Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.
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- Success in Rejuvenation Research to Date is Partial: Many Projects Still Need Our Philanthropic Support to Flourish
- Crowdfunding Initial Development of MouseAGE, a Visual Biomarker of Aging for Mice
- Restoring Osteocalcin Reverses Memory Loss in Old Mice
- Correlating Cytomegalovirus, T Cell Senescence, and Arterial Stiffness in Aging
- The Society for the Rescue of our Elders is Running Trials of Potential Rejuvenation Therapies: We Should Support This
- A Popular Science Article on Calorie Restriction Mimetic Development
- More Evidence to Reinforce "Use It or Lose It," Even in Later Life
- PCSK9 Inhibition May Reduce Cardiovascular Disease Risk via Immune Mechanisms as well as via Lowered Cholesterol
- There will be Many Marginal Senolytic Drug Candidates
- The Society for the Rescue of our Elders
- Envisaging Alzheimer's Disease as a Cascade from Amyloid to Inflammation to Tau
- Protein Synthesis Differences in Progeria Suggest Changes in the Nucleolus as a Potential Biomarker of Aging
- Induced Pluripotent Stem Cell Therapy in a Primate Model of Parkinson's Disease
- There are Many, Many Genes Associated with Longevity
- Toward Stem Cell Therapies for Osteoporosis
Success in Rejuvenation Research to Date is Partial: Many Projects Still Need Our Philanthropic Support to Flourish
The past few years have seen very encouraging progress in rejuvenation research and the commercial development of therapies. Senolytic treatments capable of clearing senescent cells, one of the root causes of aging, are moving towards human trials, with a number of companies hard at work on therapies at various stages of development. The animal data continues to roll in, and continues to look very promising, with senescent cells shown to contribute directly to an increasing number of age-related conditions. In addition the established mainstream efforts to remove age-related protein aggregates such as amyloid-β, tau, and α-synuclein are broadening the number of targets and strategies, and in addition are coming closer to success after many years of failed trials. Amyloid-β has finally been cleared from human brains in a clinical trial, and many of the newer approaches to reducing levels of various forms of aggregate seem quite promising in animal and human studies. These aggregates are another of the causes of aging and age-related disease, there is a real sense that the present time is a tipping point in this area of medical development.
As you've no doubt noticed, this zeitgeist has been reflected here at Fight Aging! in an increased consideration of startup companies and the early steps in translation of the most important lines of research from laboratory to clinic. Similarly, groups like the SENS Research Foundation and Methuselah Foundation have also focused a sizable fraction of their attention on this part of the development process. See, for example, the Rejuvenation Biotechnology conference series of the past few years that brought together academia and industry, and the Methuselah Fund launched this year.
Yet it is important to remember that all of this welcome progress, the move from non-profit research to for-profit development, with human trials on the near horizon, is only taking place for a fraction of the areas of science and technology required for comprehensive human rejuvenation. Yes, senescent cell clearance is well under way now, and both protein aggregate clearance and cell therapies seem well funded and pointed in roughly the right direction. But what about therapies to address glucosepane cross-links, a cause of blood vessel stiffening and bone fragility; or the mitochondrial DNA damage and consequent mitochondrial malfunctions that are implicated in such a wide range of age-related disease; or the scores of other forms of metabolic waste found in lipofuscin and amyloids? What about the decline and disarray of the immune system; what about steering the cancer research community towards universal therapies based on prevention of telomere lengthening, applicable to all cancers?
Aging has multiple root causes. Fixing one root cause - say if senescent cell clearance progresses stupendously well, and we're all having 75% of our senescent cells removed at a $15,000 price tag for a form of FOXO4-p53 interdiction via medical tourism sometime around 2021 - has a limited upside because it is only one root cause. Each of the categories of damage outlined in the SENS view of aging is ultimately fatal in and of itself, though it is far from clear which are more or less important to any specific aspect of aging. Remove just one and some forms of mortality will decrease considerably. Others might be postponed. Yet more might be only slightly affected, however, and they will still kill you. The upside of partial rejuvenation is nonetheless a much better prospect than anything that can be done with yesterday's medical technology, but it is only the opening chapter, not the whole story.
Yes, we should do what we can to help commercial development: invest if we are able, cheerlead and publicize if we can. But we can't become distracted from the important lines of research still underway in their earlier phases, prior to the point at which they can make the leap to startup companies, and in need of philanthropic support to move ahead. Despite the considerable evidence supporting the SENS view of aging as damage and rejuvenation as damage repair, the research community and institutional funding sources continue to give little attention to lines of work that are capable of becoming just as large and just as important as senolytic treatments to remove senescent cells. Prior to 2011, senescent cell clearance was another of those ignored lines of work: that success can and must be repeated for the others.
Of the less well supported lines of work that could turn back aging, those closest to realization appear to be: immune system restoration via some form of targeted cell killing; immune system restoration via regeneration of the thymus; pharmaceutical clearance of glucosepane cross-links; and allotopic expression of mitochondrial genes. These are all still at the stage wherein the charitable donations that we as a community can raise for specific projects, or provide to the SENS Research Foundation, make a real difference. These projects all appear to me to be a few years from reaching viability for commercial development, on average, and they all scrabble for needed funding to one degree or another. All of these should produce similar overall degrees of benefit to those produced by senolytic therapies, albeit in very different ways. This is where we can accelerate progress towards the near future of greater human longevity, just as we have in the past.
Growing success in portions of the broader field of rejuvenation research should encourage us: it shows that the support we have provided over the last decade or more has worked. Things are moving, the wheel turns. We can do the same for the parts of the field that have yet to attract the attention they need, have yet to reach the same level of enthusiasm and funding. Give it some thought.
Crowdfunding Initial Development of MouseAGE, a Visual Biomarker of Aging for Mice
The latest crowdfunding project now running at Lifespan.io is an interesting initiative to apply machine learning methods to generate a cost-effective biomarker of aging in mice based on image analysis rather than physical samples. The biomarker will then be released for free and open use by research groups. There is a need for ways to easily assess the biological rather than chronological age of subjects in laboratory studies, where biological age reflects the current level of damage, dysfunction, and mortality risk. Aging is a process based on the accumulation of molecular damage and its consequences, but until fairly recently there were no useful tests to reliably assess the current state of aging - to obtain a better, more comprehensive, and repeatable measure than just looking at skin condition, or grip strength, or any of the other simple assessments used in the past. Such simple assessments show good correlations with mortality when assessed over a sizable study population, but have too much variability to be useful for the assessment of one individual.
Why does this matter? It matters because we are now entering the era of rejuvenation therapies, and there are a range of candidate treatments under development. Sooner is better when it comes to assessing the quality of various potential therapies, so as to discard less productive paths in favor of more productive paths. Unfortunately the only truly reliable test at the moment is to wait and see what happens following treatment, for as long as it takes to measure the resulting gains in life span. This requires years in mouse studies, and is clearly impractical in human trials. What if there was a simple, reliable test that researchers generally agree accurately reflects physical age, however? Then scientists could apply the test shortly before and shortly after a treatment, quickly obtain a result, and research and development would proceed much more rapidly.
