Fight Aging! Newsletter, August 22nd 2016

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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  • Rejuvenation Biotechnology 2016 Starts Tomorrow, and Streams Online
  • More Evidence for the Inheritance of Longevity
  • A New 15,000 Challenge Grant Announced for SENS Cancer Research Crowdfunding
  • Aubrey de Grey at the Launching Longevity Panel, and Announcing Acceptance of the First Paper to be Published on MitoSENS Research
  • The Geroscience Network: Determined to Slow Aging through Medical Science
  • Latest Headlines from Fight Aging!
    • Safely Destroying Blood Stem Cells to Enable Immune System Restoration
    • Fight Aging! Invests in Ichor Therapeutics to Support Development of a SENS Damage Repair Therapy for Macular Degeneration
    • A Review Paper Following on from the Hallmarks of Aging
    • Using Magnetically Sensitive Bacteria as a Delivery Mechanism
    • A Look at the Mechanisms of Arterial Stiffening
    • Measuring Small Differences in Aging Between Populations
    • New Understanding of why ApoE4 is Associated with Alzheimer's Disease
    • Exposing Old Nerve Cells to Young Cerebrospinal Fluid
    • Twins Exhibit Slightly Lower Mortality Rates than Non-Twins
    • Investigating the Role of Hsp70 in Clearing out Damaged Proteins

Rejuvenation Biotechnology 2016 Starts Tomorrow, and Streams Online

This year's Rejuvenation Biotechnology conference, hosted by the SENS Research Foundation at the Buck Institute for Research on Aging, starts tomorrow, Tuesday August 16th. Like all of the initiatives undertaken by the SENS Research Foundation, this conference series is intended to accelerate the implementation of rejuvenation therapies based on repair of the cell and tissue damage that is the root cause of aging. Since the first of these therapies are presently in development in startup companies, and others will start to arrive in the years ahead if funding can be expanded for the necessary laboratory work, it is very much time to ensure that the technology transition from academia to industry goes smoothly. This means making connections, setting expectations, spreading an understanding of the present state of research, and putting together a community on the industry and investment side of the fence whose members are enthused and willing to get started. Nothing happens by magic in this world, and every step along the way to clinical therapies for human rejuvenation requires forethought, preparation, and hard work.

SENS Research Foundation exists to End Aging. Since 2009 we have worked to make the concept of Rejuvenation Biotechnology - the repairing of the damage which occurs to our bodies as we age - into a reality.

The 2016 Rejuvenation Biotechnology Conference is focused on taking the Rejuvenation Biotechnology Industry to the next level by addressing the question: what will it take to push emerging breakthroughs in regenerative medicine from proof-of-concept to implementation? This year's conference will answer this critical query by covering all the stages from securing funding, to production, to navigating regulation, to clinical evaluation and adoption of new treatments. Please take a look at our conference program to see all our amazing speakers.

If you have any questions while you are watching the conference just let us know by tweeting us at #RejBioCon and we'll try and get your questions answered during the Q&A or possibly after depending on how many questions there are. Just be sure you tell us which speaker you want us to ask.

Space for attendees was very limited for this convention, but fortunately in this modern day and age that doesn't stop the rest of us from listening in. The conference presentations and panels will be streamed live via YouTube:

  • Rejuvenation Biotechnology Conference Tuesday 16th from 1PM-6PM PST
  • Rejuvenation Biotechnology Conference Wednesday 17th from 8AM-12PM PST
  • Rejuvenation Biotechnology Conference Wednesday 17th from 1PM-6PM PST

The Rejuvenation Biotechnology conference series has been well received in the community, and it fills an important role. That function, helping to pull together the collaboration and support that will accelerate progress towards effective treatment of the causes of aging, will hopefully broaden and be taken up by other independent organizations as more of the necessary medical technologies come closer to realization. If you'd like a sense of how things will proceed this year, you might take a look at the many videos from Rejuvenation Biotechnology 2014 and 2015. For those who prefer reading, BioWatch News ran an entire special issue focused on Rejuvenation Biotechnology 2014 - it's very good.

More Evidence for the Inheritance of Longevity

There is plenty of evidence to show that comparative longevity for individuals within a species is to some degree inherited, running in families. Humans are no different in this regard. We might compare that with present thinking on the degree to which life expectancy in our species is genetic versus environmental, however: it is thought that genetic differences only become significant in old age, during the struggle of damaged systems to maintain some level of function. A commonly quoted assessment is that 75% of life expectancy variation is due to choice and environment, and only 25% is due to genetics. So what is the important inheritance here, genes or culture? I use the term culture in the very narrow sense of your upbringing, the habits, values, and knowledge you acquire or choose due to the influence of those around you. In the wealthier parts of the world the most important cultural outcomes for recent generations are whether or not you smoke, whether or not you become overweight, and whether or not you keep up with regular moderate exercise. Arguably formal education and a disposition towards personal wealth are important too, but the true nature of these relationships is very hard to disentangle from other associated factors when examining population statistics.

In the years ahead this will all change, and natural variations in life expectancy will become unimportant in comparison to whether or not people have access to rejuvenation therapies that can repair the molecular damage that causes aging. A class of therapy capable of adding ten healthy years to life would swamp all of the existing common lifestyle effects on human life span. After the advent of several of these types of therapy, long-term health will become almost entirely determined by medical technology. This is the goal to aim for, to lift up everyone into a future in which there is no more ill health or age-related disease, no more short straw in the genetic lottery, and life in good health is a choice for as long as desired. Freedoms of this sort must be built; they cannot simply be declared.

The paper here, like most assessments of the data for inheritance of longevity, doesn't have much to add on the contribution of genes versus environment. Genetic associations are known to exist, and they are found here as they are in other studies. I suspect that accurate assessments of the individual contributions to human longevity for all of these various factors, genes and lifestyle choices, will not be completed by the research community before they become moot. Medical progress will ultimately make natural variations in longevity just as irrelevant as natural variations in resistance to smallpox - an interesting historical question, but not one studied by any great number of people.

Long-lived parents could mean a healthier heart into your seventies

The longer our parents lived, the longer we are likely to live ourselves, and the more likely we are to stay healthy in our sixties and seventies. Having longer-lived parents means we have with much lower rates of a range of heart conditions and some cancers. A major study found that our chances of survival increased by 17 per cent for each decade that at least one parent lives beyond the age of 70. The researchers used data on the health of 186,000 middle-aged offspring, aged 55 to 73 years, followed over a period of up to eight years. The team found that those with longer lived parents had lower incidence of multiple circulatory conditions including heart disease, heart failure, stroke, high blood pressure, high cholesterol levels and atrial fibrillation. For example, the risk of death from heart disease was 20% lower for each decade that at least one parent lived beyond the age of 70 years. In addition, those with longer lived parents also had reduced risk of cancer; 7% reduced likelihood of cancer in the follow-up per longer-lived parent.

Although factors such as smoking, high alcohol consumption, low physical activity and obesity were important, the lifespan of our parents was still predictive of disease onset after accounting for these risks. The study built on previous findings which established a genetic link between parents' longevity and heart disease risk. That paper studied 75,000 participants in the UK Biobank, and found that offspring of longer-lived parents were more likely to have protective variants of genes linked to coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type 1 diabetes, inflammatory bowel disease and Alzheimer's disease.

