Fight Aging!

Regular readers will be at least passingly familiar with the commercial development of mitochondrially targeted antioxidant compounds that has taken place over the past decade. This initially attracted attention in this community because the evidence suggests that these molecules can modestly slow the progression of aging, though unfortunately not to the same degree as interventions like calorie restriction, which to my eyes at least means that serious life extension efforts are better directed elsewhere. The furthest advanced of these mitochondrially targeted antioxidants is the SkQ series of plastinquinones, currently being developed as a treatment for a few different conditions by Mitotech. It turned out that the effects on inflammatory eye conditions were considerably larger than the effects on aging, so that is the direction presently taken. Another of the compounds under development by a different set of researchers is SS-31; you'll find an introduction in the Fight Aging! archives. In the paper noted below, SS-31 is used to demonstrate that reducing oxidative stress in muscle cells doesn't slow the age-related loss of muscle mass and strength known as sarcopenia. This is a nice piece of work that might help focus future research efforts in more productive directions.

Given that straightforward antioxidants of the sort purchased in a supplement store either do nothing for health and aging or actually somewhat harm long term health, why would be expect antioxidants targeted to the mitochondria within the cell to be a different proposition? It helps to start by noting that the roles of oxidative molecules and antioxidants in the cell are manifold and complicated. Oxidative molecules cause damage by reacting with important protein machinery, but they are also used as signals. Too much is bad, and too little is bad. Exactly where there is too much or too little is also of great importance. Globally suppressing oxidative signaling via high levels of ingested antioxidants has negative effects like blocking the benefits of exercise, which depend upon that signaling. Mitochondria are central to all discussions of oxidative signaling, as they generate oxidative molecules as a result of their primary role as power plants, supplying energy store molecules to power the cell. Many of the genetic alterations and other interventions that modestly slow aging in laboratory species change mitochondrial function, either increasing or reducing the flux of oxidative molecules.

There are several likely ways in which altered mitochondrial output of oxidative molecules can affect long term health, that alteration achieved either by changing the rate at which such molecules are created, or by applying targeted antioxidants that soak them up immediately. Firstly there is hormesis: a slightly higher than usual output and the resulting damage can trigger greater and lasting repair and maintenance activities in the cell, leading to a net benefit. Or, alternatively, a lower level of output of oxidative molecules might just lead directly to less damage. Further, there are many other aspects of cellular metabolism that might run in ways better suited to a slower pace of aging if mitochondria generate either more or less oxidative molecules; that is poorly mapped and highly dependent on species, tissue, and circumstances. Lastly there is the important matter of mitochondrial DNA damage in aging. Mitochondrial dysfunction appears to be an important contribution to aging, and it is likely driven by mutational damage to DNA in the mitochondria caused by their own generation of oxidants. This DNA damage can produce mitochondria that are both dysfunctional and resistant to quality control. They quickly overtake a cell, and over the course of a lifetime ever more cells fall into this state. Their behavior contributes to degenerative aging in a range of ways, starting with the export of much larger amounts of oxidizing molecules into the surrounding tissues.

Thus rising levels of oxidative stress are considered important in many aspects of the progression of aging, but it is far from the only type of change, damage, and dysfunction taking place. So it shouldn't be a complete surprise to find that some conditions are not affected in the slightest by adjusting mitochondrial oxidant output, even when the indications suggested that outcome to be plausible enough to try. Metabolism is a ferociously complex business, incompletely understood, which is why bypassing its alteration in favor of identifying and fixing fundamental forms of damage should be a much more efficient approach to the treatment of aging and age-related conditions. We have a metabolism that works well when young, even it isn't fully understood, and researchers have a list of the fundamental, first cause differences between young and old tissues, so the goal should be to revert those differences and maintain the working system, rather than try to adjust it.

Mitochondrial ROS regulate oxidative damage and mitophagy but not age-related muscle fiber atrophy

Skeletal muscle is a major site of metabolic activity and is the most abundant tissue in the human body. Age-related muscle atrophy (sarcopenia) and weakness, characterized both by loss of lean muscle mass and reduced skeletal muscle function, is a major contributor to frailty and loss of independence in older people. Studies of humans indicate that by the age of 70, there is a ~25-30% reduction in the cross sectional area (CSA) of skeletal muscle and a decline in muscle strength by ~30-40%. Age-dependent loss of muscle mass and function has a complex aetiology and the primary biochemical and molecular mechanisms underlying this process have not been fully determined.

Oxidative stress has been suggested to be a key factor contributing to the initiation and progression of the muscle atrophy that occurs during aging. Consistent with a role of oxidative stress as a contributor to sarcopenia, studies have shown that genetic manipulations of redox regulatory systems can alter the aging process in muscle. Skeletal muscle decline with advancing age has been linked to an altered oxidative status of redox-responsive proteins and a number of studies have indicated a positive correlation between tissue concentration of oxidized macromolecules and life span including an increase in DNA damage, accumulation of oxidized proteins and increased levels of lipid peroxidation with age. In support of these findings recent quantitative proteomic approaches have further provided evidence that muscle aging is associated with a reduction in redox-sensitive proteins involved in the generation of precursor metabolites and energy metabolism, implying age-related redox changes as an underlying cause of age-related muscle atrophy.

Skeletal muscle produces reactive oxygen and nitrogen species (RONS) from a variety of subcellular sites and there is evidence that isolated skeletal muscle mitochondria exhibit an age-related increase in hydrogen peroxide (H2O2) production. Furthermore, muscle aging is associated with reduced mitochondrial oxidative-phosphorylation, reduced mitochondrial DNA (mtDNA) content, accumulation of mutated mtDNA, impaired mitophagy and increased mitochondrial permeability transition pore sensitivity, which are all proposed to contribute to the sarcopenic phenotype. Although cumulative oxidative stress has been proposed to induce age-associated reductions in mitochondrial function, this remains a controversial topic.

We and others have recently reported that pharmacological application of the mitochondria-targeted SS31 tetrapeptide can attenuate mitochondrial superoxide production in intact mitochondria of skeletal muscle fibers. This pharmacological approach complements genetic approaches, including those using targeted overexpression of the human catalase gene to mouse mitochondria. Such pharamacological agents may have substantial translational implications for the use and/or development of mitochondria-targeted antioxidants for treatment of human mitochondrial myopathies as well as mitochondrial reactive oxygen species (mtROS) mediated muscular dysfunctions. The purpose of the present study was to determine the effect of the mitochondria-targeted SS31 peptide on redox homeostasis in muscles of old mice, including mtROS and oxidative damage, mitochondrial content and mitophagy and on age-related muscle atrophy and weakness. Through this approach we aimed to determine the role of modified mitochondrial redox homeostasis on age-related loss of muscle mass and function.

Our findings demonstrated that a reduction in mtROS in response to SS31 treatment prevented age-related mitochondrial oxidative damage and improved mitophagic potential, but further demonstrated that changes in mitochondrial redox environment towards a more reduced state failed to rescue the sarcopenic phenotype associated with muscle fiber atrophy and loss of muscle mass and strength. This work has therefore identified that the age-related changes in mitochondrial redox potential play a key role in the loss of mitochondrial organelle integrity that occurs with aging, but are not involved in the processes of age-related muscle fiber atrophy.

Calorie restriction is here demonstrated to slow the progression of glaucoma in a mouse model of the condition, without affecting the rising pressure inside the eye that is usually the cause of harm. It is an interesting demonstration of the way in which the shifts in cellular metabolism that occur with calorie restriction prime cells to be more resistant to a range of stresses that typically cause significant amounts of cell death:

Glaucoma is characterized by progressive degeneration of retinal ganglion cells (RGCs) and their axons. We previously reported that loss of glutamate transporters (EAAC1 or GLAST) in mice leads to RGC degeneration that is similar to normal tension glaucoma and these animal models are useful in examining potential therapeutic strategies. Caloric restriction has been reported to increase longevity and has potential benefits in injury and disease. Here we investigated the effects of every-other-day fasting (EODF), a form of caloric restriction, on glaucomatous pathology in EAAC1-/- mice.

EODF suppressed RGC death and retinal degeneration without altering intraocular pressure. Moreover, visual impairment was ameliorated with EODF, indicating the functional significance of the neuroprotective effect of EODF. Several mechanisms associated with this neuroprotection were explored. We found that EODF upregulated blood β-hydroxybutyrate levels and increased histone acetylation in the retina. Furthermore, it elevated retinal mRNA expression levels of neurotrophic factors and catalase, whereas it decreased oxidative stress levels in the retina. Our findings suggest that EODF, a safe, non-invasive, and low-cost treatment, may be available for glaucoma therapy.

Link: https://dx.doi.org/10.1038/srep33950

Average telomere length in cells reflects some combination of cell division rates and cell replacement rates: telomeres shorten with each cell division until cells self-destruct because telomeres are too short, and replacements are generated with long telomeres by stem cells. The stem cell activity that delivers those replacements tends to decline with age, and so average telomere length tends to decrease as well. But this is highly variable between individuals and with circumstances such as illness, exercise, and so forth. Researchers only see the decline in statistics gathered across a large study population, making this a terrible measure of aging for any individual consideration. Added to this, for every paper to show some useful correlation for telomere length, there is another to show no useful correlation between teleomere length and measures of aging, such as this one that examines natural variations in telomere length and longevity in nematode worms:

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length.

Our observation that considerable telomere-length variation in the wild isolate population exists allowed us to directly test whether variation in telomere length contributes to organismal fitness. We did not see any correlation between telomere length and offspring production, suggesting that fitness in wild strains is not related to telomere length. In contrast to findings in human studies, we did not identify a relationship between telomere length and longevity. Our results confirm past findings that telomere length is not associated with longevity in a small number of C. elegans wild isolates or laboratory mutants. In summary, this study demonstrates that a variant in pot-2 likely contributes to phenotypic differences in telomere length among wild isolates of C. elegans. The absence of evidence for selection on the alternative alleles at the pot-2 locus and the lack of strong effects on organismal fitness traits suggest that differences in telomere length do not substantially affect individuals at least under laboratory growth conditions.

Link: http://dx.doi.org/10.1534/genetics.116.191148

The march of technology turns matters of philosophy into matters of practical action. The process of taking visions and making them concrete makes once airy hypotheticals relevant in everyday life. The theoria of the ancient Greeks becomes praxis. What if I could talk to my compatriot now journeyed to the far side of the sea? What if the years of men and women were not limited as the gods decreed by way of the example of Tithonus? What if I could see the very smallest building blocks of the stones and the plants? How could a city of ten million ever be governed? How would men and women live were there not the need for near all to work the land? This process continues today, and at a much accelerated pace as new capabilities emerge with each passing generation. A transition lies ahead, however. Some of the new technologies of the rest of this century will be different from those of the past in one very important way: they will allow the human mind and human nature to be changed, to be copied, to be reconstructed in software and machinery other than that of our present biology. This prospect gives weight to a range of important philosophical questions both in the futurist community and among those who carry out practical work that contributes to this future.

The question for today is this: is an exact copy of you also you? As a consideration, this is of absolutely no practical value to most people today - unless either (a) you happen to think that the Many Worlds interpretation of quantum mechanics likely reflects reality, or (b) you are signed up for cryopreservation as an end of life choice. Even then only the latter group might choose to do something as a result of having a position on this topic. The reason that this question and the voluminous philosophical discussion surrounding it are of limited perceived value to the average individual is, of course, that we cannot create copies of people. Not now, and not for a few decades yet. Most of those reading this now in 2016 will, however, live to see minds copied. Reverse engineering the human brain seems to be to be the most plausible road to the creation of artificial general intelligence. Unlike the other approaches, it quite clearly requires only the combination of sufficiently large amounts of processing power and sufficiently good understanding of the molecular biochemistry of the brain. The more of the former that is in hand the less of the latter that is needed, but both of these areas of human endeavor are moving forward at a fair pace. Praxis will start with tentative running copies of scanned neural architecture in the laboratory, and from there the process of research and development will be driven ever faster. The advantages inherent in being able to create new economic actors with a fraction of the resources needed prior to that point are enormous, and the societies that embrace this technology will dominate. By that time a position on whether a copy of you is also you will be a very necessary thing, and I don't think this is the far distant future we're talking about here. Once this revolution is well underway, and driven by economics, individuality will start to fray at the edges, and those who are comfortable with that fraying will take full advantage of it.

That is the future. But people who are signed up with cryonics providers really do need to have a position on this question now. The cryonics community is quite divided between those who believe that a copy of their preserved brain, running as an emulation, is a quite satisfactory form of survival, and those who want their original biological architecture repaired and restored. That all hinges on what you think about the ontological status of an exact copy of you. If rejuvenation research fails to deliver in time and you are forced into cryopreservation as the only viable backup plan that offers a shot at life again in the future, then your only defense against someone choosing to scan and emulate your mind - discarding your vitrified flesh along the way - is to request that this not happen. If you don't express a preference in a way that will last (a metal plate under the tongue?) then you are taking an additional chance on how the winds of culture and preference will turn in the years ahead. The part that concerns me is the economic angle I mentioned above; that it seems plausible that tremendous advantages will accrue to those who chose to abandon the concept that individuality is tied to matter and state, and instead become comfortable with both copying of the self and radical alteration of the mind from moment to moment.

As a longer examination of this divide insofar as it applies to cryonics today, I'll point out the article linked below, published earlier this year. I think the author doesn't quite get the division of views right, but it remains an interesting read. I'm a reanimator in his taxonomy, but certainly not possessed of any vitalist ideas about the necessity of a biological substrate for the human mind. It is perfectly possible to consider that the data of the mind can and will be copied and run in software on a practical basis, and still be quite attached to this present instance of the self, associated with its present set of matter, considering it a distinct and different individual from any hypothetical copy, running on a different set of matter. This instance of me is the self, the one that needs to survive for there to be a point to this exercise: the pattern that matters is this slowly changing set of atoms that moves forward through time with no major discontinuities. I might be generally well inclined towards a copy, should such a thing come to pass, but then we all tend to be generally well inclined towards people who share our views. That is about as far as it goes.

The Transporter Test and the Three Camps of Brain Preservation

People who are at least a little bit intellectually curious about making the brain preservation choice at the end of their lives are a small but growing demographic. It has been estimated at 1% of the population of most developed-world societies, and a likely smaller fraction in traditional societies. That's a small percentage, but a large number of individuals. We can also expect this group will grow as the cost and accessibility of brain preservation drops, and as validation that preservation preserves retrievable memories (and perhaps more) in animal models grows. The currently preservation-interested demographic can be easily divided into three camps, each with different expectations for the future. The folks in each camp don't always understand or talk to each other all that well, but they need to learn to get along. You'll probably grant that at some point in your future either you or your loved ones will find yourself contemplating, at least briefly, the major life choice of cryonics. Having to think about this topic may even happen earlier than you expect. Death has a way of surprising us.

Camp 1 - Reanimators

Reanimators either desire, or expect it will be necessary, to repair and reanimate (bring back to life) themselves in the form of biological bodies, in order to live again. They believe or expect, with a greater than 50% probability (and for some, essentially 100% probability), that their personal identity (personality and self-awareness) arises out of the unique physical and informational features of biology. Thus they think human minds need to be biological in order to exist. Reanimators hope to perfect a technology some call "reversible solid-state suspended animation," the ability to cryonically preserve and later reanimate human beings and brains. That is an exciting vision, and we can certainly expect some progress on that front. There are numerous examples of the new tissue and organ preservation strategies being tried in labs around the world, with the near-term goal of expanding tissue and organ banking in medicine.

Camp 2 - Uploaders

Uploaders are "patternists," meaning they believe or expect, with greater than 50% probability (and for some, essentially 100% probability), that the functional abilities (informational and computational patterns) of their biology are their true self, not their biology, which presently carries that pattern, and not their matter either, which changes constantly during their lives. Another way of defining an uploader is that they believe or expect that there is less than 50% probability that repair and reanimation of their biology or their matter will be necessary in order to wake up in the future. They expect instead to be scanned and uploaded, and wake up as a technological mind, inside some kind of technological body, in a future environment. This brain scanning and uploading technology is already much farther along than most people think. For example, neuroscience labs around the world are already using automated FIBSEM machines (a kind of electron microscopy) to scan and upload into computers detailed connectomes of small animal brains, including flies, zebrafish, and even parts of mouse brains. We don't yet understand how to read memories from these digital connectomes. But give it a little time.

Camp 3 - Uncertains

Uncertains as their name implies, don't yet buy the arguments of either of these two camps, which puts them firmly in a third camp. They talk about cryonics and brain preservation as an "experiment" or a "bet" that they'd much rather make, given the alternative experimental groups, that of either certain death or a religious afterlife. If asked, they might put the odds near 50/50 for reanimation being necessary for them to come back, or simply unknown. Some uncertains will grant that neuroscience and computer science now argue that human memories are stored in a small set of stable molecular features (most importantly, dendritic spines) in neural connectomes, and that if these are well-preserved at death, then our life's memories can very likely be scanned and uploaded to future computers, to share with our loved ones or the world. But they are typically agnostic on the question of whether all the brain's functions, including emotion, personality, and consciousness, are substrate-independent.

The Transporter Test

A good test of whether you are a reanimator, an uploader, or uncertain, and whether you have an instinctual bias to reanimation, as most folks do when they first engage with these ideas, is to ask the Transporter question, a test that uncovers your assumptions and biases with respect to the copy problem. Would you go through a Star Trek transporter (molecular scanner, disassembler, pattern storer, information beamer, and reassembler, using new molecules) if many others had done it, and claimed to still be themselves on the other end, and as far as you could tell they seemed the same? Or would you not go because you presently believe the process would cause your own death as your brain was being molecularly disassembled, and you believe your reassembled brain and body would be just some kind of unacceptable copy that only "thinks" it is you? This is a really deep question, and it depends on your view of the nature of personal identity. Consider that all three responses to this test are valid, from the point of view of members of each camp. If such a device were created, all three mental attitudes would be common, and all three would be socially reinforced as the right choice, by the members of each camp. So it should be obvious that each camp needs to learn to get along better, right?

It has been a decade since researchers first discovered the recipe for reprogramming ordinary somatic cells into induced pluripotent stem cells, capable of generating all other cell types in the same way as embryonic stem cells. This was a transformative advance, as the ease of the method allowed near any research group to work with pluripotent cells. Making use of induced pluripotency in research and medicine is still very much a work in progress, however: great strides are being made in the production of cells and tissues for drug testing and other tissue engineering for research use, but the goals of generating patient-matched cells and tissues for cell therapies and transplantation are not proceeding as smoothly as was perhaps hoped by some. This popular science article surveys the field:

Human cortex grown in a petri dish. Eye diseases treated with retinal cells derived from a patient's own skin cells. New drugs tested on human cells instead of animal models. Research and emerging treatments with stem cells today can be traced to a startling discovery 10 years ago when researchers reported a way to reprogram adult mouse cells and coax them back to their embryonic state - pluripotent stem cells. A year later, they accomplished the feat with human cells. The breakthrough provides a limitless supply of induced pluripotent stem cells (iPSCs) that can then be directed down any developmental path to generate specific types of adult cells, from skin to heart to neuron, for use in basic research, drug discovery and treating disease. The dazzling iPSC breakthrough has spurred rapid progress in some areas and posed major challenges in others. It has already proved a boon to basic research, but applying the new technology to treat diseases remains daunting. Some types of cells have proved difficult to reprogram, and even the protocols for doing so are still in flux as this is still a very young field.

Six years after the iPSCs discovery, researchers in a very different field developed a new gene-editing technology of unprecedented speed and precision, known as CRISPR-Cas9. The potent new tool has revolutionized efforts to "cut and paste" genes and has been very quickly adopted by thousands of researchers in basic biology and drug development. CRISPR's speed and precision may some day allow stem cell researchers to reach their most ambitious goal: Genetically abnormal cells from patients with inherited diseases such as sickle cell anemia or Huntington's could be reprogrammed to the pluripotent stem cell state; their genetic defects could be "edited" in a petri dish before being differentiated into healthy adult cells. These cells could then be transplanted into patients to restore normal function. While that goal is still beyond reach, many early-stage clinical trials are underway using induced iPSCs to treat diseases, from diabetes and heart disease to Parkinson's. One trial has already treated its first patient. In 2014, scientists made iPSCs from skin cells of a woman with macular degeneration and then differentiated them into adult retinal cells. Surgeons transplanted the retinal cells into her eyes in order to treat the disease - the first patient treated using iPSCs. Preparations to treat a second patient using patient-derived cells were stopped because the researchers detected a mutation in one of the genes in the iPS cells. No reports had linked the gene to cancer, but they decided not to use the stem cells to eliminate any risk.

The success of treatments relies in part on stem cells' rapid rate of proliferation. Hundreds of billions of cells may sometimes be needed for a transplantation. But if just a few of the stem cells fail to differentiate into the target adult cells, they may reproduce rampantly when transplanted and form a tumor. "It's a two-edged sword. In the pre-transplant stage, you want stem cells that proliferate very rapidly. But after the transplant, if there are only five or 10 cells that didn't differentiate into adult cells, they can reproduce infinitely. They create a kind of residue of tumor." Research to ensure that all stem cells differentiate before transplantation is now one of the main issues in this field. To eliminate cancer risk, the researchers are now "deep sequencing" the genetic makeup of each of the stem cell lines they might use. They have also decided to use donor cell lines rather than the patient's own cells. This avoids the very expensive prospect of having to carry out quality checks like deep sequencing of each patient's own pluripotent cell lines.

The originators of the iPSC methodology are concerned about public perception that the rate of progress may be slower than expected. "I am fascinated by how rapidly science is advancing. It's amazing. But for the most part, developing new treatments - doing the science, testing the safety and effectiveness of new therapies­ - takes a great deal of money and many years. Developing new treatments may take 10 years, 20 years, 30 years. That is what we have been trying to say to our patients: 'We are making great progress, so do keep up your hope. But it takes time.'"

Link: https://www.ucsf.edu/news/2016/09/404271/induced-pluripotent-stem-cells-10-years-after-breakthrough

There are presently a few different biomarkers of aging under development based on changes in patterns of DNA methylation, an epigenetic decoration to DNA that determines the rate at which specific proteins are manufactured. The molecular damage that causes aging is the same in all of us, and thus some portion of the cellular reaction to environment and circumstances will also be the same in all of us: as damage accumulates, cells change their behavior in response. A good biomarker that accurately reflects biological age can, once validated, be used to greatly speed up development of therapies that slow or repair the causes of aging. At present the only reliable way to assess outcomes is to run life span studies, something that is for many organizations prohibitively expensive when carried out in mice, and out of the question when it comes to gathering human data. If lengthy life span studies can be replaced with a biomarker measurement before and after a short period of treatment, then the cost and time taken to evaluate potential rejuvenation therapies will be greatly reduced, and many more research groups will participate in the research and development process.

A team of 65 scientists in seven countries recorded age-related changes to human DNA, calculated the biological age of blood and estimated a person's lifespan. A higher biological age - regardless of chronological age - consistently predicted an earlier death. Drawing on 13 sets of data, including the landmark Framingham Heart Study and Women's Health Initiative, a consortium of 25 institutions analyzed the DNA in blood samples collected from more than 13,000 people in the United States and Europe. Applying a variety of molecular methods, including an epigenetic clock developed in 2013, the scientists measured the aging rates of each individual. The clock calculates the aging of blood and other tissues by tracking methylation, a natural process that chemically alters DNA over time. By comparing chronological age to the blood's biological age, the scientists used the clock to predict each person's life expectancy.

"Our findings show that the epigenetic clock was able to predict the lifespans of Caucasians, Hispanics and African-Americans in these cohorts, even after adjusting for traditional risk factors like age, gender, smoking, body-mass index and disease history. We discovered that 5 percent of the population ages at a faster biological rate, resulting in a shorter life expectancy. Accelerated aging increases these adults' risk of death by 50 percent at any age." For example, two 60-year-old men both smoke to deal with high stress. The first man's epigenetic aging rate ranks in the top 5 percent, while the second's aging rate is average. The likelihood of the first man dying within the next 10 years is 75 percent compared to 60 percent for the second. The preliminary finding may explain why some individuals die young - even when they follow a nutritious diet, exercise regularly, drink in moderation and don't smoke. "While a healthful lifestyle may help extend life expectancy, our innate aging process prevents us from cheating death forever. Yet risk factors like smoking, diabetes and high blood pressure still predict mortality more strongly than one's epigenetic aging rate."

The precise role of epigenetic changes in aging and death, however, remains unknown. "Do the epigenetic changes associated with chronological aging directly cause death in older people? Perhaps they merely enhance the development of certain diseases - or cripple one's ability to resist the progression of disease after it has taken root. Future research is needed to address these questions." Larger studies focused only on cases with well-documented causes of death will help scientists tease out the relationship between epigenetic age and specific diseases. "We must find interventions that prolong healthy living by five to 20 years. We don't have time, however, to follow a person for decades to test whether a new drug works. The epigenetic clock would allow scientists to quickly evaluate the effect of anti-aging therapies in only three years."

Link: http://newsroom.ucla.edu/releases/epigenetic-clock-predicts-life-expectancy-ucla-led-study-shows

The reprogramming of ordinary somatic cells into induced pluripotent stem cells, capable in principle of then generating any other type of cell, was a major advance for cell biology and its application to medicine. It is still sufficiently recent for the implications and uses still to be a work in progress. One of the more interesting observations to emerge from the recent years of experimentation is that this reprogramming appears to erase some aspects of mitochondrial aging. Take fibroblasts with damaged mitochondria from a skin sample from an aged individual, reprogram them to generate a population of induced pluripotent stem cells, differentiate those stem cells into a new set of fibroblasts, and the resulting cell population has dramatically improved mitochondrial function. One possibility is that reprogramming triggers some aspects of the comprehensive repair programs that take place very early in embryonic development, wiping away as much of the parental molecular damage as possible. Parents are old and babies are born young, so something of this ilk must be hidden away somewhere in the repertoire of cellular behavior. That isn't to say it can be usefully applied in adults, of course: there are any number of vital, intricate structures in our organs, the brain particularly, that would probably be fatally disrupted by the operation of such a program. Time will tell.

Is this apparent mitochondrial rejuvenation actually mitochondrial rejuvenation, however? Is it fixing the all-important damage to mitochondrial DNA, for example? Every cell has hundreds of mitochondria, the descendants of ancient symbiotic bacteria, complete with a leftover fragment of the original DNA that still encodes a range of necessary proteins used in mitochondrial functions. Mitochondria still divide like bacteria to make up their numbers, even though they are treated just like any other cellular component and broken down for recycling when damaged. Their most important function is the generation of energy store molecules to power cellular operations, but this process produces oxidizing molecules as a side-effect. They damage the cellular machinery they react with, and the most vulnerable target is the mitochondrial DNA right next door. Most oxidative damage to proteins and DNA in cells is rapidly repaired, but mitochondrial DNA isn't as well protected as the DNA in the cell nucleus. Further, some forms of mitochondrial DNA damage, such as large deletions, can produce mutant mitochondria that are both dysfunction and resistant to being culled by cellular quality control mechanisms. They quickly outcompete the normal mitochondria, and a cell taken over in this way becomes dsyfunctional itself, carrying out a range of bad behavior that contributes to the progression of aging. Thus mitochondrial DNA damage is an important topic; if researchers observe what looks like mitochondrial rejuvenation, then the quality of the mitochondrial DNA is a key question.

The authors of this commentary discuss a paper published earlier this year that argues against repair of mitochondrial DNA in the course of cellular reprogramming. If confirmed that means that a potential shortcut to allow cell therapies to better treat the diseases of aging may not in fact exist: dealing with mitochondrial DNA damage when using a patient's own cells is still required, one way or another. The favored method is that outlined in the SENS proposals, using gene therapy to move critical mitochondrial genes into the cell nucleus. There are other possible approaches, though none of those seem to be as far along towards clinical application. While one door closes, another opens, however. As pointed out below, the preservation of mitochondrial damage might indicate that reprogramming as it presently stands, in which only a tiny number of cells are successfully converted, may be a good way amplify rare mutations in cell samples. That in turn might help with the still challenging task of putting reliable numbers to the degree to which mitochondrial DNA is damaged in old cells.

Aging vs. rejuvenation: reprogramming to iPSCs does not turn back the clock for somatic mitochondrial DNA mutations

The process of cellular reprogramming is believed to be able to "turn back the developmental clock" by allowing somatic cells to acquire a state that is normally associated only with embryonic stem cells (ESCs). Indeed, human induced pluripotent stem cells (iPSCs) can be obtained from aged individuals and still show the key properties of ESCs, including self-renewal, elongated telomeres, and round-shaped mitochondria with underdeveloped cristae. However, it remained to be determined whether reprogramming to pluripotency could actually erase aging-associated signatures and thus represent a rejuvenation route. A new paper now clearly demonstrates that iPSCs not only do not erase the signs of aging but, due to their clonal origin, may even reveal aging-related defects in the mitochondrial DNA (mtDNA) that were not detectable in the whole parental tissues.

Using iPSCs derived from both skin fibroblasts and peripheral blood mononuclear cells (PBMCs) researchers have shown that all iPSCs exhibited mtDNA mutations that could not be observed in the whole-tissue DNA extracts of the parental cells. These mutations were originally considered as negative by-products of reprogramming as a consequence of oxidative stress-mediated genomic damage. However, it was demonstrated that also skin fibroblasts grown as individual clones exhibit mtDNA mutations that are not seen in the pooled fibroblast population. Hence, individual cloned fibroblasts and iPSCs may both represent the progeny of a single parental fibroblast cell, thereby enabling the detection of mtDNA mutations that were already present in the original fibroblast population but remained undetectable due to their relatively low presence. Several studies indicate that mtDNA mutations, including large-scale deletions, increase with aging. In accordance, researchers detected increased presence of mtDNA mutations in fibroblasts and iPSCs derived from aged individuals compared to young individuals. Moreover, the identified mutations in somatic cells and derived iPSCs were mostly located in coding genes, while ESCs displayed mtDNA variants primarily within the non-coding D-loop. This gives further support to the notions that the majority of mtDNA alterations seen in adults is of somatic rather than embryonic origin.

An important point to be addressed was the functional consequence of the detected mtDNA mutations. The presence of mtDNA alterations that were not seen in the pooled parental fibroblasts were previously found to not cause major bioenergetic defects, as all generated iPSCs could efficiently undergo the extensive metabolic shift that is associated with cellular reprogramming. However, detailed analyses unveil diminished metabolic function in iPSCs carrying high heteroplasmic mtDNA mutations. Hence, in order to correctly employ patient-derived iPSCs for disease modeling and therapeutic studies, it will be imperative to include the detection of mtDNA integrity as part of the basic characterization toolkit. This will be especially relevant when dealing with patients of advanced age who may harbor increased amount of mtDNA mutations. Overall, this work strongly confirms that, in addition to nuclear genome integrity, mitochondrial genome integrity will become a key parameter to investigate for all medical applications of iPSCs. Furthermore, it highlights the strength of single-cell studies, which may reveal the real biological variability that pooled population studies have so far prevented to be identified. In conclusion, in order to allow faithful and meaningful discoveries, future analysis of iPSCs and their derivatives should not shy away from mitochondrial genome monitoring and single-cell technology.

Supercentenarians, people who have passed 110 years of age, are very rare. Accordingly, the sort of information on their physiology that can only be obtained through autopsy or donation of the body to science is similarly thin on the ground. It has been some years now, for example, since the evidence was first gathered to show that most supercentenarians are probably killed by transthyretin amyloidosis, something that has a smaller but significant contribution to heart disease in earlier old age. Here, researchers assess the postmortem state of the brains of four supercentenarians, an exercise that well demonstrates that the oldest of humans don't escape unscathed:

Supercentenarians (aged 110 years old or more) are extremely rare in the world population (the number of living supercentenarians is estimated as 47 in the world), and details about their neuropathological information are limited. Based on previous studies, centenarians (aged 100-109 years old) exhibit several types of neuropathological changes, such as Alzheimer's disease and Lewy body disease pathology, primary age-related tauopathy, TDP-43 pathology, and hippocampal sclerosis. In the present study, we provide results from neuropathological analyses of four supercentenarian autopsy cases using conventional and immunohistochemical analysis for neurodegenerative disorders. In particular, we focused on the pathology of Alzheimer's disease and Lewy body disease, as well as the status of hippocampal sclerosis, TDP-43 pathology, aging-related tau astrogliopathy, and cerebrovascular diseases.

Three cases were characterized as an "intermediate" level of Alzheimer's disease changes (NIA-AA guideline) and one was characterized as primary age-related tauopathy. TDP-43 deposits were present in the hippocampus in two cases. Neither Lewy body pathology nor hippocampal sclerosis was observed. Aging-related tau astrogliopathy was consistently observed, particularly in the basal forebrain. Small vessel diseases were also present, but they were relatively mild for cerebral amyloid-beta angiopathy and arteriolosclerosis. Although our study involved a small number of cases, the results provide a better understanding about human longevity. Neuropathological alterations associated with aging were mild to moderate in the supercentenarian brain, suggesting that these individuals might have some neuroprotective factors against aging. Future prospective studies and extensive molecular analyses are needed to determine the mechanisms of human longevity.

Link: http://dx.doi.org/10.1186/s40478-016-0368-6

I'm far from convinced it is the best path forward in the matter of treating aging, but much of the research community is focused on finding drugs that can alter patterns of gene expression and the operation of signaling pathways that tend to change with aging in order to run in a more youthful manner. There are hundreds of potential candidates at this point, described in the geroprotectors database; things like metformin and rapamycin are in that list. This seems to me to be putting the cart before the horse, in that these changes are not the cause of aging but rather downstream consequences of cell and tissue damage. It is possible that some benefit can be obtained by forcing a more youthful function of cells despite the underlying damage that they are reacting to, but trying to coax a damaged machine into better function without actually repairing that damage tends to be an expensive exercise in obtaining only marginal results. Most of the medicine for age-related disease created over the past century establishes the bounds of the possible here, as next to none of it touches on the root causes of aging. You can slow things down, or make things somewhat better, but you can't produce the large improvements that would be possible by reverting the damage that causes aging. Is that worth the effort now, at a time when addressing the root causes of aging is actually plausible? I'd say no. Pursue the better strategy instead, that outlined by the SENS rejuvenation research program, a focus on repair of fundamental damage rather than trying to compensate for it.

A significant rise in the proportion of seniors worldwide is underway, resulting in increasing rates of chronic, debilitating disease and long term residential care, shrinking the supporting workforce, and threatening to sink current health care systems. Prevention will be crucial moving forward. If aging can be delayed and diseases prevented, productive years can be extended and retirement age redefined. Anti-aging therapies have been sought since the dawn of human civilization, but with the rise of modern biology, big data, and information sciences, intelligent approaches to geroprotector discovery may finally be within reach. The outward features of aging, including decline in function and rise in susceptibility to stress and disease, are associated with a set of structural and functional changes at the cellular level. While these changes vary by tissue, many are genetically regulated, and many genes mediating longevity, termed gerontogenes, have been identified. The identification of these genes and experimental manipulation of their products to extend lifespan in model organisms has bolstered the notion that aging is not just a natural process but a treatable disease and added credence to the movement to identify drugs or other factors that may also extend lifespan, or, more favorably, healthspan, in humans. These are termed geroprotectors.