A range of candidate biomarkers of aging are at various stages of development. Out in front are the DNA methlyation metrics, assessing characteristic changes in epigenetic markers that occur with age. A number of groups are taking a more algorithmic approach instead, attempting to find combinations of simple measures such as grip strength that when processed together can produce a more accurate result. There has also been some experimentation in visual identification of age in humans, proceeding alongside the increased interest in facial recognition technologies that characterizes this unpleasantly surveillance-fixated era of ours. It is plausible that this line of work might achieve the accuracy of other items in the present crop of biomarkers, say a margin of error of 5-10 years of biological age, given sufficient interest and investment. If you go digging through the literature, there is supporting evidence to suggest that facial appearance is, on balance, a decent reflection of age.
So if you can do this for humans, why not for mice? The potential payoff here, if it can be made to work, is the ability to skip over all of the equipment and work needed for physical biomarkers in favor of a hands-off camera and computer system. This might be the case for most of the biomarker assessment needed in exploratory studies in mice as they are currently carried out. Thus this is a potential road to greater automation and lower cost in studies of candidate rejuvenation therapies, though how that cost profile works out in practice is of course very dependent on the details. It is certainly the case the proving out the system, finding whether or not it can be made practical, is a comparatively cheap endeavor. The developers have experience with human facial assessment, computational power is cheap, and visual machine learning is a maturing field of software development. This seems worth a try to me.
AI-powered application MouseAGE will use photos of lab animals to identify new therapeutics to treat aging and age-related diseases
Lifespan.io is launching a crowdfunding campaign to support MouseAGE, an application to assess visual biomarkers of aging in laboratory animals. This Artificial Intelligence-powered research tool, which is being developed by Youth Laboratories, will help scientists accurately determine the biological age of mice during experiments using advanced visual recognition and machine learning techniques. The project will help speed up research on rejuvenation therapeutics while collecting useful data in a more humane way.
When we are looking at other people, we can easily determine their ages and even get a rough idea of their health by looking at their skin tone, pigmentation and elasticity, their hair color, and their other characteristics. However, the human eye cannot accurately determine subtle changes in the appearance of such tiny animals as mice, and this is where MouseAGE can help. To rapidly collect data, commercial mouse breeders, research labs, and application beta testers all over the world will take and upload many mouse photos to the database. By using machine learning combined with visual recognition, MouseAGE will learn to recognize mice from images, to define their body parts, and finally to detect the subtle visual biomarkers of aging.
If successfully funded, the MouseAGE image collection tool will be available as a free mobile application by mid-October 2017. This will allow breeding houses and research institutions to begin collecting images and send them to the database. The project team hopes to collect enough data by February 2018 and will implement the algorithm for mouse age prediction by April 2018. This biomarker system will be made available as a free application shortly afterwards.
MouseAge: Photographic Aging Clock in Mice
Here at MouseAGE we are aiming to create an artificial intelligence-powered research tool to help scientists accurately determine the biological age of mice and test longevity interventions based on photographic images of mice. This will introduce the first visual biomarker for aging in mice, and will help validate potential anti-aging interventions, save animal lives, and greatly speed up the pace of longevity research. By using machine learning combined with visual recognition, MouseAGE will learn to recognize mice from images, to define their body parts, and finally to detect the subtle visual biomarkers of aging.
We have chosen to start with the C57BL/6 (the black 6) mouse strain. This is the most common lab mouse globally, so it makes sense to begin here. Collected images at this stage will total approximately 10,000, including a wide age range of the black 6 mouse - this estimate based on our earlier experience with human faces. Once we have enough photographic material, artificial intelligence training will begin.
Our primary goal is to develop the MouseAGE system so that researchers can benefit from it. This will be an application that can be installed on a personal smartphone to make, annotate, and upload images to our cloud-based system for analysis, as well as be able to perform age assessment on newly taken images. The cost includes this data collection tool for researchers, mouse recognition software and the creation of an accurate, deep-learned, mouse age assessment algorithm. This will utilize feature extraction techniques to identify visual biomarkers of mouse aging, which we want to have thoroughly tested and made available for widespread use in common lab practice.
Restoring Osteocalcin Reverses Memory Loss in Old Mice
Last year researchers showed that raising levels of osteocalcin in old mice reverses some of the age-related decline in exercise capacity. In the paper noted here, the same research group shows that increased osteocalcin also reverses some of the loss in memory function that takes place in later life, at least in mice. Taken together these are quite interesting demonstrations, and we might speculate on whether this could be a cause of improvements in the health of old mice obtained via heterochronic parabiosis, wherein the circulatory systems of an old and a young mouse are linked together. Osteocalcin levels decline with age, and in the osteocalcin studies, the increase in old mice provided by the simple approach of injection. So it doesn't seem implausible that parabiosis might increase the level of osteocalcin in the old mouse.
Currently there is some debate over how benefits emerge from the process of parabiosis. A recent study provided very good evidence to suggest that benefits occur due to a dilution of harmful factors in old blood rather than by provision of helpful factors from young blood. The studies of GDF11 levels that kicked off current interest in parabiosis are still being debated back and forth: it remains unclear as to whether the identification of GDF11 as a protein of interest is correct. So on the whole matters are still in flux in this area of study. That the researchers here produce benefits with plasma transfusion from young to old mice, something that has also had mixed evidence to date, is particularly interesting.
Back to osteocalcin; if researchers can find ways to produce some degree of benefit with supplementation of a few strategic circulating proteins, then all to the good. This nonetheless strikes me as adjusting downstream consequences of the root causes of aging - tinkering with the broken machinery to try to force it to behave rather than fixing the actual problem. Why do circulating protein levels change? They change because cells react to the accumulation of molecular damage in cells and tissues. That damage is the actual problem, and we should expect to find that repair or removal of the damage will revert changes in protein levels such as decline in osteocalcin. Given the advent of senolytic therapies to clear senescent cells - one form of repair treatment for a cause of aging - we should see that phenomenon begin to be cataloged in studies conducted over the next few years. Perhaps not for osteocalcin, depending on which form of damage causes this reaction, but certainly for some other changes.
Bone-Derived Hormone Reverses Age-Related Memory Loss in Mice
"In previous studies, we found that osteocalcin plays multiple roles in the body, including a role in memory. We also observed that the hormone declines precipitously in humans during early adulthood. That raised an important question: Could memory loss be reversed by restoring this hormone back to youthful levels? The answer, at least in mice, is yes, suggesting that we've opened a new avenue of research into the regulation of behavior by peripheral hormones."
Researchers conducted several experiments to evaluate osteocalcin's role in age-related memory loss. In one experiment, aged mice were given continuous infusions of osteocalcin over a two-month period. The infusions greatly improved the animals' performance on two different memory tests, reaching levels seen only in young mice. The same improvements were seen when blood plasma from young mice, which is rich in osteocalcin, was injected into aged mice. In contrast, there was no memory improvement when plasma from young mice engineered to be osteocalcin-deficient was given to aged mice. But adding osteocalcin to this plasma before injecting it into the aged mice resulted in memory improvement. The researchers also used anti-osteocalcin antibodies to deplete the hormone from the plasma of young mice, reducing their performance on memory tests.
The researchers then determined that osteocalcin binds to a receptor called Gpr158 that is abundant in neurons of the CA3 region of the hippocampus, the brain's memory center. This was confirmed by inactivating hippocampal Gpr158 in mice and subsequently giving them infusions of osteocalcin, which failed to improve their performance on memory tests. The researchers did not observe any toxic effects from giving the mice osteocalcin. "It's a natural part of our body, so it should be safe. But of course, we need to do more research to translate our findings into clinical use for humans."
