Fight Aging!

A recent article on the Longevity Dividend initiative included these comments from some of the backers:

One fountain of youth; hold the snake oil

"We now know that aging is modifiable in the laboratory," said Dan Perry, president of the Alliance for Aging Research. "When you do this, you also eradicate or greatly postpone the whole array of diseases that come with aging."

I know what you're thinking: You've heard all this before. We are constantly, shamelessly bombarded by profit-seekers - and yes, the complicit media - who promise an easy way out of aging, from gingko biloba to red wine to hormone or stem cell replacement therapy. So how, I asked the distinguished scientists in New Orleans, do they plan to distinguish the Longevity Dividend from all those empty promises of the past and present?

"It's a greater threat than we may sometimes realize," Perry acknowledged. "Eons of snake oil salesmen have tarnished the genuine science that's starting to emerge. Just one example is human growth hormone, and the entire industry that came up around it."

S. Jay Olshansky said every genuine anti-aging breakthrough is being seized on by hucksters and sold to a gullible public. But, he added, there's an easy way for you to tell good medicine from bad. "Part of the problem," he said, "is that when research scientists have published papers in recent decades, as soon as a glimmer appears they start selling it to the public for profit, before there are studies for safety and efficacy.

"But we are not selling anything to the public. If they are selling it now, it doesn't exist."

This is a good general rule of thumb when it comes to the intersection of health, aging, and longevity. It won't be a good rule for much longer, because the cutting edge of medical research and development is not so many years away from turning out actual first attempts at rejuvenation therapies, or ways to adjust metabolism to modestly slow aging, but it is a good rule for today and for the next few years at least.

Why? Because despite the many ways of extending life in laboratory animals there is as yet no commercially available technology that can be shown to produce more than a fraction of the health and longevity benefits of regular exercise and calorie restriction. All of the most advanced lines of research than might produce more effective ways to extend life in healthy individuals, such as some of those described in the SENS proposals, are at least five to ten years removed from early clinical access even in the best case scenarios for funding and aggressive medical tourism.

So if someone is trying to sell you a product today, with the promise that it will greatly extend your life, then that person is a huckster. Plain and simple. The best and only sensible use for your money for the foreseeable future is to provide support for the advocacy and medical research programs that will speed the advent of future rejuvenation biotechnologies, therapies that will actually extend life and restore youthful function to a meaningful degree once realized.

There has been more interest of late in how to engineer ways to sneak useful proteins past the digestive system so that they can be added to the diet but still find their way into cells. Researchers here combine this with the idea that you can dilute the proportion of damaged lipids present in cell membranes by providing a patient with a supply of undamaged lipids, larger than the body would otherwise generate on its own. I am not familiar enough with this line of work to be able to comment on how useful it is in practice, or whether the balance of evidence suggests that the observed results in trials actually occur due to the replacement of damaged lipids, as the authors state below. It is nonetheless quite interesting in the context of the membrane pacemaker hypothesis:

Lipid Replacement Therapy, the use of functional oral supplements containing cell membrane phospholipids and antioxidants, has been used to replace damaged, usually oxidized, membrane glycerophospholipids that accumulate during aging and in various clinical conditions in order to restore cellular function.

This approach differs from other dietary and intravenous phospholipid interventions in the composition of phospholipids and their defense against oxidation during storage, ingestion, digestion and uptake as well as the use of protective molecules that noncovalently complex with phospholipid micelles and prevent their enzymatic and bile disruption.

Once the phospholipids have been taken in by transport processes, they are protected by several natural mechanisms involving lipid receptors, transport and carrier molecules and circulating cells and lipoproteins until their delivery to tissues and cells where they can again be transferred to intracellular membranes by specific and nonspecific transport systems. Once delivered to membrane sites, they naturally replace and stimulate removal of damaged membrane lipids.

Various chronic clinical conditions are characterized by membrane damage, mainly oxidative but also enzymatic, resulting in loss of cellular function. This is readily apparent in mitochondrial inner membranes where oxidative damage to phospholipids like cardiolipin and other molecules results in loss of trans-membrane potential, electron transport function and generation of high-energy molecules. Recent clinical trials have shown the benefits of Lipid Replacement Therapy in restoring mitochondrial function and reducing fatigue in aged subjects and patients with a variety of clinical diagnoses that are characterized by loss of mitochondrial function and include fatigue as a major symptom.

Link: http://dx.doi.org/10.1016/j.bbamem.2013.11.010

The membrane pacemaker hypothesis suggests that one of the most important links between biology and longevity is the composition of cell and organelle membranes. If membranes are more resistant to oxidative damage then the result will be greater longevity. Differing levels of resistance can emerge in different species because of differing proportions of various lipids that make up membrane structures: some lipids are less vulnerable to peroxidation than others. Here, researchers demonstrate a good correlation between lipid profiles and longevity:

Membrane lipid composition is an important correlate of the rate of aging of animals and, therefore, the determination of their longevity. In the present work, the use of high-throughput technologies allowed us to determine the plasma lipidomic profile of 11 mammalian species ranging in maximum longevity from 3.5 to 120 years. The non-targeted approach revealed a species-specific lipidomic profile that accurately predicts the animal longevity.

The regression analysis between lipid species and longevity demonstrated that the longer the longevity of a species, the lower is its plasma long-chain free fatty acid (LC-FFA) concentrations, peroxidizability index, and lipid peroxidation-derived products content. The inverse association between longevity and LC-FFA persisted after correction for body mass and phylogenetic interdependence. These results indicate that the lipidomic signature is an optimized feature associated with animal longevity, emerging LC-FFA as a potential biomarker of longevity.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24284984

The human research that compellingly demonstrates that regular moderate exercise is very good for long term health is overwhelmingly epidemiological in nature. Researchers establish survey populations and mine existing data to find associations between health, aging, and exercise. The challenge here is always the identification of correlation versus causation: does exercise cause better health or does better health lead to more exercise? In many studies that has to be left an open question by the nature of the data and the study protocol - but some provide fairly compelling interpretations of causation.

Animal studies on the other hand leave absolutely no room for doubt on the question of exercise as a means to increase healthspan (if not maximum life span), improving long term health, slowing progression of measures of aging, and reducing incidence of age-related disease. It has been shown over and again in rigorous studies that exercise produces considerable improvements in health. The results, and the size of corresponding correlated health differences in human studies, are far better than can be achieved by any medical technology presently available in clinics.

For some researchers the data on exercise are a matter of backing up simple health advice: get out there and exercise in order to be healthier and extend your healthy life expectancy. But for others, this and investigations of the molecular biology of exercise form the ground floor for future development of exercise mimetic drugs. In an analogous way to ongoing work on calorie restriction mimetics, researchers will find ways to trigger some of the mechanisms of exercise to produce benefits without the exertion.

These research programs are producing and will continue to produce a wealth of data on how metabolism, aging, and lifestyle choices interact. But given that the benefits to health are already fully available the old-fashioned way, one has to think that perhaps all of this effort might be better directed towards research programs more likely to produce rejuvenation of the elderly - something that exercise and calorie restriction cannot achieve.

Road to exercise mimetics: targeting nuclear receptors in skeletal muscle

Skeletal muscle is the largest organ in the human body and is the major site for energy expenditure. It exhibits remarkable plasticity in response to physiological stimuli such as exercise. Physical exercise remodels skeletal muscle and enhances its capability to burn calories, which has been shown to be beneficial for many clinical conditions including the metabolic syndrome and cancer.

Nuclear receptors (NRs) comprise a class of transcription factors found only in metazoans that regulate major biological processes such as reproduction, development, and metabolism. Recent studies have demonstrated crucial roles for NRs and their co-regulators in the regulation of skeletal muscle energy metabolism and exercise-induced muscle remodeling. While nothing can fully replace exercise, development of exercise mimetics that enhance or even substitute for the beneficial effects of physical exercise would be of great benefit. The unique property of NRs that allows modulation by endogenous or synthetic ligands makes them bona fide therapeutic targets.

Exercise Training Initiated in Late Middle Age Attenuates Cardiac Fibrosis and Advanced Glycation End-product Accumulation in Senescent Rats

While it has long been postulated that exercise training attenuates the age-related decline in heart function normally associated with increased fibrosis and collagen cross-linking, the potential benefits associated with exercise training initiated later in life are currently unclear. To address this question, [rats] underwent treadmill-based exercise training starting in late middle age and continued into senescence (35 months) and were compared with age-matched sedentary rats.

Hearts were examined for fibrosis and advanced glycation end-products in the subendocardial layer of left ventricular cross-sections. Exercise training of late middle-aged rats attenuated fibrosis and collagen cross-linking, while also reducing age-related mortality between late middle age and senescence. This training was also associated with an attenuated advanced glycation end-product (AGE) accumulation with aging, suggesting a decrease in collagen cross-linking.

Researchers have for some years been investigating the mechanisms by which salamanders can regenerate limbs and organs. The hope is that either this capacity still exists in mammals in some form, dormant but able to be reactivated, or otherwise that there is something to be learned from salamander biology that might be imported to mammals to create greater feats of regeneration.

This latest research might go some way to explaining some of the contradictory results that have emerged from past work on the biology of salamander regeneration, such as whether or not their regenerative capacity declines with age:

Scientists labelled different cell types in two species of salamander in order to ascertain what kinds of cell give rise to new muscle tissue in salamanders that had lost a front leg. Salamanders are known for their remarkable ability to regenerate not only lost tails and other extremities but also the tissue of internal organs, such as the heart and brain. The traditional view is that the new tissue is formed from a population of stem cells activated when body parts are damaged; what they found, however, was that even though the two species were relatively closely related, this was true only for one.

"We show that in one of the salamander species, muscle tissue is regenerated from specialised muscle cells that dedifferentiate and forget what type of cell they've been. This is an interesting cellular mechanism that destabilises cell specialisation and produces new stem cells, as opposed to the other species, in which the new muscles are created from existing stem cells."

In the dedifferentiating species, the capacity to regenerate tissue does not decline with age, which the scientists believe can be linked to their ability to make new stem cells from muscle cells on demand. "It's important to study the process by which the salamander's muscle cells forget their cellular identity and how its modulated. It's also important to examine why their ability to regenerate is independent of age and the number of times the same tissue and body part has been regenerated."

Link: http://ki.se/ki/jsp/polopoly.jsp?d=2637&a=170899&l=en&newsdep=2637

I have long found it curious that Ray Kurzweil's public position on radical life extension omits support of specific ongoing research aimed at producing therapies for aging, such as the SENS program of rejuvenation biotechnology. This may be because he prefers to think in terms of broader trends rather than try to pick winners from present initiatives. Alternatively it may be because he sees the machine phase of medicine - the use of swarms of nanorobots capable of maintaining or replacing our biology - as emerging sooner rather than later.

As for me, I don't think that an early arrival of machine phase medicine is plausible: from where I stand it looks as though the medicine of the next four decades will be almost entirely based on control and manipulation of cells, alongside the design of proteins that complement our existing evolved set of protein machinery. We will augment and direct our own molecular biology using more molecular biology for decades before we get to the point of designing and using nanomachines that are as complex as cells without being biological at all.

So programs that are logical outgrowths of present day medicine - like SENS, pushing for repair therapies for cells and clearance of waste products - are the next step in human longevity. It's not a matter of skipping straight to nanorobotic cell replacements of the sort envisaged by Robert Freitas and others.

Most of us accept that our lives are limited. We'll have a certain number of years - more than 75, we hope, but probably fewer than 100 - and then we'll die. The world will go on without us. An awareness of our own mortality, we tell ourselves, is part of what makes is human. Not Ray Kurzweil. A renowned computer scientist and inventor, Kurzweil, 65, decided decades ago that mortality wasn't for him. He didn't have to die, and he wasn't going to, if he could help it. Fortunately, he believes he can help it - and he's been working feverishly at the task of staying alive ever since.

"How long do you think you will live?" I asked Kurzweil in a recent phone interview. He rarely misses a beat in conversation, but he was quiet for just a moment before replying. "I think I have a good chance - I would put it at 80 percent - of getting to the point where it becomes indefinite, because you'll be adding more time than is going by to your remaining life expectancy."

Technological advances won't transpire steadily over time, but rather exponentially, so that each year brings more change than the last. In fact, this is what's been happening for decades in the realm of computer processors, where it's known as Moore's law. Kurzweil believes similar laws of accelerating growth govern all forms of information technology. And he believes that all technology will eventually become a form of information technology. Ergo, technological progress is about to get really, really fast.

So why hasn't average life expectancy - or even the age of the oldest human alive - budged much over the last few decades? Kurzweil says we're just approaching what he calls "the knee of the curve." That's the point at which an exponential function starts to rocket upward. Longevity, Kurzweil explains, "is going to transform from having been a hit-or-miss affair where progress was linear ... to where it is now an information technology and therefore subject to my law of accelerating returns."

Link: http://www.slate.com/articles/technology/future_tense/2013/11/ray_kurzweil_s_singularity_what_it_s_like_to_pursue_immortality.html

The future of cancer treatment is targeting: deploying therapies that seek out and destroy cancer cells while leaving other cells unharmed, resulting in few or no side-effects. Many different approaches to achieving this end presently under research and development, and the most advanced have been in clinical trials for a few years now. Using the immune system as a starting point is one of the more promising strategies. After all, why build a whole new set of cell-targeting and cell-killing machinery when you can adapt the sophisticated, adaptive set that already exists?

Even considering only the use of immune cells as therapeutic agents there is still a very broad range of approaches that can be used to produce targeted therapies, and many varieties of potential therapy are presently either under development or in trials. This is a very active field of research, and on the whole things are looking very promising for everyone who is at least a couple of decades away from the stage of life in which developing cancer is likely. The coming generations of new therapies will be highly effective and much less debilitating. When coupled with vastly improved detection and screening technologies, the end result will be that cancer will recede from its present position as one of the principal causes of age-related mortality.

We still need rejuvenation therapies to deal with the underlying causes of degenerative aging, but given the present pace of progress, I don't feel that cancer is something to be greatly concerned about - or at least not in comparison to the other underlying aspects of aging, where there is far less ongoing work and enthusiasm for progress. Here are two recent examples of cancer immune therapies presently in the clinical trial stage of development, both of which show considerable promise:

Cancer meets its nemesis in reprogrammed blood cells

"THE results are holding up very nicely." Cancer researcher Michel Sadelain is admirably understated about the success of a treatment developed in his lab at the Memorial Sloan-Kettering Cancer Center in New York. In March, he announced that five people with a type of blood cancer called acute lymphoblastic leukaemia (ALL) were in remission following treatment with genetically engineered immune cells from their own blood. One person's tumours disappeared in just eight days. [A] further 11 people have been treated, almost all of them with the same outcome. Several trials for other cancers are also showing promise.

T-cells normally travel around the body clearing sickly or infected cells. Cancer cells can sometimes escape their attention by activating receptors on their surface that tell T-cells not to attack. ALL affects another type of immune cell, the B-cells, so Sadelain takes T-cells from people with ALL and modifies them to recognise CD19, a surface protein on all B-cells - whether cancerous or healthy. After being injected back into the patient, the reprogrammed T-cells destroy all B-cells in the person's body. This means they need bone marrow transplants afterwards to rebuild their immune systems. But because ALL affects only B-cells, the therapy guarantees that all the cancerous cells are destroyed.

Update: 50 Percent of Patients in Cedars-Sinai Brain Cancer Study Alive After Five Years

Eight of 16 patients participating in a study of an experimental immune system therapy directed against the most aggressive malignant brain tumors - glioblastoma multiforme - survived longer than five years after diagnosis. Seven of the 16 participants still are living, with length of survival ranging from 60.7 to 82.7 months after diagnosis. Six of the patients also were "progression free" for more than five years, meaning the tumors did not return or require more treatment during that time. Four participants still remain free of disease with good quality of life at lengths ranging from 65.1 to 82.7 months following diagnosis.

Results published in January at the end of the study showed median overall survival of 38.4 months. Typically, when tumor-removal surgery is followed by standard care, which includes radiation and chemotherapy, median length of survival is about 15 months. Median progression-free survival - the time from treatment to tumor recurrence - was 16.9 months at study's end. With standard care, the median is about seven months.

Even the most dangerous and challenging cancers are starting to yield in the face of more targeted approaches, and the pace of progress in the laboratory is speeding up. We can look forward to cancer as a controlled, cured condition, no worse a threat for anyone with access to modern medicine than smallpox or tuberculosis.

Like the better known amyloid-beta, the protein tau accumulates in Alzheimer's disease, and there is still much debate over exactly how this relates to damage and dysfunction. A fair portion of Alzheimer's research now focuses on clearance of amyloid and tau, often through immune therapies. We can hope that this produces technology platforms that can be turned to the removal of other forms of amyloid and unwanted proteins known to build up in old tissue. Here is an open access review that looks over what is presently known of the existing natural mechanisms that work to clear tau:

One of the defining pathological features of Alzheimer disease (AD) is the intraneuronal accumulation of tau. The tau that forms these accumulations is altered both posttranslationally and conformationally, and there is now significant evidence that soluble forms of these modified tau species are the toxic entities rather than the insoluble neurofibrillary tangles. However there is still noteworthy debate concerning which specific pathological forms of tau are the contributors to neuronal dysfunction and death in AD.

Given that increases in aberrant forms of tau play a role in the neurodegeneration process in AD, there is growing interest in understanding the degradative pathways that remove tau from the cell, and the selectivity of these different pathways for various forms of tau. Indeed, one can speculate that deficits in a pathway that selectively removes certain pathological forms of tau could play a pivotal role in AD.

In this review we will discuss the different proteolytic and degradative machineries that may be involved in removing tau from the cell. How deficits in these different degradative pathways may contribute to abnormal accumulation of tau in AD will also be considered. In addition, the issue of the selective targeting of specific tau species to a given degradative pathway for clearance from the cell will be addressed.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759803/

Here is a study that provides more data to strengthen the already well-proven correlation between regular exercise and long-term health:

Physical activity is associated with improved overall health in those people who survive to older ages, otherwise conceptualised as healthy ageing. Previous studies have examined the effects of mid-life physical activity on healthy ageing, but not the effects of taking up activity later in life. We examined the association between physical activity and healthy ageing over 8 years of follow-up.

Participants were 3454 initially disease-free men and women (aged 63.7±8.9 years at baseline) from the English Longitudinal Study of Ageing, a prospective study of community dwelling older adults. Self-reported physical activity was assessed at baseline (2002-2003) and through follow-up. Healthy ageing, assessed at 8 years of follow-up (2010-2011), was defined as those participants who survived without developing major chronic disease, depressive symptoms, physical or cognitive impairment.

At follow-up, 19.3% of the sample was defined as healthy ageing. In comparison with inactive participants, moderate, or vigorous activity at least once a week was associated with healthy ageing, after adjustment for age, sex, smoking, alcohol, marital status and wealth. Becoming active or remaining active was associated with healthy ageing in comparison with remaining inactive over follow-up. Sustained physical activity in older age is associated with improved overall health. Significant health benefits were even seen among participants who became physically active relatively late in life.