"This work helps us identify genetic variations explaining the better health of people with longer-lived parents. We prominently found genetic factors linked to blood pressure, cholesterol levels and smoking, which underlines how important these avoidable and treatable risks are. However, we also found novel genetic factors, which could provide new clues to help us understand why having longer-lived parents has health benefits. This study provides additional fuel to really bolster research efforts by us and others in geroscience, a field that seeks to understand relationships between the biology of aging and age-related diseases. Aging is the most important risk factor for common chronic conditions such as heart disease, Alzheimer's and cancer, which are likely to share pathways with aging and therefore interventions designed to slow biological aging processes may also delay the onset of disease and disability, thus expanding years of healthy and independent lives for our seniors."

Longer-Lived Parents and Cardiovascular Outcomes

Cardiovascular risk assessment currently identifies higher risk individuals through parental histories of early onset myocardial infarction. However, having relatively long-lived parents is associated with markedly lower coronary heart disease (CHD) risks and longer survival. Parental longevity associations with other common cardiovascular outcomes are little studied. We estimated associations between parents' age at death and common incident conditions plus mortality in a large middle-aged cohort.

A New 15,000 Challenge Grant Announced for SENS Cancer Research Crowdfunding

Earlier today at the Rejuvenation Biotechnology 2016 conference, the SENS Research Foundation folk announced a 15,000 challenge grant for the present OncoSENS cancer research crowdfunding effort. All donations from here forward will be matched from the grant, and the deadline for the fundraiser has been extended for another thirty days to give this a chance to run. The funds raised from the community through this initiative will be used to carry out the first high-throughput screening of drug candidates for cancers that use the alternative lengthening of telomeres (ALT) mechanism to maintain their growth. Finding ways to block ALT is a necessary part of any future universal cancer therapy based on preventing telomere extension in cancer cells: all cancers must do this to grow, and without it they will wither away. The matching fund is provided by the generosity of an anonymous donor and Christophe and Dominique Cornuejols, who you will recall have helped to build the matching funds for the past few years of Fight Aging! SENS fundraisers. Their efforts are very much appreciated! You can find the announcement at 5:18 in the conference livestream from earlier today:

Rejuvenation Biotechnology Conference, Wednesday Morning Lifestream, 5:18

Cancer will be controlled, the only question is how long it takes to achieve that goal. The next generation of immunotherapies and other very targeted approaches to kill cancer cells with few side-effects will greatly improve patient outcomes for all of the most common cancers. These therapies will still, however, have the disadvantage of being very tailored to specific cancers and attributes of cancer cells. It takes a lot of time and money to produce a new treatment for cancer, and if that treatment is specific to only one or only a few of the hundred of subtypes of cancer ... well, that isn't very efficient. There is only so much funding and only so many researchers. Tackling cancer one type at a time is just not the way to win on a short timeframe.

The strategy and economics of the situation are why it is so very important that work on a universal cancer therapy prospers. The most targetable mechanism that is known to be necessary for all cancers is telomere lengthening. Telomeres are sequences of repeated DNA that cap the ends of chromosomes, and a little of that length is lost with each cell division. This is a part of the limiting mechanism that prevents the overwhelming majority of ordinary somatic cells in our bodies from running amok to divide and replicate endlessly: cells with short telomeres self-destruct or become senescent, in either case dividing no more. Cancers can grow destructively because the mutated state of their cells has unlocked one of the few possible ways to lengthen telomeres. A range of research groups are working on the production of therapies to block telomere extension that occurs through telomerase activity, but next to no-one is working with ALT. Because individual tumors evolve rapidly, blocking both telomerase and ALT will be necessary: blocking only telomerase has already been demonstrated in animal studies to cause a cancer to switch over to ALT. Thus the SENS Research Foundation, supported by philanthropic donations from people like you and I, has stepped in to pick up the slack and get this job done. Do you want a future free from cancer? Then here is a chance to help make that happen: donate to the OncoSENS fundraiser.

Aubrey de Grey at the Launching Longevity Panel, and Announcing Acceptance of the First Paper to be Published on MitoSENS Research

Today I'll direct your attention to a couple of videos, thematically linked by the presence of Aubrey de Grey, cofounder of the SENS Research Foundation and tireless advocate for progress towards working rejuvenation therapies. For the first of the videos, de Grey recently took part in a panel discussion involving representatives of the biotechnology industry, the research establishment, and venture capital community, with the topic being the coming development of a new industry that will develop therapies to extend healthy life and turn back aging. That industry has barely started to form its earliest and smallest stage today, as the first lines of rejuvenation research reach the point of commercial viability. There are a few startups and a lot of deep pockets yet to be convinced that this is going somewhere - though the commentary in the panel is encouraged, considering those involved.

The recent Rejuvenation Biotechnology 2016 conference hosted by the SENS Research Foundation was more along the same lines, focused on creating a foundation for the near future industry that will build and provide rejuvenation therapies. The purpose of the conference series is to help smooth the way for these treatments to move rapidly from the laboratory to the clinic, to build the necessary relationships, manage expectations, and pull in the additional support needed to make best possible progress. The conference was livestreamed over the past couple of days, and at one point Aubrey de Grey announced the just-then-and-there acceptance of the first scientific publication for the MitoSENS team at the SENS Research Foundation. They are presently in the lead, at the cutting edge, among the few groups working on the project of copying mitochondrial genes into the cell nucleus to protect them from the damage of aging. Ultimately, copying all thirteen genes should completely remove the contribution of mitochondrial damage to degenerative aging, as mitochondria will no longer become dysfunctional as their local DNA is damaged. They will get the proteins they need from the cell nucleus instead. It is a worthy project, and it is always welcome to see progress on this front.

Launching Longevity: Funding the Fountain of Youth

Can technology make human longevity a reality? As the pace of discovery accelerates, scientists and entrepreneurs are closing in on the Fountain of Youth. Disrupting the aging process by hacking the code of life, promises better health and longer maximum lifespans. With many layers of complexity from science to ethics, there are still skeptics placing odds against human longevity. Venture capitalists are betting on success; putting big money on the table to fund longevity startups. Google/Alphabet and drugmaker AbbVie have invested 1.5 billion on Calico, while Human Longevity Inc. recently raised 220 million from their Series B funding round. Complementing traditional venture investment, VCs like Peter Thiel and Joon Yun have established foundations and prizes to accelerate the end of aging. Why are VCs suddenly investing heavily in longevity startups? Will extended lifespan be a privilege of the wealthy or will the benefits be accessible to all? How long before these well-funded startups bring viable products to market?

Aubrey de Grey Announces Progress in MitoSENS

Ok everybody, before I introduce the next session I just wanted to make a very small, brief, but very welcome announcement. Literally half an hour ago we received some extremely good scientific news. Those of you who have been following SENS research since before the SENS Research Foundation itself even existed will know that, about a decade ago, the very first project, the very first research program that we were able to initiate - with the help of, especially, the initial donation of Peter Thiel - was to make mitochondrial mutations harmless by essentially putting backup copies of the mitochondrial DNA into the nuclear genome, modified in such way of course that the encoded proteins would be colocated back into the mitochondria to do their job. This is an idea that was first put forward more than 30 years ago, but it is an idea that despite quite a bit of initial effort, nobody was able to make work. When I first came across this concept, in fact I'd thought of it myself, it's a pretty obvious idea really, I came to the conclusion that a lot of the despair and despondency and pessimism about this approach was premature, and that it was worth having another go, and so that was the very first project we decided to fund.

