenerated and implanted in humans. In the case of the heart, stem cells (as opposed to heart cells) adhere to the surface of the scaffold, growing into living, functioning organs inside machines known as bioreactors, which replicate the warm, oxygen-rich environment of a heart inside a mammal's body.

The goal, of course, is to build viable organs that will pump blood through an adult's body without assistance and without the threat of rejection, since the heart will be made with the recipient's own cells. Current testing in rats has involved implanting a second heart alongside the original, in hopes that the new organ will strengthen enough inside the body to take command. Taylor estimates that it will be only 10 or 15 years before a functioning heart is implanted into an adult (pediatric hearts are smaller and require less muscle, so that could happen sooner) - "if we do it right. And what I mean by that is that although it's sexy to be first, it's better to be best." Taylor expects a fully functioning liver made from a recipient's own cells will precede the heart by several years.

Link: https://www.houstoniamag.com/articles/2017/1/23/texas-heart-institute-new-research-ghost-heart

The research community is now well and truly woken up when it comes to senescent cells and aging, after long years of ignoring this corner of the field, the paper linked below is illustrative of the sort of reviews on the subject being written nowadays. It took quite a while to achieve this awakening. Good evidence for senescent cell accumulation as a contributing cause of degenerative aging has existed for decades, and on the basis of that evidence clearance of senescent cells from old tissues was included in the SENS rejuvenation research proposals when they emerged at the turn of the century. Nonetheless, even as recently as five years ago researchers still struggled to raise the funds needed for the animal studies to prove the point. Once the first of those studies was completed, in 2011, things began to move, and now we have can observe an increasing pace of investment, development of practical therapies by numerous companies, and publication of new data on the biology of senescent cells. Life extension has been demonstrated in normal mice, and a recent studies demonstrate that removing senescent cells should help to slow or reverse the progression of specific age-related diseases and turn back numerous metrics of tissue aging. It is all very promising.

How do senescent cells cause harm? Largely through signaling, it appears, as they do not make up a large fraction of cells in any particular tissue even by the end of a natural life span. If even 1% of the cells in an aged tissue have become senescent, that is enough to cause significant issues. Senescent cells generate a mix of signal molecules that, in greater volume, can become very harmful; this is known as the senescence-associated secretory phenotype (SASP). It promotes chronic inflammation, alters the behavior of nearby cells for the worse, and can damage the structure of the extracellular matrix, among other issues. Why do we accumulate senescent cells? The phenomenon of senescence in old tissue appears to be an adaptation of an embryonic development process, now turned to cancer suppression. Indeed, much of its destructiveness makes more sense in the context of embryonic growth, where tissues must be removed or growth halted in order to correctly define organ structures. Cells become senescent at the Hayflick limit on division, or in response to damage or a toxic environment. In moderation this serves to reduce the risk of cancer by shutting down replication in the most vulnerable cells, those most likely to become cancerous. Levels of cellular damage and stress increase with aging, which will in turn increase the rate at which senescent cells arise. Further, senescent cells are largely destroyed either by the immune system or their own programmed cell death mechanisms. With advancing age, the immune system becomes ever more dysfunctional due to its own burden of damage, however, and thus less capable of removing senescent cells.

Therapeutic interventions for aging: the case of cellular senescence

Cellular senescence is a stress response characterized by the induction of a permanent cell cycle arrest. Senescence represents an important barrier to tumorigenesis by limiting the growth of potentially oncogenic cells. Senescence-associated growth arrest (SAGA) is accompanied by an overactive secretory phenotype known as the senescence-associated secretory phenotype (SASP). The SASP consists of numerous cytokines, growth factors, proteases and extracellular matrix components that, depending on the physiological context, can be either beneficial or deleterious. During early stages, SASP components promote the migration and infiltration of effector immune cells through the secretion of cytokines and facilitate tissue repair and remodeling by release of growth factors and proteases; however, in later stages, persistent senescent cells negatively impact the surrounding microenvironment by impairing tissue homeostasis through complex cell and non-cell autonomous effects.

In a cell-autonomous manner, selected SASP components such as interleukin (IL)-6 and IL-8 can reinforce SAGA through autocrine pathways. However, the same secreted components can act in paracrine signaling to neighboring cells, propagating the senescent phenotype and thus potentially hampering the regenerative capacity of surrounding tissue. Similarly, in a non-cell-autonomous manner, SASP cytokines promote infiltration of immune cells, yet persistent signaling can result in disruptive chronic inflammation, a hallmark of aging and major contributor to age-related dysfunctions. Indeed, senescent cells accumulate late in life and at sites of age-related pathologies, and genetic interventions enabling the effective clearance of senescent cells in genetically engineered animal models is sufficient to delay a number of age-related phenotypes.

Accordingly, a prolonged healthspan is obtained by pharmacological interventions using a novel class of drugs termed senolytics, used to selectively ablate senescent cells. Senolytic interventions not only demonstrated the feasibility of extending healthspan but also evidenced the alleviation of a wide range of pre-existent age-related symptoms including: improved cardiovascular function, reduced osteoporosis and frailty; enhanced adipogenesis, reduced lipotoxicity and increased insulin sensitivity; improved established vascular phenotypes associated with aging and chronic hypercholesterolemia; as well as radioprotection and rejuvenation of aged-tissue stem cells.

Although regeneration capacity deteriorates with age in mammals, it remains intact in other species such as salamanders. Surprisingly, salamanders show a significant induction of cellular senescence during limb regeneration; however, rapid and effective mechanisms of senescent cell clearance operate in regenerating tissues. Accordingly, the number of senescent cells does not increase upon aging, in contrast to mammals. However, very recently senescent cells have been shown to promote tissue regeneration also in mammals, probably through secretion of specific SASP factors. Thus, pharmacological or localized assisted immunological clearance of senescent cells might potentially aid regeneration of dysfunctional aged tissues.

The various beneficial effects resulting from the administration of drugs to selectively eliminate senescent cells, or suppress the deleterious aspects of the SASP, encourage their use in the treatment of age-related disabilities and chronic diseases as a group. Unfortunately, many challenges are still to be overcome for a successful drug development program, including increased selectivity and reduction of off-target effects. The optimization of therapeutic dosage in already approved drugs, now repurposed for aging interventions, appears promising in the reduction of unwanted side-effects, as demonstrated for rapamycin using lower intermittent doses. Additionally, the development of appropriate animal models capable of demonstrating the beneficial effects using clinically relative outcomes is imperative. These models would ideally be capable of distinguishing on-target from off-target effects to enable a correct assessment of safety and efficacy at a preclinical level, and ultimately grant their use in human clinical trials. In the near future, it is most likely that interventions against cellular senescence will only be prescribed on a case-by-case basis, for specific age-related dysfunctions, in patients with a favorable risk:benefit tradeoff; as is already the case in oncology where many identified senolytics are currently under investigation. Promisingly, however, human clinical trials are already underway to evaluate pharmaceutical impacts on longevity and human aging as a whole, extending our understanding on the human biology of aging and suggesting antiaging interventions could be closer than expected.

Tauopathies, a category that includes Alzheimer's disease, are neurodegenerative conditions characterized by the accumulation of altered forms of tau protein into solid neurofibrillary tangles. This is only one of a range of proteins that exhibit this sort of behavior with advancing age, such as the various forms of amyloid, and any comprehensive future toolkit for rejuvenation will have to incorporate the means to clear out this unwanted and damaging metabolic waste. In recent years, a few signs of progress towards tau clearance therapies have emerged, and while aimed largely at treating the later stages of Alzheimer's disease at the present time, a successful therapy of this class is something that probably should be applied to everyone on a periodic basis in later life. We all accumulate altered tau, and the only differences between someone with a tauopathy and someone without are matters of degree and time.

Under ordinary circumstances, the protein tau contributes to the normal, healthy functioning of brain neurons. In some people, though, it collects into toxic tangles that damage brain cells. Such tangles are a hallmark of Alzheimer's and other neurodegenerative diseases. But researchers have shown that levels of the tau protein can be reduced - and some of the neurological damage caused by tau even reversed ­- by a synthetic molecule that targets the genetic instructions for building tau before the protein is made. The findings suggest that the molecule - known as an antisense oligonucleotide - potentially could treat neurodegenerative diseases characterized by abnormal tau, including Alzheimer's.

Researchers studied genetically modified mice that produce a mutant form of human tau that easily clumps together. These mice start showing tau tangles at around 6 months of age and exhibit some neuronal damage by 9 months. To reduce tau, the researchers used an antisense oligonucleotide, a kind of molecule that interferes with the instructions for building proteins. Genes in the DNA are copied into RNA, a messenger molecule that carries the instructions for building a protein. Antisense oligonucleotides bind to the messenger RNA and target it for destruction before the protein can be built. Such oligonucleotides can be designed to target the RNA for almost any protein.

The researchers administered a dose of the anti-tau oligonucleotide to 9-month-old mice every day for a month and then measured the amount of tau RNA, total tau protein and tangles of tau protein in their brains when the mice were 12 months old. The levels of all three were significantly reduced in the treated mice compared with mice that received a placebo. Importantly, levels of total tau and tau tangles in the brains of treated 12-month-old mice were lower than in untreated 9-month-old mice, suggesting that the treatment not only had stopped but reversed the buildup of tau.

By the time this strain of genetically modified mice reaches 9 months of age, the hippocampus - a part of the brain important for memory - typically is visibly shrunken and shows dying neurons. But with the oligonucleotide treatment, the shrinkage and cell death were halted. There was not, however, any evidence of reversal of neuronal death. The treated mice lived an average of 36 days longer than untreated mice, and they were better at building nests, which reflects a combination of social behavior, cognitive performance and motor capabilities. All of these functions can be impaired in people with Alzheimer's disease and other tau-related neurodegenerative diseases.

The researchers were intrigued by the possibility of designing studies to lower tau in people, but first they needed to see how the oligonucleotide worked in an animal more similar to people than a mouse. The researchers treated groups of healthy cynomolgus monkeys with two doses of placebo or oligonucleotide, one week apart, directly into the cerebrospinal fluid that surrounds the spinal cord and brain, just as would be done with human patients. Two weeks later, they measured the amount of tau protein and RNA in the monkeys' brains and cerebrospinal fluid. The oligonucleotide reduced both tau RNA and protein in the brain, and this reduction was mirrored in the cerebrospinal fluid.

Link: https://medicine.wustl.edu/news/drug-compound-halts-alzheimers-related-damage-mice/

Many types of cell therapy largely work through signaling; the transplanted cells do not last long and very few successfully integrate with the patient's tissue. They do, however, release signals that produce a temporary beneficial alteration in local cellular behavior, such as a suppression of inflammation in the case of more widely available mesenchymal stem cell therapies. This isn't really the desired outcome, however. It would be far better for the majority of transplanted cells to survive and take up residence, replacing or augmenting the activities of local cells. This is actually necessary for meaningful benefits to be produced in many cases, such as for age-related diseases in which some of a patient's cell populations are malfunctioning or diminished in number. A fair amount of work in the research community is focused on finding reliable ways to make this happen:

Today, a stroke usually leads to permanent disability - but in the future, the stroke-injured brain could be reparable by replacing dead cells with new, healthy neurons, using transplantation. Researchers have taken a step in that direction by showing that some neurons transplanted into the brains of stroke-injured rats were incorporated and responded correctly when the rat's muzzle and paws were touched. The study used human skin cells. These cells were re-programmed to the stem cell stage and then matured into the type of neurons normally found in the cerebral cortex.

A couple of years ago, the research team had already proven that transplanting this type of cells to the cerebral cortex enabled stroke-injured rats to move better. At the time, however, it was unclear whether the host brain really formed functioning connections with the transplanted nerve cells. Now the new study has proven that this is indeed the case. The research team used several advanced methods in the study - electron microscopy, virus-based tracing techniques, registration of activity in the transplanted cells and optogenetics. The results show that various parts of the host brain form normal, functioning connections with the transplanted neurons and that the latter change their activity when the animal's muzzle and paws are touched.

"This is the first time anyone has been able to show such a result. That some of the new nerve cells receive signals from the host brain in a normal way indicates that they have been incorporated into the stroke-injured rat's brain. In it, they have been able to replace some of the dead nerve cells. This is basic research, and it is not possible to say when we will be ready to start experiments on patients. But the objective is clear: to develop a treatment method which can repair the stroke-injured brain. Currently, there is no effective treatment which can restore function in a stroke patient once the first hours following a stroke have passed."

Link: http://www.lunduniversity.lu.se/article/transplanted-neurons-incorporated-into-a-stroke-injured-rat-brain

Today I noted the report of a proof of principle demonstration of the creation of chimeric animals that grow the organs of another species. This not the first such demonstration, but it is another step along the way to larger goals in tissue engineering. One of the potential approaches to building a large supply of new organs and tissues for transplantation is to grow humanized tissues in other species, such as pigs. This might be accomplished in many different ways, ranging from implanting seed cells or organoids into genetically altered adult animals, to creating engineered animal lineages in which all of the desired organs are at least partially humanized, compatible enough for xenotransplantation. That may involve as little as removing a few problem proteins in the case of porcine organs, but it remains to be seen how much concrete progress will be made by the current research programs with this specific focus. In the years ahead, this branch of technology will compete with therapies to regenerate organs in situ, as well as decellularization of donor organs, and efforts to grow or print suitable tissues for transplantation using only the patient's own cells as a starting point. It remains very unclear as to which of these approaches will prosper first.

Creating individual animals with one or more organs from another species requires some genetic engineering, to prevent the growth of the normal organ, followed by implantation of suitable seed cells in embryos early in the developmental process. If expanded into an industry, this methodology doesn't seem likely to result in a cost-effective supply of patient-matched tissues, given that it would require at minimum a few years to create a patient-matched organ for transplantation. It might, however, lead to multiple lines of animals, each possessed of humanized organs that can be transplanted, with little immunosuppression required, into one of the various human immunological groups. As is the case for many of the near future options for organ creation and xenotransplantation, this would be a great improvement over present shortages of donor organs, but it falls a long way short of the ideal future in which existing organs can be repaired and regenerated through some form of cell therapy or similar treatment.

Rat-grown mouse pancreases help reverse diabetes in mice

Growing organs from one species in the body of another may one day relieve transplant shortages. Now researchers show that islets from rat-grown mouse pancreases can reverse disease when transplanted into diabetic mice. The recipient animals required only days of immunosuppressive therapy to prevent rejection of the genetically matched organ rather than lifelong treatment. The success of the interspecies transplantation suggests that a similar technique could one day be used to generate matched, transplantable human organs in large animals like pigs and sheep.

To conduct the work, the researchers implanted mouse pluripotent stem cells, which can become any cell in the body, into early rat embryos. The rats had been genetically engineered to be unable to develop their own pancreas and were thus forced to rely on the mouse cells for the development of the organ. Once the rats were born and grown, the researchers transplanted the insulin-producing cells, which cluster together in groups called islets, from the rat-grown pancreases into mice genetically matched to the stem cells that formed the pancreas. These mice had been given a drug to cause them to develop diabetes.

The mouse pancreases were able to successfully regulate the rats' blood sugar levels, indicating they were functioning normally. Rejection of the mouse pancreases by the rats' immune systems was uncommon because the mouse cells were injected into the rat embryo prior to the development of immune tolerance, which is a period during development when the immune system is trained to recognize its own tissues as "self." Most of these mouse-derived organs grew to the size expected for a rat pancreas, rendering enough individual islets for transplantation. Next, the researchers transplanted 100 islets from the rat-grown pancreases back into mice with diabetes. Subsequently, these mice were able to successfully control their blood sugar levels for over 370 days, the researchers found. Because the transplanted islets contained some contaminating rat cells, the researchers treated each recipient mouse with immunosuppressive drugs for five days after transplant. After this time, however, the immunosuppression was stopped.

After about 10 months, the researchers removed the islets from a subset of the mice for inspection. "We examined them closely for the presence of any rat cells, but we found that the mouse's immune system had eliminated them. This is very promising for our hope to transplant human organs grown in animals because it suggests that any contaminating animal cells could be eliminated by the patient's immune system after transplant." Importantly, the researchers also did not see any signs of tumor formation or other abnormalities caused by the pluripotent mouse stem cells that formed the islets. Tumor formation is often a concern when pluripotent stem cells are used in an animal due to the cells' remarkable developmental plasticity. The researchers believe the lack of any signs of cancer is likely due to the fact that the mouse pluripotent stem cells were guided to generate a pancreas within the developing rat embryo, rather than coaxed to develop into islet cells in the laboratory. The researchers are working on similar animal-to-animal experiments to generate kidneys, livers and lungs.

Interspecies organogenesis generates autologous functional islets

Islet transplantation is an established therapy for diabetes. We have previously shown that rat pancreata can be created from rat pluripotent stem cells (PSCs) in mice through interspecies blastocyst complementation. Although they were functional and composed of rat-derived cells, the resulting pancreata were of mouse size, rendering them insufficient for isolating the numbers of islets required to treat diabetes in a rat model. Here, by performing the reverse experiment, injecting mouse PSCs into Pdx-1-deficient rat blastocysts, we generated rat-sized pancreata composed of mouse-PSC-derived cells. Islets subsequently prepared from these mouse-rat chimaeric pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully normalized and maintained host blood glucose levels for over 370 days in the absence of immunosuppression (excluding the first 5 days after transplant). These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by blastocyst complementation in a xenogeneic host.

Skin is one of the easier starting points for 3D bioprinting, the application of rapid prototyping technologies to the construction of living tissue. Since skin is a thin tissue, the challenging issue of producing the intricate blood vessel networks needed to supply inner cells with oxygen and nutrients can be skipped. Thin tissue sections can be supported in a suitable nutrient bath, and after transplant, patient blood vessels will grow into the new skin. Further, there is a fairly large and long-established research and development industry involved in various forms of skin regeneration. Numerous forms of prototype skin-like tissues have been created over the years, lacking many of the features of the real thing, but still useful in the treatment of, for example, burn victims. Further, skin structure is by now well understood, and considerable progress has been made in deciphering the signals and environment needed for suitable cells to self-assemble into the correct arrangements. All told, it should not be a complete surprise to see significant progress emerge in this part of the field.

Significant progress has been made over the past 25 years in the development of in vitro-engineered substitutes that mimic human skin, either to be used as grafts for the replacement of lost skin, or for the establishment of in vitro human skin models. In this sense, laboratory-grown skin substitutes containing dermal and epidermal components offer a promising approach to skin engineering. In particular, a human plasma-based bilayered skin generated by our group, has been applied successfully to treat burns as well as traumatic and surgical wounds in a large number of patients in Spain. There are some aspects requiring improvements in the production process of this skin; for example, the relatively long time (three weeks) needed to produce the surface required to cover an extensive burn or a large wound, and the necessity to automatize and standardize a process currently performed manually. 3D bioprinting has emerged as a flexible tool in regenerative medicine and it provides a platform to address these challenges.

In the present study, we have used this technique to print a human bilayered skin using bioinks containing human plasma as well as primary human fibroblasts and keratinocytes that were obtained from skin biopsies. We were able to generate 100 cm2, a standard P100 tissue culture plate, of printed skin in less than 35 minutes (including the 30 minutes required for fibrin gelation). We have analysed the structure and function of the printed skin using histological and immunohistochemical methods, both in 3D in vitro cultures and after long-term transplantation to immunodeficient mice. In both cases, the generated skin was very similar to human skin and, furthermore, it was indistinguishable from bilayered dermo-epidermal equivalents, handmade in our laboratories. These results demonstrate that 3D bioprinting is a suitable technology to generate bioengineered skin for therapeutical and industrial applications in an automatized manner.

Link: http://dx.doi.org/10.1088/1758-5090/9/1/015006

The Methuselah Foundation was an early investor in tissue engineering company Organovo, and continues to have a strong interest in accelerating progress in this field through initiatives like the New Organ programs. A while back the Methuselah Foundation kicked off their 3D bioprinter program in collaboration with Organovo, putting bioprinters into academic departments where they can be used to speed up the development of new tissue engineering methodologies. At some point in the decades ahead the research community will be capable of rapidly printing or growing near any type of tissue using a patient's own cells, and the aim here is to help bring that day closer.

Organovo, a three-dimensional biology company focused on delivering scientific and medical breakthroughs using its 3D bioprinting technology, today announced a collaboration with the Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Australia to develop an architecturally correct kidney for potential therapeutic applications. The collaboration has been made possible by a generous gift from the Methuselah Foundationas part of its ongoing University 3D Bioprinter Program. "Partnerships with world-class institutions can accelerate groundbreaking work in finding cures for critical unmet disease needs and the development of implantable therapeutic tissues. This collaboration is another important step in this direction. With the devoted and ongoing support of the Methuselah Foundation, leading researchers are able to leverage Organovo's powerful technology platform to achieve significant breakthroughs."

We have developed an approach for recreating human kidney tissue from stem cells," said the Theme Director of Cell Biology at Murdoch Childrens Research Institute. "Using Organovo's bioprinter will give us the opportunity to bioprint these cells into a more accurate model of the kidney. While initially important for modelling disease and screening drugs, we hope that this is also the first step towards regenerative medicine for kidney disease. We are very grateful to Organovo and the Methuselah Foundation for this generous support, which will enable us to advance our research with the first Organovo bioprinter in the southern hemisphere." Under Methuselah Foundation's University 3D Bioprinter Program, Methuselah is donating at least $500,000 in direct funding to be divided among several institutions for Organovo bioprinter research projects. This funding will cover budgeted bioprinter costs and key aspects of project execution.

Link: http://ir.organovo.com/phoenix.zhtml?c=254194&p=irol-newsArticle&ID=2239263

The activity undertaken by many important genes is quite subtle and conditional. Simply raising or lowering the amount of protein produced by that gene is rarely as effective as hoped in initial studies, and can be entirely counterproductive. The important activities of any specific protein might be very tissue-specific, and thus thwarted by being altered globally, or they might depend on other proteins and circumstances. The tumor suppressor p53 is a good example of the type; more p53 activity at the right times and in response to the right signals can both extend life and reduce cancer risk in mice. On the other hand, generally increased p53 activity shortens life.

The p53 protein is a part of the complex and shifting tradeoffs made between suppression of cellular replication and encouragement of cellular replication. When there is a greater risk of cancer, when cells are damaged or the cellular environment is toxic, more p53 encourages both greater repair and resistance to cellular damage and a more aggressive removal of cells most at risk by forcing them into senescence. In the normal course of regeneration and tissue maintenance, however, too much p53 suppresses the efforts of the cells that should be replicating, speeding the onset of frailty and organ failure, and over time the presence of larger numbers of senescent cells also leads to an acceleration of the aging process. Senescent cells cause a great deal of harm when they are not efficiently destroyed, either by the immune system or through programmed cell death.

It has been a decade since researchers first demonstrated a way to selectively enhance p53 activity only when needed, producing extension of life in mice. Since then, I think most of the groups involved have been quite distracted by work on telomerase gene therapies, which started in earnest at around the same time and among many of the same researchers, but which has since consumed ever more of the available time and interest. You might recall a merger of these two lines of research in which mice with enhanced telomerase and enhanced p53 activity were found to balance out with a longer life span. Since then the telomerase research has forged ahead, as I'm sure you've all noticed, but I can't say that work on selective increase of p53 activity as a method of modestly slowing aging has advanced all that much at all. The papers today are covering essentially the same ground as was covered a decade ago, and still with little impetus towards building some form of therapy from this:

Increased Arf/p53 activity in stem cells, aging and cancer

Cancer is the consequence of an aberrant gain of cellular fitness linked to the accumulation of stress and cellular damage of acute intensity. This damage occasionally provides aberrant advantages to certain cells, which can eventually lead to cancer development. The Ink4/Arf locus and p53 are regarded as the most relevant tumor suppressors based on their ubiquitous and frequent inactivation in human cancer. The Ink4/Arf locus encodes three tumor suppressor genes p15Ink4b, p16Ink4a, and p14Arf (p19Arf in mice). On one hand, p15Ink4b and p16Ink4a (called Ink4 hereafter) inhibit the formation of the cyclin-dependent kinases (CDK4 and CDK6) and cyclinD complexes during the G1 phase of the cell cycle. Hence, they prevent the transcription of genes involved in the transition to S phase, importantly the Rb/E2F1 pathway, so regulating cell cycle progression. On the other hand, Arf exerts its tumor suppressive action by inhibiting Mdm2, a ubiquitin ligase considered the major p53 regulator, thereby contributing to the activation and stabilization of p53.

The Ink4/Rb and Arf/p53 pathways are major sensors of stress that play a crucial role in early detection and elimination of cells that have suffered different types of stress including oncogene activation, DNA damage, oxidative stress, etc. While the activation of Ink4/Rb pathway induces reversible cell cycle arrest or irreversible cellular senescence-associated changes, the activation of p53 elicits a cellular response that might vary from restoration of cellular homeostasis by a transient blockade of the cell cycle to allow for DNA repair, senescence, or apoptosis. The activation of these responses depends in a complex manner, on the intensity of the triggering stress and on the cellular context. In agreement with this damage protective role, the individual or combinatory deletion of these genes promotes cancer susceptibility in multiple tissues and contexts. On the contrary, enhanced Ink4/Arf and p53 activity preserves mice from spontaneous or chemically induced cancers.

Although cancer and aging may seem opposite processes, they can be regarded as two different manifestations of the same underlying process, namely the accumulation of cellular damage. Moreover, cancer and aging may share common origins. There are several genetic or pharmacological manipulations that simultaneously modulate cancer and aging. These proofs demonstrate that cancer protection and longevity can be simultaneously modulated using different strategies and molecular mechanisms. In recent years, this is deepening the knowledge of the implications that the Ink4/Rb and Arf/p53 pathways have on the management of cellular damage associated with the aging process. The observation that several manipulations simultaneously modulate longevity and cancer protection establishes an interesting parallel with the expression of members of the Ink4/Rb and Arf/p53 pathways, which are silent or very low during development and postnatal life, while progressively increase from adulthood to old age in a broad range of tissues and species.

There is little additional information regarding p53 and aging in human, yet there is no evidence of a pro-aging function. Indeed, it has been documented that p53 is not involved in human premature aging disorders such as Hutchinson-Gilford Progeria, and it has been postulated that well-preserved p53-mediated responses are likely a key factor contributing to protection from diseases and cancer in centenarians. The above raises the possibility that Ink4/Rb and Arf/p53 pathways might have a role in aging. Thus, stress conditions cause an accumulation of DNA damage at the cellular level. Ultimately, it leads to the final activation of the Ink4/Rb and Arf/p53 pathways in order to achieve various adaptive responses to this situation. Amidst such responses is the transient block of the cellular cycle to try to repair the damage, inducing a state of senescence, or even apoptosis. Therefore, the empowerment of Ink4/Rb and Arf/p53 pathways might play an important role not only on surveillance and suppression of tumors, but also on the accumulation of cellular damage and aging. Therefore, it is reasonable to surmise that Ink4/Rb and Arf/p53 play a role also in the response to age-associated chronic stress and consequently affects aging. As activation of the Ink4/Rb and Arf/p53 pathways triggers a protective mechanism against tumor-induced stresses, they could also have anti-aging activity by alleviating the load of age-associated damage.

Significant efforts have been made to determine the impact of Ink4/Rb and Arf/p53 tumor suppressor pathways. While their protective function against cancer is firmly established, their role in aging remains controversial. In mice, it has been demonstrated that modest increases of regulated Arf/p53 activity are anti-aging while deregulated activation of p53 promotes aging. These observations are not in conflict per se and indicate that the activity of Arf/p53 could be beneficial or detrimental for aging depending on their intensity and regulation. It has recently been demonstrated that these effects are mediated through the activity of stem cells, indicating the concept of a reciprocal trade between tumor suppression, aging, and stem cell biology. Based on this, we postulate a model by which high or deregulated Arf/p53 impacts on lifespan by a decline in tissue stem cell regenerative function, but modest and regulated increases in Arf/p53 result in systemic organismal benefits ameliorating stem cell aging and maintaining tissue homeostasis. Additional work is necessary to establish the detail role and mechanism of action of p16Ink4a in aging and stem cell biology.

Many varied arguments are made against attempts to extend human life spans through medical science: overpopulation, economic impacts, boredom, stasis, that people would be aged and decrepit for longer, and so forth. The only thing they have in common is that they are all fairly ramshackle, and tend to fall apart in the face of even a mildly rigorous look at the data and the evidence. Not that this state of affairs seems to have converted all that many people to our side of the tracks. Arguments against living longer in good health have more to do with emotion, comfort zones, and signaling to peers than anything else, I'd say. The same people who, when prompted, declare that everyone should age to death on the same schedule that exists today also visit doctors when sick, would rather not live with the life expectancy of a few hundred years past, and are generally supportive of efforts to defeat age-related diseases such as cancer, Alzheimer's disease, heart disease, and so forth. They are very inconsistent in word and deed.

I see opposition to life extension as just one of many manifestations of the inherent tendencies towards conservatism and discomfort with change, any change, that are deep-set parts of the human mentality. People who are essentially comfortable here and today tend to want things to stay as they are, no matter what that state might be. If that means closing one's eyes to tens of millions of unpleasant deaths every year and the ongoing suffering of hundreds of millions more, then so be it. Yet aging and its consequences are not set in stone, and they can be changed through medical research and development. All this death and pain need not continue. That is why it is important to dismantle the half-hearted and ill-thought objections to treating aging as a medical condition and thereby extending healthy life spans. Most of the death and disease in the world could be swept away in the decades ahead, given the support and investment to do so, but today so very much of that support has instead buried its collective head in the sand.

Arguments against rejuvenation only sound reasonable because they appeal to our fears and to the blame-the-humans attitude of so many people. If you trust only your gut feelings and don't bother examining facts and data, anti-rejuvenation arguments can easily seem obviously true. Accepting an anti-rejuvenation argument requires far less mental work than understanding why the same argument isn't as sound as it appears, but that doesn't make anti-rejuvenation arguments any more 'obviously true' than their rebuttals. It is impossible to know for a fact whether or not rejuvenation will cause any given problem before we get there.

Proving that no problems will arise as a consequence of defeating ageing is not the point of rebutting objections to rejuvenation. That's not what any of my answers does. All they do is showing that objections to rejuvenation rely more often than not on fallacious reasoning, ignorance, fears, misconceptions, and wrong assumptions taken for established fact. In short, what we do when rebutting objections to rejuvenation is showing they aren't valid reasons to let ageing continue crippling and killing us. At the same time, answers to objections show why all those predictions of doom and gloom aren't as likely as they may appear. There's no certainty to be found anywhere, but this doesn't really matter-had we refrained from doing anything that wasn't proved to be 100% risk-free throughout history, we'd probably still be living in caves.

Remember: Objections to rejuvenation are about hypothetical future problems that are far from being certain. Ageing and all the suffering and deaths that come with it are a very tangible fact, happening here and now. This alone should be sufficient to forget about objections altogether and focus only on putting an end to ageing. However, rebutting objections has also another purpose: It fuels discussion. Apart from raising awareness of the problem of ageing and the feasibility of its defeat, discussion prepares us to face the new challenges an ageless future might bring. The way to a world without ageing is still long, which gives us all the time we need to prevent eternal dictators, overpopulation, and all sorts of dystopian scenarios from ever materialising.