Gpr158 mediates osteocalcin's regulation of cognition
That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-month-old mice.
A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158, an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.
Correlating Cytomegalovirus, T Cell Senescence, and Arterial Stiffness in Aging
Today I'll point out a paper that links three fairly long-standing topics in aging research: the role of cytomegalovirus infection in immune system aging, cellular senescence in the immune system, and progressive stiffening of blood vessels. The authors point out correlations rather than uncovering specific mechanisms to link these items, but it fits nicely with a range of other research on senescent T cells, ways in which senescent cells could contribute to loss of vascular elasticity, the decline of the aging immune system, and the intricate relationship between tissue maintenance and immune system activity. Disarray in regeneration is linked closely with disarray in the immune system, particularly the chronic inflammation that occurs with age. To complete the circle, in any scenario involving inflammation in aging, we nowadays have to pull in the topic of senescent cells for consideration. These cells are efficient generators of inflammatory signaling, and this appears to be a primary mechanism by which they cause harm.
Blood vessel stiffness is one of the most consequential aspects of aging. Cardiovascular disease vies with cancer for the most prevalent cause of death in our species. Stiffness in blood vessels produces hypertension, which in turn contributes to the remodeling of heart tissue that leads to heart failure. Hypertension and stiffness also increase the pace at which small vessels rupture in the brain, and other delicate organs such as the kidney, raising the pace of damage in those tissues. Finding ways to maintain blood vessel elasticity would go a long way to reduce the incidence of numerous classes of age-related disease.
Where does cytomegalovirus fit into this? This is a herpesvirus that is present in near everyone by the time old age rolls around. It is largely harmless to most people, at least in the short term, but over the long term the immune system just keeps on throwing resources at cytomegalovirus in a futile attempt to get rid of it. In an aged immune system a vast number of cells are uselessly specialized to cytomegalovirus, rather than being available for other tasks. The rate of replacement of immune cells is low in adults, and even lower in the elderly, and thus the immune system cannot recover from a state in which most active immune cells are not performing as they should. At least not without some form of outside intervention yet to be brought to the clinic, such as regeneration of the thymus, or regular infusions of patient matched immune cells grown from skin samples.
A correlation between the degree to which the immune system is engaged in its eternal losing battle with cytomegalovirus and the number of senescent T cells suggests a causal relationship, though given the present state of the field I think that a decent argument could be made for the arrow of causation to point in either direction. Are those elders most afflicted by cytomegalovirus afflicted because the immune system was already in a state of accelerated decline for other reasons, or is cytomegalovirus the cause of that decline? From historical data and comparisons between regions of today's diverse world we know that a greater burden of infectious disease has a negative impact on life expectancy. So it is tempting to look first for cytomegalovirus to be the cause, but biology is rarely as consistent as we'd like it to be.
Arterial Stiffness Is Associated With Cytomegalovirus-Specific Senescent CD8+ T Cells
Growing evidence from recent animal and human studies suggests that T cells contribute to the development of hypertension. Previously, we demonstrated that hypertensive patients have an increased frequency of replicative senescent CD8+ T cells in peripheral blood; these cells are characterized by the loss of CD28 and the acquisition of CD57 on their surface. CD28 loss in T cells is one of the most prominent changes associated with aging in humans and is caused by the repetitive antigenic stimulation of T cells. CD57 expression is known to occur during the late stage of T-cell differentiation and might be a distinct measure of replicative senescence in T cells. Compared with CD28+ or CD57- T cells, CD28null or CD57+ T cells produce more proinflammatory cytokines and exert greater cytotoxicity. These senescent T cells are known to be associated with various inflammatory diseases in humans including cardiovascular disease.
It has been also known that cytomegalovirus infection is involved in the accumulation of CD28null or CD57+ senescent T cells. In humans, cytomegalovirus is known to be one of the most important antigens for repetitive T-cell stimulation, and latent infection with cytomegalovirus has been shown to strongly exert age-associated changes on peripheral T cell homeostasis. The cytomegalovirus-seropositive population has a higher frequency of CD28null or CD57+, replicative senescent T cells than the cytomegalovirus-seronegative population. Moreover, cytomegalovirus infection is associated with a variety of chronic inflammatory processes in cardiovascular disease such as hypertension. However, it has not been elucidated how cytomegalovirus infection and senescent T cells contribute to the pathogenesis of cardiovascular disease.
Increased arterial stiffness is one of the major mechanisms underlying the pathogenesis of hypertension. Arterial stiffness is increased in the presence of conventional cardiovascular risk factors including aging. The degree of arterial stiffness is known to be associated with various markers of inflammation, suggesting that immune responses likely play a role in increasing arterial stiffness. Therefore, we investigated whether T-cell senescence is associated with arterial stiffness in the general population, as assessed using pulse wave velocity (PWV) measurements. Next, considering the antigen reactivity of senescent T cells, we examined cytomegalovirus-specific T-cell response and analyzed the relationship between these results and the degree of arterial stiffness.
The study population consisted of 415 Koreans who were recruited from subjects initially registered in the Yonsei Cardiovascular Genome cohort. Our findings demonstrate that the frequency of senescent CD8+CD57+ T cells in peripheral blood is independently correlated with arterial stiffness. Cytomegalovirus-specific T-cell responses were analyzed because cytomegalovirus is a major driving antigen for replicative senescence in T cells. We found that cytomegalovirus-specific CD8+ T cells were more frequently observed in the CD57+ population, and cytomegalovirus-specific cytokine secretion and the cytotoxic degranulation of CD8+ T cells were independently associated with PWV. These data suggest that immune aging, especially T-cell senescence that is linked to cytomegalovirus infection, might play a role in the progression of vascular aging.
The Society for the Rescue of our Elders is Running Trials of Potential Rejuvenation Therapies: We Should Support This
Nearly a decade ago ago I hopefully envisaged the Vegas Group as a fictional, near-future, informal association of like-minded people coming together to organize and fund trials of early rejuvenation therapies, a natural outgrowth of longevity-focused conferences and progress in the underlying science. I put the founding date for the Vegas Group as 2016. That might be close, as it turns out. On balance, I think that the Society for the Rescue of our Elders, established this year in the wake of the Revolution Against Aging and Death (RAAD) Festival, has a shot at becoming this association in reality. A number of quite sensible people in our community are apparently involved, and the Society for the Rescue of our Elders is in a position to harness the raw enthusiasm of two generations of longevity advocates and potential trial participants: those who started in the 1970s, tried and failed to make anti-aging medicine work, but who still have the enthusiasm for the cause, and those of today who are focused on senolytics, gene therapies, and other modern techniques that may well produce actual, functional, first generation rejuvenation therapies. The evidence to date looks good.
Individuals associated with the Society for the Rescue of our Elders are coordinating and organizing a small variety of human trials at this point, covering a number of approaches to treating aging as a medical condition. I think some of these are worth the effort and we should be cautiously enthused: primarily senolytics to remove the contribution of senescent cells to the aging process, but also other items with varying degrees of support. The important point here is that this is happening at all, that our broader community has generated an association that can potentially act as a seed, a nucleus, a rallying point for all additional efforts. Many hands can make light work, and once there exists an informal network with experience in running the trials that we want to see take place, then future trials and larger trials and clinical availability all become that much easier to organize. Once the relationships with laboratories and university groups and all the other important groups are there - well, that is the hurdle that would stop most people from proceeding, not the funds. What use money when you are corroding?