Suffice to say that it has not been quite as easy as I was hoping to make progress in that space, but progress has now been made, step by step, over the past several years, with the help especially of the absolutely amazing team we have at the research center, who work on this, headed by Matthew O'Connor. Amutha Boominathan is the number two on the team, and is absolutely indispensable, I've no idea where we'd be without her. So, what's happened half an hour ago is that for the very first time in the entire history of this project, we have got far enough to have a paper accepted in a very nice journal, Nucleic Acids Research, which reports on our progress in this area. The headline result in this paper is that we are the first team ever to get two of the proteins encoded by genes in the mitochondrial DNA simultaneously functioning in the same cell line, and of course - two is equivalent to infinity for mathematicians, you know that, right? - this is extremely heartening news, and I just wanted to let you all know, thank you.

The Geroscience Network: Determined to Slow Aging through Medical Science

Across the last twenty years or so two very important, slow-moving battles over ideas and strategy have been fought within and around the aging research community. The first was to gain acknowledgement that the treatment of aging as a medical condition is a viable goal, and thus obtain the necessary support to make progress towards that goal. Even as recently as fifteen years ago ago, after years of extending the lifespan of laboratory animals in various ways, treating aging was still more or less a forbidden topic in the research community. Thankfully we have a long way since then in the matter of ideas, and it was a tough and long-running uphill process of advocacy and persuasion - a great deal of work was required to create change. Today we can say that this first battle is near done and finished, with only the mopping up remaining to be accomplished within the scientific community. Those who a decade ago dismissed the goal of treating aging or simply remained silent are now ready to talk in public and provide support. The public at large is unfortunately still behind the times, much less informed or convinced on the matter of aging, but that will change too.

It is the second battle within the scientific community that is now more of a concern for advocates - certainly more of a concern for this advocate. That battle is to shape the research strategies that are funded and pursued: in short whether to try to modestly slow aging or to aim to build rejuvenation therapies capable of reversing aging. When it comes to the future of our health and longevity, this is just as important as the efforts needed to move the research community to support the treatment of aging at all, and at this point has much further to go to a satisfactory conclusion. Sadly we live in a world in which, for various historical and regulatory reasons, the research community is almost entirely set on trying to modestly slow aging. Research groups follow the traditional approach of drug development, searching for compounds that can alter the operation of metabolism so as to slow down some of the changes that accompany aging. This is enormously expensive and has a low rate of success - you can look at the failed efforts to produce calorie restriction mimetics, for example, such as the hundreds of millions in funding and a decade put into sirtuin research with nothing to show for it at the end. Current efforts to repurpose the drug metformin are likely to end up in the same place: enormous sums and a great deal of effort are spent chasing effects that are tiny.

Aging is all about damage accumulation. Slowing aging means a slower pace at which damage accrues. Reversing aging means repairing that damage - and thus there are ways to do much better than merely tinkering metabolism to somewhat slow down the arrival of new damage. Since the research community has a very good catalog of the damage that causes aging, researchers are in a position to build treatments to repair it, therapies that can in principle produce rejuvenation. Those treatments have been planned and visualized in great detail for years now, and in a sparse few cases are under early clinical development in startups. Yet repairing the damage of aging to produce rejuvenation is a minority concern in the broader field, with little support despite its far greater potential. This, then, is the battle fought now, to direct the research community to the far better option rather than continuing in their status quo of working towards the far worse option.

The Geroscience Network is an example of what has come from victory in the first battle of ideas, to generate much greater support for treating aging within the research community. In the past few years things have blossomed to the point at which many influential figures openly advocate for the goal of treating aging, the root cause of all age-related disease, rather than treating age-related diseases one by one. The Geroscience Network was established among those US research groups and institutions whose principals have the greatest interest in treating aging as a medical condition. To quote the pertinent part of their brief:

We hypothesize that by targeting fundamental mechanisms of aging, clinical interventions can be envisaged that could delay or prevent age-related diseases and disabilities as a group, rather than one at a time. By planning and working in a coordinated way through the Geroscience Network, we intend to accelerate development and translation of effective treatments to delay or prevent age-related disabilities and diseases.

Some of the Geroscience Network researchers recently published a selection of open access position papers in the Journals of Gerontology. The papers frame their determination to treat aging, and are focused on aspects of the strategy: how to move forward within the regulatory system, how to undertake clinical translation of potential therapies, how to build clinical trials for this new world of treating aging rather than age-related disease. Notably where specific technologies are mentioned there is little of anything that SENS rejuvenation research supporters would recognize as an effective approach to treat aging, however. The Geroscience Network is the product of researchers who have a slightly overlapping but overall quite different view of aging, which you can find described in the noted Hallmarks of Aging paper, or the later pillars of aging materials. Much of what is seen in those publications as a cause of aging, such as epigenetic changes, looks to my eyes to be a later consequence of the forms of molecular damage described in the SENS proposals. The overlapping areas where the Hallmarks of Aging and SENS agree, such as senescent cell clearance, are to be welcomed where they lead to efforts like UNITY Biotechnology, but it is still the case that more representative examples of Geroscience Network participant projects include the clinical trial of metformin and efforts to develop calorie restriction mimetic drugs, such as the failed sirtuin projects. So while on the one hand it is great to see that the treatment of aging is now well supported as a goal for the research community, it remains unfortunate that the chosen approaches are so very marginal.

Still, there is a clear path ahead for the spread of SENS technologies into the mainstream. That is to demonstrate effectiveness, the old story of bootstrapping enough success on a shoestring budget to obtain greater support from those who were originally skeptical or had their own favored but less effective approach. Senescent cell clearance is the pioneering example here: advocated in the SENS vision for fifteen years, but ignored by the vast majority of researchers. Only in the last five years, since a 2011 demonstration of effectiveness, has more of the research community started to work in this area - and now two startups are working on bringing therapies to the clinic. This example puts the future of SENS rejuvenation therapies squarely on us, the donors, the philanthropists, the supporters. We determine the degree to which SENS succeeds in spreading to the mainstream by our efforts to pull in enough funding and attention to get the research done and the prototypes built. So look at the message of the Geroscience Network researchers with some optimism: yes it is frustrating that they are headed down the wrong road, but they will adopt SENS approaches just as soon as those approaches can be proven in animal studies. Yes, it will be a hard work all the way to the finish line, but when was anything in life easy? In any case, take a look at the papers and see what you think.

Moving Geroscience Into Uncharted Waters

Research into the basic biology of aging has undergone a seismic shift in the last 10-20 years, moving rapidly from the very descriptive approach focused on the aged that was the predominant focus by the end of the last century, to a more mechanistic (and primarily genetics-driven) phase, focused less on describing the aging phenotype in different models, and more on a definition of the molecular and cellular drivers of the process. This progression was accompanied by an evolution in the concepts and ideas that have dominated the field in the past, namely free radicals, cell senescence, and caloric restriction, each of which became the seed upon which the modern foci of research now stands. Progress in a variety of research areas has crystallized into the beginnings of a conceptualization of the process, including seminal publications that described the major hallmarks or pillars of aging.