Link: https://rejuvenaction.wordpress.com/2017/01/21/the-point-of-rebutting-objections-to-rejuvenation/

Mitochondria, the power plants of the cell, evolved from symbiotic bacteria, and still carry a remnant genome of their own, entirely separate from the nuclear DNA found in the cell nucleus. Unfortunately, mitochondrial DNA is prone to deletion mutations, either due to replication errors or oxidative reactions, and some types of deletion can form the basis for runaway cellular dysfunction. This process is one of the causes of degenerative aging, and doing something about it is one of the line items on the SENS rejuvenation research agenda. As it happens, mitochondrial DNA damage accumulates more readily in some tissues than in others. It is known that this is the case in the substantia nigra, for example, and that this susceptibility is connected to the development of Parkinson's disease, a condition caused by the loss of dopamine-generating neurons in that area of the brain. Researchers here provide evidence to support the contention that Parkinson's patients are distinguished from their comparatively healthy peers not by more mitochondrial damage, but rather by the lack of a compensatory generation of more undamaged mitochondrial DNA in the affected neurons:

Somatic mitochondrial DNA (mtDNA) damage has been associated with both normal aging and neurodegeneration. Accelerated mtDNA mutagenesis causes a premature aging phenotype in mice and somatic mtDNA deletions have been shown to accumulate with advancing age in post-mitotic tissues including the brain, heart and skeletal muscle. In the brain, the dopaminergic substantia nigra is particularly susceptible to somatic mtDNA deletions, which accumulate there at substantially higher levels compared with other areas of the brain. This predilection has led to the hypothesis that mtDNA damage plays a role in the pathogenesis of Parkinson disease (PD), where neurodegeneration of the substantia nigra is the main pathological hallmark and widely accepted as the cause of the cardinal clinical features.

mtDNA deletions were shown to accumulate at similar levels in both individuals with PD and healthy controls however, and therefore do not provide a sufficient explanation for the specific vulnerability of the substantia nigra in PD. Mice accumulating high levels of mtDNA deletion due to an error-prone mtDNA-polymerase (POLG) show a concomitant increase in mtDNA copy number which is associated with nigrostriatal survival and even resistance to mitochondrial respiratory chain complex-I inhibition. Although a similar protective mechanism has not yet been identified in humans, the importance of mtDNA copy-number regulation is highlighted by the vulnerability of the substantia nigra in inherited mtDNA-depletion disorders and the increased risk of PD associated with genetic variation in genes encoding key factors of mtDNA maintenance, such as the mtDNA polymerase γ (POLG) and mitochondrial transcription factor A (TFAM). Nevertheless, the precise mechanism by which mtDNA copy-number loss contributes to brain aging and neurodegeneration remains unclear.

We hypothesized that dopaminergic substantia nigra neurons in PD are rendered vulnerable to the effects of age-dependent mitochondrial mutagenesis due to an underlying dysregulation of mtDNA homeostasis. To test our hypothesis, we employed an integrative approach to study the complete spectrum of mtDNA changes in individual neurons from individuals with PD and controls. Our sample was derived from a population-based, prospectively collected and extensively characterized cohort. To ensure our sample was homogenous and representative for sporadic PD, we excluded known monogenic causes of PD by whole-exome sequencing. Neuropathological examination confirmed Lewy-body disease in all PD samples, whereas control samples were negative for neurodegenerative markers. Our results show that dopaminergic substantia nigra neurons of individuals with PD accumulate higher levels of somatic mtDNA deletions, but not point mutations, compared with age-matched controls. Moreover, in healthy individuals, mtDNA copy number increases with age, thus maintaining the pool of wild-type mtDNA population in spite of accumulating deletions. Conversely, mtDNA copy number does not increase in individuals with PD, resulting in depletion of the wild-type mtDNA population. Our findings suggest that mtDNA homeostasis is impaired in the substantia nigra of individuals with PD.

Link: https://dx.doi.org/10.1038/ncomms13548

[This is a lightly edited reprint of an article originally published at h+ Magazine, descending from an older Fight Aging! post, and returned again now in order to preserve it for posterity.]

I'm not going to try to convince you that the foreseeable future is a wondrous place: either you accept the implications of the present rate of technological progress towards everything allowed by the laws of physics, in which case you've probably thought this all through at some point, or you don't. Life, space travel, artificial intelligence, the building blocks of matter: we'll have made large inroads into bending these all to our will within another half century. Many of us will live to see it even without the benefits of medical technologies yet to come: growing up without the internet in a 1960s or 1970s urban area will be the new 1900s farmboy youth come 2040. Just like the oldest old today, we will be immigrants from a strange and primitive near-past erased by progress, time travelers in our own lifetimes.

A century is an exceptional life for a human, but far greater spans of years will be made possible by the technologies of the 21st century. I'll plant a flag way out there on the field and claim a million years: a life of a length hard to envisage. I am an advocate for engineered human longevity, and I started on the path that led to Fight Aging! and related projects from the position that (a) immortality would be an unalloyed good if achieved, and (b) our understanding of cosmology does not yet rule out a damn good attempt at actual immortality - the "no death, ever" dictionary definition - or at least a life span of millions of years on the way to that end goal. If a million years is not long enough to figure out the aspects of the problem that cannot be answered today, I'm not sure what would be.

Despite being out there, the million year life span is not an unsupported pipe dream. Living for a million years is a goal that can be envisaged in some detail today: the steps from here to there laid out, the necessary research and development plans outlined, and the whole considered within the framework of what is permissible under the laws of physics, and what the research community believes can be achieved within the next 20, 50, or 100 years.

Biotechnology is the first necessary step on this road of a million years: the biotechnology revolution, still in its early years, is a gateway to the future insofar as it will enable us to extend our healthy life spans by repairing the evolved world of nanoscale machinery within our cells and other vital biological systems. The future is only golden for you and I personally if we live to see it, and for many of us that will require rejuvenation biotechnologies like those worked on by the SENS Research Foundation. This golden future is one in which our biochemistry does our bidding, aging can be repaired, and molecular manufacturing is in full swing. It will be an age of bioartificial bodies, minds transferred to new and more robust mechanisms, artificial general intelligences, an end to most scarcities, and indeed, anything you might imagine that the laws of physics permit and enough time has passed to develop.

A philosophy of first things first is a good way to temper visions of the far future - and explains why I spend my time talking about rejuvenation biotechnologies, cryonics, and even basic common sense health practices that might stop you cutting a mere decade from your life expectancy. If we don't complete the first rung of the ladder, that being sufficient control over our biochemistry to slow and then repair aging, then all the rest of our thoughts on radical life extension are for nothing. If I'd been born twenty years earlier, I'd have ended up primarily a cryonics advocate and volunteer. As it is, it looks like these first decades of the 21st century are the era in which the first rung on the ladder of simply remaining alive forever - which is to say building the means to continuously repair the biological damage of aging in these bodies of ours - can actually be achieved. If we can live another 50 years, grabbing a year here with good health and a year there through incremental advances in geriatric medicine, and if we can build a large enough research community interested in serious work on rejuvenation along the way, then we may live in restored youth and vigor for centuries longer.

If you project forward into the future based today's accident rates, you'll find that an ageless human sustained by biotechnologies of cellular and biochemical repair has a life expectancy in the range of 1,000 to 5,000 years. Sooner or later that piano is going to fall upon your head hard enough that even advanced medical technology cannot fix your injuries in time. So the million year life span: how could that be achieved? The short and not terribly informative answer is that it will be accomplished by using advancing technology to dramatically reduce your vulnerability to fatal accidents, murder, and other unfortunate events that produce the same outcome. Once you start looking at living for even 100,000 years in much the same shape as you are today, it becomes apparent that almost any activity bears an unavoidable minimum level of risk that will jump up and kill you. Eating, swimming, walking ... breathing. Stretch out the timeframe far enough and the improbable and fatal will eventually occur.

The way past these risks is to change your form: your risk of fatality for any given activity is a function of your human physiology. Once the research and development community has achieved the goal of practical biotechnologies for the repair and reversal of aging, that will give us all a few hundred years of life in comparative statistical safety. Technological progress will continue across that long period of time, and I can't imagine that much of the toolkit needed for the next step in long-term risk reduction will remain beyond the capabilities of the human civilizations of the 2200s. Your own personal preferences for that next step will no doubt vary, but I would get my neurons replaced - slowly, one at a time over time, to ensure continuity of the self - with some form of much more robust, easily maintained nanoscale machinery. That allows for a range of new engineering possibilities: swapping out the body for whatever machinery of transport and support best minimizes risk; moving most of the business of life into a virtual world; physically separating my neurons while still remaining alive, conscious, and active.

It shouldn't be terribly controversial at this point to talk about machines that can do the job of a neuron, store all of the same information as a neuron, and integrate fully with surrounding real neurons. Researchers in recent years have assembled lobster neuron simulators from Radio Shack components, grown proof of principle neuron-circuit interfaces, designed and simulated nanomachine replacements for other cell types, and made great inroads into manipulating the internal machinery of cells. These are toys and clunky barnstorming exercises in comparison to what lies ahead, but my point is that this is an active line of research, worked on by thousands of scientists and developers. Similarly, I would hope that interacting via virtual worlds and splitting up one's machine neurons between various locations follows fairly straightforwardly from having machine neurons in the first place. If your brain is made up of artificial neurons, why not throw in an internet connection, adjunct computer hardware, and encrypted wireless communication protocols?

Physical distribution of the self across many disparate locations is in fact the key point when it comes to considering risk over the long term. Locations have much the same issues with time, probability, and bad events as people do. Meteorites are a risk to consider, as are landslides, earthquakes, war, and volcanoes. The way to reduce your location-based risk dramatically is to spread out. You might imagine a wireless brain, using whatever the most robust communications technology of the time happens to be, scattered in a thousand separate machine bodies or vehicles across a continent, or even the whole planet. That might be good for many millennia of falling pianos of various types. However, once you start digging back into the geological and astrophysical history of the solar system, it becomes clear that spreading out over an entire planet still leaves you at risk on longer timescales. Probably not from impact events: I'll be surprised if humanity and its machine descendants fail to solve that problem within the next few centuries. But there will always be war, nearby supernovae, large solar flares, unusually massive volcanic events, and other unpleasant line items, however. Supernovae are the biggest of the known concerns, given that I expect it to be a long, long time before preventing them is a practical and ongoing business for the civilizations that follow man.

What to do about all of this astrophysical and grand geological risk? Spreading out is an option once again. Increase the size of your vehicles and neuron-machines to shrug off the worst case radiation projections for a nearby supernova. Provide them with the means to move about the solar system, and become a spacefaring entity, spread out over a sizeable selection of orbits. By that point in time, your physical presence resembles a small country of machinery, automation, and layers of delegation: perhaps you are a million heavily shielded self-powered containers and transmission systems distributed beyond Pluto's orbit. There is a trade-off for spreading out so far, however, and that is that you must slow down. The speed of thought is determined by the speed of communication between the neurons and sections of your brain. If your brain is light hours wide, you will live very slowly indeed - but with a life expectancy so long that you come out far ahead in the end.

There are other paths forward with varying degrees of risk. You might decide not to spread out, but rather live very fast by running your machine neuron brain on more capable hardware, for example; if you can pass a hundred years of subjective time in a year of real time then you have reduced your subjective risk for many fatal occurrences a hundred-fold. That would be a pleasant enough life as a part of a community of people all running at the same speed, and there is even room for technological development and research to occur at a fair pace under such a scenario. At present our still young computing technology is very, very far removed from the known theoretical limits on computational efficiency. There is a great deal of headroom for the approach of living more rapidly.

But to return to the immortality question: is immortality impractical? Given existing mortality rates and the uncertainties in the timeline for completing efforts to repair and reverse the damage of aging, it may be unlikely for many of us alive today. If progress is too slow, or we are simply unlucky in matters of health, then we won't get past the first step on the path. In other words, we will die - or at best undergo cryosuspension and its attendant risks - before the advent of sufficiently good rejuvenation biotechnology. As for the bigger picture, it is far too early to say whether immortality, the "no death, ever" version, is actually impossible. That requires further research into cosmology - so you might give it a million years or so and ask me again. Regardless, the slope of technology and possibility is curving up ahead of us to great heights, and it'll be a wild ride either way. Missing out on any of it would be a real downer, so why not spend more of your time and resources helping to get the first step accomplished? We should all support the development of rejuvenation biotechnology, as it is the gateway to a life that may ultimately prove to have few limits.

For those of us who immediately understand, at first recognition, that the opportunity to live a longer life in good health would be a fantastic thing, and in fact so wondrous that we should jump up and do something to make it happen, it is a continual puzzle that we find ourselves in a minority. How is it that we live in a world in which the majority simply doesn't care, or if prompted on the topic, declares their desire to age, suffer, and die on the present schedule? After a few years of this, one might be forgiven for thinking that we are just not very good at advocacy. But given a second consideration, we might ask why we should have to be good at advocacy at all in this situation. Isn't more good health and vigor, and an absence of horrible, debilitating age-related disease, an obvious and unalloyed good? Isn't the whole point of medicine to defeat disease and prolong health? Isn't it the case that all of these people in favor of aging and age-related death nonetheless go out and visit the doctor when they get ill, while supporting research into treatments for cancer and other age-related diseases? I don't think that we are the irrational ones in this picture.

After going on fifteen years of writing on this topic, I don't have much more of an idea than I did when I started as to why greater human longevity isn't an obvious and highly important goal for everyone. The same questions and theories back then are still here today, and there is still little data to pin down their accuracy: fear of frailty, of overpopulation, of any change, even positive, and so forth. Since it was an immediate and evident revelation for me, rather than a gradual conversion, perhaps I am not the right person to achieve that understanding. I am, however, pleased to see that despite the challenges our community of iconoclasts, heretics, revolutionaries, and rational thinkers on the subject of longevity science is greatly expanded these days. More of these folk than ever are writing and persuading, both inside and outside the scientific community. We have progressed and grown as a community, alongside progress in the state of the science.

For today, I see that the Life Extension Advocacy Foundation has set up a blog in order to help bring spread our message to new audiences. As noted by the author here, the best evidence so far suggests that the fear of being old and decrepit for longer as a result of life extension therapies is the most important factor in public opposition to greater longevity, despite the fact that scientists and advocates have repeatedly disclaimed this as a goal, and that many have noted that such an outcome is implausible to achieve even if someone was trying. On the one hand that suggests that it is simple ignorance that might be dispelled, but on the other it seems very resistant to the efforts already made, over and again, by near every public figure involved in the aging research community.

Most advocates of life extension report facing resistance to the idea of increased lifespans by medical means when trying to disseminate this idea among general public. Resistance manifests itself in many forms, ranging from concerns such as overpopulation to concerns about unequal access to life extending treatments. But the most unexpected thing is probably that people often don't want an increased lifespan at all. Surveys in different countries show, that when people are asked "how long would you like to live?", they often give a number equal to or slightly higher than the current life expectancy in a given country. But wait ... Isn't extending life for more decades a good thing that everyone should strive for? In reality we often do not see enough enthusiasm for the idea in general. So why is this?

It turns out that the reaction of general public to the idea depends on how the message is formulated. When only life extension is offered, without details of how healthy, mentally sound and good-looking an individual could become, people express less support for the idea. But when life extension is proposed as a combination of perfect physical and mental health, it changes the response dramatically, leading to many more people accepting the idea, and also showing support for the development of corresponding medical technologies. It is important to note, that there are also other factors that influence higher support for life extension and related medical innovations, reported by researchers. An interest in science, for example, appears to be the strongest predictor of a positive attitude towards medical interventions to extend life.

In some surveys, where the message did not include a promise of perfect health combined with longevity, males were found to be more likely to support life extension than females. Most likely, this can be explained by different perception of the risks. Males are found to be more likely to take the risks, so they can cope better with the risks emerging from using an innovative technology, when the long-term effects are still unknown and the volume of benefit is not clear. In other studies, however, when healthy life extension (with a "utopian" scenario) was offered, this difference between the sexes did not remain consistent, males and females were equally supportive of life extension technologies. It could be that a positive scenario does not engage the mechanisms of risk avoidance. But then, it means that solely by adding perfect health to life extension in our messages, we can significantly widen the number of our supporters. Studies like this illustrate the importance of analyzing how the nature of the message matters in furthering our cause. The advocates of rejuvenation biotechnology, including research groups and fundraisers for aging biology research, should carefully consider the messages they are using, as some of them are more efficient to encourage an informed and engaging discussion with society about the benefits of bringing aging under medical control.

Link: http://www.leafscience.org/intrinsic-resistance-to-the-idea-of-life-extension-or-wrong-messaging/

Researchers here examine the biochemistry and behavior of immune cells in the early stages of arthritis, a condition that is strongly associated with age-related increases in chronic inflammation. Inflammation in turn is associated with growing dysfunction of the immune system with age, a progressive failure that occurs for a variety of reasons, including the presence of metabolically active excess visceral fat tissue that is so common this age of cheap calories; a reduced supply of new immune cells due to declining stem cell activity and involution of the thymus; and dominance of the immune cell population by cells devoted to persistent pathogens such as cytomegalovirus, which cannot effectively assist in responding to new threats. Reducing inflammation should be helpful for arthritis patients, and some of the more common forms of stem cell therapy that achieve this outcome so far appear to be more effective than other options for many of those who undergo the treatments. For much the same reasons, senolytic therapies that target senescent cells for destruction will most likely first enter human trials as arthritis treatments, as senescent cells are another prominent cause of inflammation.

Using a novel approach for imaging the movement of immune cells in living animals, researchers have identified what appear to be the initial steps leading to joint inflammation in a model of inflammatory arthritis. "Inflammatory arthritis is caused when immune cells are recruited from the blood into the joint in a highly regulated process controlled by chemoattractants and adhesion receptors. But when the disease has become symptomatic, it is difficult to determine the initial steps that set off the recruitment of immune cells into the joint and the specific roles of the different chemoattractants. Our study was designed to more fully understand this process. The control of immune cell entry into the joint represents a major point at which new therapies could be developed to reduce the symptoms of inflammatory arthritis."

Inflammatory arthritis includes a number of autoimmune diseases of the joints - including rheumatoid arthritis and lupus - and in many cases is caused by a type of inflammation called type III hypersensitivity. That reaction results when a localized accumulation of immune complexes - antibodies bound to their antigens - is deposited in tissue and sets off an inflammatory response involving the infiltration and activation of immune cells, initially the neutrophil. Current thinking regarding type III hypersensitivity is that immune cells within tissues sense the presence of these immune complexes (ICs) through specific receptor molecules and release inflammatory factors called cytokines that activate the endothelial cells lining adjacent blood vessels to promote the recruitment of neutrophils.

To better determine the role of specific chemoattractants in type III hypersensitivity, researchers used multiphoton intravital microscopy to follow in real time the development of IC-induced arthritis in a mouse model of rheumatoid arthritis. Their experiments revealed that the presence of ICs within the joint space induces the generation of complement C5a, a component of the innate immune system, which is then displayed on the inner walls of adjacent blood vessels. C5a directly initiates the adherence of neutrophils to the vessel walls through interaction with the C5a receptor on neutrophils, which then pass into the joint space and set off inflammation. Once the inflammatory process has been initiated, neutrophils within the joint space release interleukin-1, which induces cells lining the joint space to produce chemoattractants called chemokines that further facilitate the movement of neutrophils into the joint space. Neutrophils within the joint also directly produce chemokines that amplify the cells' recruitment to and survival within the joint space.

Link: https://www.eurekalert.org/pub_releases/2017-01/mgh-tmo011817.php

The research community is presently expanding the understanding of the biochemistry and role of senescent cells in aging and age-related disease. This is happening in the wake of a series of landmark animal studies demonstrating extension of life and reversal of markers of tissue aging through selective destruction of senescent cells, events that have attracted the attention of many research groups and funding organizations. There is considerably increased investment in the field when compared to even as recently as five years ago, a time at which it was a real struggle for even prestigious research groups to raise the funds needed for animal studies of senescent cell removal. This is an object lesson for anyone who thinks science moves on the shortest path towards important gains. Significant evidence for the role of senescent cells in aging and disease has existed for decades, and the SENS proposals have included their removal as a potential rejuvenation therapy since the turn of the century. In any case, I predict that this ongoing gain in knowledge will accelerate as senolytic therapies, treatments based on the targeted removal of senescent cells, continue to prove effective on their way to the clinic. The size of the field and its funding will increase greatly.

This is going to produce interesting outcomes as researchers involved in other areas of medicine assimilate the new findings and come to appreciate the importance of senescent cells. In the cancer research community, for example, there are already established programs aiming to use the induction of senescence as a form of therapy. Cellular senescence acts as a form of defense against cancer, a way to make cells irreversibly halt replication and then largely self-destruct, or attract immune cells to destroy them. Since preventing replication and destroying cells is exactly the goal of cancer therapies, this seems a potentially viable approach. The challenge here, as researchers are now realizing, is that those newly formed senescent cells that are not destroyed go on to cause a lot of harm. Arguably this is visible in the long-term damage caused by even successful chemotherapy. Senescent cells generate a potent mix of signals, the senescence-associated secretory phenotype (SASP) that disrupts tissue structure, changes the behavior of other cells for the worse, and generates high levels of chronic inflammation.

The present state of knowledge is, however, enough to clearly envisage a class of near future cancer therapies made up of the combination of treatments to (a) induce senescence in cancer cells, (b) attempt to reduce the SASP by altering the internal processes of senescent cells, and (c) to destroy as many of these newly senescent cells as possible. I'm not convinced that trying to modulate SASP signaling is a cost-effective path forward in comparison to destruction of senescent cells, given the current state of the field, but a fair number of research groups are undertaking work in that direction. I think it to be the most complex option, requiring much more new knowledge, and with a lower chance of success for any given research group and project. Further, sufficiently good senolytic therapies should render it unnecessary: just deliver them alongside the therapy that induces senescence in cancer cells. In any case, this open access paper outlines the vision for combination therapies along these lines:

Aging tumour cells to cure cancer: "pro-senescence" therapy for cancer

In contrast to normal cells, one of the hallmarks of cancer cells is the capability to escape senescence, thus acquiring a limitless replicative potential that is the prelude to invasion, metastasis and additional features of malignancy. However, cancer cells can undergo senescence if subjected to certain insults such as oncogenic stress, DNA damage and metabolic changes. This type of senescence response occurs immediately and also independently of telomere shortening, a phenomenon known as "premature" senescence. For instance, several anticancer chemotherapies and radiotherapies are known to induce senescence in both normal and cancer cells. Senescence can also occur in tumour cells in vivo as a consequence of overexpression of oncogenes or loss of tumour suppressor genes, demonstrating for the first time that senescence acts as a barrier against tumorigenesis. Analysis of tumour samples from patients demonstrated that, whereas benign tumours accumulate markers of senescence, invasive cancers lack senescence. Subsequent publications validated these findings in different types of tumour. Given the surprising discovery that senescence limits the development of cancer, we and others envisioned targeted therapies that selectively enhanced senescence in cancer cells used for the therapy of various tumours. This approach, named "pro-senescence" therapy for cancer, differs from the chemotherapy-induced senescence that affects both normal and cancer cells.

Several small molecule inhibitors that are currently in clinical development have been reported to induce senescence in cancer. Among these compounds, inhibitors of the cyclin-dependent kinases CDK4/6 have been associated with a high percentage of responses in patients affected by breast cancer and are the most promising pro-senescence compounds currently being tested in the clinic. Compounds that enhance the level of the tumour suppressor gene p53, such as MDM2 inhibitors and PRIMA-1 analogues, have been reported to enhance senescence in tumour cells with normal and mutant p53 and are currently being tested in the clinic. Many compounds that are currently being tested at the preclinical level are also promising pro-senescence therapies. Inhibitors of SirT1, a protein deacetylase that negatively regulates p53 function in cancer, induced senescence in preclinical tumour models. MYC inhibitors can also drive a cellular senescence response.

Another challenge in the field of senescence therapy for cancer is the lack of clinically validated biomarkers for the identification of senescence in human tumours. The prognostic use of senescence-associated-β-galactosidase (SA-β-galactosidase), a well characterised in vitro marker for senescence, has been tested in small trials evaluating the efficacy of neo-adjuvant chemotherapies. Results from these trials demonstrate that this marker increases upon treatment and predicts patient outcome. However, the use of SA-β-galactosidase alone as a unique marker of senescence has been criticised since it can lead to many false positives. Recent findings have identified of new markers of senescence with prognostic relevance. However, neither SA-β-galactosidase staining nor additional markers have been used so far in large clinical trials to evaluate the efficacy of pro-senescence compounds. Thus, development of novel biomarkers that can accurately assess the occurrence of senescence in cancer patients is the need of the hour. This would help improve the stratification of patients who may respond to therapies that enhance senescence in cancer.

SASP has profound effects on the surrounding tumour microenvironment and it represents a promising target for cancer therapy. Several groups have recently proposed therapies that reprogram the SASP to enhance the tumour-suppressive role of senescence in cancer and restrain the negative effects of the SASP. For instance, we have recently shown that Stat3 regulates the SASP of Pten-loss induced cellular senescence (PICS). In Pten null senescent tumours, Stat3 activation promotes an immunosuppressive tumour microenvironment that impairs senescence surveillance. However, pharmacological inhibition of Janus kinase 2 (JAK2) in these tumours induces the reprogramming of the SASP, thus leading to an antitumour immune response that promotes the clearance of senescence tumour cells. The SASP is also controlled by mTOR (mechanistic target of rapamycin). Indeed, mTOR inhibitors reduced SASP.

The use of senolytic therapies may also enhance the efficacy of pro-senescence therapies by removing senescence cells from the tumour. Senolytic therapies may be administered concomitantly with or after pro-senescence compounds to decrease potential negative side effects of the SASP in tumours where the tumour immune clearance does not take place. As recently reported, senescent tumour cells rely on pro-survival networks and are therefore more susceptible to the inhibition of these pathways. For instance, Bcl-2/Bcl-x inhibitors may be used in combination with pro-senescence compounds to enhance the efficacy of pro-senescence therapy. Since senescent tumour cells also undergo to metabolic reprogramming, pharmacological inhibition of specific metabolic demands may be used to promote the clearance of senescent cells in tumours treated with pro-senescence therapies. Such an approach has been successfully tested in a model of lymphoma but it still remains to be validated in additional tumour models. In conclusion, we believe that pro-senescence therapy for cancer is a promising new therapeutic strategy and that in the future novel, therapies based on senescence induction in cancer will be the standard of care for the treatment of cancer patients.

In the past few weeks a fair number of papers have been published on the very straightforward relationship between exercise and cardiovascular mortality, and here is another of them. A mountain of past data demonstrates the association between greater activity and lower mortality in later life, but in human studies it is usually difficult to prove causation. For that we can turn to the equally large mountain of animal data, where experiments can be constructed to prove that differences in mortality are caused by differences in physical activity. Given all of this evidence, it would be foolish not to try to lead a more active life, and thereby suffer less in the years ahead.

Being physically inactive - sitting for long periods of time - can be so harmful to your health that experts sometimes call it "sitting disease." In fact, worldwide, physical inactivity is estimated to cause some 3.2 million deaths a year. Medical experts know that regular physical activity lessens death from all causes and death from heart disease specifically for middle-aged people. However, until now, little has been known about the benefits of exercise for older people when it comes to deaths associated with heart disease.

A new study examined whether regular leisure-time physical activity could reduce deaths from all causes, and whether it also could reduce deaths from cardiovascular disease. To study this association, researchers examined information taken from 2,465 men and women aged 65 to 74 who participated in a national health study conducted between 1997 and 2007 in Finland. The participants answered a questionnaire that assessed their lifestyle habits, including whether they smoked or engaged in exercise. Researchers also knew the participants' level of education, height and weight, blood pressure, and cholesterol levels. The research team followed the participants through the end of 2013. Then, they consulted the Finnish mortality register to determine how many of the participants had died (and what caused their deaths).

The researchers discovered that moderate- as well as high-levels of physical activity were associated with a decreased risk of heart disease and death from all causes, including from events such as strokes or heart attacks. Physical activity works in several ways to improve your heart's health. Exercise helps people maintain a healthy body weight, lowers blood pressure, reduces the risk of blood clots, helps stabilize blood sugar levels, and improves the ratio of unhealthy LDL to healthy HDL cholesterol in your body. If you are already moderately active, that is enough to make a positive impact on your health. If you're sedentary and become more active - even by taking several short walks around your home each day - you can improve your health significantly, and lower your risk of heart disease.

Link: http://www.healthinaging.org/news/research-summaries/article:01-05-2017-12-00am-physical-activity-reduces-heart-disease-deaths-for-older-adults/

There is some debate over whether accumulated stochastic nuclear DNA damage is significant in aging over the present human life span in ways other than increased cancer risk, and a lack of good studies that provide evidence to support theoretical arguments in either direction. Stochastic DNA damage is observed, different in every cell, but like many of the changes of aging this cannot yet be effectively repaired, and thus it is very challenging to distinguish its effects in isolation. On the side of arguing for significance, the mechanism by which it contributes to aging is assumed to be a growing level of general dysfunction in cellular populations. This conjecture is supported by work such as that shown here, in which specific mutations are pointed out as problematic for the normal function of tissues, but the challenge here is still that there is no good demonstration of its significance in normal aging over and above other mechanisms, such as those outlined in the SENS vision of aging. It might only be a problem if ten times as many cells are mutated than normally happens. Or a hundred times. One possible next step would be gene therapy to repair mutated instances of the gene where they occur in order to assess the size of the effect, but that sort of study hasn't taken place yet.

Though cardiovascular disease, which is characterized in part by atherosclerosis, or plaque build-up, is a leading cause of death in the elderly, almost 60 percent of elderly patients with atherosclerotic cardiovascular disease (CVD) exhibit no conventional risk factors, or just one. This and other data suggest that age-dependent risk factors that haven't yet been identified may contribute to CVD. Scientists know that accumulation of somatic DNA mutations is a feature of aging, though little data exists on the role of such mutations in age-associated disorders beyond cancer. Meanwhile, recent human studies indicate that aging is associated with an increase in somatic mutations in the hematopoietic system, which gives rise to blood cells; these mutations provide a competitive growth advantage to the mutant hematopoietic cells, allowing for their clonal expansion - a process that has been shown to be associated with a greater incidence of atherosclerosis, though specifically how remains unclear.

In this study, researchers investigated whether there is a direct relationship between such mutations and atherosclerosis. They generated an experimental model to investigate how one of the genes commonly mutated in blood cells of elderly humans, TET2, affects plaque development. Plaque formation accelerated in the models transplanted with Tet2-deficient bone marrow cells, likely through increasing macrophage-driven inflammation in the artery wall. The results strengthen support for the hypothesis that hematopoietic mutations play a causal role in atherosclerosis. "Our studies show that mutations in our white blood cells, that we acquire as we age, may cause cardiovascular disease. Understanding this new mechanism of cardiovascular disease could lead to the development of new therapies to treat individuals who suffer from heart and blood vessel ailments due to these mutations. Furthermore, because these mutations become prevalent starting at middle age, these studies suggest that genetic analyses of blood samples could add to the predictive value of traditional risk factors - high cholesterol, hypertension, diabetes, and smoking - that are currently monitored."

Link: https://www.eurekalert.org/pub_releases/2017-01/bumc-arf011917.php

There is considerable interest in the research community when it comes to answering questions about the effects of exercise and inactivity on long-term health, pace of aging, and mortality. Possibly more than the topic merits now that rejuvenation therapies and other advanced medical biotechnologies are plausible near future goals for development. Since the development of low-cost accelerometers of the sort now found in every mobile phone, the quality of data has improved to the point at which quite detailed questions on activity levels and health can be asked and potentially answered. For example, what is the dose-response curve for exercise, when measured in terms of outcomes such as incidence of age-related disease and mortality rates? Another topic that has attracted a lot of attention in the past few years is the degree to which sitting, or similar sedentary behavior, has a negative impact on health that is independent of exercise. The studies I've seen so far are divided on this question: is it the sitting or is it the overall inactivity that is harmful or correlated with harmful choices, such as a high calorie intake and putting on weight?

The challenge for many studies is that their datasets include only self-reported activity levels. As the accelerometer study linked below illustrates very well, there is enough of a difference between what people say they do and what they actually do when it comes to exercise, even given the best of intentions, to cause issues in statistical interpretation. One might go so far as to say that any study not using accelerometers should probably be treated with suspicion for anything other than the most general conclusions drawn from its data. We know that exercise is good, and we know that a completely sedentary life is about as bad as taking up smoking, but a self-reported study is no basis for establishing effects by dose, or more subtle relationships such as how the degree of periodic inactivity versus the degree of periodic activity affects health over the long term.