Link: http://dx.doi.org/10.1136/10.1136/bjsports-2013-092993

Jason Hope, you might recall, has provided half a million dollars in research funding to the SENS Research Foundation, used to establish a SENS laboratory at Cambridge in order to push forward with the Foundation's AGE-breaker program. AGE-breakers are drugs or other treatments capable of breaking down advanced glycation end-products (AGEs). These are a class of metabolic waste product that accumulate in our tissues to cause significant harm that includes the progressive loss of elasticity in skin and blood vessels.

There is, on the whole, far too little work undertaken today on AGE-breaker treatments in comparison to the benefits that a treatment could bring. What little research has taken place over the past twenty years unfortunately produced no effective therapies. As it turned out the AGEs that are important in short-lived laboratory animals are not the same at all as those that are important in humans - something that would have been challenging to identify until comparatively recently, and which resulted in promising animal studies that then went nowhere in commercial trials.

Now, however, researchers know that the vast majority of all AGEs in human tissues consist of just one type, called glucosepane - so the way is open for bold philanthropists and forward-looking researchers to build therapies that will be effective in removing this contribution to degenerative aging. Glucospane removal is one of the areas in which the SENS Research Foundation and its backers pick up the slack, undertaking important rejuvenation research that is neglected by the mainstream, even though it was exactly the mainstream research community that produced all of the studies and evidence that demonstrate the important role of glucospane in aging.

In any case, I should point out that Jason Hope runs a website and blog in which he discusses his take on philanthropy and his support for research aimed at extending healthy human life and rejuvenating the old. This makes for an interesting follow-on from yesterday's post on big philanthropy. More folk of this ilk would certainly be a good thing, and I'm always pleased to see more of the better connected people in this world of ours speaking openly of their support for rejuvenation biotechnology.

Philanthropy

Philanthropy has become a big focus for me. The organizations I have chosen to stand behind have come from many facets of my life. One of my passions has become the research done at the SENS Research Foundation. Their involvement in anti aging is not just about wanting to live forever. It's about creating a longer, better quality of life.

Foundations like SENS are taking a different approach to anti-aging. They are focused on finding cures for disease that break down the body and thus cause us to age faster than we should. Disease like Alzheimer's and heart and lung disease affect all functions of the body. Traditional medicine looks at treating these diseases after they happen. We want to focus on stopping these diseases from ever happening. We have spent so much time focused on medication for treating disease and not enough time on preventing that disease from ever happening.

By supporting scientific research that thrives through innovation and is not afraid to challenge the modern school of thought we will continue to break down walls.

A 21st Century Philanthropic Model For Philanthropy

Can you conceive of a world without age-related disease, disability and suffering? What about a world in which it's possible for the average person to live 120 healthy years? While it may sound like a utopian dream, such a world is the exact goal of some of society's most brilliant scientists and visionary leaders. At this very minute, groundbreaking work is underway at universities across the globe as researchers attempt to apply regenerative medicine to age-related disease through the repair of damage to tissue, cells and molecules within the body. While this research couldn't be possible without the leadership of the world's wealthiest philanthropists, it also relies upon the collective power of everyday people who have joined forces in their commitment to a better quality of life for all.

Traditionally, big ticket donors have been the primary target for fundraising programs. Research has consistently shown that the bulk of donor funds come from a small percentage of the wealthiest donors: in fact, a full 75 percent of funds raised come from gifts of over $1 million.

Instead of resigning themselves solely to the influence of the individual, non-profits are turning to the collective power of a group. The MFoundation's "The 300 Pledge" fundraising campaign is an exciting example of this method in practice. The 300 Pledge asks 300 funders to commit $1,000 a year for 25 years toward critical research aimed at ending age-related diseases. When broken down, this goal is manageable for many households: just $3 a day or $85 a month - less than your daily tab at Starbucks. Obviously, the model is working: to date, 291 people have taken up the challenge, with nine spots remaining.

As evidenced by the magnificent philanthropy of people like Peter Thiel, Bill Gates and others like them, it's obvious that one person can make a difference. However, fundraising challenges, like MFoundation's "The 300," also demonstrate the power of a dedicated group of people to foster real world change for the billions of people living in the world today as well as the generations that follow. In doing so, those who take up the challenge create a unique and world-altering legacy for themselves.

An accumulation of senescent cells is one of the causes of degenerative aging. These are damaged or otherwise dysfunctional cells than stop dividing and start issuing signals that are disruptive to surrounding tissues. They should be destroyed by their own programs or by the immune system, but nonetheless accumulate over time, their presence becoming increasingly harmful. Cellular senescence is thought to be a defense against cancer, and as is also the case for the shutting down of stem cell activities with age, this is a defense that bears its cost in terms of increased frailty and tissue failure.

Here researchers argue that the increasing presence of cell senescence with age is a late-life adoption of a mechanism that evolved to steer embryonic development:

Senescent cells are involved in many of the ravages of old age. Wrinkled skin, cataracts and arthritic joints are rife with senescent cells. When researchers rid mice of senescent cells, the animals become rejuvenated. Besides stopping their growth, scientists found, senescent cells also secrete a cocktail of chemicals. The chemicals they release can create chronic inflammation. They also attract certain immune cells, which seek out the senescent cells and kill them.

This behavior can actually be good for our health. As a cell's DNA gets more damaged, it runs a higher risk of dividing uncontrollably and developing into cancer. Senescent cells keep themselves from becoming cancerous by stopping their own growth and by inviting immune cells to kill them. While senescence may be a powerful defense against cancer, however, it comes at a steep cost. Even as we escape cancer, we accumulate a growing supply of senescent cells. The chronic inflammation they trigger can damage surrounding tissue and harm our health.

[Researchers have] confirmed that cells became senescent in many parts of an embryo, such as along the developing tips of the legs. By sheer coincidence [they] had also discovered senescent cells in other regions of the embryo, such as the middle ear. The researchers found no evidence that the senescent cells in embryos have damaged DNA. That discovery raises the question of how the cells were triggered to become senescent. [It is hypothesized] they did so in response to a signal from neighboring cells.

Once an embryonic cell becomes senescent, it does the two things that all senescent cells do: it stops dividing and it releases a special cocktail. The new experiments suggest that this cocktail plays a different role in the embryo than in the adult body. It may act as a signal to other cells to become different tissues. It may also tell those tissues to grow at different rates into different shapes. [Researchers suspect] that the sculpting that senescent cells carry out may be crucial to the proper development of an embryo. It's possible [that] senescence actually evolved first as a way to shape embryos; only later in evolution did it take on a new role, as a weapon against cancer.

Link: http://www.nytimes.com/2013/11/21/science/signs-of-aging-even-in-the-embryo.html

Here is news of one of a number of approaches to building bioartificial skin. As for many organs, a replacement doesn't have to be exactly the same as natural tissue. Rather it just has to be capable of at least some of the functions provided by natural tissue in order to be both beneficial and useful.

Spanish scientists [have] managed, for the first time, to grow artificial skin from stem cells of umbilical cord. [This study] shows the ability of Wharton jelly mesenschymal stem cells to turn to oral-mucosa or skin-regeneration epithelia. To grow the artificial skin, the researchers have used, in addition this new type of epithelia covering, a biomaterial made of fibrin and agarose.

One of the problems major-burn victims currently have is that, in order to apply the current techniques of artificial skin, a number of weeks are needed. That is because the skin needs to be grown from parts of the patient's healthy skin. "Creating this new type of skin using stem cells, which can be stored in tissue banks, means that it can be used instantly when injuries are caused, and which would bring the application of artificial skin forward many weeks."

Link: http://canal.ugr.es/health-science-and-technology/item/69279

Wealth does not grant vision, and arguably the process of becoming extraordinarily wealthy requires a person who does not devote a great deal of interest and effort to anything beyond running that process. Usually this involves a great deal of work, a great deal of learning, a great deal of personal growth. But if you happen to also be someone who wants to change the world in ways that require a great deal of money - such as through medical research, for example - then you probably won't get much past the level of multi-millionaire. You'll choose to start investing in doing good rather than doubling down on the money-making road.

I think that this goes some way towards explaining the conservatism and lack of vision that accompanies $100 million and larger donations to charitable causes: philanthropic structural investments we might term them. Putting that much money towards a goal requires a significant project just to understand how to best spend it, even when the aim is very clear, such as "let us cure this one disease." It is very, very rare to see this much money arrive in support of a young cause, as the people with that much money to invest have not led the lives that would lead them to understand the cutting edge of any of the fields they might support. This is really just specialization at work.

What has to happen to make it likely that someone exceedingly wealthy will donate $100 million to furthering a field of research? There must have been decades of growth, including the very earliest research interest; then a surge in the scientific output; then hundreds of millions of dollars of funding; a business cycle of new companies; a brace of failures; thousands of articles in the popular press; a backlash and down cycle; resurgence and renewed investment in the billions of dollars; tremendous progress; excitement in the public and scientific communities; tens of thousands of researchers flocking to the field; a new breakthrough every week; ten years of incremental advances demonstrated in commercial medicine; early therapies demonstrated in the field; the branch of medicine now known to every common fellow on the street.

That is what has to happen for the average exceedingly wealthy philanthropist to feel comfortable devoting time, effort, and large sums of money into making a structural investment in a field of medicine. Think of the history and presently enthusiastic, well-funded, widely supported state of stem cell research while you take a look at this article:

Sanford donates $100 million to UCSD

Philanthropist Denny Sanford is donating $100 million to UC San Diego to speed up attempts to turn discoveries about human stem cells into drugs and therapies to treat everything from cancer and Alzheimer's disease to spinal-cord injuries and weak hearts. The $100 million donation represents the core of a larger $275 million effort by UC San Diego to create some of the first clinical trials based on human stem cells, which can develop into many different types of cells, including some that can help repair tissues and organs. The newly created Sanford Stem Cell Clinical Center will enable the school to hire 20 to 25 scientists and recruit patients for drug trials.

One of the points raised by Peter Thiel and others is that this sort of support of well-established research fields is where philanthropy is at its least useful. I don't want to point to the example above to say "do better," because I don't think I have the standing to do so. Sanford has arguably done more to make the world a better place with that work than I ever will. But still: at some point the philanthropic community should figure out a way to be something other than last to the party, adding to a sure thing at the end of the day rather than boldly taking risks in the early days to more rapidly build the medical technologies needed for a better world.

I would like the near future of rejuvenation biotechnology to be something other than a twenty to thirty year climb to get to the point at which big philanthropy and the world at large notices its existence and decides that it is a legitimate field of research, worthy of additional support. To arrive at that position, billions will have been raised and spent, early therapies deployed, and thousands of scientists engaged. But it would all go so very much faster if someone would just decide tomorrow that the best thing to do was to make a $100 million investment in building the vision for rejuvenation biotechnology laid out by the SENS Research Foundation.

I know this with confidence because I've personally spent enough time over the past decade to understand the research landscape and the prospects for new and radically disruptive advances in medical biotechnology relating to aging and longevity. As a general rule, anyone with $100 million to invest has not. Such is the human condition.

The most important aspect of our era by far is the prospect for greatly extending healthy life through new medical technology. Long after everything else is forgotten, these years will be remembered as the end of degenerative aging. The new biotechnologies of rejuvenation will only happen rapidly enough to benefit those of use in mid-life if greater funding and attention is given to the best lines of research, however. This is the most important age of mankind, but we ourselves will not greatly benefit from it unless we help move things along more rapidly.

When you are deeply involved in advocacy for longevity science, it is easy to lose your memory of not caring and not knowing. Once upon a time we were all either ignorant or opposed to living longer, as most of the world remains at this time:

On the first Berlin Singularity event when a new friend propositioned the topic of life extension, I was horrified. But then I was even more troubled by the fact that I was horrified. I asked myself to set out the argument for offence. Then one by one, I realised that none of my propositions for concluding that life extension was "insane, gross, disgusting, egotistical" were actually valid. They were all marred by an extreme social and cultural bias.

Just because a thing had always been in such a way, did not mean that it was valid. Just because we had accepted aging in the past as a result of not really having any other choice, did not mean it was valid. Accepting aging was totally illogical - in the same vein that we do not accept cancers, or accidents, or any other cause of mortality. I couldn't find any differences between these diseases and the notion of aging. This wasn't about being 'immortal' (a word I think we all need to shun), but if I loved life (and the lives of those around me), why would I not want to enjoy it, healthier, for as long as I possibly could?

All the money in the world can't stop time from destroying everything. And although we may never absolve ourselves from being under it's grasp in some way or another, we're able now to confront biological time in a way never considered before. We're all racing against internal clockwork. And just like the nobleman taking apart the clock to try and gain control of the one thing that eluded him, so too are longevity research groups taking apart our internal clockwork and examining the mechanism. It's the stuff that humanity has always dreamed of. It's also one of the areas least discussed outside our relatively small circle.

Link: http://hplusmagazine.com/2013/11/22/time-and-the-transhuman-condition/

Researchers are becoming more comfortable putting forward timelines for organ printing, which we might take as a sign of progress in and of itself:

A team of cardiovascular scientists has announced it will be able to 3D print a whole heart from the recipients' own cells within a decade. "Funding is very limited as this is a new area. But as bioprinting successes occur the interest will increase and then funding - so many breakthroughs have occurred in this way with a new untested idea that is moved forward with limited resources. For bioprinting it is the end of the beginning as bioprinted structures are now under intense study by biologists."

Stuart K Williams is heading up the hugely ambitious project as executive and scientific director of the Cardiovascular Innovation Institute. Williams says he and his team of more than 20 have already bioengineered a coronary artery and printed the smallest blood vessels in the heart used in microcirculation. "These studies have reached the advanced preclinical stage showing printed blood vessels will reconnect with the recipient tissue creating new blood flow in the printed tissue."

The team has also worked on other methods of bioengineering tissue, including electrospinning for the creation of large blood vessel scaffolds that can then be joined with bioprinted microvessels. The Cardiovascular Innovation Institute is now developing bespoke 3D printers for the job with a team of engineers and vascular biologists. Though for now those printers are focusing on replicating the parts, the plan is to print the whole in one go in just three hours, with a further week needed for it to mature outside of the body. Certain parts will need to be printed and assembled beforehand, including the valves and the biggest blood vessels. "Final construction will then be achieved by bioprinting and strategic placement of the valves and big vessels," says Williams, who asserts that they are "on schedule" to build the bioficial heart within the decade marker. The bioprinter he says will be capable of achieving all the forementioned work is under construction now.

Link: http://www.wired.co.uk/news/archive/2013-11/21/3d-printed-whole-heart

The Longevity Dividend is an advocacy and education initiative that aims to gather sufficient public and political support to reshape the flow of public funds into aging science: to explicitly aim to slow aging and extend healthy life, and to greatly increase government funding for that goal via the National Institutes of Health. The initiative has been around for some years, but of late the level of organization and public advocacy has stepped up a few notches. This, the continuing success of the SENS Research Foundation in gathering support and allies in the scientific community, and Google's Calico operation are, I think, all signs of the times. Past years of persistent advocacy have succeeded in waking up some portions of the community, and the results are now emerging. This is the entry into the next cycle of development, in which there is a lot more funding and interest for medical research that might potentially extend healthy human life spans.

Investments in aging biology research will pay longevity dividend, scientists say

Finding a way to slow the biological processes of aging will do more to extend the period of healthy life in humans than attacking individual diseases alone, according to some of the nation's top gerontologists writing in the latest issue of Public Policy & Aging Report (PP&AR), titled "The Longevity Dividend: Geroscience Meets Geropolitics." The authors showcase work in the emerging interdisciplinary field of geroscience, which is based on the knowledge that aging itself is the major risk factor for most chronic diseases prevalent in the older population. "In recent years, researchers studying the biological underpinnings of the aging process have made impressive progress in understanding the genetics, biology, and physiology of aging," said GSA Executive Director and CEO James Appleby, RPh, MPH. "With adequate research support, we could be in reach of a breakthrough similar to those in public health in the 19th century and medicine in the 20th."

While researcher S. Jay Olshansky's article in the PDF linked below is much more ambitious in terms of goals and possibilities than I recall being the case for his public position in the past - there is a table in there that includes the word "immortality," for example - this is still not open support for SENS and rejuvenation of the old through repair therapies. It is support for slowing aging, which implicitly means support for the present slow road in aging research, the drug development and metabolic manipulation that is unlikely to result in great gains, and which will absorb a great deal of time and money in the course of going pretty much nowhere.

Still, a starting point is a starting point. When the Longevity Dividend folk set to work in order to dispel public misconceptions relating to overpopulation and increased infirmity in longer lives - both absolutely unfounded fears - then all efforts to extend life benefit. A rising tide raises all boats, and it is in everyone's interest to inform the public that yes, life extension in fact means health extension, and population will generally grow only slowly as human life spans become much longer.

The Longevity Dividend: Geroscience Meets Geropolitics (PDF)

The case for the longevity dividend is extremely compelling and, in theory, should be easy to make to funders, public-health professionals, and the general public. Here is the line of reasoning:

Treating diseases worked well in the past to extend healthy life, but aging has emerged as the primary risk factor for the most common fatal and disabling diseases.

The longer individuals live, the greater the influence of aging on disease expression.

Aging science offers medicine and public health a new and potentially far more effective weapon for preventing disease, extending healthy life, and avoiding the infirmities associated with old age.

Failing to take this new approach could leave people who reach older ages in the future even more vulnerable to rising disability than they are now.

Aging science represents a new paradigm of public health that has the potential to yield more effective methods of delaying most fatal and disabling diseases, extending healthy life, and reducing the prevalence of infirmities more commonly experienced at older ages

Although people who benefit from advances in aging science will probably live longer, the extension of healthy life is the primary goal. In addition, reductions in the infirmities of old age and increased economic value to individuals and societies would accrue from the extension of healthy life.

It is only a matter of time before aging science acquires the same level of prestige and confidence that medicine and public health now enjoy, and when that time comes, a new era in human health will emerge. An abundance of formidable obstacles are standing in the way, including strongly held views of how to proceed, a history of association with dubious aging interventions, and misconceptions about the goals in mind and the impact of success on population growth and the environment. Once the air clears and aging science is translated into effective and safe interventions that can be measured and documented to extend our healthy years, the 21st century will bear witness to one of the most important new developments in the history of medicine.

The article by Dan Perry is also worth reading:

Like the rough beast of the famous poem by W. B. Yeats, a scientific consensus that aging might be slowed to avert chronic diseases in older people is slouching toward serious consideration in public policy.

Richard Miller addressed a scientific audience a few years ago with an only slightly tongue-in-cheek assessment of why biogerontology has failed to be embraced as a panacea for age-related diseases and disability among the older population. Miller assessed the obstacles to finding a cure for aging as 85 percent political and 15 percent scientific. Among the political obstacles Miller noted:

Aging is viewed (incorrectly) as unalterable.