There are now over 200 substances that have shown geroprotective effects in model organisms. Human-based studies, however, may turn out to be more productive. Several of the most promising attempts at developing geroprotectors have involved identifying FDA-approved drugs with life-extending qualities and repurposing them as geroprotectors for human use. These include rapamycin and metformin. However, a number of problems still hamper the widespread approval and use of these or other drugs for this purpose. Most notably, longevity is a difficult parameter to study in humans without large, longitudinal designs, and since these drugs would presumably be administered to aging but otherwise healthy individuals, the effect size would have to be substantial and side effects almost non-existent. In addition, the FDA does not consider aging an approved disease indication. At this time, no drug has sufficiently met these conditions, and new approaches to drug discovery - and drug repurposing - are needed.

The drug discovery process is slow and expensive, burdened by many projects that dead-end before clinical trial or fail thereafter. Improved prediction of drug performance prior to lengthy experimentation would cut waste. Vast datasets now exist that enable such prediction with the help of sophisticated computational methods. Two particularly valuable datasets in this respect are the literally millions of gene expression profiles stored in repositories and a number of increasingly diverse compound screening libraries. While gene expression data can be used to pinpoint target pathways for a particular disease, compound libraries can be screened for drugs that target these pathways. All of this can be done in silico, at relatively little cost. Recently, a method was developed that would do just this - capitalize on existing gene expression data and compound libraries to improve prediction of targeted drugs. The method involves the use of an algorithm termed Oncofinder. Oncofinder quantifies Pathway Activation Strength (PAS) in a given sample based on gene expression patterns relative to another sample. Thus PAS values can be computed for a disease state in comparison to a normal state, old versus young, or any other set of physiological conditions. Here, we used an aging-based extension of Oncofinder, known as GeroScope, in a search for novel geroprotective substances.

We first quantified activation of age-related pathways in hematopoietic and mesenchymal stem cells from "old" (vs "young") human donors. We then shortlisted substances predicted to best target those pathways, restore a "young" cellular profile, and extend viability. From that list, we proceeded to experimentally test the effects of each substance in human fibroblasts. The top geroprotector, in terms of performance in both enhancing viability and rejuvenation was PD-98059, a highly selective inhibitor of MEK1 and the MAP kinase cascade. MEK inhibition along with PI-3K inhibition has been shown to decelerate cellular senescence via the mTOR/S6 pathway, a known target for anti-aging interventions. Aside from PD-98059, most of the studied geroprotectors had effects on either cellular viability or senescence features.

Link: http://dx.doi.org/10.18632/aging.101047

As I'm sure many people are aware these days, with the greater availability of historical materials and their analysis, Isaac Newton was as much alchemist as scientist. His worldview encompassed mysticism, mathematics, and cosmology in equal parts, a function of his time. You can't really pick apart Newton the scientist from Newton the mystic, Newton of the equations and proofs from Newton of the search for the philosopher's stone. A person is a fusion, not a collection of parts. You also can't paint Newton as somehow distinct from his peers in this - he was an outlier in his intelligence, his vision, and his work ethic, not in his views on alchemy. Keep this in mind as a framing device; I point it out because the mix of futile, magical endeavors and the sound application of science, both pursued with equal vigor, is far from left behind in Newton's era. It continues today, and it is of great relevance to progress (or lack thereof) in the field we all care about, advancing the state of the art in living longer, healthier lives.

I, and others in our community, believe that the "anti-aging" marketplace as it stands is both terrible and an opportunity. Ultimately if the good can chase out the bad, then these are people with clinics, funds, and the desire to do something about aging, exactly those who could do a great deal of good in pushing forward research, development, and clinical availability if they so chose. As real rejuvenation therapies emerge, the entrepreneurs of that marketplace will stop trying to sell products based on cherry-picked scientific studies, outright lies, and magical thinking. You can't make money selling tables that fall apart when the people next door sell tables that work. The same applies to medicine. Consider what a medical market with even partially effective treatments looks like: no-one today makes much of a business selling charms against heart disease. For sure, it exists, but will-workers and traveling tinkers certainly aren't the first port of call for the average individual - patients seek out doctors and clinicians in the knowledge that there are treatments that can product useful results. The end result is never an end to fraud and superstition, but the crushing of it into a tiny corner of economic activity. I suspect that this is going to be a drawn out and messy process for longevity science, however, just as it has been elsewhere in the past. Will we see clinics selling working rejuvenation therapies such as senescent cell clearance infusions in a package with nonsense like apple stem cell skin cremes? No doubt. Caveat emptor, just as true ten years from now as it is today.

Many folk feel that the "anti-aging" market is too much of a threat to have anything to do with. That it will not reform and will poison whatever it touches. Certainly there are people in there with that mix of adherence to mysticism and science that has characterized many figures in the history of science and technology, whether giants like Newton or the rank and file who get far lesser mention in the pages of history. The Life Extension Foundation principals are comfortable pushing useless nonsense on the one hand (overhyped supplements based on dubious research results taken out of context, anything that Suzanne Somers has to say about health, and so forth) while on the other hand helping to fund stem cell research trials and SENS-like programs of development such as thymic regeneration. They've given a good deal more money to those worthy causes than I have. Nonetheless, the alchemy, the alchemy. It is painful. There is a certain anxiety that people we might persuade to the cause of human rejuvenation take in things like the recent RAAD Festival, and as a consequence throw out everything they see, baby and bathwater, as the author did here. When the first few samples raised up to the light for examination are evident nonsense, why check the others carefully?

A weekend watching the promise of immortality get sold and bought at the Revolution Against Aging and Death Festival

I was invited to attend RAAD after I wrote about people who want their pets to live forever. I was initially confused by the phrase "age reversal." As it turns out, RAAD sells something more audacious than pricey cosmetics or Li'l Brad Pitt. RAAD stands for Revolution Against Aging and Death. It sells the promise of eternal youth. Also, Suzanne Somers was going to be there. The people who organized RAAD are members of the Coalition for Radical Life Extension, which is the nonprofit offshoot of People Unlimited, a Scottsdale, Arizona-based group that describes itself as "a community of people living physical immortality." People Unlimited charges a monthly membership fee, and holds regular meetings where members swap antiaging tips and listen to guest speakers. The coalition's online mission statement shoehorns immortality into a historical narrative of moral and social progress. Radical life extensionists believe that eternal life will eventually be viewed as a sort of buried human right, as soon as they convince people that they're not delusional.

Though immortalists aren't mainstream, radical life extension has a burgeoning fan base in the tech industry. Along with Alphabet's Calico, which is a secretive Google spinoff focused solely on the study of aging, other prominent antiaging research labs and biotech firms have budded up among the techno-utopians. While the search for ways to stop aging and "cure" death is booming from a business perspective, the reality of biotech solutions for age-related problems is far more nuanced than the vision presented at RAAD, where researchers spoke in highly optimistic terms about progress just around the corner. Assuming that this research will lead to insight on how we age is one thing. Assuming it will free us from the bonds of mortality is an enormous leap. And so even within the community of researchers who study old age and life extension, immortalists are considered radical, and sometimes accused of peddling pseudoscience.

To cast the widest possible net for converts, RAAD touted many different twists on the concept of living forever. No one path to immortality was placed above another. There were many different denominations of immortalists present, with a patchwork of philosophies and goals: stem-cell facials, telomerase research, transhumanism, cryonics, brain uploading, cyborgism, vitamins, blood transfusions, marathon running, sex. After she ran through her spiel, Suzanne Somers sat down with Bill Faloon, another superstar within the life extension movement. Faloon founded the Life Extension Foundation in 1980, and he was ready to back up every last irresponsible word Somers uttered. "There is a tremendous amount of peer-reviewed literature to substantiate what Suzanne has said, including diet and health," Faloon said. Faloon applauded Peter Thiel for donating money to antiaging causes. Thiel has donated to gerontologist Aubrey de Grey, who founded the SENS (Strategies for Engineered Negligible Senescence) Research Foundation. De Grey is a British man with objectively too much beard who is famous among futurists and infamous among scientists for claiming that the first person who will live to a thousand years old is alive today. He's good at raising money for antiaging research and courting celebrities to join his cause. SENS has an ad campaign that features Steve Aoki, Herbie Hancock, Edward James Olmos, and the guy who played Little Carmine on The Sopranos.

This is the messiness of the business of persuasion in action. Though I have to say that the author here is evidently smart enough to realize there's something down there at the science end of the pool, but chose to write the article this way anyway rather than working harder at the more interesting picture that is presented. Work on telomerase is arguably pretty important in aging research. Cryonics is a logical response to death in an age of technological progress. Aubrey de Grey's SENS Research Foundation is serious business, a part of the very real, very promising road to working rejuvenation therapies. Suzanne Somers on the other hand is a great illustration of the fact that business fundamentals trump everything else, including having products that actually work, or making claims that are actually sound, true, and supported by evidence. The Life Extension Foundation's Faloon has a foot in both camps. There you have the span from science to mysticism in just three people.

This is what human endeavor looks like when existing products have very marginal effects, and thus fraud is both easier to carry out and harder to suppress. But as I noted above, that will start to change soon enough. Senescent cell clearance will be in clinics five to ten years from now, alongside before and after DNA methylation biomarkers of biological age, and that will be indisputably effective in comparison to everything else out there claimed to have an impact on aging. From there matters might start to clean up somewhat, as the first of the frauds and the mystics begin to exit, stage left. Where am I going with this? Well, it would be great if everyone thought more or less the way I do about longevity science, but you have to live in the world that is, not the world that you'd like to exist. You work with the hand you've been dealt. Newton was an alchemist, and fundamentals of human nature haven't changed since then. The people getting things done today will inevitably tend to spend only a fraction of their time on projects and publicity that you or I might consider to be the most important items on the list, and many will embrace mysticism and counterproductive activities along the way. This is the way things go. It is certainly far from ideal, but still we move ahead. The end goal of a "anti-aging" community even halfway converted and backing the right approaches to human rejuvenation is, I think, too much of a potential boost to throw away because of the present situation. That means building the bridges now, in exactly the same way that bridges must be built to Big Pharma, governments, and other relevant institutions that are themselves less than ideal.

Visceral fat is the fat tissue packed around the abdominal organs, as opposed to the more visible subcutaneous fat under the skin. It is much more harmful and metabolically active. The more visceral fat tissue you have, and the longer you carry it, the shorter your life expectancy, the higher your lifetime medical costs, and the greater your risk of suffering all of the common age-related diseases. At present the research community consensus is that chronic inflammation is the major mechanism connecting these items; visceral fat tissue acts to increase inflammation through a number of processes, and inflammation is a major contributing factor to the pace at which age-related disease and dysfunction emerges.

Studies have shown that people who carry excess abdominal fat around their midsection tend to face higher risks of heart disease compared to people who have fat elsewhere. A new study adds to the growing body of evidence that regional fat deposits are harmful and further suggests that the density of the stomach fat (measured by CT scan) is just as important as how much fat you have. In general, the higher the fat content, the lower the attenuation, or fat density, that is shown on the CT image. "What's really interesting is that we show that an increase in the amount of stomach fat and a lower density fat is associated with worse heart disease risk factors - even after accounting for how much weight was gained. This hasn't been shown before. Measuring fat density is a new measure that we are still working to understand and warrants further investigation. We used it as an indirect measure of fat quality and found that lower numbers were linked to greater heart disease risk."

Researchers sought to determine whether there was a link between anatomical changes in belly fat - both its volume (quantity) and density - and changes in a broad array of cardiovascular disease risk factors during the average six-year study period. They reviewed CT scans to assess how much abdominal fat had accumulated, its location and it's density in 1,106 participants from the Framingham Heart Study who received this imaging as part of a larger study to measure coronary and abdominal aortic calcification. Participants' average age was 45 years and 44 percent were women. Both subcutaneous adipose fat, the fat just under the skin, and visceral adipose fat, the fat inside the abdominal cavity, were measured. Over the six-year follow-up period, participants had a 22 percent increase in fat just under the skin and a 45 percent increase in fat inside the abdominal cavity on average. In general, increases in the amount of fat and decreases in fat density were correlated with adverse changes in heart disease risk. Each additional pound of fat from baseline to follow up was associated with new onset high blood pressure, high triglycerides and metabolic syndrome. Even though increases in both types of fat were linked to new and worsening cardiovascular disease risk factors, the relationship was even more pronounced for fat inside the abdominal cavity compared to fat just under the skin.

Overall, associations remained significant even after adjusting for changes in BMI or waist circumference. Researchers also grouped participants into three groups according to abdominal adipose tissue volume and density change; they found that those with greater increases in fat volume and more decreases in fat density had relatively higher incidence of heart disease risk factors. In terms of next steps, more work needs to be done to understand fat density, and why and how it is associated with metabolic consequences of obesity (e.g., hypertension, abnormal cholesterol, diabetes, inflammation and insulin resistance). As well, it will be important to tease apart how less dense fat, along with simultaneous increases in the amount of fat may spur the development of harmful cardiometabolic changes.

Link: http://www.alphagalileo.org/ViewItem.aspx?ItemId=168201&CultureCode=en

Many researchers are investigating potential means to spur greater muscle growth and regeneration in older people, ways to at least partially compensate for the characteristic loss of muscle mass and strength that occurs with age, a condition known as sarcopenia. Physical weakness is a sizable component of the frailty of aging, and restoring the ability of the elderly to move and act with confidence would be a tremendous gain. The current range of candidate therapies tend not to address root causes, the underlying molecular damage that causes aging, and vary from the debatable amino acid supplementation to the very promising myostatin blockade. Here researchers propose another possible target and present initial results in mice:

Sarcopenia, age-related loss of muscle quantity and quality, is a crucial determinant of geriatric fragility. Sarcopenia increases susceptibility to muscle damage, serious falls, obesity and diabetes. Age-related changes in muscle are thought to depend on a decrease in muscle stem cells and their niche, which results in global changes in associated gene and protein expression as well as posttranslational modifications. Skeletal muscle regeneration is a multistep process. In response to stimuli generated by exercise or injury, satellite cells re-enter the cell cycle to produce myoblasts, subsequently withdraw from the cell cycle, and differentiate into myocytes, which fuse into new myotubes or with host myofibers. This fusion process is crucial for postnatal growth, maintenance and repair of skeletal muscle in the adult stage. Myotube formation is completely Ca2+ dependent, and requires net Ca2+ influx into myoblasts.

With aging, skeletal muscle shows impaired myogenic potential, which, in turn, induces atrophy. Ca2+ signaling molecules are reported to be associated with age-dependent muscle degeneration. Among the various Ca2+ sensors and channels, inositol 1,4,5-triphosphate receptor type 1 (ITPR1) expression was dramatically decreased in aged muscles and myoblasts. Here, we have provided new evidence that decreased expression of ITPR1 triggers dysregulation of Ca2+ oscillation, which in turn modulate gene expression, resulting in defective myogenesis. Ca2+ oscillation is known to modulate gene expression in many tissues, including muscle.

Multiple studies suggest an important role for the Ras-ERK1/2 pathway in the development, maintenance, and pathology of mammalian skeletal muscle. ERK activity promotes the proliferation of myoblasts and the terminal differentiation of myotubes. We further investigated whether EGFR-Ras-ERK signaling is activated in aged skeletal muscle with decreased ITPR1 expression. Notably, the age-related ITPR1 decline in mice and human skeletal muscles was correlated with increased activation of EGFR-Ras-ERK signaling. To establish whether ERK activation is responsible for inhibition of myogenesis, the ERK pathway was blocked with a specific inhibitor, U0126, in old primary myoblasts. To further evaluate the therapeutic potential of ERK signaling inhibitors for sarcopenia, we examined the effects of U0126 on impaired muscle regeneration in aged mice. U0126 was injected on a daily basis into 6 and 24 month-old C57BL/6 male mice for 13 days after injury. Quantitative real-time PCR data revealed that U0126 induced higher expression of not only myogenic regulatory genes but also those involved in hypertrophy in aged muscle. Consistently, measurements revealed that the newly formed myofibers of U0126-treated muscle had significantly larger diameters than those of controls, supporting the potential of ERK inhibitors as new candidate therapeutic agents for sarcopenia.

Link: https://dx.doi.org/10.18632/aging.101039

Since calorie restriction is the topic for the day so far, I thought I'd finish up by pointing out a recent paper that examines just one of the many concrete benefits that are produced through the practice of calorie restriction. In this case the focus is on blood vessel integrity, and the researchers demonstrate that a low calorie diet in mice reduces the risk of suffering an aneurysm, a localized weakening and consequent distortion of blood vessel walls. Aneurysms in major blood vessels ultimately lead to rupture and bleeding that is far more often fatal than survivable. Larger aneurysms in the brain can cause significant issues even without rupturing because they displace neural tissue, possibly disrupting vital functions as a result.

It isn't too difficult to walk through what is known of the various contributions that increase the risk of aneurysm, and the reasons why that risk rises with age. The first place to start is hypertension, increased blood pressure. Greater pressures means that ever lesser degrees of structural weakness will fail and bulge out into an aneurysm. Hypertension appears to be largely driven by stiffening of blood vessels, as the cardiovascular system reacts incorrectly to the feedback it is given by stiffened vessels. This loss of elasticity is in turn a consequence of cross-linking in the extracellular matrix of blood vessel walls, one of the fundamental forms of damage described in the SENS rejuvenation research portfolio. The normal processes of metabolism generate hardy sugar compounds that can link the complex collagen macromolecules of the extracellular matrix. The structure and movement of those macromolecules determines tissue characteristics such as elasticity, and cross-linking degrades that flexibility to produce stiffening. Other contributions to vascular stiffening include calcification in blood vessel walls and various secondary consequences of the chronic inflammation that accompanies aging, disrupting the signaling involved in blood vessel constriction.

Another group of mechanisms worth emphasizing are those that lead to atherosclerosis: damaged lipids in the bloodstream, such as those produced as a result of the harmful actions of cells with age-related mitochondrial damage, can cause an overreaction when they lodge in blood vessel walls. This produces lesions in which inflammation and immune cell death runs amok, growing into fatty plaques in the blood vessel wall. One of the ways in which such an atherosclerotic plaque can prove fatal is through weakening the blood vessel wall sufficiently for an aneurysm to develop and then rupture. Another is for the plaque to break apart and block a blood vessel elsewhere. Either way, the consequences are unpleasant. To the degree that atherosclerosis is a type of immune overreaction, it is accelerated by the rising levels of chronic inflammation that accompany aging.

Almost all of these processes are modestly reduced in magnitude while an individual is practicing calorie restriction. Inflammation is reduced, mitochondrial function improved, the immune system works more effectively to remove problem cells, and cells do a better job of internal quality control. Other environmental influences on the constriction of blood vessels are improved. Since calorie restriction is known to slow near all measures of aging, it perhaps isn't surprising to see it also reducing aneurysm risk. This is all relative, of course: despite the fact that calorie restriction produces perhaps the largest available long-term benefits for basically healthy individuals, you nonetheless can't reliably diet your way to a life span of a century. Rejuvenation therapies are on the horizon, however, and thus it is perhaps wise to pay attention to the few choices you can make now that are reliable and proven in their effects, likely to add a few years of health to your life span. Missing out by a few years when you could have benefited would be a terrible thing. Unfortunately, beyond calorie restriction and exercise there is little worth the candle at the moment, given the balance of evidence: efforts beyond the health basics are better directed to speeding progress towards human rejuvenation, helping the development of therapies that can repair the molecular damage that causes aging.

Consuming Fewer Calories Reduces the Risk of Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a localized enlargement of the main artery in the abdomen caused by a weakening of the blood vessel wall. With over three million cases per year in the US, preventing the development of AAA is crucial because, if the aneurysm bursts, the mortality rate can be as high as 80%. The risk of developing AAA increases with age and can be exacerbated by other factors such as smoking. Calorie restriction has been shown to have a variety of health benefits in mice and humans due to its far-reaching effects on the body's metabolism. Researchers wondered whether the risk of AAA might be reduced by a calorie-restricted diet. The researchers placed mice prone to developing AAA on a calorie-restricted diet for 12 weeks and found that the animals were less likely to develop aneurysms than control mice fed a normal diet. The calorie-restricted mice also showed lower rates of AAA rupture and death.

The researchers determined that calorie restriction reduced the levels of an enzyme called MMP2 that degrades the protein matrix surrounding blood vessels. This was because, after 12 weeks of reduced calorie intake, vascular smooth muscle cells in the wall of the aorta up-regulated a metabolic sensor protein called SIRT1, which can epigenetically suppress multiple genes, including MMP2. The researchers found that calorie restriction was unable to reduce MMP2 expression and the incidence of AAA in mice whose vascular smooth muscle cells lack SIRT1. The study suggests that reducing calorie intake can protect mice from AAA by up-regulating SIRT1.

Calorie restriction protects against experimental abdominal aortic aneurysms in mice

Abdominal aortic aneurysm (AAA), characterized by a localized dilation of the abdominal aorta, is a life-threatening vascular pathology. Because of the current lack of effective treatment for AAA rupture, prevention is of prime importance for AAA management. Calorie restriction (CR) is a nonpharmacological intervention that delays the aging process and provides various health benefits. However, whether CR prevents AAA formation remains untested. In this study, we subjected Apoe-/- mice to 12 weeks of CR and then examined the incidence of angiotensin II (AngII)-induced AAA formation. We found that CR markedly reduced the incidence of AAA formation and attenuated aortic elastin degradation in Apoe-/- mice. The expression and activity of Sirtuin 1 (SIRT1), a key metabolism/energy sensor, were up-regulated in vascular smooth muscle cells (VSMCs) upon CR. Importantly, the specific ablation of SIRT1 in smooth muscle cells abolished the preventive effect of CR on AAA formation in Apoe-/- mice. Mechanistically, VSMC-SIRT1-dependent deacetylation of histone H3 lysine 9 on the matrix metallopeptidase 2 (Mmp2) promoter was required for CR-mediated suppression of AngII-induced MMP2 expression. Together, our findings suggest that CR may be an effective intervention that protects against AAA formation.

The practice of calorie restriction is demonstrated to slow near every aspect of aging in laboratory species, and in humans it greatly improves measures of health related to risk of age-related disease. Here researchers look specifically at effects on the molecular biochemistry of cells in the brain, protective mechanisms that slow the progression and impact of age-related neurological disorders:

Mechanisms that increase longevity and, perhaps most importantly, promote longer health spans (lower or delayed incidence of age-related diseases) have always attracted attention. The most effective intervention known to date to prevent age-related decline and promote better health spans in a wide variety of organisms, ranging from yeast to primates, is caloric restriction (CR). This dietary intervention typically consists of a 20-40% reduction in caloric intake without micronutrient limitation relative to an ad libitum diet. Perhaps the most striking group of age-related diseases prevented by CR is in the brain. A large number of neurological disorders are age-related, and CR has been demonstrated to effectively prevent these disorders. CR also improves age-related declines in memory and learning abilities observed in elderly animals. Although the mechanisms by which CR exerts its effects are poorly understood, mitochondria, as master regulators of cellular metabolism, are believed to play an important role in the cellular adaptations that take place with the diet.

In the brain, increases in mitochondrial activity may change the susceptibility to excitotoxicity, a pathological process associated with many age-related neurological conditions such as stroke, Alzheimer's disease and Parkinson's disease, in which excessive activation of postsynaptic receptors results in cell death. This neurodegenerative process involves the binding of glutamate or glutamate analogues to NMDA and AMPA receptors, resulting in pathological increases in cytosolic calcium levels and a rapid decrease in ATP levels due to the activation of ionic balance restoration pathways. Mitochondria are the main site for ATP production in neurons and contribute toward cellular calcium buffering by accumulating this ion in a membrane potential-dependent manner. Indeed, interventions that increase mitochondrial calcium buffering capacity protect against excitotoxicity and related conditions. Interestingly, while intermittent fasting (a dietary intervention that consists in offering food ad libitum on alternate days) has been found to be neuroprotective under excitotoxic conditions, the effects of CR on excitotoxicity have not been well explored to date. Furthermore, mechanistic insights toward possible neuroprotective effects of this diet are still scarce. The aim of this study was to determine the effects of CR on excitotoxicity and dissect the molecular mechanisms involved.

We show that CR is also effective in preventing direct excitotoxic damage. Our data show that mitochondria in the brains of CR animals have enhanced electron transport capacity, accompanied by higher levels of some electron transport proteins and proteins involved in mitochondrial morphology and dynamics. Interestingly, the increase in electron transport chain (ETC) enzyme activities does not seem to affect the respiratory rates of isolated mitochondria. Cells seem to be able to regulate independently many different mitochondrial features. In our case, CR increases the levels of cardiolipin in the brain, while the activity of citrate synthase remains constant. Moreover, some, but not all, mitochondrial proteins are enriched in a per mitochondrion basis after CR. Some of the metabolic adaptations that CR induces in the brain seem to be mediated by molecule(s) present in the bloodstream. Indeed, CR serum promotes mitochondrial adaptations in primary neurons analogous those observed in vivo, namely protection against glutamate excitotoxicity. Previous reports in other tissues indicate that metabolic effects observed with CR can be partly reproduced in vitro using serum from animals subjected to the diet. These results support the notion that the metabolic remodeling that takes place with CR can be triggered by circulating molecules. A possible candidate is adiponectin, which is elevated in CR animals. Adiponectin protects against excitotoxicity both in vivo and in vitro.

Our results in brain mitochondria show that CR promotes sizable increases in both the rate and the accumulation capacity for calcium. As a result, under excitotoxic conditions, CR neurons possess a largely enhanced ability to buffer cytosolic calcium levels, which explains the strong resistance toward excitotoxic damage conferred by this dietary intervention both in vitro and in vivo. Overall, we demonstrate that CR is a highly effective intervention to prevent excitotoxic neuronal cell death by enhancing antioxidant capacity, mitochondrial respiratory rates, preventing mitochondrial permeability transition and thus enhancing calcium accumulation capacity, resulting in lower cell death. These properties may be central to the mechanism through which this dietary intervention promotes its many beneficial neurological effects.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12527/full

Calorie restriction, reducing calorie intake while maintaining optimal levels of micronutrients, produces beneficial alterations in near all aspects of metabolism. It extends healthy life spans in near all species investigated to date, through this effect is much larger in short-lived species that have evolved a greater plasticity of life span in response to circumstances. In humans the consensus is that it might make a difference of a few years to overall life span, but it certainly greatly improves measures of health and lowers risk of age-related disease, suggesting the effect on healthspan is probably larger. Here, researchers discuss the effects of calorie restriction and some of the candidate calorie restriction mimetic drugs. It is a lengthy paper, but worth reading if you'd like a comprehensive overview of past investigations:

The aging process is undoubtedly the single most significant contributor to disease and death. Although this has been the inevitable outcome of all life on this planet, is aging an unavoidable consequence or can it be treated and potentially cured? As of yet this question remains unanswered, but many believe that the aging process is essentially a disease. Environmental conditions, including lifestyle, can greatly affect the rate of aging. For example, obesity or excessive ingestion of calories has been linked to increased incidents of age-related pathologies. Several lines of research indicate that certain behaviors can increase our health and potentially lifespan, such as exercise and regimes to improve cardiovascular function. One such intervention is the use of dietary/caloric restriction (CR); the reduced intake of calories/nutrients without causing malnutrition. In recent years, this observation has been verified across a large number of model organisms. These observations not only demonstrated an increase in the lifespan, but also in healthspan (time spent being healthy) of these organisms coincident with a significant decrease in age-related pathologies such as cardiovascular disease, diabetes and a number of cancers. For example, when fed a diet consisting of 35% of the ad libitum intake but enriched with vitamins and minerals, mice lived an average of 53 months, compared to 35 months in the control ad libitum-fed group.

Several drugs or naturally occurring compounds in food have been found to "mimic" the phenotypes of CR and could be potential alternatives to this somewhat difficult to follow dietary regime. An obvious first question: Do these compounds mirror the effects of CR? A large body of outstanding research focuses on the impact of CR and mimetics on autophagy in the regulation of longevity and in promoting apoptosis in cancer cells; however, the mechanism and impact on genome function (gene expression) and organization (epigenetic changes and physical genome folding) are less well understood. The oxidative damage attenuation hypothesis states that increased metabolism from high levels of nutrients/calories leads to higher rates of reactive oxygen species (ROS) and that lowering these levels will prevent lipid, protein and DNA damage. Damage such as this would lead to decreased function of cellular components as well as to increased rates of mutation. However, the other side of this hypothesis states that lower metabolic rates results in decreased rates of DNA damage and increased genome stability, and thus in fewer incidents of cancer. Although this is logical, some data does indicate that there is not a significant enough change in free radical production upon CR to significantly decrease ROS levels indicating that the benefits of CR might not be elicited through this mechanism. Although CR increases lifespan, it may not be due to a reduction of the ROS levels produced by mitochondria, but may result from an increase in the expression of enzymes that protect against these highly reactive molecules, reducing net oxidative stress. However, in D. melanogaster exposed to CR, no link between lifespan extension and increased resistance to oxidative stress has been found.

The altered glucose-insulin hypothesis indicates that CR causes a decrease in the circulating levels of both insulin and glucose, leading to decreased insulin signaling. This is based on observations that decreased insulin signaling promotes increased lifespan in a variety of model organisms. Increased glucose and insulin in the circulatory system will cause peripheral cells to absorb this glucose and convert it to ATP. In addition, insulin will also send positive growth and proliferative signals, pushing cellular balance toward growth and cell division. Therefore, CR may promote increased lifespan by decreasing rates of cell division and favoring repair and maintenance. The growth hormone-IGF-1 axis hypothesis states that increased signaling through these pathways advances the aging process by promoting cell growth and proliferation. Similarly to the glucose-insulin level hypothesis, CR causes the reduction of growth hormone/IGF-1 signaling, favoring a switch from cell growth and proliferation to maintenance and repair in mice. However, in human studies over a 2 year period of CR, no change in circulating IGF-1 levels were observed. These findings hint at two potential conclusions; (1) CR does not work in humans, only in mice, or (2) CR does not impact IGF-1 levels; however, it does impact other pathways, leading to at least increased healthspan, if not lifespan.

The hormesis hypothesis states that low levels or intensity of stress leads to "priming" in which cells/tissues/organs can then withstand other stresses that would normally prove terminal. It is thought that with hormesis, cells move from active growth and proliferation to a state that favors repair and maintenance. CR may prime cells by activating stress pathways to deal with later assault such as DNA damage. Other specific observations appear to favor this model, activating transcription factors and mechanisms controlling gene expression leading to increased levels of proteins mediating cellular stress responses. A large number of gene expression studies have been performed in order to determine the impact of CR on genome function. CR is well known to elicit a change in cell behavior marked by a decrease in cell proliferation and shift to cellular maintenance and repair. Changes in phenotype are accompanied by changes in gene expression; therefore, what impact does CR have on gene expression from across the genome?

It is clear that CR results in decreased energy and changes in cellular AMP:ATP and NAD:NADH ratios. Compounds that mimic CR do so by impacting cellular function resulting energy readouts or interfering with signaling down-stream cellular energy levels. The main proteins that appear central to mediating this response are AMPK and SIRT1 which regulate cycles of deacetylation and phosphorylation of a large number of proteins to control gene expression and cellular functions. Many of the CR mimetics of naturally occurring compounds identified either modulate SIRT1/AMPK function or, for example with rapamycin, target downstream signaling hubs to mediate potential health and lifespan effects. Of these targets NF-κB and the FOXO family of transcription factors, are pivotal in promoting decreased cell proliferation and increased maintenance in normal cells, while facilitating apoptosis and cell death in cancer cells. Furthermore, although all compounds appear to confer life and healthspan extending impacts across numerous cell types and model organisms via this SIRT1/AMPK interaction, the downstream impact on genome function (gene expression) is varied, across cell-type, organism-type, and compound-type in addition to variations in experimental details (such as exposure times, drug concentrations). This suggests that although mechanisms mediating health and lifespan in response to CR and these compounds are similar, the effects on gene expression mean that these compounds may not be direct mimetics of CR or of one another.

Link: http://dx.doi.org/10.3389/fgene.2016.00142

Here I'll point out a good article on cryonics and its nuances in the online press; it includes thoughts from people working at cryonics providers, people signed up for cryopreservation, and advocates with various viewpoints. Like any community there are a range of opinions on what constitutes progress and the best strategy for moving ahead, and just as many motivations as there are individuals involved. What is cryonics? It is the low-temperature preservation of at least the brain as closely following death as possible. Early preservations in the 1960s and 1970s were a matter of straight freezing, and thus the preserved individuals are most likely characterized by extensive tissue damage due to ice crystal formation. Later preservations have used increasingly better forms of vitrification, in which cryoprotectants are perfused into tissues during the cooling process, resulting in the near absence of ice crystals and high quality preservation of fine structures. This is a technology that scientists are nowadays seeking to bring to the organ transplant industry, a way to revolutionize the logistics of that field by allowing indefinite reversible storage of donated organs for later use. It has been a few years since the reversible vitrification of a rabbit kidney followed by transplant and a few hours of function was demonstrated: work proceeds on pushing forward the state of art to the quality needed for everyday medical use, but this demonstrates the basic viability of the approach, provided the initial vitrification is of good quality. Similarly, maintenance of long term memory through vitrification and thawing has been shown in lower animals.

The point of this is life: the data of the mind is stored in fine structures in the brain, and at some point, future technology will include the necessary capabilities to restore a vitrified individual to life. That will require, at the least, a very mature and sophisticated regenerative medicine industry, incorporating rejuvenation biotechnologies after the SENS model, and equally capable applications of molecular nanotechnology to deal with the cryoprotectant and forms of damage that cells cannot handle on their own. For so long as the data is intact, the option remains for rescue at some future date. It is an open question as to the degree to which earlier cryopreservations have managed to save the individual. Ultimately reconstruction of a frozen, ice-crystal-damaged brain and its data will probably be possible, but will that be the same person if considerable extrapolation is required? Continuity of identity through the same structure associated with the data of the mind seems important, or else you become one of those folk who believe a copy of the self is the self - a dangerous idea, to my eyes. The technological side of the future of cryonics seems a safe bet. The risks all lie in whether or not you manage to obtain a good cryopreservation, and whether or not the storage company survives the intervening years. A lot of thought and effort has gone into these matters over the four decades that cryonics has been a professional concern; you can peruse the materials at Alcor's website for a sampling of it.

Thus cryonics is a wager as well as a so far small industry, a bet on technology continuing its upward trend. The odds are unknown, but infinitely better that those provided by any other end of life choice. We are heading into an era of rejuvenation therapies, but all too many people will run out of time before those therapies arrive. Are we barbarians, writing off these countless individuals? I would hope not. A fallback plan that offers some chance is better than a certainty of oblivion, and the more people who choose to sign up for cryonics, the better the chances become. A larger industry means more research and development, faster progress towards improved preservation techniques, more effective lobbying to change laws on euthanasia so as to make preservation a reliable, scheduled, low-cost event, and so forth. There is much that can be done to improve present matters, just as there is much that has been accomplished to make present day cryonics far more advanced over its beginnings.

Generation Cryo: Fighting Death in the Frozen Unknown

Alcor Life Extension Foundation is the first and largest cryonics firm in the world. Its only true competitors are the Cryonics Institute located near Detroit - a 7,000-square-foot facility that currently hosts 100 preserved individuals - and KrioRus near Moscow - the world's first cryonics firm based outside the United States. Futurist Robert Ettinger came up with the idea of cryonics in the 1960s, but it was Frederick and Linda Chamberlain who formed a nonprofit organization in 1972 dedicated to cooling recently deceased people down to liquid nitrogen temperatures, and maintaining their bodies until it was possible to "reanimate" them. They called their new California-based organization the Alcor Society for Solid State Hypothermia - "Alcor" being a faint star in the Big Dipper. After dealing with some uncomfortable political squabbles and bureaucratic hurdles in California, the organization moved its operations to Arizona in 1990. Arizona offered a stable environment, free from earthquakes, floods, and other natural disasters, and state laws that were more amenable to Alcor's unconventional activities.