The study below uses average telomere length in white blood cells as a metric for age. This is on the whole a pretty terrible biomarker, with an age-related decline that only shows up in the statistics for large populations, and even there we find studies that fail to observe correlations in various groups. For individuals it is of a very dubious value. That said, it is probably passable for the purposes of this study, insofar as it can be used to make the primary point above about the problems of self-reported data. For preference I'd rather see researchers using DNA methylation biomarkers of physical age, but if that isn't in the dataset used, then not much can be done within the time and budget allotted other than to work with what you have.

It is worth recalling that what this telomere length measurement primarily reflects is immune system health, not aging. It only reflects age through the effects of age on the immune system and its constituent parts. New immune cells are created by stem cells with long telomeres, and lose a little of that length every time they divide. Average telomere length in this measurement is thus determined by (a) stem cell activity, which is known to decline with age, (b) the rate of division of immune cells, which depends on any number of factors, from infection to other forms of ill health to the age-related malfunctions of the immune system as a whole, and (c) the number of senescent immune cells lingering with very short telomeres instead of following their peers into self-destruction. Some of these latter factors are highly variable with circumstances and on a very short time frame, which is one of the reasons as to why this isn't such a great metric for individuals, and why one has to examine the data across a large number of people to observe declines over time.

Too Much Sitting, Too Little Exercise May Accelerate Biological Aging

Researchers report that elderly women who sit for more than 10 hours a day with low physical activity have cells that are biologically older by eight years compared to women who are less sedentary. The study found elderly women with less than 40 minutes of moderate-to-vigorous physical activity per day and who remain sedentary for more than 10 hours per day have shorter telomeres - tiny caps found on the ends of DNA strands, like the plastic tips of shoelaces, that protect chromosomes from deterioration and progressively shorten with age. As a cell ages, its telomeres naturally shorten and fray, but health and lifestyle factors, such as obesity and smoking, may accelerate that process. Shortened telomeres are associated with cardiovascular disease, diabetes and major cancers. "Our study found cells age faster with a sedentary lifestyle. Chronological age doesn't always match biological age."

Nearly 1,500 women, ages 64 to 95, participated in the study. The women are part of the larger Women's Health Initiative (WHI), a national, longitudinal study investigating the determinants of chronic diseases in postmenopausal women. The participants completed questionnaires and wore an accelerometer on their right hip for seven consecutive days during waking and sleeping hours to track their movements. "We found that women who sat longer did not have shorter telomere length if they exercised for at least 30 minutes a day, the national recommended guideline. Discussions about the benefits of exercise should start when we are young, and physical activity should continue to be part of our daily lives as we get older, even at 80 years old."

Associations of Accelerometer-Measured and Self-Reported Sedentary Time With Leukocyte Telomere Length in Older Women

Emerging evidence has linked leukocyte telomere length (LTL) to modifiable factors such as smoking, body mass index, and physical activity. Sedentary behavior has also been studied in relation to LTL, but with mixed findings. In the Nurses' Health Study, there was no association of total sedentary time or specific sedentary behaviors with LTL, but in 2 recent studies, reduced sedentary time was associated with longer LTL. However, these studies were limited by several factors, including failure to measure sedentary time objectively (i.e., by accelerometer). Accelerometer-measured sedentary time is not highly correlated with self-reported time, the latter of which often underestimates actual time spent in sedentary behaviors. In a cross-sectional study, we assessed associations of accelerometer-measured and self-reported sedentary time with LTL in older white and African-American women from the Objective Physical Activity and Cardiovascular Health (OPACH) Study, an ancillary study of the Women's Health Initiative (WHI).

In the overall sample, there were 863 (58.3%) white and 618 (41.7%) African-American women. Women were aged 79.2 years, on average, ranging in age from 64 years to 95 years. Women wore the accelerometer for an average of 14.7 hours/day over an average of 6.3 days. The mean amounts of accelerometer-measured and self-reported sedentary time were 9.2 hours/day and 8.6 hours/day, respectively. The mean amounts of accelerometer-measured and self-reported moderate- to vigorous-intensity physical activity (MVPA) were 0.8 hours/day and 0.5 hours/day, respectively. Accelerometer-measured and self-reported sedentary time were weakly correlated; accelerometer-measured and self-reported MVPA were similarly weakly correlated. Women with greater amounts of accelerometer-measured sedentary time were more likely to be older, white, and obese. They were also more likely to have high blood pressure, a history of chronic diseases, a lower physical performance score, and fewer hours/day of MVPA and to have experienced a fall in the past 12 months. Women with higher self-reported sedentary time were more likely to be older, white, and obese and to have a history of chronic diseases. They also had a lower physical performance score and lower levels of self-reported MVPA, and they were less likely to be in excellent or very good health.

Among older women who were less physically active as measured by accelerometry, a greater amount of accelerometer-measured sedentary time was significantly associated with shorter LTL. Findings persisted after adjustment for demographic characteristics, lifestyle behaviors, and body mass index but were attenuated after adjustment for a history of chronic diseases and use of hormone therapy. In the full-adjustment model, LTL was on average 170 base pairs shorter in the most sedentary women compared with the least sedentary women. Since women may lose on average 21 base pairs/year, this suggests that the most sedentary women were biologically older by 8 years. Our findings have important implications for an aging population, in which greater time spent sedentary and less physical activity tends to be the norm

Although we did not observe a significant statistical interaction between sedentary time and MVPA, several studies examining joint associations of sedentary time and physical activity with adverse health outcomes have observed that disease and mortality incidence risks associated with higher sedentary time were either attenuated or eliminated among persons engaging in greater amounts of physical activity and were stronger in those with lower levels of physical activity. In our study, accelerometer-measured sedentary time was not associated with LTL among women who were more physically active. Additionally, sedentary time was not associated with LTL among women meeting current public health recommendations of ≥30 minutes/day of MVPA; in those not meeting this recommendation, higher sedentary time was associated with shorter LTL.

Astrocytes are an important class of support cell in the brain, and one of the most common cell types in brain tissue. They carry out a wide range of tasks, most of which are absolutely essential to the functions performed by neurons. A few years ago, researchers suggested that senescent astrocytes may be responsible for a sizable portion of the progression of neurodegenerative conditions, a proposal expanded and further investigated since then, with a great deal more evidence gathered. Astrocyte behavior in the brain appears to change for the worse with age in a number of ways, not all of which may be connected to cellular senescence, and some of which might be preventable in the near term. The publicity materials here outline some of the most recent findings on this topic, in which the researchers propose that transformed astrocytes are producing some form of signal that results in the death of nearby neurons, and show that these astrocytes are present in neurodegenerative conditions where such cell death occurs:

While most of us haven't heard of astrocytes, these cells are four times as plentiful in the human brain as nerve cells. Now, a team has found that astrocytes, which perform many indispensable functions in the brain, can take on a villainous character, destroying nerve cells and likely driving many neurodegenerative diseases. "We've learned astrocytes aren't always the good guys. An aberrant version of them turns up in suspicious abundance in all the wrong places in brain-tissue samples from patients with brain injuries and major neurological disorders from Alzheimer's and Parkinson's to multiple sclerosis. The implications for treating these diseases are profound." Up to now, the pharmaceutical industry has mostly targeted nerve cells, also known as neurons. But a broad range of brain disorders may be treatable by blocking astrocytes' metamorphosis into toxic cells, or by pharmaceutically countering the neuron-killing toxin those harmful cells almost certainly secrete.

Once thought of as mere packing peanuts whose job it was to keep neurons from jiggling when we jog, astrocytes are now understood to provide critical hands-on support and guidance to neurons, enhancing their survival and shaping the shared connections between them that define the brain's labyrinthine circuitry. It's also known that traumatic brain injury, stroke, infection and disease can transform benign "resting astrocytes" into "reactive astrocytes" with altered features and behaviors. But until recently, whether reactive astrocytes were up to good or evil was an open question. In 2012, researchers resolved that ambiguity when they identified two distinct types of reactive astrocytes, which they called A1 and A2. In the presence of LPS, a component found in the cell walls of bacteria, they observed that resting astrocytes somehow wind up getting transformed into A1s, which are primed to produce large volumes of pro-inflammatory substances. A2s, on the other hand, are induced by oxygen deprivation in the brain, which occurs during strokes. A2s produce substances supporting neuron growth, health and survival near the stroke site.

In a series of experiments using laboratory mice, the scientists identified three pro-inflammatory factors whose production was ramped up after LPS exposure: TNF-alpha, IL-1-alpha and C1q. In the brain, all three of these substances are secreted exclusively by microglia. Each, by itself, had a partial A1-inducing effect on resting astrocytes. Combined, they propelled resting astrocytes into a full-fledged A1 state. Next, the researchers confirmed that A1s jettison the nurturing qualities they'd had as resting astrocytes. Further experiments showed that A1s lose resting astrocytes' capacity to prune synapses that are no longer needed or no longer functional and whose continued existence undermines efficient brain function. Indeed, when the researchers cultured healthy neurons with increasingly stronger concentrations of the broth in which A1s had been bathing, almost all the neurons eventually died. This and other experiments showed that A1s secrete a powerful, neuron-killing toxin.

Finally, the researchers analyzed samples of human brain tissue from patients with Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis. In every case, they observed large numbers of A1s preferentially clustering where the disease was most active. For example, in the samples from Alzheimer's patients, nearly 60 percent of the astrocytes present in the prefrontal cortex, a region where the disease takes a great toll, were of the A1 variety. Because A1s are highly toxic to both neurons and oligodendrocytes, these findings strongly imply that A1 formation is helping to drive neurodegeneration in these diseases. An effort to identify the neurotoxin secreted by A1 astrocytes is underway. "We're very excited by the discovery of neurotoxic reactive astrocytes, because our findings imply that acute injuries of the retina, brain and spinal cord and neurodegenerative diseases may all be much more highly treatable than has been thought."

Link: http://med.stanford.edu/news/all-news/2017/01/toxic-brain-cells-may-drive-many-neurodegenerative-disorders.html

This flashy popular press article in the modern style of scrolling illustrates an important point: that it is actually quite difficult for newcomers to build a coherent picture from the varied claims and lines of research taking place in the field of longevity science. The thing that they are missing, and which takes some time to put together for yourself, is enough of an understanding of the underlying biology to make estimates of likelihood of success for given project versus the plausible scale of the outcome. Will it produce a lengthening of life or postponement of age-related disease, and for how long? Absent this understanding, most journalists tend to put all of the various work at the same level of priority and interest, and thus assemble an article from a more or less random sampling of the field, but this simply isn't the case. For example, the work on developing metformin as a way to slow aging is both unlikely to produce reliable outcomes, based on the animal data, and those outcomes will be small even if successful. The same could be said of pretty much all of the current pharmaceutical approaches that aim to alter the operation of metabolism to slow down the progression of aging - but even in that category, some, like mTOR inhibitors, are far more plausible than others. In comparison, methods of repair that remove damage and waste in tissues, like senescent cell clearance, should be a much more reliable and effective means of turning back aging, producing actual rejuvenation. These are very different things, but few journalists will have the necessary background to explore this point.

The most outspoken opponent of death by aging in the scientific community is probably Aubrey de Grey. In his mind, aging is unhealthy; a collection of undesirable side effects of being alive. He likens aging to malaria because it kills a lot of people. If you could cure it, wouldn't you? There is a growing cohort of well-credentialed scientists investigating radical life extension: geneticist Craig Venter, one of the first to sequence the human genome; biochemist Cynthia Kenyon, who discovered that a mutation in a single gene doubled a worm's lifespan and is now vice president of aging research at Google sister company Calico; and molecular biologist Bill Andrews, who led the team that discovered the human gene for telomerase, an enzyme considered critical in aging. Their promises include keeping 90-year-olds as healthy as 50-year-olds, as the Virginia-based Methuselah Foundation says; extending life to 150 years, as Andrews says; and being biologically 25 years old indefinitely, as de Grey says. We're taught that death is natural and that trying to escape it is wishful lunacy. However, these researchers have made tangible discoveries. They've published studies in highly respected journals and attracted serious amounts of funding. When they say it's possible to live longer, and maybe forever, it's tempting to believe them.

Every few months, scientists will come out with a new finding that shows how a very specific set of changes slowed down some aspects of aging in animals. Of course, each study is more insightful when viewed as part of the body of anti-aging research as a whole. To understand what researchers have accomplished in this area, it's helpful to understand what "aging" means in a scientific context. Specifically, aging refers to the time-related degradation or decline of the bodily functions necessary for survival. As we age, changes occur in our bodies on a cellular level that affect not just our heart and lungs but also our muscles and our nervous system. These changes affect all of the different systems in our bodies. And each of these systems individually begins to work a little less well as we get older, and gradually that produces the burden of dysfunction that ultimately results in disease, disability, and eventually death. We also now understand that biological age doesn't always correspond to clock age. Imagine a pair of twins: One drinks too much, eats poorly, rarely gets enough sleep, and never exercises, while the other does the opposite. The first twin is likely to age faster and develop more of those age-related diseases.

The key lies with what scientists call signaling, or how cells communicate to govern basic functions like cell repair and immune response. While errors in cell signaling can cause autoimmune diseases, diabetes, and cancer, it also turns out that modifying signaling pathways can also slow aging, at least in animals. Researchers have identified two age-related signaling pathways: the Insulin/IGF-1 signaling pathway, which is linked to growth and metabolization, and the Target for Rapamycin or TOR, which in addition to growth regulates how cells move, and replicate. The deeper you get into anti-aging science, the more you'll see these acronyms. If we can slow down that biological clock enough, the thinking goes, we could delay the onset of old age and the diseases that come with it. Centenarians, humans that manage to live to 100 years and beyond, are more likely to carry mutations that reduce the activity of the IGF-1 receptors than those who die younger. At the same time, similar studies in yeast have shown that if you genetically alter TOR signaling pathways so that they communicate less, the yeast also lived longer. In total, the research suggests if you can find ways of calming down these signaling pathways you might be able to slow down aging.

One way of reducing signal TOR pathways is unpleasant if you enjoy eating. Studies have shown that mice fed 65 percent less food lived up to 60 percent longer. Thankfully, researchers have found other interventions, that work on the same pathway. Rapamycin, an anti-rejection drug used by kidney transplant patients, has increased lifespan in mice by up to 14 percent; low-dose Aspirin increased worm lifespan by 23 percent. A national clinical trial called Targeting Aging with Metformin, or TAME, to test Metformin's anti-aging effects in humans has received FDA approval. "What we want to show is that if we delay aging, that's the best way to delay disease."

Link: https://theoutline.com/post/902/the-case-for-defeating-death

Today I noticed a set of interesting research materials in which the authors report on their investigation of links between chronic inflammation and intestinal dysfunction in aging. Growing inflammation is characteristic of aging in an age in which near everyone puts on a great deal of weight as they get older. Visceral fat tissue produces excessive inflammation through a number of mechanisms, which is one of the ways in which its presence accelerates the onset of all of the common age-related diseases. But even putting fat tissue to one side, aging is still accompanied by ever greater levels of chronic inflammation, a consequence of the progressive failure of the immune system, hampered by the fundamental cell and tissue damage of aging on the one hand, and on the other by limits to capacity that are inherent in the way in which it is structured. Unregulated inflammation due to immune system malfunction, either in the innate or adaptive components, is called inflammaging and considered by some to be a distinct process from immunosenescence, the inability of the immune system to effectively combat pathogens and destroy unwanted cells.

Intestinal dysfunction is a central feature of aging in lower species such as flies, and measures of aging in the intestines can predict mortality in this species. Further, a number of the methods shown to slow aging in flies appear to work through improved stem cell activity in intestinal tissues. Flies are not people, however, and it isn't at all clear that the intestines have anywhere near the same degree of prominence in mammalian aging. If anything, that position should probably go to the cardiovascular system in our own species, given the distribution of proximate causes of human mortality, and the way in which cardiovascular aging correlates well with many other forms of ultimately fatal age-related disease. Still, there is an increasing interest these days among aging researchers in the microbiome that dwells within the gut, and the roles that this microbial ecosystem might play in aging, especially as tissue function begins to break down, and as the immune system becomes both more easily aggravated and less effective. Considered in the bigger picture, the open access paper here makes for interesting reading; you might just skip the publicity materials.

Research Team Identifies Mechanisms of Inflammation-induced Animal Aging

Researchers have identified the aging mechanisms of animals resulting from intestinal inflammation accumulation. So far, numerous hypotheses explaining animal aging have been published and one of them is inflammation-induced aging which proposes that accumulation of inflammation is the cause of animal aging. While inflammation-induced aging theory has been one of many hypotheses explaining the aging of animals, its substance has not been clearly proven. The research team has discovered that the pericytes surrounding the endothelial cells in the intestinal tissues decrease as an animal's biological age increases and thus the blood vessel function deteriorated, including the progress of vascular leakage. Through the experiment, this study has shown that this phenomenon is due to the increase of gut-resident inflammatory cells (macrophages) and the increase of TNF-α, cytokine secreted by these cells, as well as the entailed changes in the surrounding environment of blood vessel.

"This study is significant as we have newly identified the mechanisms of aging associated with inflammation increase and opened possibilities of applied researches on aging delay through inflammation control as well as anti-aging. We will conduct follow-up studies to find ways to extend human health life by controlling inflammatory cells and vascular leakage to delay aging." This study will open a new chapter in anti-aging, a long standing challenge for mankind. It is expected that the follow-up studies on intestinal inflammation control will make a great contribution to the development of various technologies that can practically delay aging. For these purposes, it is required to explore a variety of candidate substances that are able to control gut-resident inflammation and conduct clinical researches on them.

Microvasculature remodeling in the mouse lower gut during inflammaging

Of many proposed mechanisms underlying aging, inflammaging theory proposes that chronic low-grade inflammatory status caused by life-time exposure of animals to a variety of antigens contributes to age-associated morbidity and mortality. An hallmark of age-associated chronic inflammation would be macrophage infiltration. In intestine, the epithelial lining separates internal organs from the enteric environment loaded with various foreign substances including microbiota and its metabolic products as well as nutrients and wastes. The lamina propria (LP) lying beneath the enterocytes in the intestinal villi especially that in the lower part, houses a largest pool of macrophages for maintaining mucosal homeostasis against the gut microbiota and for the constant need of epithelial renewal. Age-associated deterioration of gastrointestinal function could be ascribed to inflammaging, although substantial evidence is yet to emerge.

In this study, we propose that the antigenic burden encountered in the intestine causes macrophage infiltration during the first few months after birth and that is sustained throughout life. Under the condition of chronic inflammation, it stands to reason to polarize macrophage toward the M2-like subtype to avoid tissue injury and eventual chaotic consequences caused by activated M1 macrophage. Consistently, it has been reported that total macrophages and myeloid derived suppressor cells cumulated in the spleens and bone marrow of aged mice were mostly anti-inflammatory M2 cells in aged mice. Macrophages are the sources of both pro-angiogenic and anti-angiogenic factors, which can differentially guide vascular network formation under many pathological conditions. We therefore propose that TNF-α derived from the macrophages in aged animals skews the angiopoetin-TIE-2 signaling in vascular endothelial cells to inflammatory settings that would facilitate recruitment of immune cells through endothelial cells. Such increase in vasculature permeability entails modulation of the endothelial cell network such as loss of VE-cadherin and pericyte, as demonstrated in this study. Together, our study demonstrates for the first time, to the best of our knowledge, that sustained aggravation of inflammation leads to age-related structural changes in organ.

Another item to consider here is a possible role for cellular senescence in these interactions, though this is not mentioned by the researchers. Senescent macrophages have been proposed to play a significant role in other inflammatory conditions, such as the development of atherosclerosis. Senescent cells produce inflammation in and of themselves, and so this might form the basis for a feedback loop of accelerated dysfunction in any situation in which macrophages accumulate over the course of aging. Senescent macrophages have been identified in other tissues, so this doesn't seem like a great leap, and possibly worth further investigation in the context of this research.

The search for gene variants associated with human longevity has turned up only two reliable correlations to date, with a couple more in the tentative bucket awaiting further confirmation. The effects of all of these are not large; individually, each represents only a small increase in the odds of a longer life. The emerging picture of the genetics of longevity is one of thousands of tiny influences, near all of which are highly conditional on circumstances and other variants. The vast majority of correlations observed in any one study population are not seen in others. One of the variants still in the tentative bucket is 5q33.3, first noted a couple of years ago, and this paper is illustrative of the sort of work required in the ongoing investigation of such correlations:

The search for major longevity genes in humans has so far had limited success and only the APOE and FOXO3A genes have been found to consistently associate with human longevity. Recently, however, a third longevity locus was proposed based on the results of a genome-wide association meta-analysis including 12,736 long-lived individuals older than 85 years and 76,268 controls younger than 65 years of European descent. In this study, the single nucleotide polymorphism (SNP) rs2149954 on chromosome 5q33.3 was found to associate with survival to beyond 90 years of age. This association has afterwards been confirmed in a genome-wide association study of exceptional longevity in Han Chinese centenarians. Investigation of the effect of rs2149954 on prospective survival in the meta-analysis showed a significant association with lower all-cause mortality as well. Further investigation of cause-specific mortality in a sub-group analysis revealed that the lower mortality seen in rs2149954 minor allele carriers was partly conferred by a decreased mortality risk for cardiovascular disease, primarily due to protection from stroke. However, a protective effect of the rs2149954 minor allele on mortality independent of cardiovascular disease was also found.

Previous studies in middle-aged individuals have revealed a significant association between the rs2149954 minor allele and a decreased risk for coronary artery disease, and lower diastolic and systolic blood pressure. Also, two SNPs on chromosome 5q33.3 in high linkage disequilibrium with rs2149954, rs9313772 and rs11953630, have been reported to be associated with blood pressure and hypertension. In individuals older than 75 years the association between rs2149954 and all-cause mortality was, however, not found to be influenced by blood pressure. So, although there is an established connection between rs2149954 and different cardiovascular phenotypes, there also seems to be an effect of the variant in mechanisms other than those associated with cardiovascular disease and blood pressure regulation, at least in long-lived individuals. The role of the 5q33.3 locus in survival and longevity is therefore still partly unknown.

To further explore this, we investigated the influence of rs2149954 on age-related phenotypes previously shown to predict survival in the oldest-old: cognitive function (evaluated by a 5-item cognitive composite score and the Mini-Mental State Examination (MMSE)), physical function (evaluated by an activity of daily living (ADL) strength score, hand grip strength, gait speed, and chair stand), ADL disability, depression symptomatology, and self-rated health. In addition, self-reported diseases related to cancer and cardiovascular disease, which are among the leading causes of death, were explored. The apparent age-dependent pleiotropy in the role of the 5q33.3 locus was addressed by analyzing long-lived as well as middle-aged and elderly individuals.

In the middle-aged and elderly individuals, we found a nominally significant association between the minor allele of rs2149954 and a lower risk of hypertension. This is supported by an analysis of the diastolic and systolic blood pressure measured in the middle-aged individuals at a later follow-up assessment. Here we find that homozygous carriers of the rs2149954 minor allele have lower diastolic and systolic blood pressure, which is in line with the previously found association between rs2149954 and lower diastolic and systolic blood pressure in middle-aged individuals. Overall, our results support a role of rs2149954 in cardiovascular health, and we confirm the previously found association between rs2149954 and a lower risk of hypertension in middle-aged as well as in elderly individuals. The 5q33.3 locus thus appears to play a persistent role in cardiovascular health throughout the entire age-span investigated here, although we see a shift with age from a role in hypertension to a role in heart attack and heart failure. This shift is supported by a number of studies indicating that while high blood pressure is disadvantageous in midlife it appears to be advantageous at higher ages where it is associated with better physical and cognitive health and lower all-cause mortality. This reversal of risk has been suggested to take place around the age of 75 to 85 years and it is thus consistent with the age-related attenuation that we see for the association between rs2149954 and hypertension.

Link: http://www.aging-us.com/article/7BLY8Rs2pcKxaGP8K/text#fulltext

This popular science article walks through a new interpretation of one class of evolutionary theory of aging, envisaging the existence of aging as being necessary for the formation of complex life forms with active metabolism and high energy demands. While there are higher species that exhibit negligible senescence for much of their lifespans, such as naked mole rats and lobsters, the only definitively immortal animals are lower species such as hydra, and even then only in optimal conditions. It isn't necessary for aging to be essential for it to dominate, however: it would only need to be significantly advantageous in evolutionary competition to reach the situation we see today, in which aging is near ubiquitous in the animal world. This is nonetheless an interesting take on the current body of theory regarding the origins of aging, and dovetails nicely with the significance of mitochondria to aging today:

Life's ever-repeating cycles of birth and death are among the most fundamental principles of nature. An organism starts out as a single cell that grows and divides, develops into an embryo, matures and reaches adulthood, but then ages, deteriorates, and eventually succumbs to death. But why does life have to be cyclic, and why does it have to end in senescence and death? After all, animals like corals and marine sponges live for thousands of years and are capable of virtually infinite regeneration and cell repair. Even in more complex animals, offspring do not inherit their parents' age: every new generation starts with cells in a pristine state, with no trace of aging. If senescence is somehow suppressed in reproductive cells, why do the rest of the organism's tissues end up deteriorating and dying?

At the end of the 19th century, the German biologist August Weismann realized that complex organisms consist of two cell types: the "immortal" germline - eternally young cells that give rise to sperm and eggs - and the "disposable" somatic cells that form the rest of the body. More recently, Weismann's ideas were given an overhaul by Thomas Kirkwood in his disposability theory of aging. Kirkwood argued that the force of natural selection declines with age, as most organisms in their natural environments die due to external hazards such as predators, parasites and starvation. At the same time, organisms must invest resources into both the reproductive effort and the maintenance and repair of their somatic cells. But because the probability of surviving external threats declines with time, the optimal strategy is to allocate less and less resources into somatic maintenance as time goes by. Lack of cell repair in the later stages of the life cycle results in the progressive loss of function and gradual decay - aging.

The real-world picture turned out to be more complex than Weismann's model could have predicted. In complex animals like mammals, birds and insects, Weismann's assumption of the rigid germline-somatic cell distinction holds true: only a relatively small group of cells in an adult retain reproductive potential, while the rest become irreversibly differentiated into somatic tissue cells - liver, skin, muscle - that cannot give rise to a new organism. But this is not the case in the most ancient members of the kingdom, such as hydrae, corals and sponges. Even in their adult forms, these organisms maintain large populations of universal stem cells that can generate both somatic and reproductive cells, that is, germline and somatic cells never really segregate. It is the lack of germline sequestration that gives corals and their relatives the power of regeneration and vegetative plant-like reproduction.

Rather than being universal to all animals, the Weismann barrier appears to be a relatively recent innovation of complex organisms, evolving together with somatic aging and death. What drove the evolution of this separation is not clear, but the answer will also shed light on the origin of mortality in complex animals. There are signs that the evolution of both the germline and mortal somatic cells is related to cellular energetics. Animal cells produce energy through respiration in their mitochondria - the organelles of bacterial origin that retain their own tiny genomes, distinct from the chromosomes housed within the nucleus. Each cell contains tens and hundreds of mitochondria, and each mitochondrion has several DNA molecules. This tiny genome regulates mitochondrial function; its integrity is crucial to cellular respiration, as defective mitochondrial genes often lead to debilitating diseases, neuromuscular degeneration and early death. A large part of mitochondrial gene defects arise from random copying errors in imprecise DNA replication.

Since a large part of mitochondrial gene defects arise from random copying errors in imprecise DNA replication, as cells in a developing organism divide, their mitochondria replicate too, each time introducing new DNA mutations. In our recent scientific paper, we show that in organisms with fast mitochondrial defect accumulation, natural selection favors segregation of an isolated germline with a lower number of cell replication cycles, as it minimizes the damage to the energy-producing organelles that could potentially be transmitted to the next generation. If the pace of error accumulation is slow, however, the strict germline-somatic cell barrier should not evolve. Our model therefore suggests that "disposable" somatic cells, that gave rise to aging and mortality, has evolved as a strategy to maintain mitochondrial quality in complex organisms with multiple tissues and high energy requirements, in which mitochondrial defects accumulate relatively fast.

Link: https://singularityhub.com/2017/01/15/aging-and-death-are-the-evolutionary-price-of-complexity/

The latest analysis of data on primate longevity under conditions of calorie restriction was published today, and sides with the claims of extended longevity and improved health made a few years ago. Two long-running studies of calorie restriction in rhesus macaques commenced in the late 1980s and early 1990s, and are currently in the phase at which survival data can be discussed rather than projected. Rhesus macaques are known to have lived for longer than 40 years in captivity, but most in these circumstances die by age 35, and the average age at death is 26. This is an exceptionally long time to run a study in the modern scientific community. The cost of such studies is large, and in the present environment they are unlikely to be repeated or expanded upon in the foreseeable future. Firstly because we are entering the era of rejuvenation therapies, in which methods of modestly slowing aging such as calorie restriction will soon become irrelevant. Secondly, because there has been considerable debate in the past few years over the design of these studies, whether the results to date in fact illustrate that longer-lived primates exhibit extension of life span under calorie restricted conditions, or indeed, whether or not the results are actually useful given the issues with the studies. Still, if we want the data we are unlikely to find other sources any time soon.

An important point to keep in mind while considering this topic is that short-lived species have a greater plasticity of longevity in response to environmental circumstances, such as a lower calorie intake, and most likely to any gene therapy or pharmaceutical that mimics aspects of those environment circumstances. We know this because the practice of calorie restriction does not reliably produce 110-year-old humans, while in mice calorie restriction reliably extends life by as much as 40%. Why does this difference exist? From a molecular biology perspective it is puzzling given that the short-term changes in metabolism that take place under conditions of calorie restriction are remarkably similar in mice and people. From an evolutionary perspective, on the other hand, there is a solid theoretical explanation: calorie restriction, which evolved very early in the development of life, is a response to seasonal famine. It is a way to increase the odds of survival in an environment of scarcity that tends to last only so long. A season is a lengthy fraction of a mouse life span, but not so for humans, and so only mice experience the evolutionary pressure that leads to a proportionally large extension of life in this scenario.

Running studies in primates that live for decades is a way to try to understand to what degree we should expect calorie restriction to extend life in humans, and perhaps also to understand something of the mechanisms that ensure the outcome is a lesser degree of life extension than in short-lived mammals. Were there large communities of human practitioners of calorie restriction, the studies would not have taken place: researchers would do exactly what they do for, say, the effects of exercise, and first turn to human epidemiological data. There are, however, very few people with the necessary decades of calorie restriction behind them, so it is hard to answer questions about human long-term outcomes. The biomarkers and human studies of a few years or less suggest large benefits in terms of resistance to age-related disease, but again, there is a noted absence of effects large enough and reliable enough to show up in established databases of mortality and disease. Given the small number of practitioners, it is not entirely unreasonable to expect an effect of five to ten years to be hard to find in existing data, but much larger than this and we must start to question the plausibility.

The open access paper quoted below is very readable, and actually goes into some detail regarding differences between the studies relevant to past disputes over results. If the topic interests you, then you should certainly look over the whole thing rather than just the summary here. Does this new study add good reasons to practice calorie restriction? I'd say probably not on the whole. If you are not already sold on the rapid and sizable beneficial effects to health that are produced via a calorie restricted diet, or at least sizable in comparison to what any widely available medical technology can do for basically healthy people today, then I can't imagine that the endorsement here will be much of an additional attraction. It is one more data point atop a large and compelling mountain of data points. Being healthy for the long term does require some effort, and that will continue to be the case for a while yet. Being rescued from aging and ill health by progress towards rejuvenation therapies may indeed happen, but when it will happen is a question mark. So why shorten the odds for your own future by letting things go today?

Caloric restriction improves health and survival of rhesus monkeys

A clear understanding of the biology of ageing, as opposed to the biology of individual age-related diseases, could be the critical turning point for novel approaches in preventative strategies to facilitate healthy human ageing. Caloric restriction (CR) offers a powerful paradigm to uncover the cellular and molecular basis for the age-related increase in overall disease vulnerability that is shared by all mammalian species. CR extends median and maximum lifespan in most strains of laboratory rodents and also delays the onset of age-related diseases and disorders. Lifespan is also extended by CR in most short-lived species, including the unicellular yeast, nematodes and invertebrates. There has been rapid progress in identifying potential mechanisms of CR utilizing these models. These short-lived species are well suited for the investigation of the underlying mechanisms of CR due to the relative ease in their genetic manipulation, extensive genetic and developmental characterization, low cost, and significantly reduced timeframe for completion of longevity studies. A key question underpinning this body of work is whether the biology of CR, and its ability to delay ageing and the onset of disease, applies to humans and human health.