Aging research is not simply an academic pursuit, it actually holds more promise in terms of helping mankind than most or all other biomedical fields. In terms of health and human suffering, it is well known that four out of five older Americans suffer from at least one chronic disease, and more than half suffer from multiple comorbidities. Aging being the major risk factor for all those diseases, it follows that research into aging could be pivotal in our efforts to reduce the suffering associated with the ravages of old age. In addition to the direct health issues, it has been calculated that care for the elderly currently accounts for 43% of the total health care spending in the United States. By delaying aging even by a lesser degree than currently achieved in animal models, there will be significant gains both in terms of health and wealth. The enormous advances in basic aging research, coupled with the promises described in the previous paragraphs, led to the concept of geroscience, a field that aims to understand the molecular and cellular mechanisms responsible for aging being the major risk factor and driver of common chronic conditions and diseases of the elderly. Of course, there is considerable work to be done in order to bring the field forward and move aging biology towards translation. Major areas in need of further development include, in the preclinical space, the development of better, reliable, and predictive biomarkers, as well as development of metrics for health, including resilience.

Barriers to the Preclinical Development of Therapeutics that Target Aging Mechanisms

An effective preclinical pipeline for developing interventions that target fundamental aging processes could one day transform medicine. However, at the Geroscience Network retreat, it was evident that the best potential strategies for drug discovery and development were not perceived as uniform among those working in the field. In some sense this is not surprising, as researchers have yet to define what is needed to develop a mechanism-based aging therapeutic with clinical utility. Still, the discordance among leaders in the field was enlightening-revealing many unanswered questions and unmet challenges in the discovery and preclinical development of drugs that target mechanisms of aging.

Recent, fundamental advances in our understanding of aging biology have brought the prospects of therapeutic interventions to extend health span and treat age-related diseases and disabilities as a group closer to reality. Despite the growing numbers of promising genetic and pharmaceutical interventions, significant work and financial investment are still needed in order to translate these basic science discoveries into the clinic. To this end, clinical trial strategies relevant to human frailty and resilience must first be established in validated invertebrate and vertebrate models. In addition, standardized preclinical drug development pathways are desperately needed. Some barriers to the clinical translation of therapies that target fundamental aging processes can be overcome by developing new preclinical testing approaches and clinical trials strategies, as well as and funding impediments unique to aging interventions. Together, we must engage in dialog and establish a framework to facilitate the translation of candidate compounds into effective drugs that promote health span and target age-related disorders in humans.

Frameworks for Proof-of-Concept Clinical Trials of Interventions That Target Fundamental Aging Processes

The successful translation of therapies that target fundamental aging processes into routine clinical interventions could transform the practice of medicine and human health. A number of candidate drugs (many already FDA-approved for other indications) have shown promise in preclinical studies. This Geroscience Network retreat developed ideas for proof-of-concept clinical trials that could be the next step in translating interventions that target fundamental aging processes into clinical practice. We described three frameworks for proof-of-concept trials, targeted at age-related diseases, geriatric syndromes, and resilience to acute stressors. Some aspects of clinical trial design are common to all three, whereas some require unique consideration in each framework. Importantly, proof-of-concept clinical trials would serve to test and advance the "geroscience hypothesis" that targeting the fundamental biology of aging will affect a range of age-related outcomes. Trial outcomes would be multidimensional and include outcomes related to the mechanism of action of the intervention; specific to the disease, syndrome, or stress under study; related to off-target effects of the intervention; and broadly relevant to the mechanisms and physiology of aging. Finally, several concrete steps could greatly accelerate the progress of clinical trials of interventions that target basic aging processes, including the development of standardized templates for trial design, toolkits for standardized outcome measurements, the establishment of a national geroscience biobank, and the development of specialist trial and training centers in the Geroscience Network.

Strategies and Challenges in Clinical Trials Targeting Human Aging

Clinical trials that target fundamental aging processes in humans are a novel concept that presents unique challenges and enormous opportunities. Challenges include selection of appropriate study populations, study designs, interventions, and outcomes. We presented two models that conceptualize trial designs for interventions that target fundamental aging processes in long-term and acute settings, defined by extension of health span and resilience to acute stressors, respectively. However, in order to gain the full support of federal and private sectors for development of therapeutics that target aging in humans, it is important to have "aging" or aging-associated outcomes such as frailty, functional decline, and multimorbidity designated as conditions eligible for registration by the FDA. Evidence from human studies is emerging that indicates certain interventions can target multiple age-related conditions simultaneously, potentially by interfering with the aging process itself. With the aging population projected to grow exponentially in the near future, clinical studies that can demonstrate the protective effect of these therapeutics during acute and chronic perturbations in aging humans are more timely than ever. Thus, delaying or preventing the disabilities that occur as a consequence of the aging process would result not only in tremendous cost savings for the healthcare system but also in gains for society on the whole from the increase in productive contributions from older members of society.

Resilience in Aging Mice

Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance healthspan and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects.

At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt.

Latest Headlines from Fight Aging!

Safely Destroying Blood Stem Cells to Enable Immune System Restoration

Destroying and recreating the immune system is a potentially very effective way to treat autoimmune conditions, as the basis of that condition lies in the broken configuration and memory of existing immune cells. The aging immune system has similar problems in its population and cell behaviors, problems that might be removed by replacing all immune cells wholesale. Present strategies to destroy the immune system require harsh chemotherapy, however, which makes it hard to justify on a cost-benefit basis for anything except the most harmful of conditions. Undergoing chemotherapy of this nature has a high mortality rate, and long-term harm to the survivors is on a par or worse than life-long smoking. Chemotherapy will be replaced in the years ahead, however. The research noted here is one step towards selective removal of all immune cells without harmful side-effects, a capability that will open the door to a range of ways to safely rejuvenate an age-damaged immune system and bring an end to autoimmunity:

Blood stem cell transplantation, widely known as bone marrow transplantation, is a powerful technique that potentially can provide a lifelong cure for a variety of diseases. But the procedure is so toxic that it is currently used to treat only the most critical cases. Now, researchers have come up with a way of conducting the therapy that, in mice, dramatically lowers its toxicity. If the method eventually proves safe and effective for humans, it potentially could be used to cure autoimmune diseases like lupus, juvenile diabetes and multiple sclerosis; fix congenital metabolic disorders like "bubble boy" disease; and treat many more kinds of cancer, as well as make organ transplants safer and more successful.

To successfully transplant blood stem cells, a patient's own population of blood stem cells must be killed. Currently, this is done using chemotherapy or radiotherapy, treatments that are toxic enough to damage a variety of organs and even result in death. To avoid these terrible side effects, the researchers composed a symphony of biological instruments that clear the way for blood stem cell transplantation without the use of chemotherapy or radiotherapy. The scientists started with an antibody against a cell surface protein called c-kit, which is a primary marker of blood stem cells. Attaching the antibody to c-kit resulted in depletion of blood stem cells in immune-deficient mice. However, this antibody alone would not be effective in immune-competent recipients, who represent a majority of potential bone marrow transplant recipients. The researchers sought to enhance the effectiveness by combining it with antibodies or with biologic agents that block another cell surface protein called CD47. Blocking CD47 liberated macrophages to "eat" target cells covered with c-kit antibody.