Alcor may be a not-for-profit 501(c)(3), but it needs to be profitable to survive, and to ensure the long-term prospects of those preserved at the facility. The core staff of Alcor - all of whom are signed up - have a vested interest in the success of the company. Alcor CEO Max More says, "We want this for ourselves." Registering with Alcor comes at a price. To help pay for it, most clients take out a second life insurance policy and name Alcor as the beneficiary. To ensure that Alcor can take possession of the deceased, clients donate their bodies to the organization for scientific study. And yet, very few people are actually ready to go the distance. Around 2.6 million people die each year in the United States. Alcor, the world's leading cryonics institute, has only 1,569 full members after four decades - and that includes the 148 patients currently in cryostasis. Undaunted, More says that there will be a tipping point, that cryonics will "eventually be the norm" and even "a regular fixture of medical care." He sees hospitals of the future having the expertise and facilities to perform their own cryopreservations. He compared the slow buy-in to the length of time it took germ theory and open heart surgery to be accepted. "The current problem is that it's hard to sell something without a guarantee. We make absolutely no promises about our offering-and in fact, we even provide our clients with a lengthy list of all the things that could go wrong."

A surprising number of things can and do go wrong, from the moment death is declared to the lowering of a body into the shiny dewar. With advance warning of death, a standby team is dispatched to wait until clinical death has been declared. Within seconds, the patient is placed in an ice bath to start cooling, and a mechanical respirator is used to restart circulation. The goal is to maintain normal bodily processes, even after "clinical death" has been declared. Decomposition starts almost immediately. The team then administers 16 different kinds of medication, including propofol to suppress consciousness in the event that cardiopulmonary support unintentionally revives the patient. Even at this early stage in the process, the line that divides life and death is blurred. The other medications work to reduce metabolism and stave off other problems that occur when the body stops functioning. The idea isn't to freeze the body, but to take it down to slightly above the freezing point of water to prepare it for transportation to Alcor. This is the ideal scenario, but there can be catastrophically long delays. Each passing hour or day following clinical death means preservation will be that much lower in quality. As Alcor likes to say, "Time is trauma."

Sometimes, disapproving family members deliberately refrain from alerting Alcor that one of their clients has passed away, in direct violation of the recently deceased's wishes. If a person was crushed by a streetcar, there may not be much left to preserve. Likewise, an autopsy will almost certainly result in a seriously compromised cryopreservation. And if the person died of an aggressive brain tumor or neurodegenerative disorder, any memories or aspects of personality that were damaged by the disease will almost certainly not be restored at a future date. Once the body arrives at Alcor, it's quickly taken to the operating room. For whole-body preservations, surgeons connect all the major blood vessels of the heart to a heat exchanger (a device that lowers the patient's body temperature to a few degrees above the freezing point of water), and a perfusion machine, which delivers chemicals to the body. The idea is to wash out the body's blood and other fluids as quickly as possible, and replace them with a cryoprotectant. This high-tech gel is gradually added to the body to prevent ice crystal formation - the mortal enemy of biological sustainability. The quality of this process varies according to the state of the patient. Things tend to go smoothly for people with a fully-functioning circulatory system, but for others, who have had prior surgery or other conditions, this can lead to less than ideal conditions. Aneurysms and bleeding in the brain are not good.

Alcor prides itself on transparency and commitment to "evidence based cryonics," and it publishes detailed case reports for each preservation. These reports include notes about deficiencies and problems that happened during the process. Despite Alcor's strict protocols, there's no proof that its method of cryopreservation is actually working. For all we know, every single person at the facility is a goner. Alcor has published micrographs of cryogenically preserved brain cells on its website, and claim the images "demonstrate good structural preservation with dehydration artifacts, but no ice damage." But as More himself admits, they haven't been able to prove that the neural connections have remained intact, though he remains hopeful. Kenneth Hayworth, president and co-founder of the Brain Preservation Foundation and an expert in the burgeoning science of connectomics, is critical of Alcor's micrographs. Hayworth says that chemical fixation, in conjunction with cryonics, is the future of brain preservation, and that Alcor has it all wrong. Alcor, on the other hand, steadfastly believes that chemical fixation is a catastrophe. The process uses aldehyde to fix the brain in place, preventing any shrinking on account of dehydration (a serious problem during the cooling process). More says this is a big no-no because it's irreversible, and that this "destructive" form of preservation is not a true form of survival. He and others believe this process will essentially kill the individual - and all their biological bits - for all time. More admits that the resulting brain scans could help future scientists reconstruct an individual, but many Alcor members argue that it would be a mere copy of that individual. "Not a lot of people will accept that."

Aschwin de Wolf, the editor of Cryonics Magazine and CEO for Advanced Neural Biosciences, says it's good that Hayworth and others are holding Alcor to a high standard, because it pushes the science of cryonics forward. Having said this, he worries that Hayworth is rehashing old misconceptions about Alcor's techniques. "For a long time cryonicists were criticized for causing ice formation in the brain and now that we have eliminated this phenomenon through vitrification we are told that electron micrographs do not look like controls yet. We know this! Hayworth's position seems to be that a cryonics organization should only offer cryopreservation services if its electron micrographs are indistinguishable from controls. That seems an extreme and ethically troublesome position to me. As long as we have good reason to believe that the original state of the brain can be inferred from the altered state, offering cryonics services is not only reasonable but an ethical mandate."

Robin Hanson, an economist at George Mason, has been an Alcor member since the 1990s, and he says it rarely crosses his mind. "It hasn't occupied very much of my attention or thought over the years. It's not some kind of part-time job that requires your constant attention." Simon Smith, a Toronto-based digital health marketer, husband, and father of two, has been an Alcor member for nearly a decade, and he concurs. "I think it's like a life insurance policy. A lot of people have life insurance policies, but they don't walk around thinking about them everyday." Smith is disheartened at the slow pace of technological development. An avid futurist and life extension advocate, he'd like to see more emphasis placed on technologies that will prolong human life, whether it be advances in pharmacology, biotechnology, molecular nanotechnology, or improvements to cryogenic techniques. But he remains optimistic. "The odds of reanimation being successful are better today than they've ever been and are continuously getting better, while the odds of coming back from burial, cremation or every other alternative remain the same."

This review paper takes a look at some of what is known of the contribution of mitochondrial dysfunction to age-related loss of muscle mass and strength, progressing towards the condition known as sarcopenia. The hundreds of mitochondria packed into every cell act as power plants; these evolved descendants of symbiotic bacteria are responsible for, among many other things, generating chemical energy stores to power cellular operations. This process also produces potentially disruptive reactive oxygen species as a byproduct, but the structures most likely to take the brunt of that disruption are the mitochondria themselves. Mitochondrial damage is important in the aging process, producing a growing population of dysfunctional cells that export harmful reactive molecules into surrounding tissues, giving rise to damaged proteins that contribute to a range of age-related conditions. Declining energy store production is also a significant problem in tissues that need greater amounts of energy to function and maintain themselves, such as muscles:

Loss of muscle mass and muscle wasting are clinical symptoms associated with many chronic diseases as well as with the aging process. The loss of muscle mass accompanied by a decrease in muscle strength and resistance which occurs in the elderly is termed sarcopenia. In the population over 65 years of age, this decay in muscle function is particularly associated with increased dependence, frailty, and mortality. In fact, sarcopenia is the main cause of disability among the elderly. Among the mechanisms that contribute to sarcopenia have been described the decrease in physical activity, the decrease in anabolic hormones, and an increase in proinflammatory cytokines as well as the increase in catabolic factors. Further, recent studies have also identified that not only mitochondrial metabolic dysfunction but mitochondrial dynamics and mitochondrial calcium uptake too could be involved in the degeneration of skeletal muscle mass. A growing body of evidence suggests that muscle quality plays a systemic role in the aging process. Thus, it has become apparent that mitochondrial status in muscle cells could be a driver of whole body physiology and organism aging.

Reactive oxygen species (ROS) are produced in the mitochondria as a byproduct of an inefficient transfer of electrons through the electron transport chain (ETC). During the aging process, ROS production increases as well as mitochondrial damage and dysfunction. These phenomena have also been observed in age-associated diseases. In fact, it is supposed that the observed increase in ROS is derived from a decline in mitochondrial function. Interestingly, in flies, the development of genetic sensors which can be targeted specifically to a tissue or to an organelle within the cell is helping to reveal which tissues are subject to redox dysregulation during aging. Increased production of ROS in aged and age-related phenotypes has also been observed to be accompanied by alterations in mitochondrial DNA (mtDNA) quality and quantity. It has been proposed that increases in ROS could easily target the mtDNA which lacks histone protection. Furthermore, it is argued that with aging, DNA repair mechanisms efficiency decline and could lead to mutations in mtDNA.

Consistent with the paradigm, in mice, it has been found that ROS production is increased in aged muscles and directly affects the complex V (ATP synthase) of the ETC, oxidizing, thereby preventing the synthesis of ATP by the oxidized protein. One possible consequence of this process is that the damaged mtDNA promotes the biogenesis of damaged mitochondria, in turn producing more ROS, enabling a vicious cycle to continue. Contrasting these results, recent deep sequencing of mitochondrial genomes in mice suggests, otherwise, that mutations in the mtDNA arise from replication errors during early life. Increased ROS species in the cell have also been associated with diminished ROS scavengers activities during aging. Interestingly, recent evidence has demonstrated that genetic manipulation of mitochondrial antioxidants, given by the overexpression of human mitochondrial catalase in old mice, protects from oxidative damage and age-associated mitochondrial dysfunction, together with protecting from energy metabolism diminution in age. Several questions remain open regarding the behavior of ROS during organism and muscle aging. For example, when in lifespan do ROS first appear in the muscle? Or which concentrations of ROS are required to alter the gene and protein networks that ensure mitochondria and muscle quality functions? These are still matters to be addressed.

Link: http://dx.doi.org/10.1155/2016/9057593

In this op-ed, Aubrey de Grey of the SENS Research Foundation argues that finding effective ways to treat the causes of the aging process should be the highest priority for our societies. No other single thing causes anywhere near as much suffering, loss, and death, and yet few resources are devoted to bringing an end to aging. Few people seem to realize just how plausible it is to build rejuvenation therapies in the near future given the present advanced state of biotechnology and medical research. Some of those therapies are under development in startup companies even today, but much more work remains ahead, at present supported only by a low level of funding. So much more could be achieved, and far more rapidly, given sufficient material support.

What is medicine for? Surely an easy question, right? Apparently not. I have always believed that the purpose of medicine is to alleviate the suffering caused by ill-health and death. One must include both, because death itself is very effective in ending the suffering caused by ill-health, and even though there is vibrant debate concerning the appropriate access to assisted suicide, society overwhelmingly adopts the policy that life is sacred and must be extended at virtually all cost. Or does it? There is a bizarre contradiction in our collective approach to the ill-health of old age. On the one hand we are happy to allocate billions upon billions to the quixotic pursuit of extended but functionally impaired life, under the banner of geriatric medicine, but on the other hand we overwhelmingly express deep ambivalence, if not outright opposition, to the idea of future medicine that would actually work - that would entirely abolish those ailments and maintain youthful mental and physical function to much greater chronological ages. When asked to consider such a world, most people are far more inclined to raise concerns about how society would manage the likely side-effect of increased average longevity, than to pay any attention whatever to the prospective alleviation of so much suffering.

The ill-health of old age currently accounts not only for over 70% of deaths worldwide but also for a similar proportion of medical expenditure. In the industrialised world, these numbers are in the region of 90%. What if we had medicine that would prevent the conditions on which all that money is spent? The money would be saved! Sure, the medicines that achieved this prevention would themselves cost money, but there is no reason (not even any hypothetical reason) why prevention should not be better (i.e. cheaper) than cure in this case as it usually is. And that's just the start. Do you, or does anyone you know, have a parent with advanced Alzheimer's or any other age-related chronic disease? How much productivity is lost from the burden of caregiving as a result? It's astronomical. And beyond that, consider the wealth that the elderly could contribute to society if only they remained able-bodied. The economic benefit would be unimaginable.

How is this not completely obvious to everyone? My only explanation is that the powers that be are just as irrational about aging as the rest of society. There can be no doubt that policy-makers are acutely aware of the economic realities that I summarise above, but their decisions are based on their perceptions of the impact on their priorities. And it seems that policy-makers remain convinced that it is not in their interests to inject relatively minuscule sums into research that could pay for itself literally millions of times over. Why? Only two explanations seem available. One is that the reward is further in the future than the current electoral cycle, such that whatever the logic of such a course, it would be against the nearer-term vested interests of the political elite. The other is that these decision-makers truly feel, in spite of all the scientific evidence trumpeted by biogerontologists every day, that the probability of actual success (i.e., of a substantial hastening of the defeat of ageing) from such expenditure really is less than one in a million, thus outweighing the benefit that success would bring. Neither such attitude is remotely excusable.

Link: https://www.opendemocracy.net/neweconomics/anti-aging-medical-research-must-be-our-top-priority/

In the open access paper I'll point out today, the authors dig into some of the details of DNA methylation changes that occur with aging, seeking to build a better biomarker of aging. This methylation is one of the epigenetic decorations to DNA that act to alter the expression of particular genes, determining whether or not the encoded proteins are produced. The methylation status of genes changes constantly in response to circumstances, differently in every tissue, one small portion of the countless interacting feedback loops that drive the behavior of cells. The cell and tissue damage of aging is the same for everyone, however, and so are the reactions to that damage, even though happenstance, lifestyle choices, and genes conspire to create some variation in the pace at which aging progresses. Thus there are patterns of DNA methylation that are distinctive for people at a given point in the progression of degenerative aging, and those patterns can be picked out of the constant changes that occur due to other environmental factors. Some of these patterns better reflect chronological age, others better reflect biological age, but there is much left to be done to expand and improve upon the existing discoveries in this field.

Why is this important? Primarily for economic reasons. At present it costs a great deal of time and money to assess whether or not a potential therapy that might produce a slowing or reversal of aging in fact works. Researchers have to run life span studies, and as the focus moves from lower animals into mice the cost per study rises to millions of dollars and the time taken rises to years. Yet without those studies, obtaining the proof and support to justify further development is impossible. You might look at the progress towards senescent cell clearance, one of the SENS approaches to rejuvenation biotechnology, over the past decade as an example. Despite the established body of evidence for the role of senescent cells in aging, that line of research didn't start to pull in meaningful support until researchers managed, against all the odds, to raise enough funding to run a study in mice and demonstrate extended life span through removal of senescent cells. Now, five years after those results were published, there are funded startups and numerous research groups working on building a variety of senescent cell clearance therapies. Looking ahead for the field of aging research as a whole, imagine that these lengthy and expensive mouse life span studies could be replaced with very short studies that assess a biomarker of aging, apply the therapy, wait a few weeks, then assess the biomarker again. That would dramatically reduce the cost, get many more research groups into the field, and allow many more approaches to be proved or disproved fairly rapidly. The iterative process of research and development would speed up considerably.

So, to the degree that DNA methylation is a path to a good biomarker of biological age, one that will change quickly and predictably when a real, actual, working rejuvenation therapy is applied, we should all be cheering progress in DNA methylation research. The present DNA methylation clocks are not as accurate as researchers would like them to be, however. There is definitely room for improvement, and all such improvement will - in the end - be reflected in the bottom line: the cost of running studies to assess potential treatments for aging, and thus the cost of progress in the treatment of aging as a whole. Greater reductions in costs will bring larger increases in the output of the research and development communities. The more progress here the better, as no-one is getting any younger yet. All of that said, I should note that the publicity materials here make what is to my eyes a complete hash of the meaning and significance of this research, so you might want to just skip straight to the paper.

Youthful DNA in old age

The DNA of young people is regulated to express the right genes at the right time. With the passing of years, the regulation of the DNA gradually gets disrupted, which is an important cause of ageing. A study of over 3,000 people shows that this is not true for everyone: there are people whose DNA appears youthful despite their advanced years. The researchers charted the regulation of the DNA of over 3,000 people by measuring the level of methylation at close to half a million sites across the human DNA. They were looking for sites where the difference in regulation increased between people as life progressed. Unexpectedly, these sites were closely linked to the activity of genes that were known from studies in worms and mice to play a central role in the ageing process. Not everyone in the study showed equal evidence of an age-related dysregulation of the DNA. Some elderly people had DNA that was regulated as if they were still 25 years old. In these individuals, genes characteristic of the ageing process were much less active. The next step will be to find out whether such people stay healthier for longer. "Obviously, health depends on more than just the regulation of our DNA. But we do think that the dysregulation of the DNA is a fundamental process that could push the risk of different diseases in the wrong direction. In cancer cells, we found changes in the regulation of the DNA at the same sites as if the differences occurring with ageing were a precursor of the disease. We therefore want to study whether a dysregulated DNA increases the risk of different forms of cancer and, conversely, a "youthful" DNA is protective."

Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Studies of model organisms such as yeast, nematodes, and mice have shown that the accumulation of cellular damage is a fundamental cause of ageing across species. Epigenetic dysregulation is thought to play a key role in this process. Numerous human population studies have now shown that changes in DNA methylation of CpG dinucleotides, a key epigenetic mechanism, are strongly associated with chronological age. Although these epigenetic changes are in part a by-product of age-related changes in the cellular composition of the studied tissue, many age-related differentially methylated positions (aDMPs) observed in blood samples are independent of cell composition, and aDMPs have proven to be a useful tool to predict chronological age. However, aDMPs may not be the most informative marker of the ageing process since they were discovered as close correlates of chronological age instead of biological age. Moreover, only a small proportion of aDMPs are associated with expression changes, suggesting that their functional implication may be limited. In contrast, DNA methylation changes that increasingly diverge from chronological age may reflect the increasing inter-individual variation in health that occurs with increasing age. Initial studies, although small or lacking a genome-wide view, indicated that an increasing variability of DNA methylation with age indeed exists.

In the current study, we charted the occurrence of age-related variably methylated positions (aVMPs) across the genome. We evaluated the methylation at 429,296 CpG sites for increased variability with age in whole blood samples from 3295 individuals aged 18 to 88 years. We discovered and validated 6366 age-related variably methylated positions (aVMPs). While aVMPs were commonly associated with the expression of (neuro)developmental genes in cis, they were linked to transcriptional activity of genes in trans that have a key role in well-established ageing pathways such as intracellular metabolism, apoptosis, and DNA damage response. Of interest, tumors were found to accumulate DNA methylation changes at CpG sites of aVMPs, thus supporting the long-standing notion that ageing and cancer are in part driven by common mechanisms.

Our data show that the genomic regions accumulating variability in ageing populations are highly specific and reproducible. Hence, although the increase in variability may have a stochastic component, the regions affected by this phenomenon are well-defined and not stochastic. Intriguingly, associations of aVMP methylation with gene expression in trans extended to genes known to play a role in ageing. In older individuals who had an aged DNA methylation profile as compared with young individuals, we observed a downregulation of genes involved in metabolism. The upregulation of ageing pathways, as observed in old individuals with an aged methylome, has been reported previously in hematopoietic stem cells in mice and humans, for which macromolecular or DNA damage may be the driving force. Of note, many of the trans-genes we identified are involved in the DNA damage response and are frequently mutated in various cancers. Hence, genomic stress, due either to hyperproliferation or DNA damage, may drive upregulation of well-established ageing pathways, downregulation of intra-cellular metabolism, and altered regulation by proteins associated with increased variability of DNA methylation. In contrast to aDMPs, aVMPs show a striking variability in DNA methylation at higher ages. Two individuals of the same age may display highly distinct methylation patterns across aVMPs, where one of them may have a DNA methylation profile at aVMPs that is similar to that of young individuals. Therefore, aVMPs fulfill a primary prerequisite for a biomarker of biological age.

One observation that has emerged in recent years from large epidemiological studies of health and longevity is that greater time spent sitting correlates with a higher risk of death and thus shorter life expectancy. This even seems to be independent of amount of exercise carried out while not sitting, though that aspect of the findings needs further reinforcement to rise to the level of evidence for the more general association between level of inactivity and mortality rates. As for most statistical human studies it is a challenge to move from correlation to understanding the directions and mechanisms of causation, though as ever we can reference the numerous animal studies in which it is shown that increased activity is very definitely a cause of reduced mortality. This latest paper to look at the "chair effect" is more food for thought on the topic. The national differences suggest that this, like most correlations, reflects the operation of numerous interacting environmental factors:

Exercising and not spending so much time on the couch tend to be some of these good intentions. 31% of the worldwide population does not meet the current recommendations for physical activity according to several studies. In addition, a lack of exercise is associated with major noncommunicable diseases and with deaths of any cause - inactivity is the culprit behind 6% to 9% of total worldwide deaths. Today's lifestyle has an impact on these numbers. In fact, various studies over the last decade have demonstrated how the excessive amount of time we spend sitting down may increase the risk of death, regardless of whether or not we exercise. A new study now estimates the proportion of deaths attributable to that 'chair effect' in the population of 54 countries, using data from 2002 to 2011. "It is important to minimise sedentary behaviour in order to prevent premature deaths around the world, cutting down on the amount of time we sit could increase life expectancy by 0.20 years in the countries analysed."

The results reveal that over 60% of people worldwide spend more than three hours a day sitting down - the average in adults is 4.7 hours/day - and this is the culprit behind 3.8% of deaths (approximately 433,000 deaths/year). The highest rates were found in Lebanon (11.6%), the Netherlands (7.6%) and Denmark (6.9%), while the lowest rates were in Mexico (0.6%), Myanmar (1.3%) and Bhutan (1.6%). Spain falls within the average range with 3.7% of deaths due to this 'chair effect'. The authors calculate that reducing the amount of time we sit by about two hours (i.e., 50%) would mean a 2.3% decrease in mortality (three times less), although it is not possible to confirm whether this is a causal relationship. Even a more modest reduction in sitting time, by 10% or half an hour per day, could have an immediate impact on all causes of mortality (0.6%) in the countries evaluated.

Link: http://www.agenciasinc.es/en/News/Sitting-for-long-periods-of-time-is-the-cause-of-4-of-deaths-worldwide

If cancer results from mutation, then why don't species with more cells have more cancer? That is clearly not the case. Whales, for example, have a lower rate of cancer than humans despite having something like a thousand times as many cells as we do. Mice have a much higher rate of cancer than we do. This is Peto's paradox in a nutshell, and the observation is the basis for a range of fundamental research that seeks to understand large variations in cancer rates across mammalian species, and then perhaps do something with that understanding. This paper looks at the evolutionary origins of this variation between species of differing sizes:

Multicellularity is risky. Every cell could, in principle, escape the checks and balances of healthy organisms that keep individual cells from proliferating in an uncontrolled manner and cause cancer. If having many cells is risky, then having even more cells should be even riskier. If the hazard rate increases with age, then a longer life should progressively increase cancer risk. Hence, large, long-lived organisms are expected to suffer a higher lifetime cancer risk than small, short-lived organisms. This does not seem to be the case; an apparent contradiction known as Peto's paradox. There is significant recent interest in Peto's paradox and the related problem of the evolution of large, long-lived organisms in terms of cancer robustness. Peto's paradox, however, is circular. The paradox relies on assuming a certain lifespan, after which the cancer risk during that lifetime is evaluated. This seems the wrong procedure. Lifespan is a function, among others, of cancer robustness: organisms are long-lived because they are cancer robust. If not, then they would be short-lived. One cannot next expect that they are not cancer robust and should therefore have a higher lifetime cancer risk, based on the very same lifespan that derives from high cancer robustness. Similarly, large organisms exist because they are cancer robust; one cannot next expect that they are not.

Because no set of competing risks is generally prevalent, it is instructive to temporarily dispose of competing risks and investigate the pure age dynamics of cancer. In addition to augmenting earlier results, I show that in terms of cancer-free lifespan large organisms reap greater benefits from an increase in cellular cancer robustness than smaller organisms. Conversely, a higher cellular cancer robustness renders cancer-free lifespan more resilient to an increase in size. This interaction may be an important driver of the evolution of large, cancer-robust organisms. Large, long-lived animals can exist if and only if they are cancer robust; one cannot next expect them to have a higher lifetime cancer risk because they are not cancer robust. The observation that (cells of) large, long-lived organisms must be more cancer robust than (those of) small, short-lived organisms is shrewd and of great importance, but should have been the endpoint. The expectation that large, long-lived animals should have a higher lifetime cancer risk than small, short-lived organisms is an unnecessary and faulty extra step, as is the resulting paradox when that prediction remains unconfirmed. Given that whales live up to 200 years and weigh up to 200,000 kg, their cancer dynamics differ from those of humans, and the "promise of comparative oncology" stands.

Link: https://dx.doi.org/10.1098/rspb.2016.1510

I see that the Zuckerbergs have set themselves the ambitious goal of ending disease over the course of this century. Don't forget that these are the spokespeople for an organization, not a few individuals making choices. Billionaires are effectively each the head of their own small state with its own politics and varied goals, the center of circles of delegation and machination, and frequently have less freedom to direct resources than you might think they do. Nonetheless:

Chan Zuckerberg Initiative announces $3 billion investment to cure disease

The Chan Zuckerberg Initiative just announced a new program informally called Chan Zuckerberg Science to invest $3 billion over the next decade to help cure, prevent, or manage all disease. The money will bring together teams of scientists and engineers "to build new tools for the scientific community." Part of the $3 billion will go to a $600 million investment in Biohub, a new physical location that which will unite researchers from Stanford, Berkeley, and UCSF with elite engineers to find new ways to treat disease. The majority of deaths are caused by heart disease, infectious disease, neurological disease, and cancer, so those are the areas where the program will concentrate its efforts. Mark Zuckerberg showed visible gusto, noting how our country spends 50x more on treating people who are sick than curing diseases so people don't get sick. "We can do better than that!" he exclaimed. To change this, Zuckerberg explained there must be a shift towards long-term thinking for research that requires more funding than typical academic grants can sustain. That's where his $45 billion fortune comes in.

Ambitious goals are good; far too few people with significant resources also choose to aim high, and the simple possession of wealth certainly doesn't magically grant vision. It is welcome to see that at least some of the wealthy of the world are waking up to the fact that this is an age of biotechnology in which the sky is the limit. The cost of medical research and development has plummeted over the past three decades. Yes, it is true that the straitjacket of regulation ensures that it is ever more costly to actually deploy medicine to the clinic, and that all to many promising lines of research never even get to that point since they couldn't be profitable. That fact serves to hide the reality from casual observers, which is that the actual research itself has become very cheap, and the state of the art in the lab is moving ever further ahead from the state of the art in the clinic. Any line of work using the tools of the biotechnology industry has experienced the same curve in costs and capabilities over the past few decades as computing and telecommunications, the result of advances in materials science and processing power. This is a time to aim high.

You might recall that Sean Parker is funding cancer immunotherapy at a fairly large scale, and then there is the Gates Foundation, funding work on a number of infectious diseases, Paul Allen's large-scale funding for mapping a range of human biochemistry, the Google founders' Calico Labs venture, Larry Ellison's past funding for aging research, and so forth. Where disease and the cause of disease is the target most of these are neither ambitious nor visionary exercises, however. While they bring a large amount of money to the table, very few manage to blaze a new path with that funding. They largely follow the current mainstream strategy, fund later stage scientific work, more development than research, and tend to only incrementally improve outcomes. The Ellison Medical Foundation essentially become a small arm of the National Institute on Aging, for example, and we can point to nothing that changed greatly as a result of those years of additional budget. There is a good chance, given the way things tend to go, that Calico and the Parker Institute for Cancer Immunotherapy will end up at the same destination - incremental increases in funding for existing projects, no meaningful change in strategies that have produced only small gains over the years, no bold steps, no radical advances. It often seems that the more funding one can bring to bear, the more one is constrained to do nothing new with it. To be sure more funding for research is better than less funding for research, but there is a very large difference between investing intelligently and taking calculated risks for a shot at large gains in medical capabilities and simply investing in the current mainstream, whatever that might be. Real, radical progress and the foundation for the next generation of medicine tends to come from the fringes of a field, not the established institutions.

The Zuckerberg vision is a good one, but we shall see how that translates to reality in the years ahead. There is only one way to bring an end to heart disease and the other diseases of aging, and that is to control the causes of aging - to repair or make irrelevant the molecular damage that gives rise to degeneration, decline, and disease, as outlined in the SENS proposals. I will be pleasantly surprised to see that approach showing up anywhere in practice in this venture, however, as it isn't yet reflected in the mainstream consensus on strategy in the research community. The bold visions of past ventures largely gave way to work that was prosaic and mediocre in ambition, subsumed by the short-term targets of small, incremental gains. So on the one hand I'm not optimistic that this, rather than any other past or existing venture, will be the one to break the mold. On the other hand there's a lot to cheer about when people with access to world-changing levels of resources acknowledge that ending disease is a viable goal for this age of biotechnology, and set their sights on it, in word at least. That is a part of the persuasion that must continue to happen in order to bring ever more resources to bear on progress in medicine, and in order to have a decent chance at realizing the potential of medical science to bring an end to all of the presently common causes of death. The more funding that there is in general, the more of that funding that we can persuade to go towards SENS-like strategies that stand a real chance of producing radical improvements in health and longevity, rather than the mainstream research strategies that largely cannot achieve such goals soon enough to matter.

Most research into the mechanisms of aging starts with cells and then moves to short-lived species such as flies or nematode worms - easier to manage than mice, and the short life spans mean that more work can be carried out for a given amount of funding and time. Only later do more promising projects move to the use of mice. At each stage of the process, from cells to worms, from worms to mice, from mice to people, many research results fail to prove relevant. Worms are not mice, and mice are not people. There are significant differences, for all that many of the most fundamental aspects of aging and cellular biochemistry are remarkable similar in all of these species. The paper here, the full text in PDF format only I'm afraid, is an interesting attempt to put some numbers to the degree to which nematodes and mice are different in the matter of aging and interventions that slow aging.

Given the existence of subtle but important differences that can produce the results outlined here, then it may well be the case that the development of reliable biomarkers of aging should be prioritized to a greater degree and work in nematodes and the like largely abandoned in favor of short mouse studies that assess effects on aging through the use of biomarker tests. The discussion below should be considered in the context of the comparatively small changes in life span achieved by most interventions, where it is reasonable to ask how that change came about and whether it was due to an influence on aging or some other factor. The future of the field, assuming that SENS rejuvenation research prospers, is to create increases in life span and health span so large that there is no room for debate as to what is taking place.

It has been argued that an extension of lifespan may not necessarily be concrete evidence of a retardation of the aging process. In this view, a lifespan-extending intervention may simply remedy deficiencies in the environment or in the genetic make-up of one particular strain. The intervention would therefore extend lifespan by correcting specific flaws rather than altering the aging process. These considerations create a conundrum: if lifespan is not a reliable measure of aging, how can we confirm that a particular manipulation truly affects the aging process? One approach is to assess physiological phenotypes which are known to deteriorate with age, such as cognition or the functioning of the cardiovascular or immune systems, in order to detect similarities or discrepancies with the patterns observed in control strains. An alternative criterion is to consider whether a particular manipulation changes how mortality rates increase with age. This is based on the hypothesis that the increased incidence of the age-related pathological changes that characterizes the aging process is reflected in changing mortality rates.

In the Gompertz model of mortality, 'G' describes the rate at which mortality rates accelerate with age and 'A' represents the initial mortality rate at time 0. 'A' is strictly theoretical as a mortality rate, since there can be no actual mortality at time 0. Instead, it can be determined by extrapolation from mortality rates at greater ages, and does not necessarily correspond to true mortality rates at birth or during youth. Decreasing 'A' extends lifespan by shifting the inflection point of the curve rightwards, such that it occurs proportionally later in age, relative to maximum lifespan. There is no change in the apparent "slope" of the curve. In contrast, decreasing 'G' extends lifespan by decreasing the slope. 'A' has been described as measuring the vulnerability to disease unrelated to the onset of aging, or the effect of the environment on mortality. Changes to 'A' will alter mortality rates evenly across the lifespan of the population. In contrast, since the parameter 'G' can be considered a rate constant for the age-related increase of mortality of a sample or population, it is often given a pre-eminent role as an indicator of the "rate of aging". This is a logical hypothesis, since an increased or decreased 'G' would likely reflect the rate at which physiological conditions are declining with age. Therefore it is often assumed that interventions that extend lifespan by slowing aging, rather than by alleviating some age-independent pathology, will be associated with a decreased 'G'.

Since a substantial number of studies reporting changes in mouse lifespan resulting from genetic manipulations have now been published, we hypothesized that a correlation-based approach may be a more powerful technique to search for patterns in Gompertz parameter shifts. For example, a negative correlation between lifespan and 'G' across long-lived lines of mice would suggest that their extended longevity was due to a decreased rate of aging. By the straightforward method of plotting Gompertz parameters against lifespan we found that most of the genetically-driven variability in lifespan between normal- or long-lived groups of mice was due to changes in 'A', not in 'G'. In fact, 'G' remained remarkably invariant for different groups of wild-type mice as well as for mice with genetic variations that extend lifespan. The only exceptions to this trend were some interventions which acutely shortened lifespan. We also found this to be true for a collection of inbred mice strains studied under uniform conditions as part of the Mouse Phenome Database. Thus, with the exception of some severe lifespan-shortening interventions, lifespan in laboratory mice is largely determined by factors that affect initial vulnerability, rather than age-dependent mortality rate acceleration. In contrast to mice, we found lifespan to be associated with changes in 'G', not 'A', among long-lived C. elegans mutants. This was true as a trend across long-lived mutants, and was also observed by analysing changes to Gompertz parameters among numerous replicate studies of the well-characterized daf-2, isp-1, and eat-2 mutants.

Link: http://dx.doi.org/10.1534/genetics.116.192369

The tissue engineering community is making rapid progress in discovering techniques to reliably grow functional tissue structures from cells. The challenge of producing blood vessel networks remains, however, so these tissues are small in size. Any larger and the inner cells would not receive sufficient oxygen and nutrients. This is not to say that these organoids are useless - far from it. They will revolutionize many areas of research by replacing the use of animal models and greatly speeding up activities such as drug discovery and testing. Further, for many tissues the transplantation of multiple organoids to be integrated into an existing organ is a potentially viable approach to improving function and treating degenerative conditions: consider that many organs function as filtration devices or chemical factories, and these functions are only loosely connected to the present shape and location of the organ. To mention one example from recent years, there is nothing to prevent liver, pancreas, and thymus organoid tissue from usefully functioning inside lymph nodes rather than their usual location. Lungs are a less flexible situation, but it is still the case that organoids may be the basis for a useful transplantation strategy in addition to benefiting research efforts:

By coating tiny gel beads with lung-derived stem cells and then allowing them to self-assemble into the shapes of the air sacs found in human lungs, researchers have succeeded in creating three-dimensional lung organoids. The laboratory-grown lung-like tissue can be used to study diseases including idiopathic pulmonary fibrosis, which has traditionally been difficult to study using conventional methods. "While we haven't built a fully functional lung, we've been able to take lung cells and place them in the correct geometrical spacing and pattern to mimic a human lung." The researchers started with stem cells created using cells from adult lungs. They used those cells to coat sticky hydrogel beads, and then they partitioned these beads into small wells, each only 7 millimeters across. Inside each well, the lung cells grew around the beads, which linked them and formed an evenly distributed three-dimensional pattern. To show that these tiny organoids mimicked the structure of actual lungs, the researchers compared the lab-grown tissues with real sections of human lung. "The technique is very simple. We can make thousands of reproducible pieces of tissue that resemble lung and contain patient-specific cells."