To date three independent studies of rhesus monkeys (Macaca mulatta) have tackled the question of translatability of CR to primate species. The University of Maryland rhesus monkey study was the first to report a positive association of CR with survival with a 2.6-fold increased risk of death in control animals compared to restricted. The primary focus of the study was not CR however, and analysis was based on comparing 109 ad libitum fed males and females from colony records at that facility, including insulin resistant and diabetic animals, to only eight male CR monkeys. Two other studies focused specifically on the impact of CR in healthy male and female rhesus monkeys: one at the National Institute on Aging (NIA) involving 121 monkeys; and the other at the University of Wisconsin Madison (UW) with 76 monkeys. The same statistical team was engaged for analysis of data from both studies. The UW study has reported beneficial effects of CR, including significant improvements in health and age-related survival, and all-cause survival. In contrast, the NIA study reported no significant impact of CR on survival, although improvements in health were close to statistical significance. The basis for the contrasting outcomes from these two parallel studies has not been established. Analysis of limited published bodyweight data indicated that the controls were not equivalent between the two studies, pointing to fundamental differences in study design and implementation. Therefore, to more fully assess possible explanations for the discrepant findings between the two studies, we have conducted a comprehensive assessment of longitudinal data from both sites highlighting differences that may have contributed to the dissimilar outcomes.

Data from both study locations suggest that the CR paradigm is effective in delaying the effects of ageing in nonhuman primates but that the age of onset is an important factor in determining the extent to which beneficial effects of CR might be induced. In the UW study, reduced bodyweight, reduced adiposity and reduced food intake of the CR monkeys were associated with improved survival, with CR monkeys of both sexes surviving longer than controls, ∼28 and ∼30 years of age for males and females respectively, and longer than the median age for monkeys in captivity (∼26 years of age). Although an impact of CR on survival was not detected within the NIA old-onset cohort, comparison to the UW study shows that bodyweight was significantly lower in both control and CR groups of males and females than in their UW control counterparts, and was largely equivalent to that of UW CR. All males and females from the NIA old-onset groups consumed fewer calories than their counterpart controls from UW, instead both control and CR were closely aligned with food intake values of UW CR.

Importantly, the median survival estimates for old-onset males were very high, similar to what has been reported previously as the 90th percentile for this species (∼35 years of age). Six of the original 20 monkeys have lived beyond 40 years of age, the previous maximal lifespan recorded, and one old-onset CR male monkey is currently 43 years old, which is a longevity record for this species. Median survival estimates for old-onset females, ∼27 and ∼28 for controls and CR respectively, were also greater than national median lifespan estimates, with one remaining female currently 38 years of age. The clear benefit in survival estimates for monkeys within the old-onset cohort compared to UW controls suggests that food intake can and does influence survival. The lack of difference between control and CR old-onset monkeys suggests that a reduction in food intake beyond that of the controls brings no further advantage. The minimum degree of restriction that confers maximal benefit in rhesus monkeys has not yet been identified but is an active topic of investigation. Taken together, data from both UW and NIA studies support the concept that lower food intake in adult or advanced age is associated with improved survival in nonhuman primates.

The catalogue of pathologies identified in aged monkeys is shared with aged humans. The definitions used to identify morbidity were determined by veterinary staff and were essentially equivalent at both sites. A shared feature of both studies is the beneficial effect of CR in lowering the risk for age-related morbidity by more than two-fold. The beneficial effects extended to diseases that are among the most prevalent in human clinical care including cancer, cardiovascular disease and parameters associated with diabetes. A lower incidence of cancer was one of the first health benefits of CR documented and is considered to be a hallmark of CR in rodents. The incidence of cancer was lower in CR monkeys at both locations indicating that tumour suppression is a conserved feature of mammalian CR. CR also lowered the incidence of cardiovascular disorders at UW, and NIA monkeys from either diet group appear to have been protected compared to UW control monkeys.

Given the obvious parallels between human and rhesus monkey data, it seems highly likely that the beneficial effects of CR would also be observed in humans. Reports from the multicenter CALERIE study of short-term CR in humans document changes in bodyweight, body composition, glucoregulatory function and serum risk factors for cardiovascular disease in response to CR. These outcomes in humans align well with reports on rhesus monkey CR, confirming that the primary response to CR is conserved between these two species, and suggesting that the underlying mechanisms may also be conserved. In conclusion, the NIA and UW nonhuman primate ageing and CR studies address a central concept of relevance to human ageing and human health: that the age-related increase in disease vulnerability in primates is malleable and that ageing itself presents a reasonable target for intervention. The last two decades have seen considerable advances in ageing research in short-lived species and investigations of the mechanisms of CR have been prominent in this work. It will be particularly informative to determine the degree to which consensus hallmarks of ageing described in recent publications also manifest in primate ageing. The tissues and longitudinal data stored over the course of these two highly controlled monkey studies present a unique resource that can be used to identify key pathways responsive to CR in primates, to uncover primate-specific aspects of the basic biology of ageing, and to determine molecular basis for nutritional modulation of health and ageing. Processes impacted by CR would be prime targets for the development of clinical interventions to offset age-related morbidity, and identification of factors involved in the mechanisms of CR will be pivotal in bringing these ideas to clinical research and human health care.

In recent years it has become clear that we all suffer many tiny, unnoticed strokes as we age. These involve the rupture or blockage of small blood vessels in the brain and resulting damage and cell death in a very small area of tissue. Hypertension, the age-related increase in blood pressure, and consequences of other forms of cell and tissue damage on blood vessel integrity speed up this process, and the aggregate effect of these microstrokes explains some of the correlation between cardiovascular aging and neurodegeneration. Here, researchers make a start on understanding the scale of this effect in living brains:

Evidence overwhelmingly supports a link between cognitive decline and cerebrovascular diseases. Not only do individuals with cerebrovascular diseases have a much higher incidence of cortical microinfarcts (mini-strokes), but post-mortem histological and in vivo radiological studies also find that the burden of microinfarcts is significantly greater among people with vascular cognitive impairment and dementia (VCID) than in age-matched, non-demented individuals. Until now, the mechanisms by which these miniscule lesions (~0.05 to 3 millimeters in diameter) contribute to cognitive deficits including dementia have been poorly understood. Findings from a recent study provide crucial information for better understanding the impact of microinfarcts, showing that the functional deficits caused by a single microinfarct can affect a larger area of brain tissue and last longer than was previously thought to be the case.

The functional effects of microinfarcts are extremely difficult to study. Not only are most microinfarcts difficult to detect with standard neuroimaging techniques, mismatches between in vivo functional data and post-mortem histological evidence make it nearly impossible to connect microinfarcts to the timeline of cognitive decline. "These infarcts are so small and unpredictable, we just haven't had good tools to detect them while the person was still alive. So, until now, we basically just had post-mortem snapshots of these infarcts at the end of the dementia battle as well as measures of the person's cognitive decline, which might have been taken years before the brain became available for study. Even though a person may experience hundreds of thousands of microinfarcts in their lifetime, each event is extremely small and thought to resolve in a matter of days. It's been estimated that, overall, microinfarcts affect less than 2% of the entire human brain. But those estimates of tissue loss are based only on the 'core' of the microinfarct, the area of dead or dying tissue that we can see in routine, post-mortem, histological stains."

To investigate their theory of broader impacts, the team developed a mouse model so that they could examine the effects of individual cortical microinfarcts on surrounding tissue function in vivo over several weeks post-event. The team used photothrombosis to occlude a single arteriole in the barrel cortex of mice fitted with cranial windows. They then compared functional readouts of sensory-evoked brain activity, indicated by activity-dependent c-Fos expression or in vivo two-photon imaging of single vessel hemodynamic responses, to the location of the microinfarct core. Post-mortem, c-Fos immunostaining revealed that an area estimated to be at least 12-times greater in volume than the microinfarct core had been affected by the event. Furthermore, in vivo, two-photon imaging of single vessel, sensory-evoked hemodynamics found that neuronal activity across the affected tissue area remained partially depressed for 14 to 17 days after the microinfarct. Together, these data indicate that functional deficits caused by a single microinfarct occur across a much larger area of viable peri-lesional tissue than was previously understood and that the resulting deficits are much longer-lasting.

Link: https://www.eurekalert.org/pub_releases/2017-01/muos-tle011117.php

Heterochronic parabiosis, linking the circulatory systems of an old and a young mouse, benefits the old mouse in that it reduces some measures of aging. Researchers initially focused on possible beneficial signals in young tissues and blood, but more recent research suggests that the outcome may occur because harmful signals present in old tissues and blood are diluted. If this is the primary mechanism, it would explain why transfusion of young blood to old individuals does not appear produce similar effects in animal studies. Here researchers claim evidence for one such harmful signal:

The effects of blood on ageing were first discovered in experiments that stitched young and old mice together so that they shared circulating blood. Older mice seem to benefit from such an arrangement, developing healthier organs and becoming protected from age-related disease. But young mice aged prematurely. Such experiments suggest that, while young blood can be restorative, there is something in old blood that is actively harmful. Now researchers seem to have identified a protein that is causing some of the damage, and have developed a way to block it.

The researchers found that the amount of a protein called VCAM1 in the blood increases with age. In people over the age of 65, the levels of this protein are 30 per cent higher than in under-25s. To test the effect of VCAM1, researchers injected young mice with blood plasma taken from older mice. Sure enough, they showed signs of ageing: more inflammation in the brain, and fewer new brain cells being generated, which happens in a process called neurogenesis. Blood plasma from old people had the same effect on mice. When researchers injected plasma from people in their late 60s into the bodies of 3-month-old mice - about 20 years in human terms - the mice's brains showed signs of ageing. These effects were prevented when researchers injected a compound that blocks VCAM1. When the mice were given this antibody before or at the same time as old blood, they were protected from its harmful effects.

Some teams have begun giving plasma from young donors to older people, to see if it can improve their health, or even reduce the effect of Alzheimer's disease. But for the best chances of success, we'll also need to neutralise the damaging effects of old blood. Other researchers comment that it is "surprising that a single protein seems to have such a huge effect," but the results need to be replicated by another lab. A drug that protects people from the effects of old blood would be preferable to plasma injections. Should transfusions from young donors turn out to be effective, it would be difficult to scale this up as a treatment for all. Drugs that block harmful proteins in our own blood would be cheaper, safer and more accessible.

Link: https://www.newscientist.com/article/2118105-antibody-can-protect-brains-from-the-ageing-effects-of-old-blood/

For a number of years now, mechanistic target of rapamycin (mTOR) has been the focus of a fair amount of research into aging. Goals include gaining a better understanding of the way in which metabolism determines natural variations in longevity, and also establishing means by which the pace of aging might be modestly slowed via long-term pharmaceutical alteration of metabolic processes. I don't consider this to be the most effective way forward for longevity science, but evidently a lot of people do. mTOR appears to be a factor in a range of genetic and other interventions shown to slow aging to varying degrees in laboratory animals, but for most of these so many changes take place in cellular biochemistry that it remains a challenge to talk definitively about root causes or most important mechanisms.

So far the search for drug candidates to target mTOR has produced few if any outstanding new leads. Rapamycin is the starting point, and has been shown to extend life span in mice, but it has side-effects that make it undesirable for widespread use in humans. Researchers have been exploring the expanding suite of rapalogs, drugs with similar structures and effects, but so far nothing has jumped to the fore by virtue of a large enough improvement to demand immediate clinical development. mTOR forms two complexes in the course of interactions relevant to aging, mTORC1 and mTORC2. There is a school of thought that suggests the problems inherent in rapamycin and similar compounds arise because they affect both of these complexes. There is evidence to suggest that targeting mTORC1 while leaving mTORC2 alone would capture beneficial outcomes without many of the problem side-effects - but easier said than done with pharmaceuticals given the tools to hand. The real issues in the biochemistry are also probably more complex than this simplistic view of the situation.

The paper linked below is characteristic of continued exploration of pharmaceutical databases in search of better options, as well as the increasing complexity of the underlying theory that steers this exploration. The biochemistry of aging, the intricacy with which it progresses from moment to moment, is enormously complex. The paper is also characteristic of an increasing interest in cellular senescence in all areas of the aging research community. With the proof that removal of senescence cells extends life in mice, and increasing evidence for the role of senescent cells in specific age-related diseases, researchers now have to fit these findings into the many and varied existing views of aging, or give senescence greater prominence where already present. In the case of mTOR, researchers demonstrated last year that mTOR inhibition appears to slow the approach of cells towards replicative senescence, the state that occurs at the Hayflick limit on cell replication, which is one of the reasons why it appears here as a yardstick for measuring the effects of alternatives to rapamycin.

Gerosuppression by pan-mTOR inhibitors

Rapamycin slows down aging in yeast, Drosophila, worms, and mice. It also delays age-related diseases in a variety of species including humans. Numerous studies have demonstrated life extension by rapamycin in rodent models of human diseases. The maximal lifespan extension is dose-dependent. One explanation is trivial: the higher the doses, the stronger inhibition of mTOR. There is another explanation: mTOR complex 1 (mTORC1) has different affinity for its substrates. For example, inhibition of phosphorylation of S6K is achieved at low concentrations of rapamycin, whereas phosphorylation of 4EBP1 is insensitive to pharmacological concentrations of rapamycin. Unlike rapalogs, ATP-competitive kinase inhibitors, also known as dual mTORC1/C2 or pan-mTOR inhibitors, directly inhibit the mTOR kinase in both mTORC1 and mTORC2 complexes.

In cell culture, induction of senescence requires two events: cell cycle arrest and mTOR-dependent geroconversion from arrest to senescence. In proliferating cells, mTOR is highly active, driving cellular mass growth. When the cell cycle gets arrested, then still active mTOR drives geroconversion: growth without division (hypertrophy) and a compensatory lysosomal hyperfunction (beta-Gal staining). So senescence can be caused by forced arrest in the presence of an active mTOR. Senescent cells lose re-proliferative potential (RPP): the ability to regenerate cell culture after cell cycle arrest is lifted. Quiescence or reversible arrest, in contrast, is caused by deactivation of mTOR. When arrest is released, quiescent cells re-proliferate. In one cellular model of senescence (cells with IPTG-inducible p21), IPTG forces cell cycle arrest without affecting mTOR. During IPTG-induced arrest, the cells become hypertrophic, flat, SA-beta-Gal positive and lose RPP. When IPTG is washed out, such cells cannot resume proliferation. Loss of RPP is a simple quantitative test of geroconversion. Treatment with rapamycin during IPTG-induced arrest preserves RPP. When IPTG and rapamycin are washed out, cells re-proliferate.

Recently, we have shown that Torin 1 and PP242 suppresses geroconversion, preventing senescent morphology and loss of RPP. In agreement, reversal of senescent phenotype was shown by another pan-mTOR inhibitor, AZD8085. Pan-mTOR inhibitors have been developed as cytostatics to inhibit cancer cell proliferation. Cytostatic side effects in normal cells are generally acceptable for anti-cancer drugs. However, cytostatic side effects may not be acceptable for anti-aging drugs. Gerosuppressive (anti-aging) effects at drug concentrations that are only mildly cytostatic are desirable. Pan-mTOR inhibitors differ by their affinity for mTOR complexes and other kinases. Here we studied 6 pan-mTOR inhibitors (in comparison with rapamycin) and investigated effects of 6 pan-mTOR inhibitors on rapamycin-sensitive and -insensitive activities of mTOR, cell proliferation and geroconversion: Torin 1, Torin 2, AZD8055, PP242, KU-006379 and GSK1059615.

As predicted by theory of TOR-driven aging, rapamycin extends life span and prevents age-related diseases. Yet, rapamycin (and other rapalogs such as everolimus) does not inhibit all functions of mTOR. Inhibition of both rapamycin-sensitive and -insensitive functions of mTOR may be translated in superior anti-aging effects. However, potential benefits may be limited by undesirable effects such as inhibition of cell proliferation (cytostatic effect) and cell death (cytotoxic effect). In fact, pan-mTOR inhibitors have been developed to treat cancer, so they are cytostatic and cytotoxic at intended anti-cancer concentrations. Yet, the window between gerosupressive and cytotoxic effects exists. At optimal gerosuppressive concentrations, pan-mTOR inhibitors caused only mild cytostatic effect. For Torin 1 and PP242, the ratio of gerosuppressive (measured by RPP) to cytostatic concentrations was the most favorable. The ratio of anti-hypertrophic to cytostatic concentration was similar for all pan-mTOR inhibitors. Gerosuppressive effect of pan-mTOR inhibitors (as measured by RPP) was equal to that of rapamycin because it is mostly associated with inhibition of the S6K/S6 axis. Yet anti-hypertrophic effect as well as prevention of SA-beta-Gal staining and large cell morphology was more pronounced with pan-mTOR inhibitors than with rapamycin. Also, at optimal concentrations, all pan-mTOR inhibitors extended loss of re-proliferative potential in stationary cell culture more potently than rapamycin.

At gerosuppressive concentrations, pan-mTOR inhibitors should be tested as anti-aging drugs. Life-long administration of pan-mTOR inhibitors to mice will take several years. Yet, administration of pan-mTOR inhibitors can be started late in life, thus shortening the experiment. In fact, rapamycin is effective when started late in life in mice. Optimal doses and schedules of administration could be selected by administration of pan-mTOR inhibitors to prevent obesity in mice on high fat diet (HFD). It was shown that high doses of rapamycin prevented obesity in mice on HFD even when administrated intermittently. Testing anti-obesity effects of pan-mTOR inhibitors will allow investigators to determine their effective doses and schedules within several months. It would be important to test both rapamycin-like agents such as Torin 1 and rapamycin-unlike agent such as Torin 2 or AZD8085. Selected doses and schedules can then be used to extend life-span in both short-lived mice, normal and heterogeneous mice as well as mice on high fat diet. These experiments will address questions of theoretical and practical importance: (a) role of rapamycin-insensitive functions of mTOR in aging. We would learn more about aging and age-related diseases. (b) can pan-mTOR inhibitors extend life span beyond the limits achievable by rapamycin.

Despite all the publicity, Human Longevity Inc. is a personalized medicine company rather than a longevity science company, intended to be the seed for a new industry that provides an incremental advance on present day customization of medicine through use of genetics. As I've said for a while now, this sort of application of genetics is not the path to significant enhancement of human longevity. All that this industry can do in the near term is inform us more accurately as to why the natural variations in human longevity exist, and provide ways to move someone from a slightly lower life expectancy bracket into a slightly higher life expectancy bracket. The latter is something that you can do for yourself today by undertaking exercise or calorie restriction. This is fiddling small change in the bigger picture. In that bigger picture, it is clear that we all age for the same underlying reasons: exactly the same forms of accumulated cell and tissue damage drive aging in all of us. Effective therapies to treat the causes of aging - and thereby produce radical life extension of decades at first and centuries later - will repair this damage, and will thus be exactly the same for everyone, with a massive scale of production to drive down the costs. The expensive undertaking of highly personalized medicine is simply not all that important when it comes to rejuvenation and the future of human longevity.

Craig Venter's latest venture, Human Longevity, Inc., or HLI, creates a realistic avatar of each of its customers - they call the first batch 'voyagers' - to provide an intimate, friendly interface for them to navigate the terabytes of medical information being gleaned about their genes, bodies and abilities. Venter wants HLI to create the world's most important database for interpreting the genetic code, so he can make healthcare more proactive, preventative and predictive. Such data marks the start of a decisive shift in medicine, from treatment to prevention. Venter believes we have entered the digital age of biology. And he is the first to embark on this ultimate journey of self-discovery. HLI has now submitted an analysis of its first 10,000 human genomes for publication, passing a milestone in creating what Venter hopes will be the world's largest, most comprehensive database of information to help transform healthcare and find answers to one of the oldest questions of all: is it possible to defy the ravages of ageing?

In 1998 Venter unveiled the privately funded Celera Genomics, which incurred the wrath of his peers in the public genome programme. He found himself battling with some of the world's biggest scientific institutions. The race propelled him onto front pages around the world when Celera unveiled its first human genome alongside the publicly funded version. Today, everybody in the field wants genomics to be part of medicine, he says. When it came to deciding where to bring about that merger, and finish the job that he started with Celera, Venter returned to the West Coast. On the coast, occupying land owned by the university, Venter has built the Californian campus of his not-for-profit J. Craig Venter Institute. He also set up Synthetic Genomics. This company is trying to understand the basic software of life and rewrite it to create novel organisms that can produce fuel, chemicals and medicines.

To synthesise the insights from these ventures, Venter founded HLI with stem cell pioneer Robert Hariri and technology entrepreneur Peter Diamandis, founder of the XPRIZE Foundation. Venter regards HLI as Celera on steroids. "The whole idea behind this is to identify the risk, then modify that risk so that you end up with longer periods of normal health. That is what the patient wants too. The patient does not want just more years but quality years." HLI started out stockpiling human genomes by sequencing them for partners that needed the data for research. This is only one ingredient of what Venter hopes will become the biggest genotype-phenotype database in the world. "Right now, we know less than 1 per cent of the genome in terms of how to really interpret it. Even with that, that's extremely valuable in being able to start this new preventative medicine paradigm where this information can help people understand their own health risk and hopefully save a lot of lives." So far, HLI has amassed the sequences of around 20,000 whole genomes, says Venter. But, of course, he wants even more. The company has room for more sequencing facilities on its third floor and is considering a second centre in Singapore, planning to rapidly scale to sequencing the genomes of 100,000 people per year - whether children, adults or centenarians, and including both those with disease and those who are healthy. By 2020, Venter aims to have sequenced a million genomes.

Venter wants to move from basic genetics to impacting individual lives "very directly. The most important part of that is nothing to do with the genome directly, but measuring phenotype and physiology and understanding their medical risk. That is what the microbiomes of its patients too - their cargo of gut microbes, which play a key role in health. Most valuable of all, Venter wants to link these various -omes to patients' phenotypes: their anatomy, physiology and behaviour. To do this, standard body measurements, online cognitive tests and blood samples are taken. The Health Nucleus adds yet more data using non-invasive tests. My tour begins with the room where HLI conducts a total body scan to create the avatars that inhabit its app. We pass through a succession of white rooms. There's one where visceral fat (which is linked to type 2 diabetes and cardiovascular disease) muscle volume, grey matter, white matter and more.

"We will be developing the evidence around this to make the case for preventive medicine." HLI has more work to do, such as organise a randomised controlled trial to compare the outcomes of people who get the tests with those who do not. Not everyone is convinced that HLI's testing will translate into improved health. Venter says that criticisms stem from the conservative nature of the medical community, notably when it comes to keeping the costs of screening under control. "That is the medical establishment saying: we want to keep doing what we do, we want to see people after they develop symptoms and have something wrong with them. The 'human longevity approach' is the exact opposite."

Link: https://newrepublic.com/article/128977/whats-wrong-craig-venter

Researchers here add more data to the known correlations between specific measures of fitness and cognitive function in later life. There are any number of potential mechanisms linked to exercise that might explain a slower age-related decline in memory and learning capacity in people who better maintain physical fitness, such as the state and activity of the immune system in the brain, as well as mitochondrial function, and vascular integrity. Pinning down specific contributions and the relative importance between mechanisms is, of course, a challenge.

Older adults who experience good cardiac fitness may be also keeping their brains in good shape as well. In what is believed to be the first study of its kind, older adults who scored high on cardiorespiratory fitness (CRF) tests performed better on memory tasks than those who had low CRF. Further, the more fit older adults were, the more active their brain was during learning. Healthy young (18-31 years) and older adults (55-74 years) with a wide range of fitness levels walked and jogged on a treadmill while researchers assessed their cardiorespiratory fitness by measuring the ratio of inhaled and exhaled oxygen and carbon dioxide. These participants also underwent MRI scans which collected images of their brain while they learned and remembered names that were associated with pictures of unfamiliar faces.

The researchers found that older adults, when compared to younger adults, had more difficulty learning and remembering the correct name that was associated with each face. Age differences in brain activation were observed during the learning of the face-name pairs, with older adults showing decreased brain activation in some regions and increased brain activation in others. However, the degree to which older adults demonstrated these age-related changes in memory performance and brain activity largely depended on their fitness level. In particular, high fitness older adults showed better memory performance and increased brain activity patterns compared to their low fitness peers. The increased brain activation in the high fitness older adults was observed in brain regions that show typical age-related decline, suggesting fitness may contribute to brain maintenance. Higher fitness older adults also had greater activation than young adults in some brain regions, suggesting that fitness may also serve a compensatory role in age-related memory and brain decline.

Link: https://www.eurekalert.org/pub_releases/2017-01/bumc-ofa011317.php

The annuities and pensions industries, private and public, include some of the largest of all financial institutions. Collectively they are enormous, representing a staggering amount of money under management. To simplify a complex picture greatly, most of these programs take the form of a wager against longevity. The competing companies that issue annuities and manage pensions make offers of future payments to their customers based on the consensus predictions of life expectancy, and on their own private models that seek to improve on that consensus for specific demographics and thereby price the future more effectively than their competitors. Customers seek the greatest payout, while companies seek the payout that will maximize overall profit by some mix of attracting more customers from competitors and greater per customer profit. Customers that live longer than expected drain away profit, but historically this has been balanced by those who died early, as the consensus mortality predictions have on the whole been pretty good in the past.

Still, signing a contract is a long bet, realized over decades, and this is an era of very rapid progress in biotechnology, coupled with an important change in the focus of the medical research community, now looking at the causes of aging where before they did not. I have said for years that I think it likely that a majority of the presently outstanding wagers against longevity have now become very bad for the issuing companies. Why is this the case? Because it is plausible that the first rejuvenation therapies will be comparatively cheap, become quickly and widely available via medical tourism within a few years of their discovery, and prove effective. By "effective" I mean something in the ballpark of adding five years to the life expectancy of the average 60-year old. From where I stand, it looks like senescent cell clearance via senolytic drugs has the strong possibility of realizing this sort of outcome. Five years of additional payments for a large percentage of contracts would be a real issue for financial institutions: while an increasing amount of hedging has been voiced by actuaries over the past decade, the consensus models in the actuarial industry make no provision for a sudden jump in life expectancy along these lines. No company has priced in this possibility, as they'd be quickly outcompeted by their less wary competitors. Thus a large fraction of the contracts issued over the past 20-30 years, and of those issued today, are going to look increasingly risky as senescent cell clearance moves ahead.

Chaos in the financial industry as a result of all this is not a distant possibility, either. The solvency of financial institutions is a matter of perception as well as hard figures, but beyond this consider that annuities and pensions have been packaged and resold as derivatives, or otherwise used as collateral for leverage by the issuing organizations. Companies have borrowed on the value of their annuity and pension contracts, and high levels of leverage are very common these days, causing vulnerability to sudden changes in expectations. This is a failing of our era, as exhibited in numerous financial instruments over the past few decades; mortgages spring to mind, for example. The values of annuity and pension contracts packaged for the financial industry are assessed on an ongoing basis on an expectation of future income and expenses. As the consensus for future longevity shifts, companies will be greatly impacted or even bankrupted as a result of changes in predicted future outcomes, magnified by the leverage of assets.

To be clear, pensions are already heading towards a bad end in many countries even without the advent of effective rejuvenation therapies. Government bodies and other entities have found it all too easy to make unsustainable promises, or to let themselves be effectively looted by present caretakers. Insolvency and unsustainable future obligations are everywhere. This is one of many forms of widespread corruption in which those with the ability and the short-term interest steal from the public purse in the expectation that higher powers in government will bail them out. Historically, this doesn't seem like an unreasonable expectation, sad to say. So the losses will be spread out over the population, or kicked down the road for some future generation to be bankrupted by. Sooner or later there will be a major collapse in economic stability or currency or government in the affected regions - and the sooner the better, as the longer this goes on, the worse and more protracted the collapse that will result. Life will go on afterwards, the progression to the long-term golden future picking up where it left off, but all of this short-sightedness and self-sabotage in the near term is so very needless.

One of the ways in which the savaging of the annuities and pensions industry might be minimized is through a bailout of some sort. This is, as I said, quite a likely outcome given recent history, but all it does is make the larger economic problem worse. Further, it will probably happen again as new rejuvenation therapies emerge. Another possibility is for this industry to lobby for dissolution or alteration of existing contracts, which again seems like a plausible outcome, essentially the use of political power to carry out a form of fraud by force upon every counterparty who signed something that later proved inconvenient. It is also possible that the availability of senolytic therapies via medical tourism, and at a reasonably low cost, will not lead to widespread adoption rapidly enough to bankrupt annuity and pension companies. This seems to me unlikely to help make the problem very much smaller, however. This scenario would make the problem occur later, further down the line, say a decade after it might have happened with rapid adoption of therapies. If an increase of five years of life extension is bankrupting in 2020, it is likely to still be highly problematic in 2030: the majority of the problem contracts be will still be around, active, and their owners expecting to be paid for a long time yet.

Do I think it is worth putting money into an annuity? I think this is a good wager in a world in which issuing companies have infinite resources, but this isn't that world. Sooner or later you will get cut off, via one of the mechanisms mentioned above. The important risk is that this might happen sooner to the point at which you'd have been better off investing elsewhere. The whole situation is very uncertain on timing and outcomes over the next few decades, and that is rather the point I'm trying to make here.

Researchers here quantify the degree to which exercise has immediate anti-inflammatory effects. This is one of the many ways in which exercise is beneficial for health. Rising chronic inflammation is characteristic of aging and the failing immune system, and contributes meaningfully to the progression of all of the common age-related diseases. Less inflammation is a good thing when considering long-term health.

It's well known that regular physical activity has health benefits, including weight control, strengthening the heart, bones and muscles and reducing the risk of certain diseases. Recently, researchers found how just one session of moderate exercise can also act as an anti-inflammatory. The findings have encouraging implications for chronic diseases like arthritis and for more pervasive conditions, such as obesity. The study found one 20-minute session of moderate exercise can stimulate the immune system, producing an anti-inflammatory cellular response. "Each time we exercise, we are truly doing something good for our body on many levels, including at the immune cell level. The anti-inflammatory benefits of exercise have been known to researchers, but finding out how that process happens is the key to safely maximizing those benefits."

The brain and sympathetic nervous system - a pathway that serves to accelerate heart rate and raise blood pressure, among other things - are activated during exercise to enable the body to carry out work. Hormones, such as epinephrine and norepinephrine, are released into the blood stream and trigger adrenergic receptors, which immune cells possess. This activation process during exercise produces immunological responses, which include the production of many cytokines, or proteins, one of which is TNF - a key regulator of local and systemic inflammation that also helps boost immune responses. "Our study found one session of about 20 minutes of moderate treadmill exercise resulted in a five percent decrease in the number of stimulated immune cells producing TNF. Knowing what sets regulatory mechanisms of inflammatory proteins in motion may contribute to developing new therapies for the overwhelming number of individuals with chronic inflammatory conditions."

Link: http://ucsdnews.ucsd.edu/pressrelease/exercise_it_does_a_body_good_20_minutes_can_act_as_anti_inflammatory

This popular science piece is characteristic of a prevalent and hostile view of the growing practice of patient-funded clinical trials. In this model the patient pays a sizable portion of the costs, which certainly makes it a lot easier to gather larger amounts of data, as the trial organizers don't have to seek the funding themselves. On the other hand, it tends to rule out the ability to carry out a blind trial in which not everyone actually gets the treatment, as well as other similar refinements. That is a problem if the goal is to search for and quantify marginal effects, but if the point is to discover or rule out large effects, I'd argue that control groups are not necessary. The control in that case is the established progression for patients who do not get the treatment, or who undergo existing, marginal treatments. We are at the stage in the development of medicine to treat aging in which marginal effects, such as those resulting from the use of metformin as a calorie restriction mimetic, should be discarded as uninteresting. Once at the stage of trying things in human studies, the research community should be filtering for significant effects, such as those obtained by clearance of senescent cells. Given the poor state of funding for aging research in general, methods that can pull in more resources to obtain more data should be applauded.