With the CD47 marker blocked and the antibody attached to c-kit proteins, the immune system effectively depleted the animals' blood-forming stem cells, clearing the way for transplanted blood stem cells from a donor to take up residence in the bone marrow and generate a whole new blood and immune system. The success of these techniques in mice raises hopes that similar techniques will succeed in human patients. "If it works in humans like it did in mice, we would expect that the risk of death from blood stem cell transplant would drop from 20 percent to effectively zero. If and when this is accomplished, it will be a whole new era in disease treatment and regenerative medicine."

Fight Aging! Invests in Ichor Therapeutics to Support Development of a SENS Damage Repair Therapy for Macular Degeneration

Ichor Therapeutics is spinning off a startup venture to work on turning SENS Research Foundation technology for the clearance of age-related metabolic waste into a treatment for macular degeneration. In the spirit of doing rather than just talking about doing, Fight Aging! has invested a modest amount to help fund this research and development project, alongside others you might recognize such as philanthropist Michael Greve. With all of the other fundraising going on at the moment, I should say that this is a very late notice of events that took place months ago; the funding round was being assembled around the same time as Fight Aging! invested in Oisin Biotechnologies at the start of the year. Raising funds for startups is one of those things that always takes longer than you think to finalize, however, even when accounting for the fact that it is going to take longer than you think.

Those familiar with the last decade of SENS rejuvenation research in the LysoSENS program will know that the metabolic byproduct called A2E is implicated as a contributing cause of retinal cell dysfunction and death in macular degeneration. This compound is one of many resilient types of waste making up the lipofuscin mix that builds up in older cells. These compounds are resistant to being broken down, so accumulate in the lysosomes, structures within the cell that act as recycling plants. As lysosomes become bloated they cease to function correctly, and cells fall into a garbage catastrophe, unable to maintain themselves in good condition. Many age-related conditions might be usefully slowed or reversed by ways to effectively clear out the important and most damaging forms of lipofuscin constituents from where they gather in the lysosome. It is good to see this work progressing.

Age-related Macular Degeneration (AMD) is a presently incurable eye condition leading to partial loss of vision and affects as many as 15 million Americans and millions more globally. AMD has a significant impact on an individual's quality of life through decreased independence and increased fall risk as well as the psychological and financial burden that vision loss can cause. Ichor Therapeutics began operating in the space in late 2014 after completing a material and technology transfer agreement with SENS Research Foundation for exclusive rights to a pre-clinical enzyme augmentation therapy platform for AMD and Stargardt's macular degeneration, a juvenile onset form of the disease. Another partnership fueling the scientific innovation at Ichor is with Syracuse University, a major research institution in the North Eastern United States. The partnership supports the long term corporate profitably of Ichor Therapeutics through a licensing agreement for exclusive rights to jointly developed intellectual property in the AMD market.

The recently completed transfer agreement provides additional resources to the well-established AMD research initiative at Ichor Therapeutics. Most recently, this initiative has received additional support in the form of a 600,000 program investment from Kizoo Tech Ventures, Fight Aging!, and several private investors. Ichor Therapeutics CEO Kelsey Moody said, "Our advances towards a treatment for AMD have excited many in the industry. We are fortunate to have such a deep network of scientific advisors, clinicians, collaborators, and investors who share our vision in advancing our therapeutic pipeline as quickly as possible." These resources and partnerships will continue to drive Ichor Therapeutics' AMD program, which has early results suggesting effective methods to treat the early, moderate, and late stages of AMD. Currently available treatments largely focus on the late stage only, leading to many patients going untreated. The implications of an Ichor developed therapy could mean millions of individuals could retain or regain their sight. To this end Ichor Therapeutics is continuing to develop lead candidates and assess safety and efficacy in mouse models of the disease.

A Review Paper Following on from the Hallmarks of Aging

This open access review of the mechanisms of aging is a followup of sorts to the noted Hallmarks of Aging paper, in which researchers followed the SENS model of breaking down aging into a set of actionable causes. There is some overlap between the SENS view of molecular damage and the Hallmarks view of metabolic dysregulation - cellular senescence is noted in both, for example - but from a SENS perspective the Hallmarks list includes a lot of things that are either markers of damage or later consequences of damage, not causes of aging. This well illustrates what has long been a major challenge in aging research, which is that cellular biochemistry is so very complex that there is still plenty of room to argue over whether important mechanisms in aging and age-related disease are causes or consequences of one another.

Getting the relationships right is vital to the development of life-extending therapies, as only the treatment of causes will prove to be very effective - and as things stand most of the field is working on patching over consequences instead, a strategy doomed to be both expensive and produce only marginal benefits. The only way to settle these debates over cause and consequence any time soon is to produce rejuvenation therapies that actually work, which is one of many reasons why advocacy for SENS research and development is so important. Sadly, in this paper as elsewhere, the ambitions with regard to aging and longevity are small: giving a greater priority to adjusting diet and lifestyle is the primary conclusion found at the end, and we all know just how little that can achieve in the grand scheme of things. No lifestyle will give you more than very tiny odds of reaching a century of aging, and no lifestyle choice can prevent you from aging and declining along the way. Only biotechnology that addresses the causes of aging can do more.

The human superorganism (i.e., the host and its microbiome) is a complex metabolic system in which nutrient intake, physical activity, and elimination of waste orchestrate anabolic and catabolic reactions that ultimately determine development, maturation, and aging. After many years of being subordinate to the surge in cellular and molecular biology, the study of metabolism is now experiencing its own Renaissance. A clear understanding is emerging of the key roles that metabolites play in all biological processes, including physiological and pathological aging.

We have previously classified the nine candidate hallmarks of aging into three categories. The primary hallmarks (genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis) are the main causes of molecular damage underlying aging. The antagonistic hallmarks (deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence) mediate beneficial effects at low levels and protect the organism from damage and nutrient scarcity but become deleterious at high levels. Finally, the integrative hallmarks (stem cell exhaustion and altered intercellular communication) are the culprits of aging and arise when the accumulating damage cannot be compensated by homeostatic mechanisms. All these denominators of aging have important repercussions on cellular metabolism. Here, we describe the links between each hallmark of aging and metabolic perturbations, discuss current strategies to manipulate metabolism for increasing healthspan and lifespan, and elaborate on the major threat posed to public health in the developed world, i.e., the incipient "westernization" of lifestyle.

Aging complicates the maintenance of cellular and organismal metabolic homeostasis, hence favoring an imbalance in metabolic landscape that self-amplifies and eventually becomes clinically manifest. Thus, anti-aging interventions such as calorie restriction may operate in the context of a metabolic reprogramming that (1) ensures efficient nutrient utilization and (2) enhances stress resistance. Although such a metabolic reprogramming may be extremely broad and hence difficult to modulate pharmacologically, it may be subjected to some unifying principles. In particular, the signal-transduction cascades and metabolic circuitries rewired in the course of aging may operate in the context of a limited number of modules that redistribute nutrients and other resources from anabolism to non-toxic catabolism, hence favoring homeostasis preservation.