Moreover, when researchers added certain molecular factors to the 3-D cultures, the lungs developed scars similar to those seen in the lungs of people who have idiopathic pulmonary fibrosis, something that could not be accomplished using two-dimensional cultures of these cells. Idiopathic pulmonary fibrosis is a chronic lung disease characterized by scarring of the lungs. The scarring makes the lungs thick and stiff, which over time results in progressively worsening shortness of breath and lack of oxygen to the brain and vital organs. After diagnosis, most people with the disease live about three to five years. Though researchers do not know what causes idiopathic pulmonary fibrosis in all cases, for a small percentage of people it runs in their families. To study the effect of genetic mutations or drugs on lung cells, researchers have previously relied on two-dimensional cultures of the cells. But when they take cells from people with idiopathic pulmonary fibrosis and grow them on these flat cultures, the cells appear healthy. Using the new lung organoids, researchers will be able to study the biological underpinnings of lung diseases including idiopathic pulmonary fibrosis, and also test possible treatments for the diseases. To study an individual's disease, or what drugs might work best in their case, clinicians could collect cells from the person, turn them into stem cells, coax those stem cells to differentiate into lung cells, then use those cells in 3-D cultures. Because it's so easy to create many tiny organoids at once, researchers could screen the effect of many drugs.

Link: http://newsroom.ucla.edu/releases/ucla-researchers-use-stem-cells-to-grow-3-d-lung-in-a-dish

If you have an interest in telomerase research, and anyone following developments in the science of aging really should pay attention to telomerase research, then you might find a recent special issue of Genes to be worth reading. It collects a dozen or so papers on the subject, adding to a growing number of reviews, calls to action, and discoveries published in the last couple of years in the field of telomere and telomerase biology. You might look at a very readable review from Maria Blasco's lab, published earlier this year, for example. The researchers there are leaders in telomerase gene therapy, and have demonstrated benefits and a slowing of aging in mice via this path. It remains to be seen how well it will translate to humans, though there are certainly people out there willing to try.

It is possible to describe cancer and aging as two sides of the same coin; the evolved systems that act to suppress cancer also suppress tissue maintenance, and the decline in stem cell activity with age that causes a slow decay of tissue function is a trade-off, balancing death by cancer against death by frailty and organ failure. Cellular replication and growth is the commonality in cancer and maintenance: one is uncontrolled growth, the other controlled growth. One of the most important mechanisms in our cellular biochemistry is the Hayflick limit, and telomeres are a part of the system that creates that limit. Telomeres are lengths of repeated DNA that cap the ends of chromosomes. Every time a cell divides some of that length is lost. When telomeres become too short, a cell halts replication and either destroys itself or becomes senescent and is soon thereafter destroyed by the immune system. Healthy tissues are in a state of balance between loss of cells to the Hayflick limit and the delivery of new cells with long telomeres, created by stem cells. How do stem cells constantly create new daughter cells with long telomeres? They use telomerase to maintain long telomeres: the primary function of telomerase is to add more of the repeating telomeric DNA sequences to the ends of chromosomes.

This ornate situation has evolved because it ensures that cancer incidence is kept low enough for it not to impede evolutionary success. The majority of cells have a limited ability to replicate, and only a small number of cells have unlimited replication rights. This greatly reduces vulnerability to cancerous mutations. Still, cancer happens, and it occurs when cells mutate in one of the few ways that can unlock telomerase or alternative lengthening of telomeres activity, or when stem cells mutate in ways that break their regulatory programs. For cancer researchers, interfering in telomere lengthening is the road to the grail of a universal cancer therapy, a single way to shut down all of the hundreds of types of cancerous tissue. On the other side of the coin, for aging, increased telomerase activity is thought to be a way to spur greater tissue maintenance in older individuals, though the processes by which this happens are many, varied, and much debated, just as the full list of mechanisms of action for stem cell therapies is a matter still under investigation. There is some thought that an increased level of telomerase activity will increase cancer risk, as damaged cells will be allowed to replicate far more often than they have evolved to replicate. Though by the same token, stem cell therapies should be similarly risky. So far the benefits look to outweigh the harms. It may be that our evolutionary point of balance has a fair amount of wiggle room.

Special Issue "Telomerase Activity in Human Cells"

The activity of the reverse transcriptase telomerase is a canonical function to maintain telomeres, the ends of linear chromosomes. Telomeres shorten in the absence of telomerase, causing senescence and ageing. In contrast to other organisms, telomerase activity is downregulated early in development in many somatic human tissues. However, some cell types, such as lymphocytes, adult stem cells, and endothelial cells retain, or can upregulate, telomerase activity. Importantly, this activity is strongly controlled by physiological conditions. In contrast, telomerase activity is continuously expressed at a high level in the majority of cancer cells, contributing to their indefinite proliferation potential. Although telomerase activity has been vigorously investigated over the last few decades, many questions still remain open regarding the mechanisms of physiological regulation in normal cells, as well as its up-regulation during tumourigenesis. The complex regulation at the levels of transcription, splicing, and posttranscriptional activation certainly contribute to that. Recently, interventions into its activation to counteract telomere shortening in healthy tissues, as well as its inhibition as tumour therapy, have been suggested and trials have been started with no final breakthrough yet. Thus, we still need to better understand the biology and regulation of telomerase activity in order to interfere with it successfully.

Telomerase Regulation from Beginning to the End

The vast body of literature regarding human telomere maintenance is a true testament to the importance of understanding telomere regulation in both normal and diseased states. In this review, our goal was simple: tell the telomerase story from the biogenesis of its parts to its maturity as a complex and function at its site of action, emphasizing new developments and how they contribute to the foundational knowledge of telomerase and telomere biology. Telomeric integrity has implications in both cancer and aging, as telomere attrition serves as a key checkpoint in the control of cell proliferation by triggering replicative senescence. There are two broadly defined mechanisms of telomere maintenance in humans: telomerase-mediated maintenance and ALT (alternative lengthening of telomeres). However, the complexity of each of these mechanisms becomes more evident with every new publication in the field of telomere biology. Approximately 80% of cancers are immortalized by constitutive activation of telomerase to maintain telomeres throughout rapid cellular proliferation. Additionally, defects in telomerase and other telomere maintenance components cause premature aging syndromes like dyskeratosis congenita (DC), due to progressive telomere shortening and subsequent proliferative blocks. As such, greater knowledge of telomerase regulation and its contribution to telomere homeostasis will contribute to our understanding of human disease and natural cellular processes alike.

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Many chronic conditions in humans are associated with chronic inflammation, immune system impairment and accelerated aging. In addition, abnormalities in telomere/telomerase system of these patients have been reported in many of these disorders. Since telomerase, an enzyme directly associated with aging, is inactive in most cell types in a mature organism and active in immune system cells, one can easily hypothesize that the immune system dysfunction/accelerated aging observed in chronic conditions is connected with telomeres and telomerase biology. Indeed, a connection of this nature seems to exist since shortened telomeres, observed in aged cells, cause an inflammatory cascade whereas, at the same time, NF-κB, a master regulator of inflammation, seems to directly induce telomerase transcription as stated above. Moreover, many researchers documented correlations between lower telomerase activity and/or shorter telomeres in immune system cells and elevated cytokines in blood serum from patients with chronic disorders. One should also bear in mind that, although aging is a multifactorial and complex procedure, healthy aging and longevity are believed to be associated with longer telomeres and lower inflammation profiles among older individuals. Despite all of the above, and despite the accumulating data of a strong interconnection between telomerase regulation/activity and inflammation, the mechanistical details and the molecular pathways of this connection have not been uncovered yet.

Telomerase: The Devil Inside

Emerging evidence over the last decade supports the idea that telomere length-independent functions of telomerase are also important for its function, both in normal and tumor cells. Interestingly, current research also revealed that telomeres may sense cellular stress (such as genotoxic stress, oncogenic or aneuploidy-inducing mutations) that result from harmful mutations that lead to genome instability and induce senescence in cells with intact checkpoints. Although the mechanistic details of the 'sensing' process are yet to be revealed, this new function of telomeres, thought to be a result of accumulating replication stress at the telomeres, seems to be independent of telomere length. In this context, telomerase relieves this cellular protective mechanism by mitigating telomere replication stress and this function of telomerase apparently is separate from its telomere elongation activity. In light of the recent discoveries hinting at novel, telomere length-independent roles of telomeres and telomerase, attempts at modulating telomerase activity to improve organ function and longevity must be seriously reconsidered. In this line, interfering with telomerase activity and its extracurricular functions for cancer therapy seems to be an attractive strategy again but new concepts need to be taken into account.

Role of Telomerase in the Cardiovascular System

Aging is one major risk factor for the incidence of cardiovascular diseases and the development of atherosclerosis. One important enzyme known to be involved in aging processes is telomerase reverse transcriptase (TERT). It has been proposed for a long time that telomerase activity is absent from human somatic cells. However, there is accumulating evidence that substantial telomerase activity is present in differentiated, non-dividing somatic cells of the cardiovascular system. This is of particular importance since cardiovascular diseases (CVD) are still the leading cause of death worldwide. All of these diseases have a primary defect in the heart or in the blood vessels, and there is emerging evidence that telomerase has a protective effect against CVD. Understanding this enzymes' functions in these tissues could, in the long run, help to reveal the therapeutic potential of activating TERT in cardiovascular diseases.

A fair number of researchers are mining the biochemistry of highly regenerative species in search of the differences that enable regrowth of damaged organs. There is the hope that these differences are in at least some cases small enough that human tissues could be adjusted to perform far greater feats of regeneration. At this point it is far too early to say how likely this is, how long the mapping process will take, or how difficult it will be to build therapies when the relevant differences are identified. There have been a few interesting discoveries in recent years, and this is the latest of these:

In contrast to other vertebrates including humans, the newt can regenerate, even as an adult, an entire retina from retinal pigment epithelium (RPE) cells. In adult vertebrate eyes, the RPE is a highly differentiated monolayer-cell-sheet laminating the back of the neural retina (NR) and functions as a partner of the NR for vision. Mature RPE cells, as a rule, do not proliferate under physiological conditions. In the adult newt, RPE cells in the intact eye are also mitotically inactive, but when the NR is removed from the eye by surgery, RPE cells lose their epithelial characteristics and detach from each other as well as from the basement membrane (Bruch's membrane), giving rise to the aggregates of mesenchymal-like cells with multipotency, named RPE stem cells (RPESCs), in the vitreous cavity. RPESCs are subsequently divided into two cell populations which undergo proliferation, so that they can differentiate into two epithelial layers of progenitor cells (named pro-NR and pro-RPE layers) that eventually regenerate new functional NR and RPE, respectively.

It remains unknown how such a sophisticated mechanism for retinal regeneration evolved in the newt. It would be difficult to understand this mechanism solely by the mechanisms underlying RPE-to-NR transdifferentiation which can be induced in a restricted time frame during embryonic development. In these cases, the RPE does not lose its epithelial characteristics, but directly switches into the neuroepithelium, giving rise to the NR while losing the RPE. On the other hand, our recent studies revealed a similarity in early behaviour of RPE cells between adult newt retinal regeneration and human retinal disorders such as proliferative vitreoretinopathy (PVR). In PVR, when the NR suffers a wound from a traumatic injury, RPE cells - as in the newt - start to lose their epithelial characteristics while acquiring the ability to migrate and proliferate. However, unlike in the newt, these cells eventually transform into myofibroblasts, a major component of both the epi- and sub-retinal membranes which close the wound of the NR, but finally withdraw the NR by contraction, leading to a loss of vision. In this process of transformation (classified as the epithelial-mesenchymal transition, or EMT), it has been suggested that RPE cells pass through a multipotent state. Such multipotent RPE cells in humans, which were also named RPESCs, are regarded as the cells corresponding to the newt RPESCs.

Perhaps, in the newt, something may have happened in early processes of retinal disorders like PVR during evolution, so that the fate of RPESCs was directed toward retinal regeneration. If this is the case, when retinal regeneration in the newt is impaired in early processes, symptoms of PVR would become apparent. In this study, we examined this hypothesis. For this, we created for the first time a transgenic newt enabling RPE-targeted gene regulation and successfully hindered retinal regeneration by knocking down the expression of Pax6 in RPESCs.

It would be difficult to understand by comparison with eye development how normal reprogramming by Pax6 prevents RPE cells from transforming into myofibroblast-like cells. This issue would be of mature RPE cells. Pax6 may function even as a key factor that revises a default program which is booted in mature RPE cells after retinal injury and leads them to EMT. It must be noted here that Pax6 may be expressed in human RPESCs which give rise to myofibroblast cells in PVR. In the newt, something might have happened in RPE cells during evolution so that Pax6 can work properly for retinal regeneration while inhibiting EMT. Further understanding of how Pax6 works in reprogramming RPE cells in the adult newt in comparison with the homologous system in humans is necessary not only to uncover the changes that occurred in the newt during evolution but also to unlock the potency of in vivo retinal regeneration from RPE cells in humans. These findings would lead, in the future, to a novel clinical treatment of RPE-mediated retinal disorders that inhibits the EMT of RPE cells while promoting retinal regeneration in the eyes of patients.

Link: http://dx.doi.org/10.1038/srep33761

Aging is not a linear process, and different causes and consequences of aging run at different paces at different times in later life. In most cases, the rate of decline accelerates. All of our biological support systems, large-scale and small-scale, interact with one another. Damage and dysfunction in one speeds up the progression of damage and dysfunction in others. Just look at failure of cellular maintenance operations, degrading the effectiveness of all tissues, or the decline of the immune system, which is responsible for culling dangerous cells, assisting in healing, and numerous other jobs beyond the better known function of defense against invading pathogens. Here, researchers provide one example among many of the way in which specific manifestations of aging speed up as the years pass:

Presbycusis, or age-related hearing loss (ARHL), affects approximately two-thirds of adults older than 70 years and four-fifths of adults older than 85. It is a major public health concern that is associated with numerous deleterious effects. Currently, there is a global demographic change that has resulted in an increase in the number of older adults. In the United States, the population of individuals older than 80 years is expected to double in the next 40 years. The majority of research in ARHL, however, groups participants older than 70 years into a single category, thus obscuring changes in the severity of hearing loss as individuals live to 80 years or older.

This study included 647 patients 80 to 106 years of age who had audiometric evaluations at an academic medical center (141 had multiple audiograms). The degree of hearing loss was compared across the following age brackets: 80 to 84 years, 85 to 89 years, 90 to 94 years, and 95 years and older. From an individual perspective, the rate of hearing decrease between 2 audiograms was compared with age. The researchers found that changes in hearing among age brackets were higher during the 10th decade of life than the 9th decade at all frequencies for all the patients (average age, 90 years). Correspondingly, the annual rate of low-frequency hearing loss was faster during the 10th decade. Despite the universal presence of hearing loss in this sample, 382 patients (59 percent) used hearing aids. "More attention should be on counseling patients on accepting hearing aids in a longitudinal primary care setting, especially in the population living to 80 years or older."

The scientists here urge greater use of existing compensatory mechanisms, but should also be urging greater funding for work on regenerative medicine for the causes of age-related deafness. There are a number of promising lines of research focused on neurodegeneration in the connections between ear and brain on the one hand and regrowth of hair cells in the ear on the other, for example.

Link: http://media.jamanetwork.com/news-item/rate-of-hearing-loss-increases-significantly-after-age-90-hearing-aids-underused/

The SENS Research Foundations's latest crowdfunding campaign, hosted by Lifespan.io, was focused on one of a number of vital projects in the development of a universal cancer therapy. I'm pleased to note that the campaign closed successfully yesterday, having raised more than $70,000 for this research initiative from nearly 550 donors. The SENS Research Foundation cancer team will be using the funds for the first rigorous exercise of an alternative lengthening of telomeres (ALT) assay to find potential drug candidates that can suppress the ALT mechanisms used by some cancers to sustain their growth.

All cancers must lengthen their telomeres in order to grow, and to do so they abuse either telomerase or ALT. Shutting down telomere lengthening in tumors is thus an approach that should halt any cancer in its tracks. From a strategic point of view, this is enormous difference when compared to the cancer research and development of recent history, in which most therapies are only applicable to a small number of the hundreds of subtypes of cancer. Progress is necessarily slow in that paradigm. There are too many varieties of cancer and too few researchers to keep doing things that way if the goal is to win, to control cancer in the same way and to the same degree as we control most serious infectious disease. The strategy must change, and a class of therapy that works for all cancers, but costs no more to develop than any of the more limited therapies of the past, is just the sort of thing to aim for.

A number of research groups are working on telomerase suppression in cancer, but next to no-one is working on ALT in anywhere near as meaningful a way. Left to its own devices, cancer tends 90% to telomerase and 10% to ALT. Further, telomerase research is fairly well established as a result of its role in stem cell biology and possibly aging, while ALT is a small field with much more left to discover, so this focus on telomerase is understandable. Unfortunately, suppressing telomerase is quite capable of causing a tumor to evolve to use ALT instead - this has been demonstrated in mice. Therefore any effective universal cancer therapy based on a blockade of telomere lengthening must use both approaches at the same time. Someone has to pick up the slack on ALT research, and this is where the SENS Research Foundation comes in. Funds in hand, the researchers can now start working through the most likely prospects in the standard drug library. This should help to obtain a much better understanding of the best directions to take in order to suppress ALT, and in the best possible outcome finds drugs that might be of some use for patients suffering one of the 10% of cancers that use ALT.

Watching progress day to day from the sidelines, I have to say that this was a tough fundraiser - one of the first we've had these past few years that proved to be a real challenge. The target was reached only because a number of very generous donors stepped up to the plate and put up sizable matching funds when they saw that the outcome was in question. As to why this particular crowdfunding effort was a challenge, why is it suddenly harder now, well, that has been discussed here and there. There are a few hypotheses. The first is simply donor fatigue: this community has given very generously to multiple projects over the past few years, but there are only so many of us at the present time. This year's SENS Research Foundation crowdfunding campaign, unlike last year's, followed immediately on the heels of a successful $50,000 fundraiser for senescent cell clearance work in mice, also via Lifespan.io.

The second hypothesis is that during the fundraiser Michael Greve pledged $10 million to SENS rejuvenation research and the companies that will emerge from that research. There is never a bad time for a large donation to be made, and the SENS Research Foundation has justifiably spent much of their time and effort focused on the Project|21 initiative of which this donation is a part. It is always hard to say whether such large donations are going to inspire or reduce donations from the community in the short term. I've seen it go both ways in the past, and it is just as hard to say after the fact whether that was a factor here. We should all be feeling pretty triumphant after the events of this year, frankly. It is a big boost to ongoing efforts to persuade people who can invest large amounts that SENS is the right path forward, and in the long term more large donations mean more of everything as the years go by: a larger community, more grassroots donations, more research and development.

The third and perhaps most interesting hypothesis is that many members of the community of SENS rejuvenation research supporters don't consider cancer to be their problem, as it were. Perhaps people see the vast sums that go towards cancer research and think that this is an area already adequately covered. Or perhaps it is a cognitive disconnect between aging research and cancer research, seeing them as two separate edifices - which they are in many ways at the level of established funding institutions, charities, and advocacy, but not when it comes to the biochemistry of the situation. On the money front, there is a great deal of funding for aging research as well as cancer research, but that doesn't render efforts like those of the SENS Research Foundation irrelevant. The large scale funds in these fields are almost entirely devoted to the status quo of research, work that is only producing incremental gains at best. These are fields that need to be disrupted and led in a more productive direction. That in turn means that there must be funding for the early stage research and novel lines of work that lead to radical leaps and improvements in medicine, and that funding must almost always come from outside the mainstream - a very large proportion of it is philanthropic, just as in this case.

A tough fundraiser is a sign to change strategy a little, I think. I'm fairly certain that it would be hard to repeat last year's $250,000 success at this point. So this year Fight Aging! will be doing something different to support the SENS Research Foundation as the year comes to a close. More on that later.

We all grow old and all lose cognitive function, but different people of the same age exhibit quite a wide range of variation in losses and remaining capabilities. Most researchers are far more interested in investigating relative differences in natural aging, as this aids in the mapping of exactly how aging progresses, than they are interested in building treatments for aging, sad to say. So we see a lot of studies of this sort, generating a greater understanding that is both irrelevant and useless for the age of rejuvenation therapies to come. It won't meaningfully contribute to the production of treatments that can repair the causes of cognitive aging, and after those treatments are widely available no-one will get to the point of suffering this form of degeneration.

A study examines a remarkable group of older adults whose memory performance is equivalent to that of younger individuals and finds that certain key areas of their brains resemble those of young people. While most older adults experience a gradual decline in memory ability, some researchers have described older adults - sometimes called "super agers" - with unusually resilient memories. For the current study, the team enrolled 40 adults ages 60 to 80 - 17 of whom performed as well as adults four to five decades younger on memory tests, and 23 with normal results for their age group - and 41 young adults ages 18 to 35. "Previous research on super aging has compared people over age 85 to those who are middle aged. Our study is exciting because we focused on people around or just after typical retirement age - mostly in their 60s and 70s - and investigated those who could remember as well as people in their 20s."

Imaging studies revealed that these super agers had brains with youthful characteristics. While the cortex - the outermost sheet of brain cells that is critical for many thinking abilities - and other parts of the brain typically shrink with aging, in the brains of super-agers a number of those regions were comparable in size to those of young adults. "We looked at a set of brain areas known as the default mode network, which has been associated with the ability to learn and remember new information, and found that those areas, particularly the hippocampus and medial prefrontal cortex, were thicker in super agers than in other older adults. In some cases, there was no difference in thickness between super agers and young adults. We also examined a group of regions known as the salience network, which is involved in identifying information that is important and needs attention for specific situations, and found preserved thickness among super-agers in several regions, including the anterior insula and orbitofrontal cortex."

Critically, the researchers showed not only that super-agers had no shrinkage in these brain networks but also that the size of these regions was correlated with memory ability. One of the strongest correlations between brain size and memory was found in an area at the intersection of the salience and default mode networks. Previous research has shown that this region - the para-midcingulate cortex - is an important hub that allows different brain networks to communicate efficiently. Understanding which factors protect against memory decline could lead to important advances in preventing and treating age-related memory loss and possibly even various forms of dementia. "We desperately need to understand how some older adults are able to function very well into their seventh, eight, and ninth decades. This could provide important clues about how to prevent the decline in memory and thinking that accompanies aging in most of us."

Link: http://www.massgeneral.org/about/pressrelease.aspx?id=1987

Eusocial insects are distinguished by queens that share the same genes as the workers but that, in many species, have a far longer life span. The expression of genes associated with aging is very different in queens, something that has been observed in both ants and bees. Given this, these species can serve as a laboratory in which to gather evidence for and against a variety of hypotheses about aging, its causes, and the degree to which specific causes are important. This paper is one example among many:

Since senescence is a detrimental process with important societal and economic impacts, substantial effort has been invested into understanding its causes and many theories have been proposed to explain its origins. One of these theories proposes that senescence is caused by macromolecular damage that accumulates with age due to incomplete somatic maintenance. Lifespan is thus expected to be modulated by investment into physiological processes of damage prevention and repair. So far, investigations of somatic maintenance have mostly focused on systems of damage prevention such as anti-oxidants, and have for the most part refuted the hypothesis that longevity is achieved through damage prevention. A possible explanation for this patterns is that there is a limited potential to freely modulate the amount of reactive oxygen species because they are important signalling molecules. Such constraints are unlikely to apply to systems of macro-molecular repair, which may effectively affect lifespan by modulating the accumulation of damage with age.

Various forms of macromolecular damage have been linked to senescence. For example, DNA may be damaged or mutated in several ways, and there is evidence from mammalian studies that mutations to genes involved in DNA repair accelerate senescence. Similarly, the cellular accumulation of damaged proteins can be toxic and a range of maintenance mechanisms exist to keep this accumulation in check, many of which have been linked to ageing and longevity. One such mechanism is the Ubiquitin Proteasome System (UPS), which degrades mis-folded or damaged proteins by labelling them with ubiquitin and subsequently degrading them. Subunits of the proteasome involved in the UPS have been found to be associated with lifespan and stress resistance in a range of species, from yeast to humans.

The aim of this study is to investigate whether natural variation in lifespan is associated with differential expression of genes involved in the repair of DNA and proteins. To study the role of these somatic repair genes, we take advantage of the striking variation found in social insects, where queens and workers can differ in their lifespan by more than an order of magnitude. Importantly, the difference in lifespan must be due to differences in gene expression, since there are usually no genetic differences between castes. A particularly interesting species for studies of ageing is the ant Lasius niger, where queens can survive as long as 29 years whereas workers live for only one or two years even in laboratory conditions. Since lifespan is expected to be modulated by investment into somatic damage repair, we test the prediction that queens of L. niger have higher expression of somatic repair genes than workers.

Our analysis of 20 somatic repair genes revealed that queens and workers did not differ in their pattern of expression in 1-day-old individuals. The level of expression of these genes increased with age and this up-regulation was slightly greater in queens than in workers, resulting in significantly queen-biased expression of the 20 somatic repair genes in 2-month-old individuals in both legs and brains. Similarly, analysis of 244 genes related to DNA repair revealed no effect of caste on expression in 1-day-old individuals, but a greater up-regulation with age in queens than workers, resulting in significant queen-biased expression in the legs of 2-month-old individuals. Overall, the combination of these analyses indicates a lack of concerted differences in somatic repair gene expression between 1-day-old queens and workers, but a significantly higher level of expression in queens than workers in 2-month-old individuals.

Overall, the differences in somatic repair gene expression that we have identified between queens and workers are consistent with the hypothesis that longevity is associated with investment into somatic repair. This contrasts with results from studies investigating the process of damage prevention through anti-oxidant enzymes in social insects, where expression of antioxidant genes was found to be higher in workers than queens, perhaps to compensate for workers' the increased levels of activity. Our results suggest that damage repair may be more relevant to lifespan than removal of antioxidants. One reason for this could be the important role that antioxidants play in critical biological processes, which prevents them from being freely modulated.

Link: http://dx.doi.org/10.18632/aging.101027

Today I thought I'd point out one of the recent results to emerge from the discovery that DNA methylation patterns correlate well with age. These patterns best correlate not with chronological age, but with biological age, as they reflect the pace at which cell and tissue damage has accumulated. They are thus a potential biomarker capable of distinguishing natural variations in the pace of aging between individuals. The authors of the paper linked below show that, per their chosen forms of DNA methylation assessment of age, stroke patients tend to be biologically older. This all ties together very well: age-related diseases are caused by an accumulation of molecular damage. That damage takes the same form in every individual, and thus the cellular reactions to that damage are much the same. These reactions include alterations in DNA methylation, a part of the epigenetic system of controls that determine whether and how rapidly various proteins are manufactured from their genetic blueprints. Variations in aging between individuals take the form of more or less damage at a given age, and thus these methylation patterns reflect an earlier or later age by level of damage. More damage means a greater risk of biological systems failures, such as chronic age-related disease or incidents like stroke.

The paper below is but one example of a range of initiatives focused on building and trialing accurate biomarkers of biological age. DNA methylation patterns are the best and most advanced of these to date; there has been something of a blossoming in this part of the field as researchers eagerly apply and attempt to validate this class of biomarker. For example, a recent study showed that older age as assessed by a methylation clock correlates with higher mortality. This isn't just about the gloomy matter of being able to quantify exactly where in the downward spiral of degenerative aging any one particular individual might be, however. The real advance in the state of the art that accompanies a reliable biomarker for aging is the ability to quickly and cheaply assess the potential of newly developed rejuvenation therapies. At present the only way to figure out whether something works or not is to, at minimum, run a lifespan study in a large enough number of mice to ensure statistical significance. That is something that tends to cost millions and take years, and such a high level of required investment means that there is far less experimentation and development than might otherwise be the case. But if that can be cut down to a month-long study with a biomarker test at beginning and end? Well, a much larger set of laboratories and projects now become contenders - and, as an added bonus, the proposals that don't in fact work will be quickly winnowed rather than lingering on in a state of uncertainty.

One thing to take away from this particular paper is that there is a still a fair way to go for DNA methylation - or another approach to a biomarker of biological age - to reach desirable levels of accuracy. It is still better than other candidate biomarkers, but at present would only be capable of detecting fairly large effects if used to assess interventions intended to slow or reverse the aging process. That might be good enough for the type of therapies proposed in the SENS vision of rejuvenation biotechnology: large positive effects on molecular damage and aging are the goal, after all. As work on the SENS approach of senescent cell clearance progresses, we'll soon enough be seeing DNA methylation biomarkers used as a matter of course in mouse studies of that rejuvenation treatment, I'd imagine.

Ischemic stroke patients are biologically older than their chronological age

Ischemic stroke (IS) is a complex age-related disease with high mortality and long-term disability. Despite current attention to risk factors and preventive treatment, the number of stroke cases has risen in recent decades, likely because the aging population has increased. Stroke pathogenesis involves a number of different disease processes as well as interactions between environmental, vascular, systemic, genetic, and central nervous system factors. Approximately 10% of IS occurs in individuals younger than 50 years, which is called "young stroke". In older patients, stroke remains associated with the traditional risk factors: hypertension, hypercholesterolemia, diabetes mellitus, and obesity.

The epigenetic marker that has been studied most extensively is DNA methylation (DNAm), which is essential for regulation of gene expression. This mechanism consists of the covalent addition of a methyl group to a cytosine nucleotide, primarily in the context of a CpG dinucleotide. This dinucleotide is quite rare in mammalian genomes (~1%) and is clustered in regions known as CpG islands. Methylation of the CpG island is associated with gene silencing. DNAm is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. Given its dynamic nature, epigenetics has been referred to as the interface between the genome and the environment.

Age-related changes in DNA methylation are well documented, and two recent studies used methylation measured from multiple CpGs across the genome to predict chronological age in humans. Hannum et al created an age predictor from whole blood DNA, based on a single cohort of 656 individuals aged 19 to 101 years. Horvath developed a multi-tissue age predictor using DNA methylation data from multiple studies. Both models are based on the Illumina BeadChip. The difference between chronological age and methylation-predicted age, defined as average age acceleration (Δage), can be used to determine whether the DNAm age is consistently higher or lower than expected. These age predictors are influenced by clinical and lifestyle parameters, they are predictive of all-cause mortality, indicating that they are more suggestive of biological age than of chronological age.

Age is one of the main risk factors for stroke. We hypothesized that biological age would be even more closely associated with stroke risk, and that "young stroke" patients may be undergoing accelerated aging, with a higher biological than chronological age. We examined a cohort of 123 individuals, 41 controls and 82 patients with IS, matched by chronological age. We initially used two approaches described in the literature to predict biological age, the Hannum and Horvath methods. The average biological age of controls showed a mean Hannum-predicted age higher than their chronological ages by a mean of 1.1 years; their Horvath-predicted age was lower than their chronological ages by 4.6 years. In patients with IS, we observed a Hannum-predicted age higher than their chronological age by a mean of 3.3 years, statistically significant compared to controls. Their Horvath-predicted age was lower than their chronological ages by 3.2 years. DNAm age had a strong positive correlation with chronological age in control samples (0.93 for both Hannum and Horvath methods, and 0.94 between the Hannum- and Horvath-predicted ages). In IS cases, the correlations were lower (0.83 for the Hannum method, 0.72 for the Horvath method, and 0.82 between the two. Although both age predictors showed high accuracy in our samples, Hannum DNAm age performed better, with fewer differences in chronological age in controls and better correlation in patients with IS than the Horvath method.

The sensitivity analysis evaluating which age predictor performed better in our study determined that the Hannum predictor was superior. This is likely because this method is constructed on the basis of DNA methylation data from whole blood, like our data, while the Horvath method is constructed on a range of different tissues and cell types. In conclusion, we found that IS status was associated with a significant increase in Hannum DNA methylation, likely as a consequence of the accumulation of cardiovascular risk factors, and near signification with Horvath method. Patients with IS were biologically older than controls, a difference that was more obvious in young stroke. This could open up the possibility of useful new biomarker of stroke risk.

Hypertension, increased blood pressure with age, is caused by stiffening of blood vessels. That stiffening is in turn caused by some combination of cross-linking, cellular senescence, calcification, and inflammation. Cross-linking is probably the largest contribution, but until methods of clearing cross-links are created it will be hard to say for sure. Persistent cross-links are formed when sugary compounds, the vast majority of them based on glucosepane, link together molecules in the extracellular matrix, limiting their range of movement. This causes a loss of elasticity in tissues like skin and blood vessels, and that in turn leads to hypertension, and then everything caused by hypertension: detrimental remodeling of heart tissue, damage to brain and kidneys as small vessels and delicate structures are destroyed, and so forth. The higher the blood pressure the worse the long-term prognosis. This research measures just how many lives might be saved through the development of therapies to clear the cross-links that produce arterial stiffness, something that, sad to say, very few groups outside the SENS Research Foundation are working on:

Intensive treatment to lower systolic blood pressure to below 120 would save more than 100,000 lives per year in the United States. Two thirds of the lives saved would be men and two thirds would be aged 75 or older, according to the study. Current guidelines recommend keeping systolic blood pressure below 140 mm Hg. "When the treatment goal was lowered to a maximum of 120 mm HG, there was a huge reduction in mortality. Few other medical interventions have such a large effect." To determine whether intensive treatment to lower systolic blood pressure could alter mortality, the researchers applied findings from the Systolic Blood Pressure Intervention Trial (SPRINT) to the U.S. adult population.

The SPRINT trial, which included more than 9,350 adults ages 50 and older who had high blood pressure and were at high risk for cardiovascular disease. The SPRINT trial found there was a 27 percent reduction in mortality from all causes when systolic blood pressure was lowered to below 120 mm Hg, compared to the standard care of lowering blood pressure to below 140 mm Hg. While saving lives, an intensive blood pressure regimen also would cause serious side effects. The study estimated that approximately 55,500 more episodes of low blood pressure, 33,300 more episodes of fainting and 44,400 additional electrolyte disorders would occur annually with implementation of intensive systolic blood pressure lowering in U.S. adults who meet SPRINT criteria. Most of these effects would not be expected to have lasting consequences and would be reversible by lowering blood pressure medications.

High blood pressure, or hypertension, is a leading risk factor for heart disease, stroke, kidney failure and other health problems. An estimated 1 in 3 people in the United States has high blood pressure. In the SPRINT study, patients who were treated to achieve a standard target of less than 140 mm Hg received an average of two different blood pressure medications. The group treated to achieve a target of less than 120 mm Hg received an average of three medications. Using data from the National Health and Nutrition Examination Survey, researchers determined that more than 18.1 million American adults met the criteria of patients enrolled in the SPRINT trial. They estimated that, among these 18.1 million adults, fully implementing an intensive regimen to lower systolic blood pressure below 120 mm Hg would prevent approximately 107,500 deaths per year.

Link: http://www.newswise.com/articles/lowering-systolic-blood-pressure-would-save-more-than-100-000-lives-per-year-study-finds

Researchers here claim that the use of cold plasma, ionized gas, can improve wound healing. Other research in past years has suggested that tinkering with the electromagnetic environment of tissues can produce changes in cellular behavior, so this isn't completely out of left field. The effects seem fairly marginal at this point, however, and note that this particular study is in cell cultures, not living tissues, though past efforts have looked at effects on animals and people. The outcome of this study suggests that what they are looking at is perhaps some form of hormesis, whereby a little damage triggers greater repair efforts in cells for a net gain, but bear in mind that cell cultures are very different in many ways when compared with actual tissues.