In the case of the approach being trialed here by Ambrosia, as mentioned earlier this year I think our expectations should be low, and the outcome I expect is for there to be no significant benefit. The only ethical question worthy of consideration is whether those involved then do the right thing: publish the data, shut up shop, and move on to the next project. Transfusions of young blood to old individuals are not producing benefits in mice, and there is reason to think that the beneficial outcomes observed in old mice due to parabiosis, the linking of circulatory systems between an old and a young individual, are due to factors or circumstances not replicated by periodic transfusion. It isn't difficult to imagine that beneficial outcomes require the youthful system reacting in a dynamic way to the presence of aged signals, for example, or - as suggested by some researchers recently - that it is nothing more than a consistently maintained dilution of problem signals in the aged environment.

Just off a winding highway along the Pacific coast in Monterey, California, is a private clinic where people can pay $8,000 to have their veins pumped with blood plasma from teenagers and young adults. Jesse Karmazin is the entrepreneur who made the practice possible, by launching a clinical trial on the potential of "young blood" through his startup Ambrosia. He says that within a month, most participants "see improvements" from the one-time infusion of a two-liter bagful of plasma, which is blood with the blood cells removed. Several scientists and clinicians say Karmazin's trial is so poorly designed it cannot hope to provide evidence about the effects of the transfusions. And some say the pay-to-participate study, with the potential to collect up to $4.8 million from as many as 600 participants, amounts to a scam. Ambrosia says it will enroll almost anyone over 35, and the fees of $8,000 per person could add up. But Karmazin rejects the idea he is out to generate profits. He says that money is needed to cover the cost of clinical procedures, laboratory tests, and the plasma.

What's certain is that it's based on some intriguing if inconclusive science. Karmazin says he was inspired by studies on mice that researchers had sewn together, with their veins conjoined, in a procedure called parabiosis. Over the last decade or so, such studies have offered provocative clues that certain hallmarks of aging can be reversed or accelerated when old mice get blood from young ones. Yet these studies have come to conflicting conclusions. Further, parabiosis experiments offer little insight into how Ambrosia's one-time transfusions will affect people. Despite such uncertainties, the potential of young blood to treat disease is being explored in a number of clinical trials.

In 2014, Stanford University neuroscientist Tony Wyss-Coray demonstrated that old mice had increased neuron growth and improved memory after about 10 infusions of blood from young mice. That prompted Wyss-Coray to launch a small company, Alkahest to test transfusions of plasma from young people in the treatment of Alzheimer's disease. Alkahest's clinical study is more conventional than Ambrosia's: it does not charge participants, it expects to enroll only 18 volunteers, and it is initially looking at how well the elderly can tolerate small doses of plasma. Like several other researchers and bioethicists, Wyss-Coray worries about the fact that Ambrosia's trial is funded by participants rather than investors. "People want to believe that young blood restores youth, even though we don't have evidence that it works in humans and we don't understand the mechanism of how mice look younger."

The formal goal of the Ambrosia study is to measure the effect of young plasma on about 100 biomarkers. Before the infusion, and one month after, all participants have their blood analyzed for biomarkers. But Irina Conboy, a professor at the University of California, Berkeley, thinks the biomarker results will be meaningless: for one thing, the study lacks a control arm with patients who don't get plasma. Blood biomarkers, she says, change for many reasons. She's also wary of Alkhest's study on Alzheimer's patients. Last year, she and colleagues found that older mice whose blood was partially replaced with younger blood saw few benefits. "Both studies are hurt by the same problem, and the problem is that there is no evidence to suggest that an infusion of plasma from young to old animals reverses aging."

Link: https://www.technologyreview.com/s/603242/questionable-young-blood-transfusions-offered-in-us-as-anti-aging-remedy/

Now that much more attention and funding is turning to cellular senescence as a cause of aging, a fair number of new discoveries are being made regarding the specific links between age-related disease and the growing presence of senescent cells in old tissues. Some of them seem almost obvious in hindsight, connections that researchers should have long assumed to be likely, such as senescent foam cells accelerating the progression of atherosclerosis. Now that senescent cells can be cleared effectively in the laboratory, proof of these connections is comparatively simple to obtain, and so the evidence is piling up month after month. The open access paper I'll point out today provides evidence for another connection that has the look of something that should be self-evident in hindsight, between cellular senescence and the harmful side-effects of cancer chemotherapy. It is PDF only at the time of writing, I'm afraid.

Chemotherapy at the levels needed to suppress cancer is enormously unpleasant, sometimes even fatal, and no-one with any other option would ever undergo such a treatment. Worse, it has a large impact on future life expectancy, as the outcomes for cancer survivors having undergone chemotherapy look much the same as those of life-long smokers. But why is chemotherapy so harmful? We can point to numerous side-effects ranging from outright toxicity to dysregulation of important cellular activities in a number of organs. The one thing that all chemotherapies should achieve along the way is to create a lot of senescent cells, however. Cellular senescence is a defense against toxic environments and cellular damage, and in modest amounts it lowers the risk of cancer by shutting down replication in those cells most at risk. Beyond producing senescence in bystander cells by putting them under stress, chemotherapy should also make a lot of cancerous cells senescent. For many chemotherapy drugs that is the intended goal. As is always the case for senescent cells, many will be destroyed by the immune system or their own self-destruct programs, but a fraction will linger. Chemotherapy might be thought of as the equivalent of decades of normal creation and destruction of senescent cells, run through on fast forward.

The harm caused by senescent cells is a matter of signaling. They secrete a mix of molecules, the senescence-associated secretory phenotype (SASP), that spurs chronic inflammation, damages the surrounding extracellular matrix, changes the behavior of normal cells for the worse, and more. If 1% of the cells in a tissue are senescent, that is sufficient to cause measurable dysfunction and decline in most organs. Given this, it seems very logical that to the degree chemotherapy pushes cells into a senescent state, it will harm patients in the long term via these mechanisms. This is an opportunity as well as a realization, however: in the years in which chemotherapy is on the way out, to be replaced by immunotherapy and other approaches, it might be made less damaging to patients through the use of therapies to clear out the senescent cells created during cancer treatments.

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse

Cellular senescence is a complex stress response whereby cells irreversibly lose the capacity to proliferate, accompanied by numerous changes in gene expression. Many potentially oncogenic insults induce a senescence response, which is now recognized as a potent tumor suppressive mechanism. Other senescence-inducing stimuli include radiation, genotoxic drugs, tissue injury and remodeling, and metabolic perturbations. Moreover, senescent cells accumulate with age in several vertebrate organisms, and their elimination can delay the onset of several age-associated disorders in mice. Senescent cells most likely promote aging through the senescence-associated secretory phenotype (SASP): the increased expression and secretion of inflammatory cytokines, chemokines, growth factors and proteases.

Genotoxic and cytotoxic drugs are widely used as anti-cancer therapies. Most such agents target proliferating cells through distinct, cell cycle-dependent mechanisms. Their cytotoxicity for many types of dividing cells often leads to side effects, which include immunosuppression, fatigue, anemia, nausea, diarrhea and alopecia. Moreover, clinical studies of cancer survivors treated during childhood suggest that some chemotherapies causes a range of long-term side effects that resemble pathologies associated with aging, including organ dysfunction, cognitive impairment and secondary neoplasms. Many chemotherapeutic drugs alter cellular states, including the induction of senescence, in cancer cells and the tumor microenvironment. Therapy-induced senescence (TIS) can stimulate immunosurveillance to eliminate tumor cells, but can also be a source of chronic inflammation and drug resistance. Indeed, a recent study showed that treatment of breast cancer patients with anthracycline and alkylating agents durably induces cellular senescence and a SASP in a p16INK4a-dependent, telomere-independent fashion. Expression of the tumor suppressor p16INK4a increases with age and is a robust senescence marker in numerous mouse and human tissues.

To more precisely assess the physiological effects of TIS in vivo, we used a recently described mouse model (p16-3MR) in which p16INK4a-positive senescent cells can be detected in living animals, isolated from tissues, and eliminated upon treatment with an otherwise benign drug. Using this approach, we determined the contribution of senescent cells to a variety of common short and long-term chemotherapy toxicities. Additionally, we used a senescence marker to assess the relationship between senescent cells and chemotherapy toxicity in human patients. We show that TIS cells contribute to local and systemic inflammation, as determined by increased expression of pro-inflammatory SASP factors in tissue and increased levels of inflammatory cytokines in sera, which is reduced after removal of senescent cells in vivo using p16-3MR transgenic mice. Further, the elimination of senescent cells limited or prevented the development of multiple adverse reactions to chemotherapy.

In addition, weeks after chemotherapy treatment, TIS cells were important for bone marrow suppression and development of cardiac dysfunction, both limiting factors for the use of some chemotherapeutic agents, particularly the anthracyclines. The promotion of cardiac dysfunction might be due to either cardiac senescent cells, which we show are primarily endothelial cells, or senescence-induced inflammation. Senescent non-tumor cells were important for cancer relapse and spread to distal tissues after chemotherapy, at least in the breast cancer model we used. Moreover, clearing senescent cells increased overall spontaneous physical activity in the presence or absence of cancer. Importantly, these murine findings were validated in a human cohort, showing that p16INK4a expression in peripheral T-cells predicts chemotherapy-induced fatigue in human patients with breast cancer. We believe this latter finding is consistent with recent work showing that aging is the major risk factor for long term (more than 2 or more than 5 years) fatigue after chemotherapy treatment.

The data presented here show a direct role for TIS cells in mice, and a strong correlation between fatigue and senescent cells in humans. An alternative approach, then, is to develop therapies that can selectively target senescent cells (senolytics) and/or the SASP, an approach that recently showed promise. Indeed, the administration of a senolytic agent, ABT-263, efficiently eliminated senescent cells, improved physical activity, and reduced cancer relapse in mice treated with Doxorubicin. Such therapeutic approaches will, of course, need to carefully consider whether there are beneficial effects of TIS, such as promoting the repair of tissues damaged by the chemotherapy or the potential of senescent cells to activate the immune response to tumor cells. Nonetheless, the pharmacological removal of senescent cells from the tumor microenvironment might be an innovative strategy to limit toxicities of current chemotherapies with consequent improvements in the health span and possibly life span of cancer patients.

Fifty years ago, the first human was cryopreserved in the hopes of future revival. To this day, cryopreservation remains the only chance at a longer life in the future for all those who will age to death prior to the advent of effective rejuvenation therapies. James Bedford's preservation was a straight freezing with all the attendant tissue damage, unlike the vitrification techniques used today. It is certainly the case that future restoration would require exceptionally comprehensive control and manipulation of molecular biology, of the sort enabled by a mature molecular nanotechnology industry. The degree to which the data of his mind still exists despite ice crystal and fracture damage, or can be reconstructed, is an open question left to be answered by future generations.

Cryonics has long been expected to be a last in first out endeavor should it succeed: those preserved more recently, and thus with better preservation techniques, will be the easiest to revive - though of course "easiest" is a relative measure here. All of cryonics is in effect a wager on a decent preservation process, survival of the preservation organization, and then a golden future of advanced technology and great wealth. That is nonetheless a wager that looks very favorable in comparison to the alternative options at the end of life.

Bedford was preserved a few years prior to the establishment of professional cryonics organizations, and in that early stage of the industry some of those organizations were poorly run. Preserved individuals were lost to thawing. Of all the initial patients from the late 1960s and early 1970s, only Bedford remains. Depending on where you wish to draw the line between life and death, he might be counted as the world's oldest surviving human. For so long as the data of the mind remains, encoded in the fine structures of brain tissue, there is the possibility of future restoration in an age of far greater and more capable technology.

Dr. James Hiram Bedford, a former University of California-Berkeley psychology professor died of renal cancer on Jan. 12, 1967. Bedford was the first human to be cryonically preserved - that is, frozen and stored indefinitely in the hopes that technology to revive him will one day exist. He's been at Alcor since 1991. His was the first of 300 bodies and brains currently preserved in the world's three known commercial cryonics facilities: Alcor; the Cryonics Institute in Clinton Township, Michigan; and KrioRus near Moscow. Another 3,000 people still living have arranged to join them upon death.

Cryonics patients are no longer frozen, but "vitrified." First, the body is placed in an ice-water bath. Then, ice-resistant chemicals are pumped into the body, taking the place of water in the blood. That way, in the next step, when the body or brain is cooled to well-below freezing using nitrogen gas, it hardens without forming cell-damaging ice. Vitrification has been used to effectively preserve blood, stem cells, and semen. But restoring life to a vitrified human - or to an organ as complex as the brain - remains an unfathomably distant prospect. If there is a divide on cryonics in the scientific community, it's between neuroscientists willing to state that reanimation is at least within the realm of physical possibility, and those who believe it's so unlikely that selling even the hope is unethical.

Bedford's preservation in the pre-vitrification days was a crude, ad hoc affair. He legally died in a southern California nursing home at the age of 73, after donating his body to the Life Extension Society, a group of early cryonics enthusiasts. Hours after death he was injected with the solvent dimethyl sulfoxide in an attempt to stave off tissue damage, packed in a Styrofoam box of dry ice, and eventually submerged in liquid nitrogen. For the next 27 years, Bedford's liquid-nitrogen-filled chamber was constantly on the move, as various cryonics companies folded or were forced to move for insurance or regulatory problems. The $100,000 he'd set aside to pay for his body's long-term care evaporated as his wife and son faced legal challenges from other family members objecting to his unconventional resting place. From 1977 to 1982, frustrated with the high cost of maintenance, they appear to have kept his unit in a self-storage facility in southern California, occasionally topping off the liquid nitrogen themselves. Upon his wife's death in 1982, Bedford's body and container were entrusted to the company that became Alcor. Then-director Jerry Leaf, who died and was cryopreserved in 1991, took out a life insurance policy on himself to fund Bedford's ongoing care.

Link: https://qz.com/883524/fifty-years-frozen-the-worlds-first-cryonically-preserved-humans-disturbing-journey-to-immortality/

One of the original researchers involved in telomere length studies is currently publishing a book on general health. It is in no way novel in the lineage of such things save for the relentless emphasis on telomeres, the repeating DNA sequences that cap the ends of chromosomes. Telomeres shorten with each cell division, and stem cells generate daughter cells with fresh, long telomeres, so the average length in a cell type is some function of cell division rates and stem cell activity. The thing is, telomere length as presently measured in immune cells from a blood sample is actually a terrible biomarker (of aging or health status) for individual purposes: the well-publicized erosion of average telomere length with age is a statistical phenomenon that only shows up in the data for large populations, and even there it isn't a robust measure. Pick one individual and their health concerns and it isn't yet at all clear that telomere length measures have any practical utility. Two people with the same condition can have quite different telomere lengths, and changes over time are not yet correlated well with health status for any one individual. This is far worse for use in diagnostic medicine than the sort of long-standing metrics obtained from standardized blood tests at the present time.

Molecular biologist Elizabeth Blackburn shared a Nobel Prize for her research on telomeres - structures at the tips of chromosomes that play a key role in cellular aging. But she was frustrated that important health implications of her work weren't reaching beyond academia. So along with psychologist Elissa Epel, she has published her findings in a new book aimed at a general audience - laying out a scientific case that may give readers motivation to keep their new year's resolutions to not smoke, eat well, sleep enough, exercise regularly, and cut down on stress. The main message of "The Telomere Effect," is that you have more control over your own aging than you may imagine. You can actually lengthen your telomeres - and perhaps your life - by following sound health advice, the authors argue, based on a review of thousands of studies.

Telomeres sit at the end of strands of DNA, like the protective caps on shoelaces. Stress from a rough lifestyle will shorten those caps, making it more likely that cells will stop dividing and essentially die. Too many of these senescent cells accelerates human aging. This doesn't cause any particular disease, but research suggests that it hastens the time when whatever your genes have in store will occur - so if you're vulnerable to heart disease, you're more likely to get it younger if your telomeres are shorter. Other researchers in the field praised Blackburn and Epel's efforts to make telomere research relevant to the general public, though several warned that it risked oversimplifying the science. "I think it's a very difficult thing to prove conclusively" that lifestyle can affect telomere length and therefore lifespan, said Harvard geneticist and anti-aging researcher David Sinclair. "To get cause-effect in humans is impossible, so it's based on associations." Judith Campisi, an expert on cellular aging at the Buck Institute for Research on Aging in Novato, Calif., said the underlying research is solid. "If you have a terrible diet and you smoke, you're definitely shortening your life, and shortening your telomeres. Short telomeres increase the likelihood of cells becoming senescent and producing molecules that lead to inflammation, which is a huge risk factor for every age-related disease. So there is a link there, it's just not this exclusive magic bullet, that's all."

One of the challenges with telomere research is that most studies measure the length of telomeres in blood cells. But it may be that the liver is aging faster or slower than the blood - we're not all one age throughout. By measuring telomere length in the blood, "what you're really reporting on is the capacity of immune stem cells to function well," said Matt Kaeberlein, who studies the molecular basis of aging at the University of Washington. "What this may be really telling us is the immune system may be particularly sensitive to lifestyle and environmental factors." Kaeberlein said he's only at the periphery of telomere research, but is skeptical about the predictive value of shorter versus longer telomeres. "It's not at all clear whether the methods are quantitative enough or of high enough resolution to really make those kinds of arguments. I think it has the potential to be a biomarker predicting health outcomes, but I don't know that I would feel comfortable saying people should make lifestyle changes based on a measure of their telomere length."

Link: https://www.statnews.com/2017/01/03/aging-control-telomere-effect/

There are a number of young startup biotechnology companies presently working on the basis for rejuvenation therapies. Many of the interesting ones are focused on senescent cell clearance, the class of therapy that is arguably closest to the clinic. Some of those, like Oisin Biotechnologies, are supported by our community: seed funding from non-profits like the Methuselah Foundation and SENS Research Foundation, and angel funding from some of the same folk as put up matching funds for the yearly SENS rejuvenation research fundraisers. Typically, however, after the initial declaration of intent these companies go silent. Unless you're an insider, the next thing you'll hear will be some way down the line, a declaration of either success or failure following the initial few years of research and development. Why is this the case? Don't companies want greater public exposure? If you've ever been involved in a small startup, the silence won't be all that surprising. But since most of us haven't, it might seem a little inexplicable. What is going on here?

There are two reasons as to why this silence is the usual state of affairs for the first few years of most startup companies. The first reason is that talking to the outside world is a low priority task for most classes of company in their earliest stages. The big risk is not that no-one will know that you're striving to prove a thesis in business or research, but rather that you'll simply fail, or fail to achieve the goal within the runway provided by current funding. Unless publicity is a prerequisite to avoid near-future failure, and for most companies it isn't, then it will tend to drop off the bottom of the to-do list. That work vanishes along with every other non-essential task, and usually quite a few tasks that would be considered essential in a more sedate environment. The typical state of action in any early stage startup is that there is far too much to accomplish, too few people to accomplish it with, and the clock is ticking loudly on the way to seemingly impossible deadlines. This is just the way of things. No matter how carefully you scope the work at the outset, it always multiplies. Successful teams narrow the focus considerably and quickly jettison nonessential work. For biotechnology companies, "nonessential" covers pretty much everything except the actual labwork and the financial and legal work needed to run a company and raise funding.

The second and more important reason for silence relates to the government regulation of fundraising. If you've ever worked inside an early stage startup, then you'll have noticed that when raising capital, half of the founders and executives essentially vanish for months. Raising venture funding is a full time job, one added to the other full time job of actually running the startup. It is the regulatory rules, and not the workload, that keeps the company quiet, however. In the US, the Securities and Exchange Commission (SEC) rules regarding venture investment are baroque, and there is a layer of convention and precedent atop the regulation as written that guides companies to only a few of the many possible options for organizing the process, but the bottom line is that selling part of an early stage company to investors via an open, public solicitation is very hard to achieve in a cost-effective manner. The disadvantages in terms of time, risk, and transaction costs far outweigh any possible advantage. Thus founders opt for private fundraising efforts, working through their personal connections to reach potential investors.

It isn't hard to see the regulatory capture at work in this situation; the existing regulations on public versus private fundraising are a large part of why the venture community exists in its present highly networked and nepotistic form. Unfortunately, any sort of public disclosure of progress during the fundraising process might be considered solicitation by the SEC, resulting in possible censure or legal action against a company and its founders - and so companies go quiet when fundraising. This is starting to change a little with the new crowdfunding rules introduced this year, but they bring their own significant disadvantages, not least of which being a lack of convention to guide expectations regarding what SEC bureaucrats will and will not consider actionable violations. The SEC is the epitome of selective, capricious enforcement of unclear rules, which is why convention and precedent have become so important, and why founders err on the side of caution when it comes to public communications.

The idealized view of a successful startup is that it kicks off with a little seed funding from the founders, using those resources to obtain evidence for the initial thesis in some way. Then on the basis of that evidence, assuming success, the next stage is to obtain further funding, raised in a friends and family round. That funding is used to improve the evidence to the point at which institutional investors would be willing to join in - and hopefully by that point, the evidence is something along the lines of revenue from actual customers, or a working prototype therapy proved in mice, or similar. Then the company opens what is known as a series A round, solicits professional investors, raises much more money than was obtained from founders, friends, and family, hires staff, slows the pace a little, and starts to look more like a regular company thereafter as it moves towards profitability. Following series A there is typically more public communication and a lengthy gap before any further funding rounds. This is the idealized view, however. In reality, there might be any number of discrete or opportunistic fundraising events prior to series A. Over this span of time, the company founders are typically making a range of new connections in their industry and in the venture and angel community, and any sort of recent publicity for the company would constrain the ability to turn those connections into funds that can be usefully applied to ensuring the company succeeds.

So, frustrating as it might be, public silence is the way of things for early stage companies for the foreseeable future.

The development of robust and reliable biomarkers that reflect biological age is a necessary step for the future development of rejuvenation therapies. The existence of such biomarkers will make it much less expensive and time-consuming to assess the effectiveness of potential new therapies at all stages of the research and development pipeline, which in turn will lead to more rapid progress in this field. Here, researchers assess changes in gene expression in neurons and their supporting cells in brain tissue, and find that the changes in glial cells are those that best correlate with age:

The relationship between aging and neurodegeneration raises the possibility of shared transcriptional and post-transcriptional gene regulation programs; however, we still lack a comprehensive transcriptome-wide picture of the effects of aging across different human brain regions and cell types. Apart from the study of region-dependent microglial response to aging, the importance of both region- and cell-type-specific changes in the aging brain remains poorly understood. Studies have been hampered by the limited availability of cross-regional post-mortem tissue across a range of ages. To overcome these limitations, we analyzed gene expression patterns in ten brain regions (including cortical and sub-cortical areas) using more than 1,800 brain samples from two large independent cohorts, representing the most comprehensive human aging brain gene expression analysis to date. We report striking changes in cell-type-specific expression patterns across different brain regions, which revealed major shifts in glial regional identity upon aging in the human brain.

By current consensus, astrocyte (AC) and neuronal numbers appear generally preserved in aging. It is clear, however, that Alzheimer's disease (AD) and other neurodegenerative diseases for which age is a major risk factor are associated with inflammatory changes mediated by microglia (MG). Our findings show that cell-type-specific genes delineate samples based on both age group and brain region. Aging was the major determinant of glia-specific gene expression shifts in regional identity, while such changes were not evident in neuron-specific genes. Genes specific for neurons and oligodendrocytes (OLGs) generally decreased their expression upon aging, while MG-specific genes increased their expression profiles, consistent with the known MG activation in aging. A trend toward increased expression of MG-specific genes was observed in all regions upon aging, with corresponding upregulation of genes with immune or inflammatory functions.

In addition to glial changes, we also observed a decreased number of neurons with large cell bodies, which represent approximately 20% of neurons in the cortex. Although we did not attempt to directly identify the neuronal subtypes in the present study, neurons with the largest cell bodies are likely to be associative pyramidal neurons. Furthermore, these neurons were previously indicated to be most vulnerable to aging. While our analysis indicates that the decrease in these pyramidal neurons may be the primary source of the downregulation of neuron-specific genes, our findings regarding the cortical neuronal cells remain speculative due to the limited number of individuals used for the imaging analyses.

Age is the major risk factor for both Alzheimer's disease (AD) and Parkinson's disease (PD), the two most prevalent neurodegenerative diseases. It is becoming clear that the pre-clinical stage of AD begins decades before clinical manifestation. This pre-clinical stage has been termed "the cellular phase," because it involves changes in interactions among all cell types in the brain, with the most dramatic changes taking place in AC, MG, and vasculature. We find a corrosion of glial region-specific gene expression in aging, with the genes specific for AC, MG, and endothelial cells being the best predictors of age. By simultaneously assessing changes in cell-type-specific genes across multiple brain areas, our study takes a step toward providing a comprehensive framework of the molecular and cellular changes in human aging. While our primary aim was to deconvolute the cell-type-specific signatures present within large databases of age-related transcriptional changes, we also made a step toward interpreting these in light of changes in counts of OLGs and neuronal cells. Integration of further genome-wide and single-cell data from human tissues samples and cell and animal models will be required to fully understand the cellular and molecular mechanisms underlying the observations in our study. Altogether, our study indicates that the cellular changes during aging involve a dramatic shift in the regional identity of glia, and it provides a resource for further studies of the relationship between aging and the cellular phase of dementia.

Link: http://dx.doi.org/10.1016/j.celrep.2016.12.011

One of the challenges inherent in testing potential methods of restoring lost retinal function is that mice cannot readily explain the degree to which their sight is restored. So the researchers here can demonstrate restored light sensitivity and neural integration of transplanted retinal tissue, but they cannot say how the procedure will affect quality of vision without going on to trial the technique in human subjects.

Retinal degeneration is mostly a hereditary disease that is characterized by the death of photoreceptors - the light-sensitive neurons in the eye - which eventually leads to blindness. While many have attempted to treat the disease through retinal transplants, and some have shown that transplanting graft photoreceptors to the host without substantial integration can rescue retinal function, until now, no one has conclusively succeeded in transplanting photoreceptors that functionally connect to host cells and send visual signals to the host retina and brain. The researchers studied this problem using a mouse model for end-stage retinal degeneration in which the outer nuclear layer of the retina is completely missing. This is an important issue because in clinical practice this type of therapy would most likely target end-stage retinas in which of the photoreceptors are dead and the next neurons up the chain do not have any input.

Researchers have recently shown that 3D retinal sheets derived from mouse embryonic stem cells develop normal structure connectivity. "Using this method was a key point. Transplanting retinal tissue instead of simply using photoreceptor cells allowed the development of more mature, organized morphology, which likely led to better responses to light." In order to assess the success of the transplantations, the team integrated some modifications to the retinal sheets and the model mice. They used a fluorescent protein to label the ends of the photoreceptors, which is where they would connect to the host neurons - the bipolar retinal cells - and ultimately the brain. After labeling the host retinal bipolar cells with a different fluorescent protein, they found that the labeled cell terminals from the graft did indeed make contact with the cells labeled in the host, indicating that the newly grown photoreceptors naturally connected themselves to the bipolar cells in the model mice.

To assess whether the mice could see light, the researchers used a behavioral learning task. Mice with normal vision can learn to associate sounds or light with different events. While the model mice who lacked a photoreceptor layer in their retinas could not learn to associate anything with light before surgery, they could after the transplant, provided that a substantial amount of the transplant was located in the correct place. This means that not only did the new cells in the retina respond to light, but the information traveled to the brain and could be used normally to learn. "These results are a proof of concept for using induced pluripotent stem cell (iPSC)-derived retinal tissue to treat retinal degeneration. We are planning to proceed to clinical trials in humans after a few more necessary studies using human iPSC-derived retinal tissue in animals. Clinical trials are the only way to determine how many new connections are needed for a person to be able to 'see' again."

Link: http://www.riken.jp/en/pr/press/2017/20170111_1/

Alzheimer's disease is both an amyloidosis and a tauopathy. The dysfunction and death of neurons is driven by rising levels of amyloid-β and altered forms of tau, both of which form solid deposits in brain tissue. The accumulation of misfolded proteins and metabolic waste in this way is characteristic of aged tissues and happens to everyone, but in Alzheimer's patients the process is far more pronounced, the solid aggregates far more abundant. The relationship between these aggregates and the death of neurons is very complex, and at some levels the details still much debated, involving a cascade of intermediary interactions and proteins. There is plenty of room for new theory and new discoveries. In an open access paper I noticed recently, and linked below, researchers provide evidence for the progression of Alzheimer's to be more than just an additive consequence of amyloid and, separately, tau. The two forms of aggregrate and the consequences of their presence interact with one another to make the outcome worse than that.

This should probably not be all that surprising. All of our biological systems interact with one another, directly and indirectly, and at all scales, whether considering nanoscale processes inside a single cell or macroscopic process linking the behaviors of organs. Consider the effects of changing blood pressure and the number of different organs impacted, for example. When it comes to the forms of cell and tissue damage that cause aging, these too interact with one another. To pick one example, the declining effectiveness of the immune system accelerates the contribution of cellular senescence to aging, allowing ever more of these unwanted cells to linger rather than be destroyed. In turn senescent cells create greater levels of chronic inflammation, making the immune system more dysfunctional than it would otherwise be. Similar interactions are either known or there to be found between other classes of damage: mitochondrial DNA deletions; cross-linking in the extracellular matrix; and so forth. This synergy between forms of damage, creating a downward spiral of accelerating malfunction and breakage, is prevalent in all complex systems, not just in our biology.

What does all this mean for ongoing work on producing a viable therapy for Alzheimer's disease? It is already clear that both amyloid-β and tau aggregates should be cleared, with amyloid clearance somewhat ahead of tau clearance at the present time. The dominant strategy of immunotherapy has proven to be a far greater challenge to implement than desired, with the first tangible, promising results in human trails only recently achieved. One thing to consider is that, depending on the degree of synergy, the first successful therapy for amyloid-β clearance may be more effective than hoped, even though it leaves all of the tau in place. It may also mean that a combination of poor therapies that only partially impact both amyloid-β and tau might be worth trying, even though each on its own isn't effective enough to move beyond trials. That said, one of the other major challenges in treat Alzheimer's is that more than half of the patients suffer from other forms of dementia as well, commonly vascular dementia, and that distinct pathology may well mask many of the benefits produced by clearance of amyloid or tau. Repairing the later stages of neurodegeneration is a challenging business, all things considered.

Synergistic interaction between amyloid and tau predicts the progression to dementia

Alzheimer disease (AD) is characterized by the progressive accumulation of extracellular amyloid-β (Aβ) plaques, intracellular inclusions of hyperphosphorylated tau in tangles, and neuronal degeneration. The most widely accepted model of AD progression proposes a cascade of neuropathological events in which abnormal levels of Aβ, neurofibrillary tangles, and neurodegeneration precede dementia. The idea of pathophysiological progression was incorporated by the criterion for predementia phase of AD, which recognizes that the coexistence of abnormal Aβ and neurodegeneration biomarkers better identify mild cognitive impairment (MCI) patients who will progress to dementia. This notion has been supported by recent observations demonstrating that MCI Aβ+ individuals with neurodegenerative changes have higher rates of neuropsychological decline as compared with MCI biomarker negative participants. Yet a key question that remains unanswered is whether the highest rate of progression to dementia in MCI Aβ+ individuals with downstream cascade abnormalities is due to a synergistic effect between the coexistent brain pathologies or simply the sum of their deleterious effects.

Given the emphasis of the current literature on the combination of Aβ and neuronal degeneration biomarkers, the clinical fate of MCI patients with abnormal Aβ plus p-tau proteins is scarcely known. The importance of characterizing the synergistic effect between Aβ and p-tau on the development of dementia goes beyond the understanding of the mechanisms of disease progression. Determination of such synergism has immediate implications for the population enrichment of clinical trials testing anti-amyloid or anti-tau therapy. For example, if Aβ and p-tau synergistically determine dementia, the enrichment of clinical trial populations with carriers of both pathologies would increase the rate of clinical progression without loss of therapeutic effectiveness. Conversely, if Aβ and p-tau simply add their deleterious effects on cognitive decline, carriers of both pathologies would lead to a reduced therapeutic effectiveness of an intervention targeting only one of these proteinopathies, given the residual effect of the untreated protein on the clinical course of the disease.