Drugs that actually slow aging cannot be tested in time to show a profit within the CEO's lifetime; whereas drugs purported to slow aging are highly profitable even though they don't work.

A politician who wants to "conquer cancer" is a hero.

A politician who wants to "slow aging" is a nut-case.

Regardless of which of Miller's hurdles are most daunting, the fact remains that federal funding of biomedical research continues to pursue cures and better treatments for specific diseases, especially for those with vocal constituencies. Recent developments, however, including congressional interest and creation of the trans-NIH Geroscience Interest Group (GSIG), are setting the stage for a determined push for increased federal support for age-modifying research with clinical potential.

SENS and rejuvenation research is still not a part of this funding picture. Those involved are generally much more conservative, or at least feel the need to appear so in public. I think it will take more years of steady growth in funding and support for SENS, and the emergence of one or two important technology demonstrations in rejuvenation resulting from ongoing SENS Research Foundation projects for it to start to feature in discussions of large-scale funding and goals. All funding at this level is political, the public funding much more so of course, and change is slow.

I noticed this study today which reinforces the well-known correlation between wealth and longevity, but more strongly reinforces the point that people age at different rates. If you have developed more pronounced age-related disease or disability at 70, then your odds of reaching 90 are not so good in comparison to your more healthy peers. Aging is damage, and age-related disease and degeneration is the visible manifestation of that damage. Insofar as we have control over the pace of aging, that is a matter of good lifestyle choices: exercise, calorie restriction, good use of preventative medical resources, and so forth. There is also the matter of supporting research so as to improve the capabilities of the medical technologies available in your old age - a factor much more important than the others when it comes to determining your expected length of life.

To identify factors associated with survival to the age of 90 years old in 70+ elderly people [we examined data from] 75 randomly selected administrative communities in Gironde and Dordogne (France) [containing members of the] PAQUID prospective cohort on brain and functional ageing. A sub-sample of 2,578 community dwellers aged 70 years and over at baseline in 1988 [were followed] over 20 years. Data on socio-material environments, lifestyle, health, perceived health, and family background were collected at home every 2-3 years over 20 years, with a prospective update of vital status. Participants were compared according to their survival status (subjects who reached 90 compared to those who did not).

Some factors associated with survival were common to both genders, whereas some others appeared gender specific. For men, tenant status (hazard ratio, HR=1.46), former or current smoking (HR=1.17), disability (respective HR of 1.50, 1.78 and 2.81 for mild, moderate and severe level), dementia (HR=1.51), a recent hospitalisation (HR=1.32), dyspnoea (HR=1.32), and cardiovascular symptoms (HR=1.15) were associated with lower chance of becoming nonagenarian. Conversely, regular physical activity (HR=0.74) was associated with higher chance of survival.

For women, the presence of a professional help (HR=1.19), living arrangements (HR=1.29 and HR=1.33), disability (respective HR of 1.55, 1.95 and 2.70 for mild, moderate and severe disability), dementia (HR=1.54), a recent hospitalisation (HR=1.19), diabetes (HR=1.49), and dyspnoea (HR=1.20) were associated with lower chance of becoming nonagenarian. Conversely, satisfaction of level income (HR=0.87), comfortable housing (HR=0.81), length of living in the dwelling (HR=0.80 upper to 6 years), regular physical activity (HR=0.89) and a medium (HR=0.79) or good (HR=0.68) subjective health, were associated with higher chance of becoming nonagenarian.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24257572

Researchers have demonstrated that acarbose, a drug used to treat type 2 diabetes, extends life in mice. This should probably be taken as speculative until more studies are run, as another treatment for type 2 diabetes, metformin, has erratic results on life span in rodent studies. Like metformin, the mechanism of action for arcabose involves influencing glucose metabolism, though in a completely different way.

Studies of this nature take place because the high costs of regulation in medical development, along with the reluctance of regulators to approve anything new these days, make it more cost-effective to find marginal new uses for existing drugs than to go out and develop new therapies or new classes of therapies. It is unfortunate that so much research time is diverted into channels that cannot result in radical breakthroughs or great advances.

A drug commonly used to treat type 2 diabetes increases the median lifespan of male mice by 22 percent. The effects of the drug known as acarbose were smaller in female mice, producing only a 5 percent increase in lifespan. The study also found that the effect on maximum lifespan was similar in male and female mice, increasing longevity by 11 percent and 9 percent, respectively. "The new results on acarbose support the idea that drugs may someday be developed to prevent many diseases while also slowing the aging process itself."

Acarbose [is] believed to work by slowing the digestion of starches, which prevent rapid increases in blood sugar levels after meals. Most of the mice in the study die of some form of cancer. Authors say the longer lifespan of the acarbose-treated mice suggests that the drug may, through unknown pathways, help to prevent cancer as aging proceeds. [Because] acarbose is known to be safe for long-term human use, it may be possible for clinical researchers to evaluate its effects on aging and age-related diseases, both in people who take the drug to treat their diabetes, and in healthy volunteers. "Further studies in mice may shed light how the cellular and physiological connections between acarbose and control of glucose levels may influence the pace of aging."

Link: http://www.uofmhealth.org/news/archive/201311/diabetes-drug-helped-male-mice-live-longer-smaller-effect

Cryonics is the science and industry of preserving the physical structure of the mind on death, indefinitely preventing its decay through low-temperature storage. At some point future technology will be capable of restoring a preserved individual to active life - and given what we know about aging and the pace of development in biotechnology, it is likely that this will be long past the point at which degenerative aging is cured, and complete control over growth, disease, and regeneration is achieved. Those are arguably easier challenges than that of restoring a vitrified brain into a new body. The difficulty is irrelevant if you can wait for decades or centuries, of course. Time is on the side of the cryopreserved provided that the institutions of cryonics continue for the long term.

The Alcor Life Extension Foundation is one of the small number of cryonics providers, a long-term venture dating back four decades to the early days in which cryonics moved from overambitious amateur venture to a more professional medical undertaking. If you take a look at the Alcor News blog, you'll find a link to a recent Nova video segment that didn't run on air, but can be viewed online:

Cryonics

Since 1972, a company called Alcor has been preserving legally dead people at very low temperatures. The hope is that, in the future, scientists will be able to revive these "patients," giving them a chance for eternal life. It may sound like the stuff of science fiction, but host David Pogue met with Alcor president and CEO Max More to tour the facility and learn about the field of "cryonics."

NARRATOR: Near the hot desert just outside of Phoenix, Arizona is a company called Alcor. Despite the high temperature outside, within, over 100 human bodies are being preserved at very low temperatures. Host David Pogue met with the president and CEO Max More to learn about the field of cryonics.

DAVID POGUE: So who's in this gallery here?

MAX MORE: These are some of our patients. We call them patients because we don't regard them as dead people. The idea is that what we call death today is somewhat of an arbitrary line. Really it's today's doctors giving up and saying, "There's nothing more I can do for this person and I'm letting them go." What we're doing is we're saying, "Let's not quit there. Let's give the future a chance to bring these patients back."

As it turns out Alcor has a YouTube channel these days. I shouldn't be at all surprised - any organization of any size either has a channel or should have a channel, with YouTube or a similar service. It's an obvious step when it comes to outreach and education, provided your budget rises to at least the modest level required to produce informative videos of a suitable quality. So if you take a look you'll find a brace of videos from the Alcor 40 conference held last year, as well as a series of FAQ videos to explain cryonics and its role in medicine. For example:

In this in-depth analysis of Cryonics, Alcor President, Max More, explores how Cryonics is, in fact, simply an extension of critical care medicine.

The proteome is the set of all proteins expressed by an organism; stability in expression levels over time indicates fewer changes in the operation of metabolism, which might also indicate slower aging. Looking at proteomic stability as a hallmark of longevity seems a little tautological to me, but nonetheless now that the tools exist to cheaply and accurately measure genome-wide gene expression levels you will see researchers talking about this data and how it relates to degenerative aging. Long-lived naked mole rats, for example, appear to have a more stable proteome across their lifespans, and here we see that this is also the case for the longest-lived clam species:

Bivalve mollusks have several unique traits, including some species with exceptionally long lives, others with very short lives, and the ability to determine the age of any individual from growth rings in the shell. Exceptionally long-lived species are seldom studied yet have the potential to be particularly informative with respect to senescence-resistance mechanisms. To this end, we employed a range of marine bivalve mollusk species, with lifespans ranging from under a decade to over 500 years, in a comparative study to investigate the hypothesis that long life requires superior proteome stability. This experimental system provides a unique opportunity to study closely related organisms with vastly disparate longevities, including the longest lived animal, Arctica islandica.

Specifically, we investigated relative ability to protect protein structure and function, both basally and under various stressors in our range of species. We found a consistent relationship between species longevity, resistance to protein unfolding, and maintenance of endogenous enzyme (creatine kinase) activity. Remarkably, our longest-lived species, Arctica islandica (maximum longevity of more than 500 years), had no increase in global proteome unfolding in response to several stressors. Additionally, the global proteome of shorter-lived species exhibited less resistance to temperature-induced protein aggregation than longer-lived species.

A reporter assay, in which the same protein's aggregation properties was assessed in lysates from each study species, suggests that some endogenous feature in the cells of long-lived species, perhaps small molecular chaperones, was at least partially responsible for their enhanced proteome stability. This study reinforces the relationship between proteostasis and longevity through assessment of unfolding, function, and aggregation in species ranging in longevity from less than a decade to more than five centuries.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24254744

This open access review paper on the characteristic changes of aging that occur in lung tissue and function illustrates the importance of immune system decline as a component of the frailty of aging. It impacts all of the major organs. Reversing the structural issues that cause much of the decline in immune response would be an early quick win in the development of human rejuvenation, and the necessary therapies - such as targeted destruction of unwanted immune cells, and replacement with cells grown from the patient's stem cells - could be implemented independently of all of the other necessary line items in a rejuvenation toolkit, and implemented within the next couple of years with no great advances in the state of the art:

There are many age-associated changes in the respiratory and pulmonary immune system. These changes include decreases in the volume of the thoracic cavity, reduced lung volumes, and alterations in the muscles that aid respiration. Muscle function on a cellular level in the aging population is less efficient. The elderly population has less pulmonary reserve, and cough strength is decreased in the elderly population due to anatomic changes and muscle atrophy. Clearance of particles from the lung through the mucociliary elevator is decreased and associated with ciliary dysfunction.

Many complex changes in immunity with aging contribute to increased susceptibility to infections including a less robust immune response from both the innate and adaptive immune systems. Considering all of these age-related changes to the lungs, pulmonary disease has significant consequences for the aging population. Chronic lower respiratory tract disease is the third leading cause of death in people aged 65 years and older.

With a large and growing aging population, it is critical to understand how the body changes with age and how this impacts the entire respiratory system. Understanding the aging process in the lung is necessary in order to provide optimal care to our aging population. This review focuses on the nonpathologic aging process in the lung, including structural changes, changes in muscle function, and pulmonary immunologic function, with special consideration of obstructive lung disease in the elderly.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825547/

A fair-sized fraction of present aging research relates to epigenetic changes that occur with aging. Epigenetics is the study of gene expression, the process by which proteins are produced from genetic blueprints, and the many different ways in which gene expression changes in response to health and environmental factors. The machineries of life are controlled by dynamic alterations in circulating levels of specific proteins, and these ongoing changes in metabolism feed back into one another to produce a responsive, self-regulating system of enormous complexity.

The cellular and molecular damage of aging causes characteristic changes in gene expression, and these can be picked out from the more general set of random - or perhaps just less well-understood - changes in gene expression that occur over time. Researchers are primarily cataloging these changes, but some are also using increasingly efficient tools to restore the gene expression of specific genes to youthful levels in animal studies. To my eyes this will be the basis for therapies to treat age-related conditions that will prove to be more effective than the present state of the art. Nonetheless, it isn't the direct road to rejuvenation, as changing gene expression that is altered in response to damage doesn't deal with the underlying issue, which is the existence of that damage.

(As has been pointed out in comments on past posts, there isn't a clear line to be drawn between manipulating protein levels in a way that is less helpful versus doing so in a way that actually does address underlying damage. If you can alter levels of a protein so as to spur greater clearance of undesired misfolded protein aggregates, for example, then you are in fact creating some degree of rejuvenation. You are removing damage. But if, as is usually the case, changing gene expression to restore youthful operation of a system does nothing to repair underlying damage to that system, then it cannot be the best path forward. Consider, for example, restoring stem cell activity through changed gene expression: this most likely comes with a raised risk of cancer, as stem cell decline with aging is most likely an evolved response to increasing levels of damage in stem cells. Turn off that response and cancer rates should increase, even through great benefits to health through increased tissue maintenance can be realized).

A handful of recently published research results are illustrative of the sort of work being done at the intersection of epigenetics and aging.

Inflammatory skin damage in mice blocked by bleach solution, study finds

[Researchers] tested the effect of daily, 30-minute baths in [dilute] bleach solution on laboratory mice with radiation dermatitis. They found that the animals bathed in the bleach solution experienced less severe skin damage and better healing and hair regrowth than animals bathed in water. They then turned their attention to old - but healthy - laboratory mice.

"Multiple research studies have linked increased NF-kB activity with aging. We found that if we blocked NF-kB activity in elderly laboratory mice by bathing them in the bleach solution, the animals' skin began to look younger. It went from old and fragile to thicker, with increased cell proliferation." The effect diminished soon after the dilute-bleach baths were stopped, indicating that regular exposure is necessary to maintain skin thickness. "We found that the bleach solution oxidizes and inhibits an activator necessary for NF-kB to enter the nucleus, essentially blocking NF-kB's effect."

Aging Impacts Epigenome in Human Skeletal Muscle

The results came from the first genome-wide DNA methylation study in disease-free individuals. DNA methylation involves the addition of a methyl group to the DNA and is involved in a particular layer of epigenetic regulation and genome maintenance. In this study researchers compared DNA methylation in samples of skeletal muscle taken from healthy young (18 - 27 years of age) and older (68 - 89 years of age) males. [Researchers] looked at more than 480,000 sites throughout the genome. "We identified a suite of epigenetic markers that completely separated the younger from the older individuals - there was a change in the epigenetic fingerprint."

Scientists identified about six-thousand sites throughout the genome that were differentially methylated with age and that some of those sites are associated with genes that regulate activity at the neuromuscular junction which connects the nervous system to our muscles.

Aging erodes genetic control, but it's flexible

In yeast at least, the aging process appears to reduce an organism's ability to silence certain genes that need to be silenced. Now [researchers] who study the biology of aging have shown that the loss of genetic control occurs in fruit flies as well. In several newly published experiments they show that gene silencing via chromatin in fruit flies declines with age.

They also showed that administering life span extending measures to the flies, such as switching them to a lower calorie diet or increasing expression of the protein Sir2, restores the observed loss of gene silencing due to age.

Orexin restores aging-related brown adipose tissue dysfunction in male mice

The aging process causes an increase in percent body fat, but the mechanism remains unclear. In the present study we examined the impact of aging on brown adipose tissue (BAT) thermogenic activity as potential cause for the increase in adiposity. We show that aging is associated with iBAT morphological abnormalities and thermogenic dysfunction. In-vitro experiments revealed that brown adipocyte differentiation is defective in aged mice. Interscapular brown tissue in aged mice is progressively populated by adipocytes bearing white morphological characteristics. Aged mice fail to mobilize intracellular fuel reserves from brown adipocytes and exhibit deficiency in homeothermy.

Our results suggest a role for orexin-signaling in the regulation of thermogenesis during aging. Brown fat dysfunction and age-related assimilation of fat mass was accelerated in mice in which orexin-producing neurons were ablated. Conversely, orexin injections in old mice increased multilocular morphology, increased core body temperature, improved cold tolerance, and reduced adiposity. These results argue that BAT can be targeted for interventions to reverse age-associated increase in fat mass.

A hormetic process is one in which a little damage spurs damage repair mechanisms into an extended effort, leading to a net positive gain. A number of means of extending life in laboratory animals involve hormesis, and many of those involve mitochondria, the power plants of the cell that emit damaging reactive molecules as a side-effect of their operation. Dial up the output of those reactive molecules and the rest of the cell will react with a greater level of housekeeping operations. Something like this is thought to be one of the mechanisms linking exercise to greater health and longevity, for example.

Mitochondrial dysfunction is usually associated with aging. To systematically characterize the compensatory stress signaling cascades triggered in response to muscle mitochondrial perturbation, we analyzed a Drosophila model of muscle mitochondrial injury. We find that mild muscle mitochondrial distress preserves mitochondrial function, impedes the age-dependent deterioration of muscle function and architecture, and prolongs lifespan.

Strikingly, this effect is mediated by at least two prolongevity compensatory signaling modules: one involving a muscle-restricted redox-dependent induction of genes that regulate the mitochondrial unfolded protein response (UPRmt) and another involving the transcriptional induction of the Drosophila ortholog of insulin-like growth factor-binding protein 7, which systemically mitophagy. Given that several secreted IGF-binding proteins (IGFBPs) exist in mammals, our work raises the possibility that muscle mitochondrial injury in humans may similarly result in the secretion of IGFBPs, with important ramifications for diseases associated with aberrant insulin signaling.

Link: http://dx.doi.org/10.1016/j.cell.2013.09.021

Calorie restriction extends life and improves health in nearly every species tested to date. Sensing of levels of methionine, an essential amino acid, appears to be one of the controlling mechanisms involved in the shift of metabolism into a state that ensures greater longevity. Reduction in dietary methionine without reducing calories has been show to extend life in rats and mice, for example. Here researchers demonstrate that it can do so in yeast as well:

It is established that glucose restriction extends yeast chronological and replicative lifespan, but little is known about the influence of amino acids on yeast lifespan, although some amino acids were reported to delay aging in rodents. Here we show that amino acid composition greatly alters yeast chronological lifespan. We found that non-essential amino acids (to yeast) methionine and glutamic acid had the most significant impact on yeast chronological lifespan extension, restriction of methionine and/or increase of glutamic acid led to longevity that was not the result of low acetic acid production and acidification in aging media.

Remarkably, low methionine, high glutamic acid and glucose restriction additively and independently extended yeast lifespan, which could not be further extended by buffering the medium (pH 6.0). Our preliminary findings using yeasts with gene deletion demonstrate that glutamic acid addition, methionine and glucose restriction prompt yeast longevity through distinct mechanisms.

Link: http://dx.doi.org/10.1371/journal.pone.0079319

One of the most important divides in the aging research community today is that between the view of aging as a result of the stochastic accumulation of cellular and molecular damage and the view of aging as resulting from an evolved genetic program. The former is the majority position, but the programmed aging camp is fairly vocal these days. Personally, I fall into the aging as damage camp based on my understanding of the literature. The programmed aging view is certainly interesting, but I think its proponents have a steeper hill to climb when it comes to proving their theories.