Researchers have found that treating cells with cold plasma leads to their regeneration and rejuvenation. This result can be used to develop a plasma therapy program for patients with non-healing wounds. Non-healing wounds make it more difficult to provide effective treatment to patients and are therefore a serious problem faced by doctors. These wounds can be caused by damage to blood vessels in the case of diabetes, failure of the immune system resulting from an HIV infection or cancers, or slow cell division in elderly people. Treatment of non-healing wounds by conventional methods is very difficult and in some cases impossible. Cold atmospheric-pressure plasma refers to a partially ionized gas (the proportion of charged particles in the gas being close to 1%) with a temperature below 100,000K. Its application in biology and medicine has been made possible by the advent of plasma sources generating jets at 30-40°C.

An earlier study established the bactericidal properties of low-temperature plasma, as well as the relatively high resistance of cells and tissues to its influence. The results of plasma treatment of patients with non-healing wounds varied from positive to neutral. The authors' previous work prompted them to investigate the possibility that the effect of plasma treatment on wound healing could depend on application pattern (the interval between applications and the total number of applications). Two types of cells were used in this study, viz. fibroblasts (connective tissue cells) and keratinocytes (epithelial cells). Both play a central role in wound healing. The first set of samples (cells) was treated by plasma once (A), while the second and the third sets were treated two (B) and three (C) times with 48 and 24 hour intervals respectively. The effect of plasma treatment on cells was measured. In fibroblast samples, the number of cells increased by 42.6% after one application (A) and by 32.0% after two applications (B), as compared to the untreated controls. While no signs of DNA breaks were detected following plasma application, an accumulation of cells in the active phases of the cell cycle was observed, alongside a prolonged growth phase. "The positive response to plasma treatment that we observed could be linked to the activation of a natural destructive mechanism called autophagy, which removes damaged organelles from the cell and reactivates cellular metabolic processes."

Link: https://mipt.ru/english/news/cold_plasma_will_heal_non_healing_wounds

The SENS Research Foundation has assembled a set of narrated cellular biochemistry animations that serve as an introduction to the various distinct projects that make up the field of rejuvenation biotechnology. The videos outline the forms of cell and tissue damage that are the root cause of aging and age-related disease, as well as the classes of therapy that could, once constructed, either repair that damage or bypass it entirely. Since aging is exactly an accumulation of damage and the consequences of that damage, repair of the damage is the basis for rejuvenation, the reversal and prevention of degenerative aging and all age-related disease. The goal for the near future is to align ever more of the research community and its funding institutions with this goal, and make real progress towards bringing an end to the pain, suffering, and disease of aging.

Introducing SENS - Metabolism, Damage, Pathology

Many things go wrong with aging bodies, but at the root of them all is the burden of decades of unrepaired damage to the cellular and molecular structures that make up the functional units of our tissues. As each essential microscopic structure fails, tissue function becomes progressively compromised - imperceptibly at first, but ending in the slide into the diseases and disabilities of aging. SENS Research Foundation's strategy to prevent and reverse age-related ill-health is to apply the principles of regenerative medicine to repair the damage of aging at the level where it occurs. We are developing a new kind of medicine: regenerative therapies that remove, repair, replace, or render harmless the cellular and molecular damage that has accumulated in our tissues with time. By reconstructing the structured order of the living machinery of our tissues, these rejuvenation biotechnologies will restore the normal functioning of the body's cells and essential biomolecules, returning aging tissues to health and bringing back the body's youthful vigor.

ApoptoSENS - Clearing Senescent Cells

Senescent cells began their existence skin cells, or as related cells that normally play supporting roles in other organs, but were forced into an abnormal state where they lost the ability to divide and reproduce themselves as a protective response to some danger. In addition to halting growth, senescent cells secrete abnormally large amounts of proteins that inflame the immune system and degrade the normal supporting tissue architecture. The relatively small number of such cells in a youthful tissue is so small as to be harmless, but after decades of accumulation, the number becomes large enough that their abnormal metabolic state begins to pose a threat to surrounding, healthy tissues. Larger numbers of senescent cells in a tissue make it more vulnerable to the spread of cancer, contribute to inflammation, and skew the local activity of the immune system.

The most straightforward approach to dealing with these cells is to destroy them. There are two main approaches that could be used to achieve this: (1) develop a drug that is toxic to the unwanted cells, or that makes them commit suicide, but that doesn't harm healthy, normal cells; or (2) stimulate the immune system to selectively seek out and kill the target cells. The most likely way to selectively target these abnormal cells would be to make use of the distinctive molecules that occur on their surfaces. Luckily, different cell types tend to have different things on their surfaces, which play particular parts in their specialized roles in the tissue, so it is a matter of identifying and targeting cell-surface markers that are specific to these abnormal cell types.

AmyloSENS - Dissolving the Plaques

The most well-known form of extracellular junk is beta-amyloid: the stifling, web-like material that forms plaques in the brains of patients with Alzheimer's disease, and also (more slowly) in everyone else's, and impairs cognitive function. There are also a variety of similar aggregates that form in other tissues during aging and contribute to age-related diseases, including islet amyloid in type 2 diabetes and senile cardiac amyloidosis, which is a major contributor to heart failure. In fact, there is some evidence that senile cardiac amyloidosis may be the main cause of death in people who survive beyond age 110.

Extracellular aggregates can be removed from the brain and other areas of the body by specialized antibodies that hone in specifically on them and remove them from the tissue. There two main ways to introduce these antibodies into a person: "active" and "passive" vaccines. "Active" vaccines introduce a small fragment of the amyloid to stimulate the cells of the immune system to target the amyloid and remove it. "Passive" vaccines involve making the antibodies outside of the body, and introducing them directly via injection. More recently, a third and extremely promising variation on this approach has been developed. Researchers have discovered that a subset of human antibodies have catalytic activity against a particular antigen, breaking it down into smaller and less harmful fragments instead of trapping it for removal or destruction by other immune cells.

GlycoSENS - Breaking Extracellular Crosslinks

Many of the major structural features of the body are built out of proteins that are laid down early in our life, and then more or less have to last for a lifetime. The healthy functioning of these tissues relies on these constituent proteins maintaining their proper structure. Such proteins are responsible for the elasticity of the artery wall, the transparency of the lens of the eye, and the high tensile strength of the ligaments, for example. But occasionally, blood sugar (and other molecules in the fluids in which these tissues are bathed) will react with these proteins, creating chemical bonds called crosslinks. Crosslinks act like molecular "handcuffs," taking two neighboring proteins that were previously able to move independently of one another and binding them together.. In the case of the artery wall, for instance, the crosslinking of strands of the protein collagen prevents them from spreading apart from one another to accommodate the surge of the pulse being driven forward by the pumping action of the heart. As more and more strands of collagen become crosslinked together over time, the blood vessels to become ever more rigid, leading to a gradual rise in systolic blood pressure with age. With the loss of the cushioning effect provided by free-moving collagen in the blood vessels, the force of the surge of blood that is driven into the arteries by the pumping action of the heart is carried directly to organs like the kidneys and the brain, damaging to the structures that filter our blood and that connect the functional regions of our brain, and putting us at risk of a stroke.

Fortunately, the crosslinks that occur as chemical accidents in our structural tissues have very unusual chemical structures, which are not found in proteins or other molecules that the body makes on purpose. This should make it possible to identify or design drugs that can react with the crosslinks and sever them, without breaking apart any essential structural bystanders. So the search is on now to develop new and more human-specific crosslink breakers. It's now known that the single greatest contributor to total unintentional collagen crosslinking in humans is a very complex molecule called glucosepane; therefore, drugs that cleave this molecule are likely to have the strongest rejuvenative effect on tissue elasticity.

RepleniSENS - Replacing Lost Tissues

Every day, our cells are damaged by both tiny molecular-level insults and by obvious trauma. Some of these damaged cells are repaired, but others are either destroyed, or forced into a dysfunctional 'senescent' state where they can no longer divide, or commit 'cellular suicide' (apoptosis) for the greater good of the body. Some of the lost cells are replaced by the pools of specialized, tissue-specific stem cells, but the degenerative aging process makes these stem cell pools less effective at repair over time. The net result is that over the course of many decades, long-lived tissues like your brain, heart, and skeletal muscles begin to progressively lose cells, and their function becomes increasingly compromised.

The solution to this problem involves the rejuvenation biotechnologies with which most people are most familiar: cell therapy and tissue engineering, the science of growing organs for transplant in an artificial, biodegradable scaffold outside the body. The foundations of this form of medicine lie in the transplantation of organs and tissues that we already use to replace the blood of chemotherapy patients or the kidneys of dialysis patients. In addition to replacing lost, dying, or dysfunctional cells, the ability to engineer new cells and tissues gives us an opportunity to use them as delivery systems for other rejuvenation biotechnologies.

LysoSENS - Reversing Heart Disease

The proteins and other constituents of our cells are all eventually damaged as the result of biochemical accidents that occur during normal metabolism, or simply outlive their usefulness. Cells have a variety of systems for breaking down and recycling such unwanted materials, allowing them to clear garbage out of the way and reuse the raw materials. One such system is the lysosome, a kind of cellular "incinerator" that contains the most powerful enzymes in the cell for breaking mangled molecules down into manageable pieces. However, sometimes these constituents are so badly fused together that not even the lysosome is able to tear them apart. And if something can't be broken down in the lysosome, there's nowhere else for it to go: it just stays there until either the lysosome disastrously ruptures, or the cell itself is destroyed.

Since the root of the problem is that the lysosome is unable to break down all of these stubborn waste products, the most direct solution is to supply them with new enzymes that can degrade those wastes. And fortunately, we know that enzymes capable of breaking down these materials exist - specifically, in the soil bacteria and fungi that help to decompose dead bodies. If such enzymes didn't exist, then the planet would be ankle-deep in the undegraded lysosomal wastes left over from the cells of 600 million years of animal life on this planet. So the idea would be to identify the enzymes these organisms use to digest lysosomal wastes, modify them a bit to help them work in the slightly different environment of the human lysosome, and then deliver them to where they need to go in our cells.

OncoSENS - Stopping Cancer at the Starting Line

Two types of damage accumulate in our genes as we age: mutations and epimutations. Mutations are damage to the DNA sequence itself, whereas epimutations are damage to the "scaffolding" of that DNA, which controls how and when genes get turned on in the cell. For practical purposes, both mutations and epimutations ultimately harm us in the same way: by causing abnormal gene expression. So what kind of harm can the changes in gene expression resulting from (epi)mutations cause? The one that most people know about is cancer, which is the result of a series of (epi)mutations that happen in sequence in the cell, leading to its uncontrolled growth.

Fortunately, a strategy to achieve extremely strong protection against cancer does exist, although its implementation is extremely challenging. This strategy is based on the one inescapable vulnerability that all cancer cells share in common: their absolute need to renew their telomeres. Because cancer cells reproduce at a furious pace, they quickly reach the ends of their telomeric "ropes," and need to find a way to lengthen them again in order to keep going. Successful cancer cells are the ones that have evolved mutations that exploit one of the cell's two systems for renewing telomeres: either a primary system called telomerase, or in a few cases an "alternative" system appropriately called Alternative Lengthening of Telomeres (ALT). If a nascent cancer can't find a way to seize hold of the telomerase-lengthening machinery, their telomeres will run down, their chromosomes will fray, and the cell will be destroyed before it can kill us. So despite their diversity, all cancer cells share one critical thing in common: they are absolutely dependent for their survival on their ability to hijack telomerase (or, less frequently, ALT). This fact has led the search for drugs that inhibit telomerase activity in cancer cells to become one of the hottest areas of cancer research today.

MitoSENS - Preventing Mitochondrial Aging

Mitochondria are the living machines within cells that act as their "power plants," converting the energy-rich nutrients in our food into ATP that directly powers biochemical reactions in the cell. Unlike any other part of the cell, mitochondria have their own DNA (mtDNA), separate from the DNA in the cell's nucleus, where all the rest of our genes are kept. Just like real power plants, mitochondria generate toxic waste products in the process of "burning" food energy as fuel - in this case, spewing out highly-reactive molecules called free radicals, which can damage cellular structures. And the mtDNA is especially vulnerable to these free radicals, because it is located so close to the center of its production. At worst, a free radical "hit" to the mtDNA can cause major deletions in its genetic code, eliminating the mitochondria's ability to use the instructions to make proteins that are critical components of their energy-generating system. Lacking the components needed to produce cellular energy the normal way, these mutant mitochondria enter into an abnormal metabolic state to keep going - a state that produces little energy, while generating large amounts of waste that the cell is not equipped to metabolize. Perversely, the cell tends to hang onto these defective, mutant mitochondria, while sending normal ones to the recycling center, so if just one mitochondrion suffers a deletion, its progeny quickly take over the entire cell.

It would be ideal if we could prevent mitochondrial deletions from happening, or fix them after they've occurred before they can do harm; unfortunately, the state of the science is nowhere near the point where this would be a realistic goal. Instead, the MitoSENS strategy is to accept that mitochondrial mutations will occasionally happen, but engineer a system to prevent the harm they cause to the cell. We can do this by putting "backup copies" of the mitochondrial genes into the nucleus, where they cannot be damaged by free radicals generated in the mitochondria. That way, even if the original genes in the mitochondrial are deleted, the backup copies will be able to supply the proteins needed to keep normal energy production going, allowing the cellular power plants to continue humming along normally and preventing them from entering into the toxic, mutant metabolic state.

Researchers here look into protein synthesis rates in nematodes engineered to live twice as long via manipulation of the DAF-16 gene, analogous to FOXO in mammals. The goal is to reach for a better understanding of the relationship between various classes of molecular damage, quality assurance mechanisms, repair activities, and rate of aging. This is, needless to say, a very complex topic, full of counterintuitive results and baroque interactions between intricate evolved subsystems of the cell.

Cellular protein quality can be maintained by proteolytic elimination of damaged proteins and replacing them with newly synthesized copies, a process called protein turnover. Protein turnover rates have been estimated using SILAC (stable isotope labeling by amino acids in cell culture) in prokaryotes and eukaryotes. The last decade has witnessed a growing interest in the analysis of whole-organism proteome dynamics in metazoans using the same approach. Progressive decrease in protein synthesis and proteolytic clearance through the autophagosomal and proteasome systems with age results in a strong increase in protein half-life in many species, including nematodes. This finding led to the formulation of the protein turnover hypothesis, stating that the increase in protein dwell time with age results in the accumulation of damaged and misfolded proteins. The progressive decrease in general protein turnover might be responsible for the ultimate collapse of proteome homeostasis in aging cells, possibly also driving the aging process itself.

In this vein, it is expected that increased protein turnover rates would help to maintain a young undamaged proteome and extend the lifespan. However, in yeast and C. elegans, genetically induced attenuation of protein synthesis extends, rather than shortens, the lifespan. Moreover, proteomic studies suggest that low overall protein synthesis is a hallmark of long-lived C. elegans, either by dietary restriction or by mutation in the insulin signaling pathway. Similar findings have been reported for diet-restricted mice. Hence, why does reducing protein synthesis promotes lifespan extension? And how can this be reconciled with the protein turnover hypothesis, which predicts enhanced turnover rates in long-lived organisms? We hypothesized that DAF-16-dependent longevity in C. elegans is supported by differential protein turnover. Downregulating turnover of the majority of proteins could save much energy, which, in turn, could be spent at prioritized maintenance of specific proteins that are crucial to extend the lifespan. To test this hypothesis, we produced a dataset that reveals patterns of intracellular protein dynamics in the C. elegans model and shifts of these patterns that occur in the long-lived daf-2 mutant via DAF-16 activation.

Contrary to our hypothesis, we did not discover a delineated set of proteins with turnover priority in daf-2 mutants. The majority of the detected proteins (56%) exhibit prolonged half-lives in daf-2, whereas turnover of the remaining proteins is unchanged. Only three proteins (CPN-3, ASP-4, and VIT-6) display marginally significant higher turnover rates in daf-2, but they lack a clear biological relationship. One of our most notable observations is the drastic slowdown in turnover of the translation machinery in daf-2 mutants. This slowdown coincides with decreased levels of ribosomal proteins and enzymes with predicted function in ribosome assembly and biogenesis we and others observed earlier and probably relates to the decreased protein synthesis rates in this mutant. Our observation of decreased protein turnover in daf-2 mutants is not entirely surprising. In agreement with our observations, researchers demonstrated extended ribosomal and mitochondrial half-lives in long-lived, calorie-restricted mice. The insulin/IGF1 signaling pathway is a main activator of anabolic metabolism; hence, it is conceivable that mutants in this pathway show reduced protein turnover. This reduction allows the worm to save much energy, which may be diverted to other processes that support longevity, such as the synthesis of trehalose, a chemical chaperone that stabilizes membranes and proteins, for which a role in daf-2 longevity has already been shown.

Link: http://dx.doi.org/10.1016/j.celrep.2016.07.088

You'll no doubt recall that the Pew Research Center ran a survey a few years back showing that most people didn't want to live longer lives, were that possibility on offer through progress in medical science. There are indications that this result is obtained because the mistaken assumption that people make is that longevity assurance therapies would lead to a longer period of old age rather than a longer period of youthfulness. Later studies suggest that people are all for longer lives if that prospect is explicitly tied to remaining healthy and youthful. Pew Research more recently followed up with a related survey on selection of enhancement technologies to expand or increase human capacities, resulting in a similar set of data for some of the technologies that will become available in the near future. For my money, there are clearly large differences between what people say at the dawn of a new technology, and what they later do when that technology is available.

For millennia, humans have been dreaming about vaulting past our biological limits, from natural constraints on our intellect and physicality to our very mortality. But now, according to some researchers and futurists, we may be on the cusp of a scientific revolution that could give each of us an opportunity to cross these boundaries and live longer and stronger than any human being before us. And yet, a pair of Pew Research Center surveys on life extension and human enhancement show that many U.S. adults are not ready to embrace these possibilities, whether it be in their own lives or in society more broadly. In our 2013 survey on radical life extension, 56% of adults said they would not want to live at least 120 years, which is considered the current upper limit of the human life span. Likewise, roughly two-thirds of adults in our 2016 poll on human enhancement said they would not want a brain chip implant to improve their cognitive abilities (66%) or synthetic blood to augment their physical abilities (63%). American adults were somewhat more open to the possibility of using gene editing to reduce the risk of serious disease in babies, with 48% saying they would be interested, but a similar share (50%) said they would not want to use the technology on their baby.

For many people, both potential advancements also raised concerns about increasing social inequality. Two-thirds of those polled about radical life extension thought the option would only be available to the wealthy. At least as many in the human enhancement survey shared this concern, saying that moving forward with the three emerging technologies outlined in the survey - brain implants, synthetic blood and gene editing for babies - would increase inequality because they would only be available to those who are well-off. Two-thirds of American adults also said scientists would offer life extension technologies before their impact was fully understood. Again, this wariness is matched and even exceeded in the human enhancement survey; more than seven-in-ten adults said brain, blood and gene enhancements would be employed before their effects were fully understood.

Even though the two surveys were conducted separately, they are thematically linked, since research efforts to dramatically extend human life and to "enhance" human beings are occurring in tandem and sometimes together. In fact, the line between the two areas often is blurred. Many scientists and advocates who want to make people stronger and smarter also want to make them healthier and longer-lived, and those who are working to increase longevity and limit the effects of aging in human beings often want to enhance their capabilities as well. One interesting difference between our polling work on life extension and on human enhancement involves the factors that are contributing to these views. It turns out that religion plays a more prominent role in driving people's concerns about human enhancement than life extension. For instance, among highly religious people (based on an index of common measures), only 24% say they would want cognitive enhancement, compared with 44% of those with low levels of religious commitment. A similar gap exists when these two groups are asked about gene editing and synthetic blood.

Link: http://www.pewresearch.org/fact-tank/2016/09/13/americans-are-wary-of-enhancements-that-could-enable-them-to-live-longer-and-stronger/

Some years ago now, how time flies, the Methuselah Foundation funded the tissue engineering company Organovo when it was still in its earliest startup stages. That investment continues to do well, in all senses, as Organovo has gone on to build a range of technologies relating to bioprinting and growth of sections of functional tissue from cells. The folk at Organovo recently announced a new product for research and development initiatives based on manufacture of kidney tissue to order, and the Methuselah Foundation principals took the opportunity to point out to supporters just how far things have come. The funds invested in Organovo were provided by donors like you and I, given in the hopes that the Methuselah Foundation could put them to good use in advancing the state of the art. In this, as in many other areas, success has followed success. As other companies are funded by the Methuselah Foundation and SENS Research Foundation, such as Oisin Biotechnologies, we'll be seeing more of this sort of thing in the future.

To all our Supporters and Friends,

We have some exciting developments we want to share with all of you who have given your time and financial support! Methuselah Foundation's goal, from its beginning, has been to extend healthy human life. Our mission is to make 90 the new 50 by the year 2030. Your financial support continues to make it possible for the foundation to explore and implement science that is bringing our goal closer, both for our supporters, and for all the rest of humanity. Over eight years ago we had a shared vision with Organovo to create "New parts for People" - viable human tissue with the goal to create bioidentical human organs and 3D tissue to, among other things, alleviate the organ shortage plaguing the entire world. This shared vision motivated the Methuselah Foundation to provide the seed money that would allow Organovo to begin its work on this goal. It's worth noting that at the time we invested foundation funds into Organovo it was the most turbulent financial landscape this country had seen since the 1929 stock market crash, while the goals we were all pursuing were still considered next to impossible by most. Still, we saw the need to consider Return On Mission ahead of potential Return On Investment.

From the very beginning, we have been judiciously opportunistic in leveraging donated funds. The exciting news we want to share with you bears out what an effective strategy this is: this past week, Organovo announced it had created the world's first ever 3D architecturally correct human kidney tissue assays. Those in the scientific and medical fields can recognize the significance of this achievement, and we also want to talk to you about some of the amazing implications that this brings. (You can also read their press release).

According to the National Institutes of Health developing a new intervention or treatment currently takes about 14 years and can cost nearly 2 billion dollars. Despite this effort, failure rates can still be as high as 95%. Some 30% may fail because they are toxic, despite promising pre-clinical trials. Another 60% that show promise in animal testing do not work on humans. This means years can go by before patients can receive any benefit from all this hard work. All that now has the potential to change. With the ability to create architecturally correct 3D human tissue, we can cut off as much as a decade of time and hundreds of millions, even billions of wasted drug development dollars. The ability to test with viable human tissue is also making animal testing (already illegal in the EU) obsolete!

What else does this mean? It will mean that due to the greatly reduced costs, more drugs can be tested, faster and vastly more accurately - exponentially increasing the rate we find new and better SENS-relevant interventions and cures. Tantalizingly, there have been drugs in the past that were pulled from the shelves because, although they were effective for 99% of the population, a tiny number of people experienced adverse effects, resulting in such drugs being pulled from the market. Viable human tissue testing will allow companies to test for the genetic markers that react negatively to otherwise effective drugs and screen for them. This means access to many more drugs and treatments that can now be made available for those for whom the treatments are effective, and held back from those who would have adverse reactions.

There are yet many more exciting advances to come and you will find them outlined in greater detail at the Methuselah Foundation blog in upcoming posts. We will also update you in future emails and videos at our website to give the advances we are making. Remember, it is your support that has made this possible! You can show your continuing support for our work by donating, and please feel free to share this news with your friends and colleagues! We look forward to sharing the fruits of our future achievements together!

Sincere thanks to you all,

Methuselah Foundation

P.S. You might also read an interesting perspective on Organovo's achievement from one of the leading 3D printing blogs.

Organovo Announces Initiation of Commercial Contracting for ExVive Human Kidney Tissue

Organovo, a three-dimensional biology company focused on delivering scientific and medical breakthroughs using its 3D bioprinting technology, today announced that it has begun commercial contracting for its second tissue service, the ExVive Human Kidney. This kidney proximal tubule model is a natural expansion of the Company's preclinical product and service portfolio, allowing customers to study the effects of drug exposure on a key portion of the human kidney relevant to drug discovery and development.

The ExVive Human Kidney has demonstrated important functional aspects that offer significant value in preclinical testing, including: (1) Demonstrated proximal tubule function for more than four weeks, as measured by gamma-glutamyl transferase (GGT) production; (2) Tissue-like complexity that supports the detection of injury, compensation, and recovery; (3) Physiological expression of key transporters as measured by gene and protein expression, which allows for the assessment of kidney toxicity and drug:drug interactions by modeling normal tissue function; (4) Modulatable activity of key renal transporters P-gp, SGLT2, and OCT2, demonstrating a high correlation to difficult to replicate human biology; (5) Demonstrated toxicity of model kidney toxicant cisplatin, and inhibition of toxicity when blocking OCT2 function, demonstrating specific inhibition of cisplatin transport through a known transporter; and (6) Barrier function (permeability) comparable to in-vivo values, as measured by trans-epithelial electrical resistance (TEER).

Organovo launches second 3D bioprinted tissue service, the ExVive Human Kidney

ExVive Human Kidney, a 3D bioprinted proximal tubule model, will allow for clients and researchers to better study the effects that drugs and certain treatments have on the human kidney, effectively opening the doors for advanced drug discovery and development. So far, a number of commercial orders for the innovative product have already been placed with Organovo. According to a press release, the 3D bioprinting company is also already collaborating with a number of toxicology panels and transporter studies as part of an early access program for their new product. Organovo has made a name for itself within the 3D bioprinting industry for its innovative and disruptive bioprinted tissue services. Both the ExVive Human Kidney and Liver products offer the unique opportunity for pharmaceutical researchers to replicate complex cell-cell interactions and elements of tissue architecture to test and determine the effects of drugs on the organ. The company's 3D bioprinted tissues have opened the doors for more rapid and cost efficient drug discovery process.

The accumulation of senescent cells is one of the causes of aging. If even 1% of the cells in a tissue become senescent, that small fraction has been shown to have very damaging effects on the function and behavior of the majority non-senescent cells. The most direct path towards addressing this problem is to selectively destroy senescent cells throughout the body every few years, and companies such as Oisin Biotechnologies and UNITY Biotechnology are working towards that goal. Many researchers are more interested in altering the behavior of senescent cells for the better, however, something that I see as an inferior path, but that fits more closely with the scientific impulse to completely map senescence as a cellular phenomenon: to produce a full understanding of the molecular biology of the processes involved. Fortunately, the sort of mapping work shown here should also make it easier to selectively target senescent cells for destruction in the years ahead.

Researchers have succeeded in identifying genes that control cellular senescence - permanently arrested cell growth. The process involved treating liver cancer cells using anticancer drugs of various concentrations, inducing apoptotic cell death and cellular senescence, and comparing gene expression levels. By developing drugs that suppress the activity of these genes, this discovery has potential applications for creating new highly-effective anticancer drugs, or use in anti-aging drugs. Living organisms experience various stresses during their lifespans. These stresses include radiation, ultraviolet rays, and chemical substances that directly damage DNA and cause cancer. Organisms are able to speedily repair DNA when it is damaged, but when the damage is severe, they manifest two different cell responses: apoptosis - a type of controlled cell death - and cellular senescence, which permanently suspends cell growth. Both these responses prevent the cell which suffered DNA damage from proliferating and becoming cancerous.

The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. If cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays to identify the genes in which a rise in transcription levels could be observed. They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence.

There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them. If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products.

Link: http://www.kobe-u.ac.jp/en/NEWS/research/2016_09_13_01.html

It is always pleasant to see the emergence of new advocacy efforts that support the sort of rejuvenation research carried out by the SENS Research Foundation, and here I'll point out one that I had not noticed until quite recently. That there are enough people out there working on projects of this nature for things to slip past is a positive sign in and of itself. The community of supporters is growing.

First and foremost it is important to understand that aging is not something mystical or incomprehensible. Aging with all its symptoms and all its associated diseases is caused by the accumulation of damage in our bodies over time coupled with a lack of repair thereof. These damage types are at the root of all the degenerative processes that happen to the human body as we get older as well as all the diseases of old age. It turns out there are comprehensive answers on how to effectively combat and reverse each of these damage types already. Research with the focus on ending aging is happening in independent laboratories around the world, mostly funded and coordinated by the SENS Research Foundation. In short: By repairing the body using treatments that we are capable of developing using today's technology we can effectively treat and reverse aging. This is extremely good news!

Why have I not heard about this in the news? It's really quite frustrating. New concepts, rejuvenation research in particular (just try talking to anyone about it), tend to take a while to catch on and in this case time will mean the difference between life and death, health and suffering for millions. There is this notion that living longer translates to a prolonged period of frailty and suffering when this research is about the exact opposite: restoring youthful vigor. To most people rejuvenation remains an impossible pipe dream because they don't pay attention or take the time to inform themselves about medical advances or progress in research. They have their viewpoint defined by pro-aging movies and other popular media. As long as the general population does not change their mind about how they feel about rejuvenation research, governments and the mainstream media won't take it up as a serious field of research. History has shown how much resistance there is towards new ways of thinking and how irrational that resistance seems when looking back. The more radical the idea, the bigger the resistance. To believe that aging is avoidable or indeed reversible may be the most fundamental paradigm shift that humanity has ever had to go through and as ridiculous as this may sound to future generations, we currently live in a world where most people frown upon the idea of being young and healthy for as long as they desire.

What can I do to support rejuvenation research? Put simply: New medical technologies don't fund themselves. The future we get is the future we choose to invest in. The war on aging has already begun. It is happening now and it can be won within our lifetime if we push to reach human longevity escape velocity. The SENS Research Foundation is spearheading the movement and has the most feasible and comprehensive approach to curing aging. They are a non profit organization, their research is thorough, well documented and transparent so it is easy to follow along with their progress, plans and goals. That is why our vote goes to them for support. We live in an exciting time where we have the chance to see a world free of involuntary suffering, frailty and death from aging and age related diseases, but if we want to be around to see this world become a reality we need to do our part in supporting the research. The most important part is continuous funding and advocacy. Talk about this subject matter with other people, spread awareness and excitement and sign up for a monthly donation on the SENS Research Foundation website today for a future unbounded by an inevitable age-related demise.

Link: http://www.thewaronaging.com/

The article I'll point out today opens by distinguishing capitalized Transhumanism from lower case transhumanism. These are visions of the future grown in that fertile square of ground whose corners are marked by contemporary science fiction, the cutting edge of engineering, the cutting edge of science, and the entrepreneurial community. The real entrepreneurial community, I mean, the people who quietly get things done, not the loud internet-focused groups that you tend to read about in the media. Transhumanism with a small t is a simple description of what we will achieve with technology: we will transform ourselves and surpass all present limits upon the human condition. We will eliminate pain and suffering from the world. We will become enormously powerful and knowledgeable. We will live in perfect health, if not forever, then certainly for a very, very long time. This is inevitable, a flowering that will continue a long-running exponential trend in technology, the limits of which are still far distant from where we stand today. Transhumanism with a capital T is a movement, initially to forge, discuss, and spread the concepts of transhumanism, but more the case nowadays to work on implementing the first of the necessary technologies. Being a movement, Transhumanism will fade as it succeeds. There are no such things as tableists when there is a table in every room, after all.

Still, you can't wander far in the biotechnology, space development, and artificial intelligence communities without bumping into a Transhumanist, and that is without even mentioning the fields of rejuvenation research or cryonics. Or, as is increasing likely today, you'll bump into someone who expects much the same future and makes much the same arguments about technology and its uses, but who wouldn't consider himself or herself a Transhumanist. That is what I mean when I say that the movement fades to the degree that it succeeds. The ideas hammered out by a small number of people in the 1980s and 1990s have now more or less become the mainstream of serious thought about the future. An important lesson here is that you might be absolutely and completely correct, but if you are saying something that differs from the current mainstream, it will still take twenty years for people to come around to your way of looking at the world. Another lesson is that you should pay attention to science fiction writers; they are usually at least as far ahead as the better scientists when it comes to interpreting science and exploring possible consequences, and typically considerably better at organizing their message.

As we enter the era in which rejuvenation biotechnology is slowly becoming a reality, it is worth recalling the debt we owe to the people who propagated and expanded the concepts of radical life extension before the turn of the century, around the time at which the Usenet transitioned to the early web. We should also not forget those who carried out early projects and fundraising as well, a number of whom are no longer with us. I gained my introduction to transhumanism around that time, and I think unlikely I'd be quite as sensibly focused on the long game of an end to aging without that exposure to the energetic idea factories of the Extropy Institute, cryonics advocates, and related Usenet communities of the time. Outside those groups, there was all too little ambition, all too little vision, and all too little science among those who talked about intervention in aging. It is no coincidence that of the people involved in those transhumanist communities, many have gone on to found or become in involved in transformative efforts in a variety of fields. This a process still underway, and the companies, non-profits, and technologies grown from the seeds sown twenty years ago are still young, still in the process of becoming. What we are doing today is supporting and reinforcing work that is increasing known and appreciated, a far different activity from founding an entire field with ideas alone, but just as vital. Twenty years from now, several types of rejuvenation therapy will be available in the clinic, and some of will have seen that process through, end to end, getting old over the course of it. It is a golden age we live in, but what is to come is far brighter and more valuable yet.

The author under discussion in the article here, like many journalists, is clumsy with the science, but more pertinently looks too hard for balance. Better medicine at a lower cost is better medicine at a lower cost. Less suffering and death is less suffering and death. There is no downside. Yet all too many otherwise sensible people strive to find things to be gloomy about. Would you rather live with the medicine of today or the medicine of sixty years ago, when the research community was still struggling to treat heart disease and many dangerous infections in an effective way? This isn't a hard question to answer, but why do people struggle so greatly when presented with the idea of a world in which everyone simply suffers to a much lesser degree than they do today? If you want to see someone run a mile, show them a better life, or at least that is how it seems to me some days.

Transhumanism Is Inevitable

"Transhumanism is becoming more respectable, and transhumanism, with a small t, is rapidly emerging through conventional mainstream avenues," Eve Herold reports in her astute new book, Beyond Human. While big-T Transhumanism is the activist movement that advocates the use of technology to expand human capacities, small-t transhumanism is the belief or theory that the human race will evolve beyond its current physical and mental limitations, especially by means of deliberate technological interventions. "I began this book committed to exploring all the arguments, both for and against human enhancement. In the process I have found time and again that the bioconservative arguments are less than persuasive."

Herold opens with a tale of Victor Saurez, a man living a couple of centuries from now who at age 250 looks and feels like a 30-year-old. Back in dark ages of the 21st century, Victor was ideologically set against any newfangled technologies that would artificially extend his life. But after experiencing early onset heart failure, he agreed have a permanent artificial heart implanted because he wanted to know his grandchildren. Next, in order not to be a burden to his daughter, he decided to have vision chips installed in his eyes to correct blindness from macular degeneration. Eventually he agreed to smart guided nanoparticle treatments that reversed the aging process by correcting the relentlessly accumulating DNA errors that cause most physical and mental deterioration. Science fiction? For now.

The killer app of human enhancement is agelessness - halting and reversing the physical and mental debilities that befall us as we grow old. Herold focuses a great deal of attention on the development of nanobots that would patrol the body to repair and remove the damage caused as cellular machinery malfunctions over time. She believes that nanomedicine will first achieve success in the treatment of cancers and then move on to curing other diseases. "Then, if all goes well, we will enter the paradigm of maintaining health and youth for a very long time, possibly hundreds of years," she claims. Perhaps because research is moving so fast, Herold does not discuss how CRISPR genome-editing will enable future gerontologists to reprogram old cells into youthful ones. Herold effectively rebuts bioconservative arguments against the pursuit and adoption of human enhancement. One oft-heard concern is that longevity research will result in a nursing-home world where people live longer but increasingly debilitated lives. That's nonsense: The point of anti-aging research is not to let people be old longer, but to let them be young longer. Another argument holds that transhuman technologies will simply let the rich get richer. Herold notes that while the rich almost always get access to new technologies first, prices then come down quickly, making them available to nearly everyone eventually. She is confident that the same dynamic will apply to these therapies.