Our current knowledge on the metabolic manipulations that may improve health in the elderly and hence extend longevity are still in their infancy, although there is no doubt that a combination of regular exercise and appropriate diet can delay the onset and progression of all the hallmarks of aging. Formulating dietary recommendations is complicated, and personalized advice from a nutritionist may be recommendable in some situations. Nonetheless, we surmise that an increase in food-free intervals, a reduction in overall caloric and animal protein intake, as well as a general shift from health-compromising food to a Mediterranean diet rich in fibers and complex carbohydrates may have sizeable anti-aging effects, especially when combined with regular physical activity.

Using Magnetically Sensitive Bacteria as a Delivery Mechanism

There are all sorts of interesting and potentially useful tools to be found in the bacterial world. In some cases the species itself can be repurposed as a tool, as is the case in this research. The scientists took a type of bacteria, magnetococcus marinus, that is sensitive to both magnetic fields and local oxygen level and adapted it to deliver drugs into the most active regions of a tumor:

Researchers have developed new nanorobotic agents capable of navigating through the bloodstream to administer a drug with precision by specifically targeting the active cancerous cells of tumours. This way of injecting medication ensures the optimal targeting of a tumour and avoids jeopardizing the integrity of organs and surrounding healthy tissues. As a result, the drug dosage that is highly toxic for the human organism could be significantly reduced. "These legions of nanorobotic agents were actually composed of more than 100 million flagellated bacteria - and therefore self-propelled - and loaded with drugs that moved by taking the most direct path between the drug's injection point and the area of the body to cure."

When they enter a tumour, the bacteria can detect in a wholly autonomous fashion the oxygen-depleted tumour areas, known as hypoxic zones, and deliver the drug to them. This hypoxic zone is created by the substantial consumption of oxygen by rapidly proliferative tumour cells. Hypoxic zones are known to be resistant to most therapies, including radiotherapy. To move around, the bacteria rely on two natural systems. A kind of compass created by the synthesis of a chain of magnetic nanoparticles allows them to move in the direction of a magnetic field, while a sensor measuring oxygen concentration enables them to reach and remain in the tumour's active regions. By harnessing these two transportation systems and by exposing the bacteria to a computer-controlled magnetic field, researchers showed that these bacteria could perfectly replicate artificial nanorobots of the future designed for this kind of task. "This innovative use of nanotransporters will have an impact not only on creating more advanced engineering concepts and original intervention methods, but it also throws the door wide open to the synthesis of new vehicles for therapeutic, imaging and diagnostic agents. Chemotherapy, which is so toxic for the entire human body, could make use of these natural nanorobots to move drugs directly to the targeted area, eliminating the harmful side effects while also boosting its therapeutic effectiveness."

A Look at the Mechanisms of Arterial Stiffening

This open access paper provides a perspective on some of the mechanisms of stiffening of blood vessels, though curiously without talking much about cross-linking of important structural molecules in the extracellular matrix. This stiffening is one of the most dangerous and damaging immediate consequences of the cell and tissue damage that lies at the root of aging. It causes hypertension, a condition of chronic high blood pressure, and a consequent detrimental remodeling of heart tissue. This leads to many of the varieties of cardiovascular disease, including an increased rate of breakage of tiny blood vessels in the brain, each destroying a tiny amount of tissue, but collectively causing a deterioration of cognitive function. Ultimately this results in vascular dementia, heart failure, and other fatal conditions. But it all starts with a loss of elasticity in blood vessels driven by mechanisms such as senescent cell accumulation, cross-link formation, and calcification in blood vessel walls.

Stiffening of the aorta and large elastic arteries is a hallmark of vascular aging. It has a number of adverse haemodynamic consequences, including a major contribution to isolated systolic hypertension. When measured by aortic pulse wave velocity (aPWV), it is highly predictive of clinical cardiovascular disease events independent of blood pressure, both in the general population and in groups with additional risk factors. Formerly thought to be simply a marker of atherosclerosis, the pathology of aortic stiffening may differ, at least in part, from that of atherosclerosis. Thus, in primate models of atherosclerosis, aPWV is reduced compared to non-atherosclerotic controls, at least in the early stages of atherosclerosis. In humans, aPWV is largely independent of risk factors other than age and blood pressure and is not elevated in the presence of non-calcified atheromatous plaque. The prognostic importance of arterial stiffening and the fact that it may be driven by a specific pathology distinct from atherosclerosis makes it an appealing target to prevent cardiovascular disease events.

In older subjects, calcification occurs in the media of the arterial wall around elastin fibres ('elastocalcinosis') and within atherosclerotic plaque in the intima. Although often regarded as distinct entities, intimal and medial calcifications often coexist. Arterial stiffening is closely associated with calcification, an association that could be explained by coexistent atherosclerosis. However, animal models show that medial calcification (in the absence of atherosclerosis) increases arterial stiffness, suggesting a direct causal relation between calcification and stiffening. Using combined computed tomography and magnetic resonance imaging to measure calcification and atheroma in the Twins UK population, we have shown that even though calcification often colocalises with atherosclerotic plaque, the association of stiffness with calcification is not explained by coexistent atheromatous plaque. Furthermore, the correlation between calcification and stiffness is explained by shared genetic factors distinct from those responsible for atherosclerosis. Arterial calcification is now known to be an active process resembling osteogenesis in which vascular smooth muscle cells undergo osteoblastic differentiation, expressing many of the proteins associated with bone formation and releasing vesicles into the extracellular matrix which serve as nucleation sites for the accumulation of hydroxyapatite crystals.

Whilst calcification may represent the later stages of a degenerative arteriosclerotic process that can be detected macroscopically, it is likely to be initiated by elastin degradation and a change in the type of collagen, which may also contribute to arterial stiffening independent of calcification. Such a degenerative process may relate to repetitive mechanical stress. It is thought to promote calcification through elastin-derived soluble peptides (matrikines or elastokines) which activate smooth muscle cell osteogenic differentiation and increase matrix affinity for nucleating mineral deposition. Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix including elastin, and in vivo, MMP-mediated elastin degradation is closely associated with both medial calcification and increased arterial stiffness. MMPs are also implicated in cutaneous elastin degradation that may parallel changes in the arterial wall. MMP9 expression in the skin, for example, has been shown to relate to arterial stiffness.

Measuring Small Differences in Aging Between Populations

The advent of tools capable of accurately assessing the state of biological aging, such as measurement of changes in DNA methylation patterns, means that researchers can now produce additional and more robust data on quite small differences in longevity that exist when comparing various human populations. Measurement doesn't say much about why these differences exist: there we are back to discussing the degree to which it is genetics versus lifestyle and culture. Nonetheless, this particular study provides good evidence for the utility of DNA methylation as a biomarker of aging, given that the results match up fairly well with those obtained from statistical population data. Having a reasonably accurate measure of biological age is very important for the future development of rejuvenation therapies, as it will make it much faster and cheaper to determine what works and what doesn't work. The cost of research and development will be greatly reduced if researchers can immediately test the results of a potential rejuvenation therapy rather than having to wait and see what it does to health and life span.

