Fight Aging! Newsletter, February 29th 2016

February 29th 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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  • Engaging the Elephant: the SENS Research Foundation on the Need for Debate on Rejuvenation Research
  • A Little Backstory for UNITY Biotechnology
  • The Global Healthspan Policy Institute Wants Your Support in Lobbying for TAME Metformin Trial Funding
  • Using Epigenetic Measures of Age to Determine that Cellular Aging is Distinct From Cellular Senescence
  • Project: Help to Crowdfund the Sinclair Lab NMN Calorie Restriction Mimetic Lifespan Study in Mice
  • Latest Headlines from Fight Aging!
    • GDF11 Levels Correlate with Mouse Strain Life Spans and are Strongly Heritable
    • Many Methods of Modestly Slowing Aging in Laboratory Species are Gender Specific
    • Regenerating the Thymus to Treat Age-Related Autoimmunity
    • An Improved System for Testing Lipofuscin Removal
    • Existing Drug Found to Slow Progression of Transthyretin Amyloidosis
    • Rejecting the Mistaken Idea that the Defeat of Aging Would Somehow Diminish the Value of Human Life
    • Theorizing on Oxidized Cholesterol as a Driving Mechanism for Alzheimer's Disease
    • Commentary on a Connection Between Mitochondrial Dysfunction and Cellular Senescence
    • Even Small Gains in Healthy Longevity Bring Huge Economic Benefits
    • Reopening Development of β-secretase Inhibitors as a Therapy for Alzheimer's Disease


The latest newsletter from the SENS Research Foundation turned up in my in-box today, and includes some interesting thoughts on advocacy. The SENS Research Foundation remains one of the best and most effective of organizations dedicated to bringing about the creation of therapies capable of greatly extending the healthy human life span - in fact, therapies capable in principle of rejuvenation, turning back the clock by repairing the forms of cell and tissue damage that cause aging. Other organizations, like Calico, are investing vastly more money, but since they aren't funding the right sort of scientific programs, they may as well not exist. Their only value lies in the fact that they may, later, choose to adopt approaches based on repair of cell and tissue damage that SENS-funded and SENS-encouraged research groups demonstrate to be effective, such as senescent cell clearance.

It is frustrating to see such potential sitting right at the sideline, flirting with doing something useful yet not crossing that line, but that is sadly the way things work in longevity science. The overwhelming majority of funding and effort is devoted to metabolic tinkering - such as work on calorie restriction mimetics - that cannot possibly produce meaningful gains in human life span, while programs that can in principle produce indefinite healthy life spans must struggle to gain even a small amount of funding.

The SENS approach of damage repair to reverse aging rather than metabolic manipulation to slow aging is nonetheless slowly gaining ground in this challenge for support and adoption. This is illustrated by, among other things, the fact that there is now more than one venture funded company working on aspects of SENS rejuvenation biotechnology. Nonetheless, there is still a long way to go towards the goal of the mass adoption of SENS research and development goals by a large swathe of the research community, and the goal of the same public support for the defeat of aging as there is for the defeat of cancer. Advocacy for this cause remains very important and very much needed.

SENS Research Foundation Newsletter, February 22, 2016

On January 19, 2016, Intelligence Squared hosted a debate on the motion: "Lifespans Are Long Enough". Arguing for the motion were Ian Ground, a Philosopher and Lecturer at the University of Newcastle, and Paul Root Wolpe, Director, Emory Center for Ethics. Arguing against the motion were Aubrey de Grey, Chief Science Officer of SENS Research Foundation, and Brian Kennedy, CEO and President of the Buck Institute for Research on Aging.

At SENS Research Foundation, we know that the tragic lack of funding for damage-repair-oriented research into these conditions is in part due to simple lack of awareness, which is why one major goal of SENS Research Foundation's outreach program is to increase global awareness of the potential of our approach. We also know that the vast majority of humanity is on our side when it comes to changing the way the world researches and treats age-related disease. The amount of time and money already going into attempts to mitigate diseases like Alzheimer's speaks volumes here. Anyone who has watched the deterioration of a beloved family member, or had to address caregiving needs for a person suffering from dementia, or seen the sadness and frustration of a loved one losing one ability after another as every life activity becomes a source of pain would jump at the chance to provide genuine relief for age-related maladies to those they care about.