This Is What Immortality Looks Like

There's a day in the not-too-distant future when incorrigible smokers, having blackened their lungs beyond function, will have access to a shiny new artificial pair; when cancer patients will mobilize microscopic nanobots in their bloodstreams to eradicate disease; when diabetes will be nothing more than a bad memory on account of an effective blood-sugar management system. People who are alive today will be taking advantage of such medical developments. Meet Victor, the future of humanity. He's 250 years old but looks and feels 30. Having suffered from heart disease in his 50s and 60s, he now has an artificial heart that gives him the strength and vigor to run marathons. His type 2 diabetes was cured a century ago by the implantation of an artificial pancreas. He lost an arm in an accident, but no one would know that he has an artificial one that obeys his every thought and is far stronger than the original. He wears a contact lens that streams information about his body and the environment to his eye and can access the internet anytime he wants through voice commands. If it weren't for the computer chips that replaced the worn-out cells of his retina, he would have become blind countless years ago. Victor isn't just healthy and fit; he's much smarter than his forebears now that his brain has been enhanced through neural implants that expanded his memory, allow him to download knowledge, and even help him make decisions.

While 250 might seem like a ripe old age, Victor has little worry about dying because billions of tiny nanorobots patrol his entire body, repairing cells damaged by disease or aging, fixing DNA mistakes before they can cause any harm, and destroying cancer cells wherever they emerge. With all the advanced medical technologies Victor has been able to take advantage of, his life has not been a bed of roses. Many of his loved ones either didn't have access to or opted out of the life-extending technologies and have passed away. He has had several careers that successively became obsolete due to advancing technology and several marriages that ended in divorce after he and his partners drifted apart after 40 years or so. His first wife, Elaine, was the love of his life. When they met in college, both were part of a movement that rejected all "artificial" biomedical interventions and fought for the right of individuals to live, age, and die naturally. For several decades, they bonded over their mutual dedication to the cause of "natural" living and tried to raise their two children to have the same values.

Then, one day, Victor unexpectedly had a massive heart attack. Having a near-death experience shook him to the core. When Victor asked his cardiologist whether he would live to see his new grandchild born, the answer was, "Probably not." His cardiologist disapproved of his refusal to accept an artificial heart. Artificial hearts had completely replaced biological heart transplants because they could not be rejected by the body, were widely available, and were far more durable than biological hearts. Victor's life after the surgery was remarkable. He suddenly had more energy and mental clarity than he had enjoyed for 20 years. In fact, it was only then that he realized how terribly sick he had been. The fluid in his lungs and the swelling in his body completely disappeared, and he told Elaine that he felt like an entirely new man. His long-held ideology about aging and dying "naturally" suddenly seemed stubborn and irrational. He noticed that even though Elaine was relieved and grateful that he was still alive, she wasn't changing her mind about her own dedication to allowing the aging process to proceed without any drastic intervention. Elaine's death was the hardest thing Victor had ever had to face. She stuck by her decision to accept only palliative care, and within three months, she had passed away at home with their children and grandchildren around her. Her death was peaceful, but Victor was anything but at peace. His last days with Elaine were greatly complicated not only by grief but by an irreconcilable anger at her. He was unable to accept her decision to reject the nanotech cure that had already saved millions of lives.

Trying too hard, I feel. We already live bathed in the pathos of lost lives; deaths past, deaths to come, all crosses we must bear, and none of this by our choice. How, again, is less of that a bad thing? How is it so terrible for aging and death and health to in fact be choices, fully under our control?

It is fairly well settled in evolutionary theory that there is a trade-off between short-term development versus longer-term tissue maintenance. Species that mature and reproduce quickly tend to have shorter life spans. This relationship also exists when comparing natural variations between individuals within the same species, and here researchers present evidence for this effect in human populations.

Generalized life history theory postulates a trade-off between development and maintenance explaining the considerable variation of traits like age at maturation, age at first reproductive event, number of offspring, size and lifespan across and within species. It is debated whether the variation in human lifespan can also be explained by such trade-offs. Observational studies in women have shown early and above average fecundity to come at a cost of longevity. The life history of men has no distinct mark of the end of development as menarche in women, but negative correlations between number of offspring and life-span after age 50 have also been reported for males. This could be explained as males invest more in physical strength and growth, which is associated with attractiveness and dominance, two traits important for male fitness.

Professional athletes push their physical performance to the maximum and keep accurate track of these achievements. Consequently, their personal record is an accurate representation of the age of their peak performance. Under the assumption that professional athletes train at maximum intensity, this peak performance is an accurate read-out of the maximal physiological capacity of the individual. Because athletes compete intensely, the rank of peak performances is an accurate comparison of these maximal physiological capacities of athletes. According to theory of life history regulation, the period before the peak performance could be considered as development, while the decline in physical capabilities after setting a personal record is a hallmark of the ageing process.

We used a unique historical cohort of 1055 Olympic track and field athletes from 41 different nationalities from the Olympic Games from 1896 through 1936. Track and field is a large group of similar sports for individual performance where the results are measured on a continuous scale. Technological advancements contribute only little to basic body functions like running, throwing and jumping, which are critically dependent on physical strength and coordination. Athletic games are therefore an ideal group of sports to use in this study. Mean age at personal record was 24.9 years. Mean age at death was 72.1 years. To compare peak performance of athletes from different disciplines and sexes we standardized age at, and rank of the personal record per discipline and sex. Athletes who had a peak performance one standard deviation earlier showed 17-percent increased mortality rates compared to those who reached their personal record later in life. Independent of the age of their personal record, athletes who ranked one standard deviation higher than their peers showed 11-percent increased mortality rates compared to those who were ranked lower.

It is tempting to speculate about the underlying biological mechanisms of this developmental constraint. Some have suggested that growth and subsequently, larger size, result in a body which costs more energy to maintain, explaining the higher pace of ageing. The mTOR pathway, which regulates growth in early life and pace of ageing in late life, is a potential molecular pathway that can explain for the observed trade off. Others have suggested that hormonal regulation of development and maintenance could play a role, as has been observed for the GH-IGF signaling pathway explaining the size-life span trade off in domestic dogs, and the muscle mass-immune competence trade-off mediated by testosterone observed in primates and other species. All mechanistic explanations are plausible and it needs to be studied which pathways are causal, and at which we can intervene to secure longer and healthier lives.

Link: http://dx.doi.org/10.18632/aging.101023

Of late researchers have been investigating a possible role for transposable elements, or transposons, in degenerative aging. These are DNA sequences that can move around in the genome, and the incidence of such movement increases with age. This fits in with the general consensus that stochastic mutation of nuclear DNA is a cause of aging, through disarray of normal cellular operations. This view is disputed in some quarters by the suggestion that outside of cancer risk the effect isn't significant over the present human life span in comparison to other forms of damage. In the case of transposons, whether it is a cause or consequence of other age-related changes in cellular biology is still up for debate. The work here adds a little more to the evidence already in hand:

A new study increases and strengthens the links that have led scientists to propose the "transposon theory of aging." Transposons are rogue elements of DNA that break free in aging cells and rewrite themselves elsewhere in the genome, potentially creating lifespan-shortening chaos in the genetic makeups of tissues. As cells get older, prior studies have shown, tightly wound heterochromatin wrapping that typically imprisons transposons becomes looser, allowing them to slip out of their positions in chromosomes and move to new ones, disrupting normal cell function. Meanwhile, scientists have shown that potentially related interventions, such as restricting calories or manipulating certain genes, can demonstrably lengthen lifespans in laboratory animals. "In this report the big step forward is towards the possibility of a true causal relationship. So far there have been associations and suggestions that to all of us make sense, but you need the data to back up your opinion."

In one set of experiments, the team visually caught transposable elements in the act of jumping around in fruit flies as they aged. They inserted special genetic snippets into fat body cells, the equivalent of human liver and fat cells in flies that would glow bright green when specific transposable elements move about in the genome. Under the microscope the scientists could see a clear pattern of how the glowing "traps" lit up more and more as the flies aged. The increase in transposon activity was not steady as flies grew older. The data show that the timeframe in which transposable element activity really begins to increase is tightly correlated with the time when the flies start to die. Several experiments in the paper also show that that a key intervention already known to increase lifespan, a low-calorie diet, dramatically delays the onset of increased transposon activity.

To further explore the connection between transposon expression and lifespan, the team tested the effects of manipulating genes known to improve heterochromatin repression that are not only found in flies, but also in mammals. For example, increasing expression of the gene Su(var)3-9, which helps form heterochromatin, extended maximal fly lifespan from 60 to 80 days. Increasing expression of a gene called Dicer-2, which uses the small RNA pathway to suppress transposons, added significantly to lifespan as well. For all the new results, the researchers say it's still not quite time to declare outright that transposons are a cause of aging's health effects. But new experiments are planned. For example, the team will purposely encourage expression of transposable elements to see if that undermines health and lifespan. Another approach could be to use the powerful CRISPR gene editing technique to specifically disable the ability of transposable elements to mobilize within the genome. If that intervention affected lifespan, it would be telling as well.

Link: http://news.brown.edu/articles/2016/09/lifespan

Aubrey de Grey, who should need little introduction here, is cofounder of the SENS Research Foundation, while Matthew O'Connor leads the foundation's in-house research efforts. O'Connor's focus is on the allotopic expression of mitochondrial genes, the complicated form of gene therapy needed to copy versions of these genes from the vulnerable mitochondrial genome into the much more secure nuclear genome, but altered in such a way that the resulting proteins can find their way back to the mitochondria where they are needed. Earlier today de Grey and O'Connor stopped by /r/futurology at Reddit to answer questions on this and other SENS rejuvenation research initiatives. One of the many benefits brought by this modern age of near zero cost communication is the way in which the barrier between researchers, supporters, and the public at large has faded to the point of non-existence. Any interested party can in a few minutes find out who is working in any specific areas of interest and reach out with questions or offers of support. Any researcher can find out where the interested parties congregate to talk about their research and join in. That was science fiction just a few decades ago. The world moves at a fast pace.

Once allotopic expression of the thirteen crucial mitochondrial genes involved in oxidative phosphorylation is realized, undergoing this gene therapy will ensure that the accumulation of mitochondrial DNA damage that occurs over the years no longer contributes to degenerative aging as it does today. It will be an actual, working narrowly focused rejuvenation therapy. As an incidental benefit, this technology will also provide cures for a range of inherited mitochondrial diseases. This work has been underway both at the SENS Research Foundation and in allied labs for some years now, and the biotech company Gensight has been founded on success in allotopic expression of the gene ND4. The SENS Research Foundation in-house team recently achieved success for the mitochondrial genes ATP6 and ATP8, and had a paper accepted by a noted journal, which all in all is a great step forward in a field that has proven to be quite challenging. I've pulled out some of the questions and answers from the AMA for posterity:

Aubrey de Grey and Matthew O'Connor AMA!

What is the updated timeline for when a MitoSENS-based therapy could be available for humans, and what would be its impact?

I think we're still several years away, which means any prediction of a timeline is pure speculation - but it's definitely accelerating.

For those that want to be alive when SENS 1.0 is here, what else can we do besides caloric restriction? Brisk walking?

Raise money for SENS Research Foundation! Seriously. The difference you can make to your own chances by hastening the arrival of SENS far exceeds what you can do with lifestyle etc. The less wealthy you are, the more people you probably know who are wealthier than you are. So, sure, it'll be the money of the people you persuade, rather than your own money, but that doesn't change what I said. Everyone can make a difference if they put real effort into advocacy.

Could you please tell what will be the next stage of the MitoSENS project, are you going to try to reproduce mitochondrial gene relocation in animals?

Yes we want to take this into animals next and yes we are starting now. I don't have any results to share yet but we are in the very earliest stages of pre-mouse work now. We are working in mouse cells to make sure that we can get our process working in cells before we move into whole mice.

Are you guys considering or taking advantage of the power of deep learning to accelerate your research into aging?

We are definitely interested in this. Alex Zhavoronkov, one of our foremost associates, now runs a company named Insilico Medicine which is spearheading that approach.

Now we have great results how long do you think it will be before we can do the same with the other 11 genes and are these genes technically any more or less challenging than the two already done?

Yes, there is reason to believe that some of the other 11 will be harder than ATP8 and ATP6. In fact, ATP6 is itself much harder than ATP8 and our results with that aren't as strong as with ATP8. We have some technologies that we've tested already that seem to work a bit with the harder genes and we're layering on additional levels of mitochondrial targeting and import. The hard thing is how complicated it gets when we start combining multiple targeting strategies together and quantifying their affects. We are building a rigorous system so that we can test variables in a matrix and clearly determine what works and what doesn't.

How long do you think it will take before we can reverse surface level aging : hair loss, gray hair and wrinkles? Which of the 7 damages types do we need to solve to make it happen?

Wrinkles are mainly from crosslinking, an area that was pretty much stalled for 20 years until our breakthrough publication in Science last October; still a way to go but we're now making rapid progress. Hair loss and grey hair are mostly a cell loss problem, and rejuvenating the epidermal stem cell population (as well as melanocytes specifically) is something a lot of people are making good progress on; check out the work of Elaine Fuchs and Fiona Watt and Colin Jahoda especially. The main thing to keep in mind here on the science side is that the technologies needed to rejuvenate appearance and to rejuvenate internal organs are broadly the same. And on the broader picture, just as we don't care whether people give us money for selfish reasons or for humanitarian reasons just so long as they give it, we also appreciate that changing the zeitgeist of the longevity quest is inextricably linked with hastening the science.

How can grassroots activism most effectively be leveraged to hasten the defeat of aging?

The key thing is to tackle both feasibility and desirability together, which paradoxically means tackling them separately. People are scared to get their hopes up, and they dismiss the feasibility issue because they have already decided that success would be a bad idea, and at the same time they dismiss the desirability issue because they have already decided that the whole concept is a pipe dream. So, first force your interlocutor into understanding that that linkage is logically absurd and thus into addressing the two questions separately. Then, give them the best arguments.

What about mitochondrial diseases that are caused by point mutations in the mitochondrial DNA? Won't these misfolded proteins still being produced compete with the corrected proteins now being produced by your imported RNA?

This is a hard question. We don't really know how effectively our engineered genes will compete with existing mutant (or non-mutant for that matter) proteins. We and others have done some work on it, but the answers aren't satisfying for me yet. We are at the conceptual stages of designing a rigorous method of quantifying this. It is not clear that mutant proteins much exist in "normal" aging though, so it might be a non-issue for aging but a very important question for inherited mitochondrial disease. Recently a new mouse model has been developed that accumulates deletions at an accelerated rate. It is a "binary system" that allows the problem to be activated in a tissue-specific manner by crossing with specific other mice, so it's very versatile. I expect that it will be quite useful.

Robert K. Naviaux, mitochondrial expert, asserts that their dual (or even primary) function is as an exquisitely sensitive alarm system, triggering the 'cell danger response' to chemical or microbial threats. How does this sit with the understanding so far in the MitoSENS project?

I'm going to give a snap reply that our mitoSENS project might not help this kind of "homeostasis" problem, if that problem isn't caused by the loss of mitochondrially encoded genes. Mitochondrial are indeed complex organelles with much cross-talk with the rest of the cell so our philosophy is always that the underlying problem needs to be addressed. If the problem is in the nuclear genes then that's what needs to be fixed. If the problem is in the lysosome - resulting in reduced mitochondrial turnover - then we need to fix the lysosome rather than the mitochondria. It is often forgotten that mitochondria are constantly recycled even in non-dividing cells, and thus that the only damage they can possibly accumulate other than as a side-effect of something extramitochondrial is DNA damage, and only then if somehow mutant mitochondrial DNA is selected for. Historical aside: after Harman first suggested the role of mitochondria in aging in 1972, the only published reaction by anyone prominent was that Alex Comfort in 1976 rejected it on exactly this basis. He did not, of course, consider the bizarre possibility that mutant mitochondrial DNA could be selected for, which was only shown in 1993.

You've mentioned that SENS 1.0 therapies, when perfected, will add maybe around 30 years of healthy lifespan. Does that mean that it's impossible for them to work indefinitely long without needing any improvements? If so, why?

Yes, that's what it means. Here's an example that may explain it: crosslinking. Once we are able to break glucosepane, we'll be able to reduce crosslinking by a big factor - for sake of argument let's say 50% - but we won't be breaking any other crosslinks. Thus, eventually the total amount of crosslinking will return to old-age levels even if we blitz the glucosepane every year. So, we need to carry on with the introduction of therapies that hit the next most abundant link, and the next, etc.

Do you think we will see major steps and results in mice in the next 5 years?

Yess, there's a chance of that; I'd say in 6-8 years there's at least a 50% chance. And by "major" I mean robust mouse rejuvenation, i.e. seriously life-extending interventions that start in middle age. For first generation human therapies my current 50% prediction is 20-25 years. We might see human gene therapies in patients with mitochondria disease in much shorter periods of time. If these work the chances of it working on aging increase dramatically!

I want to ask about the potential for CRISPR to impact longevity research. Could CRISPR potentially do this? If so, is CRISPR accurate enough?

CRISPR is getting very, very error-free now, so I am sure it will be a big tool in implementing SENS. We have developed a way to use it in combination with a bacterial virus; our method allows the insertion of lots of DNA (even up to 100kb potentially) in one go, into a defined location on the chromosome, so we would aim to do all the aspects of SENS that require new genes that way - mitochondrial DNA backups of course, but also enzymes to degrade waste products, and suicide genes to eliminate death-resistant toxic cells. Increased accuracy means a lower probability that a given CRISPR construct will do a bad thing, which in turn means that we can introduce more constructs (whether all at the same time or over repeated administrations) while remaining at an acceptable risk of bad things, which in turn means we can hit more cells.

Is it ever too late to start studying microbiology? What are some things an aspiring longevity researcher should take into account before dedicating themselves to such a cause?

No, never too late - whether microbiology, molecular biology, or any other biology. The main thing to take into account when starting out is that you shouldn't specialise too soon, because aging affects the body at every level of organisation, hence to have the best insighhts you need a god grounding in every area of biology.

How old do you think the youngest person is today that will never have a chance to benefit from the coming longevity revolution?

I prefer to answer the converse question, how old is the oldest person who will benefit! I still think that person could be in their 60s, or even 70 now. Remember, though, that will be a person who would naturally live to 110 without SENS.

Since you began your public mission to now, has progression of our knowledge in the field of gerontology progress exceeded your expectations?

It's gone more slowly than I expected, but only because it has continued to be crippled by lack of funding. We're doing our best, but another digit on our pathetic $4M annual budget would probably treble our rate of progress.

It seems that recently there's been a bit more attention into anti-aging/gerentology research from mainstream research institutions. How has that affected the work you do at SENS?

It's huge that really respected people like Craig Venter and Peter Diamandis are in this now, as well as really respected companies like Google. It's making a lot of previously skeptical people take notice, and we are hopeful that it will soon translate into better funding - we really need that. As for variety of lines of thought, the more the better: the main problem SENS had in years past in gaining general expert acceptance was that too many experts had already become wedded to particular prior ideas.

Given that yeast cells don't have some of the seven classes of SENS damage to worry about, wouldn't it be easier to first create a line of yeast cells that can be kept indefinitely youthful? Or is this in fact more difficult than creating an indefinitely youthful multi-cellular organism as intra cellular damage can no longer be continually spread between daughter cells?

Much easier, yes, but that's exactly what makes it not informative for translation to the clinic. The second half of your question makes less sense though, because multicellular organisms that matter, i.e. complex ones, have plenty of long-lived non-dividing cells as well as dividing ones. Only simple ones like Hydra can combat aging in the way you describe.

Has Calico reached out to you and your team at all?

We reached out to Calico very energetically when they were getting going but they basically blew us off. We are dismayed that they are not taking advantage of our expertise. Maybe they will start to do so eventually.

Any plans to translate the research into a gene therapy for a specific inherited mitochondrial disease?

Well to get into the nitty gritty a little bit, there are exceedingly few patients who have been discovered to have mutations specific to ATP8, less than 5 that I know of. ATP6 has more, but still very few. The gene therapy advancement that needs to happen is to get gene therapy technology approved that can be used outside of the eye. Then it will be easier to get these individual mitochondrial gene therapies approved.

What increase in health and lifespan can we expect from solving just mitoSENS out of the seven SENS fields?

Maybe there will be synergistic health affects of applying more than one, but less than seven fundamental rejuvenations, but we won't know until we try. There is some evidence that just tampering with mitochondria can improve the health of old rodents.

Back at the outset of the SENS research programs, the estimated cost to prototype allotopic expression of all 13 oxidative phosphorylation mitochondrial genes in mice was ~$150M and ten years. MitoSENS has had probably something like a $10-15M investment (very fuzzy number). What is your current thinking on remaining costs and time now that the project is 20-25% of the way towards a prototype?

We've spent a lot less than $10M on this project so far. Total from all groups working in the field must be much much more than $15M. I will get it working in mice for much less than $150M.

If I understand correctly, the CYB protein is about 50% larger than ATP6. After your "many failed attempts", do you now have an understanding of what is preventing its import into the mitochondria, and, if so, what can be done to work around it?

CYB is both bigger and thought to be more "hydrophobic" than other mitochrondial proteins. I really like working on CYB though for two reasons: One is that I think that once we solve CYB we will have solved all 13 genes. The other is that CYB is the only mitochondrially encoded subunit of OxPhos complex III, which makes it a very simple system to study. We have cells that are null for CYB (similar to, but more simple than the cells that we used in the current publication) so we have a great system to test our innovations in.

Do you think that allotopically expressing ATP6 and ATP8 could have a measurable life extension effect in mice? Or it's more probable that all 13 genes must be allotopically expresed in order to see some improvement?

I think we would need to do all 13 to get some health affect in normal wild type animals, but there might be some tricks we can use to get it to work on some mutant mouse models.

With the advent of CRISPR, would it make more sense now than it did previously to code the cell to make catalase and target it to regularly be delivered to the mitochondria?

Catalase (and other anti-oxidants) can prevent some damage, but not reverse it. I'm more excited about the current generation of mitochondrially-targeted drugs that can act as anti-oxidants and/or mitochondrial activity boosters (in various ways). I'm betting that these next generation drugs will be even more effective than "natural" methods of preventing mitochondrial damage transgenically and we know that they will be easier to get approved by the FDA.

Evidence for the relevance of mitochondrial damage to the progression of degenerative aging can be found in many places, such as when comparing species with divergent life spans and metabolic needs. Birds and bats have significantly higher metabolic rates than we ground-based mammals, but along with that they also have much longer life spans than you might expect given their size. So the thinking goes, the evolutionary adjustments to mitochondria, the power plants of the cell, that were needed for flight have also produced a greater resistance to the mitochondrial molecular damage that contributes to aging. As this open access paper shows, there are mitochondrial differences that seem significant for longevity even between bird species. This isn't to say that we should be trying to alter our mitochondria via gene therapy to make them more like longer-lived species, however. No, we should instead take this and other similar research as indicators that more funding and attention should go towards rejuvenation therapies that focus on mitochondrial repair, ways to completely remove this contribution to aging rather than just slowing it down.

Mitochondria play an essential dual role in homeotherms by encoding proteins that form the essential components of the mitochondrial energy generation pathway, oxidative phosphorylation (OXPHOS). OXPHOS generates heat that is used to maintain the organism's body temperature and energy that is utilised for synthesis of adenosine triphosphate (ATP) to perform work. This is achieved "at the cost" of reactive oxygen species (ROS) and free radical production due to electron leakage from the respiratory chain. The mitochondrial theory of ageing suggests that ROS contribute to a progressive accumulation of somatic mutations in DNA during an individual's lifetime leading to both a decline in the bioenergetic function of mitochondria and to cell apoptosis associated with ageing and has been associated with a wide range of age-related diseases, but the relationship between ROS levels and ageing is not a simple one.

As an originally free-living prokaryotic organism that was engulfed by a precursor of the modern eukaryotic cell about two billion years ago, cytoplasmic mitochondria have retained their own plasmid-like circular genome (mitochondrial DNA, mtDNA). Mitochondrial genome regulation is vital for normal assembly and functional operation of the complexes involved in oxidative phosphorylation (OXPHOS), and therefore, for ATP production and metabolic homeostasis. Many of these functions are fundamental cellular processes and hence the mitogenome organisation appears highly conserved across vertebrates. In birds, several different arrangements of mitochondrial gene order have been observed and in some species the noncoding control region (CR) sequence with the adjacent genes have been duplicated creating a second non-coding region sometimes referred to as the pseudo control region (YCR). YCRs appear to have originated independently and sporadically in several distantly related taxa across the avian phylogeny.

Birds have several biochemical and life characteristics that should increase the risk of reactive oxygen species (ROS) damage to their mtDNA relative to mammals. Such characteristics include higher metabolic rates, higher body temperatures, higher blood glucose levels, seasonally high blood lipid levels and very high total lifetime energy expenditures. As such one would reasonably predict that relative to mammals, birds should age faster and have higher mutation rates rendering them more prone to cancer and other pathologies. Yet, paradoxically, most birds live longer compared to similar sized mammals in absolute and relative terms and although estimated mutation rates vary greatly across avian phyla, they are on average up to four times lower than those in comparable mammals. To the best of our knowledge, the presence of two sets of CR sequences is mainly an avian specific phenomenon, and the relationship between this feature and mitochondrial function has not been fully investigated. Considering the extraordinarily long life spans of birds and the pivotal role of the mitochondria in energy metabolism, the major aim of the work presented here is to explore the possibility that the additional sequences in the YCR are associated with variation in avian longevity.

Around 60% of the variation in lifespan of higher animals can be explained by body mass: animals that diverge from this basic allometry of life span may harbour unique longevity enhancing features and their study may lead to new insights into the evolutionary forces shaping longevity and aging. To explore a possible link between YCR duplication and longevity, we correlated longevity/body mass with presence/absence of YCR sequence for a total of 92 avian families. We detected a relationship between a duplicated control region and longevity. This, we believe, strongly argues for a positive functional role of these duplicated sequences in those species that carry them. We hypothesize that there are two, not incompatible, possibilities that relate to the mitochondrial ageing hypothesis. Extra control region sequences may result in constant increased mtDNA copy number and/or increased flexibility and speed of cellular response when increased metabolism is required to cope with environmental stresses. This mechanism might effectively lower local ROS damage from increased metabolic throughput during periods of stress response. A second possibility is that extra copies of the control region sequences protect mtDNA from the age related effects of sequence losses and hence offer the opportunity for species to retain higher levels of functional mitochondria into later life, hence slowing the negative effects of accumulated mitochondrial deletions on senescence. Alternatively, our results may simply reflect a molecular marker of long-lived species, rather than being the causative agent for that longevity. Our results suggest that even if truly causative the associated effect is a relative minor one accounting for around a 15% difference in life expectancy for an average sized family with and without the YCR.

Link: http://dx.doi.org/10.18632/aging.101012

Kelsey Moody's Ichor Therapeutics is one of number of biotech ventures to have emerged from the SENS rejuvenation research community over the past decade. Earlier this year Fight Aging! invested a small amount in Ichor's initiative to push forward with the development of clearance of metabolic waste compounds from the lysosome. The company will be building upon work carried out at the SENS Research Foundation in order to create a therapy for age-related macular degeneration, as the existence of these waste compounds appears to be an important root cause of retinal damage. I think that Moody's talent for the business side of things is quite well illustrated by the fact that he can engineer the publication of a press article like this one:

Inside a laboratory tucked in the LaFayette hills south of Syracuse, a small biotech company is quietly developing drugs that may show promise to treat, prevent and possibly even reverse macular degeneration, a disease that's a leading cause of vision loss. The new drug therapies being developed and tested are designed to work on two varieties of the eye disease: age-related macular degeneration and juvenile-onset macular degeneration, said Kelsey Moody, who founded the biotech company Ichor Therapeutics in 2013. Moody was a second-year medical student when he started his company with a $540,000 grant from Life Extension Foundation, a Florida-based non-profit that funds research in aging, age-related diseases and ways to extend human lifespan. Ichor has so far attracted more than $3.2 million from investors, foundations and local government.

Moody says he's particularly interested in age-related diseases because he said they don't get as much attention and visibility as other types. If the treatments for macular degeneration work, the enzymes, derived from several sources, will be available as an injection. Moody is in what he calls "stealth mode" right now as he works to test the validity of the treatments, so he's not giving away too many details about them. He plans to publish his findings once he, in conjunction with Syracuse University, secures patents to protect his work. Age-related macular degeneration is the leading cause of vision loss and blindness in people older than 50. Moody said his team believes macular degeneration is caused in part by "junk that accumulates in the eye" over time. Just so much debris can build up in the eye before it begins to cause problems, he said. There are multiple types of this substance that accumulate, and Moody said it may cause the eye disease or it could be a side effect of it. He said Ichor has developed "therapeutic" enzymes that break down that "junk" or particles. "Either we hit a home run and cure the disease or, if that fails, we have the answer to the important question of what happens when we get rid of the junk."

Dr. Szilard Kiss, an ophthalmologist and an associate professor of ophthalmology at Weil Cornell Medical College, who is familiar with research into this condition and read up on Moody's work, said Moody is aiming at the A2E molecule which is one of the components of that toxic buildup. Other researchers are working on this as well, but without success to date. "It's a tough nut to crack, as it's difficult to soak up that A2E. If what Ichor is doing works and can treat the dry form and prevent the wet form of macular degeneration, it would be really great." Robert P. Doyle, a Syracuse University chemistry and biology professor and an associate professor of medicine at SUNY Upstate Medical University, agrees with Kiss. "The science behind what Ichor is doing is very sound," said Doyle, who is working with Moody to patent the drug treatments. "The technology is very new, and there's no reason it won't work, but it will of course have to be validated." Doyle, who says he and Moody will publish a paper soon, said Moody excels both as a research scientist and as a businessperson. "He's done an awful lot of scientific research in his career before starting his own company, but he also has an MBA and is good at business. He has good ideas and he is willing to have them challenged. He's fearless."

Link: http://www.syracuse.com/empire/index.ssf/2016/09/cny_research_startup_raises_3_million_plus_to_develop_treatment_for_vision_loss.html

Today I'll point out a two open access papers on the mapping of genetics, epigenetics, aging, and age-related disease. There is a lot of this sort of work taking place these days: it is ever easier to raise funding for any sort of work on genetics, and this is the beginning of the age of practical gene therapy. Intervening in the aging process to slow or reverse aging, as opposed to trying to patch over the late stage consequences of specific age-related diseases without actually touching the processes of aging itself, remains a comparatively small initiative within the aging research community. Most funded work on aging goes towards cataloging and mapping, a part of the great life science initiative to produce a comprehensive atlas of living biology from top to bottom: how our cells and tissues work, and how every function of every biological system changes over time, understood all the way down to the roles of individual molecular interactions. This is an enormous project, staggering in scope, with the present vast databases of molecular biochemistry just a sketch of the outline of the whole when held up against the bigger picture. Barring revolutionary advances in automation and computation this project will be nowhere near complete even several decades from now.

To the extent that factions within the scientific community prioritize complete understanding of aging above interventions in aging based on what we do already know, they have decided that no significant progress on lengthening life will be made in our lifetimes. If this view dominates, the future will be much the same as the recent past, in that the steady upward slope of small gains in adult life expectancy will continue, with the bulk of these benefits arising from incidental side-effects of the standard medical approach to late-stage aging and age-related disease. The patches will get better, but a patched and damaged system still fails; the patch can only delay the inevitable. The most important debate in medical research today is between those who prioritize full understanding and slow progress towards slowing aging versus those who want to take the current catalog of known differences between old and young tissue and fix them in advance of full understanding. That will cost a lot less and achieve answers on the relevance of this damage to aging and rejuvenation far more rapidly than any other methodology.

Unfortunately, gathering greater support and adoption of work on biological repair and rejuvenation is still an uphill battle, despite successes in the making such as senescent cell clearance, an approach gathering more attention these days. The majority of research into aging looks a lot more like the open access papers linked here, which is to say it is interesting, largely focused on genetics, generates a lot of data, and is of little practical use in the near term. Altering gene expression levels in the hopes of improving the situation for older people is somewhat like adjusting the fuel balance of a rusted and worn engine in the hopes that it will run a little longer. It misses the point, the direct and most useful thing that could be done to improve matters. The grand map of molecular biochemistry is absolutely something that should be constructed, and will be of great use to the next generation of biotechnologies - but to focus on that entirely is to sacrifice countless lives, when the research and development community could also be building the first generation of therapies that will help bring an end to degeneration aging.

Discover the network mechanisms underlying the connections between aging and age-related diseases

Although our knowledge of aging has greatly expanded in the past decades, it remains elusive why and how aging contributes to the development of age-related diseases (ARDs). In particular, a global mechanistic understanding of the connections between aging and ARDs is yet to be established. We rely on a network modelling named "GeroNet" to study the connections between aging and more than a hundred diseases. By evaluating topological connections between aging genes and disease genes in over three thousand subnetworks corresponding to various biological processes, we show that aging has stronger connections with ARD genes compared to non-ARD genes in subnetworks corresponding to "response to decreased oxygen levels", "insulin signalling pathway", "cell cycle", etc.

Based on subnetwork connectivity, we can correctly "predict" if a disease is age-related and prioritize the biological processes that are involved in connecting to multiple ARDs. Using Alzheimer's disease (AD) as an example, GeroNet identifies meaningful genes that may play key roles in connecting aging and ARDs. The top modules identified by GeroNet in AD significantly overlap with modules identified from a large scale AD brain gene expression experiment, supporting that GeroNet indeed reveals the underlying biological processes involved in the disease.

Systematic analysis of the gerontome reveals links between aging and age-related diseases (full text is PDF only)

In model organisms, over 2,000 genes have been shown to modulate aging, the collection of which we call the "gerontome". Although some individual aging-related genes have been the subject of intense scrutiny, their analysis as a whole has been limited. In particular, the genetic interaction of aging and age-related pathologies remains a subject of debate. In this work, we perform a systematic analysis of the gerontome across species, including human aging-related genes. First, by classifying aging-related genes as pro- or anti-longevity, we define distinct pathways and genes that modulate aging in different ways. Our subsequent comparison of aging-related genes with age-related disease (ARD) genes reveals species-specific effects with strong overlaps between aging and age-related diseases in mice, yet surprisingly few overlaps in lower model organisms.

We discover that genetic links between aging and age-related diseases are due to a small fraction of aging-related genes which also tend to have a high network connectivity. Other insights from our systematic analysis include assessing how using datasets with genes more or less studied than average may result in biases, showing that age-related disease genes have faster molecular evolution rates and predicting new aging-related drugs based on drug-gene interaction data. Overall, this is the largest systems-level analysis of the genetics of aging to date and the first to discriminate anti- and pro-longevity genes, revealing new insights on aging-related genes as a whole and their interactions with age-related diseases.

We first characterized functions and pathways overrepresented in pro- and anti-longevity genes. Major anti-longevity pathways and processes include insulin signaling, growth hormone signaling and mTOR signaling. Key pro-longevity pathways include p53, cell cycle and autophagy. Although such pathways and processes are known to be related to aging, it is interesting that they are classified as anti-and pro-longevity in our systematic analysis of the genetics of aging. Differentiation between anti-longevity and pro-longevity genes and processes can provide additional clues about aging-related processes and can help identify other genes with a similar effect on aging. In order to find relations between aging and ARD, we compared aging-related gene sets with ARD genes. Limitations of our study include the fact that possibly many genes associated with longevity and disease remain to be identified, and the causal genes in many genetic associations with disease are still unknown. In spite of these caveats, our results show an association between aging and ARDs at the genetic level, although this is surprisingly species-specific with a stronger overlap in mice than in invertebrates (flies and worms) and practically no overlap in yeast.