Why is this an important difference of opinions? It is important because the types of therapy that work well in the world where aging is damage are not so good in a world in which aging is programmed, and vice versa. We are already in a situation in which all too much of the funding for longevity science goes towards research programs that are only capable of producing expensive, marginal outcomes: drug development aimed at slowing aging that attracts funding because it can be sold as a slight evolution of the present methodology of medical research and development. That it can't possibly lead to rejuvenation or indeed any significant result soon doesn't matter: people get funded, and researchers for better or worse chase the funding that can be obtained, not the funding that might be obtained in a better world.

(To my eye it is up to advocates to change the funding landscape: researchers don't tend to try anywhere near aggressively enough. It requires someone from outside the system of patronage and relationships to come in and kick people until they start doing what they should and what is sensible).

But back to programmed aging. This situation, a focus on drug development aimed at slowing aging, or patching over the consequences of damage by altering specific protein levels to resemble the youthful amounts, will only get worse if the programmed aging camp successfully increases their influence in funding circles. To the programmed aging viewpoint the entire problem is that protein levels are wrong, and aging can be reversed by reverting them - reprogramming the machinery. From the aging as damage viewpoint this is the cart before the horse, an approach doomed to expensive failure because it doesn't fix the underlying cause of aging, which is to say the damage itself.

The way to short circuit this slowly ongoing cultural and scientific debate is for a proposed methodology of rejuvenation through damage repair - such as SENS - to be implemented in the laboratory. The cost of this is very low, on a par with the cost of developing a single drug in the present regulatory environment. If SENS works, which is to say significantly extends the life and restores the health of old animals, then we can probably throw programmed aging theories out of the window in short order. Theory is theory, but proof is proof.

The SENS research community is not so many years away from being able to do just this for some aspects of the SENS program. The more money we can raise for their research, the faster it goes.

The Russian biogerontology community is very much ground zero for new work on programmed aging, and with language barriers lowering and increased scientific collaboration between regions a lot more of their publications come to my attention. The open access journal Biochemistry (Moscow) regularly runs issues packed with papers on aging as an evolved genetic program. This is the case again in Volume 78(9), and as always it makes for interesting reading even while disagreeing.

Arguments Against Non-programmed Aging Theories

Until recently, non-programmed theories of biological aging were popular because of the widespread perception that the evolution process could not support the development and retention of programmed aging in mammals. However, newer evolutionary mechanics theories including group selection, kin selection, and evolvability theory support mammal programmed aging, and multiple programmed aging theories have been published based on the new mechanics.

Some proponents of non-programmed aging still contend that their non-programmed theories are superior despite the new mechanics concepts. However, as summarized here, programmed theories provide a vastly better fit to empirical evidence and do not suffer from multiple implausible assumptions that are required by non-programmed theories. This issue is important because programmed theories suggest very different mechanisms for the aging process and therefore different mechanisms behind highly age-related diseases and conditions such as cancer, heart disease, and stroke.

Phenoptosis as Genetically Determined Aging Influenced by Signals from the Environment

Aging is a complex and not well understood process. Two opposite concepts try to explain its causes and mechanisms - programmed aging and aging of "wear and tear" (stochastic aging). To date, much evidence has been obtained that contradicts the theories of aging as being due to accumulation of various damages. For example, creation of adequate conditions for the functioning of the organism's components (appropriate microenvironment, humoral background, etc.) has been shown to cause partial or complete reversibility of signs of its aging.

Programmed aging and death of an organism can be termed phenoptosis by analogy to the term apoptosis for programmed cell death. The necessity of this phenomenon [has] been justified by the need for population renewal according to ecological and evolutionary requirements. Species-specific lifespan, age-dependent changes in expression pattern of genes, etc. are compatible with the concept of phenoptosis.

However, the intraspecific rate of aging was shown to vary over of a wide range depending on living conditions. This means that the "aging program" is not set rigidly; it sensitively adjusts an individual to the specific realities of its habitat. Moreover, there are indications that in rather severe conditions of natural habitat the aging program can be completely cancelled, as the need for it disappears because of the raised mortality from external causes (high extrinsic mortality), providing fast turnover of the population.

Post-Reproductive Life Span and Demographic Stability

Recent field studies suggest that it is common in nature for animals to outlive their reproductive viability. Post-reproductive life span has been observed in a broad range of vertebrate and invertebrate species. But post-reproductive life span poses a paradox for traditional theories of life history evolution. The commonly cited explanation is the "grandmother hypothesis", which applies only to higher, social mammals.

We propose that post-reproductive life span evolves to stabilize predator-prey population dynamics, avoiding local extinctions. In the absence of senescence, juveniles would be the most susceptible age class. If juveniles are the first to disappear when predation pressure is high, this amplifies the population's risk of extinction. A class of older, senescent individuals can help shield the juveniles from predation, stabilizing demographics and avoiding extinction. If, in addition, the life history is arranged so that the older individuals are no longer fertile, the stabilizing effect is further enhanced.

Advanced Glycation of Cellular Proteins as a Possible Basic Component of the "Master Biological Clock"

During the last decade, evidence has been accumulating supporting the hypothesis that aging is genetically programmed and, therefore, precisely timed. This hypothesis poses a question: what is the mechanism of the biological clock that controls aging? Measuring the level of the advanced glycation end products (AGE) is one of the possible principles underlying the functioning of the biological clock. Protein glycation is an irreversible, non-enzymatic, and relatively slow process. Moreover, many types of cells have receptors that can measure AGE level. We propose the existence of a protein that has a lifespan comparable to that of the whole organism. Interaction of the advanced glycation end product generated from this protein with a specific AGE receptor might initiate apoptosis in a vitally important non-regenerating tissue that produces a primary juvenile hormone. This could result in the age-dependent decrease in the level of this hormone leading to aging of the organism.

Using gene therapy to alter levels of specific proteins in a targeted fashion is an intermediary advance in medicine for age-related conditions. Practical applications of this technology should provide an improvement over what came before, but at the same time they don't treat the underlying issue, which is the accumulation of cellular and molecular damage that causes aging and the diseases of aging. At some point the medical community must change its focus from patching over the problem to addressing its root causes.

[Researchers] have successfully tested a powerful gene therapy, delivered directly into the heart, to reverse heart failure in large animal models. The new research study findings [are] the final study phase before human clinical trials can begin testing SUMO-1 gene therapy. SUMO-1 is a gene that is "missing in action" in heart failure patients.

[In an earlier trial] a gene known as SERCA2 is delivered via an inert virus - a modified virus without infectious particles. SERCA2 is a gene that produces an enzyme critical to the proper pumping of calcium out of cells. In heart failure, SERCA2 is dysfunctional, forcing the heart to work harder and in the process, to grow larger. The virus carrying SERCA2 is delivered through the coronary arteries into the heart during a cardiac catheterization procedure. Studies show only a one-time gene therapy dose is needed to restore healthy SERCA2a gene production of its beneficial enzyme.

But previous research [discovered] SERCA2 is not the only enzyme that is missing in action in heart failure. [The] SUMO-1 gene is also decreased in failing human hearts. But SUMO-1 regulates SERCA2a's activity, suggesting that it can enhance the function of SERCA2a without altering its levels. A follow-up study in a mouse model of heart failure demonstrated that SUMO-1 gene therapy substantially improved cardiac function. This new study tested delivery of SUMO-1 gene therapy alone, SERCA2 gene therapy alone, and a combination of SUMO-1 and SERCA2.

In large animal models of heart failure, the researchers found that gene therapy delivery of high dose SUMO-1 alone, as well as SUMO-1 and SERCA2 together, result in stronger heart contractions, better blood flow, and reduced heart volumes, compared to just SERCA2 gene therapy alone.

Link: http://www.eurekalert.org/pub_releases/2013-11/tmsh-ngt111113.php

An example of early stage progress towards building new kidney tissue to replace aged or diseased kidneys, or for use in bioartificial kidney devices:

For the first time, [researchers] have generated three-dimensional kidney structures from human stem cells, opening new avenues for studying the development and diseases of the kidneys and to the discovery of new drugs that target human kidney cells. Scientists had created precursors of kidney cells using stem cells as recently as this past summer, but [this] team was the first to coax human stem cells into forming three-dimensional cellular structures similar to those found in our kidneys.

[The] findings demonstrate for the first time that pluripotent stem cells (PSCs)-cells capable of differentiating into the many cells and tissue types that make up the body-can made to develop into cells similar to those found in the ureteric bud, an early developmental structure of the kidneys, and then be further differentiated into three-dimensional structures in organ cultures. UB cells form the early stages of the human urinary and reproductive organs during development and later develop into a conduit for urine drainage from the kidneys. The scientists accomplished this with both human embryonic stem cells and induced pluripotent stem cells (iPSCs), human cells from the skin that have been reprogrammed into their pluripotent state.

Link: http://www.salk.edu/news/pressrelease_details.php?press_id=648

As you might be aware, the SENS Research Foundation is the leading light when it comes to funding the most meaningful research into human rejuvenation. The Foundation staff have the plan, the allied network of researchers and laboratories, and are gathering the necessary funds from philanthropists and a grassroots community of supporters. I strongly encourage you to read the Foundation's research and annual reports to see for yourself that it is the real deal. This is an age of biotechnology in which we no longer have to hope and handwave when it comes to reversing degenerative aging: the way forward to producing future therapies capable of rejuvenating the old and preventing age-related disease is very clear indeed.

Rejuvenation Therapies: All It Takes Is Money

Researchers stand ready and interested. All it will take to get the job done is money and a couple of decades of hard work by hundreds of scientists. But mainly the money: funding is ever the limiting factor, not the availability of researchers or the need for a plan.

This year the SENS Research Foundation has set a year end fundraising target of $100,000 from donors and the community by the end of December. The funds will be used to expand Foundation research and other programs. This is the time of year when people traditionally turn to making charitable donations, but I have to say that this is definitely a stretch goal for our community: the past year has seen numerous funded projects, several in just the last few months alone. Supporters have given tens of thousands of dollars to help fund advocacy and research projects that advance the state of the art.

Fight Aging! Puts Up $15,000 In Matching Funds

Stretch goal or not, I am going to do my part to help make this happen. Through sheer and unlikely happenstance the princely sum of $15,000 recently landed in my lap, out of the blue, and with no strings attached. Sometimes fortune smiles upon us. I am putting this forward as a matching fund for donations to the SENS Research Foundation:

Fight Aging! will match, 1:1, the next $15,000 donated to the SENS Research Foundation before the end of December 2013.

So take the step and donate to help fund the best and the most promising rejuvenation research. I'll match your donation.

Why Fund Rejuvenation Research Now?

Now is the time! For one the research itself is tantalizingly close to applicable results: a few years of sustained funding is all that separates us from laboratory demonstrations of a way to replace age-damaged mitochondrial DNA or a way to remove the greatest contributing factor to loss of skin elasticity, in both cases opening the path to eliminating those contributions to aging.

Secondly it is very self-evident that funding given to research now will snowball and attract much more research funding in the future. In fact this has already happened: our comparatively small community has bootstrapped its way into generating somewhere in the vicinity of $25-30 million of funding for our brand of longevity science and advocacy since the turn of the century. Barely a tenth of that came from the grassroots and the early supporters, but that tenth is by far the most important portion, and those who make it the most important donors. Without the grassroots, without the community and its support and its advocacy, the larger donations never happen: wealth follows the crowds in science funding, and the crowds follow the early adopters.

Yet this is still the ground floor. These are still the early days, in which small acts can make a vast difference to the future of human health and longevity. Most people don't yet know or care about what can be achieved. New billion dollar research communities and vast medical development industries still lie ahead. In 2025 we will look back at 2010-2015 as being a point of takeoff, another early part of the upward curve in which ever more people funded new and revolutionary longevity science instead of giving to the old per-disease foundations, and in which the old institutions began to pay more attention to research into aging: its slowing, and its reversal.

There are precious few times in life when you can stand at a juncture with enough foresight to know that you can swing the odds meaningfully. Most such opportunities slip past us, realized too late. But if you are here now, reading this post, then you are almost certainly one of the folk who knows enough to make a difference.

So Help Me Out Here: Help Us All Live Far Longer and Healthier Lives

Donate! Help the SENS Research Foundation undertake that next research project, make that next investment in a new lab, move that next step towards realizing the means to rejuvenate the old and prevent age-related pain, frailty, and disease.

Targeted killing of cancer cells is the future of cancer treatment, an approach that results in better outcomes and fewer side-effects. Numerous different mechanisms to target and destroy specific types of cell have been developed in recent years, and one of these involves the use of natural or engineered viruses that preferentially attack cancer cells:

Oncolytic viruses (OVs) are tumor-selective, multi-mechanistic antitumor agents. They kill infected cancer and associated endothelial cells via direct oncolysis, and uninfected cells via tumor vasculature targeting and bystander effect. Multimodal immunogenic cell death (ICD) together with autophagy often induced by OVs not only presents potent danger signals to dendritic cells but also efficiently cross-present tumor-associated antigens from cancer cells to dendritic cells to T cells to induce adaptive antitumor immunity.

With this favorable immune backdrop, genetic engineering of OVs and rational combinations further potentiate OVs as cancer vaccines. OVs armed with GM-CSF or other immunostimulatory genes, induce potent anti-tumor immunity in both animal models and human patients. Combination with other immunotherapy regimens improve overall therapeutic efficacy.

OVs provide a number of potential advantages as cancer vaccines over conventional therapies. First, OVs are tumor-selective, thus in situ cancer vaccines, providing higher cancer specificity and better safety margin. Second, immunogenic/inflammatory types of cell death, including recently characterized "immunogenic cell death" (ICD) of cancer and stromal cells induced by OVs provides a natural repertoire of tumor-associated antigens (TAAs) in conjunction with danger signals to elicit anti-tumor immunity.

Link: http://dx.doi.org/10.1186/1476-4598-12-103

Scientist Steven Austad is well known in the field of aging research. For the past few years he has penned a column for a Texas paper - the sort of public engagement that I'd like to see more researchers undertake on a regular basis. Here he writes on the topic of cryonics, which is something else I'd like to see more researchers do on a regular basis, even if they clearly need to better investigate the topic first:

Cryonics is the idea - or more precisely, the hope - that by freezing your body after death, future scientists will be able to bring that body back to life. Why future scientists would want to do this isn't exactly clear. Maybe there will be no more pressing problems in the future than bringing dead people back to life. Anyway, assuming they wanted to for some reason, the real hope is not that only your body would be brought back to life, but that you would be brought back to life. Something like awakening after surgery.

Cryonics embodies a rather touching faith in scientific progress. Or maybe it embodies only an exceptional fear of death. In either case, it raises some interesting philosophical questions. What would it take for that newly re-animated body to still be "you?" With a little tweaking of existing technology, we could create a genetically identical copy of you as we've already done in mice, dogs, and a number of other species, by cloning a cell from your current body. But that wouldn't really be you, because it wouldn't have your memories or experiences.

Memories are the key. Thus, the frozen head. As long as your brain still contains your memories, your re-animated head could be thought of as you. As for the rest of your body, any science sophisticated enough to bring your head back to life should no doubt be able to give you the body you want. I'll have to think about whose body I'd like.

Besides, keeping only your head saves money. Cryonics is not cheap. Prices I've seen range from about $30,000 for a budget deal to several hundred thousand, not including the currently unknown cost of re-animating you and putting a body to that head. Long lines of freezers packed with bodies like so many popsicles uses a lot of expensive liquid nitrogen and takes up a lot of space, for who knows how many years? Freezers full of hat box-size containers are comparatively economical and good for the profit margin.

There do seem to be some formidable scientific barriers though, even if you assume that re-growing a body is feasible. For one thing, no one has brought something even as simple as a single cell back from being dead, not that I'm sure how much effort has been put into doing so. Another issue is that our memories are thought to be a product of the number and strength of very delicate electrical connections among our billions of brain cells. Memory can be seriously disrupted by something as simple as a blow to the head. So preserving those things through a complete cessation of all brain electrical activity and the inevitable postmortem damage to brain cells seems more than a little far-fetched. Also, if you died of a stroke or dementia, sorry, you're out of luck. Those critical memory centers were destroyed even before you died.

Whatever your opinion of cryonics, to my mind the head thing needs rethinking. The important thing obviously is preservation of the brain. So why not freeze just the brain rather than the whole head? If science proceeds to the point where they can re-grow a complete body, surely it will be able to give me a better head.

Cryonics is a process of low-temperature vitrification rather than freezing these days, which is an important distinction to make. Frozen tissue is damaged by ice crystal formation, vitrified tissue is not to any significant degree. Vitrified cells and even organs in recent years have in fact been restored from this form of low-temperature storage. There is also good evidence to show that the fine structures of neurons that store the data of memory are well preserved by vitrification.

Most people who undertake cryonics are of modest means, and cryonics providers are not run as for-profit companies at this time. The cost of cryonics is generally managed through a life insurance policy. With enough forethought a tiny monthly payment puts you in good shape for a future cryopreservation - and it is certainly the case that organizing your own end of life choices requires planning ahead. Last minute decisions tend to run poorly.

Why preserve the whole head? Because trying to do otherwise is more likely to result in damage to the brain and will raise costs by requiring more skill and training for paramedical staff. The cryopreservation process has to happen fairly rapidly and involves perfusion of cryoprotectant chemicals. Adding an additional major operation to that process, while at the same time removing a layer of protection from the brain, doesn't sound like a great plan to me.

Link: http://www.mysanantonio.com/life/life_columnists/steven_austad/article/A-head-start-on-immortality-4983926.php

The SENS Research Foundation is presently the leading scientific and advocacy organization when it comes to rejuvenation research. Foundation staff coordinate, fund, and carry out the most promising fundamental research into ways to repair cellular and molecular damage that causes degenerative aging. Success in this line of research will result in therapies that can reverse the course of aging, restoring vigor and health to old, frail people, and preventing everyone else from ever becoming old and frail.

The Foundation has grown to a $4 million yearly budget since its creation, these funds provided by philanthropic and grassroots donors. Most of this is used to fund research projects that will advance the state of the art in areas vital to human rejuvenation that are neglected by the mainstream research community. To continue to advance this aim, the Foundation leadership is setting an ambitious community fundraising goal for the remainder of the year, as outlined in an email that arrived today:

Help Us Meet Our Year-End Goal

On behalf of SENS Research Foundation, we would like to thank you for your support throughout 2013. Thanks to your generous donations of time, money, and encouragement, we have been able to continue advancing our work to cure - not just treat, but cure - the diseases of aging. We are accomplishing this goal by funding promising new research, building a strong, collaborative community, and training the next generation of bright, young scientists. No doubt the best example of all of these aspects of our mission in 2013 was our biennial SENS Conference held at the University of Cambridge in September.

The SENS6: Reimagine Aging Conference attracted a record number of leading scientists, clinicians, students, and other supporters. All were amazed at the progress made since SENS5 and were confident that the current work and newly fostered collaborations of the SRF community would lead to more crucial advances in tackling the debilitating diseases of aging. However, in order to continue to increase our impact on advancing the field of regenerative medicine, we need your help. Simply put, more funding will mean more researchers and more labs making cures for the diseases of aging a reality.