That said, some people still maintain an abstract objection to the very notion of living beyond what they consider a 'natural' lifespan. This puts a damper on their enthusiasm for programs like SENS Research Foundation's, which, if successful, could result in more people living longer as an incidental effect of the rejuvenation biotechnologies that protect them from sickness and frailty. Some individuals are uncomfortable with this scenario. We want to reach these people too, and perhaps introduce them to points of view they may not have considered before, in the hopes they might come to see that we all ultimately want the same thing: a world with the least possible amount of needless suffering.

This recent Intelligence Squared debate in particular did a great job of engaging the 'elephant in the room' we often contend with in our attempts to communicate our mission and goals to a wider audience, i.e., the fact that fixing age-related disease will necessarily mean fewer people 'dying of old age'. More to the point, longer healthspan may be inextricable from longer lifespan due to simple biological realities.

It is up to each person to determine their position on this matter, but from the standpoint of our work, SENS Research Foundation maintains that it is an ethical imperative to prevent the undeniable suffering caused by age-related disease. We don't expect to cure disease through debate, but participating in these events can be a great way to introduce people to new perspectives - perhaps even ones that change their minds and encourage them to support our research. Speaking of supporting our research, remember that as a 501(c)(3) public charity, SRF depends on you to help enable critical research, as well as our education and outreach programs. Please consider making a generous contribution today.


UNITY Biotechnology made a big splash a few weeks ago to announce their venture funding and intent to develop a senescent cell clearance technology to treat age-related disease by removing one of its causes. The press linked the company to researchers involved in proof of concept work in mice that has been ongoing since 2011, using a clever system of genetic engineering to eliminate senescent cells first in an accelerated aging mouse lineage and then in mice that age normally. This culminated in a life span study showing 25% life extension in mice through this methodology, which clearly sets the stage for much greater interest in this approach to the treatment of aging as a medical condition. This is good news all round, since Strategies for Engineered Negligible Senescence (SENS) advocates and researchers have been calling for progress towards senescent cell clearance for more than a decade, and now the rest of the research community is finally catching up.

UNITY Biotechnology didn't emerge from nothing, and isn't just an outgrowth of the particular research group noted in the press material. It is more a union between that group, Buck Institute researchers who have been working on the same challenge, and a preexisting commercial venture with its own potential technology for senescent cell clearance. This makes sense, as the genetic engineering approach used in mice as a proof of concept would essentially have to be ripped up and rebuilt from scratch in order to be useful in humans. That is a poor alternative if there is some other approach to build on instead. As I pointed out last year, if you go digging there is a lot of dark matter out there from the past ten years when it comes to efforts to clear senescent cells. There are patents on a variety of approaches, and a number of dead, quiet, or dormant small companies that clearly never got to the point at which they could convince the venture community to fund their work.

One of these companies is Cenexys, started by the same successful entrepreneur who is at the helm of UNITY Biotechnology. There are relationships there with established biotechnology company Kythera Biopharmaceuticals, and with the Buck Institute group run by Judith Campisi where a lot of senescent cell work has taken place in recent years. Cenexys was probably just a holding company for the senescent cell clearance intellectual property: if you take a look at relevant patent registrations, you'll find the following patents, and note that they are now assigned to UNITY Biotechnology.

Use of engineered viruses to specifically kill senescent cells (2013)

Polypeptides, viruses, methods and compositions provided herein are useful for the selective elimination of senescent cells. Method aspects include methods for inducing apoptosis in a senescent cell comprising administering to the cell a polynucleotide, virus, host cell, or pharmaceutical composition described herein. Other methods include expressing a pro-apoptotic gene in a senescent cell comprising administering to the cell the polynucleotide, virus, or pharmaceutical composition as described herein.

Immunogenic compositions for inducing an immune response for elimination of senescent cells (2013)

Provided herein are immunogenic compositions (vaccines) and methods for immunizing a subject with the immunogenic compositions for inducing an adaptive immune response directed specifically against senescent cells for treatment and prophylaxis of age-related diseases and disorders, and other diseases and disorders associated with or exacerbated by the presence of senescent cells. The immunogenic compositions provided herein comprise at least one or more senescent cell-associated antigens, polynucleotides encoding senescent cell-associated antigens, and recombinant expression vectors comprising the polynucleotides for use in administering to a subject in need thereof.