Although several studies have shown that Aβ and p-tau independently predict disease progression, a hypothetical framework proposes that both proteinopathies synergistically potentiate downstream neurodegeneration. The presence of such a synergism would suggest that the effect of Aβ and p-tau on the progression of AD taken together is greater than the sum of their separate effects at the same level. In fact, recent findings from our laboratory support this framework showing that the synergistic effect between brain Aβ and p-tau rather than neurodegeneration drives AD-related metabolic decline in a cognitively normal population. Similarly, in vivo studies conducted in controls have suggested that p-tau modulates the link between Aβ and brain atrophy or behavioral changes, whereas animal model literature has demonstrated a synergistic effect between Aβ and p-tau peptides, leading to downstream synaptic and neuronal dysfunctions.

Here, in a longitudinal analysis conducted in amnestic MCI individuals, we tested the hypothesis that the synergism between Aβ aggregation and tau hyperphosphorylation determines progression from amnestic MCI to AD dementia. In this study, we found that amnestic MCI Aβ+/p-tau+ individuals had the highest rate of cognitive decline and progression to dementia, as compared to all other biomarker groups. Remarkably, our regression models confirmed that a synergistic rather than additive effect between Aβ and p-tau determined greater cognitive decline and clinical progression in amnestic MCI Aβ+/p-tau+. Furthermore, we found that only among amnestic MCI Aβ+/p-tau+ individuals, did the baseline values of Aβ and p-tau biomarkers predict cognitive and clinical impairments.

Overall, our results suggest the synergism between Aβ and p-tau as an important element involved in the progression from amnestic MCI to AD dementia. This finding extends previous studies conducted in cognitively normal persons demonstrating that the synergism between Aβ and p-tau determines functional and structural abnormalities. This study revealed that the link between Aβ levels and progression to AD dementia depends on the p-tau status. This finding sheds light on the literature showing conflicting results reporting the association between Aβ and cognition. From a clinical perspective, if replicated, such a synergism has important implications in understanding the dynamics of progression to dementia. From a therapeutic perspective, one can derive important predictions from the existence of a synergistic interaction between Aβ and p-tau in AD. For example, one can predict that therapeutic interventions targeting either Aβ or p-tau pathology might similarly mitigate AD progression. Furthermore, the same synergistic model implies better effectiveness of a combined therapeutic approach targeting both, Aβ and p-tau, pathological pathways.

As I've been saying for the past couple of years, gene therapies are straightforward enough and cheap enough to carry out that people are doing it, usually quietly, but it is happening. You only have to be connected enough to know a biotechnologist or two with the right skills, as the example here shows. The stage of the adventurous and the self-experimenters is an important part of the development of any new medical technology, helping to overcome institutional reluctance while gathering initial data on how best to approach such treatments in practice. The next part of the process, something that does requires much greater funding and participation from the research and development community, will happen over the next few years; it involves making the therapies more robust, the outcomes more reliable, and assembling the suite of tools and clinics needed for those tasks. That is certainly the goal of BioViva, and as they move forward, others will join them.

There is more than enough evidence for the potential utility of enhancement gene therapies based on producing greater muscle growth and improved metabolism via increased follistatin or myostatin knockout, ranging from numerous animal studies to existing natural human and animal mutants to myostatin antibody trials. There is also considerable interest in telomerase gene therapies, though I'd like to wait for more data on that front before diving in myself, given the potential cancer risk. Once these initial approaches are out there, available, and the methodologies of gene therapy have progressed to the point at which there is reliably comprehensive cell coverage - especially in stem cells, as that will determine how lasting the effect is - then a score of other genes bear further investigation and consideration as targets for enhancement therapies.

While I applaud those who set out to undergo gene therapy today, as their work is necessary to move matters along in this age of overabundant caution and oppressive regulation of every activity, I can't say as I think the fellow here made a good choice of gene. This has the look of a more sophisticated form of the hormone therapies practiced over the past few decades, approaches that really don't have a good impact on aging, and outside of correcting deficiencies are not something that should benefit or is expected to benefit someone in normal health for their age. Increased growth hormone, if anything, is exactly the opposite of what animal and human studies suggest is good for longevity.

Last June at a plastic surgeon's office in Davis, California, at Brian Hanley request, a doctor had injected into his thighs copies of a gene that Hanley, a PhD microbiologist, had designed and ordered from a research supply company. Then, plunging two pointed electrodes into his leg, the doctor had passed a strong current into his body, causing his muscle cells to open and absorb the new DNA. The effort is the second case documented of unregulated gene therapy, a risky undertaking that is being embraced by a few daring individuals seeking to develop anti-aging treatments. The gene Hanley added to his muscle cells would make his body produce more growth-hormone-releasing hormone - potentially increasing his strength, stamina, and life span.

Hanley, 60, is the founder of a one-man company called Butterfly Sciences, also in Davis. After encountering little interest from investors for his ideas about using DNA injections to help strengthen AIDS patients, he determined that he should be the first to try it. "I wanted to prove it, I wanted to do it for myself, and I wanted to make progress," says Hanley of his decision to arrange an experiment on himself. Most gene therapy involves high-tech, multimillion-dollar experiments carried out by large teams at top medical centers, with an eye to correcting rare illnesses like hemophilia. But Hanley showed that gene therapy can be also carried out on the cheap in the same setting as liposuction or a nose job, and might one-day be easily accessed by anyone. In an attempt to live longer, some enthusiasts of anti-aging medicine already inject growth hormone, swallow fullerenes, or gulp megavitamins, sometimes with disregard for mainstream medical thinking. Now unregulated gene therapy could be the next frontier.

Hanley's undertaking has caught the attention of big league scientists. His blood is now being studied by researchers at Harvard University at the laboratory of George Church, the renowned genomics expert. Church says he knows of a handful of other cases of do-it-yourself gene therapy as well. "And there are probably a lot more, although no one is quite sure, since regulators have not signed off on the experiments. This is a completely free-form exercise." At least one additional person who underwent self-administered gene therapy is a U.S. biotech executive who did not want his experience publicly known because he is dealing with the U.S. Food and Drug Administration on other matters. Hanley says he did not secure the approval of the FDA before carrying out his experiment either. The agency requires companies to seek an authorization called an investigational new drug application, or IND, before administering any novel drug or gene therapy to people. "They said 'You need an IND' and I said, 'No, I don't,'" recalls Hanley, who traded emails with officials at the federal agency. He argued that self-experiments should be exempt, including because they don't pose any risk to the public.

So what happens next? The U.S. Food and Drug Administration could get involved, intervening with warning letters or site visits or auditing his ethics board. The plastic surgeon-whose name Hanley wished to keep confidential-could face questions from California's medical board. Companies that supply plasmids might start taking a closer look at who is ordering DNA and what they plan to do with it. Or perhaps authorities will simply look the other way because Hanley experimented on himself. Hanley is proud of what he's done. He created a company, secured patents, made new contacts, identified a gene therapy that has plausible benefits for people, thought in detail about the risks, and offered himself up as a pioneering volunteer.

Link: https://www.technologyreview.com/s/603217/one-mans-quest-to-hack-his-own-genes/

There are a number of very promising lines of work in dental regenerative medicine these days, in regenerating parts of teeth or whole teeth, and in preventing the causes of cavities and gum disease. Here, researchers have developed a comparatively simple approach that greatly increases the normally inadequate regeneration of damaged dentine in teeth. They went on to demonstrate that this can be used as the basis for a treatment to repair large cavities:

Following trauma or an infection, the inner, soft pulp of a tooth can become exposed and infected. In order to protect the tooth from infection, a thin band of dentine is naturally produced and this seals the tooth pulp, but it is insufficient to effectively repair large cavities. Currently dentists use man-made cements or fillings, such as calcium and silicon-based products, to treat these larger cavities and fill holes in teeth. This cement remains in the tooth and fails to disintegrate, meaning that the normal mineral level of the tooth is never completely restored.

However, researchers have proven a way to stimulate the stem cells contained in the pulp of the tooth and generate new dentine - the mineralised material that protects the tooth - in large cavities, potentially reducing the need for fillings or cements. The novel, biological approach could see teeth use their natural ability to repair large cavities rather than using cements or fillings, which are prone to infections and often need replacing a number of times. Indeed when fillings fail or infection occurs, dentists have to remove and fill an area that is larger than what is affected, and after multiple treatments the tooth may eventually need to be extracted. As this new method encourages natural tooth repair, it could eliminate all of these issues, providing a more natural solution for patients.

Significantly, one of the small molecules used by the team to stimulate the renewal of the stem cells included Tideglusib, which has previously been used in clinical trials to treat neurological disorders including Alzheimer's disease. This presents a real opportunity to fast-track the treatment into practice. Using biodegradable collagen sponges to deliver the treatment, the team applied low doses of small molecule glycogen synthase kinase (GSK-3) inhibitors to the tooth. They found that the sponge degraded over time and that new dentine replaced it, leading to complete, natural repair. Collagen sponges are commercially-available and clinically-approved, again adding to the potential of the treatment's swift pick-up and use in dental clinics.

Link: http://www.kcl.ac.uk/newsevents/news/newsrecords/2017/01-January/Natural-tooth-repair-method-using-Alzheimer's-drug-could-revolutionise-dental-treatments.aspx

Today I'll point out a review of one protein, pregnancy-associated plasma protein-A (PAPP-A), for which levels can be reduced or interactions inhibited in order to slow aging in mice. A decade ago, researchers claimed life extension on a par with calorie restriction in a study of mice lacking PAPP-A. More recently, evidence was assembled to show better thymic and immune function in old mice with this mutation, findings elaborated upon in a later paper. The consensus to date is that this life extension in mice is due to both lowered cancer incidence and slowed aspects of aging, and that insulin-like growth factor 1 (IGF-1) and related insulin metabolism is important in these effects. Cancer incidence is split of as it is generally considered to be only loosely coupled to aging - that it is possible to produce therapies and alterations that affect cancer rate without greatly affecting aging, and possibly vice versa. You might recall some debate along these lines for the life extension produced by rapamycin in mice.

The web of mechanisms and feedback loops that operates within a cell is enormously complex and intricate. The circulating levels of specific proteins are the switches and dials of cellular behavior, and they all influence one another, usually quite indirectly. No alteration can be made in isolation. On the other hand, that means that there are potentially dozens of feasible ways to tamper with any one core mechanism relevant to the ways in which metabolic processes determine natural variations in longevity. The challenge lies less in finding ways to modestly slow aging in laboratory animals, given that there are now scores of methodologies for slowing aging to some degree in various species, and more in understanding exactly why any particular intervention has that effect. Mapping of the links between proteins and genes and various cellular mechanisms proceeds slowly: it is an enormous job. That is one of the reasons why I'm less in favor than many of attempts to alter metabolism to slow aging. A great deal of work is required to gain the understanding needed in order to produce gains that rarely match those of calorie restriction. I'd like to see better outcomes than that in the future.

Insulin and IGF-1 are at the center of those metabolic processes and mechanisms most studied by the research community in the context of natural variations in aging and longevity. So it shouldn't be surprising to find more links uncovered here than for other mechanisms, perhaps. Many methods that slow aging can be attributed to their influence on this slice of metabolism, and the outcomes often look very similar to the beneficially altered metabolic state produced by the practice of calorie restriction. Some decades from now, once the dust has settled and much more of cellular metabolism has been comprehensively mapped, it will be interesting to see just how many of today's long-lived mutant lineages are in fact long-lived because their altered biochemistry involves some facet of the underlying cellular reaction to starvation. Today the map isn't good enough to answer that question all that well. But is this all, PAPP-A and similar methods, worth chasing with major investments in medical research? If you think that calorie restriction mimetics are a good thing, then perhaps. But this isn't the path to rejuvenation after the SENS vision for repair of the causes of aging, and not an approach capable in principle of radical life extension of decades and more. If you aim for small gains, small gains tend to be what you achieve at the end of the day.

PAPP-A: a promising therapeutic target for healthy longevity

The main known function of PAPP-A is to increase local IGF bioavailability through cleavage of inhibitory IGFBPs, in particular IGFBP-4. Indeed, PAPP-A is probably the only physiological IGFBP-4 proteinase. PAPP-A-induced enhancement of local IGF action through proteolysis of IGFBP-4 has been demonstrated in vitro and in vivo in several different systems. Reduced IGF signaling has been associated with longevity and increased healthspan. Therefore, a reduction in PAPP-A proteolytic activity represents a novel approach to indirectly decrease the availability of bioactive IGF. For therapeutic intervention, such a strategy is expected to moderately restrain IGF signaling and hence cause fewer adverse effects compared to direct inhibition by targeting the IGF receptor.

Both male and female PAPP-A knockout (KO) mice on chow diet live 30-40% longer than wild-type (WT) littermates, with no secondary endocrine abnormalities. Circulating levels of growth hormone (GH), IGF-I, glucose, and insulin were not significantly different between PAPP-A KO and WT mice in this study. PAPP-A KO mice also live longer when fed a high fat diet starting as adults. Thus, PAPP-A deficiency can promote longevity without dietary restriction. Furthermore, this extended lifespan is not a secondary consequence of a small body size because PAPP-A KO mice rescued from the dwarf phenotype by enhanced IGF-II expression during fetal development retain their longevity advantage. Finally, conditional knockout of the PAPP-A gene in adult mice also resulted in a 20% extension of lifespan. End-of-life pathology showed delayed occurrence of fatal neoplasias and indicated decreased incidence and severity of conditions with age-related degenerative changes, such as cardiomyopathy, nephropathy, and thymic atrophy in PAPP-A KO mice compared to WT littermates.

Several mouse models with reduced GH-stimulated IGF-I expression by liver and low levels of circulating IGF-I (Snell, Ames dwarf, GH receptor KO) have also been found to have extended longevity. On the other hand, transgenic mice over-expressing GH exhibit a shortened lifespan. It is important to note that PAPP-A KO mice have normal levels of circulating IGF-I (and GH) and their phenotype reflects reduction in local IGF action. Unlike the GH mutant mice that have postnatal growth retardation, deletion of the PAPP-A gene manifests itself early in fetal development as proportional dwarfism. The lifespan extension in the Snell, Ames dwarf, and GH receptor KO models reflects GH tone rather than IGF-I bioavailability.

Low circulating PAPP-A has been associated with adverse effects on placental function and fetal growth in humans. Although the role of PAPP-A in human pregnancy is not understood, PAPP-A is believed to be important for placental development. Therefore, targeting PAPP-A during human pregnancy is not likely to be a viable strategy. The involvement of PAPP-A in normal tissue repair processes also suggests a possible need to suspend PAPP-A targeting temporarily during such conditions. For example, PAPP-A increases bone accretion primarily by increasing IGF bioavailability important for prepubertal bone growth. Fracture repair in PAPP-A KO mice is temporally compromised, but not prevented from normal resolution. Similarly, controlled increases in PAPP-A expression are seen in healing human skin, indicating that wound healing may be delayed as a consequence of PAPP-A targeting.

Experimental evidence is accumulating that inhibition of PAPP-A has the potential to promote healthy longevity. It is clearly advantageous that targeting of PAPP-A has the benefit of a single intervention that affects multiple adverse changes with age, not just a single condition. PAPP-A is present in the extracellular environment, and its activity is therefore amenable to pharmacologic intervention. Strategies to inhibit PAPP-A have recently been developed and tested in experimental models. Rather than the active site of PAPP-A, a unique substrate-binding exosite, critical for proteolytic cleavage of IGFBP-4, is targeted. This efficiently eliminates activity toward IGFBP-4, but does not interfere with cleavage of other possible substrates of PAPP-A. Inhibition will target discrete conditions with increased PAPP-A activity, resulting in moderate restraint of IGF signaling and minimizing side effects. However, much remains to be learned about stages in life at which mice, and possibly humans, are susceptible to improvements in long-term health by manipulation of PAPP-A.

An accumulation of senescent cells is one of the causes of aging, and periodic removal of senescent cells is therefore one of the foundations for near future rejuvenation therapies. The first generation of these treatments will likely be available via medical tourism within the next couple of years, but we'll be waiting five years or more for comprehensive human data and passage through the regulatory systems of the US and Europe. For those who have been following events in the nascent senescent cell clearance industry, there won't be much that is new in this popular press article on UNITY Biotechnology, but it is nonetheless an interesting read:

In 2011, Jan van Deursen's team at the Mayo Clinic published research showing that when scientists regularly eliminate senescent cells from mice, the animals remain youthful longer; older mice who got similar treatment appeared to stop aging, based on measures of their mobility, muscle mass, and fat storage. When Nathaniel David saw the paper, he knew had to talk to the authors. Within 72 hours, he and Van Deursen were discussing forming a company. "This is my sixth company. You get kind of pattern recognition on things that feel 'druggable.'"

David was part of the team at Kythera Biopharmaceuticals, bought in 2015 by Allergan for $2.1 billion. Kythera's claim to fame was the development of Kybella, a drug for double chins that literally explodes fat cells. While the Food and Drug Administration considers double chins a reasonable therapeutic target for drug development, it doesn't feel the same way about aging. So even though Van Duersen's Mayo Clinic team showed this past February that clearing senescent cells from middle-aged mice led to a 20% increase in average lifespan versus control animals, UNITY has to focus its therapies on certain conditions. Anyway, David bristles at the idea that UNITY is an "anti-aging" company. The claim, he says, implies that biologists have already figured out what controls the fundamental ticking of the human aging clock. They haven't. Meanwhile, David expects UNITY to test its first drug, for osteoarthritis (OA) of the knee, in humans within 18 months.

Right now, patients with OA of the knee typically get cortisone injections into the joint every few months to treat the pain. Those shots appear to temporarily shut down senescent cells' ability to secrete proteins that cause inflammation, which essentially is the immune system turning on normal tissue, resulting in damage and stiffness. UNITY's drug will be delivered similarly through regularly scheduled injections, but would instead trigger the cells' deaths. Since the offending cells would be gone instead of temporarily muted, their injection could be given every year or two. If you had to pick one medical indication or element associated with aging to go after, says Matt Kaerberlein, an expert in the biology of aging at the University of Washington, "osteoarthritis is a great place to be. It's a specific indication, but it's a indication that could have a huge impact of quality of life for a lot of people."

There are concerns about side effects. For one, senescent cells also play a role in preventing cancer: cells can go into senescence to avoid become cancerous, acting as a sort of cancer emergency brake. David says the key is to make sure that UNITY's drugs don't "screw with the emergency brake." In other words, the company's therapies must avoid preventing cells from becoming senescent, and rather just eliminate them once they've gone down that path. Second, senescent cells play a role in healing wounds, and are often recruited to areas in the body where there's been trauma. Research done by Unity cofounder Judith Campisi has shown that in animals without senescent cells, wounds take longer to heal. A challenge facing Unity is figuring out dosing and treatment schedules to ensure that some senescent cells are available to restore tissues.

For David, the serial entrepreneur, the science behind UNITY is simply irresistible. And the excitement in his voice is audible when he talks about people aging in calendar years without deteriorating physically. While David doesn't believe that his company's therapies will radically increase lifespan, he does see an opportunity to profoundly extend "health span" - body part by body part. "Rather than dying at age 83, demented and catheterized in your bed, how'd you like to die at 107 on the tennis court while winning or be killed by a jealous lover at 112? That's in the realm of the possible with this biology."

Link: https://qz.com/878446/unity-biotechnology-cure-for-aging/

Here I'll point out another of the articles going up at the Life Extension Advocacy Foundation, this time on the topic of the naturalistic fallacy where it occurs in opposition to healthy life extension. Our community would like to build medical therapies that address the causes of aging, thereby ending age-related disease and greatly extending healthy human life spans. It has always surprised me to find that most people, at least initially, object to this goal. It seems perfectly and straightforwardly obvious to me that aging to death, suffering considerably along the way, is just as much a problem to be overcome as any other medical condition that causes pain and mortality. Yet opposition exists, and that opposition is one of the greatest challenges faced when raising funding and pushing forward with research and development of rejuvenation therapies.

When it comes to treating aging as a medical condition the naturalistic fallacy is voiced in this way: aging is natural, what is natural is good, and therefore we shouldn't tamper with aging. If you look around at your houses, your computers, your modern medicine, and consider that such an objection is perhaps just a little late to the game, and hard to hold in a self-consistent manner, then you're probably not alone. Notably, the same objection is rarely brought up when it comes to treating specific age-related diseases, or in the matter of therapies that already exist. People who are uncomfortable about radical changes to the course of aging and who speak out against the extension of human life are nonetheless almost all in favor of cancer research, treatments for heart disease, and an end to Alzheimer's disease. Yet age-related diseases and aging are the same thing, the same forms of damage and dysfunction, only differing by degree and by the names they are given. Objecting to the treatment of aging on naturalistic grounds without also objecting to near all modern medicine is a deeply incoherent position. The whole and entire point of medicine is to defeat the natural causes of pain, debility, and death.

The word 'unnatural' conjures up feelings of doom and dread, and it is unfortunately often used by critics of science as a way to justify their own concerns. It is argued that interfering with the natural order of things is wrong and against nature, and therefore increasing lifespans thanks to scientific advancements is something we should not be doing. From an early age, most of us are taught that 'natural' is good and always preferable. Concepts like 'natural organic food is better,' 'natural remedies are always the best option,' and so on are all deeply ingrained into our culture. With this in mind, it is easy to understand why some people may consider the advanced medicines and next generation therapies science is developing being somehow unnatural.

We have always sought ways to protect our health and extend human lifespan. But there are methods that already existed when we were born, and methods appearing later. Most people would not consider washing their hands, taking medicines, or undertaking surgery as being bad - unnatural or unethical - because we are used to their existence. These are ways to extend life. But we tend to feel anxious when we encounter something new. Part of this reaction is biologically programmed: during human evolution, new things might turn out to be dangerous, and wariness could be a successful strategy. But another part is related to the deficiency of knowledge about the new intervention and the indirect consequences of its application.

In case of need, such as the need to cure a severe and aggressive disease, we welcome even radical interventions like gene therapy, because we know for sure that the alternative is probably death - and nothing can be worse than that. But let's remember that the various aging processes lead to the development of deadly diseases, like cancer, Alzheimer's, Parkinson's, heart disease and stroke, which makes any attempts to bring these processes under medical control highly ethical. A number of researchers are currently debating if aging should be considered a disease or a syndrome itself, and some suggest including aging as a disease under the International Classification of Diseases (ICD-11). If accepted as part of ICD-11 it could create an opportunity for the medical industry to test and register new interventions for addressing the aging processes. This would then allow healthy middle aged patients to use these interventions even in the absence of age-related diseases, in order to prevent or postpone their manifestation.

As so-called life extension technologies are no more than medical technologies focused on preventing age-related diseases at very early stage and sustaining health throughout life, it is obvious that they should be considered in the same way as any other form of medicine. They are no more unnatural than the medicines we already use today. The development of medical technologies, their implementation, and the efforts to make them accessible and affordable to every human being reflect the universal goal of the continuous improvement of health.

Link: http://www.lifeextensionadvocacyfoundation.org/education/unnatural/

The long-term response to calorie restriction has long been of interest to the aging research community, and particularly in the past few decades as the tools of biotechnology allowed for a more detailed analysis of the metabolic changes that accompany a reduced calorie intake. A restricted diet extends healthy life spans in near all species tested to date, though to a much greater extent in short-lived species than in long-lived species such as our own. Considerable effort is presently devoted to the development of drugs that can replicate some fraction of calorie restriction - more effort than is merited in my opinion, given that the optimal result for extension of human life span achieved via calorie restriction mimetics will be both hard to achieve safely and very limited in comparison to the gains possible through rejuvenation therapies after the SENS model. Repairing damage within the existing system should be expected to outdo attempts to change the system in order to slow the accumulation of damage, in both efficiency and size of result.

Not everyone is interested in the long term, however. The short term health benefits of calorie restriction appear quickly and are surprisingly similar in mice and humans, given that calorie restriction in mice results in significantly extended life and calorie restriction in humans does not. The beneficial adjustments to metabolism and organ function are for the most part larger and more reliable than similar gains presently achievable through forms of medicine. That is more a case of medical science having a long way to go yet than calorie restriction being wondrous, however. Still, the short term benefits are coming to the attention to wider audience within the research and medical community. For example, calorie restriction and fasting are proving to be useful adjuvant treatments that improve outcomes for cancer patients: you might recall an interview with one of the researchers involved, as well as a paper from a few years back showing that periodic fasting improves recovery of the immune system from the damage caused by chemotherapy. In addition there is good evidence for calorie restriction and fasting to improve the outcomes following surgery, priming the body for the stress of that experience. Researchers have made some inroads in tracing the important mechanisms in this effect, as outlined in the following open access review paper:

Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes

Dietary restriction (DR), or reduced food intake without malnutrition, was found in 1935 to extend lifespan of laboratory rats. Since that time, longevity extension by DR has been demonstrated in numerous experimental organisms from yeast to non-human primates. Fortunately, DR confers other important benefits that do not require long periods of food restriction, including increased resistance to multiple forms of acute stress. One of the biggest planned stressors many people will face in their life is that of major elective surgery, which carries inherent risks of complications. A novel concept in surgical risk mitigation emerging from basic research on DR and aging is dietary preconditioning, or short-term DR lasting one week or less prior to surgery. In rodent models of surgical stress ranging from ischemia reperfusion injury (IRI) to vascular restenosis (intimal hyperplasia), short-term DR or fasting before surgery, followed by a return to normal food intake after surgery, leads to improved outcomes.

Because of the plethora of physiological and molecular changes that occur even upon short-term restriction of a single essential amino acid from the diet, identification of critical downstream mechanisms of DR-mediated protection against surgical stress is challenging. Elucidation of upstream nutrient-sensing pathways such as GCN2 and mTORC1, for which genetic full-body or tissue-specific knockout models are available, has proven a critical step forward. Using experimental designs in which dietary interventions are combined with genetic models lacking upstream nutrient sensors that fail to gain protection upon DR, two major downstream mechanisms involving increased prosurvival insulin signaling and endogenous H2S production have recently been elucidated.

How does the DR-mediated improvement in hepatic insulin sensitivity contribute to protection from hepatic IRI? In addition to regulating energy metabolism, insulin can act as a prosurvival factor via negative regulation of apoptosis. Consistent with this mechanism of action, circulating insulin levels and antiapoptotic signaling are both increased in the hours after liver reperfusion in wild-type mice preconditioned on DR, while this effect is absent in mice with constitutive insulin resistance. Taken together, these data suggest that a major mechanism of DR action is via increased insulin sensitivity prior to an injury, which then facilitates increased prosurvival signaling and reduced hepatocyte apoptosis after injury.

Although toxic at high levels, endogenously produced H2S by one of three evolutionarily conserved enzymes is now recognized to have pleiotropic cytoprotective, anti-inflammatory and vasodilatory effects resulting in cardioprotection and resistance to ischemic injury. H2S also has direct antioxidant properties, and can participate in mitochondrial energy production by donating electrons to the mitochondrial electron transport chain protein SQR, with a potential role in protection from ischemia. Since pharmacological delivery of H2S also protects in models of surgical stress, as well as more broadly in preclinical models of cardiovascular disease, it remains to be seen if supplementation with exogenous sources of H2S, or increased endogenous H2S production through dietary or other means, will ultimately turn out to be more beneficial in the context of surgical stress resistance.

The findings that short-term fasting or restriction of food intake - on the order of days to a week - leads to robust functional benefits in rodents has profound implications for the mechanism of DR action in mammals. Rather than previous notions of DR as an intervention whose benefits accumulate over long periods of time due to reduced calorie intake, DR is now viewed as a rapid adaptation to the mild stress of calorie and/or nutrient deprivation with the potential to protect against many other forms of stress. This new understanding has important practical implications for attempts to leverage DR against clinically relevant endpoints, including planned surgery. If future clinical trials identify brief DR regimens or pharmacological DR mimetics that are safe and effective against the stress and potential complications of surgery, how would this change current preoperative nutritional standards? With few exceptions, there is currently no consensus on what should or should not be eaten up to 1 day prior to surgery, so long as the patient is not suffering from malnutrition.

Currently, the duration of preoperative fasting used as an "anesthetic precaution" in humans is likely too short to tap into DR benefits, while the progressive clinical application of existing nutritional guidelines promotes an alternate although not mutually exclusive concept of increased nutrition immediately prior to surgery. Future clinical trials are required to test the safety, feasibility, and potential efficacy of short-term DR, including extended periods of fasting, to reduce risk of surgical complications and improve outcomes. If successful, this approach has the potential to change the paradigm for preoperative nutritional care based on concepts derived from research into the basic biology of aging.

Is it possible to assemble a useful biomarker of biological aging from a combination of existing metrics easily obtained via blood tests? This is an open question, but a number of research groups have made the attempt. To be useful, it would have to work at least as well as the DNA methylation biomarkers currently under development. The combination of metrics outlined in this open access paper is a start in that direction, but much more work and validation is needed. A robust, discriminating biomarker that reflects biological age, the level of molecular damage to cells and tissues and consequences thereof, would allow faster development, verification, and improvement of rejuvenation therapies. Without such a tool, it is very slow and expensive to determine the degree to which any particular candidate therapy has beneficial long-term effects on healthy life span. That in turn makes it hard to discard less effective approaches in favor of more effective approaches, and the greater cost means that less progress is made for a given investment in research and development.

The steady increase in human average life expectancy in the 20th century is considered one of the greatest accomplishments of public health. Improved life expectancy has also led to a steady growth in the population of older people, age-related illnesses and disabilities, and consequently the need for prevention strategies and interventions that promote healthy aging. A challenge in assessing the effect of such interventions is 'what to measure'. Chronological age is not a sufficient marker of an individual's functional status and susceptibility to aging-related diseases and disabilities. As has been said many times, people can age very differently from one another. Individual biomarkers show promise in capturing specificity of biological aging, and the scientific literature is rich in examples of biomarkers that correlate with physical function, anabolic response, and immune aging. However, single biomarker correlations with complex phenotypes that have numerous and complex underlying mechanisms is limited by poor specificity.

Moving from a simple approach based on one biomarker at a time to a systems analysis approach that simultaneously integrates multiple biological markers provides an opportunity to identify comprehensive biomarker signatures of aging. Analogous to this approach, molecular signatures of gene expression have been correlated with age and survival, and a regression model based on gene expression predicts chronological age with substantial accuracy, although differences between predicted and attained age could be attributed to some aging-related diseases. The well-known DNA methylation clock developed by Horvath has been argued to predict chronological age. Alternative approaches that aggregate the individual effects of multiple biological and physiological markers into an 'aging score' have also been proposed. These various aging scores do not attempt to capture the heterogeneity of aging. In addition, many of these aging scores use combinations of molecular and phenotypic markers and do not distinguish between the effects and the causes of aging.

Here we propose a system-type analysis of 19 circulating biomarkers to discover different biological signatures of aging. The biomarkers were selected based upon their noted quantitative change with age and specificity for inflammatory, hematological, metabolic, hormonal, or kidney functions. The intuition of the approach is that in a sample of individuals of different ages, there will be an 'average distribution' of these circulating biomarkers that represents a prototypical signature of average aging. Additional signatures of biomarkers that may correlate to varying aging patterns, for example, disease-free aging, or aging with increased risk for diabetes or cardiovascular disease (CVD), will be characterized by a departure of subsets of the circulating biomarkers from the average distribution. We implemented this approach using data from the Long Life Family Study (LLFS), a longitudinal family-based study of healthy aging and longevity that enrolled individuals with ages ranging between 30 and 110 years.