Your support will enable us to:

Accelerate and add new research projects by expanding the SRF Research Center

Make the collaborative effects of the SENS Conference annual rather than biennial

Expand our internship program and add a national student symposium

We've set an end-of-year funding challenge to raise at least $100,000 between today and December 31, 2013. If you've been thinking about contributing, this is a great time to show your support. Please consider making your tax deductible donation to us today at http://www.sens.org/donate.

If you are interested in setting up a matching grant please contact us.

Thank you,

Mike Kope, CEO
Aubrey de Grey, CSO
Tanya Jones, COO

Some of the items added to the SENS Research Foundation website in the past months were also featured, illustrating the work of the Foundation scientists and allied researchers over the past year. It is well worth looking through to see the tangible results that emerge from directly funding targeted research.

New SENS6 Highlights Video

Please take a few minutes to enjoy our latest video featuring highlights of the SENS6 Conference. We hope that you will enjoy the opportunity to experience the sights and sounds of this amazing event. SENS6 brought together leading research scientists and other visionaries in the field of regenerative medicine from around the world.

The Science Behind SENS

Curious about what SRF's work actually entails? Interested in the technical details of cutting-edge rejuvenation biotechnology research? If so, you'll definitely want to visit our Research Blog. This section of our website features project updates, descriptions of the concrete actions we are taking to eradicate age-related disease, and in-depth discussions of significant biogerontology topics from our CSO team.

Check back often for more news about what we're up to in the laboratory, and be sure to take a look at our downloadable Research Report (PDF) if you haven't already.

New and Better Clinical Trials for Rejuvenation Biotechnologies - July 31, 2013

2013 Research Report (part 1 of 12): Lysosomal Aggregates - September 01, 2013

Unbinding the Mummies: Human Testing of Rejuvenation Biotechnology Targeting α-Synuclein Begins - October 02, 2013

2013 Research Report (part 2 of 12): Mitochondrial Mutations - October 09, 2013

2013 Research Report (part 3 of 12): Cancerous Cells - October 18, 2013

2013 Research Report (part 4 of 12): Extracellular Matrix Stiffening - November 01, 2013

2013 Research Report (Part 5 of 12): Lysosomal Aggregates - November 8, 2013

Staff at the SRF Research Center

Summer Internship Applications: Coming In January 2014. Each year the SENS Research Foundation Summer Internship Program supports training the best undergraduate researchers at leading research institutions around the world. Applications will be available on the SRF website starting January 2014. Mark your calendars, so you can be the first to apply for these amazing research opportunities.

You can learn more about the internship program and the research projects of past interns in our video spotlights and Education Blog posts.

SRF's Mitochondrial Mutations Project Awarded LongeCity Grant

The Mitochondrial Mutations project team, led by Senior Research Scientist Dr. Matthew O'Connor at our Mountain View Research Center, was awarded a LongeCity Research Grant last month. LongeCity is an international non-profit organization that, among other things, supports small-scale science initiatives "to conquer the blight of involuntary death." In two short months, seventy supporters donated over $7,500 which was matched with a $14,000 grant from LongeCity to fund SRF's work to rescue mutated mitochondrial DNA.

To help fund this and other research projects, please visit http://www.sens.org/donate. As a 501(c)(3) public charity, SENS Research Foundation relies on your support to continue our mission to change the way the world researches and treats age-related disease.

Below is quoted a mainstream media piece on Dmitry Itskov's 2045 Initiative, an exemplar of that section of the futurist community who look forward to non-biological strategies for extending life. The underlying goals of reverse engineering the brain, building brain simulations, and integrating technology with neural tissue and functions are very much in the air these days, and a number of large US and European projects are underway in this space.

At the tender age of 32, Dmitry Itskov is not yet a billionaire, although a lot of respected news outlets think otherwise. He is a millionaire many times over - a survivor of the dot-com bubble who made his fortune building a media empire in Russia. Like many people who become extremely rich very quickly, he has decided to invest some of his money in innovative, forward-looking endeavors. But his idea is more ambitious than most: radical life extension.

In 2011, Itskov founded the 2045 Initiative, which is named for the year when he intends to complete the project's ultimate goal: to outwit and outrun mortality itself. His "avatar" project is a four-stage process, beginning with the development of androids directed by brain-computer interfacing - mind-controlled robots, in other words. It would culminate in a computer model of a person's brain and consciousness, which could be uploaded into a machine for posterity. An eternal problem, solved.

To achieve cybernetic immortality and turn what he calls his "science mega-project" into a reality, Itskov's 2045 Initiative is funding labs around the world; Itskov is both investing his own money and raising external capital, building support among entities ranging from Ivy League universities to large corporations to even the Dalai Lama. Even if Itskov doesn't reach his final goal of radical life extension via avatars, the amount of attention he's bringing and money he's investing in neurotech research have many people excited. And Itskov is just one in an increasingly crowded field.

While I don't agree that the end goal here is useful from a practical standpoint - a copy of you is not you - the next few decades are certainly going to be a very interesting time in applied neurotechnology.

Link: http://www.slate.com/articles/business/billion_to_one/2013/11/dmitry_itskov_2045_initiative_eternal_living_through_science.html

Accumulating excess fat tissue is bad for you. The mechanisms might derive largely from the presence of visceral fat tissue, which causes chronic inflammation and large changes in the operation of metabolism, leading to metabolic syndrome. It is also possible that other mechanisms related to nutrient sensing are at work, shifting portions of your biology into a fast-aging mode that evolved in some common ancestor to accelerate reproduction in times of plenty. Equally, being overweight tends to accompany sedentary behavior, and lack of exercise is very harmful to long-term health.

Regardless, it seems like a good idea to avoid becoming fat: the weight of evidence to show that it will harm your future health is heavy indeed, especially when it comes to cardiovascular disease:

Overweight and obesity likely cause myocardial infarction (MI) and ischemic heart disease (IHD); however, whether coexisting metabolic syndrome is a necessary condition is unknown. To test the hypothesis that overweight and obesity with and without metabolic syndrome are associated with increased risk of MI and IHD [we] examined 71,527 individuals from the Copenhagen General Population Study and categorized them according to body mass index (BMI) as normal weight, overweight, or obese and according to absence or presence of metabolic syndrome.

For MI, multivariable adjusted hazard ratios vs normal weight individuals without metabolic syndrome were 1.26 in overweight and 1.88 in obese individuals without metabolic syndrome and 1.39 in normal weight, 1.70 in overweight, and 2.33 in obese individuals with metabolic syndrome. For IHD, results were similar but attenuated. Among individuals both with and without metabolic syndrome there were increasing cumulative incidences of MI and IHD from normal weight through overweight to obese individuals.

These findings suggest that overweight and obesity are risk factors for MI and IHD regardless of the presence or absence of metabolic syndrome and that metabolic syndrome is no more valuable than BMI in identifying individuals at risk.

Link: http://dx.doi.org/10.1001/jamainternmed.2013.10522

The protein signaling mechanisms surrounding insulin and insulin-like growth factor (IGF-1) are one of the better studied portions of the overlap between metabolic biochemistry and natural variations in longevity. They influence all of the core aspects of our biology: growth, regeneration, and other vital cell activities. Thus despite the years of work researchers still lack a truly clear picture of how it all fits together: this is a ferociously complex area of study, in which every molecular mechanism influences many other molecular mechanisms. Isolating any one portion of the interlinked systems making up the biology of life is next to impossible.

Another comparatively well-studied and related area is autophagy, the collection of quality control processes by which cells clear out damaged components and unwanted waste compounds. More autophagy is consistently linked to enhanced longevity in laboratory animals, and shows up as a candidate mechanism for the extended life generated by a range of genetic alterations and environmental changes, such as the practice of calorie restriction. This makes sense: aging is most likely nothing more than an accumulation of damage, and more autophagy means less of that damage accumulating per unit time. Many researchers think that when it comes to slowing aging all roads lead to improved autophagy. Surprisingly, there hasn't been as much of a drive to produce autophagy-enhancing drugs as I would have expected by this time, despite some quite compelling demonstrations of the restored organ function that could be produced in old patients.

Here we have research that bridges the two regions of study I've sketched above: tracing the alterations to metabolism that link insulin and insulin-like signaling with autophagy.

Protein interplay in muscle tied to life span

Fruit flies are notoriously short-lived but scientists interested in the biology of aging in all animals have begun to understand why some fruit flies live longer than others. They have documented a direct association between insulin and life span, for example, and have observed a tradeoff between prolific reproduction and longevity. A new study, which may have broad implications across species, ties those findings more closely together by tracing an insulin signaling cascade through to protein quality control in muscle tissue and shortened life span.

The central feature of the study [is] the newly discovered role of the fruit fly equivalent of the mammalian protein complex activin. They found that it blocks the natural mechanism in muscle cells for cleaning out misfolded proteins, leading to a decline in muscle performance. In what [scientists] think is no coincidence, blocking the activity of that activin equivalent, called dawdle, can lengthen a fly's life span by as much as 20 percent, about 10 days.

Activin Signaling Targeted by Insulin/dFOXO Regulates Aging and Muscle Proteostasis in Drosophila

It is widely known that reduced insulin/IGF signaling slows aging in many contexts. This process requires the forkhead transcription factor (FOXO). FOXO modulates the expression of many genes, and the list of those associated with slow aging is impressive. But there are few data indicating the mechanisms or genes through which FOXO actually slows aging. Here, we identify a novel FOXO target, dawdle, the Activin-like ligand in fruit flies.

Activin signaling through the Smad binding element inhibits the transcription of Autophagy-specific gene 8a (Atg8a) within muscle, a factor controlling the rate of autophagy. Expression of Atg8a within muscle is sufficient to increase lifespan.

These data reveal how insulin signaling can regulate aging through control of Activin signaling that in turn controls autophagy, representing a potentially conserved molecular basis for longevity assurance. While reduced Activin within muscle autonomously retards functional aging of this tissue, these effects in muscle also reduce secretion of insulin-like peptides at a distance from the brain. Reduced insulin secretion from the brain may subsequently reinforce longevity assurance through decreased systemic insulin/IGF signaling.

Not surprisingly, the details uncovered by these researchers have the look of a two-way feedback loop. Little in biology is a one-way street, which is one of the many reasons it is very hard to even understand the metabolism of longevity, let alone safely alter it. The existence of this complexity is why I favor strategies for enhancing longevity that do not rely upon altering an aged metabolism, but instead aim to restore it to a youthful state by repairing damage. This is an important distinction to make, and it will become ever more important in the years ahead.

Is medical research funding at all rational in its amounts and distributions? Well, no, evidently not, since SENS rejuvenation research is not a billion dollar a year field, and all current research aimed at producing better ways of treating or eliminating age-related disease taken together is a tiny economic activity when compared to, say, making candy or small collectible dolls. But even within the existing research and funding community, it can be argued that priorities do not align with a utilitarian approach to aging and age-related disease:

The global population is aging and although age remains the primary risk factor for all major causes of death, no priorities for aging research exist. After reviewing the literature on mortality modelling we found that different chronic processes underlie mortality before and after reproductive age. To identify priorities in aging research, we propose a simple ranking method that uses the percentage of deaths attributable to each disease for the over-60 population, on the basis that, rather than being the result of individual risk factors, these deaths are largely due to underlying senescent processes.

Our ranking suggests that vascular aging, led by ischaemic heart disease and stroke, is the most important focus for aging research. The availability of funding, however, is not currently aligned with health priorities and we believe that rectifying this disconnect may improve societal health outcomes.

Link: http://dx.doi.org/10.1089/rej.2013.1508

The cardiovascular system loses its flexibility with age, a process thought to be related to a build up of cross-links, calcium deposits, and other unwanted compounds in the extracellular matrix. Reversing this portion of age-related degeneration should be a comparatively straightforward matter of building drugs to break down or remove these metabolic byproducts. Researchers here investigate another possible culprit in the process:

Heart valves calcify over time, and [scientists] are beginning to understand why. [They] found through studies of pigs' heart valves that age plays a critical role in the valves' progressive hardening, and the problem may be due to the infiltration of a protein known as von Willebrand factor (VWF). VWF helps regulate blood clotting in both pigs and humans but [it] finds its way over time into the collagen-rich interior of the valve tissues. Because clotting is not an issue in collagen, there is no apparent need for VWF to be present. The researchers went looking for a connection to the calcium nodules that form in the tissues and make the valves' leaflets less flexible, which decreases blood flow to the heart.

[Researchers] tested how valve interstitial cells that produce calcium nodules in diseased valves respond to VWF. When interstitial cells were intentionally exposed to VWF, "there was a dramatic increase in the size of the nodules at every age. Endothelial cells on the outside of the valve are making most of these (clotting-related) proteins. We found they don't just float away into the blood or stay on the valve surface. Some of them penetrate down into the tissue."

What remains to be seen is why. Heart valves are in motion from birth to death and are perhaps the most active connective tissue in the body. The researchers suspect the breakdown of collagen over time, as well as the constant stretching of the valve, opens gaps through which the proteins can travel. "As you get older, collagen becomes less organized. Because the distinct arrangement of extracellular matrix disappears, I think proteins like VWF permeate inside the valve more than what you would see in young, healthy adults."

Link: http://news.rice.edu/2013/11/07/clotting-protein-hardens-aging-hearts/

Cryonics is a process of low-temperature preservation for your brain (and optionally body) on death. Cryoprotectant chemicals are infused into your tissues during a cooling process so as to produce a glass-like vitrification rather than freezing, minimizing formation of ice crystals and preserving the fine neural structures that contain the data of your mind. At some point in the future it will become possible to revive and restore an individual to life from even as radical a procedure as this. The technologies needed can currently be envisaged: swarms of guided nanomachines capable of repairing and altering cellular structures down to the level of individual proteins, combined with near-complete control over the growth, state, and behavior of cells that will evolve from present day stem cell research.

The process of cryopreservation is not something that can be thrown together at the drop of a hat. Preparation is needed. This is especially true because we cannot legally choose the time our own death, and thus much of the expense and complexity of cryonics involves standby teams and the uncertainty inherent in the process of natural death. It is an ugly thing that the responsible, individual choice of assisted euthanasia is forbidden in our society. It forces people to suffer needlessly in their final, frail days, and further creates an entirely avoidable increase in expense and decrease in reliability of cryopreservation.

Cryonics standby groups are often volunteers, and they go above and beyond to make cryopreservations happen even under the least optimal of circumstances, just as do the staff at organizations such as Alcor and the Cryonics Institute. All too many people fail to carry out the necessary preparations, and someone ends up having to pick up the slack. In a better world than this cryonics would be a large enough business to spur the creation of intermediaries who fulfill a role similar to that of insurance companies merged with paramedical organizations, working to ensure better end of life treatment and organization for cryonics patients. Unfortunately we do not yet live in that world, and so there are examples such as this:

Alcor's 118th Patient

A-2694 completed sign-up paperwork just four days before being pronounced and we confirmed receipt of payment for his cryopreservation on the day of pronouncement. The patient was admitted to a hospital in the Czech Republic on Wednesday October 23. Initially, a relative told us that doctors had claimed that conducting cryopreservation procedures in that country would be illegal. That turned out to be incorrect, although there is a requirement to conduct a postmortem. Fortunately, either because of the patient's dual citizenship or because a close relative was physically present to dismiss that requirement, no postmortem was required. Although payment for cryopreservation had not yet been received, the patient's brother had the wisdom to wire sufficient funds to allow us to begin preparations (with the invaluable assistance of international funeral directors Rowland Brothers in London) and to send Medical Response Director Aaron Drake to the Czech Republic.

We had hoped to perform a field cryoprotection for the first time. This would have allowed us to cryoprotect the patient and ship him on dry ice. Just recently, we had positioned supplies in England for this purpose. Unfortunately, this turned out to be impossible. In part, this was due to the extremely close time frame for the patient's sign-up. More critically, however, we ran into incredibly bad luck in that on the day our supplies were to be moved from England to the patient's location, England was hit by the massive St. Jude storm. Winds of up to 80 mph led to cancelled flights and other major travel disruptions. Even if the patient had been well enough to move him to Germany (as we had suggested), field cryoprotection would not have been feasible.

The patient's location in the Czech Republic added further difficulties. It turned out that the hospital lacked any ice facilities - a situation that would never happen in a US hospital. When the patient's condition (based on very limited medical information) seemed to be critical, Aaron Drake got on a flight to the Czech Republic on Sunday October 27. The patient was pronounced while Aaron was still in transit, then placed in the hospital morgue at around 2 degrees Celsius. All the dry ice in the area was purchased and used to cool and pack the patient for air transport to Alcor. A-2694 arrived at Phoenix Sky Harbor International Airport early in the evening of Friday November 1 and at Alcor around 9:00 pm. The transfer into cool down took a little over an hour. At the time of writing (November 7), the patient is close to completing the cool down process.

Don't leave your preparations to the last minute. By doing so you make tightly-run organizations stretch themselves on your behalf: they will do their best at short notice, as happened here, but the end result may still be a poor cryopreservation. The preservation process needs to begin as soon as possible after death, and any delay is not a good thing: perhaps the damage accrued might be repairable by far-future technology, but there is every likelihood that it might not, as much of the vital data that makes up you as an individual is lost. That might as well be death.

Cells continually accumulate damage in the form of metabolic waste products and broken or misfolded protein machinery. Several systems toil to remove this damage on an ongoing basis, and the efficiency of these systems is linked to longevity: more cellular housekeeping is a good thing. Unfortunately, and as is the case for all aspects of our biology, these housekeeping processes become less efficient with age, most likely overwhelmed by forms of damage and waste products that they cope poorly with.

You might be familiar with the lysosome and its role in recycling damaged cellular components, and know that lysosomal activity declines with aging due to a build up of hardy waste compounds that our biology isn't equipped to break down. There are other components of the housekeeping system in our cells, however, and they also fail with age. Just as there are potential means to restore lysosomal recycling to youthful efficiency, so too will there be ways to rejuvenate these other housekeeping systems. For example, here researchers demonstrate restoration of the effectiveness of the ubiquitin-proteasome system, important in the clearance of misfolded proteins:

Levels of damaged proteins increase with the age of different species, including fungi, flies, worms, bats, birds, rodents, and humans. Several principal possibilities have been suggested to explain this apparently universal accumulation of damaged/misfolded proteins, including a diminished capacity for protein quality control, which encompasses the removal of damaged and misfolded proteins by the proteasome. Indeed, the function of the 26S proteasome decreases during aging in several human tissues, senescent primary cultures, and whole organisms, pinpointing the proteasome as a possible malefactor behind age-related damage propagation.

Here, using yeast as a model system, we show that while the level and potential capacity of the 26S proteasome is maintained in replicatively aged cells, the UPS is not functioning properly in vivo. As a consequence cytosolic UPS substrates are stabilized, accumulate, and form inclusions.