I have in the past suggested that at some point the "anti-aging" marketplace, whose participants have built an industry and pipeline and customer base on the basis of selling things that don't work, will gravitate to the first potential approaches that do in fact work. A significant fraction of those involved are still believers in the original goal - to meaningfully turn back aging. The Society for the Rescue of our Elders, like the RAAD Festival, emerges from the Life Extension Foundation crowd. They have always had the burden of being supplement and "anti-aging" focused, but their initiatives have been incrementally stepping towards engagement with the most promising new medical technology, and I suppose that the current explosion of interest in senolytics has finally tipped things over the edge. Rejuvenation therapies are almost here, cheap candidate drugs exist, and it would be foolish to think that the "anti-aging" community would ignore this development. In the present environment, an alliance between those who can bring funding and a broad base of interested participants and those who know the presently most promising science and medical initiatives could go a long way. That is exactly what may be happening here.
I can say that had I the funds to pay for organizing a trial of one of the more promising senolytic drug candidates, I'd certainly be interested in coordinating with the people who are already running a small senolytic trial with the Society for the Rescue of our Elders. There are, I think, any number of individuals ten or twenty years my senior with the resources to do just that, were they aware of the opportunity. One of them already has. In my hypothetical had-I-the-funds trial, I'd collar a dozen volunteers in their late 40s, a selection of the assays I suggested would be good for a single-person experiment, and look for significant effects in the demographic who are just starting to see the first declines of aging. It would be an interesting counterpoint to the current - and quite sensible - strategy of restricting trials to people in their late 60s and older, possessed obvious manifestations of aging. Larger and more pressing problems make it easier to quantify the results of treatments like clearance of senescent cells. But aging doesn't start at 60, and the ideal time to begin rejuvenation therapies is earlier in life. Therefore we want to be able to prove that the first senolytic drugs are or are not capable of producing meaningful outcomes at those earlier ages.
The Society for the Rescue of our Elders is still at the stage of understanding how to best manage the self-assembly of a community, and how to channel help. But they have a contact form, they have an email address. If you can help to make things happen, given a network of connections to laboratories, clinics, and research groups, let them know. Tell them what you can bring to the table and ask for their contacts, then see what can be made to happen. It is a much better path that sitting around waiting for someone else to do the work of bringing therapies to the clinic.
A Popular Science Article on Calorie Restriction Mimetic Development
This popular science piece covers some of the major themes of recent years in the development of calorie restriction mimetic drugs, pharmaceuticals intended to recreate at least a little of the beneficial metabolic response to lowered calorie intake. The article is a cut above the average in terms of quality, but I remain bothered that this line of work receives so much attention in comparison to far better approaches to the treatment of aging, such as the SENS portfolio of therapies based on repair of the molecular damage that causes aging.
Calorie restriction mimetics cannot produce rejuvenation, and cannot do more than slightly slow aging. They are enormously challenging and expensive to develop, as illustrated by the past fifteen years of investment and failure: there is still no viable, reliable, useful choice if you want to take a calorie restriction mimetic drug, and there is still no full accounting of the cellular biochemistry of the calorie restriction response. The drug candidates on the table such as metformin, mTOR inhibitors, and autophagy enhancers are all some combination of only marginally effective, possessed of unreliable data from animal studies, or producing undesirable side-effects. None come close to the reliability and benefits of calorie restriction itself, but even that buys little in humans, considered in context of the bigger picture of what is possible via the SENS approach of damage repair. People taking a hypothetical perfect calorie restriction mimetic would still age and die on much the same schedule as their untreated peers, gaining only modest benefits. We can do better than this.
Soon to be 50, the respected head of an Australian medical institute is contemplating the latest offering from the anti-ageing industry. It's a product that tops up the levels of nicotinamide adenine dinucleotide (NAD+), a commonplace chemical made by our bodies that is crucial for our metabolism. He's not alone. Leonard Guarente has been taking NAD+ boosters for years; and in 2015 started a company, Elysium, to market them. There are likely thousands of users by now. Something has changed in the anti-ageing field. Eccentrics and gullible-types have always availed themselves of anti-ageing remedies. Dubious supplements feed a mushrooming $30 billion industry. But when evidence-clamouring scientists start popping a pill, you sit up and take notice. Like the soon-to-be-50 Australian professor, most aren't aiming to extend their lifespan; they are aiming to extend their "health span" - the period of time before the diseases of ageing catch up with them.
The rough rule of thumb in nematode worms is: restrict calorie intake by 30% and see up to a 30% increase in lifespan. The effects are smaller in mice and even smaller in primates. Not many people have the willpower to adhere to a lifelong diet, though occasional "fasting mimicking diets" seem to have beneficial effects. Nevertheless the holy grail has been to find a drug that could mimic fasting. Calorie restriction flips a metabolic switch from "abundance" to "austerity". Like when you get a big salary cut, you don't go adding extensions to the house; you hunker down, live modestly, recycle your old things and delay your plans to have babies. Somehow responding to this stress also lengthens lifespan. These days researchers think autophagy plays a big part in the lengthening. For instance, recent studies on mice and humans shows that fasting accelerates the refurbishing of tissues, clearing away damaged "senescent cells" while turning on renewing stem cells.
You might think with all the epiphanies of the past 30 years, surely we know enough about ageing to go full speed ahead with interventions? All the candidate compounds, so far, seem to hack into the same pathway triggered by calorie restriction. Well, yes - but this rabbit hole goes very deep. Over the years, one compelling theory has been that it controls the integrity of mitochondria, the engines of our cells which clearly degenerate as we age. According to the theory, the corrosive by-products of cellular combustion - free radicals - cause ongoing damage as an inevitable consequence of being alive. But numerous recent experiments show that slowing the generation of free radicals in mice or flies doesn't actually slow the ageing process. In fact, it seems to have the opposite effect. Nowadays the paradigm shift is that stress signals like those from free radicals, fasting, or exercise trigger an adaptive anti-ageing response. It doesn't mean past theories are entirely wrong. It's just that there is a lot of other stuff going on in ageing as well.
None of this means the era of anti-ageing medicine has to wait for us to explore every blind alley of the rabbit hole. Indeed, most of the researchers I spoke with passionately believe they are more than ready to start testing the plethora of promising new compounds in their pipelines. What's needed is the faucet at the end - the regulatory framework that will incorporate "ageing" as a medical indication.
More Evidence to Reinforce "Use It or Lose It," Even in Later Life
Most older people exercise the body and mind far less than they should; as a consequence some degree of the frailty observed in old age in wealthier parts of the world is preventable, a case of neglect rather than unavoidable outcome. You can't choose not to age, yet, but you can choose to exert yourself in order to make matters better than they would otherwise be. There are plenty of studies to show that, even in very late life, greater levels of mental and physical activity produce benefits. In this paper, the researchers dig deeper to see if certain forms of activity can be tied to specific benefits in cognitive function and physiology, but given the current poor state of health maintenance in the general population, I think it more important as yet another set of evidence to show that "use it or lose it" is very real.