The overlap analyses of anti- and pro-longevity genes shows differences in musculoskeletal, nervous system and cardiovascular diseases. The identified overlaps suggest that the musculoskeletal and nervous systems are related to pro-longevity genes while anti-longevity genes seem more associated with cardiovascular diseases. Looking at ARD classes which overlap with human aging-related genes, a significant overlap is verified for all classes as expected, except for immune system diseases. The nutritional and metabolic diseases, the neoplasms, the cardiovascular diseases and the nervous system diseases have the most significant overlap with human aging-related genes. Eye diseases, respiratory tract diseases (which we considered a negative control) and immune system diseases had the least overlap, but it is important to mention that these are (together with musculoskeletal diseases) the age-related disease classes with fewer genes.

The main conclusion from this work is that aging and age-related diseases are related and share more genes than expected by chance. Human aging-related genes showed a considerable overlap with ARDs. These overlaps are driven by a small subset of aging-related genes which are associated with various age-related diseases and are hubs in networks. Besides, the extent of overlaps decreases with the increase of evolutionary distance, and yeast aging-related genes show practically no overlap with ARDs. Novel differences in overlapping age-related disease classes between anti- and pro-longevity genes were observed: Nervous system and musculoskeletal diseases seem more associated with pro-longevity, while cardiovascular diseases have a stronger association with anti-longevity genes. Moreover, network analyses suggest the existence of intermediate genes which promote the associations between aging and age-related disease genes.

That lower levels of growth hormone lead to greater longevity in short-lived mammals has been comprehensively established. The longest-lived genetically engineered mice are those in which the growth hormone activity has been suppressed in some way, such as via knockout of the growth hormone receptor. Short-lived species have far more plastic life spans than we do, however: the analogous population of humans with a growth hormone receptor mutation, those with Laron syndrome, certainly don't exhibit the same large increase in life span. So to what degree do natural variations in growth hormone activity impact human longevity? The open access paper here adds more data to the existing evidence:

Genetic disruption of the insulin/insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway can delay aging and promote longevity in a wide variety of species. In mammalian species, growth hormone (GH) plays a pivotal role in the regulation of the IIS pathway and mutations affecting GH action have consistently been shown to alter lifespan. Increased longevity in mice can be induced by mutations that result in GH deficiency. However, little is known about how more subtle differences in GH/IGF-1 secretion would affect human longevity. Interestingly, female centenarians were found to be enriched for rare mutations causing slight IGF-1 resistance and resulting in a somewhat smaller stature. Likewise, we previously observed that a combination of polymorphisms in the GH/IIS pathway, linked to smaller stature in female octogenarians, was associated with better survival in old age. However, to the best of our knowledge, no study has assessed the association of human longevity with GH secretion.

GH secretion by somatotrophic cells in the anterior lobe of the pituitary gland is stimulated by growth hormone-releasing hormone (GHRH) and inhibited by somatostatin, both produced by the hypothalamus. GH exerts its functions by binding to GH receptors located on tissue target cells. A key function of GH is to stimulate production of IGF-1 by the liver, which subsequently inhibits GH secretion via negative feedback. Circulating IGF-1 is mostly bound to binding proteins of which insulin-like growth factor binding protein 3 (IGFBP3) is the most abundant. The IGF-1/IGFBP3 molar ratio is considered an indicator of IGF-1 bioavailability. In humans, many other tissues besides the liver express GH receptors indicating that GH may exert effects independent from IGF-1. To identify determinants of human longevity, the Leiden Longevity Study (LLS) included offspring of long-lived families that are enriched for exceptional longevity and partners thereof, serving as a control group. Indeed, offspring were found to have less age-related diseases and reduced mortality compared with controls. Previously, no differences were observed between offspring and controls in circulating IGF-1 concentrations. However, the magnitude and control of GH secretion have not yet been studied in human familial longevity. Therefore, we aim in this study to compare GH secretion parameters and the strength of GH secretion control signals between offspring of long-lived families and age-matched controls.

The two main findings of this study are that GH secretion is lower and more tightly controlled in subjects enriched for familial longevity compared with age-matched controls. The observed association between reduced GH secretion and human familial longevity is in line with experimental studies in mice, which found that reduced GH action resulted in extended health and lifespans. Our results implicate the highly conserved GH/IGF-1 signaling pathway, which has been linked to delayed aging and longevity in numerous animal models, is also linked to human longevity. The observed differences in GH secretion between offspring and controls can probably not be explained by a faster clearance of GH from the blood, as the slow half-life was comparable between groups. We hypothesize that the offspring are therefore more efficient in regulating the magnitude and the timing of GH secretion. Our data strengthen the hypothesis that GH/IGF-1 signaling is a conserved mechanism implicated in mammalian longevity.

Link: http://onlinelibrary.wiley.com/doi/10.1111/acel.12519/full

The research linked here is an excellent example of the way in which most initiatives in medicine focus on compensatory adjustments to the disease state rather than on addressing root causes. The authors of this paper produce a beneficial reduction in age-related increase in blood pressure by altering the operation of vasoconstriction, an approach which does nothing at all to address the stiffening of blood vessel tissues that causes the high blood pressure of hypertension, and is therefore somewhat limited in the scope of improvements that it can produce. Even mild hypertension is so very damaging to health in old age that any approaches to safely reducing blood pressure should be celebrated, but nonetheless a research community that adopts a strategy of ignoring root causes is a research community that will continue to produce marginal therapies that can only modestly delay the inevitable results of aging. Only by repairing the root cause damage that results in age-related changes like arterial stiffening and hypertension can the length of healthy life be greatly extended, and age-related disease ended entirely.

Advancing age is a universal, potent, and currently un-modifiable risk factor for the development of hypertension and cardiovascular disease. Essential hypertension (high blood pressure (BP) without a secondary cause) is nearly an absolute consequence of aging in developed nations, affecting 60% of Americans over the age of 60 and 80% of the rapidly growing population over 80. Hypertension (HTN) is a substantial source of morbidity and mortality in the elderly, as high BP increases the risk of heart attack, stroke, vascular dementia, heart failure, kidney failure, and death. Despite this, only half of hypertensives over 50 years of age are controlled with current therapies.

The kidney is an established target of many antihypertensive therapies because it is a critical regulator of BP by modulating sodium and water balance. Perhaps less appreciated is the concept that in response to increases in blood volume from renal mechanisms and vasoconstrictor pathways that are enhanced with aging, smooth muscle cells (SMC) in the resistance vasculature constrict, thereby increasing peripheral vascular resistance and exacerbating hypertension. Thus, the vasculature is also an important contributor to the development of hypertension and to BP control. In humans and rodents, vascular aging is associated with enhanced vascular oxidative stress and increased responsiveness to the vasoconstrictor hormone angiotensin II (AngII) and these factors contribute to enhanced vasoconstriction with aging. However, the molecular mechanisms driving these vascular changes that contribute to hypertension with aging have not been elucidated.

Although the adrenal hormone aldosterone and its mineralocorticoid receptor (MR) are well known regulators of BP by promoting renal sodium reabsorption in the kidney, we previously demonstrated that MR is also expressed and functional in human vascular SMC. Moreover, we found that mice with MR specifically deleted from SMC in adulthood (SMC-MR-KO mice), are protected from the modest aging-associated rise in systolic BP that occurs in MR-intact mice, despite no change in renal function, sodium handling, or serum aldosterone levels. Rather, aged SMC-MR-KO mice had decreased vasoconstriction in response to increased intravascular pressure (termed myogenic tone) and were protected from AngII-induced vasoconstriction and vascular oxidative stress, important drivers of vascular dysfunction and hypertension with aging. Thus, the SMC-MR-KO mouse was used to explore mechanisms driving vasoconstriction with aging as these mechanisms may contribute to hypertension in elderly humans and could suggest new therapeutic strategies to improve BP control. We discovered that with aging, MR expression rises in resistance vessels along with a decline in microRNA (miR)-155 and increased expression of predicted miR-155 targets including the L-type calcium channel (LTCC) subunit Cav1.2 and the angiotensin type-1 receptor (AgtR1), genes that contribute to vasoconstriction and oxidative stress in aging mice. Restoration of miR-155 in aged vessels decreased target gene expression and vasoconstriction. Finally, in older humans, changes in miR-155 levels in response to MR antagonism correlated with improved BP response to therapy.

Overall, these data provide new insight into mechanisms driving vasoconstriction with aging that may contribute to the associated rise in BP. The data are consistent with the model in which enhanced SMC-MR expression and activity in aging resistance vessels suppresses vascular miR-155 transcription resulting in increased LTCC and AgtR1 expression. In this way, SMC-MR contributes to maintenance of myogenic tone and LTCC-induced constriction and primes the vasculature for enhanced AngII-induced oxidative stress and vasoconstriction, important components of the vascular aging phenotype that contributes to hypertension with aging. These results support the need for further studies in humans to determine if miR-155 could be a biomarker of MR activation in the setting of vascular aging with important implications for improving BP control in the rapidly aging population.

Link: http://insight.jci.org/articles/view/88942

The publicity materials and paper linked below discuss the identification of a cell type and related mechanisms responsible for calcification of blood vessels. The focus is on the environment of kidney disease, and thus on kidney tissue, but we might hope that this has a broader relevance to the age-related calcification that occurs in all blood vessels over the years. The more that is known of blood vessel calcification, the better the odds that something might be done about it soon enough to matter for you and I. The deposition of calcium in blood vessel walls is considered to be an important contribution to the loss of elasticity in these tissues. The stiffening of blood vessels with age drives the development of hypertension, an increase in blood pressure. Hypertension and stiffening cause detrimental remodeling of heart tissue that leads towards heart failure, as well as ever greater breakage of tiny blood vessels, such as in the brain, where the resulting tissue damage produces cognitive decline. Most forms of age-related cardiovascular dysfunction are exacerbated by hypertension: the higher the blood pressure, the worse the long-term prognosis.

While calcification in blood vessels is universally agreed to be a bad thing for the reasons given above, it is one of the many age-related changes for which there is no robustly defended line that can be drawn, leading through clearly demarcated steps, starting from an increase in fundamental forms of cell and tissue damage, the wear and tear caused by the normal operation of our biology, and ending with an increase in calcification. There is, however, a fair amount of evidence that can be used to argue over whether or not calcification is itself a fundamental form of damage, whether or not it is secondary to other forms of damage and change, and the nature of the processes that cause it. For example, calcification may be made worse by the presence of metabolic waste, of a type that the SENS Research Foundation has worked on clearing. It is also argued to be made worse by inflammation and by destruction of elastin, the basis for tissue elasticity. Sedentary individuals exhibit more calcification, as do those who report more time spent sitting.

The best path to deal with calcification depends on whether or not it is a fundamental form of damage. If it is a downstream effect of the classes of molecular damage outlined in the SENS vision for rejuvenation therapies, then the fix for calcification, as for near all aspects of aging, is to build those therapies, capable of repairing the root cause molecular damage. If calcification has a cellular cause, in that specific types of cells are changing their behavior in increasing numbers to deposit calcium where they should not be depositing calcium, then that scenario makes it much more likely that this is a secondary or later effect of other molecular damage. This unwanted change in cell behavior has been seen by other researchers in recent years, in heart tissue, for example. Separately, various therapeutic approaches based on removing the calcium deposits have been suggested by research groups over the years. It is likely that these approaches would be needed in addition to damage repair for people who have already grown old; simply repairing other forms of damage may not lead to the removal of excess calcium that has already accumulated. On this front it has been suggested to make use of osteoclasts, the cells responsible for dismantling bone, or, more conventionally, some form of chelation.

Scientists find culprit responsible for calcified blood vessels in kidney disease

Scientists have implicated a type of stem cell in the calcification of blood vessels that is common in patients with chronic kidney disease. The research will guide future studies into ways to block minerals from building up inside blood vessels and exacerbating atherosclerosis, the hardening of the arteries. "In the past, this calcification process was viewed as passive - just mineral deposits that stick to the walls of vessels, like minerals sticking to the walls of water pipes. More recently, we've learned that calcification is an active process directed by cells. But there has been a lot of controversy over which cells are responsible and where they come from."

The cells implicated in clogging up blood vessels with mineral deposits live in the outer layer of arteries and are called Gli1 positive stem cells. They have the potential to become different types of connective tissues, including smooth muscle, fat and bone. In healthy conditions, Gli1 cells play an important role in healing damaged blood vessels by becoming new smooth muscle cells, which give arteries their ability to contract. But with chronic kidney disease, these cells likely receive confusing signals and instead become a type of bone-building cell called an osteoblast, which is responsible for depositing calcium. "We expect to find osteoblasts in bone, not blood vessels. During kidney failure, blood pressure is high and toxins build up in the blood, promoting inflammation. These cells may be trying to perform their healing role in responding to injury signals, but the toxic, inflammatory environment somehow misguides them into the wrong cell type. We found Gli1 cells in the the calcified aortas of patients in exactly the same place we see these cells in mice. This is evidence that the mice are an accurate model of the disease in people."

Further supporting the argument that Gli1 cells are driving the calcification process, the researchers showed that removing these cells from adult mice prevented the formation of calcium in their blood vessels. "A drug that works against these cells could be a new therapeutic way to treat vascular calcification, a major killer of patients with kidney disease. But we have to be careful because we believe these cells also play a role in healing injured smooth muscle in blood vessels, which we don't want to interfere with."

Adventitial MSC-like Cells Are Progenitors of Vascular Smooth Muscle Cells and Drive Vascular Calcification in Chronic Kidney Disease

Mesenchymal stem cell (MSC)-like cells reside in the vascular wall, but their role in vascular regeneration and disease is poorly understood. Here, we show that Gli1+ cells located in the arterial adventitia are progenitors of vascular smooth muscle cells and contribute to neointima formation and repair after acute injury to the femoral artery. Genetic fate tracing indicates that adventitial Gli1+ MSC-like cells migrate into the media and neointima during atherosclerosis and arteriosclerosis in ApoE-/- mice with chronic kidney disease. Our data indicate that Gli1+ cells are a major source of osteoblast-like cells during calcification in the media and intima. Genetic ablation of Gli1+ cells before induction of kidney injury dramatically reduced the severity of vascular calcification. These findings implicate Gli1+ cells as critical adventitial progenitors in vascular remodeling after acute and during chronic injury and suggest that they may be relevant therapeutic targets for mitigation of vascular calcification.

Researchers here propose that alterations in fatty acid metabolism in aged heart tissue make up one of the contributing factors to the age-related loss of function in the heart, a process that eventually leads to heart failure and death. As a mechanism this is is situated somewhere in the middle of the chain of cause and consequence that starts with molecular damage caused by the normal operation of metabolism, a sort of biological wear and tear, then passes through a complex series of reactions to that damage, some helpful and some harmful, and finally leads to functional failure in organs as the network of damage and consequences becomes too much.

Age-related cardiac dysfunction is a major factor in heart failure. The elderly accounts for at least 80% of patients with ischemic heart disease, 75% of patients with congestive heart failure, and 70% of patients with atrial fibrillation. Heart failure with either lower or preserved ejection fraction is common for hospitalized patients with cardiac abnormalities. Cardiac aging, which is evident in both humans and mice, plays an important role for both types of heart failure. Several components of cardiac function, including energetic homeostasis, adrenergic signaling, and mitochondrial dysfunction, can be compromised during aging. Balanced cardiac lipid metabolism is critical for normal function of the heart. Any deviation toward either increased or reduced fatty acid metabolism may be detrimental for cardiac function, primarily depending on the type of pathophysiological challenge. Aging-related cardiomyopathy has been associated with downregulation of peroxisome proliferator-activated receptor (PPAR)-α, which is a central regulator of cardiac fatty acid metabolism and cardiac lipid accumulation. Thus, impairment of fatty acid metabolism may at least partially account for the aggravation of cardiac function that occurs with aging.

The heart normally consumes a large amount of ATP in order to pump more than 7,000 liters of blood on a daily basis. For the production of ATP that is needed for this massive amount of work, the heart oxidizes fatty acids, glucose, lactate, ketone bodies, and amino acids as energy-providing substrates. Fatty acid oxidation (FAO) is a major component of the energy production process as it accounts for the generation of approximately 70% of cardiac ATP. FA utilization in healthy hearts is a complex process that includes several steps, including: FA uptake, transfer of fatty acids into the mitochondria, and oxidative phosphorylation for ATP production. The flawless transfer of fatty acids from cellular uptake to mitochondrial oxidation prevents accumulation of excess lipids. A study in humans showed that aging decreases myocardial FA utilization and FAO without any difference in myocardial glucose utilization. Several types of cardiac dysfunction are associated with impaired FAO, which frequently leads to lipid accumulation characterized as cardiac lipotoxicity.

Although cardiac toxic lipids have been associated with cardiac dysfunction, it has not been studied thoroughly whether they mediate aging-related cardiomyopathy, as well as what lipid-driven signaling mechanisms may be involved. Various studies have established a correlation between cardiac lipid accumulation and aging in humans and animal models. Several proteins of the energy production machinery that mediates processing of FAs and ATP production are regulated at the transcriptional level by PPARα. The importance of PPARα inhibition in accelerating cardiac aging was demonstrated in 20-month-old rats that were treated with the lipid lowering drug atorvastatin, which increases PPARα expression. The treatment with atorvastatin reduced cardiac hypertrophy, collagen deposition, oxidative stress, expression of inflammatory cytokines, and the aging marker β-galactosidase. Although reduced cardiac PPARα expression has been associated with aging-related cardiomyopathy, the underlying mechanisms that mediate the beneficial effect of PPARα have not been fully elucidated.

In summary, cardiac FAO is important for lipid metabolism homeostasis and normal cardiac function. Inhibition of FAO leads to increased cardiac lipid content, which is often accompanied by increased levels of toxic lipids. These lipids compromise cardiac function via β-adrenergic receptor desensitization, which is driven by activation of the protein kinase C signaling pathway. Aging-related cardiomyopathy is associated with reduced cardiac levels of PPARα, a master regulator of cardiac FAO, as well as with inhibition of β-adrenergic receptor signaling and mitochondrial dysfunction. These components of cardiac lipotoxicity that are also involved in cardiac aging indicate therapeutic targets that may alleviate age-related cardiomyopathy.

Link: http://dx.doi.org/10.3402/pba.v6.32221

Calorie restriction produces improved health and extended longevity in most species, with a much larger effect in short-lived species that tend to have very plastic life spans in response to circumstances. One of the many interesting results to emerge from calorie restriction research is that this effect on health and longevity can be manipulated by altering systems of perception, work that has largely been carried out in flies and nematodes. Calorie restriction effects can be reduced by exposing flies to the presence of more food without letting them eat it, for example, and tinkering with the sensory neurons responsible for identifying and characterizing food content can induce some of the effects of calorie restriction without reducing calorie intake. Researchers here link serotonin signaling with the mechanisms of food sensing, and show that disrupting it has a fairly sizable effect on fly life span under some dietary conditions:

Limiting the amount of protein eaten, while still eating enough to avoid starving, has an unexpected effect: it can slow down aging and extend the lifespan in many animals from flies to mice. Previous work suggests that how an animal perceives food can also influence how fast the animal ages. For example, both flies and worms actually have shorter lifespans if their food intake is reduced when they can still "smell" food in their environment. However, the sensory cues that trigger changes in lifespan and the molecular mechanisms behind these effects are largely unknown.

Researchers therefore asked whether fruit flies recognize protein in their food, and if so, whether such a recognition system would influence how the flies age. Flies that had been deprived of food for a brief period tended to eat more protein than other flies that had not been starved. The researchers then revealed that serotonin, a brain chemical that can alter the activity of nerve cells, plays a key role in how fruit flies decide to feed specifically on foods that contain protein. Further experiments revealed also that flies age faster when they are allowed to interact with protein in their diet independently from other nutrients, despite eating the same amount. Disrupting any of several components involved in serotonin signaling protected the flies from this effect and led to them living almost twice as long under these conditions.

Researchers propose that the components of the recognition system work together to determine the reward associated with consuming protein by enhancing how much an animal values the protein in its food. As such, it is this protein reward or value - rather than just eating protein itself - that influences how quickly the fly ages. Further work is now needed to understand how the brain mechanisms that allow animals to perceive and evaluate food act to control lifespan and aging.

Link: http://dx.doi.org/10.7554/eLife.16843

The path from laboratory to clinic is a lengthy one. It helps to keep an eye on specific projects across the years to better calibrate one's expectations for new lines of research. Today's example of the mitochondrially targeted antioxidant molecule SkQ1, a form of plastiquinone, has been under development for quite the long time, starting with Russian lab work that first attracted my notice ten years ago - and of course had been going on for quite some time prior to that, stuck on the wrong side of the language barrier to catch the best opportunities for investment and interest. Following years of animal studies of various sorts, SkQ1 is presently being brought to the clinic by the European company Mitotech. They are in the midst of a human trial for dry eye syndrome and have recently obtained a patent in the US:

Mitotech S.A., a Luxembourg based clinical stage biotechnology company focused on age-related disorders, announced that it received a U.S. patent covering deceleration of aging in living organisms by its lead compound SkQ1. "The main aspect of the mechanism of action of our lead compound is protecting mitochondria from oxidative stress, which is a confirmed key factor in cell aging. That's one of the reasons SkQ1 proved to be effective in a wide spectrum of models of age-related disorders. This particular patent, however, may pave the way for Mitotech to pursue aging as a standalone indication. Of course, that would be a major undertaking in terms of the volume of clinical development and regulatory work, but we think it's an attractive opportunity and the field is wide open for a break-through technology."

One of the more intriguing outcomes of targeted mitochondrial antioxidant research is that it has shown promise as a treatment for a number of quite different eye conditions, such as cataracts, glaucoma, and dry eye syndrome. That is the path that was eventually chosen for initial commercial development. Dry eye syndrome is not to be dismissed lightly; ask anyone unfortunate enough to have suffered it. It is quite prevalent in old age and produces an negative impact on quality of life far larger than one might imagine would result from the tiny systems failures that cause the condition. That said, the reason that this community is interested in mitochondrially targeted antioxidants is because of the possibility that they can slow one of the forms of damage that contributes to degenerative aging, within which dry eye syndrome is but the tiniest mote.

As for any discussion of mitochondrially targeted antioxidants such as plastiquinones, SS-31, and MitoQ, it is worth taking a moment to point out that they are very different from the common or garden antioxidants that you can buy in the store. It is generally accepted in the research community that taking general antioxidant supplements is modestly harmful over the long term. In animal studies it tends to reduce life span by a modest amount. One of the mechanisms by which this might occur is that antioxidants will intercept and suppress the excess reactive oxygen species generated during exercise. That excess is a signal, and spurs a range of activities that result in everything from additional cellular maintenance to muscle repair and growth. This is something to bear in mind. Mitochondrially targeted antioxidants, on the other hand, localize to the mitochondria in cells. They primarily soak up reactive molecules there, not generally throughout tissues. This produces a range of effects because mitochondria are of great importance to cellular metabolism, and also of great importance in the aging process.

There are a couple of things going on for mitochondria in aging. The one that is the subject of more research is a downstream result of the many forms of molecular damage in aging, in which mitochondrial operation in cells declines in general, and tissues suffer as a result. This is a very complex and still poorly understood situation governed by epigenetics and scores of related, interdependent reactions to the low-level damage of aging, and which varies widely between tissue types and individuals. The less well researched issue is that mitochondria suffer damage to their DNA, separate from that of the cell nucleus. If genes essential to normal mitochondrial operation are deleted or damaged as a result, then the mutant mitochondria can either replicate more rapidly or become more resistant to quality control than their undamaged peers - it isn't clear which is the case at this point. Regardless, such mutants quickly take over cells and run rampant, turning these host cells into damaging exporters of reactive molecules that can cause all sort of harm in tissues both near and far. How does this DNA damage come about? It might be breakage during replication, but the consensus candidate has long been the generation of reactive oxygen species that happens inside mitochondria, right next door to their vulnerable DNA. Experiments with increased levels of natural mitochondrial antioxidants such as catalase provide supporting evidence for this proposition. Delivering artificial mitochondrially targeted antioxidants is thought to reduce the pace of mutational damage, and thus modestly improve healthy life span in this way.

Given the complexity of mitochondrial biochemistry, and its influential role on metabolism as a whole, I should say that almost everything I've said above has been disputed by one or more research groups at some point in time. The consensus is of varied resilience and always under attack. When it comes to the effects of mitochondrially targeted antioxidants on various medical conditions, their relevance may be as much damping down some of the oxidative signaling produced by mitochondria in inflamed tissues, or protecting mitochondria from an influx of oxidative molecules arriving from elsewhere, as anything else. This seems to help slow progression of a number of diseases with inflammatory components, as inflammation and oxidative stress go hand in hand. For all the focus on aging in the materials on SkQ1, the more rigorous life span studies of SkQ1 show only modest extension of life in short-lived animals, such as the recent demonstration of 10% life extension in flies. This is really not large enough to make it something that I'd consider worth chasing as an intervention in aging; short-lived species have very plastic life spans, and a 10% gain in flies is small in comparison to, say, the outcomes for calorie restriction. Get out there and exercise more and eat less, and you'll probably be doing more for your long-term health. If, however, as seems to be the case, these targeted antioxidants can have a significant positive impact on the later stages of a fair number of different age-related diseases that involve raised levels of oxidative stress and inflammation, well, then that was still research and development time well spent, even if it wasn't the outcome hoped for.

This popular science article takes a look at one of the groups working on characterizing the role of FGF21 in aspects of aging. Genetic engineering to increase levels of FGF21 extends life in mice, and also improves the function of the thymus and thus the immune system, as the thymus is where some classes of immune cell mature after their creation in the bone marrow. FGF21 is also involved in the beneficial effects of calorie restriction on health and longevity, but there appear to be significant differences between mice and humans on this count - and there must be significant differences somewhere in the biochemistry of the calorie restriction response, as human life spans are nowhere near as plastic in response to circumstances and therapies as those of mice. Calorie restriction extends mouse life spans by as much as 40%, but certainly doesn't do that for people despite being very beneficial for health.

Most mice start showing signs of aging by 2 years old. These mice didn't. Instead they entered what should have been their twilight years with vigor, approaching their third birthday free of the disease and the decreased mobility expected in animals their age. In a laboratory setting, regular mice would have a life expectancy of around three years, but these mice lived much longer, almost four years. Their secret was a hormone called fibroblast growth factor-21 (FGF21) that has an extraordinary effect on the immune system. Beginning in 2007, researchers began studying the hormone and its effects on mice genetically engineered to produce more of it. In 2012, scientists published a study finding that the hormone increased the lifespan of mice by as much as 40 percent. Last January, it was shown that in addition to extending the life expectancy of mice, FGF21 protects against the loss of immune function that comes with age.

The research into FGF21 builds on previous studies showing that severely restricting food intake can extend the lifespan of several different animals. Increasing levels of FGF21, which is secreted by the liver during fasting and helps the body adapt to starvation, seems to provide the benefits of dieting without limiting food intake. FGF21 plays an important role in the thymus, a small organ located between the lungs that has an integral role in the immune system. When functioning properly, the thymus produces infection-fighting T cells, but as we age the thymus becomes fatty and stops producing T cells capable of fending off infection. As a result, the immune system is compromised, becoming more susceptible to both infection and certain forms of cancer. But increasing levels of FGF21 in the thymus fends off the organ's age-induced decline, allowing it to continue to produce T cells to battle infection.

The aging field in general has picked up over the last five to 10 years. "There's more people proposing work related to aging and definitely more funding. Normally you get a drug approved by the FDA to treat a disease. But this is different. You're not trying to slow the progression of disease. You're trying to slow the progression of aging, and aging is not a disease, so it's a different paradigm." The focus on this new paradigm comes from a growing realization in the scientific community that as we age, we become more susceptible to such a wide variety of diseases that developing effective treatments for aging itself might be something of a cure-all. "Aging is the biggest risk factor for chronic diseases. The association between aging and chronic disease is stronger than the association between smoking and lung cancer. So, if you understand what is happening during aging, how it is happening and what are the mechanisms, cellular and molecular, then we may be able to delay the onset of diseases like Alzheimer's, arthritis, diabetes, certain cancers, kidney disease, macular degeneration, you name it. All these diseases are all linked to aging. I think the question we are more interested in is not just longevity, but actually the health and lifespan. So that extension of lifespan is associated with reduction of morbidity, or a period of life where we are free of disability. That is the real goal. Nobody wants to live an additional 40 years in a bed."

Link: http://www.connecticutmag.com/Blog/Health-Wellness/September-2016/Yale-Researchers-Study-Life-Extending-Hormone/

The Immortalist Society is one of the oldest of all cryonics groups, being originally founded back at the very start of the modern cryonics movement. The organization is presently seeking the funds to set up a research prize for technological progress in reversible organ cryopreservation. Research prizes are consistently shown to work pretty well when it comes to spurring investment and advancement in research and development, and for this particular technology it seems to be a good time for such an effort. You might look back at the Brain Preservation Prize competition that took place over the past few years to see how that worked to draw attention to the specific goals of the prize founders, and to improve the state of the art in cryopreservation. The intended goal for the Immortalist Society prize is plausible given the current state of work on cryopreservation techniques, a growing number of new entries into this research community, and the initial proof of principle demonstration of reversible cryopreservation of a rabbit kidney some years ago. Reversible cryopreservation for use in the organ transplant field is a gateway likely to lead to greater investment in cryonics technologies and greater acceptance of cryopreservation as a sensible end of life choice, given the lack of other options.

Currently there is a critically short window of time during which a donated organ remains viable, so distance and transport are major obstacles to treatment. Today an organ donor and a recipient must be matched immediately for any chance of a successful transplant. The challenges involved with matching a patient and a donor, relative to distances and timing, mean that thousands of potentially life-saving donor organs are unused every year. The Cryoprize is a grassroots initiative to solve these challenges and help these people get the life-saving treatment they need. Our goal is to encourage and reward the critical research needed to eliminate the current obstacles to successful organ transplants. Cryobiology, the science of preserving tissues and organs at ultra-low temperatures, can provide the solution. An organ successfully preserved by cryogenic means would remain viable indefinitely, eliminating the challenges of transport and distance. Permanent organ banks could be established, much the same as the blood banks hospitals rely on today.

The goal of the Cryoprize is to award a minimum of fifty thousand dollars to any individual or group that is able to place one of several mammalian organs at cryogenic temperatures, transplant the organ into a mammalian animal for a period of at least nine months, and show, during that time period, proper clinical function of the organ. The organs in question are the heart, lung, kidney, liver and pancreas. The prize amount to be awarded has as an initial goal a minimum of $50,000, with the further goal that the prize grow to at least $1 million. The prize is sponsored by The Immortalist Society, a non-profit organization dedicated to longevity research and outreach. But we need your help to fund this initiative. Please donate today, in any amount, and help us save lives.

Link: http://www.cryoprize.com/

Age Reversal Therapeutics is an initiative launched by quite the varied set of people: leaders from the "anti-aging" marketplace's Life Extension Foundation, a SENS Research Foundation researcher, a selection of biotech industry veterans, a practitioner of anti-aging medicine, and a reputable genetics researcher quite well known in our community. Strange bedfellows indeed - a meeting of many houses of the broader community interested in aging, houses that typically don't have much to do with one another, and indeed in some cases don't think much of one another. The basic plan here is to raise money from investors and then put it into some of the most promising of recent research and development initiatives in the treatment of aging. It is intended to be one of those hybrids that is something like a company and something like an investment fund. You can read their plans in some detail in their large PDF prospectus; scroll all the way down past the legal and fiscal matters to page 124 for the discussion of what exactly they intend to fund and the overall goals of the venture.

It is my belief that over the long term the currently terrible "anti-aging" marketplace will see the useless pills, creams, supplements, and potions replaced by rejuvenation technologies that actually work - as those technologies emerge from the scientific community, that is. The "anti-aging" marketplace always was, to a very large degree, a pipeline established by earnest believers in the end goal of extending healthy life spans, but who were unfortunate enough to have found that calling well in advance of the existence of any way to meaningfully alter the course of aging. Having the heart in the right place doesn't excuse what came next, of course, in which any old junk was thrust into the market in order to make money from the credulous, and thanks to the megaphone of marketing the whole concept of intervening in the aging process became synonymous in many eyes with rampant fraud over the course of the last few decades of the last century. This history does explain why some of the notable companies in the space, such as the supplement seller Life Extension Foundation, do in fact devote funding to legitimate research that you and I might approve of: stem cell trials, SENS programs, cryopreservation technology, targeted cancer therapies, and the like.

Age Reversal Therapeutics represents one of a number of possible next steps beyond those activities, now that the environment and awareness of aging as a therapeutic target has advanced to the point at which the rejuvenation therapy of senescent cell clearance is under development in startups, Calico Labs and Human Longevity have raised large sums, and other efforts make it clear that there is money out there for meaningful commercial work on the problem of aging. The question is how to take this new enthusiasm among for-profit investors and turn it into the research funding still needed to push new rejuvenation therapies to the point of commercial viability. Years of work and millions of dollars in fundraising yet remain to be accomplished to reach that point in most cases. The SENS Research Foundation has launched Project|21 as one possible answer to this question. Age Reversal Therapeutics is another possible answer. There are other groups out there taking the more traditional paths of establishing venture funds or starting their own companies. Old habits die hard, sad to say, and most investors are not yet willing to abandon profit as the primary marker of success, when the only real measure of success is future health and longevity. What use is financial profit to those crippled by age, who cannot buy the only thing they really want?

I think the next ten to twenty years of transition in the "anti-aging" marketplace from junk and outright lies to therapies that work is going to be messy for any poorly educated consumer. For people like me it will be increasingly hard to draw good lines between good and bad initiatives. We are absolutely going to see clinics marketed as anti-aging salons selling fully functional senescent cell clearance treatments in a package with entirely useless apple stem cell facial scrubs, and making little effort to educate their customers as to where the benefit comes from. We will eventually see clinics selling packages wherein, unlike the obvious example above, I cannot make a good judgement call as to which components are worth the candle. The glass half full view is that this will be much better than the present situation. An "anti-aging" marketplace in which only 10% of the products actually work is still 10% better than what we have today. So to the degree that the Age Reversal Therapeutics principals find new sources of significant investment from the Life Extension Foundation sphere of influence, then go on to fund projects that I agree with, and note that rejuvenation of the thymus is on their list, for example, and further manage to push the results into clinics for medical tourism and trials for validation, then I'm all in favor of the mess that lies ahead. It will certainly beat the present mess, featuring as it does a complete lack of ways to effectively treat aging as a medical condition.

But I encourage you to explore the Age Reversal Therapeutics website and form your own opinions. Certainly there is always the lingering suspicion that a venture led by the Life Extension Foundation and other "anti-aging" marketplace principals will go on to fund projects that I would characterize as useless at best and objectionable at worst. We shall see. I choose to be cautiously optimistic, and believe that, if the funding can be found, this has the potential to become something that looks a lot like the Life Extension Foundation's research funding program shorn of the Life Extension Foundation itself.

The brain is a machine like all of our organs, and aging gradually destroys its function. All of the various forms of outright dementia are caused by processes that take place in all of us: accumulation of metabolic wastes; failure of clearance and maintenance processes; dysfunction of the immune system and consequent neuroinflammation; diminished rate of creation and integration of new neurons; the countless tiny undetected strokes caused by structural failure of small blood vessels; and so on. As this damage accumulates, there is a steady decline in function. Much of this, however, consists of later consequences of fundamental damage. For example the ongoing destruction of brain tissue in small amounts due to tiny strokes is driven to a considerable degree by stiffening of blood vessels and consequent hypertension, which at root is caused by some combination of inflammation, cellular senescence, and calcification and cross-linking in the extracellular matrix of blood vessel walls. If those line items can be addressed, then the later consequences will be prevented, and the decline of cognitive abilities postponed.