By integrating a PGPD-HSP104 recombinant gene into the genome, we were able to constitutively elevate protein disaggregase activity, which diminished the accumulation of protein inclusions during aging. Remarkably, this elevated disaggregation restored degradation of a 26S proteasome substrate in aged cells without elevating proteasome levels, demonstrating that age-associated aggregation obstructs UPS function. The data supports the existence of a negative feedback loop that accelerates aging by exacerbating proteostatic decline once misfolded and aggregation-prone proteins reach a critical level.

Link: http://www.impactaging.com/papers/v5/n11/full/100613.html

One approach to mimic the effects of calorie restriction is to replace an important molecular component of the diet with some other substance that cannot be processed in the necessary ways by an individual's metabolism. This is easier to achieve in lower animals, and here is an example of the way in which researchers use this and other simple ways to extend life in order to narrow down the search for the genes and mechanisms by which metabolism determines longevity:

Glucose restriction mimicked by feeding the roundworm Caenorhabditis elegans with 2-deoxy-D-glucose (DOG) - a glucose molecule that lacks the ability to undergo glycolysis - has been found to increase the life span of the nematodes considerably.

To facilitate understanding of the molecular mechanisms behind this life extension, we analyzed transcriptomes of DOG-treated and untreated roundworms obtained by RNA-seq at different ages. We found that, depending on age, DOG changes the magnitude of the expression values of about 2 to 24 percent of the genes significantly, although our results reveal that the gross changes introduced by DOG are small compared to the age-induced changes. We found that 27 genes are constantly either up- or down-regulated by DOG over the whole life span, among them several members of the cytochrome P450 family.

The monotonic change with age of the temporal expression patterns of the genes was investigated, leading to the result that 21 genes reverse their monotonic behaviour under impaired glycolysis. Put simply, the DOG-treatment reduces the gross transcriptional activity but increases the interconnectedness of gene expression. However, a detailed analysis of network parameters discloses that the introduced changes differ remarkably between individual signalling pathways. We found a reorganization of the hubs of the mTOR pathway when standard diet is replaced by DOG feeding.

By constructing correlation based difference networks, we identified those signalling pathways that are most vigorously changed by impaired glycolysis. Taken together, we have found a number of genes and pathways that are potentially involved in the DOG-driven extension of life span of C. elegans. Furthermore, our results demonstrate how the network structure of ageing-relevant signalling pathways is reorganised under impaired glycolysis.

Link: http://dx.doi.org/10.1371/journal.pone.0077776

A fair number of new research results have appeared in the past few weeks relating to ways to modestly reduce the pace of cognitive aging. As we age the mind declines due to a range of failures in the physical structure of the brain that arise from the SENS catalog of low-level cellular and molecular damage of aging. One of the more important ways in which the physical structure of the brain is impacted is via failing cardiovascular health, meaning both a degeneration of the overall process of effectively driving blood through the brain and also a progressive failure of blood vessels, involving loss of tissue elasticity and structural integrity. You might read up on vascular dementia to see how the late stages of this process go, but it is worth remembering that significant damage and failing function exists in the brain's network of blood vessels long before it rises to the level of diagnosis as a named disease or catastrophic structural failure such as a stroke.

Aging is a progressive, accelerating decline that starts with small consequences and minor losses of function, easily ignored. But these small degenerations will also be repaired in a future of rejuvenation therapies: no-one will wait for decades before undergoing periodic treatments to repair the harms that accumulate in our biochemistry. The next big goal for medical science, something to work towards over the next half century, is an assurance of perfect health for everyone, continuing for as long as desired.

We are still a way away from that point, however, and so the researchers of today continue to point out that exercise remains one of the most effective means available to slow the onset of degenerative aging. That we live in an age of biotechnology and progress and that exercise is still head and shoulders above most medical technologies should really be taken as a challenge. We can do better, and we should do better, and we must do better if we want to live longer in good health.

Study finds aerobic exercise improves memory, brain function and physical fitness

For the study, sedentary adults ages 57-75 were randomized into a physical training or a wait-list control group. The physical training group participated in supervised aerobic exercise on a stationary bike or treadmill for one hour, three times a week for 12 weeks. Participants' cognition, resting cerebral blood flow, and cardiovascular fitness were assessed at three time points: before beginning the physical exercise regimen, mid-way through at 6 weeks, and post-training at 12 weeks.

Exercisers who improved their memory performance also showed greater increase in brain blood flow to the hippocampus. Using noninvasive brain imaging techniques, brain changes were identified earlier than memory improvements, implicating brain blood flow as a promising and sensitive metric of brain health gains across treatment regimens.

"Physical exercise may be one of the most beneficial and cost-effective therapies widely available to everyone to elevate memory performance. These findings should motivate adults of all ages to start exercising aerobically. In another recent study, we have shown that complex mental training increases whole brain blood flow as well as regional brain blood flow across key brain networks. The combination of physical and mental exercise may be the best health measures to improve overall cognitive brain health. We have just begun to test the upper boundaries of how we can enhance our brain's performance into late life."

Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging

Physical exercise, particularly aerobic exercise, is documented as providing a low cost regimen to counter well-documented cognitive declines including memory, executive function, visuospatial skills, and processing speed in normally aging adults. Prior aging studies focused largely on the effects of medium to long term (more than 6 months) exercise training; however, the shorter term effects have not been studied. In the present study, we examined changes in brain blood flow, cognition, and fitness in 37 cognitively healthy sedentary adults (57-75 years of age) who were randomized into physical training or a wait-list control group.

The physical training group received supervised aerobic exercise for 3 sessions per week 1 h each for 12 weeks. Participants' cognitive, cardiovascular fitness and resting cerebral blood flow (CBF) were assessed at baseline (T1), mid (T2), and post-training (T3). We found higher resting CBF in the anterior cingulate region in the physical training group as compared to the control group from T1 to T3. Cognitive gains were manifested in the exercise group's improved immediate and delayed memory performance from T1 to T3 which also showed a significant positive association with increases in both left and right hippocampal CBF identified earlier in the time course at T2.

These data suggest that even shorter term aerobic exercise can facilitate neuroplasticity to reduce both the biological and cognitive consequences of aging to benefit brain health in sedentary adults.

There is plenty of evidence to suggest that variations in human longevity are to some degree inherited, though there is also a great deal of room to argue over which mechanisms might be involved. Here is another research result to add to existing data on this subject:

Offspring of long-lived individuals have lower risk for dementia. We examined the relation between parental longevity and cognition and subclinical markers of brain ageing in community-dwelling adult offspring. Offspring participants with both parents in the Framingham Heart Study, aged ≥55 years and dementia-free underwent baseline and repeat neuropsychological (NP) testing and brain magnetic resonance imaging (MRI). Parental longevity was defined as having at least one parent survive to age ≥85 years.

Of 728 offspring (mean age 66 years, 54% women), 407 (56%) had ≥1 parent achieve longevity. In cross-sectional analysis, parental longevity was associated with better scores on attention and a lower odds of extensive white matter hyperintensity on brain MRI. The association with white matter hyperintensity was no longer significant in models adjusted for cardiovascular risk factors and disease.

In longitudinal analysis (6.7 ± 1.7 years later), offspring with parental longevity had slower decline in attention, executive function and visual memory, and less increase in temporal horn volume. The associations persisted in fully adjusted models.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24212919

Researchers here argue that calorie restriction extends life in nematode worms by causing mitochondria to emit more reactive oxygen species, which leads to a reaction from neurons that sense this higher level of oxidative stress. Their evidence is fairly compelling: we'll have wait and see how this can be reconciled with the good evidence for the benefits of calorie restriction in mammals to derive at least in part from loss of visceral fat tissue and sensing of levels of methionine.

Dietary restriction (DR) extends lifespan and promotes metabolic health in evolutionary distinct species. DR is widely believed to promote longevity by causing an energy deficit leading to increased mitochondrial respiration. We here show that inhibitors of mitochondrial complex I promote physical activity, stress resistance as well as lifespan of Caenorhabditis elegans despite normal food uptake, i.e. in the absence of DR. However, complex I inhibition does not further extend lifespan in dietarily restricted nematodes, indicating that impaired complex I activity mimics DR.

Promotion of longevity due to complex I inhibition occurs independently of known energy sensors, including DAF-16/FoxO, as well as AAK-2/AMPK and SIR-2.1/sirtuins, or both. Consistent with the concept of mitohormesis, complex I inhibition transiently increases mitochondrial formation of reactive oxygen species (ROS) that activate PMK-1/p38 MAP kinase and SKN-1/NRF-2. Interference with this retrograde redox signal as well as ablation of two redox-sensitive neurons in the head of the worm similarly prevents extension of lifespan.

These findings unexpectedly indicate that DR extends organismal lifespan through transient neuronal ROS signaling rather than sensing of energy depletion, providing unexpected pharmacological options to promote exercise capacity and healthspan despite unaltered eating habits.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3817383/

Researcher Alex Zhavoronkov of the Biogerontology Research Foundation has been somewhat focused on the economic side of aging research in recent years. You might look over his work on the International Aging Research Portfolio, that tracks worldwide funding in this field, and his recently published book, entitled "The Ageless Generation: How Advances in Biomedicine Will Transform the Global Economy", to pick two examples.

Zhavoronkov sent me a note today to point out a new paper in which he and his co-author take a look at relationships between biomedical research and development and economic growth. I should note that a part of the context in which this paper exists is that this is an age of political angst over the intersection of spending, entitlements, pensions, and growing longevity, characterized by the growing sense that politicians and bureaucrats have engineered a catastrophe from what should be the unmitigated benefit of longer healthy lives. Much has been sold down the river for short term gains claimed by a few. Thus there are many in the community who feel that presenting human rejuvenation as a potential solution to a future of centralized, ever-more-costly healthcare will go some way towards attracting the greater attention and funding that is needed for faster progress towards defeating the diseases and degeneration of aging.

For my money, I think that fiscal disaster on a national scale is a political problem with political solutions - you can't solve the fall of a government through overspending with biotechnology. Those at the top will just find other ways to waste and steal. However, the examination of links between aging, longevity, advancing biotechnology, and economic growth is valid and useful in and of itself. It is an interesting field, says much about what the sort of work we should be funding, and doesn't receive the level of attention that it should. Zhavoronkov had this to say:

I think that this is possibly the most important paper I have published so far. We are showing that the economy will grow if governments focus on supporting long-term basic science projects like SENS that are focused on increasing productive longevity and re-focusing the healthcare spending on extending productive life.

The paper is open access, albeit in PDF format only, so take a look:

Biomedical Progress Rates as New Parameters for Models of Economic Growth in Developed Countries

While the doubling of life expectancy in developed countries during the 20th century can be attributed mostly to decreases in child mortality, the trillions of dollars spent on biomedical research by governments, foundations and corporations over the past sixty years are also yielding longevity dividends in both working and retired population. Biomedical progress will likely increase the healthy productive lifespan and the number of years of government support in the old age.

In this paper we introduce several new parameters that can be applied to established models of economic growth: the biomedical progress rate, the rate of clinical adoption and the rate of change in retirement age. The biomedical progress rate is comprised of the rejuvenation rate (extending the productive lifespan) and the non-rejuvenating rate (extending the lifespan beyond the age at which the net contribution to the economy becomes negative).

We propose a model that takes into account progress in the biomedical sciences, which in turn affects the size, growth and productivity of the population. In the model, the rate of biomedical progress is the sum of the rejuvenation rate, the rate at which the functions required to perform useful work that were lost to aging or disease are restored, and non-rejuvenating rate, which increases lifespan, but does not restore lost functions.

We hypothesize that, over the past two decades, economic growth in the developed countries has been partially defined by the ratio of the rejuvenation rate to the overall biomedical progress rate and the retirement age. The biomedical progress rate extends the lifespan and decreases the mortality rates of the population, while the rejuvenation rate allows for the increased productivity of older workers and increases in the retirement age.

We propose that the increase in the ratio of the rejuvenation rate to the overall biomedical progress rate will result in economic growth. This hypothesis is supported by recent studies showing that the acceleration of aging research focused on increasing longevity and postponing age-related diseases and not the treatment of age-related diseases. Another source of economic growth may come from accelerating the rate of clinical adoption by reducing the time it takes for a biomedical discovery to reach the patient.

The effects of population aging on economic growth remains a controversial topic in macroeconomics with conflicting schools of thought. While there are many models and simulations that account for population aging, the new parameters introduced in this paper may help enrich the models demonstrating both positive and negative effects of aging on the economy and help model scenarios that go beyond extending historic trends in longevity.

Too many people take it as read that there are too many people. The assumption of overpopulation as a reality is the great myth of our time, held despite the obvious figures on the table to show that this planet of ours could comfortably support many multiples of the present population even with today's technology. It is the legacy of the success of the environmentalist movement, which transcended the reasonable portions of the original agenda to transform itself into something of a civic religion somewhere along the way. It is a strange twist to the cultures we create to see that the average person in the street now thinks that many of our greatest achievements should be torn down or relinquished and even that human existence is a net negative.

Yet where there is poverty and suffering, that state exists despite present wealth and opportunities to generate wealth, not because of the number of people involved. There is more than enough food, more than enough resources, and more of an excess of both are being created with each passing year. These are political and distribution issues, problems of organization, kleptocracy, and simple inhumanity. Waste amid the potential for plenty.

The prevalence of the overpopulation myth is, I think, one of the important contributing factors to public opposition to extending healthy human life span. Much of the public is convinced that there exists a present crisis of population that will lead inevitably to some form of resource collapse - which is far from the case, but facts in evidence never played much of a role in these sorts of slow-moving hysteria in the past. These patterns of belief even extend into the community of futurists and supporters of longevity science, and hence you'll sometimes see articles such as this one:

When our most precious and hard fought for successes give rise to yet more challenges life is revealing its Sisyphean character. We work as hard as we can to roll a rock up a hill only to have it crush us on the way down. The stones that threatens us this time are two of our global civilization's greatest successes - the fact that children born are now very likely to live into old age and the fact that we have stretched out this old age itself so that many, many more people are living into ages where in the past the vast majority of their peers would be dead. These two demographic revolutions when combined form the basis of what I am calling the Longevity Crisis.

Ultimately in terms of the sustainability of our species [the present] decline in the birth rate is a very good thing. Demographics, however, is like a cruise ship - it is hard to turn. In the lag time the world's population is exploding as societies are able to save the lives of children but continue to have nearly as many of them. We are living through the turning. [It] took humanity roughly 250,000 years to reach 1 billion of us in 1900, but thereafter the rate of growth skyrocketed. There was only a little over a century between our first billion and second billion. 40 years later in 1960 we numbered 3 billion. Only 14 years after that we reached the 4 billion mark and the time between adding another billion would shorten to about a mere dozen years with 5 billion reached in 1987, 6 billion following 12 years later in 1999, and 7 billion a dozen after that in 2011.

Thankfully, the rate of population growth is slowing. It will take us 14 years to pass the 8 billion mark and 20-25 years to reach what will perhaps be the peak of human population during this era - 9 billion in 2050. Though comforting we shouldn't necessarily be sanguine in light of this fact - we are still on track to add to the world the equivalent of another China and Europe by the middle of the century. Certainly, these people will, with justice, hanker after a middle class lifestyle putting enormous pressures on the global environment. Add to that the effects of climate change and it seems we are entering a very dangerous and narrow chute through which humanity must pass.

Some people feel threatened by large numbers. But numbers alone mean nothing and say nothing. They carry no information or context, and to base fear of the future rather than optimism on the fact that one number is changing is an emotional reaction, not a rational analysis.

Link: http://ieet.org/index.php/IEET/more/searle20131109

Researchers here take a novel approach to produce accelerated healing in laboratory animals, and go some way towards identifying the mechanisms involved, which link portions of the immune system and gut microbe ecosystem with healing capacity. It is possible that the immune system component of this research will yield ways to patch over progressive age-related dysfunction in those aspects of immune function associated with healing.

Wound healing capability is inextricably linked with diverse aspects of physical fitness ranging from recovery after minor injuries and surgery to diabetes and some types of cancer. Impact of the microbiome upon the mammalian wound healing process is poorly understood. We discover that supplementing the gut microbiome with lactic acid microbes in drinking water accelerates the wound-healing process to occur in half the time required for matched control animals.

Further, we find that Lactobacillus reuteri enhances wound-healing properties through up-regulation of the neuropeptide hormone oxytocin, a factor integral in social bonding and reproduction, by a vagus nerve-mediated pathway. Bacteria-triggered oxytocin serves to activate host immune T regulatory cells conveying transplantable wound healing capacity.

This study determined oxytocin to be a novel component of a multi-directional gut microbe-brain-immune axis, with wound-healing capability as a previously unrecognized output of this axis. We also provide experimental evidence to support long-standing medical traditions associating diet, social practices, and the immune system with efficient recovery after injury, sustained good health, and longevity.

Link: http://dx.doi.org/10.1371/journal.pone.0078898

I'm not a big fan of the phrase "successful aging." It is a popular shorthand among researchers who investigate means of slowing aging and reducing incidence of age-related disease, but who do not wish to talk in public about extending human life span. So it is a problematic fig leaf on that count, but it is also a contradiction in terms. Aging is damage and degeneration, and so what if you manage to die, slowly and painfully, a shadow of your former self, just a little later than your peers? Why is that counted a success?

When we look elsewhere in the medical community, this lack of ambition and acceptance of disease is not what we see. Take cancer research, for example: it doesn't matter how many months that scientists manage to add to a terminal patient's life span, you'll never hear them talking about "successful terminal cancer" as a desired outcome. The measure of success in cancer research is to produce a cure, and that should also be the measure of success for aging, so that the research community aims to prevent and reverse age-related degeneration and disease, such as through implementation of the SENS proposals. Anything less is ridiculous: it is to say that degeneration, pain, and suffering are acceptable, and we should do nothing much about it. That is clearly the antithesis of what should mean to be involved in medical research and development.

I think that Maria Konovalenko of the Science for Life Extension Foundation is correct in noting here that the phrase "healthy aging" has essentially all of the same issues given the way it is presently used in the research and medical communities. It is a contradiction in terms: aging is explicitly the process of becoming less healthy. The fundamental definition of aging is that it is a rise in the chance of dying due to increasing tissue dysfunction, which doesn't sound a great deal like health to me.

There Can Be No Healthy Aging

[Craig Venter's institute] has received 1.25 million dollars from the Ruggles Family Foundation to study the biomarkers of healthy aging. This study makes no sense to me, because they want to look at the differences in health between sick people and even sicker people and call the results of the study markers of healthy aging. They propose to measure the right things, but what the study planners are missing here is the fact that aging itself is a disease. Aging can't be healthy, because the underlying biological mechanisms that are causing age-related pathologies are active also in those aged individuals, who don't have those diseases.

These people are considered to be just old, but not sick. That's exactly what's wrong with perception of aging. Everyone who reached a certain age is considered to be simply old, but not ill. However this person is 100% not healthy in a biological sense, because a lot of detrimental processes have already started their poisonous actions and altered the youthful state of the organism.