The human hippocampus (HC) is affected not only by pathological aging such as in Alzheimer's disease but also by the normal aging process resulting in deficits in memory, learning, and spatial navigation at old age. Magnetic resonance-studies indicate an atrophy rate of the hippocampus and the nearby parahippocampal gyrus of 2-3% per decade, which is further accelerated in the very old age where there is an annual loss of 1% over the age of 70. On the other hand more recent research has shown that the HC counts among the few brain regions with the ability to generate new neurons throughout the lifespan.
In animal models physical activity has been identified as a key mechanism that can drive this adult neuroplasticity. In humans, research has focused on the effects of aerobic fitness and training on volumes and perfusion of the HC. Results reveal that higher cardiorespiratory fitness levels (VO2 max) are associated with larger hippocampal volumes in late adulthood, and that larger hippocampal volumes may, in turn, contribute to better memory function. Furthermore, some investigations also assessed possible physiological mediators of the observed neuroplasticity, such as brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). However, the role of cardio-respiratory fitness in modulating hippocampal gray matter volume is still under debate.
The hippocampus is also involved in spatial navigation and in motor sequence consolidation suggesting that motor skill learning and motor fitness can have impact on hippocampal volume without any cardio-respiratory change. Hence, the HC seems not only crucial for long-term memory consolidation, learning and spatial navigation, but also for balancing. Intact balance is essential for social mobility and quality of life in aging. Hence, physical intervention programs should take this function into account, too.
In this respect dancing seems to be a promising intervention since it requires the integration of sensory information from multiple channels (auditory, vestibular, visual, somatosensory) and the fine-grained motor control of the whole body. Behavioral studies have already provided evidence of better performance in balance and memory tasks in elderly dancers, but the underlying neural mechanisms have not been addressed comprehensively so far. Knowing that aerobic, sensorimotor and cognitive training contribute to hippocampal volume, which also seems to be associated with balancing capabilities, we initialized a prospective, randomized longitudinal trial over a period of 18 months in healthy seniors. Two interventions were compared: a specially designed dance program, during which subjects constantly had to learn new choreographies, and a traditional fitness program with mainly repetitive exercises.
Before and after intervention, balance was evaluated using the Sensory Organization Test and HC volumes were derived from magnetic resonance images. Fourteen members of the dance (67.21 ± 3.78 years, seven females), and 12 members of the fitness group (68.67 ± 2.57 years, five females) completed the whole study. Both groups revealed hippocampal volume increases mainly in the left HC (CA1, CA2, subiculum). The dancers showed additional increases in the left dentate gyrus and the right subiculum. Moreover, only the dancers achieved a significant increase in the balance composite score. Hence, dancing constitutes a promising candidate in counteracting the age-related decline in physical and mental abilities.
PCSK9 Inhibition May Reduce Cardiovascular Disease Risk via Immune Mechanisms as well as via Lowered Cholesterol
A range of new approaches to lowered cholesterol aim to improve upon statins in reducing the incidence of cardiovascular disease. One of the most promising of these involves inhibition of PCSK9. How does lowered cholesterol help? Oxidized cholesterol in the bloodstream rises with age as a result of increased oxidative stress throughout the body, and these damaged molecules can irritate blood vessel walls. Cells react by generating inflammatory signals, calling in immune cells to help remove the cholesterol. Unfortunately, these cells may be overwhelmed by the damaged cholesterol. This gives rise to areas of damage that grow to become fatty atherosclerotic lesions, weakening and distorting blood vessels, and ultimately causing death or serious injury when they rupture. When there is less cholesterol, the progression of this condition is slowed. Does PCSK9 inhibition in fact produce all of its benefits through lowered cholesterol, however? The results here suggest that it also interferes with the inflammatory aspect of atherosclerosis.
T cells and dendritic cells are common in atherosclerotic plaques. Atherosclerosis is a chronic inflammatory process in which activation of these immune cells may play a major role in the development of cardiovascular disease. Researchers developed an experimental system to directly study how these immune cells from human atherosclerotic plaques are activated in order to discover mechanisms and potential therapies. Specifically, they examined proprotein convertase subtilisin kexin 9 (PCSK9), which is known to target the low-density lipoprotein (LDL) cholesterol receptor for degradation, resulting in increased LDL levels. Knowledge of this mechanism has led to the development of PCSK9 inhibitors, which lower LDL cholesterol.
Researchers investigated the immune effects of PCSK9 on the induction of dendritic cell maturation and T cell activation by oxidised LDL. T cells were isolated from patients with atherosclerotic plaques and from healthy individuals. Human peripheral blood monocytes were differentiated into dendritic cells. The dendritic cells were pretreated with oxidised LDL and then co-cultured with T cells from atherosclerotic plaques and from blood. The researchers found that oxidised LDL promoted the maturation of dendritic cells. These dendritic cells then mediated the activation of T cells into T helper cells. Oxidised LDL also induced PCSK9. PCSK9 inhibition reversed the effects of oxidised LDL on dendritic cells and T cells. Dendritic cell maturation was repressed, as was the activation of T cells.
"We demonstrated for the first time that PCSK9 inhibition reversed the effects of oxidised LDL on immune activation. This changed a pro-inflammatory profile into an anti-inflammatory state that is potentially anti-atherosclerotic. Our study suggests that the benefits of PCSK9 inhibition extend beyond lowering LDL cholesterol."
There will be Many Marginal Senolytic Drug Candidates
Senolytic compounds are those that can destroy senescent cells with minimal harm to other cells. Since a slow accumulation of senescent cells is one of the causes of aging, effective senolytics will be a form of rejuvenation therapy - and a high-class one at that, since senolytics have the potential to be both cheap and needed only once every few years at most. Now that research aimed at discovery of senolytic drug candidates is underway in earnest, we should expect that one of the outcomes will be a large number of compounds that are in fact not so great at this job: small effects, not discriminating enough in effects on senescent versus normal cells, or otherwise unsuitable. A good sign that the effect size in humans will likely be small is that the compound is already in widespread use, as is the case for most extracts from well-studied plants. I think this one is likely to be an example of the type, along with flavenoids such as fisetin and quercetin.
Intrinsic skin aging is a complex biological phenomenon mainly caused by intracellular stressors. Among various factors that accelerate intrinsic aging, the major causes are cellular senescence and mitochondrial dysfunction. When proliferating cells are exposed to various types of stressors, they may undergo growth arrest, termed as cellular senescence. Senescent cells exhibit various phenomena, such as cell-cycle arrest, gene expression changes, and secretion of inflammatory cytokines. Reactive oxygen species (ROS) mainly accelerate cellular senescence and also play a role in determining the lifespan of mammalian cells. Although senescent cells are relatively rare in young organisms, their number increases with aging. Senescent cells secrete numerous factors that have harmful effects on cells.
Kaempferia parviflora Wall. ex Baker, commonly called black ginger, has been used as a dietary supplement and traditional medicine in tropical countries. K. parviflora is reported to have antioxidative, anti-inflammatory, antiviral, and anticancer activities. However, its effect on intrinsic skin aging has not been verified. We investigated the inhibitory effect of K. parviflora on intrinsic skin aging process by evaluating its effect on cellular senescence and mitochondrial dysfunction using H2O2-exposed human dermal fibroblasts. In addition, its effect on skin aging phenotypes was evaluated using hairless mice.