We used an agglomerative algorithm to group LLFS participants into clusters thus yielding 26 different biomarker signatures. To test whether these signatures were associated with differences in biological aging, we correlated them with longitudinal changes in physiological functions and incident risk of cancer, cardiovascular disease, type 2 diabetes, and mortality using longitudinal data collected in the LLFS. Signature 2 was associated with significantly lower mortality, morbidity, and better physical function relative to the most common biomarker signature in LLFS, while nine other signatures were associated with less successful aging, characterized by higher risks for frailty, morbidity, and mortality. The predictive values of seven signatures were replicated in an independent data set from the Framingham Heart Study with comparable significant effects, and an additional three signatures showed consistent effects. This analysis shows that various biomarker signatures exist, and their significant associations with physical function, morbidity, and mortality suggest that these patterns represent differences in biological aging.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12557/full

While there are some engineered mammalian lineages that can heal small wounds without scarring, further investigations of the biochemistry involved have yet to lead to a robust clinical treatment. Other lines of research are starting to look more promising, however. Here researchers demonstrate early implementations of a methodology that may prove to be the basis for a practical therapy to reduce scar tissue formation in wound healing:

Fat cells called adipocytes are normally found in the skin, but they're lost when wounds heal as scars. The most common cells found in healing wounds are myofibroblasts, which were thought to only form a scar. Scar tissue also does not have any hair follicles associated with it, which is another factor that gives it an abnormal appearance from the rest of the skin. Researchers used these characteristics as the basis for their work - changing the already present myofibroblasts into fat cells that do not cause scarring. "Essentially, we can manipulate wound healing so that it leads to skin regeneration rather than scarring. The secret is to regenerate hair follicles first. After that, the fat will regenerate in response to the signals from those follicles."

The study showed hair and fat develop separately but not independently. Hair follicles form first, and the researchers previously discovered factors necessary for their formation. Now they've discovered additional factors actually produced by the regenerating hair follicle to convert the surrounding myofibroblasts to regenerate as fat instead of forming a scar. That fat will not form without the new hairs, but once it does, the new cells are indistinguishable from the pre-existing fat cells, giving the healed wound a natural look instead of leaving a scar.

As they examined the question of what was sending the signal from the hair to the fat cells, researchers identified a factor called Bone Morphogenetic Protein (BMP). It instructs the myofibroblasts to become fat. This signaling was groundbreaking on its own, as it changed what was previously known about myofibroblasts. "Typically, myofibroblasts were thought to be incapable of becoming a different type of cell, but our work shows we have the ability to influence these cells, and that they can be efficiently and stably converted into adipocytes." This was shown in both the mouse and in human keloid cells grown in culture. These discoveries have the potential to be revolutionary in the field of dermatology. The first and most obvious use would be to develop a therapy that signals myofibroblasts to convert into adipocytes - helping wounds heal without scarring.

Link: https://www.pennmedicine.org/news/news-releases/2017/january/using-fat-to-help-wounds-heal-without-scars

A large proportion of present research into the mechanisms of aging seeks the underlying reasons that link good lifestyle choices with greater life expectancy and lower incidence of age-related disease. When considered in the grand scheme of things, looking towards a future of rejuvenation and life spans ultimately extended by centuries and more, this is a fairly parochial concern: natural variations in longevity will cease to be important shortly after the clinical availability of the first generation of rejuvenation therapies based on the SENS research portfolio. Nonetheless, most investigative research is focused on what takes place today, on the way in which the current operation of metabolism determines the current pace of aging. The open access paper linked below is a good example of the type, focused on glucose metabolism, dysregulated in those who become overweight and diabetic, and the anti-diabetic drug acarbose. In the sense that today's large population of obese and diabetic individuals are a natural experiment in the human biochemistry of aging, members of the research community would like to learn what they can from this data.

Most of the readers here will know that type 2 diabetes is a lifestyle condition for the vast majority of patients, arising due to the effects of excess visceral fat tissue. This abnormal metabolic state in effect accelerates the damage of aging, through mechanisms such as increased chronic inflammation, but also others that stem from the malfunctioning glucose metabolism that diabetic patients exhibit. Researchers have used diabetes in animal models as a substitute for the aging process on a routine basis for decades, as the progression is more rapid and thus the studies are less costly in time and money. Diabetic patients have a shorter life expectancy and greater incidence of age-related disease than their healthy peers. This is also true, to a lesser degree, of those with lower levels of metabolic disorder and visceral fat, people who are on the way to full-blown diabetes but not there yet.

There are a range of drugs that interact with the dysfunctional diabetic metabolism to make matters less terrible, but no substitute for just losing the weight - low-calorie diets work pretty well even in later stage type 2 diabetes, and it is quite amazing that so few people actually undertake this course of action given the reliably positive outcomes. Among these drugs, acarbose is interesting because it has been shown to modestly extend life in normal mice. The effect of the drug is to inhibit uptake of carbohydrates from the diet, and thus reduce the delivery of new glucose into the workings of metabolism. That result suggests that we could all benefit to some degree from a lower intake of complex carbohydrates, such as the readily available sugar that is everywhere these days, not just the overweight and the diabetic. The authors of the paper here go into some detail while considering the mechanisms involved, though note that, like many researchers, they are unwilling to step beyond compression of morbidity within the existing human life span as a viable goal to aim for.

Targeting glucose metabolism for healthy aging

Aging is considered the largest risk factor for a variety of chronic and metabolic diseases. Unlike many risk factors (i.e., smoking, diet, weight gain), aging, by strict definition as the act of growing old, has not historically been considered to be modifiable. Aging and risk of disease development are so well intertwined that skepticism surrounding the idea of longevity extension persists, as a longer lifespan is considered by some as simply a prolonged opportunity to develop additional age-related diseases. Despite this concern, contemporary pursuit of methods to increase lifespan and healthspan through the process of slowing the accumulation of age-related damage to cells and tissues continues. Conceivably, an intervention to extend lifespan and/or healthspan would act through slowing the fundamental aging process(es) rather than preventing a single disease. It is possible that interventions to slow the aging process may result in an individual experiencing an extension of healthspan without significant increases to lifespan, as it is currently unknown if maximal lifespan can be extended in humans. Therefore, an individual might experience a compressed window of morbidity by living the great majority or potentially the entirety of lifespan without developing the disorders now commonly associated with aging.

A common co-morbidity observed in aging is metabolic dysfunction. While metabolic (e.g., glucose and mitochondrial) dysfunction is frequently associated with aging, the causal relationship between aging and metabolic dysfunction remains to be fully understood. The risk relationships among age and metabolic associated diseases suggest some factors may be better primary targets for longevity interventions than others. For instance, curing cancer may not necessarily be expected to significantly affect the subsequent risk for type 2 diabetes (T2D) or cardiovascular disease. In contrast, cardiovascular disease and T2D are more widely recognized as possible contributors to neurological disease risk and when remediated, could reduce the risk of dementia and neurodegenerative disease. Considering the coordinate increase in risk for a number of chronic diseases with advancing age and given the unclear interrelationship between these diseases, a stronger case might be made for targeting glucoregulatory control to decrease disease risk and consequently improve longevity. In fact, T2D is a significant risk factor for most other age-related diseases. If glycemic control were successfully maintained with advanced chronological age, this might slow the aging process, potentially delaying or preventing the development of multiple age-related diseases, allowing an individual to live healthier for longer.

Exactly which cellular or molecular mechanism(s) is primarily responsible for the associations of elevated glucose with chronic disease risks is not fully understood. Proposed causative mechanisms leading to accelerated aging include direct methods such as amplified and inappropriate glycosylation events, along with the production of advanced glycation end products that damage cellular functions from DNA repair to structural integrity and indirect contribution to the production of reactive oxygen species. Alternatively, maintenance of glycemic control may function as a biomarker of health maintenance from the cell to the organismal level. As such, one might expect a range of interventions targeting diverse mechanisms could share this glucoregulatory phenotype, resulting from some combination of maintained integrity of the cell, organelles, hormonal signaling or other factors coordinating metabolism and ultimately aging across the organism. Thus by indirect means, changes in glucose levels could significantly impact transcriptional programs or hormonal signaling to coordinately regulate processes currently known (or unknown) to influence the aging process (e.g., mitochondrial function, autophagy).

Glucose dysregulation, measured as either hypoglycemia or hyperglycemia, can result from problems along the entire glucose uptake, production, and metabolism spectrum. Hyperglycemia is commonly associated with advancing age and can occur as a result of decreasing insulin release in response to glucose and/or increased insulin resistance by tissues. Recent surveys of the adult population in the United States suggest that ≥50% of individuals over 45 years of age have T2D or prediabetes. This prevalence is greater with increasing age, with ∼80% of adults 65 or older showing glucose dysregulation. Thus, impaired glycemic control is approaching epidemic proportions both in the U.S. and throughout the world. Although the source of the metabolic imbalance driving glucose dysregulation may have multiple contributors, a surfeit of energy intake with increasing body weight and BMI are proposed to contribute.

One of the most direct methods of maintaining glucose homeostasis is through diet/nutritional interventions. Paramount among these is the dietary restriction (DR) or calorie restriction (CR) paradigm. Despite these reported health benefits, life-long dietary restriction in humans remains challenging given the current state of modern society in developed countries that has shifted from a limited food supply a century ago to nutritional excess today. Therefore, the identification of interventions that promote health and longevity independent of obligatory food intake reductions has been proposed as an alternative means to "mimic" the physiologic benefits of CR and reap health and longevity gains - a hypothetical class of compounds termed calorie restriction mimetics (CRMs).

The similarities between glucose dysregulation in aging and glucose dysregulation with T2D have led to the hypothesis that an effective CRM could be found by targeting glucoregulatory control. If an intervention is able to improve glucose regulation to treat or prevent T2D, it may prevent development of glucose dysregulation commonly observed with aging. The most well-known T2D drug that has been tested as a CRM is metformin. Metformin is reported to act through multiple pathways; however, the best-characterized pathway is through the activation of the cellular energy regulatory sensor AMP-activated protein kinase (AMPK). More recent pre-clinical work has highlighted another class of diabetic control agents that work upstream of insulin (and presumably metformin-related targets) while providing health and longevity benefits in lab models - namely the α-glucosidase inhibitor acarbose (ACA). When consumed with a complex carbohydrate-containing meal, ACA acts as a competitive inhibitor to carbohydrate breakdown along the brush border of the small intestine, resulting in reduced enzymatic degradation and absorption of glucose from complex carbohydrates. This inhibitor effect lowers the post-prandial blood glucose elevation in a dose-dependent manner.

Studies with non-diseased humans and rodents, as well as diabetic individuals, have described beneficial metabolic effects, most notably as reduced post-prandial blood glucose excursions with ACA. Insulin sensitivity is slightly improved with ACA, though post-prandial insulin levels do not show a consistent significant decrease. While the molecular, inhibitory action of ACA is well-detailed, fewer studies have attempted to explore the effect ACA has on specific nutrient retention from the diet and specifically if the weight loss sometimes reported with ACA administration is the result of reduced overall energy retention from the diet. Given the important roles of insulin signaling and IGF1 in body weight homeostasis and longevity, the benefits of ACA are more likely a result of the slowed uptake of sugars from the diet, resulting in lower post-prandial glucose excursions and moderated insulin responses. Considered as a whole, even in the absence of overt disease, these data suggest targeting glucoregulatory maintenance by acarbose or other means may be a viable nutritional target for maintaining health and delaying aging.

Researchers continue to expand the types of tissue that can be produced in small amounts to form organoids, lacking the integrated blood vessel network needed to support larger sections, but otherwise at least partially functional. This stage of development in the tissue engineering field offers considerable benefits, both as a way to speed up research with a cheaper alternative to animal studies, but also the potential for transplantation. Even small tissue patches can be an effective therapy for some conditions: the tissue will integrate with the body, and blood vessels will grow in to support it. For organs that are essentially chemical factories or filters, such as the kidney and liver, transplant of numerous functional organoids grown from a patient's own cells may well prove to be good enough to address a number of presently incurable degenerative conditions. Here, researchers demonstrate construction of stomach tissue organoids:

Scientists report using pluripotent stem cells to generate human stomach tissues in a petri dish that produce acid and digestive enzymes. Researchers grew tissues from the stomach's corpus/fundus region. The study comes two years after the same team generated the stomach's hormone-producing region (the antrum). The discovery means investigators now can grow both parts of the human stomach to study disease, model new treatments and understand human development and health in ways never before possible. "Now that we can grow both antral- and corpus/fundic-type human gastric mini-organs, it's possible to study how these human gastric tissues interact physiologically, respond differently to infection, injury and react to pharmacologic treatments." The current study caps a series of discoveries since 2010 in which research teams used human pluripotent stem cells (hPSC) - which can become any cell type in the body - to engineer regions of the human stomach and intestines. They are using the tissues to identify causes and treatments for diseases of the human gastrointestinal tract. This includes a study in which scientists generated human intestine with an enteric nervous system. These highly functional tissues are able to absorb nutrients and demonstrate peristalsis, the intestinal muscular contractions that move food from one end of the GI tract to the other.

A major challenge investigators encountered in the current study is a lack of basic knowledge on how the stomach normally forms during embryonic development. "We couldn't engineer human stomach tissue in a petri dish until we first identified how the stomach normally forms in the embryo." To fill that gap, the researchers used mice to study the genetics behind embryonic development of the stomach. In doing so, they discovered that a fundamental genetic pathway (WNT/β-catenin) plays an essential role in directing development of the corpus/fundus region of the stomach in mouse embryos. After this, researchers manipulated the WNT/β-catenin in a petri dish to trigger the formation of human fundus organoids from pluripotent stem cells. The team then further refined the process, identifying additional molecular signaling pathways that drive formation of critical stomach cell types of the fundus. These include chief cells, which produce a key digestive enzyme called pepsin, and parietal cells. Parietal cells secrete hydrochloric acid for digestion and intrinsic factor to help the intestines absorb vitamin B-12, which is critical for making blood cells and maintaining a healthy nervous system. It takes about six weeks for stem cells to form gastric-fundus tissues in a petri dish. Researchers now plan to study the ability of tissue-engineered human stomach organoids to model human gastric diseases by transplanting them into mouse models.

Link: https://www.cincinnatichildrens.org/news/release/2017/stem-cells-generate-human-stomach

Alzheimer's is a single defined medical condition that may soon be split into numerous forms, separate named diseases with distinctive differences that happen to look very similar in their later stages. The characteristic changes of Alzheimer's include the accumulation of amyloid-β and altered tau protein in solid depositions in brain tissues, but just as there are different types of tau aggregates involved in the various tauopathies, there may well be subtly different classes of amyloid-β aggregates involved in various forms of Alzheimer's disease.

At the core of Alzheimer's disease are amyloid-beta (Aβ) peptides, which self-assemble into protein fibrils that form telltale plaques in the brain. Now, the results of a study suggest that certain fibril formations are more likely to appear in cases of rapidly progressive Alzheimer's disease, as opposed to less-severe subtypes. The findings increase scientists' understanding of the structure of these fibrils, and may eventually contribute to new tests and treatments for Alzheimer's disease. "It is generally believed that some form of the aggregated Aβ peptide leads to Alzheimer's disease, and it's conceivable that different fibril structures could lead to neurodegeneration with different degrees of aggressiveness. But the mechanism by which this happens is uncertain. Some structures may be more inert and benign. Others may be more inherently toxic or prone to spread throughout the brain tissue."

Prior research has demonstrated that Aβ fibrils with various molecular structures exhibit different levels of toxicity in neuronal cell cultures, a finding confirmed in subsequent mouse trials. One study even demonstrated that Aβ fibrils cultured from patients with rapidly progressive Alzheimer's disease are different in size and resistance to chemical denaturation than those isolated from patients with more slowly progressing disease. Building on these observations, researchers set out to better characterize the structures of these fibrils and get a better handle on the potential correlations between structure and disease subtype. They examined 37 brain tissue samples from 18 deceased individuals - some with rapidly progressive Alzheimer's disease and others who had experienced more common subtypes - with solid-state NMR spectroscopy. The process can be incredibly labor intensive, because solid-state NMR requires milligram-scale quantities of isotopically labeled fibrils. In order to prepare the samples, the team had to amplify and label structures in brain tissue and generate "seeds" - short bits of fibrils - and grow them with synthetic peptides. "You have to make individual samples for individual patients, one by one. It takes about half a year to one year of work. It's not a high-throughput technique. The main barrier is that it's not an easy thing to do and it takes a long time. We were able to look at some 30 tissue samples, and that was really a tour de force."

After examining the solid-state NMR spectra, the researchers found that one specific fibril structure appeared to be statistically correlated with both typical Alzheimer's disease and posterior cortical atrophy Alzheimer's - a condition that involves disruption of visual processing. The researchers also found that range of different fibril structures are statistically correlated with the rapidly progressive disease subtype. "The work shows that distinct clinical presentations of the disease are associated with particular packings of the amyloid beta molecules in the fibrils. Our goal is not really to develop a diagnostic procedure for the clinic. It's to try to understand something fundamental about how the disease develops."

Link: http://www.the-scientist.com/?articles.view/articleNo/47926/title/Forms-of-Alzheimer-s-May-Display-Unique-Plaque-Structures/

Osiris Green is a new clinical services business just getting underway, offering assessment of a DNA methylation biomarker of aging as a consumer product. For the customer it works much like the established consumer services for DNA sequencing that look at alleles and single nucleotide polymorphisms, such as 23andme, in that you send off a saliva sample and get back the results. DNA methylation is one of the forms of epigenetic decoration that controls the pace at which proteins are produced from their genetic blueprints, these markers constantly changing in every cell in response to circumstances and environment. For some years now patterns of DNA methylation have looked very promising as the foundation for a biomarker of aging, a way to assess biological age rather than chronological age. We age because we accumulate forms of cell and tissue damage that occur due to the normal operation of metabolism. That damage then spirals out to cause the wide variety of age-related diseases and disability, but at the base of it all we all age in the same fundamental way and for the same reasons, albeit at slightly difference paces due to our different choices and experiences. Therefore we all share the same cellular reactions to damage, and two people with much the same damage load and degree of aging should have quite similar DNA methylation patterns for at least some genes, there to be picked out from the noise of other changes.

A good biomarker of aging is an important component for the near future development of rejuvenation therapies, such as the senescent cell clearance treatments presently under development. Researchers can evaluate the effectiveness of senescent cell clearance in terms of proportion of these unwanted cells removed, and, based on the evidence showing cellular senescence to contribute to aging and age-related disease, expect to find that long-term health is improved. But how to then determine the results in terms of years of life expectancy gained as a result of that treatment? The only existing approach is to wait and see, which is expensive and time-consuming in animal studies, and out of the question for human trials. A biomarker for biological age that can be applied immediately before and immediately after an alleged rejuvenation treatment changes the entire picture of development, however. It enables a far more rapid assessment of therapies and lines of research, speeding up progress towards effective clinical treatments for the causes of aging. This is why I'm most pleased to see progress towards offering DNA methylation biomarker implementations as a paid service. Commercial development is an important part of breaking this technology out of the laboratory, getting more human data, trying different patterns, and settling upon the optimal set of genes to evaluate. I recently had the chance to talk to Neil Copes at Osiris Green and ask a few questions about this initiative and his thoughts on the industry:

Who is Osiris Green? How did you get together and decide that this was the thing to be doing in this new industry?

Currently, Osiris Green Inc. is myself and Dr. Clare-Anne Canfield, who I've known now for over two decades. Osiris Green really began in 2003 when she and I decided that extending human lifespan was the most important thing that we should be working on. We enrolled at the University of South Florida and earned our PhD's in Cell, Molecular, and Microbiology because of that decision. We officially started the company then after we graduated. By the way, the name Osiris Green isn't just a reference to Osiris, the green-faced Egyptian god of resurrection and regeneration. It's also a reference to a chapter titled "The Green Face of Osiris" in Dr. Michael West's 2003 book "The Immortal Cell," which is actually part of what initially inspired us to pursue lifespan extension in the first place.

The company began with the idea of providing customers with ways to measure various biological parameters that might correlate well with chronological age. We wanted ways for people to easily monitor their own aging at the cell and molecular level, with the idea being that these services could help in evaluating different antiaging therapies. Also, we liked the idea of building databases of anonymized user data that could let people match lifestyle parameters (diet, exercise, etc.) to trends in the molecular results. We began putting together protocols for proteomic and metabolomic profiling of blood and saliva (which closely mirrors the molecular contents of blood). We eventually developed a saliva-based proteomic profiling assay, but the cost for a single test - $200 to $500 depending on the depth of the analysis - seemed pretty prohibitive for most customers. Dr. Canfield and I started looking for faster and cheaper alternatives, which is when we began playing around with ideas for measuring gene promoter methylation. In the end I think it was a fortunate switch - DNA methylation states tend to have a tighter correlation to chronological age than other parameters, as detailed by all the excellent work coming from Steve Horvath.

How did you settle on the particular combination of genes you are testing?

We wanted a method that would be cheaper than using a genome-wide analysis or working with microarrays. I remembered a 2011 paper from Eric Vilain's lab linking chronological age with a fairly linear trend in methylation in the promoters of a small set of genes. We did a test run using just the TOM1L1 and NPTX2 promoters, which were among the top genes in the paper and fairly easy to work with from a technical standpoint. The initial results looked good so we developed the service from there.

You are forging ahead with your own implementation of part of the Horvath approach to epigenetic age; how are you validating it?

We're still a fairly small operation. So far validation has consisted of getting as much saliva as we could from friends and family members, and processing the samples. We then used CpG methylation and known chronological ages to calibrate our model. So far the linear model is estimating samples with an error of 7 years standard deviation from chronological age. The idea then is to continue performing estimates on paid samples and refining the model as necessary, even providing new estimates on older samples so that users can continue to get any refinements to their existing data as time goes on.

The Horvath and Hannum DNA methylation results have been out there for a while now. Why do you think it took so long for efforts like Osiris Green to emerge?

Because we're just now at a point as a species where real life extension is becoming a technological possibility. As such, public interest in life extension is slowly coming around. In 2003 when Dr. Canfield and I started working on our goal, the number of researchers in the field seemed disturbingly low. Since then, a decent amount of talent and funding has started flowing into lifespan research, due both to the advancing technology and to the efforts of people like Dr. Aubrey de Grey to bring awareness to the field. If this trend continues, I imagine the number of similar services as ours - and of life extension oriented companies in general - will only increase. Regardless of what happens with Osiris Green, I find it comforting that so many people and companies are now working on the problem in earnest.

Where do you see this broader field of rejuvenation research going over the next decade? Where does Osiris Green fit in to this picture?

I suspect that we'll see more clinical applications of the life extension technologies that are currently emerging. Human aging is a multifaceted problem, so the various ways to attack it are going to be diverse. I'm hoping to see things emerge like clinical trials of thymic regeneration coupled with immune system resets to eradicate anergic T cells; more and more senolytic drugs developed along with effective treatment regimens; and finally some useful age-breaker drugs making their way to market. Honestly, I'm in this for the long-haul, so I'm hoping to mold Osiris Green to help and provide services in any way that I can. In the short term, I'd like to simply expand the range of age-related markers that we can measure for customers, and to provide better and better resources for people interested in human aging.

If this works really well, and Osiris Green is flooded with customers, what is the next mountain to climb?

Oddly enough, Dr. Canfield and I have recently become fairly interested in the study of long-lived animals. Short-lived organisms, like C. elegans and Drosophila are cheap and easy to work with in a lab environment, and they make for quick experiments, but honestly they're bad models for longer-lived organisms like humans. Researchers are using these short-lived animals in an effort to extend human lives, but nature has already found ways for vertebrates to live longer natural lifespans than us. Dr. Canfield actually just finished writing a book that's a survey of the world's long-lived organisms, and the list of creatures that are relatively close to us evolutionarily is longer than most people realize. This list even includes animals like the American alligator and many species of turtle that are easily accessible in central Florida where we are located. We're currently involved with setting up a nonprofit organization for the study and conservation of long-lived species, and we're hoping that we can apply some of what we've learned from Osiris Green to build DNA methylation models for developing nonlethal ways to assess animal lifespans in the wild.

Excess visceral fat tissue is very bad for long-term health. Being obese is by some measures as harmful as a smoking habit when it comes to remaining life expectancy. Even modest amounts of excess weight have a measurable negative impact on the future trajectory of health and longevity. There is an enormous mountain of data to support these points, ranging from large human studies to simple but compelling experiments in which the surgical removal of fat from mice leads to extended life spans. Unfortunately we evolved in an environment of scarcity and so find it a challenge to stay slim in an environment of plenty; this is a high class problem to have in exchange for an end to unavoidable famine and malnutrition, but a problem nonetheless.

One of the contributing causes of degenerative aging is the growing presence of senescent cells in tissues. While investigating the effects of changes in the amount of fat tissue in mice, researchers here find evidence to suggest that some portion of the damage done by fat tissue occurs because it hosts many more senescent cells than would otherwise be present in the body. These cells produce a mix of inflammatory signals, and may well be a sizable cause of the well-known link between visceral fat and increased inflammation. Chronic inflammation alone drives a faster progression of most of the common fatal age-related conditions, and that is without considering all of the other damage done due to the signaling produced by senescent cells.

With obesity rates on the rise, more individuals are attempting to lose weight for improved health. Unfortunately, the vast majority of weight loss attempts are short-lived and are followed by weight gain. That is, for individuals that successfully achieve weight loss of at least 10%, approximately 80% will regain the weight in the first year alone. Repeated attempts at weight loss results in a phenomenon referred to as weight cycling. As global rates of obesity increase, weight cycling is becoming increasingly common. Unfortunately, clinical studies have produced conflicting results with some studies suggesting that weight cycling may decrease lifespan while others suggest that weight cycling has no negative effect. Review of these clinical studies suggests that inclusion of confounding factors, such as unintentional weight loss, likely accounts for the discrepancies and that further research is needed.

In attempts to perform a controlled animal study, our laboratory set out to evaluate the impact of lifelong weight cycling on longevity in mice. Results of this study showed that weight-cycled mice lived significantly longer than obese mice (801 vs 544 days), suggesting that periodic, repeated, weight loss attempts were preferable to no weight loss attempts in obese mice. To better understand the molecular changes that occur during weight cycling, we analyzed cellular senescence via senescence-associated β-galactosidase staining in white adipose tissue (WAT) and circulating levels of activin A, a recently identified marker of cellular senescence.

In this study and in agreement with other studies, we show that obesity induced by a high fat (HF) diet results in a significant increase in senescent cells in WAT compared to low fat (LF) controls. Circulating activin A levels were also increased in the HF group compared to the LF controls. Importantly, our data indicate that 28 days of weight loss are sufficient to significantly reduce the number of senescent cells as shown by significantly reduced activin A levels and a significant reduction in senescent beta-galactosidase stained cells in inguinal and retroperitoneal WAT depots. Of note, since inguinal and retroperitoneal WAT were the most responsive to the weight loss, there appears to be a depot specific difference in cellular senescence in response to this dietary manipulation.

Recently a comprehensive study identified activin A as a marker for cellular senescence in humans and mice. In this study, it was determined that i) human senescent fat cell progenitors release activin A, ii) activin A impedes the normal function of stem cells and fat tissue, iii) older mice have higher levels of activin A in both their blood and fat tissue than young mice, and iv) eliminating senescent cells from mice leads to lower levels of activin A. Since most procedures used to determine senescent cell accumulation require tissue collection, the discovery of a circulating marker of cellular senescence represents an important step for detection of senescent-related disease. This is particularly important in a clinical setting since blood is relatively easy to collect. Research has shown there is a correlation between obesity and increased cellular senescence, which may account for increased mortality and progression of age-related diseases. Thus, the possibility of senolytic treatment (agents that clear senescent cells), particularly in WAT, has been suggested as a potential therapeutic target. For those reasons, clearance of senescent cells in WAT with senolytic agents or, as we show here, with dietary manipulation, may be a promising approach for treatment of metabolic syndrome, type 2 diabetes, and other age-related complications.

Link: https://dx.doi.org/10.3233/NHA-1614

The present candidate senolytic drugs that produce selective destruction of senescent cells, done as a means to prevent their contribution to the aging process, all arrive from the cancer research community, where they have been tested for their ability to destroy cancerous cells. Piperlongumine is no exception. Here researchers explore more its likely mechanisms, with a focus on the outcome of increased oxidative stress in the cell due to reduced levels of the antioxidant glutathione, among other possibilities. Recent research suggests, however, that increased oxidative stress isn't the mechanism by which cells are pushed into self-destruction by piperlongumine. While adding new information, the research noted below - there is an open access paper in addition to the publicity materials - doesn't greatly clarify the uncertainty over the way in which piperlongumine works, nor does it clarify whether the method is the same for cancerous and senescent cells. Like many drugs, piperlongumine influences a large number of distinct processes in the cell, and there is no comprehensive map of outcomes. The reason why it is interesting as a potential senolytic therapy, versus other cancer drugs where the mechanisms of action are better mapped, is that it has far fewer side-effects in comparison.

Scientists have uncovered the chemical process behind anti-cancer properties of a spicy Indian pepper plant called the long pepper, whose suspected medicinal properties date back thousands of years. The secret lies in a chemical called piperlongumine (PL), which has shown activity against many cancers. Using x-ray crystallography, researchers were able to create molecular structures that show how the chemical is transformed after being ingested. X-ray crystallography allows scientists to determine molecular structures that reveal how molecules interact with targets - in this case how PL interacts with a gene called GSTP1. Viewing the structures helps in developing drugs for those targets. PL converts to hPL, an active drug that silences GSTP1. The GSTP1 gene produces a detoxification enzyme that is often overly abundant in tumors. "We are hopeful that our structure will enable additional drug development efforts to improve the potency of PL for use in a wide range of cancer therapies."

Glutathione S-transferase pi 1 (GSTP1), is frequently overexpressed in cancerous tumors and is a putative target of the plant compound piperlongumine (PL), which contains two reactive olefins and inhibits proliferation in cancer cells but not normal cells. PL exposure of cancer cells results in increased reactive oxygen species and decreased glutathione (GSH). This data in tandem with other information led to the conclusion that PL inhibits GSTP1, which forms covalent bonds between GSH and various electrophilic compounds, through covalent adduct formation at PLs C7-C8 olefin, while PLs C2-C3 olefin was postulated to react with GSH. However, direct evidence for this mechanism has been lacking.

To investigate, we solved the x-ray crystal structure of GSTP1 bound to PL and GSH to rationalize previously reported structure activity relationship studies. Surprisingly, the structure showed a hydrolysis product of PL (hPL) was conjugated to glutathione at the C7-C8 olefin, and this complex was bound to the active site of GSTP1; No covalent bond formation between hPL and GSTP1 was observed. Mass spectrometric (MS) analysis of reactions between PL and GSTP1 confirmed that PL does not label GSTP1. Moreover, MS data also indicated that nucleophilic attack on PL at the C2-C3 olefin led to PL hydrolysis. Although hPL inhibits GSTP1 enzymatic activity in vitro, treatment of cells susceptible to PL with hPL did not have significant anti-proliferative effects, suggesting hPL is not membrane permeable. Altogether, our data suggest a model wherein PL is a prodrug whose intracellular hydrolysis initiates the formation of the hPL:GSH conjugate, which blocks the active site of and inhibits GSTP1 and thereby cancer cell proliferation.

Link: http://www.utsouthwestern.edu/newsroom/news-releases/year-2017/jan/anticancer-plant-westover.html

Every year Edge runs an annual question, publishing a few hundred short responses from noted scientists and other thinkers. A number of the folk who run companies or otherwise make waves relating to the development of therapies to treat aging are in this list, so it is usually interesting to see what they have to say. These year, awareness of the prospects for aging to be treated as a medical condition appears to be spreading, as it is mentioned in passing in a number of responses beyond the two linked below. The question for this year is "What scientific term or concept should be more widely known?", but that is somewhat beside the point; it is just a prompt to encourage people to riff on whatever their particular areas of interest might happen to be at the moment.