Here's what important - we need to change the perception of aging, so there would be no confusing terms like "healthy aging", which is an oxymoron. It's like "dignified poverty", or "merciful tyrant". Aging is not and can not be healthy. Aging is itself a disease. It is also the cause of many other maladies like Alzheimer's and stroke, and many others. We have to stop using the term healthy aging, because it is already making us conduct poorly designed research experiments.

One branch of tissue engineering focuses on the creation of scaffolds that mimic enough of the features of the extracellular matrix or local cellular environment to encourage regrowth. With suitable chemical signals a scaffold can guide the normal processes of regeneration to fill out its structure with suitable tissue, as demonstrated here for bone regrowth:

Researchers [have] created a bio patch to regenerate missing or damaged bone by putting DNA into a nano-sized particle that delivers bone-producing instructions directly into cells. The team started with a collagen scaffold. The researchers then loaded the bio patch with synthetically created plasmids, each of which is outfitted with the genetic instructions for producing bone. They then inserted the scaffold on to a 5-millimeter by 2-millimeter missing area of skull in test animals. Four weeks later, the team compared the bio patch's effectiveness to inserting a scaffold with no plasmids or taking no action at all.

The plasmid-seeded bio patch grew 44-times more bone and soft tissue in the affected area than with the scaffold alone, and was 14-fold higher than the affected area with no manipulation. Aerial and cross-sectional scans showed the plasmid-encoded scaffolds had spurred enough new bone growth to nearly close the wound area, the researchers report.

The plasmid does its work by entering bone cells already in the body - usually those located right around the damaged area that wander over to the scaffold. The team used a polymer to shrink the particle's size and to give the plasmid the positive electrical charge that would make it easier for the resident bone cells to take them in. "The delivery mechanism is the scaffold loaded with the plasmid. When cells migrate into the scaffold, they meet with the plasmid, they take up the plasmid, and they get the encoding to start producing PDGF-B, which enhances bone regeneration."

Link: http://now.uiowa.edu/2013/10/bio-patch-can-regrow-bone

Here is a better set of publicity materials describing recent research in which scientists demonstrated enhanced regeneration in mice:

By reactivating a dormant gene called Lin28a, which is active in embryonic stem cells, researchers were able to regrow hair and repair cartilage, bone, skin and other soft tissues in a mouse model. Lin28, first discovered in worms, functions in all complex organisms. It is abundant in embryonic stem cells, expressed strongly during early embryo formation and has been used to reprogram skin cells into stem cells. It acts by binding to RNA and regulating how genes are translated into proteins. [The] researchers found that Lin28a also enhances the production of metabolic enzymes in mitochondria, the structures that produce energy for the cell. By revving up a cell's bioenergetics, they found, Lin28a helps generate the energy needed to stimulate and grow new tissues.

"Efforts to improve wound healing and tissue repair have mostly failed, but altering metabolism provides a new strategy which we hope will prove successful. Most people would naturally think that growth factors are the major players in wound healing, but we found that the core metabolism of cells is rate-limiting in terms of tissue repair. The enhanced metabolic rate we saw when we reactivated Lin28a is typical of embryos during their rapid growth phase."

"We already know that accumulated defects in mitochondrial metabolism can lead to aging in many cells and tissues. We are showing the converse - that enhancement of mitochondrial metabolism can boost tissue repair and regeneration, recapturing the remarkable repair capacity of juvenile animals." Further experiments showed that bypassing Lin28a and directly activating mitochondrial metabolism with a small-molecule compound also had the effect of enhancing wound healing. This suggests the possibility of inducing regeneration and promoting tissue repair with drugs.

Link: http://www.sciencedaily.com/releases/2013/11/131107123144.htm

As the research community continues to improve our understanding of the mechanisms of regeneration, ever more potential ways to improve healing and regrowth should emerge as a result. Stem cell therapies are one outcome of this research: having found the cells that do much of the work to keep our tissues in shape, we can now think about directing them, growing more of them, reversing their decline in aging, transplanting them between individuals, and so forth. But this is far from the only type of approach that might arise. Evolution doesn't tend to produce systems that are optimized for the best possible outcome for individuals: we can see that in the ease with which researchers can adjust any one of a handful of genes to extend healthy life in laboratory mice. Similarly we should expect there to exist numerous small genetic or metabolic changes that produce improved regeneration in mammals, but which have not been selected for by evolution in most species.

On this topic a couple of research results were publicized today, illustrating the sort of work that kicks off further investigations aimed at improving human regeneration, either globally or in specific tissue types:

Scientists identify clue to regrowing nerve cells

Axons are the branches of nerve cells that send messages. They typically are much longer and more vulnerable to injury than dendrites, the branches that receive messages. In the peripheral nervous system cells sometimes naturally regenerate damaged axons. But in the central nervous system, comprised of the brain and spinal cord, injured nerve cells typically do not replace lost axons.

Working with peripheral nervous system cells grown in the laboratory, [researchers] severed the cells' axons. [They] learned that this causes a surge of calcium to travel backward along the axon to the body of the cell. The surge is the first step in a series of reactions that activate axon repair mechanisms. In peripheral nerve cells, one of the most important steps in this chain reaction is the release of a protein, HDAC5, from the cell nucleus, the central compartment where DNA is kept. The researchers learned that after leaving the nucleus, HDAC5 turns on a number of genes involved in the regrowth process. HDAC5 also travels to the site of the injury to assist in the creation of microtubules, rigid tubes that act as support structures for the cell and help establish the structure of the replacement axon.

When the researchers genetically modified the HDAC5 gene to keep its protein trapped in the nuclei of peripheral nerve cells, axons did not regenerate in cell cultures. The scientists also showed they could encourage axon regrowth in cell cultures and in animals by dosing the cells with drugs that made it easier for HDAC5 to leave the nucleus. When the scientists looked for the same chain reaction in central nervous system cells, they found that HDAC5 never left the nuclei of the cells and did not travel to the site of the injury. They believe that failure to get this essential player out of the nucleus may be one of the most important reasons why central nervous system cells do not regenerate axons.

"This gives us the hope that if we can find ways to manipulate this system in brain and spinal cord neurons, we can help the cells of the central nervous system regrow lost branches. We're working on that now."

Researchers reactivate gene to rejuvenate tissue repair

[An] RNA-binding protein, Lin28a, promotes tissue repair by reactivating a metabolic state reminiscent of the juvenile developmental stage. [Researchers] showed that reactivation of Lin28a - a gene that is normally turned on in fetal but not adult tissues - substantially improved hair regrowth and accelerated tissue repair after ear and digit injuries. "Our work found that Lin28a promotes regeneration through a metabolic mechanism. This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration."

There is much debate over the origins and causes of the well-known decline in regenerative capability with age, characterized by reduced numbers of stem cells and reduced stem cell activity in tissue maintenance, among other mechanisms. A mainstream position is that this is an evolved response to damage, lengthening life by reducing the risk of cancer that might result from damaged stem cells, but at the cost of increasing frailty. There are other views, of course:

There is a viewpoint that suppression of the proliferative capacity of cells and impairment of the regeneration of tissues and organs in aging are a consequence of specially arisen during evolution mechanisms that reduce the risk of malignant transformation and, thus, protect against cancer. We believe that the restriction of cell proliferation in an aging multicellular organism is not a consequence of implementing a special program of aging.

Apparently, such a program does not exist at all and aging is only a "byproduct" of the program of development, implementation of which in higher organisms suggests the need for the emergence of cell populations with very low or even zero proliferative activity, which determines the limited capacity of relevant organs and tissues to regenerate. At the same time, it is the presence of highly differentiated cell populations, barely able or completely unable to reproduce (neurons, cardiomyocytes, hepatocytes), that ensures the normal functioning of the higher animals and humans.

Apparently, the impairment of regulatory processes, realized at the neurohumoral level, still plays the main role in the mechanisms of aging of multicellular organisms, not just the accumulation of macromolecular defects in individual cells. It seems that the quality of the cells themselves does not worsen with age as much as reliability of the organism control over cells, organs and tissues, which leads to an increase in the probability of death.

Link: http://www.ncbi.nlm.nih.gov/pubmed/24085520

Researchers here use dead people as their initial study group, an approach which has some advantages. One could imagine setting up a very large and cost-effective study based on introducing a simple skin sample procedure into standard end of life medical care, and then matching those results to genetic data drawn from existing large studies of old people. Researchers would only have to match age and gender between the deceased and living individuals from another body of study results in order to start producing value.

To investigate longevity-associated genes based on a comparison between dead and surviving populations, a total of 71 cases of dead individuals were treated as the death group, and healthy volunteers who were matched with the dead individuals based on sex and age were recruited as the survival group. Alleles of 13 CODIS short tandem repeats loci were determined. The cross-validation was performed based on differences between the two groups in both frequency values and ages.

The frequency value of the D18S51-17 alleles was significantly higher in the dead group than in the survival group, and the frequency value of the D2S1338-18 allele was statistically lower in the dead group than in the survival group. The mean age of the subjects with the D2S1338-18 allele was also significantly higher than that of the subjects without D2S1338-18, and no significant difference was observed with respect to the other three alleles. The results suggest that D2S1338-18 is associated with longevity.

Link: http://dx.doi.org/10.1016/j.gene.2013.08.070

Only lower organisms seem able to prosper via evolutionary strategies that involve some combination of agelessness, radical transformation of body structure, and hyperefficient regeneration. The candidates for truly immortal animals are few and far between: species such as Turritopsis dohrnii, a tiny jellyfish that runs its development cycle in reverse rather than age and die, and hydra, which might achieve immortality through exceedingly effective always-on tissue regeneration. Strategies of this nature can work because these are comparatively simple organisms, lacking the specialization and complexity of higher animals such as we mammals. Gaining a complex neural network and brain seems to go hand in hand with losing exceptional regenerative capabilities - which seems reasonable, although it is still an open question as to exactly why this is the case.

One thing to consider as a result is that while studying these apparently immortal species might teach us interesting things about biology, it probably won't result in anything of practical use in medicine in the near term. Bear in mind that it will be a long haul to mine useful medical applications from the far better funded and more advanced study of long-lived mammals such as naked mole rats and whales, which are very close relatives to us in comparison to jellyfish and hydra. But the biochemistry that keeps a hydra going is more likely to result in destruction and cancer than benefits if implemented in a human: many of our structures, especially those in the brain, need to be around for the long-term, not constantly replaced with new tissue, or discarded in the course of a radical change of body structure.

Here researchers make an early and speculative hypothesis on the role of FOXO in the move from simple, highly regenerative organisms to complex, less regenerative organisms. FOXO genes (the O category of the forkhead box family) have been studied for some years by researchers seeking to understand and catalog the means by which metabolism determines longevity. Like many other longevity-related genes they influence broad collections of central and important processes related to genetic transcription, cell proliferation, and stress tolerance. There is no simple set of dots to join between point A and point B: these are networks of interlinked feedback loops.

FOXO in aging: Did evolutionary diversification of FOXO function distract it from prolonging life?

In this paper we contrast the simple role of FOXO in the seemingly non-aging Hydra with its more diversified function in multicellular eukaryotes that manifest aging and limited life spans. From this comparison we develop the concept that, whilst once devoted to life-prolonging cell-renewal (in Hydra), evolutionary accumulation of coupled functionality in FOXO has since 'distracted' it from this role. Seen in this light, aging may not be the direct cost of competing functions, such as reproduction or growth, but the result of a shift in emphasis in a protein, which is accompanied by advantages such as greater organismal complexity and adaptability, but also disadvantages such as reduced regeneration capacity. Studying the role of FOXO in non-aging organisms might, therefore, illuminate the path to extend life span in aging organisms.

Stem cells and aging from a quasi-immortal point of view

Understanding aging and how it affects an organism's lifespan is a fundamental problem in biology. A hallmark of aging is stem cell senescence, the decline of functionality, and number of somatic stem cells, resulting in an impaired regenerative capacity and reduced tissue function. In addition, aging is characterized by profound remodeling of the immune system and a quantitative decline of adequate immune responses, a phenomenon referred to as immune-senescence. Yet, what is causing stem cell and immune-senescence?

This review discusses experimental studies of potentially immortal Hydra which have made contributions to answering this question. Hydra transcription factor FoxO has been shown to modulate both stem cell proliferation and innate immunity, lending strong support to a role of FoxO as critical rate-of-aging regulator from Hydra to human. Constructing a model of how FoxO responds to diverse environmental factors provides a framework for how stem cell factors might contribute to aging.

Here is one example drawn from many ongoing lines of research aimed at the development of stem cell treatments for a broad variety of injuries. Enhanced regeneration will be a strong theme in the new medical technologies of the next two decades:

A stem cell therapy previously shown to reduce inflammation in the critical time window after traumatic brain injury also promotes lasting cognitive improvement, according to preclinical research. Cellular damage in the brain after traumatic injury can cause severe, ongoing neurological impairment and inflammation. Few pharmaceutical options exist to treat the problem. About half of patients with severe head injuries need surgery to remove or repair ruptured blood vessels or bruised brain tissue.

A stem cell treatment known as multipotent adult progenitor cell (MAPC) therapy has been found to reduce inflammation in mice immediately after traumatic brain injury, but no one had been able to gauge its usefulness over time. [Researchers here] injected two groups of brain-injured mice with MAPCs two hours after the mice were injured and again 24 hours later. One group received a dose of 2 million cells per kilogram and the other a dose five times stronger.

After four months, the mice receiving the stronger dose not only continued to have less inflammation - they also made significant gains in cognitive function. A laboratory examination of the rodents' brains confirmed that those receiving the higher dose of MAPCs had better brain function than those receiving the lower dose. "Based on our data, we saw improved spatial learning, improved motor deficits and fewer active antibodies in the mice that were given the stronger concentration of MAPCs."

Link: http://www.uthouston.edu/media/story.htm?id=1aa60db0-e4b5-4b5c-a450-db6fb8ffda04

VesCell was one of the first of the present generation of commercialized stem cell therapies in which a patient's own cells are taken, expanded, and then returned to the body. The company was notable for marketing in the US while setting up clinics elsewhere in the world to evade onerous FDA restrictions on stem cell therapies: medical tourism at its finest. These sorts of treatments are only now becoming available in the US thanks to the fact that over the past fifteen years a range of pioneers successfully developed commercial clinical applications beyond the reach of US regulators. Otherwise we'd still be waiting and FDA bureaucrats would still be forbidding commercialization of stem cell research, demanding ever more trials and data.

Regeneration of the occluded peripheral arteries by autologous stem cell therapy is an emerging treatment modality for no-option patients with peripheral artery disease (PAD). The purpose of this study was to assess safety and efficacy of in vitro-expanded, peripheral blood-derived, autologous stem cells (VesCell) in no-option patients with PAD. A phase II, open-label, randomized clinical study was performed on 20 patients to investigate the safety and efficacy of VesCell therapy at 1 and 3 months of follow-up. The long-term (2 years) efficacy of the therapy was also evaluated.

No side effects of VesCell therapy were found. During the 3 month follow-up in the control group, one death occurred and six major amputations were performed; in the treated group, there were no deaths or major amputations. The difference of limb loss is significant between the two groups. At 2-year follow-up in the control group, two deaths and six major amputations occurred; in the treated group, there were three major amputations. At 3-month follow-up, the change in hemodynamic parameters showed a significant increase in the treated group over the control group; in the treated group, further improvement was detected at 2 years. As the result of the VesCell treatment, change in pain score, wound healing and walking ability test showed an improvement compared with the control group; at 2 years, incremental improvement was observed.

Peripheral blood-derived, in vitro-expanded autologous angiogenic precursor therapy appears to be a safe, promising and effective adjuvant therapy for PAD patients.

Link: http://www.celltherapyjournal.org/article/S1465-3249(13)00549-5/abstract

Mitochondria are the power plants of the cell, working in herds to produce the energy stores that power other cellular processes. They are the evolved descendants of symbiotic bacteria and as such the blueprints for some of their protein machinery are encoded in their own DNA, separate from the DNA in the cell nucleus. This mitochondrial DNA is inherited wholesale from the mother, and numerous common variants known as haplogroups are distributed among the world's cultures and population.

Mitochondrial damage and function appears to be very important in the aging process and many common age-related diseases. In recent years evidence has accumulated to suggest that some variants of mitochondrial DNA are just plain better than others, but linking these genetic variations to damage and function remains a work in progress. Still, the genetic lottery we all participate in very definitely applies to the mitochondria we inherit, and not just our nuclear DNA. So far the widespread variant known as haplogroup H looks like a winner:

Variations in Human Response to Calorie Restriction

Before 1920 there is no significant difference between the longevity of individuals in haplogroup H and U. During the caloric restriction of the Great Depression, 1920-1940, haplogroup H shows significant increase in longevity compared to haplogroup U [with a] mean difference [of] 2.6 years.

Mitochondrial Haplotypes Correlate With Dementia Risk

Participants from haplogroup T had a statistically significant increased risk of developing dementia and haplogroup J participants experienced a statistically significant 8-year [cognitive decline], both compared with common haplogroup H.

Here is another paper demonstrating a possible facet of the superiority of haplogroup H mitochondrial DNA:

Increased intrinsic mitochondrial function in humans with mitochondrial haplogroup H

It has been suggested that human mitochondrial variants influence maximal oxygen uptake (VO2max). Whether mitochondrial respiratory capacity per mitochondrion (intrinsic activity) in human skeletal muscle is affected by differences in mitochondrial variants is not known. We recruited 54 males and determined their mitochondrial haplogroup. Haplogroup H showed a 30% higher intrinsic mitochondrial function compared with the other haplogroup U. There was no relationship between haplogroups and VO2max.

Interestingly, we are moving into an era in which wholesale replacement of mitochondrial DNA throughout the body is a practical possibility. This was accomplished in mice via protofection eight years ago, and since then numerous research groups have achieved mitochondrial DNA replacement in cell cultures via other mechanisms. In the future you will have optimal mitochondrial DNA, periodically replaced to clear out any damage that might have occurred.

But it is of course that damage that is the important factor here, not the details of your mitochondrial haplogroup. We age in part because our mitochondrial DNA becomes damaged, that being the start of a long chain of cause and effect that leads to dysfunctional cells, floods of harmful reactive compounds, and eventually fatal manifestations such as atherosclerosis. So work on mitochondrial DNA replacement is important because it will lead to a way to mitigate and reverse one facet of degenerative aging, not because you will be able to have an athlete's mitochondria as the result of a simple clinical procedure.

Practical human rejuvenation lies in the near future: the means to reverse age-related degeneration and restore youthful function to the old, thereby extending healthy life and eliminating age-related disease. With the right sea changes in scientific funding, so that organizations like the SENS Research Foundation become the mainstream of the aging research community, rejuvenation therapies could well arrive by the late 2030s. If the present mainstream focus on gently slowing aging continues as is, however, then it will take much longer to realize rejuvenation. But however long it takes, some fraction of those people presently alive will have been born too early.