Based on our results, KPE was found to attenuate cellular senescence in H2O2-treated fibroblasts and hairless mice by suppressing SA-β-gal activity and the expression of cell-cycle inhibitors. The restrained expression of cell-cycle inhibitors upon KPE treatment activates the E2F group, which is responsible for cell proliferation. In addition, KPE prevents cellular senescence by regulating the PI3K/AKT signaling pathway. In conclusion, KPE delays intrinsic skin aging process by inhibiting cellular senescence and mitochondrial dysfunction. KPE does not only attenuate cellular senescence through inhibition of the p53/p21, p16/pRb, and PI3K/AKT signaling pathways but also improve mitochondrial biogenesis through PGC-1α stimulation. Consequently, KPE prevents wrinkle formation, skin atrophy, and loss of elasticity by increasing collagen and elastic fibers in hairless mice.
The Society for the Rescue of our Elders
The Society for the Rescue of our Elders initiative arises from the same circle of people who run the Life Extension Foundation and the RAAD festival, and is one of the more promising items I've seen emerge from that group. If they put their minds to it, they should be well able to run useful human trials of senolytic drug candidates and a range of other nascent rejuvenation therapies as these treatments emerge - trying all of the more reliable and useful treatments from mouse studies in human volunteers in order to accelerate progress.
My complaint in the past has been that their efforts get corrupted by their supplement business, and other forms of useless nonsense, but so far that isn't visible here. It is certainly possible to argue the utility of some of the proposed trials, my usual complaints about SENS damage repair to reverse aging on the one side versus tinkering with metabolism to slightly slow aging on the other, but they're all backed by research groups in one way or another. While this particular initiative isn't quite ready for widespread attention yet, there is a signup form, and there is a contact email address if you have thoughts or offers of support to convey. For my part, I am certainly willing to participate in a sensibly designed senolytics trial, should the opportunity arise at a reasonable cost, and I'm sure many of the folk in the audience here are of much the same opinion.
The Society for the Rescue of our Elders has no bylaws, incorporating documents, or other legal structure. Its sole purpose is to unite people in ways that will accelerate the availability of rejuvenation technologies to benefit all of humanity, including members of the group. The Society for the Rescue of our Elders consists of about 1,000 individuals who have demonstrated their desire to donate, invest, and/or actively participate in advancing human age reversal studies.
The Society for the Rescue of our Elders is similar to groups formed in the past to advance a science when the medical profession showed little interest. In 1767 a few wealthy and civic-minded citizens in Amsterdam gathered to form the Society for Recovery of Drowned Persons. Amsterdam is a city of canals and hence people fell in and drowned. It thus became the birthplace for the teaching and promotion of the resuscitation of dead persons. The Society for Recovery of Drowned Persons introduced scientific principles and techniques. Following successes of the Amsterdam society, rescue societies sprang up in most European capitals in the 18th century, all with the goal of finding a way of successfully resuscitating victims of sudden death. Many of these techniques (or variations of them) are used in modern emergency medical practice."
Our mission is to demonstrate statistically-significant human age reversal so that an eruption of charitable and capitalistic forces will compete to induce even longer, healthier lifespans. We live in an era whereby limitations on maximum lifespans are likely to be soon vanquished. Each day our research is delayed, we grow older and frail. There is tremendous urgency to move human rejuvenation projects forward. Funding has been secured for some clinical studies. The costs of certain projects, however, will require them to be self-funded. In these cases, each study subject will have to pay their portion of expenses of being part of the study.
The dasatinib/quercetin study of senolytics therapy will commence shortly and funding was provided by a long-time Life Extension Foundation supporter. It is divided into three phases to test different dose timing. Phase One is now fully enrolled, but other phases are still enrolling subjects. Participants can travel to Los Angeles or Idaho and must be available for two weekends in a row.
The NAD+ infusion study has commenced and funding has been secured to cover 100% of this study's cost. This study is fully enrolled. Future studies that will test NAD+ infusions for Parkinson's, Alzheimer's, and stroke patients, are being planned. Let us know if you'd like to participate. The rapamycin study site has been moved to Southern California. Funding has been secured to cover 100% of this study's cost. The primary cost of this and some other studies are the extensive clinical and biomarker measures that must be done to assess if biological age reversal is occurring. Enrollment for this study is currently open.
The GDF11 trial is planned to initiate in Nassau, Bahamas around October of this year and will require each study participant to self-fund $7,800 for one year's treatment, which includes costs of extensive clinical and biomarker measurements. A clinical trial studying the immunomodulatory properties and cost-effectiveness of mesenchymal stem cells as an alternative treatment for chronic autoimmune conditions is commencing.
The thymus regeneration study will be based in California but is available nationwide. The cost to participate in a one-year trial will be a maximum of $28,000, which includes medications, MRI scans of the thymus (optional), and high-tech monitoring of immune status. The expected re-growth of the thymus gland (based on preliminary results from a 10-patient pilot study) may provide immune restoration benefits.
Young plasma transfer studies (also called Therapeutic Plasma Exchange) will initially be conducted at several sites in Florida, North Carolina, Colorado and Southern California. We anticipate more sites in the U.S. later this year. Two treatment protocols will be offered, one using 5% albumin and immunoglobulins (plasma components derived from young donors), and the other using directed/designated young donor plasma. Comprehensive testing, including early detection testing for Alzheimer's and immune senescence markers will be offered in both protocols. The expected cost for six infusions including comprehensive measurements of possible efficacy is estimated at $50,000.
Envisaging Alzheimer's Disease as a Cascade from Amyloid to Inflammation to Tau
Alzheimer's disease is marked by an accumulation of solid deposits of amyloid-β and modified tau protein. It is also an inflammatory condition, like many age-associated diseases, and past evidence suggests that reduced inflammation can improve matters, while greater levels of chronic inflammation are a risk factor for developing Alzheimer's. What is cause and what is consequence in all of this, however? The authors of this study propose that the order of causation is amyloid, inflammation, then tau. If so, then amyloid clearance therapies should be better than anti-inflammatory strategies, as and when they can be made to work effectively in humans.
In the brains of people with Alzheimer's disease, there are abnormal deposits of amyloid beta protein and tau protein, and swarms of activated immune cells. But scientists do not fully understand how these three major factors combine to drive the disease. Researchers exposed immune cells normally found in an activated, inflammatory state in Alzheimer's brains to tiny clusters of amyloid beta - or oligomers, which are believed to be the most harmful forms of the protein. "Our thinking was that the amyloid beta oligomers would activate an inflammatory response in these immune cells, and we wanted to see if this would induce pathological forms of tau when given to neurons."
The researchers then focused on the fluid in which the immune cells had been growing. This fluid, which was filled with inflammatory factors resembled the fluid in which these cells typically live inside human brains. The team added this fluid to cultures of human cortical neurons. The neurons soon developed abnormal, bead-like swellings along their axons and dendrites. This "neuritic beading" has been seen in Alzheimer's patients and has been considered an early sign of neuronal damage, although it hasn't been clear how beading was connected to abnormal tau or if the beading led to Alzheimer's disease. The team then looked for tau in the beads and found a striking accumulation of it, though it was in an abnormal form, modified in a different way than previously thought. This modification is thought by the researchers to cause tau to become aggregated.