The two people I pulled from the crowd for this post are Gregory Benford, who is now well underway on his third notable career, this time as a biotechnologist focused on the use of drugs to adjust epigenetics in aging, and Aubrey de Grey of the SENS Research Foundation, who should need little introduction to this audience. These are representative figures from the two sides of a very important divide in the research and development of therapies to treat aging. On the one side we have attempts to modestly slow the pace of aging and onset of age-related disease through drugs, largely attempting to mimic existing natural effects that enhance longevity, such as calorie restriction, exercise, or the outcome of selective breeding to postpone reproduction. This is strongly associated with ongoing efforts to map the biochemistry of aging at the detail level, such as epigenetic and other changes in cellular biochemistry and signaling: greater coverage of the map is needed in order to make progress. On the other side we have efforts like the SENS rejuvenation research portfolio, in which the existing long-established identification of the root cause molecular damage of aging is used as the guide to work towards therapies that can repair that damage, thus turning back aging. The more comprehensive the repair, the more that aging should be halted or reversed.

The difference between these two approaches is night and day. Mapping the biochemistry of cells is enormously expensive and slow, and even a perfect replication of the biochemistry of calorie restriction - something that will be very, very hard to achieve at our present level of technology - will do comparatively little for human longevity, even though it would be very beneficial for overall health. We know this because calorie restriction practitioners don't live very much longer than the rest of humanity. If the effect was as large as it is in mice - 40% or so - it would have been discovered in antiquity. On the other hand SENS-style damage repair therapies are comparatively cheap to build, and produce more reliably beneficial outcomes, as illustrated by present development of senescent cell clearance approaches. They don't require anywhere near as much expensive, time-consuming new research in order to guide this development. Collectively, the effects on human life span will be determined by the effectiveness of the repair, with what should be very high upper limits if started early enough in life. The essential opposition of these two approaches is highlighted in the commentaries below, independently and sight unseen on the part of the authors.

Gregory Benford: Antagonistic Pleiotropy

Aging comes from evolution. It isn't a bug or a feature of life; it's an inevitable side effect. Exactly why evolution favors aging is controversial, but plainly it does; all creatures die. It's not a curse from God or imposed by limited natural resources. Aging arises from favoring short-term benefits, mostly early reproduction, over long-term survival, when reproduction has stopped. Thermodynamics doesn't demand senescence, though early thinkers imagined it did. Similarly, generic damage or "wear and tear" theories can't explain why biologically similar organisms show dramatically different lifespans. Most organisms maintain themselves efficiently until adulthood and then, after they can't reproduce anymore, succumb to age-related damage. Some die swiftly, like flies, and others like we humans can live far beyond reproduction.

In 1957 George Williams proposed the theory called antagonistic pleiotropy. If a gene has two or more effects, with one beneficial and another detrimental, the bad one exacts a cost later on. If evolution is a race to have the most offspring the fastest, then enhanced early fertility could be selected even if it came with a price tag that included decline and death later on. Because ageing was a side effect of necessary functions, Williams considered any alteration of the ageing process to be impossible. Antagonistic pleiotropy is a prevailing theory today, but Williams was wrong: we can offset such effects. Wear and tear can be countered. Wounds heal, dead cells get replaced, claws regrow. Some species are better at maintenance and repair. Some pursued this by deliberately aging animals, like UC Irvine's Michael Rose. Rose simply didn't let fruit fly eggs hatch until half each fly generation had died. This eliminated some genes that promoted early reproduction but had bad effects later. Over 700 generations later, his fruit flies live over four times longer than the control flies. These Methuselahs are more robust than ordinary flies and reproduce more, not less, as some biologists predicted. I bought these Methuselah flies in 2006 and formed a company, Genescient, to explore their genetics. We discovered hundreds of longevity genes shared by both flies and humans. Up-regulating the functioning of those repair genes has led to positive effects in human trials. So though aging is inevitable and emerges from antagonistic pleiotropy, it can be attacked. Recent developments point toward possibly major progress.

Aubrey de Grey: Maladaptation

Many years ago, Francis Crick promoted (attributing it to his long-time collaborator Leslie Orgel) an aphorism that dominates the thinking of most biologists: "Evolution is cleverer than you are." This is often viewed as a more succinct version of Theodosius Dobzhansky's famous dictum: "Nothing in biology makes sense except in the context of evolution." But these two observations, at least in the terms in which they are usually interpreted, are not so synonymous as they first appear. Most of the difference between them comes down to the concept of maladaptation. A maladaptive trait is one that persists in a population in spite of inflicting a negative influence on the ability of individuals to pass on their genes. Orgel's rule, extrapolated to its logical conclusion that evolution is pretty much infinitely clever, would seem to imply that this can never occur: evolution will always find a way to maximize the evolutionary fitness of a population. It may take time to respond to changed circumstances, yes, but it will not stabilize in an imperfect state. And yet, there are many examples where that is what seems to have occurred. In human health, arguably the most conspicuous case is that the capacity to regenerate wounded tissues is lost in adulthood (sometimes even earlier), even though more primitive vertebrates (and, to a lesser extent, even some other mammals) retain it throughout life.

Why is this so important to keep in mind? Many reasons, but in particular it's because when we get this wrong, we can end up making very bad evaluations of the most promising way to improve our health with new medicines. Today, the overwhelming majority of ill-health in the industrialized world consists of the diseases of late life, and we spend billions of dollars in the attempt to alleviate them - but our hit rate in developing even very modestly effective interventions has remained pitifully low for decades. Why? It's largely because the diseases of old age, being by definition slowly-progressing chronic conditions, are already being fought by the body to the best of its (evolved) ability throughout life, so that any simplistic attempt to augment those pre-existing defenses is awfully likely to do more harm than good. The example I gave above, of declining regenerative capacity, is a fine example: the body needs to trade better regeneration against preventing cancer, so we will gain nothing by an intervention that merely pushes that trade-off away from its evolved optimum.

Fibrosis is a form of scarring, important in many medical conditions, notably those of the liver, and a process that increases in many internal organ tissues with advancing age. Inappropriate levels of cellular construction of fibrotic structures disrupts the proper function of tissues, leading to dysfunction and disease. Researchers here look into the underlying mechanisms driving that age-related increase in fibrosis, and suggest that the problem lies in a reduced ability to clear out fibrosis rather than an increased tendency to generate these structures in response to damage. The researchers point to the presence of cross-links as one possible contributing cause for that change, which is yet another reason to push for greater support of efforts to produce therapies to clear cross-links.

Liver fibrosis results from a sustained wound healing response due to chronic liver injury and occurs when extracellular matrix (ECM) production exceeds ECM degradation. Activated hepatic stellate cells (aHSCs) are the main cells involved in fibrogenesis as the key source of ECM compounds and a major modulator of hepatic inflammation. Next to aHSCs, the hepatic macrophages also promote fibrosis progression by driving HSCs activation, by releasing pro-inflammatory and pro-fibrogenic factors and by supporting the infiltration of pro-fibrogenic immune cells. Liver fibrosis reversibility has been documented for several years. In animal models, liver damages reverse and fibrotic scar degradation occurs when the hepatotoxic agent is removed or when a normal biliary outflow is restored after common bile duct ligation. Evidences of fibrosis regression come also from clinical practice, especially after the arrival of new anti-viral therapies enabling high rate of hepatitis C virus (HCV) eradication. During fibrosis resolution, aHSCs disappear by senescence, inactivation or apoptosis while inflammatory and pro-fibrogenic macrophages differentiate into pro-resolution cells able to secrete large quantities of fibrolytic matrix metalloproteinases (MMP) and anti-inflammatory cytokines.

The human liver is affected by aging. It manifests by a reduced volume and blood flow as well as by cellular changes such as increased oxidative stress, decreased number and dysfunction of mitochondria, accelerated cellular senescence and decreased regenerative ability. Aging is also a risk factor for several specific hepatic diseases. In non-alcoholic fatty liver disease (NAFLD), evolution from simple steatosis to steatohepatitis and fibrosis occurs more frequently in old patients. In HCV chronic infection, age at time of infection is a strong determinant of fibrosis progression. Although those data emphasize the susceptibility due to aging to develop more severe disease and significant fibrosis, the mechanisms underlying this propensity are not fully understood. In viral hepatitis, an impaired immune response against foreign antigens may explain a different immunopathogenesis in the elderly and more sustained hepatic fibrotic process. In rodents, a more severe fibrosis is also observed in older animals but mechanisms remain debated. Aging-dependent hepatic susceptibility to toxic agents, reduced ECM proteins degradation and variation in inflammatory cells infiltrating the injured liver are discussed as differences in rodent genetic strains may explain at least partially divergent results. Interestingly, evidence points to a quantitatively different ECM turnover according to the age of rat models. Indeed, type I and II collagen turnover was significantly reduced in old compared to young animals, while type IV and V collagen and biglycan degradation biomarkers were significantly upregulated in old rats.

In this work, we reproduced a higher susceptibility to fibrosis in old mice compared to young mice after repetitive administrations of carbon tetrachloride (CCl4). A single dose of CCl4 disrupts hepatocytes integrity that wound healing processes tend to restore. In case of repeated exposures, recurrent profibrotic stimulation occurs prior to the resolution of the previous healing round. In our study, Collagen I and alphaSma mRNA were significantly upregulated in treated groups compared to controls but no difference was observed between age-groups, mitigating the role of variable fibrogenic processes in the severity of ECM deposition. Rather, this is in favor of an equal propensity to initiate profibrotic events in response to a toxic injury.

MMPs are involved both in fibrosis progression and resolution through their ability to degrade virtually all compounds of the ECM. The capacity of the liver to resorb scar or in the contrary to "preserve" the pathologic matrix accumulated after injury will depend on the balance between MMPs and their respective inhibitors. Among all MMPs, MMP-13 is the main interstitial collagenase in rodents and largely involved in fibrosis resolution. We observed a strong induction of Mmp13 gene expression in young mice at peak of fibrosis while old mice expressed significantly less Mmp13 mRNA. No difference was noticed concerning tissue inhibitor metalloproteinases (TIMPs) expression suggesting that the balance MMP/TIMP was overtly tilted in favor of matrix degradation in young mice but less so in old ones. This was confirmed by the nearly complete clearance of scar matrix in young animals 4 days after the last toxic injection while virtually no remodeling occurred in old mice, and by the reduced collagenolytic activity in this last group.

We demonstrated a higher proportion of thick and dense collagen fibers in old mice as well as an enhanced expression of the enzymes involved in collagen maturation changes. There are features that limit fibrosis remodeling: old, pauci-cellular, thick and heavily cross-linked septae resist proteases degradation. More than biochemical impact on matrix fibrils, cross-linking enzymes support also HSCs activation by maintaining a stiff environment and may have immunomodulatory functions in liver fibrosis influencing the changes in balance between fibrogenesis and fibrolysis.

To date, no antifibrotic therapy exists besides the suppression of the causative agent. Our work, demonstrating that liver fibrosis is less prone to reverse in old animals, has several clinical implications. First, impact of aging on reduced ability for fibrosis degradation may partially explain some disappointing results of antifibrotic agents in clinical trials while promising when preclinically tested. Indeed, pre-clinical studies usually use young animals (6-8 weeks old) while patients concerned by treatment classically suffer from fibrosis that has developed over decades rather than weeks in animals. Secondly, our study highlights the importance to target the correct underlying processes in the perspective of an effective therapy. Based on our results, this target may be different according to the age of the patients, and therapies supporting the fibrolysis or opposing the cross-linking of the matrix might be of particular interest in an old population.

Link: http://dx.doi.org/10.18632/aging.101124

More than a decade after the SENS view of the causes of aging was first assembled, the noted Hallmarks of Aging paper attempted another catalog of the important processes of aging. There is some overlap between the two, though I'd categorize portions of the Hallmarks of Aging list as secondary or later processes in aging, not primary causes, and thus poor targets for intervention. In both cases the aim of putting together such a list is to treat aging as a medical condition, though the Hallmarks of Aging authors were much more oblique when it came to stating the end goal of extended healthy human life spans, something that continues to be an issue in many parts of the research community. The goal of medical control over aging and radical extension of healthy life spans is important and desirable, and the failure of much of the scientific community to clearly say as much is why we need advocacy organizations like the SENS Research Foundation and Life Extension Advocacy Foundation, the latter of which is revamping their web presence at the moment. Among the new content going up at the Life Extension Advocacy Foundation site is this tour of the Hallmarks of Aging outline, explained for laypeople:

According to modern science, aging is the accumulation of damage that the body cannot completely eliminate, due to the imperfections of its protection and repair system. As a result, bodily functions start to deteriorate, leading ultimately to the development of age-related diseases. Aging comprises of a number of distinct and interconnected processes which we will explore briefly. Once you begin to understand the processes of aging it becomes possible to understand the ways we might intervene against them in order to treat and prevent age-related diseases, hence enabling people to live healthier lives for longer.

Genomic instability is considered one of the main causes of aging. Somatic cells are constantly exposed to a range of sources of DNA damage. When DNA is damaged, some proteins can stop being produced or can have the wrong shape, which, in turn, compromises the function of the cell. When there are many cells with this kind of damage in the organ, some important body functions can start to deteriorate. DNA damage during aging appears to be a stochastic process. However, chromosomal regions such as the telomeres have a somewhat more predictable pattern of deterioration. Telomere loss is technically a subset of genomic instability but warrants its own category as a form of aging damage due to this more predictable nature. Telomeres are a protective cap at the end of a chromosome. Each time a cell divides, telomeres get increasingly shorter and once they become critically short the cell ceases to divide and enters replicative senescence, better known as the Hayflick limit. Importantly, as telomeres shorten they influence the gene expression profile (the production of proteins) of a cell changing it from a functionally young one to an old one.

Changes to gene expression patterns (deactivation of useful genes and activation of potentially harmful ones) are a key influence in aging. Generally speaking, these changes (known as epimutations) lead to detrimental changes in gene expression patterns. Epigenetic alterations are a complex and not fully understood process. They can be considered almost like a program in a computer, but in this case it is the cell, not the computer, being given instructions. Ultimately these changes contribute to the cell moving from an efficient "program" of youth to a dysfunctional one of the old age. However the process appears to be plastic and is not the one-way process people once assumed. Indeed recent research shows that epigenetic alterations can be made to reverse this process of aging to restore youthful function and increase lifespan.

Proteostasis is the process by which cells control the abundance and folding of the proteins - building blocks of each cell. Proteostasis consists of a complex network of systems that integrates the regulation of gene expression, signaling pathways, molecular chaperones and protein degradation systems. Aging is linked to the impairment of proteostasis and the various quality control systems it incorporates. Even during regular operation misfolding of proteins can occur and they are immediately broken down and recycled. However with aging and the decline of proteostasis misfolded proteins increase and lead to aggregation.

The scientific evidence to date suggests that anabolic signaling (internal alarm about the abundance of nutrients) appears to accelerate aging, and that decreased nutrient signaling is shown to extend lifespan. We see from experiments that adjusting signalling using substances like rapamycin to mimic limited nutrient availability can increase lifespan in mice. Consistent with deregulated nutrient sensing, we see that dietary restriction increases lifespan in various species. There is also increasing evidence for the healthspan benefits of dietary restriction in humans.

Mitochondria are the "power plants" of the cells: they convert the energy-rich nutrients into energy store molecules that directly power the biochemical reactions in the cell. Unlike any other part of the cell, mitochondria have their own DNA (mtDNA), especially vulnerable to damage from free radicals. A free radical strike to the mtDNA can cause deletions in its genetic code, destroying the mitochondria's ability to make proteins that are critical components of their energy-generating system. Without the ability to produce cellular energy the normal way, these damaged mutant mitochondria enter into an abnormal metabolic state to survive. This state produces little energy, and generates large amounts of waste that the cell cannot metabolize. Strangely, the cell favours keeping these defective, mutant mitochondria, while recycling normal ones. Whilst this only happens to a few cells in our body, these cells do a large amount of damage to the body as a whole.

As the body ages, increasing amounts of cells enter a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful signals known collectively as the senescent associated secretory phenotype (SASP). Senescent cells normally destroy themselves via a programmed process called apoptosis and they are removed by the immune system. However, the immune system weakens with age, increasing numbers of these senescent cells escape this process and build up. By the time people reach old age significant numbers of these senescent cells have accumulated in the body and cause havoc, driving the aging process further and increasing the risk of diseases.

Every day, our cells are damaged. Some of these damaged cells are successfully repaired and keep serving the body. Others are either completely destroyed via apoptosis, or become dysfunctional and enter a 'senescent' state where they can no longer divide. Some of these lost cells are replaced from reserves of tissue-specific stem cells, but the aging process makes these stem cell pools less effective at repairs over time, and eventually those reserves run out. Over the passage of time, long-lived tissues, such as those in the brain, heart, and skeletal muscles, begin to progressively lose cells, and their function becomes increasingly compromised. Muscles weaken, and don't respond to exercise. The brain loses neurons, leading to cognitive decline and dementia. Ultimately the loss of reserves of replacement cells leads to the failure of tissue repair and is a significant driver of aging.

Aging causes changes to communication outside of the cell, which ultimately affects the function of all cells and tissues. Cellular communication has endocrine, neuroendocrine or neuronal origins. One of the best known age-related changes in intercellular communication is chronic inflammation (often called 'inflammaging'), which implies an increasingly rising background level of inflammation as we age. In addition to inflammatory signals, the so called bystander effect, in which senescent cells induce senescence in neighboring cells through the toxic signals they give off, is also a part of altered intercellular communication.

A suspected cause of degenerative aging is the accumulation of sugary metabolic wastes known as advanced glycation end-products (AGEs). These are wastes that are in some cases hard for our metabolism to break down fast enough or even at all. Some types, such as glucosepane, can form cross-links, gumming together important proteins like those making up the supporting extracellular matrix scaffold. The properties of elastic tissues (skin and blood vessel walls) derive from the particular structure of the extracellular matrix, and cross-links degrade that structure, preventing it from functioning correctly. AGE presence contributes to blood vessel stiffening with age, and is implicated in hypertension and diabetes.

Link: http://dx.doi.org/10.1016/j.cell.2013.05.039

The last SENS rejuvenation research fundraiser of 2016 ended a couple of days ago, with the donations from hundreds of supporters going to the SENS Research Foundation in order to support ongoing scientific programs aimed at bringing an end to aging. Aging is a medical condition with root causes, just like any other, and effectively addressing those causes will allow degenerative aging to brought under control, halted, and reversed. That is the difference between the medicine of yesterday, which didn't have any great impact on the causes of aging, and the medicine of tomorrow, which will. Still, it isn't a sure thing for any specific time frame: most of the relevant areas of research, and the researchers involved, need a lot of help to overcome the technical hurdles and lack of funding endemic in early stage scientific endeavors. That is why we need organizations like the SENS Research Foundation, working to remove roadblocks and fund the areas of great scientific promise, but that are largely neglected by the mainstream. It is why we need grassroots, popular support for rejuvenation research, both to sustain these organizations and to light the way - with donations, discussion, and advocacy - for the more conservative wealthy philanthropists and foundations involved in the support of medical research. The more we help ourselves in the matter of aging research, the more additional help will arrive.

I'm pleased to note that, thanks to the many generous donors and those who put up challenge funds to match donations, $300,000 was raised in the main fundraiser over the course of November and December: $150,000 from donors and $150,000 from a matching fund provided by the Forever Healthy Foundation. In addition a little over $60,000 was pledged as monthly donations to be made over the next year by new SENS Patrons: $30,000 from donors and $30,000 from a challenge fund assembled by Josh Triplett, Christophe and Dominique Cornuejols, and Fight Aging! The SENS Research Foundation hasn't yet updated their site for the last minute donations from December 31st, but those numbers won't change too much. This is on top of the $70,000 raised through a crowdfunding project earlier in the year to support the OncoSENS work: scanning for drug candidates capable of suppressing alternative lengthening of telomeres, which is one half of a universal cancer therapy based on blockade of telomere lengthening. Of course, SENS Project|21 also launched in 2016, founded with a $10 million pledge from Michael Greve of the Forever Healthy Foundation. All in all it was a banner year for SENS Research Foundation funding. The enthusiastic support of our community over the years has helped build up to this, one donation, one act of advocacy, one conversation at a time. Every contribution helps, and many hands make light work.

For my part, while we didn't hit the $72,000 goal for SENS Patron pledges, the amount contributed and the number of people willing to sign up for monthly donations ensures that we'll be trying this again. Patronage is of course as old as science, and the SENS Research Foundation is definitely powered by the patronage of wealthier individuals like Aubrey de Grey, Peter Thiel, and Jason Hope. Until last year, however, the SENS Research Foundation fundraisers didn't do much with the newer crowdfunded patronage models for philanthropy by everyday individuals: collaborating to support the sciences with many modest donations. There is precedent. The very successful Methuselah 300 group provided the funds needed for much of the early success of the Methuselah Foundation, but that initiative stayed with the Methuselah Foundation when SENS rejuvenation research spun off into the SENS Research Foundation, even though the 300 donations continue to fund SENS research programs as they did before the split. I'd like to see some of that recaptured in the form of SENS Patrons, hundreds of people making a meaningful difference not just with their donations, but also because they are a very visible sign of material support and enthusiasm. The phenomenon known as social proof is a significant factor in whether wealthier philanthropists commit to an organization. Much as we'd like everyone to be perfectly rational about aging and rejuvenation research, those with the most to give are also the most conservative in the causes they support. They usually follow the crowd, or to be more charitable, rely on the analysis provided by the members of that crowd.

In any case, onward and upward! The trajectory of these fundraisers is heading upward if you look at the history: $60,000 in 2013, $150,000 in 2014, $250,000 in 2015, $360,000 in 2016. In each of these years, I can honestly say I had no idea how to reach that target; it seemed at the time an impossible mountain. Yet you, the readership here at Fight Aging! and the broader community beyond, rose to the challenge. Only this year were there times when it seemed donor exhaustion had set in, and generous individuals stepped in at several points to kickstart things with a timely five-figure donation. There is only so much that any one community can give in support of even the most vital cause without first growing in size; all along, bringing the ideas of rejuvenation biotechnology to new audiences, to gain new supporters, was as much the point as raising funds in these initiatives. This is still the case. So something to add to your resolutions for 2017: talk to someone new about the SENS Research Foundation and the prospects for reversing aging in our lifetime. You never know where it might lead.

There are two important battles in the matter of aging research. The first is to convince people that aging should be treated as a medical condition at all. This has, finally, largely been won within the scientific community, or at least those parts of it that matter, but is still very much an ongoing concern when it comes to the public and potential sources of large-scale funding. The second battle is between the classes of theory of aging that determine what types of therapy should be developed. On the one hand there is the prevailing majority view of aging as the result of accumulated molecular damage to cells and tissues, that in turn produces all sorts of further harm and reactions in cellular behavior. That means therapies should aim to repair that damage, though, sadly, most researchers who hold to the damage theories of aging are in fact more focused on therapies that only slow down the rate at which damage accumulates. On the other hand, there is the growing minority view of aging as an evolved program in which epigenetic changes cause changes in cellular behavior that in turn lead to the accumulation of damage. There is a lot of debate within the programmed aging community as to the nature of this program and its relationship with evolutionary theories on aging, but regardless of that, the basic concept implies that repair of damage is marginal and therapies should try to revert epigenetic changes that occur with age, such as via the use of drugs or gene therapies to alter cell behavior.

So we have two views of aging that stand in opposition to one another because the strategy for development of therapies that emerges from each is opposed. The yet-to-be-developed therapies thought to be effective in one paradigm are expected to be marginal in the other - and that matters greatly for those of us likely to age to death if the wrong lines of development come to dominate the field for too long. If you think that damage is the first cause of aging, then tinkering with epigenetics is evidently going to do little good. If you think that epigenetic changes are the first cause of aging, then repairing the damage without changing cellular operations is not the way to go. Interestingly, I think that the past decade of growth in publications and discussion of programmed aging has its roots in changes outside the scientific community; that it has a lot to do with the widespread adoption of automated translation technologies, as these have enabled closer ties between the Russian and English language aging research communities and their supporting network of advocates and funding sources. The Russian aging research community is much more in favor of programmed aging, and provides the necessary critical mass of thought and work to bring programmed aging to a larger audience in the English-language community.

For my part, I think that the best argument against programmed aging is that there are forms of metabolic waste that the body cannot effectively break down. Components of lipofuscin and glucosepane cross-links for example. You can change all the epigenetics you want, assuming a way can be found to force cells into a replica of their youthful state, but that won't enable them to clear out that harmful waste. Further, there is plentiful evidence for higher levels of these metabolic waste compounds to contribute directly to age-related pathologies, and it would be hard to postulate a way for that to happen with it also producing epigenetic changes in cells. These two points interact to strongly suggest that programmed aging is incorrect. I'm also of the mind that this debate will be settled fairly conclusively within the next decade, as the first therapies resulting from both sides are deployed. My expectation is that efforts to repair damage will produce robust rejuvenation and that efforts to restore youthful epigenetic patterns and signaling in cell environments will, where successful, produce results that look a lot like those achieved via stem cell therapies to date - putting damaged cells back to work, but not repairing underlying causes of aging. Regeneration, to some degree, but not rejuvenation. These are quite different outcomes, and should be clearly distinct from one another once biomarkers of aging are used in their assessment. At the moment, however, I suspect there is a quite of lot of confusing regeneration for rejuvenation taking place.

Twenty years ago, I first started writing that aging is something the body does to itself, a body function, rather than deterioration or loss of function. Journals would not even send my submission out for peer review. The conflict with prevailling evolutionary theory was just too deep. But in the interim, the evidence has continued to pile up, and many medical researchers have taken the message to heart in a practical way, setting aside the evolutionary question and just pursuing approaches that seem to work. The most promising developments in anti-aging medicine involve changing the signaling environment rather than trying to "fix what goes wrong" with the body.

My popular book exploring the evolutionary origins of aging (and implications for medical science) came out in June, and an academic version of the same content came out in October. Gandhi taught me, "First they ignore you, then they laugh at you, then they fight you, then you win." The paradigm of programmed aging passed this year from stage 2 to stage 3, with prominent articles arguing against the possibility of programmed aging. Current Aging Sciences devoted a full issue to the question. I welcome the discussion. This is a debate that colleagues and I have sought to initiate for many years. There are powerful theoretical arguments on one side, and diverse empirical observations on the other. The scientific community will eventually opt for empiricism, but not until theory digs in its heels and fights to the death. A basic principle of evolution is at stake, and many theorists will rise to defend the basis of their life work; but a re-evaluation of basic evolutionary theory is long overdue. The idea that fitness consists in reproducing as fast as possible is no longer tenable. For plants, this may be approximately true. But animal populations cannot afford to reproduce at a pace faster than the base of their food chain can support. Animals that exploit their food supply unsustainably will starve their own children, and there is no evolutionary future in that. This is a principle that links together entire ecologies, and the foundation of evolutionary theory will have to be rewritten to take it into account.

For many years, I put forward the argument that programmed aging means there are genes that serve no other purpose than to hasten our death, and that medical research should be targeting the products of those genes. But in recent years, epigenetics has eclipsed genetics as the major theme in molecular biology. Everything that happens in the body is determined by which genes are expressed where and when. The vast majority of our DNA is devoted not to coding of proteins but to promoter and repressor regions that control gene expression with exquisite subtlety. There has been a growing recognition of aging as an epigenetic program. As we get older, genes that protect us are dialed down, and genes for inflammation and apoptosis are dialed up so high that healthy tissue is being destroyed. Many epigenetic scientists have discovered this, and they find it natural to see aging as a programmed phenomenon.

A few years ago, I wrote about transcription factors as the key to aging. At first blush, it seems that an epigenetic program is just as amenable to pharmaceutical intervention as a genetic program. Transcription factors bind to DNA and turn whole suites of genes on and off in a coordinated way. This summer, I had a chance to work in a worm genetics lab and consult closely with people who know the experimental details. I learned that there is no clear line between functional proteins and transcription factors, that many proteins have multiple functions, and that metabolites feed back to control gene expression. I still believe that there are one or more aging clocks that inform the body of an age-appropriate metabolic state, and synchronize the aging of different systems. Telomere length is one such clock. If we can reset an aging clock, the body will repair and clean itself up. If we can reset several clocks, the body may be able to restore itself to a younger state. But I recognize the possibility that the clock is diffused through the detailed epigenetic status of a trillion cells, and may be beyond the reach of foreseeable technology. Short of resetting the aging clock, there are several technologies just over the horizon that should offer substantial life extension benefit. I believe the best prospects are senolytics (ridding the body of senescent cells), telomerase activators (rejuvenating old stem cells), and adjusting blood levels of key hormones and cytokines that increase or decrease with age.

Link: http://joshmitteldorf.scienceblog.com/2016/12/31/epigenetics-and-the-direction-of-anti-aging-science/

Exercise helps to slow the age-related loss of muscle mass and strength known as sarcopenia, something we should all bear in mind as we age. This open access paper reporting on a study of exercise and aging in mice is one of a number to provide evidence on this topic. Beyond helping to slow the onset of physical frailty, exercise also improves numerous other aspects of our cellular biochemistry and organ function over the long term. There is no available medical technology, as yet, that can do anywhere near as much for overall health, and thus it is a very good idea to put in the effort to make and maintain good lifestyle choices as best as possible while we await the arrival of future rejuvenation therapies. A few years here or there might make the difference between living to benefit from these technologies or missing out.

In men and women, the annual rate of muscle mass loss is reported as approximately 0.9 and 0.7%, respectively, after the age of 75 years. Sarcopenia can be greatly accelerated by physical inactivity and poor nutrition, and loss of function is more pronounced in the muscles of the lower limbs. Sarcopenia can result in severe muscle weakness and contributes to frailty, reduced mobility, diminished independence, and an increased susceptibility to falls and fractures, with escalating costs to the global healthcare system. Resistance exercise is an effective intervention used to counteract the detrimental effects of sarcopenia. In humans aged 60 years and older, marked gains in strength, muscle mass, functional mobility, muscle protein synthesis, and mitochondrial function have been observed after progressive resistance training programs that range from 8 weeks to 1 year. These studies provide evidence that elderly men and women (including nonagenarians) are physiologically capable of adapting to progressive loading, and in some instances have reported relative gains in muscle strength and mass that are comparable to younger individuals and between sexes.

Voluntary wheel running (endurance or aerobic exercise) is often used to monitor the long-term benefits of exercise, with rodent models being widely used due to their relatively short lifespan; a 24-month-old mouse is considered roughly equivalent to a 70-year-old human. Although an age-related decline in voluntary wheel running is well documented in mice and rats, relatively small amounts of physical activity can have many benefits. Beyond the protection of muscle mass, long-term voluntary wheel running has a variety of physiological benefits including decreased weight gain, restoration of neuromuscular junction (NMJ) architecture, and preserved muscle innervation, increased mitochondrial biogenesis and autophagy, improved oxygen uptake (VO2 max), and the overall metabolic enhancement of the skeletal muscle. Investigations in young men and elderly women (aged 22 to 75 years) show that combined resistance and endurance training can contribute to greater gains in muscle strength and/or mass, compared with endurance exercise alone. Whether resistance exercise (with progressive loading of voluntary wheel running) can increase the hypertrophic potential of aging muscles has not been thoroughly tested in rodents.

The present study investigates the effect of 34 weeks of voluntary resistance wheel exercise (RWE) initiated from mid-life (15 months of age) on skeletal muscle mass and function in male and female C57BL/6J mice (aged 23 months). Overall, our data show that the introduction of resistance wheel running from middle age was effective in preventing sarcopenia in the hindlimb muscles of both male and female mice. Specifically, weights of the exercised quadriceps, gastrocnemius, and EDL muscles at 23 months were maintained at values similar to 15 months, while mass of the soleus muscles increased. The maintenance of muscle mass into old age was accompanied by striking changes to morphological and molecular parameters of the muscles, including myofiber size and type, with some increased markers of mitochondrial and autophagic activity. Since exercising muscles produce many factors with systemic effects, it is possible that other tissues may subsequently feedback and contributes (indirectly) to the prevention of sarcopenia, by exercise. This study shows that aging mice of both sexes have a good capacity for such resistance exercise and that this exercise helps to maintain healthy old muscles.

Link: https://dx.doi.org/10.1186/s13395-016-0117-3