A friend of mine in the life extension movement who is approaching age 65 once lamented that he might be part of the last generation that will not be able to take advantage of the rejuvenation biotechnologies that become available to the next generation. I wish I could believe him because it means that I may still be in time! Unfortunately, interest in anti-aging research and cryonics is rather low (to put it mildly), even among baby boomers who one might expect to be painfully aware of the aging process. It is rather disturbing to me that the aging process itself is not being identified as a source of misery, disease, separation, and oblivion. Then again, perhaps I am just too impatient and unable to see the larger picture.

The practical production of liquid nitrogen from liquefied air was first achieved by Carl von Linde in 1905, although liquid nitrogen only became widely available commercially after World War II. The idea of cryonics was introduced to the general public in the mid-1960s. Since liquid nitrogen (or liquid helium) is an essential requirement for human cryopreservation it is interesting to recognize that there was only a difference of roughly 20 years between cryonics being technically possible and the first efforts to practice cryonics. Is this an outrageously long delay? I doubt anyone would argue this.

Similarly, while the idea of rejuvenation has always appealed to humans, I doubt anyone can credibly claim that there has been a long delay between our recognition of biological senescence and the desire to see aging as a biotechnological challenge to overcome. While there is no massive global movement to fight aging yet, the desire to conquer aging is as old as the exposition of (secular) modern evolutionary biology itself. Are we too impatient?

What is disappointing, however, is the widespread passive acceptance of aging and death by the majority of people. Thinking about this issue, it struck me that until recently our (educational) institutions and research programs were shaped by generations that were perhaps eminently amenable to accepting the inevitability of aging. Expecting these institutions and research programs to change their objectives overnight may not be completely realistic. It is undeniable, however, that the idea that aging is not something that is to be passively accepted but something that can be stopped and reversed is gradually winning more converts.

From where I stand, the best thing to do is not to agonize over the odds but rather work to help shape the odds. Donate to research, persuade your friends, advocate for rejuvenation science, help make cryonics an ever more viable alternative for those who do not have enough time to wait for life-extending therapies, and more. There is plenty that can be done, and still all too few people working on it.

Link: http://www.evidencebasedcryonics.org/2013/10/05/born-too-early/

It is pleasant to see larger, more conservative research institutions being much more aggressive in publicizing longevity science and the goal of extending the healthy human life span. It shows that the old scientific and funding institution culture of hiding and suppressing any work on aging that might be relevant to extending life is done with and over. When the research community talks openly about their goals, levels of funding and public support rise.

Nowadays the more important battle is fought to ensure that the best strategies for extending life are those that are funded: for example none of the lines of research mentioned in the article below are in any way relevant to the SENS vision of rejuvenation through damage repair. Despite the talk of rejuvenation they instead reflect the mainstream focus on altering genes and metabolism to slow down the progression of aging, which is a harder, slower, less certain road to a less useful outcome.

Eleven leading scientists from the California Institute for Quantitative Biosciences (QB3) - a state-funded consortium founded by UC San Francisco, UC Berkeley and UC Santa Cruz - presented their latest research findings and anti-aging strategies at a daylong symposium earlier this month called "The Science of Staying Younger Longer." The goal of this research area is rejuvenation: longer, healthier life, free from the costly and debilitating chronic diseases associated with aging and a too-early demise. Better living in old age is a growing priority as a bulging population of baby boomers enters their golden years.

Thanks primarily to better control over infectious diseases through improved sanitation, vaccines and antibiotics, Americans live on average more than three decades longer than they did a century ago. But today tantalizing research findings from different scientific disciplines - including genetics, immunology, cell biology, diabetes research and microbiology - are raising hopes for another revolutionary increase in life expectancy.

"Perhaps rejuvenation therapies will appear in less than a decade, if we pool our resources and skills," said Regis Kelly, PhD, director of QB3 and organizer of the event on the UCSF Mission Bay campus. At UCSF, researchers have led important research to identify the treatment needs of elderly patients, including disabled patients and individuals with HIV infection; they have made breakthroughs in accurately diagnosing dementias, a major malady of old age; and they have identified what may be biological underpinnings for aging at the genetic and biochemical level.

Link: http://www.ucsf.edu/news/2013/10/109921/anti-aging-research-advances-featured-qb3-symposium

The research company Prana Biotechnology has been touting the results of a recent study in which one of their drug candidates demonstrated a meaningful impact on cognitive decline in old mice:

Prana's PBT2 Reverses Memory Loss in Normal Aging (PDF)

Typically mice live for 24 to 30 months, developing progressive cognitive impairment from 16 to 18 months. Age related cognitive decline is associated with measurable structural and biochemical changes in the brain, which were significantly improved by PBT2. In the study 22 month old mice were treated with PBT2 for a total of 12 days. PBT2 restored learning and memory. The old mice treated with PBT2 performed learning and memory tasks to the same level exhibited by young mice and significantly better than untreated old mice. PBT2 Increases markers of neurogenesis and neuron number [and] increases numbers of synapses in the hippocampus.

So what is going on here under the hood? Prana researchers focus on the biochemistry of interactions between metals and proteins, in particular the role of what are known as metal chaperones, and they theorize that disruption of the normal adult state of these interactions is a significant contribution to age-related neurodegeneration. An open access position paper from last year outlines this viewpoint with a particular focus on Alzheimer's disease (AD):

Metal Chaperones: A Holistic Approach to the Treatment of Alzheimer's Disease

Metal chaperones (or metallochaperones) are compounds that function to shuttle metal ions to specific intracellular target proteins. This facilitation of metal transport is distinct from metal chelators or buffers, which function to exclude or deplete metals from discrete cellular compartments to thereby limit biological interactions of key metal ions. Cumulatively, however, these processes serve to maintain tight regulatory control over cellular metal ion homeostasis such that the intracellular concentration of freely available metal ions (such as copper and zinc) is close to zero.

Such a high level of control at many cellular "levels" is essential in limiting potentially deleterious interactions of redox active transition metal ions, which are implicated in the pathogenesis of a number of disorders including AD. The involvement of metal ions in disease extends the breadth from being involved in creating an adverse cellular milieu (which among other things, may promote cell death through the activation of particular pathways that lead to degeneration) through to direct involvement in the generation and toxicity of the principle toxic moiety in diseases such as AD.

Metal chaperones (which have also variously been referred to as "ionophores" and "metal-protein attenuating compounds") may represent the "sweet spot" of metal-targeted therapeutics for AD because they foster the maintenance and/or restoration of metal ion homeostasis which then impacts a raft of "healthy" and "pathological" cellular pathways that ultimately promotes "normal" function. Such context-dependent modulation of metal levels may prove critical for long-term therapeutic strategies that target metal ions.

The recent press and mouse study is accompanied by an open access paper. By the sound of it the mechanism of action here remains to be pinned down, but the outcomes are good enough to move this forward in the development process. So this compound may in the end turn out to work via means that have little to do with metals. It may or may not be in any way reducing levels of the fundamental cellular and molecular damage that cause aging, either directly or indirectly, and it may or may not be minimizing harmful responses to that damage. We shall see - only further research can determine the answers.

A Novel Approach To Rapidly Prevent Age-Related Cognitive Decline

The loss of cognitive function is a pervasive and often debilitating feature of the ageing process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis.

There was a breadth of biological effects within the brain following PBT2 treatment in the aged mice. While it is not possible to discern which of these was the principal driver of the cognitive benefit observed, it is likely to have resulted from a PBT2-mediated improvement in the function of different cellular pathways that are critical to synaptic plasticity and cognitive function. In the longer term, these improvements are likely to synergise with the effects observed on neuronal health and connectivity to foster a long-term improvement in both brain and cognitive health. As deficits in many of these same pathways are implicated in a variety of disorders, this also establishes a landscape where PBT2 may be efficacious in the treatment of a broad spectrum of diseases.

That this activity has also translated to improved cognition in a short-term Phase IIa human clinical trial of AD provides strong support for the efficacy of this compound in restoring normal brain function. The use of metal chaperones, such as PBT2, as novel therapeutic compounds for the treatment of both "normal" and "pathological" cognitive decline is strongly endorsed by these findings and warrant further mechanistic investigation into the precise mechanism of action of this class of compound, as well as human clinical trials to validate these rodent data.

Looking for longevity-assurance mechanisms in long-lived animals is a growth concern these days, though it is still largely an aspect of the slow road in longevity science. It is possible that researchers will make discoveries that will help the development of means to repair specific forms of cellular and molecular damage that cause aging in humans, but the focus is usually on determining ways to alter the operation of human metabolism so as to gently slow down aging. Look at the community who investigate the biochemistry of calorie restriction so as to develop drugs to mimic its beneficial effects on health and longevity, for example.

Slowing aging safely by creating a new operating state for our cellular biology is a very challenging and expensive endeavor, and one which will yield little benefit for people who are already old. In comparison keeping the metabolism we have while working to periodically remove the damage that degrades its operation sounds like a much better plan, and one that will help the old by actually rejuvenating them.

Here is a popular science piece that looks at the work of one of the researchers involved in comparative studies of the genetics of aging in varied animal species:

Accumulating damage in cells is commonly thought to result in aging, but Gladyshev doesn't think even that assumption has been carefully tested. He pointed to the trash can in his fourth-floor office and noted that it could fill up with garbage, but that would not mean that his ability to do work would change.

So Gladyshev came up with a new way to probe aging. Instead of looking for clues by studying longer- and shorter-lived individuals of a particular species, why not look at the diversity of an entire class of organisms? Evolution, he notes, has been better at tweaking the life spans of organisms than any laboratory researchers have been: among mammals, there can be a gigantic variation in life span between different species. What, he wonders, are the genetic differences that mean an elephant can live for 70 years, a squirrel can reach its 20th birthday, but a shrew may expire after just one?

Gladyshev will collect samples from 50 mammals whose natural lives vary, from the longest- to the shortest-lived. Recently, for example, he enlisted a team of Russian scientists to gather samples from the Brandt's bat, a five-gram mammal that has been documented to live 41 years. Gladyshev and the Russian researchers described the bat's genome, and compared it with other mammals. They identified genetic alterations in genes that may be involved in lifespan, and Gladyshev hopes to examine those genes in greater detail to see whether they play a role in the tiny creature's remarkable longevity.

By eventually comparing gene activity in many mammals, he hopes to identify genes and control mechanisms that might control aging - and provide potent targets for researchers hoping to develop therapies that could extend life or combat diseases of aging.

Link: http://www.boston.com/news/science/blogs/science-in-mind/2013/10/31/long-lived-mammals-may-hold-clues-about-how-reverse-aging/AJnmPc9lrsDtlysnAHtIjJ/blog.html

Photoacoustic therapy involves the use of carefully modulated laser light to rapidly dump energy into very specific locations in a tissue, where flash heating will destroy the intended target. Work to date involves, for example, delivering carbon nanotubes to cancer cells and then using laser light to explode the nanotubes. Researchers are now considering the potential for forms of photoacoustic therapy to destroy aggregrates of misfolded proteins associated with neurodegenerative disease:

[Researchers] have made a discovery that may lead to the curing of diseases such as Alzheimer's [and] Parkinson's through photo therapy. [It] is possible to distinguish aggregations of the proteins, believed to cause the diseases, from the the well-functioning proteins in the body by using multi-photon laser technique.

If the protein aggregates are removed, the disease is in principle cured. The problem until now has been to detect and remove the aggregates. The researchers now harbor high hopes that photo acoustic therapy, which is already used for tomography, may be used to remove the malfunctioning proteins. Today amyloid protein aggregates are treated with chemicals, both for detection as well as removal. These chemicals are highly toxic and harmful for those treated. With multi photon laser the chemical treatment would be unnecessary. Nor would surgery be necessary for removing of aggregates. Due to this discovery it might, thus, be possible to remove the harmful protein without touching the surrounding tissue.

These diseases arise when amyloid beta protein are aggregated in large doses so they start to inhibit proper cellular processes. Different proteins create different kinds of amyloids, but they generally have the same structure. This makes them different from the well-functioning proteins in the body, which can now be shown by multi photon laser technique.

This may be overly optimistic on a few counts: firstly that the amyloid is definitely the disease agent in all cases, versus a secondary effect - though the research community should still work to remove it, as it is an enumerated difference between healthy and diseased tissue. Secondly it may not be as straightforward as hoped to deliver heat via laser only to amyloid without causing secondary damage to delicate nearby structures in neurons and synapses. You might recall that a community-funded attempt to break down liposfuscin through modulated laser light didn't go so well on that count. It proved more challenging than expected to keep the heat and damage constrained to just the lipofuscin. Still, this should just be another technical hurdle to overcome.

Link: http://www.eurekalert.org/pub_releases/2013-11/cuot-lmb110113.php

Biology is enormously complex, and it should never really be a surprise to find that different parts of the body have evolved different methodologies for achieving the same goal - such as tissue maintenance, to pick one example. So while it seems to be the case that small populations of stem cells support most or all of our tissues, offering the opportunity for researchers to build therapies based on enhancing the activities or increasing the numbers of these stem cells, there may be some exceptions to this rule. There may also be separate and distinct methods of tissue maintenance that operate in parallel to one another, and until they have been discovered and cataloged who can say whether one might be easier to manipulate than the others? At this point all could be candidates for regenerative therapies.

In this context, here is an interesting report on recent research into kidney regeneration, which strongly suggests that stem cells are not the agent at work here:

A new model for organ repair

Harvard Stem Cell Institute (HSCI) researchers have a new model for how the kidney repairs itself, a model that adds to a growing body of evidence that mature cells are far more plastic than had previously been imagined. After injury, mature kidney cells dedifferentiate into more primordial versions of themselves, and then differentiate into the cell types needing replacement in the damaged tissue. This finding conflicts with a previously held theory that the kidney has scattered stem cell populations that respond to injury.

Benjamin Humphreys [was] suspicious of the kidney stem cell repair model because his previous work suggested that all kidney cells have the capacity to divide after injury. He and his colleagues decided to test conventional wisdom by genetically tagging mature kidney cells in mice that do not express stem cell markers; the hypothesis being that the mature cells should do nothing or die after injury. The results showed that not only do these fully differentiated cells multiply, but they can multiply several times as they help to repair the kidney. This new interpretation of kidney repair suggests a model by which cells reprogram themselves; similar to the way mature cells can be chemically manipulated to revert to an induced pluripotent state.

"One has to remember that not every organ necessarily is endowed with clear and well-defined stem cell populations, like the intestines or the skin. I'm not saying that kidney stem cells don't exist, but in tissues where cell division is very slow during homeostasis, there may not have been an evolutionary pressure for stem cell mechanisms of repair." He plans to apply his kidney repair discovery to define new therapeutic targets in acute kidney injury. The goal would be to find drugs that accelerate the process of dedifferentiation and proliferation of mature kidney cells in response to injury, as well as slow down pathways that impair healing or lead to scar tissue formation.

Below is a link to the paper, which is unfortunately not open access:

Differentiated kidney epithelial cells repair injured proximal tubule

When epithelial cells in the proximal portion of the nephron are damaged they rapidly proliferate to repair the damage to the kidney. Whether a stem cell is responsible for this proliferative response or not is controversial. Although a scattered population of cells can be found in the human proximal tubule that seem to have stem-cell characteristics, they could also represent isolated damaged cells that have dedifferentiated and lost their epithelial characteristics. We resolve these conflicting models using genetic lineage analysis to demonstrate that fully differentiated proximal tubule cells not only proliferate after injury, but they also upregulate apparent stem-cell markers. This study shows that epithelial dedifferentiation is responsible for repair of mouse proximal tubule, rather than an adult stem-cell population.

One of the challenges inherent in identifying meaningful associations in aging is that degeneration is a global phenomenon: every tissue accumulates damage and becomes increasingly dysfunctional. It may be that for any two features of aging you care to compare, the only underlying link is that damage occurs. People with more damage have more dysfunction in both areas, people with less damage have less dysfunction in both areas. It isn't necessarily the case that these two features have any direct interaction with one another at all. It's worth bearing this in mind when reading the results of correlation studies in aging, as there has to be a much better argument than just the fact of correlation to establish a link of causation:

Even for elderly people with no signs of dementia, those with hardening of the arteries are more likely to also have the beta-amyloid plaques in the brain that are a hallmark of Alzheimer's disease. "This is more evidence that cardiovascular health leads to a healthy brain."

The study involved 91 people with an average age of 87 who did not have dementia. Researchers took scans of the participants' brains to measure any plaques in the brain. The amount of stiffness in the participants' arteries was measured about two years later. Half of all participants had beta-amyloid plaques. People with beta-amyloid plaques were more likely to have high systolic blood pressure, higher average blood pressure and higher arterial stiffness as measured with the brachial-ankle method. For every unit increase inbrachial-ankle arterial stiffness, people were twice as likely to have beta-amyloid plaques in the brain.

Arterial stiffness was highest in people who had both amyloid plaques and white matter hyperintensities in the brain, or brain lesions. "These two conditions may be a 'double-hit' that contributes to the development of dementia. Compared to people who had low amounts of amyloid plaques and brain lesions, each unit of increase in arterial stiffness was associated with a two- to four-fold increase in the odds of having both amyloid plaques and a high amount of brain lesions. This study adds to growing evidence that hardening of the arteries is associated with cerebrovascular disease that does not show symptoms. Now we can add Alzheimer's type lesions to the list."

Link: http://www.eurekalert.org/pub_releases/2013-10/aaon-ieh100813.php

Removing growth hormone or blocking its activities tends to makes mice live longer. The record for longest-lived genetically engineered mice is held by those in which growth hormone receptor is eliminated, for example. Here is an example of another methodology:

There is increasing evidence that the hormonal systems involved in growth, the metabolism of glucose, and the processes that balance energy intake and expenditure might also be involved in the aging process. In rodents, mutations in genes involved in these hormone-signaling pathways can substantially increase lifespan, as can a diet that is low in calories but which avoids malnutrition. As well as living longer, such mice also show reductions in age-related conditions such as diabetes, memory loss and cancer.

Many of these effects appear to involve the actions of growth hormone. Mice with mutations that disrupt the development of the pituitary gland, which produces growth hormone, show increased longevity, as do mice that lack the receptor for growth hormone. However, these animals also show changes in a number of other hormones, making it difficult to be sure that the reduction in growth hormone signaling is responsible for their increased lifespan.

[Researchers] have now studied mutant mice that lack a gene called GHRH, which promotes the release of growth hormone. These mice, which have normal levels of all other pituitary hormones, lived for up to 50% longer than their wild-type littermates. They were more active than normal mice and had more body fat, and showed greatly increased sensitivity to insulin.

Some of the changes in these mutant mice resembled those seen in animals with a restricted calorie intake, suggesting that the same mechanisms may be implicated in both. [However], caloric restriction further increased the lifespans [of] GHRH knockout mice, indicating that at least some of the effects of caloric restriction are independent of disrupted growth hormone signaling.

Link: http://dx.doi.org/10.7554/eLife.01098