"Latinos live longer than Caucasians, despite experiencing higher rates of diabetes and other diseases. Scientists refer to this as the 'Hispanic paradox.' Our study helps explain this by demonstrating that Latinos age more slowly at the molecular level." Latinos in the U.S. live an average of three years longer than Caucasians, with a life expectancy of 82 versus 79. At any age, healthy Latino adults face a 30% lower risk of death than other racial groups. Researchers used several biomarkers, including an "epigenetic clock", to track an epigenetic shift linked to aging in the genome. Epigenetics is the study of changes to the DNA molecule that influence which genes are active but don't alter the DNA sequence itself. The team analyzed 18 sets of data on DNA samples from nearly 6,000 people. The participants represented seven different ethnicities: two African groups, African-Americans, Caucasians, East Asians, Latinos and an indigenous people who are genetically related to Latinos. Called the Tsimane, the latter group lives in Bolivia.

When the scientists examined the DNA from blood - which reveals the health of a person's immune system - they were struck by differences linked to ethnicity. In particular, the scientists noticed that, after accounting for differences in cell composition, the blood of Latinos and the Tsimane aged more slowly than other groups. The research points to an epigenetic explanation for Latinos' longer life spans. For example, the biological clock measured Latino women's age as 2.4 years younger than non-Latino women of the same age after menopause. "We suspect that Latinos' slower aging rate helps neutralize their higher health risks, particularly those related to obesity and inflammation. Our findings strongly suggest that genetic or environmental factors linked to ethnicity may influence how quickly a person ages and how long they live."

The Tsimane aged even more slowly than Latinos. The biological clock calculated the age of their blood as two years younger than Latinos and four years younger than Caucasians. The finding reflects the group's minimal signs of heart disease, diabetes, hypertension, obesity or clogged arteries. "Despite frequent infections, the Tsimane people show very little evidence of the chronic diseases that commonly afflict modern society. Our findings provide an interesting molecular explanation for their robust health." In another finding, the researchers learned that men's blood and brain tissue ages faster than women's from the same ethnic groups. The discovery could explain why women have a higher life expectancy than men.

New Understanding of why ApoE4 is Associated with Alzheimer's Disease

It is by now well known that the ApoE4 variant of Apolipoprotein E is associated with a higher risk of Alzheimer's disease in many populations. This is thought to be the case because this variant is less effective in roles that influence the breakdown of amyloid-β, a form of metabolic waste that accumulates in Alzheimer's patients. Researchers here provide evidence that ApoE4 is also relevant to the harmful accumulation of damaged tau protein, another form of waste that is associated with Alzheimer's disease. This should probably be taken as an indication that greater attention should be given to the development of ways to clear tau aggregates as well as amyloid aggregates:

For decades, scientists have known that people with two copies of a gene called apolipoprotein E4 (ApoE4) are much more likely to have Alzheimer's disease at age 65 than the rest of the population. Now, researchers have identified a new connection between ApoE4 and protein build-up associated with Alzheimer's that provides a possible biochemical explanation for how extra ApoE4 causes the disease. Apolipoprotein E comes in three versions, or variants, called ApoE2, ApoE3 and ApoE4. All the ApoE proteins have the same normal function: carrying fats, cholesterols and vitamins throughout the body, including into the brain. While ApoE2 is protective and ApoE3 appears to have no effect, a mutation in ApoE4 is a well-established genetic risk factor for late-onset Alzheimer's disease. Previous reports have suggested that ApoE4 may affect how the brain clears out amyloid-β, but what was happening at the molecular level wasn't clear.

Scientists had previously uncovered hints that ApoE4 might degrade differently than the other variants, but the protein that carried out this breakdown of ApoE4 was unknown. To find the protein responsible for degrading ApoE4, researchers screened tissues for potential suspects and homed in on one enzyme called high-temperature requirement serine peptidase A1 (HtrA1). When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells - and more of the breakdown products of the protein. "There's been an idea tossed around that ApoE4 breakdown products could be toxic. Now, knowing the enzyme that breaks it down, we have a way to actually test this idea." But it's not just a lack of full-length ApoE or an increase in its fragments that may be causing Alzheimer's in people with ApoE4. Researchers also found that ApoE4 - because it binds so well to HtrA1 - keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer's.

Exposing Old Nerve Cells to Young Cerebrospinal Fluid

In recent years a growing number of researchers have investigated the effects of putting old tissue into a young supporting environment. Typically this involves parabiosis: joining the circulatory systems of an old mouse and a young mouse. Given a knowledge what exactly is different between old and young environments, work also be carried out in cell cultures, however. Researchers have been using these methodologies to search for and evaluate potentially important signaling changes that occur with aging. Of particular interest are changes that impact stem cell populations, causing them to become less active, as the decline in stem cell activity with age is an important contribution to frailty and loss of function. In the research noted here, scientists are focused on cerebrospinal fluid and neural tissues rather than blood and the cardiovascular system, but find similar signs of an ability to spur greater stem cell activity in old tissue:

Researchers have discovered that the choroid plexus, a largely ignored structure in the brain that produces the cerebrospinal fluid, is an important regulator of adult neural stem cells. The study also shows that signals secreted by the choroid plexus dynamically change during aging which affects aged stem cell behavior. Stem cells are non-specialized cells found in different organs. They have the capacity to generate specialized cells in the body. In the adult brain, neural stem cells give rise to neurons throughout life. The stem cells reside in unique micro-environments, so-called niches which provide key signals that regulate stem cell self-renewal and differentiation. Stem cells in the adult brain contact the ventricles, cavities filled with cerebrospinal fluid (CSF) that bathes and protects the brain. The research team has now shown that the choroid plexus is a key component of the stem cell niche, whose properties change throughout life and affect stem cell behavior.

The researchers uncovered that the choroid plexus secretes a wide variety of important signaling factors in the CSF, which are important for stem cell regulation throughout life. During aging, the levels of stem cell division and formation of new neurons decrease. The research team showed that although stem cells are still present in the aged brain, and have the capacity to divide, they do so less. "One reason is that signals in the old choroid plexus are different. As a consequence stem cells receive different messages and are less capable to form new neurons during aging. In other words, compromising the fitness of stem cells in this brain region. But what is really amazing is that when you cultivate old stem cells with signals from young fluid, they can still be stimulated to divide - behaving like the young stem cells. We can imagine the choroid plexus as a watering can that provides signals to the stem cells. Our investigations also open a new route for understanding how different physiological states of the body influence stem cells in the brain during health and disease, and opens new ways for thinking about therapy."

Twins Exhibit Slightly Lower Mortality Rates than Non-Twins

Researchers here report on an interesting finding emerging from epidemiological data on twins, in that twins exhibit modestly lower mortality rates than the rest of the population. The paper focuses on the support and relationship angle, referencing the marriage effect on life expectancy, but I think that one could just as well field arguments based on effects in the womb, statistical differences in physical robustness, or a number of other items linked to longevity in human or animal studies that have shown up in the literature over the past few decades. Ultimately this is all interesting but irrelevant to the future of human longevity: small natural differences will be overwhelmed by the results of progress in medicine if things go well. A few years either way won't much matter when rejuvenation therapies can add decades of healthy life, something that may well happen within our lifetime if enough support goes to the right lines of research.