The finding of abnormal tau in the neuritic beads indicated that these beads could mark tau's entry into the Alzheimer's disease process. Within the beads, researchers also found high calcium levels, which are known to harm neurons and are considered an important feature of neurons in people with Alzheimer's. "We think these neuroinflammatory factors trigger this cascade. They flood the neuron with calcium. And we think that once the calcium accumulates, it causes tau to become abnormally modified. This probably leads to a snowball effect: tau detaches from microtubules and is trafficked throughout the neuron, ending up in these beads. One possibility is that these tau-filled beads are the sites where the classic tangle-like aggregates of tau will eventually emerge, which is the hallmark of Alzheimer's disease."
Researchers used mass spectrometry to sort out the amyloid beta-induced neuroinflammatory molecules that had triggered the calcium influx and neuritic beading. They were able to show that one protein in particular, MMP-9, was responsible for some of these adverse effects. "MMP-9 is an inflammatory protein shown to be elevated in the brains of Alzheimer's patients. In our study, we show that MMP-9 alone can trigger a calcium influx that floods the neuron." The researchers also identified the protein HDAC6, which originates from within neurons and concentrates in the neuritic beads. Normally, HDAC6 is thought to detect unwanted protein aggregates within neurons and transport them away for disposal. However, blocking HDAC6 stopped nearly all beads from forming in these experiments. Both of these proteins have been found to be elevated in affected areas of Alzheimer's brains. Drug companies are now developing and testing HDAC6 inhibitors, which have performed surprisingly well in early studies, although it has not been fully understood how these inhibitors work. "Our work might explain why HDAC6 inhibitors have shown such early promise."
Protein Synthesis Differences in Progeria Suggest Changes in the Nucleolus as a Potential Biomarker of Aging
Researchers here note changes in the nucleolus in both old cells and cells from progeria patients, and suggest that these changes may be characteristic enough in normal aging to serve as a biomarker to assess biological age. There is great interest in the research community in establishing a low-cost, reliable biomarker of this nature, as it would considerably speed up the assessment of potential rejuvenation therapies, those that address the root causes of aging. Currently it is an expensive and time-consuming process, as studies must run long enough to observe the results of a treatment upon mortality rates.
Progeria is not accelerated aging, but has superficially similar outcomes. This rare condition is of interest because the form of molecular damage that is prevalent in this condition, mutated lamin A that causes structural and other irregularities in cells, is also found to a small degree in normal aging. It is an open question as to whether or not that matters in comparison to the laundry list of other forms of molecular damage found in old tissues. So secondary effects observed in progeria patients, those downstream of the lamin A issue, may well not be in any way relevant to normal aging. Even if the observation dovetails with existing knowledge, as is the case here, it could still be peculiar to the progeroid tissue environment and its particular distribution of forms of cellular damage, and so caution is required. Still, the findings in normal cells carried out as a part of this study are intriguing.
Scientists have found that protein synthesis is overactive in people with progeria. The work adds to a growing body of evidence that reducing protein synthesis can extend lifespan - and thus may offer a useful therapeutic target to counter both premature and normal aging. "The production of proteins is an extremely energy-intensive process for cells. When a cell devotes valuable resources to producing protein, other important functions may be neglected. Our work suggests that one driver of both abnormal and normal aging could be accelerated protein turnover."
Initially, researcher were interested in whether mutation was making the lamin A protein less stable and shorter lived. After measuring protein turnover in cultured cells from skin biopsies of both progeria sufferers and healthy people, she found that it wasn't just lamin A that was affected in the disease. "We analyzed all the proteins of the nucleus and instead of seeing rapid turnover in just mutant lamin A and maybe a few proteins associated with it, we saw a really broad shift in overall protein stability in the progeria cells. This indicated a change in protein metabolism that we hadn't expected."
Along with the rapid turnover of proteins, the team found that the nucleolus, which makes protein-assembling structures called ribosomes, was enlarged in the prematurely aging cells compared to healthy cells. Even more intriguing, the team found that nucleolus size increased with age in the healthy cells, suggesting that the size of the nucleolus could not only be a useful biomarker of aging, but potentially a target of therapies to counter both premature and normal aging. The work supports other research that appears in the same issue showing that decreasing protein synthesis extends lifespan in roundworms and mice. The researchers plan to continue studying how nucleolus size may serve as a reliable biomarker for aging.
Induced Pluripotent Stem Cell Therapy in a Primate Model of Parkinson's Disease
Cell therapy continues to be a promising approach to establishing a treatment for Parkinson's disease. The intent is to replace the dopamine-generating neurons that are lost as the condition progresses. Researchers here report on the past few years of a cell transplant study carried out in monkeys made to exhibit the same cell loss that is produced by Parkinson's in humans. Unlike earlier efforts, the researchers here are using induced pluripotent stem cells in order to generate the neurons to be transplanted.
One of the last steps before treating patients with an experimental cell therapy for the brain is confirmation that the therapy works in monkeys. Researchers have now shown that monkeys with Parkinson's disease symptoms show significant improvement over two years after being transplanted neurons prepared from human induced pluripotent stem cells (iPS cells). The study is expected to be a final step before the first iPS cell-based therapy for a neurodegenerative disease.
Parkinson's disease degenerates a specific type of cells in the brain known as dopaminergic (DA) neurons. It has been reported that when symptoms are first detected, a patient will have already lost more than half of his or her DA neurons. Several studies have shown the transplantation of DA neurons made from fetal cells can mitigate the disease. The use of fetal tissues is controversial, however. On the other hand, iPS cells can be made from blood or skin, which is why researchers plan to use DA neurons made from iPS cells to treat patients.
To test the safety and effectiveness of DA neurons made from human iPS cells, researchers transplanted the cells into the brains of monkeys. It is generally assumed that the outcome of a cell therapy will depend on the number of transplanted cells that survived, but the researchers found this was not the case. More important than the number of cells was the quality of the cells. "Each animal received cells prepared from a different iPS cell donor. We found the quality of donor cells had a large effect on the DA neuron survival." To understand why, he looked for genes that showed different expression levels, finding 11 genes that could mark the quality of the progenitors. One of those genes was Dlk1. "We are investigating Dlk1 to evaluate the quality of the cells for clinical applications."
Another feature of the study that is expected to extend to clinical study is the method used to evaluate cell survival in the host brains. The study demonstrated that magnetic resonance imaging (MRI) and position electron tomography (PET) are options for evaluating the patient post surgery. The group is hopeful that it can begin recruiting patients for this iPS cell-based therapy before the end of next year.
There are Many, Many Genes Associated with Longevity
Researchers have found hundreds of genes that can be manipulated to at least modestly extend longevity in various laboratory species, though the size of the effects diminish as species life span increases. Short-lived species have life spans that are far more plastic in response to environmental and genetic changes. Since proteins group into interaction networks, most of these genetic manipulations are different ways to adjust the same few core underlying processes. Mapping metabolism sufficiently to understand all of this is an ongoing process, but one that seems unlikely to contribute greatly the near future of human longevity. Unfortunately, adjusting the operation of metabolism is a poor path to the treatment of aging in comparison to repair of the molecular damage that causes aging: it can only slow aging, not reverse it; the past fifteen years have demonstrated that it is expensive and produces few useful therapies; the potential for additional years of healthy life is low. Nonetheless, it remains the primary focus of the research community.