Compositions and methods for detecting or eliminating senescent cells to diagnose or treat disease (2014)

Disclosed are agents (e.g., peptides, polypeptides, proteins, small molecules, antibodies, and antibody fragments that target senescent cells) and methods of their use for imaging senescent cells in vivo and for treating or preventing cancer, age-related disease, tobacco-related disease, or other diseases and disorders related to or caused by cellular senescence in a mammal. The methods include administering one or more of the agents of the invention to a mammal, e.g., a human. The agents, which specifically bind to senescent cells, can be labeled with a radioactive label or a therapeutic label, e.g., a cytotoxic agent.

UNITY Biotechnology is the brand under which the final assembly of technology, money, and will for this line of research came together, after some years of groundwork, which clearly involved filing (arguably overly) broad patents on anything that looked promising. At any point in time over the past five years someone could have funded a senescent cell clearance approach and started good work on making it real. Things are always late, however, coming together well past the point at which they are obvious to many in the industry, especially when you have to convince outsiders to give you venture funding. This is why it is very rare for any company to emerge alone, and UNITY Biotechnology is only one of a number of efforts. There are competitors I know about, such as Oisin Biotechnologies whose founders have assembled an impressive gene therapy approach, and no doubt competitors I don't know about because they are either quiet groups internal to Big Pharma entities, or scientists elsewhere in the world with nascent senescent cell clearance technology and the connections to launch a company sometime in the next year or two.

The breadth of these patents unfortunately doesn't give much of an indication as to what exactly the UNITY Biotechnology staff is working on for their first attempt at a senescent cell clearance technology, other than to suggest that they are indeed doing nothing with the genetic engineering proof of concept used in the mouse life span studies. Tagging senescent cells and then sending engineered immune cells to destroy them wouldn't be a terrible guess, however. Immunotherapy is certainly a very viable approach to targeted cell destruction; a lot of time and effort goes toward this sort of immunotherapy in the cancer research community, for example.


The Global Healthspan Policy Institute (GHPI) is a recently launched group whose principals are focused on much the same goals as the researchers of the Longevity Dividend initiative, which is to say pulling a lot more public funding into aging research aimed at extending healthy human life spans. The chosen methodology is the traditional one of lobbying and political action, aimed at politicians and bureaucrats who influence budgets relevant to the National Institutes of Health, the National Insitute on Aging in particular, and other public sources of medical research funding.

The first public initiative for the GHPI is to petition and lobby for political support and public funding for the proposed TAME human trial of metformin as a drug to treat aging. The expectation that this will produce meaningful results in terms of extended health seems low to me, unfortunately: the animal study evidence for metformin to influence aging is scattered, contradictory, and terrible. This drug is, however, very safe, already approved, and widely used for decades. Arguably the real purpose of this exercise is to push the FDA into accepting a trial for a treatment aimed explicitly at intervention in aging rather than the treatment of any specific disease, using a vehicle - metformin - that regulators can't possibly object to on other grounds. Then the door stands open to anyone else with a potential therapy to treat the causes of aging. The FDA is otherwise a roadblock for all who wish to work within the US regulatory system, as its bureaucrats have up until this point not recognized aging as a medical condition and thus blocked any possible treatments for aging from entering the approval process. This in turn echoes back down the chain of research and development to make raising funding very challenging.

Ask Congress to Fund the First FDA-Approved Drug Trial to Prevent Cancer and Other Diseases of Aging

Aging brings illness. All of our major diseases get worse as we age, including heart disease, cancer, arthritis, dementia, cataract, osteoporosis, diabetes, hypertension, and Alzheimer's disease. Now for the first time in history, the US Food and Drug Administration has approved human testing of a drug to slow human aging that would decrease the risk for all of these illnesses, dramatically lowering healthcare costs and boosting quality of life for the elderly. Named "one of the most innovative projects of the year" by the Washington Post and the subject of the hit Ron Howard documentary "The Age of Aging", the TAME/Metformin study would take place in research centers nationwide.

Unfortunately, this study will not be funded by drug companies. Metformin has a long history treating diabetes, so it is known to be safe, but its also past the early phase where a drug company will invest in a drug because it can own it and profit by it. So the only way for this landmark drug trial to move forward is to be funded by Congress, much like they have funded thousands of other studies. The Global Healthspan Policy Institute is leading this charge. We are a non-profit think tank and policy institute that does not represent any government agency, corporation, or medical center. We have many allies in Congress who love the project, but we need your help with specific members of Congress whose position on appropriations committees can make or break this movement.