While studies of extreme longevity clustered within human families have indicated at least some genetic role in determining lifespan at very advanced ages, twin studies, which offer the opportunity to disentangle the genetic and environmental factors for a given trait, indicate genetic factors are responsible for only a modest amount of the variation (20-30%) in human lifespan and that the role of genetic factors is minimal before age 60, but increases thereafter. Although twin studies that focus on the correlation in age-at-death have yielded important insights into the role of genetics in human lifespan, the determinants of human survival patterns are immensely complex and change with age - i.e. while genetic factors play an increasingly larger role at advanced ages, environmental, social, and behavioral factors influence survival patterns much more heavily at younger ages. Perhaps owing to this complexity and the traditional structure of twin survival studies, less is known about differences in survival across age by zygosity, the underlying mortality processes that produce these differences, or the role of zygosity itself in shaping age patterns of survival.

Using data from the Danish Twin Registry and the Human Mortality Database, we show that monozygotic (MZ) twins have greater cumulative survival proportions at nearly every age compared to dizygotic (DZ) twins and the Danish general population. We examine this survival advantage by fitting these data with a two-process mortality model that partitions survivorship patterns into extrinsic and intrinsic mortality processes roughly corresponding to acute, environmental and chronic, biological origins. Overall, we find a survival advantage for MZ twins over DZ twins of both sexes at nearly every age and of DZ twins over the general population, but that different processes confer these advantages at different ages. For females, the survival advantage at all ages can be attributed to lower extrinsic mortality rates. Among males, extrinsic advantages account for the survival advantage up to about age 65 where the overall survival advantage begins to narrow and MZ males show better intrinsic survival than DZ males and DZ males show better intrinsic survival compared to the general population.

This research has documented a 'twin protection effect' akin to a marriage protection effect where a socially close relationship contributes to better survival outcomes throughout most of life. Notably, while we find evidence for a health protection effect arising from zygosity, the use of twin data allows us to avoid the confounding issue of self-selection that studies of marriage and health often encounter. Research on marriage protection effects as well as the findings presented in this paper are part of a larger body of literature that documents the importance of social support and cohesion for mortality and longevity outcomes. In this case greater survival for MZ twins over DZ twins and DZ twins over the general population is driven by lower extrinsic mortality at most ages, which is a likely consequence of the social bond between twins buffering against risky behaviors, providing emotional or material assistance during times of stress exposure, and promoting health-enhancing behaviors.

Investigating the Role of Hsp70 in Clearing out Damaged Proteins

Heat shock proteins such as the Hsp70 family are involved in the housekeeping processes that keep cells functioning well by destroying damaged proteins. They become active in response to stresses that cause a higher rate of damage to the protein machinery within cells, such as toxicity or heat - and hence the name. Many of the genetic alterations and other interventions shown to modestly slow aging in short-lived laboratory animals involve increased cellular maintenance in one way or another, so there is some interest in the research community in building therapies to artificially increase such maintenance activities. So far this hasn't resulted in useful approaches, however, and thus the only reliable way to improve these matters in your own life is still to exercise and practice calorie restriction - increased cellular maintenance is one of the ways in which these lifestyle choices make a difference to long-term health. There is no doubt value in going beyond this to seek much greater increases in cellular maintenance through medical science, but the large sunk costs and lack of results so far suggests that other, more direct means of repairing important forms of cell and tissue damage will be cheaper and more effective. Here I'm thinking of the SENS research proposals; the present state of natural repair processes would be sufficient given the existence of rejuvenation therapies capable of as-needed damage repair of the more critical issues.

One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. Members of the 70 kDa-heat shock protein (Hsp70) family are, in their function as molecular chaperones, involved in folding of newly synthesized proteins and refolding of damaged or misfolded proteins, as well as in assembly and disassembly of protein complexes. The role of Hsp70 in protection against oxidative stress-related damage has been widely accepted. However, to our knowledge, a possible function of Hsp70 in promoting the removal of oxidized proteins has not been investigated. In the current study, we are able to demonstrate not only the involvement of Hsp70 in protection against the oxidative stress-related accumulation of oxidized proteins, but also in their proteasomal degradation.

Hsp70 knockdown and prevention of Hsp70 induction during stress resulted in significantly increased levels of protein carbonyls after hydrogen peroxide treatment. Although heat shock proteins can refold mildly disordered proteins, it is clear that heat shock proteins are not able to repair covalently-modified oxidized proteins nor to reverse oxidative protein modifications. Thus, we suggested that Hsp70 must somehow be implicated in the removal of oxidized proteins. Moreover, Hsc70 deficiency did not lead to changes in protein carbonyl levels and, therefore, Hsc70 seems not to have a major role in this process. Albeit, Hsp70 and Hsc70 have a quite similar structure, it appears that their participation in (oxidative)-stress induced protein degradation is different. It is postulated that both proteins differ in their C-terminal regions, which may result in different cellular functions. Hsc70 is an important housekeeping protein, mostly responsible for the folding of newly synthesized proteins and involved in maintaining protein homeostasis in non-stressed conditions. In contrast, Hsp70 is mainly responsible for a rapidly inducible cell protection following stress situations. Relating to this, we have shown that Hsc70 expression is not affected by oxidative stress, while Hsp70 expression is induced about two-fold in our cellular model, which is comparable to results obtained in other cell lines. Since oxidative damage to proteins leads to their unfolding, the 'heat shock response' is activated and the expression of molecular chaperones is increased.

We demonstrated the ability of Hsp70 to bind oxidized proteins in vitro, as well as in our cell model and in vivo. Interestingly, these oxidized proteins bound to Hsp70 did not show a higher polyubiquitination, which further supports the widely accepted assumption that oxidized proteins are degraded by the 20S proteasome in an ubiquitin-independent way. It has been demonstrated that oxidized proteins are not preferentially ubiquitinated and that an intact ubiquitination system is not required for their degradation. Using various techniques, we demonstrated that Hsp70 interacts additionally with the 20S proteasome, confirming our hypothesis that Hsp70 seems to mediate the interaction between oxidized proteins and the 20S proteasome.

Taken together, the results presented in our current study demonstrate the involvement of the stress-inducible molecular chaperone Hsp70 in the 20S proteasomal degradation of oxidized proteins. We suggest that in the early phase after oxidative stress, Hsp70 binds to partially unfolded oxidized proteins and keeps them in a soluble, degradable form. Oxidized proteins bound to Hsp70 can then migrate to 20S proteasomes where they can be efficiently degraded. Thus, besides the direct recognition of oxidized protein substrates by the 20S proteasome, there seems to be another, Hsp70-mediated, way to catalyze the efficient degradation of oxidized proteins. Future studies should investigate the involvement of co-chaperones/interacting proteins and co-factors which may be involved in this process and which modulate the ability of Hsp70 to mediate shuttling of oxidized proteins to the 20S proteasome. Moreover possible interaction sites of Hsp70 on 20S proteasome subunits remain to be identified. Furthermore, there is increasing evidence that the stress-related inducibility of Hsp70 expression declines in aged cell models and organisms and that the chaperones are overloaded in aged cells due to increasing formation and accumulation of oxidized proteins and. Thus, modulating Hsp70 levels may be a possible pharmaceutical goal to maintain protein homeostasis and prevent the formation of toxic protein aggregates that can disrupt cellular function.

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