Hundreds of genes, when manipulated, have been shown to affect the lifespan of model organisms (yeast, worm, fruit fly, and mouse). These genes, further denoted as longevity-associated genes, LAGs, could be defined as those whose modulation of function or expression results in noticeable changes in longevity - lifespan extension or accelerated aging. We have previously investigated the characteristic features of LAGs and found that (i) they display a marked diversity in their basic function and primary cellular location of the encoded proteins; and (ii) LAG-encoded proteins display a high connectivity and interconnectivity. As a result, they form a scale-free protein-protein interaction network ('longevity network'), indicating that LAGs could act in a cooperative manner.
Many LAGs, particularly those that are hubs in the 'longevity network', are involved in age-related diseases, including atherosclerosis, type 2 diabetes, cancer, and Alzheimer's disease, and in aging-associated conditions such as oxidative stress, chronic inflammation, and cellular senescence. The majority of LAGs established in yeast, worms, flies, and mice have human orthologs, indicating their conservation 'from yeast to humans'. This assumption was also supported by studies on specific LAGs or pathways such as Foxo, insulin/IGF1/mTOR signaling, Gadd45, and cell-cell and cell-extracellular matrix interaction proteins.
Now, the existing databases on orthologs allow for an essential extension of the analysis of LAG orthology, far beyond the traditional model organisms and humans. In particular, the data deposited in the InParanoid database Eukaryotic Ortholog Groups include orthologs for the complete proteomes of 273 species. Here, we report the results of an unprecedentedly wide-scale analysis of 1805 LAGs established in model organisms, available at Human Ageing Genomic Resources (HAGR) GenAge database, with regard to their putative relevance to public and private mechanisms of aging.
Our wide-scale analysis of longevity-associated genes (LAGs) shows that their orthologs are consistently overrepresented across diverse taxa, compared with the orthologs of other genes, and this conservation was relatively independent of evolutionary distance. Moreover, many worm LAGs were discovered by postdevelopmental RNA interefence on genes essential for growth and development, and this predominantly resulted in lifespan extension. That is, postdevelopmental suppression of genes that are vital early in life but are detrimental later in life, can be beneficial for longevity. The orthologs of these LAGs are also highly overrepresented across diverse taxa. Altogether, the C. elegans analysis suggests that antagonistic pleiotropy might be a highly conserved principle of aging.
An important observation in our study was that the majority of manipulations on LAG orthologs in more than one model animal resulted in concordant effects on longevity. This strengthens the paradigm of 'public' longevity pathways and of using model animals to study longevity, even across a large evolutionary distance. This notion is further strengthened when combined with the observation that the existence of an ortholog is probably accompanied by a preserved role in longevity. Yet, we also observed LAGs with ortholog presence only in a limited number of taxa, or that displayed discordant effects when tested in more than one species, which could, at least in part, be attributed to 'private' mechanisms of aging. Definitely, more comparative studies are warranted to better discriminate between private and public mechanisms, with unified methods of intervention and evaluation in mind.
Toward Stem Cell Therapies for Osteoporosis
The proximate cause of age-related osteoporosis is a growing imbalance between the distinct mechanisms and cell populations that are responsible for creating and breaking down bone tissue. It is plausible that delivering more cells capable of building bone may usefully patch over the situation to some degree - but it is only a patch, and it does only address this one majority cause of weakened bone in old people, and it does so without addressing the underlying causes, such as presence of senescent cells. Further, there are other unrelated causes of weakened bone in older individuals, including the persistent cross-linking of molecules in the bone extracellular matrix that makes bone less resilient. Nonetheless, as the authors here point out, a great many stem cell trials that might produce effects on the progression of osteoporosis are already taking place, without recording that data because they are focused on the treatment of other conditions. There is an opportunity to learn more about the utility of stem cell therapies for this condition with comparatively little additional effort.
Osteoporosis is caused by an imbalance between the tightly regulated process of bone formation by osteoblasts and resorption by osteoclasts. Primary osteoporosis is defined as bone loss attributed to aging or a decline in sex hormones associated with aging. This age-related osteoporosis involves the gradual loss of bone caused by insufficient bone formation.
The lack of an overall mechanistic understanding of what drives age-related osteoporosis has hindered the development of anabolic therapy appropriately targeting the etiology of the disease. It is hypothesized that decrease in the number and function of bone and bone marrow (BM)-derived mesenchymal stromal cells (MSCs) - a heterogeneous population comprising skeletal stem cells (SSCs), osteoblastic cells, and fibroblasts - lies at the root of age-related bone loss. Specifically, age-related changes in the proliferative and differentiation capacity of BM-MSCs are suspected, and recent evidence suggests that the loss of SSCs, which are a rare subset of MSCs, could be the most relevant event in the progression of senile bone loss. Thus, treatment strategies aimed at replenishing the MSCs compartment - and by extension SSCs - or augmenting endogenous populations of these cells, could result in bone growth and combat age-related osteoporosis.
A number of preclinical studies have been undertaken to determine whether MSC-based cell transplantation can induce bone formation. We have recently reported that transplantation of unmodified, low-passage MSCs prevents age-related osteoporosis in a mouse model. At the 6-month time point, we showed that transplanted animals displayed markedly increased bone formation, as well as higher osteoclast numbers. This led to improved bone quality and turnover, and importantly, sustained microarchitectural competence. Complementary to our work, studies documenting proof of principal that MSC transplantation can prevent senile osteoporosis in mouse models of accelerated aging present consistent findings.
Before the full benefit of SSC therapy can be leveraged toward bone regeneration, certain basic, translational, and clinical scientific questions will need to be answered. First, SSCs have only recently been characterized in murine models, and aside from one study documenting a BM stromal cell possessing some properties of SSCs (the generation of the hematopoietic microenvironment), this cell remains unidentified. As such, the human SSC still needs to be located, and fully characterized for phenotypic characteristics and cell surface antigen profile. Second, once identified, methods need to be developed to ensure the cell can be harvested and expanded to clinically relevant quantities. Stem cells often lose their multipotent, and self-renewal capabilities soon after removal from their native environment, therefore techniques will need to be optimized to enable large scale culture. Finally, although the safety and tumorigenic profile of MSCs has been fully evaluated and deemed safe, necessary due diligence will need to be performed on SSCs.
With over 500 clinical trials using MSCs registered with clinicaltrials.gov and numerous others being conceived, there presents a tremendous opportunity to maximize the scientific value of these expensive, laborious studies. The ability to co-operate, and leverage the availability of large, well-characterized cohorts of patients receiving MSCs (or other cell therapy/regenerative medicine agents) will maximize resource utilization. The ubiquitous nature of age-related bone loss in humans makes it an ideal candidate for regenerative medicine. Thus, we propose an ancillary study for osteoporosis to assess bone formation gains after systemic MSC transplant. By teaming up with other, even multiple, clinical trials the necessary number of patients could be more readily reached. This innovative model could be used to assess stem cell effects on various diseases in patients with existing comorbidities and chronic disease from trials that would normally only focus on one of the patient disease states. Significant savings can be achieved using an ancillary model in cell therapy due to cost sharing of expensive cell isolation, manipulation, and patient delivery.