Cognition is critical for functional independence as people age, including whether someone can live independently, manage finances, take medications correctly, and drive safely. In addition, intact cognition is vital for humans to communicate effectively, including processing and integrating sensory information and responding appropriately to others. Cognitive abilities often decline with age. It is important to understand what types of changes in cognition are expected as a part of normal aging and what type of changes might suggest the onset of a brain disease. It is imperative to understand the effects of age on cognition because of the rapidly increasing number of adults over the age of 65 and the increasing prevalence of age-associated neurodegenerative dementias. Because many more people are living longer, the number of people with age-associated neurodegenerative dementias also is increasing rapidly. The Alzheimer's Association estimates that 5.2 million people in the United States had a clinical diagnosis of Alzheimer disease (AD) in 2014, and the number of people with a diagnosis of AD is projected to increase to 13.8 million people in 2050, unless effective preventative or treatment strategies are developed. Thus, it is vital to understand how age impacts cognition and what preventative or treatment strategies might preserve cognition into advanced age. Any approaches that could decrease the negative effects of age on cognition or decrease the risk of developing a neurodegenerative dementia would have a tremendous impact on the quality of life of millions of older adults in the United States.

Cognitive abilities can be divided into several specific cognitive domains including attention, memory, executive cognitive function, language, and visuospatial abilities. Each of these domains has measurable declines with age. For each of these domains, a subject must first perceive the stimulus, process the information, and then respond. Both sensory perception and processing speed decline with age, thus impacting test performance in many cognitive domains. For example, auditory acuity begins to decline after age 30, and up to 70% of subjects age 80 have measurable hearing loss. Also, speech discrimination and sound localization decrease in advance age. In addition to these change in sensory perception, there is a clear decline in processing speed in advancing age with older adults performing these activities more slowly than younger adults. This slowing of processing speed causes worse test performance on many types of tasks that involve a timed response. The most noticeable changes in attention that occur with age are declines in performance on complex attentional tasks such as selective or divided attention. Selective attention is the ability to focus on specific information in an environment while at the same time ignoring irrelevant information. Divided attention is the ability to focus on multiple tasks simultaneously, such as walking an obstacle course and answering questions. Normal subject performance declines progressively with age on these more complex attentional tasks. However, simple attention tasks such as digit span are maintained in normal subjects up to age 80.

Executive cognitive function involves decision making, problem solving, planning and sequencing of responses, and multitasking. Each of these areas of executive cognitive function declines with advancing age. Executive cognitive function is particularly important for novel tasks for which a set of habitual responses is not necessarily the most appropriate response and depends critically on the prefrontal cortex. Performance on tests that are novel, complex, or timed steadily declines with advancing age, as does performance on tests that require inhibiting some responses but not others or involve distinguishing between relevant and irrelevant information. In addition, concept formation, abstraction, and mental flexibility decline with age, especially in subjects older than age 70. There are age-related declines in aspects of visuospatial processing and constructional praxis. Visual recognition of objects, shapes, gestures, and conventional signs remains stable into advanced age. However, visuoperceptual judgment and ability to perceive spatial orientation decline with age. A person's ability to copy a simple figure is not affected by age, but ability to copy a complex design declines with age. On standard IQ measures such as block design and object assembly, much of the declines with age are due to time, but when time is factored out, there are still declines in test performance with increasing age.

Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906299/

For most of the past decade the SENS Research Foundation has helped to fund work by various groups on allotopic expression of mitochondrial genes, a way to both cure mitochondrial disease and, more importantly, prevent mitochondrial DNA damage from contributing to the aging process. Allotopic expression works by creating backup copies of important mitochondrial genes in the cell nucleus, altered such that the resulting proteins can make their way back to the mitochondria where they are needed. Some of that work gave rise to Gensight in France, where researchers are commercializing the ability to move one of these genes into the nucleus. Last year a crowdfunding initiative provided the funds for the SENS Research Foundation in-house scientific team to finalize demonstration of allotopic expression of two more genes. The open access paper resulting from that work was recently accepted for publication, and here it is:

Mitochondria carry out oxidative phosphorylation principally by using pyruvate, fatty acids and amino acids to generate adenosine triphosphate (ATP). In animals, mitochondria are the only cellular organelles that possess their own DNA, mitochondrial DNA (mtDNA), which in humans contains 37 genes including genes encoding mitochondrial tRNAs, mitochondrial rRNAs and 13 oxidative phosphorylation (OxPhos) complex proteins. Both pediatric and adult-onset diseases have been identified that are caused by point mutations or partial deletions in mtDNA. Mitochondrial diseases tend to be fairly complex, with patients often presenting with multiple symptoms, and/or suffering from symptoms that differ between patients with the same mtDNA mutation. Traditional approaches include palliative treatments such as surgery or drugs, but are of limited use for mitochondrial diseases because they fail to address the underlying defect in the mtDNA.

Gene therapy may have the potential to treat mitochondrial disease, but many challenges exist. Direct transfection of replacement genes into mitochondria is extremely challenging. As an alternative, allotopic expression (the translocation of genes from their normal location in the mitochondria to the nucleus, followed by expression in the cytoplasm and re-insertion into the correct location in the mitochondria) was proposed as a potential method of gene therapy for congenital mutations over 25 years ago. This technique introduces additional challenges as, in addition to transfection into the cell, the allotopically expressed gene product must also translocate to the mitochondria and integrate into the appropriate protein complex. Nature already uses such targeting methods with the vast majority of proteins that comprise the mitochondrial proteome that are encoded by the nuclear genome.

In the time since allotopic expression of mitochondrially-encoded proteins was first proposed, several groups have attempted the method with mixed results. ATP6 protein was shown to integrate into Complex V (CV) and partially rescue growth of ATP6 mutant cells. ATP6 expression was also able to partially rescue mutant CHO cells while exogenous ND4 expression has been claimed to rescue rodent models of Leber's hereditary optic neuropathy. Mutant MT-ND1 cells were complemented by allotopic expression of ND1 with dramatic changes in the bioenergetics state and tumorgenic potential of the mutant cells. On the other hand, allotopically expressed ND6 protein localized to the mitochondria but failed to import properly or complement the loss of ND6 function. Allotopically expressed CYB was found to be similarly difficult to import into the mitochondria.

In order to unequivocally demonstrate functional import of a codon-corrected mtDNA gene, we sought to work in a system that was completely null for a mitochondrially encoded protein. We chose a transmitochondrial cybrid cell line which was derived from a patient whose mtDNA contained a nonsense mutation in ATP8. We have further characterized the cells and found them to contain reduced levels of ATP6 protein. Here, we demonstrate stable protein expression and mitochondrial import of ATP6 and ATP8 in the mutant cells. Tests for ATP hydrolysis / synthesis, oxygen consumption, glycolytic metabolism and viability all indicate a significant functional rescue of the mutant phenotype (including re-assembly of Complex V) following stable co-expression of ATP8 and ATP6.

Link: http://dx.doi.org/10.1093/nar/gkw756

The last few days have arrived for this year's SENS Research Foundation crowdfunding campaign, focused on important groundwork to establish a universal therapy for all types of cancer. There are still a few thousand dollars left in the matching fund, so donations are still being matched. Cancer is just as much a part of aging that must be ended, brought completely under control, as all of the other line items in the SENS rejuvenation research portfolio, and this year is the first time that the SENS Research Foundation has run a fundraiser for this program.

Hopefully there is no need to remind the audience here that the SENS Research Foundation, and important ally the Methuselah Foundation, have in recent years achieved great progress in the field of rejuvenation research on the basis of our donations and our support. Some of the high points you'll find mentioned here and there at Fight Aging!: support and ongoing expansion of the mitochondrial repair technologies now under development at Gensight; seed funding Oisin Biotechnologies for senescent cell clearance; unblocking efforts to clear glucosepane cross-links that stiffen tissues; running the lauded Rejuvenation Biotechnology conferences; and many more. If only all charities produced as great an impact with as few resources - and if only we were further along in the bootstrapping of an industry focused on the development of rejuvenation therapies. But we are where we are, and it remains wholly our opportunity as grassroots activists to light the way for others, to point out the research programs most likely to produce great gains in human health and longevity, and to attract a larger community of supporters to help out. They will be drawn by the fact we are a growing crowd, and that we have declared our support and expectation of good results from these programs: from senescent cell destruction, from mitochondrial repair, from glucosepane cross-link clearance, and from the others of the SENS program.

These SENS rejuvenation biotechnologies are unified by the theme of picking out specific areas of research that have been or are presently largely ignored, but that are also essential to the production of enormously beneficial outcomes in medicine, great leaps ahead rather than the incremental plodding that is the more usual state of medical progress. We live in an era of enormously rapid progress in biotechnology, and our medicine should reflect that fact - but in all too much of the research community there is a decided lack of ambition, and a culture that prefers to inch forward by increments. The entire point of the SENS vision, and the activities of the SENS Research Foundation and its allies, is to demonstrate that timidity and incrementalism can be bypassed to the benefit of all. There are large gains in health out there to be had, if the right strategy is chosen for research and development.

When it comes to the matter of aging that strategy is to focus on repairing the fundamental biomolecular damage of aging, the well-cataloged changes that distinguish old tissues from young tissues, and which have no other cause beyond the normal operation of healthy metabolism. These are forms of biological wear and tear, if you like, the accumulation of waste products and tiny breakages that spiral out into dysfunction and organ failure. For cancer research, meanwhile, the situation is more akin to an economic revolution, or disruptive advance in technology. Because all cancers must lengthen their telomeres, and because telomere lengthening is governed by a small number of processes, there is the opportunity to change the focus of cancer research from an endless procession of expensive new therapies, each targeting a tiny number of the hundreds of subtypes of cancer, to one single therapy that can effectively suppress all cancers. That is a huge difference, and turns the complete medical control of cancer from a distant future prospect into something that might be achieved from start to finish in a few decades.

The SENS Research Foundation's contribution to this project, the work that we as philanthropists choose to fund, is to run an assay with new tools against the standard drug library to find candidates to suppress alternative lengthening of telomeres (ALT). This should lead to a better understanding of how to build very effective therapies for ALT cancers, and in the best scenario will produce the starting point for a first wave of general therapies that can be applied to these cancers within a few years from discovery, based on repurposing known drugs. Other research groups are working on suppressing telomere lengthening by blocking telomerase, but it is becoming increasingly clear that telomerase cancers are quite capable of switching to become ALT cancers if provoked. The effectiveness of this road towards a universal cancer treatment depends on the blockade of both ALT and telomerase, but next to no-one has been working on ALT. This is where the SENS Research Foundation scientists, supported by you and I, can do their part to make this new approach to cancer a reality, by picking up this neglected but vital line of research and making the same success of it as they have in other areas.

How to make this happen? All we have to do is donate, mention this to our friends, say something to the world about how important it is that the whole of cancer research be transformed in this way. It is a golden opportunity to do something here and now to help build the type of future that we want to see.

The proximate cause of osteoporosis is a growing imbalance between the activities of osteoclasts, responsible for removing bone, and osteoblasts, responsible for creating bone. As is true of most issues in aging today, there is no clear line to be drawn between the fundamental damage that is the root cause of aging and the final link in the chain, which is to say differing cell behavior in bone remodeling. A great deal remains to be mapped, for all that enough is understood of the root causes to work towards repairing them. Unfortunately the majority of the research community tends to focus on proximate causes, which here means constructing therapies capable of adjusting the balance of activities for osteoclasts and ostoblasts. There are a range of potential approaches, but these researchers have settled on manipulation of a regulatory protein that diminishes bone absorption and increases bone deposition. A number of groups are working on this initiative, and new progress was recently reported:

Osteoporosis particularly affects elderly women: the bone's structure weakens and the risk of suffering fractures rises. Patients are advised to have a healthy diet and perform physical exercises; when the risk of bone fractures is high, medicine preventing further bone loss is prescribed in addition. In the search for better treatments for this disease the protein Sclerostin, which plays an important role in bone metabolism, is of major interest. When its function is impeded, bone resorption diminishes and bone re-growth is stimulated. First clinical trials with a Sclerostin-inhibiting antibody showed promising results in that the bone mass of participants suffering from osteoporosis increased.

Currently, studies are continued at several locations. In a collaborative project novel Sclerostin-inhibiting antibodies were generated and analysed for their suitability as osteoporosis treatment option. Now, for the first time scientists crystallized an antibody effective against Sclerostin and analysed its mode of action in detail. "Our findings could have a positive impact on the design of new inhibitory antibodies targeting Sclerostin." In this project, ten promising antibodies were developed in the initial round. After testing in cell culture one showed the favoured activity to neutralize Sclerostin. An in-depth analysis of the binding epitopes was performed using peptide chemistry and NMR spectroscopy. From these methods the binding site of the antibody in Sclerostin could be deduced. "Until now, we could only determine the structure of the antibody alone."

Link: https://www.uni-wuerzburg.de/en/sonstiges/meldungen/detail/artikel/osteoporose-antikoerper-kristallisiert-1/

It is undeniably the case that some older people are in relatively good shape when compared to their peers, and even when compared to individuals a decade or two younger. Aging is a process of damage accumulation, and thus you don't get to have a longer life expectancy in later life without being in better shape. In earlier old age a majority of the difference is made by lifestyle choices, but the longer you live the more of the difference becomes genetic in nature, the degree to which your physiology can resist or accommodate various forms of damage. Over the last decade researchers have increasingly worked to quantify exactly how the older people with better health are different from those who suffer more and die younger. This is all interesting work, but actually of little relevance to the future of human longevity. When, in the years ahead, clinics can repair the damage that causes aging, no-one will ever get to the point at which genetic differences and the ability to soldier on while very damaged become significant. Learning how a damaged system can better operate is really nowhere near as important as learning how to repair the damage.

In a pilot study on some of the oldest people of the world, researchers discovered that the perfusion of organs and muscles of the centenarians was as efficient as that in people who were 30 years younger. Results of the CIAO (Cilento Intitiative on Aging Outcome) pilot study suggest that low blood levels of the peptide hormone adrenomedullin (bio-ADM) are an indicator for such a good microcirculation. Making longevity measurable has long been a scientific goal as it could open up the avenue to a systematic identification of factors contributing to an extended life span.

The team carried out comprehensive health and life style assessments of two study groups that live in the Cilento region, located in the province of Salerno in southern Italy: In the first were 29 so-called 'SuperAgers' (median age 92 years), while the second was made up of 52 younger relatives (median age 60 years, living in the same household) who are expected to live just as long because they have the same genetic background and have been exposed to the same environmental and lifestyle factors. Blood biomarker analyses measured levels of the heart-function biomarker MR-proANP, as well as a marker for kidney function (penKid) and bio-ADM. The last is a regulator of vasodilation and blood vessel integrity, which both affect blood pressure. The results were compared to those of a cohort of 194 healthy persons (median age 63.9 years), who were monitored over eight years in the earlier Malmö Preventive Project (MPP).

As expected, low values of MR-proANP and penKid among the subjects in the two younger control groups indicated no signs of heart or kidney dysfunction. In contrast, both biomarkers were elevated in the SuperAgers, possibly due to the process of organ aging. However, even though the older group had levels of the two biomarkers that were as high as those found in patients experiencing heart failure (HF) or acute kidney injury (AKI), they were in clinically good condition. Surprisingly, in the group of SuperAgers, the bio-ADM values - which are often pathologically elevated in HF or AKI patients - were as low as those in both reference groups. Very low concentrations of this biomarker indicate a well-functioning endothelial and microcirculatory system allowing good blood perfusion of organs and muscles. A good microcirculation is what makes marathon runners perform better at the same heart rate than the average man or woman on the street.

Link: http://www.eurekalert.org/pub_releases/2016-09/sg-gmi_1090216.php

The paper I'll point out today is a timely one, given that the SENS Research Foundation's fundraiser for early stage work on a therapy for alternative lengthening of telomeres (ALT) cancers is nearing its close. There are still thousands of dollars left in the matching fund, so give it some thought if you haven't yet donated. The search for ways to safely sabotage ALT is a useful, important line of research because (1) blocking telomere lengthening is a path to a universal cancer therapy, (2) those research groups presently working on it are all looking to achieve this goal by interfering in the activities of telomerase, (3) cancers can switch from using telomerase to using ALT, and (4) next to no-one is working on ways to suppress ALT mechanisms. It seems fairly clear based on the evidence to date that the universal cancer therapy that lies ahead, built by inhibiting telomere lengthening, must involve a blockade of both telomerase and ALT. The open access paper below reinforces this point, the authors investigating how exactly cancers switch from telomerase to ALT to maintain their dangerous growth.

Cancer research today has a grand strategy problem. There is only so much funding and only so many researchers, but hundreds of subtypes of cancer. Therapies tend to be highly specific to the peculiarities of one type of cancer or a small class of cancers, meaning that great expense and time leads to a treatment that is only applicable for a fraction of cancer patients, all too often a tiny fraction. Further, since tumors evolve at great speed, any one individual patient's cancer may find its way out from under the hammer by changing its signature and mode of operation. All is not doom and gloom, however. Consider that the research community could build a therapy applicable to all cancers with little to no modification, where the cost of development would be no greater than any one of the highly specific therapies presently in use and under development. That therapy would be, of course, based on the blockade of telomere lengthening. The act of telomere lengthening is fundamental to all cancers, and without it tumors can neither grow nor sustain themselves: every cell loses a little of its telomeres with each division, and those with short telomeres self-destruct or become senescent. There is no expectation that any cancer would be able to evolve a way around a loss of telomere lengthening: these are core cellular mechanisms, not amenable to radical change or reinvention by simple mutational damage. The promise here is that the economics of cancer research and development could be entirely changed for the better, and that every cancer would become tractable, open to effective treatment.

The SENS Research Foundation cancer program staff propose to use an assay for ALT activity to assess the contents of the standard drug library for anti-ALT capabilities. The hope is that this will turn up potential candidates for further development, as well as shed more light on the most promising molecular mechanisms and targets to consider for the goal of shutting down ALT entirely, and further lend support for other groups to join in and help speed progress. In many ways ALT is a much easier target than telomerase. No normal adult cell uses ALT, so it is possible to take an indiscriminate, and therefore less costly approach to treatment without harming the patient. Telomerase is essential to stem cells, however, and so forms of targeting will be essential for that side of the future of cancer therapies. The paper linked here adds to the weight of evidence indicating that anti-ALT therapies are a necessary complement to the anti-telomerase therapies that are presently in the early stages of development.

Switch telomerase to ALT mechanism by inducing telomeric DNA damages and dysfunction of ATRX and DAXX

Continuous telomere loss which derives from DNA replication, drives the fusion of chromosome ends, leads to cell cycle arrest and induces cell senescence. However, tumour cells can maintain telomere length and proliferation through telomerase reactivation or the alternative lengthening of telomeres (ALT) mechanism. It is reported that approximately 85-90% of cancer types are telomerase-positive, which use its RNA subunit (termed TR or TERC) as a template and its telomerase reverse transcriptase (TERT) to maintain chromosomal ends. Due to lack of telomerase activity in human somatic cells, telomerase is considered as a potential target of cancer therapy. However, this strategy would be ineffective in several human cancers, which are lack of detectable telomerase activity and utilize the ALT mechanism relying on recombination-mediated telomere elongation. Previous studies have shown that anti-telomerase therapy provoked a switch from telomerase activity to the ALT mechanism in mice. Furthermore, it has been shown that the ALT is an alternative mechanism for telomere maintenance during oncogenesis, which would ultimately decrease the effectiveness of anti-telomerase treatment. Therefore, identifying the mechanism of ALT induction and the telomerase-ALT switch is beneficial in resolving the bottlenecks of anti-telomerase therapy.

ALT-positive cells typically contain abnormally heterogeneous telomeres, ALT-associated promyelocytic leukaemia bodies (APBs) and extrachromosomal TTAGGG repeats (ECTRs). Despite understanding the hallmarks of ALT, the mechanism of ALT induction remains unknown. The study of ALT activation which transformed a telomerase-positive cell line into an ALT-positive cell line in vitro is rare. Recently, several factors have been shown to contribute to ALT formation. It has been reported that the depletion of a histone chaperon ASF1 resulted in ALT cells induction and long telomeres elongation concomitant with inhibition of telomerase activity. Since the ALT mechanism is a recombination-mediated lengthening mechanism, the clustering of telomeres caused by DNA damage response (DDR) promotes homology-directed telomere synthesis, suggesting that DDR may play an important role in ALT induction. Further, somatic mutations of the histone variant H3.3, alpha-thalassemia X-linked syndrome protein (ATRX) and death associated protein (DAXX) have been found in ALT cancers. They are chromatin remodeling factors at telomeres, which are responsible for ALT activity. Furthermore, it has been shown that ATRX inhibits ALT and relates to telomerase assembly and depositing. Although single and double deletion of ATRX and DAXX could not initiate the ALT mechanism, histone management dysfunction and chromatin structure disorder might provide a suitable genomic environment for ALT induction. Lastly, telomerase activity plays very important role in ALT repression. Inhibition of telomerase activity might promote ALT induction. It has been shown that genetic extinction of telomerase in T cells of ATM knockout mice results in tumor emergence, concomitant with the increase of APB and C-circles.

To determine the mechanism by which telomerase-positive cancer cells switch to ALT and to elucidate the mechanism of ALT induction, we induced telomere-specific DNA damage, disrupted the function of the ATRX/DAXX complex and inhibited telomerase activity in telomerase positive cancer cells, which successfully transformed a telomerase-positive cell line into a ALT-positive cell line.

Telomeres are lengths of repeated DNA at the ends of chromosomes. Telomeres shorten with each cell division, and when they get too short cells self-destruct or become senescent. Thus their average length in any particular tissue, in our species at least, where other factors are less important, is a function of how often cells divide and how often the stem cells supporting that tissue deliver replacement cells with long telomeres. Telomere length is presently measured in immune cells from a blood sample, and this introduces a whole range of other influences based on the current status of the immune system. Average telomere length is fairly dynamic for any individual in response to circumstance and illness, and when measured across large populations tends to trend downwards with aging - which one might expect given the decline in both immune system and stem cell function that occurs in later life. Variation is large between individuals, however, and when looking at any specific individual it really isn't clear that measurement of telomere length is of much practical use in medicine: it is a terrible candidate for a biomarker of aging and health in that respect.

Telomeres are nucleoprotein complexes that cap the ends of linear chromosomes. Telomeric DNA decreases with age and shows considerable heterogeneity in the wider population. There is interest in the application of telomere length measures as a biomarker of general health or "biological age," and the possibility of using mean telomere length to gauge individual disease risk, and to promote lifestyle changes to improve health. This study examined the effectiveness of telomere length as a biomarker for an individual's current overall health status by assessing several measures of general health including SF-36v2 score, current smoking status and a comprehensive obesity phenotype. Participants were from the Canterbury Health, Ageing and Lifecourse (CHALICE) cohort, a New Zealand population based multidisciplinary study of aging. Telomere length measurements were obtained on DNA from 351 peripheral blood samples at age 49-51, using a quantitative polymerase chain reaction assay.

No associations were found between telomere length measured at age 49-51 and any measures of current health status. The only significant association observed was between telomere length and gender, with females having longer telomere length than men. Our results suggest that telomere length measurements are unlikely to provide information of much predictive significance for an individual's health status.

Link: http://dx.doi.org/10.1002/ajhb.22906

As a companion piece to the news of amyloid clearance in Alzheimer's patients from earlier this week, in which the outcome was not enough of an improvement to suggest that amyloid accumulation is the only issue, this article looks at a range of recent evidence for Alzheimer's disease to be a condition with multiple significant causes, some of which may be fairly independent of one another.

When pursuing an elusive beast, hunters look for the traces it leaves behind as clues to its whereabouts. Geneticists are employing a similar method to hunt variants linked to Alzheimer's disease (AD), with changes in the brain representing the variants' traces. By correlating biomarker changes with genetic factors, researchers gain clues to the mechanism of action of these genes. A common theme emerged when various groups reported finding distinct sets of factors that influenced amyloidosis versus tau degeneration. The findings imply that these processes have different underlying causes. Other research homed in on specific genes involved in atrophy, in some cases analyzing known AD genes for associations. To many researchers, the data reinforce that to prevent the progression of AD it will be important to treat not only factors that affect amyloid, but also those that affect neurodegeneration.

Previous data have long identified a disconnect between amyloid and atrophy. The regions affected by each form distinct, though overlapping, patterns in the brain. In addition, many older people have brain atrophy without amyloid accumulation. Researchers wondered if amyloid and atrophy might involve distinct risk and protective factors. To test this idea, they analyzed data from Mayo Clinic Study of Aging participants aged 70-90. The cohort comprised 713 cognitively healthy controls, 148 people with mild cognitive impairment, and 12 with AD dementia. For amyloidosis, as expected, older age and the presence of an ApoE4 allele heightened risk. Being a man, or having ApoE2, protected against plaques. However, little else affected amyloid deposition. In contrast, many factors contributed to atrophy. Lifestyle choices such as smoking associated with brain shrinkage, as did numerous chronic diseases of aging, such as hypertension and diabetes.

The data argue that Alzheimer's progression is more complex than simply amyloidosis driving tangles that in turn drive atrophy. Instead, different factors affect each process. The researchers tweaked the common AD analogy that amyloid acts as the gun and tau the bullet by saying that amyloid is the gun and degeneration the bullet. The speed of the bullet varies, they believe, based on risk factors that have nothing to do with amyloid. How do tau tangles fit in? Neurodegeneration has often been thought of as synonymous with tangles, but tau PET imaging data has now made clear that the brain can shrink without any tangles present. To specifically compare risk factors for amyloidosis, for tangles, and for atrophy, researchers analyzed a smaller cohort of 326 cognitively normal participants who had undergone tau imaging. They found that amyloidosis was the main factor driving tau pathology, in agreement with recent imaging studies. In turn, tangles drove some atrophy. However, here, too, the researchers calculated that many other factors affected neurodegeneration independently of amyloid or tau deposits.

Link: http://www.alzforum.org/news/conference-coverage/amyloid-and-neurodegeneration-have-different-underlying-genetics

In the paper I'll point out today, researchers use an intriguing method to transiently spur greater neurogenesis and integration of new neurons into neural circuits in older mice. Mice undergoing the procedure exhibited better memory function than those that did not. The interesting part of their approach is that it involves disrupting some fraction of the established neural connections between older neurons, a feat accomplished in a reversible way. During the period of time in which these connections between older neurons are somewhat disrupted, the surrounding tissue reacts by dialing up both the pace at which new neurons are created and also their integration into neural circuits. When the disruption is removed, the connections between older neurons reestablish themselves. So in this fashion the researchers get to have their cake and eat it too: the existing neural circuitry is preserved, but also expanded and strengthened by the newly created neurons.

This approach suggests it is possible that any method of temporarily interrupting neural connections might lead to the same outcome. Equally, the reaction observed may be very dependent on the specific part of the structure of the synapse that is suppressed, and thus on the specific few proteins involved. Hard to say at this point: there is still a great deal to be accomplished in terms of mapping the biochemistry of structures associated with neural function, and how that biochemistry relates to specific functions such as memory retrieval and discrimination. What is clear based on the past few decades of research is that a higher level of neurogenesis is beneficial across the board: it increases the ability of the adult and aging brain to heal, adapt, and learn. It most likely modestly postpones the progression and impact of age-related neurodegeneration, but beyond that it has the look of an enhancement that, if it could be achieved safely, every human being should undergo, leading to improved cognitive function at all ages. Just like artificially increased autophagy and calorie restriction and exercise mimetics, therapies to meaningfully increase neurogenesis are definitely on the to-do list for the research community, but nowhere near any form of practical clinical realization despite the many and varied demonstrations in laboratory animals that have taken place in past years.

Making memories stronger and more precise during aging

"The hippocampus allows us to form new memories of 'what, when and where' that help us navigate our lives, and neurogenesis - the generation of new neurons from stem cells - is critical for keeping similar memories separate." As the human brain matures, the connections between older neurons become stronger, more numerous, and more intertwined, making integration for the newly formed neurons more difficult. Neural stem cells become less productive, leading to a decline in neurogenesis. With fewer new neurons to help sort memories, the aging brain can become less efficient at keeping separate and faithfully retrieving memories.

The research team selectively overexpressed a transcription factor, Klf9, only in older neurons in mice, which eliminated more than one-fifth of their dendritic spines, increased the number of new neurons that integrated into the hippocampus circuitry by two-fold, and activated neural stem cells. When the researchers returned the expression of Klf9 back to normal, the old dendritic spines reformed, restoring competition. However, the previously integrated neurons remained. "Because we can do this reversibly, at any point in the animals life we can rejuvenate the hippocampus with extra, new, encoding units." The authors employed a complementary strategy in which they deleted a protein important for dendritic spines, Rac1, only in the old neurons and achieved a similar outcome, increasing the survival of the new neurons.

In order to keep two similar memories separate, the hippocampus activates two different populations of neurons to encode each memory in a process called pattern separation. When there is overlap between these two populations, researchers believe it is more difficult for an individual to distinguish between two similar memories formed in two different contexts. If the memories are encoded in overlapping populations of neurons, the hippocampus may inappropriately retrieve either. If the memories are encoded in non-overlapping populations of neurons, the hippocampus stores them separately and retrieves them only when appropriate. Mice with increased neurogenesis had less overlap between the two populations of neurons and had more precise and stronger memories, which, according to the researchers, demonstrates improved pattern separation. Mice with increased neurogenesis in middle age and aging exhibited better memory precision.

Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits

The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased neural stem cell activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and neural stem cell activation, leaving the dentate gyrus modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the dentate gyrus. Rejuvenation of the dentate gyrus by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.

Heavy isotopes are variants of atoms with one or more extra neutrons. Only some configurations are stable, such as the deuterium in heavy water, hydrogen with an extra neutron, or carbon-14, containing two more neutrons than the standard carbon atom. The chemical properties of a heavy isotope are slightly different, usually too slight to matter: heavy water is the exception to the rule, as it is toxic in large amounts, while heavy carbon isotopes appear to have little to no effect on living organisms. In recent years it has been shown that raising short-lived species, those with quite plastic life spans, on a low dosage of heavy water appears to modestly slow aging. This may be because it grants greater resistance to oxidative damage for some important parts of cell's molecular machinery, but may also simply be a matter of hormesis, in that a low level of damage or toxicity triggers greater levels of cell maintenance and repair, leading to a net benefit. From a practical point of view, this, like all ways to modestly slow aging, is probably only of interest as a tool for those researchers attempting to map the biochemistry of aging. It isn't a path to rejuvenation.

In a recent effort to look for the intrinsic factors that cause aging, we have discovered a potential candidate. By examining the intracellular small-molecule metabolites in yeast cells undergoing aging, we found that as yeast cells age, the overall heavy isotopic content, such as that of carbon-13, nitrogen-15, and hydrogen-2 (deuterium) declines in the amino acids, an essential group of metabolites that serve as building blocks in protein biosynthesis and precursors in all living organisms. Moreover, supplementing heavy isotopes through nutritional uptake extends the lifespan of yeast by more than 80% in aging assays, likely via eliciting a dietary-restriction-like effect. If this observed trend represents a wide-spread phenomenon in the isotopic composition of the metabolome, proteome, and genome in other organisms as well, new perspectives on understanding aging and retarding the end of life may open up.

Before our observation of heavy isotope decline during organismal aging, deuterium-bearing heavy water has been shown to promote longevity or improve certain health aspects in several organisms, including fruit flies, rodents, and humans. In fruit flies, transient exposure to heavy water at juvenile stages extends lifespan, and the exposure does not affect the health and reproduction. However, a dosage of 50% heavy water shortens the lifespan, and the relative lifespan shortening by heavy water was ameliorated by temperature elevation from 10 to 30°C, suggesting a protective effect of heavy water on fruit fly survival in hot conditions where accelerated metabolic rate normally reduces longevity. Improved thermoresistance was indeed observed at the protein, cell, and organism levels in fruit flies upon heavy water treatment. Similarly, a driving factor in temperature-compensated effects by heavy water was observed to alter the phase relation in circadian oscillation. The heavy water effect is increasingly more pronounced with rising temperature. However, the mechanism is still unknown. The similarity in the biological responses between heavy water and low temperature also correlate well with the general observation that fruit flies and worms have longer lifespan, and retarded brain degeneration when maintained at low temperature.

Several functional studies have shown that deuterated polyunsaturated fatty acids, even supplied in a minor fraction (20-50%), can protect yeast and mammalian cells from reactive oxygen species (ROS) damage to mitochondria. In whole animals, 25% heavy water was able to normalize high blood pressure induced by high salt diet in rats, possibly through suppressing hypertension-related elevation in calcium uptake. These effects would surely extend lifespan. In yeast, we also showed that heavy water extends chronological lifespan in a dosage-dependent manner. This pro-longevity effect could be essentially abrogated by mild dietary restriction or mitochondrion removal. Heavy water also suppresses the endogenous ROS generation, which could ameliorate the background chemical damages from ROS and lead to long-term improvement in fitness and survival rate. All these protective effects indicate that heavy water functions as a metabolism modifier to promote longevity, a feature that could be amenable to implementation in the context of other well-known anti-aging interventions.

Link: http://onlinelibrary.wiley.com/doi/10.1002/bies.201600040/full

The advent of CRISPR/Cas9 is making gene therapy so much cheaper and easier that uses previously rendered impractical are now more plausible to attempt. For example, cancers are driven by a very wide range of mutations, such as those disabling cancer suppression genes. A possible approach is to develop a stable of gene therapies that repair those mutations when they are present, starting with the most common, and thus shutting down cancer cells and halting their growth. The large number of different genes and mutations to target has meant that this strategy would make little sense without the large reduction in the cost of building and deploying gene therapies that CRISPR has created. The challenge of uptake of a gene therapy into cells, how to guarantee that near all cells in a tissue have their genes modified, is still not yet solved, but that will come in the next few years - everyone in the field needs a solution to that problem in order to proceed, and so all eyes are upon it.

CRISPR/Cas9 is likely one of the most revolutionary tools in biotechnology, with tremendous implications for a broad range of biological and medical disciplines. As programmable scissors this technology allows cleavage of DNA at predefined sites in the genome of cells. Now researchers have found a way to utilize the technology to diagnose and inactivate cancer mutations, thereby accelerating cancer research. "Mutations in cancer cells are identified at increasing speed through next generation sequencing, but we mostly do not know, which of these mutations are actually driving the disease and which ones are rather benign." The authors first analyzed how many of the more than 500,000 reported cancer mutations could theoretically be targeted and found that more than 80% of the mutations could be cleaved with the currently most popular CRISPR/Cas9 system. The research group then demonstrated that they could specifically cleave a panel of common cancer mutations without significantly targeting the healthy, wildtype alleles.

Moreover, expression of Cas9 together with the cancer-specific guide (g)RNAs was able to unmask mutations that drive cell growth and viability in cancer cell lines. "This is an important advance, because we can now rapidly separate driver from passenger mutations. This is currently a bottleneck in cancer research. Because each cancer shows a specific combination of many mutations, this scientific approach could improve cancer diagnostics as mutations that promote cancer growth could be specifically identified. Based on the obtained results an individualized therapy could be initiated.

Link: http://www.eurekalert.org/pub_releases/2016-08/tud-ctt083116.php