Petition: Tell Congress to Fund Critical Healthspan Research

Right now, the federal government spends billions each year in medical research seeking to cure one disease at a time - while virtually ignoring the underlying processes that eventually lead to a whole host of fatal diseases. It is estimated that 75 percent of the 1.9 trillion spent on all health care in the United States stems from preventable chronic health conditions - but only 1 percent is allocated to protecting health and preventing illness.

Every year Congress sets the Department of Defense's budget, which contains a "Peer Reviewed Medical Research Program" just for research like the TAME/Metformin drug trial. Join us in asking Congress to allocate funds. To get started they need 13 million per year for the first two years for the TAME/Metformin study that will span 6 years for a total cost of 64 million. Funding will be given to 14 university locations around the country - including possibly in your state - that will study a total of 3,000 people.

Let's plant the seeds for a future where we can all have more healthy, productive years of life - where major diseases can be stopped before they ever begin, and no one has to shoulder the burden of rising healthcare costs. Tell your representative today!

I'm sure you all know my opinions on engaging with a broken system of regulation and on metformin by now, so I won't do more than summarize. I think that the damage done to the pace of progress by the FDA is best fought by avoiding that agency so as to make it irrelevant, not by legitimizing it through engagement, and the best way to do this is for treatments to be deployed to clinics outside the US and accessed via medical tourism, just as happened for stem cell medicine. More bluntly, I see work on metformin in connection with aging as a waste of effort. It is a comparatively bad choice, as compared to, say, rapamycin analogs, within what is itself a comparatively bad class of initiatives to treat aging, mining existing drugs to find those capable of marginally slowing the aging process. This approach is both expensive and capable of producing at best poor results that are of little use to people already old and damaged. It boggles the mind that so much time and effort is spent on this type of research and development in an age in which senescent cell clearance and other forms of damage repair for living beings, capable in principle of rejuvenation of the old, and already producing much more robust results in animal studies, are in or nearing clinical development.

I understand that I'm in a minority in holding these views, that the majority of the community would rather fight for change within the present system, and that there are people geared up and ready to go with the TAME organizational and lobbying efforts. But if people absolutely must have this fight with the FDA, to expend significant resources to try to change the system from within, I'd rather it was happening two or three years from now for the first trials of senescent cell clearance therapies - a rejuvenation treatment with a high expectation of producing meaningful and reliable benefits in humans, rather than something that I expect to produce results that lie somewhere between nothing and a tiny statistical benefit.

I encourage you all to make up your own minds of course, and you should certainly take a look at what the Global Healthspan Policy Institute is up to, and keep an eye on their progress in the years ahead.


One of the research groups involved in developing biomarkers of aging based on characteristic epigenetic changes published a most interesting paper earlier this month, linked below, in which they use their tools to investigate cellular senescence and cell aging. Biomarkers to measure biological age, the degree to which an individual is damaged and their biology has become dysfunctional in response to that damage, are an important line of development. An effective biomarker might be used to quickly assess the overall benefits of a potential rejuvenation therapy in mammals. As an alternative to running full life span studies this would dramatically reduce the time and cost required for such research. Cheaper research and faster results are certainly good for the pace of progress where they can be achieved.

Individual cells age, accumulating metabolic waste and unrepaired damage in the case of long-lived cells, or marching towards the Hayflick limit placed on the number of divisions permitted them in the case of short-lived somatic cells, but the relationship between cellular aging and tissue aging is not a straightforward one. A living being is a a dynamic system in which the majority of cells that make up its tissues are at some point replaced, on a schedule of days or months in most cases. Only in the central nervous system and a few other places do we find individual cells lasting a very long time, even the whole lifetime, and in which the steady accumulation of damage and waste are more important factors. In most tissues the importance is the pace of turnover, the number of lingering senescent cells that behave badly and refuse to die, the level of waste in the environment outside cells, and the quality of the stem cells that are responsible for producing a supply of new somatic cells to keep tissue functional.

Cells become senescent, removing themselves from the cycle of division and replication in response to a range of circumstances: damage, a toxic local environment, short telomeres as a result of reaching the Hayflick limit, and so forth. This probably serves to reduce cancer risk, at least initially, but senescent cells generate harmful signals that degrade surrounding tissues and produce localized inflammation. As their numbers grow, this damaging behavior contributes meaningfully to degenerative aging. As illustrated by recent research linking mitochondrial dsyfunction and cellular senescence, cells are very complicated machines: senescence isn't a single uniform state, not all senescent states are similar, and nor is it the case that all of the states that can be created in the laboratory are known to occur to a significant degree in living tissues. So this is an interesting area of cellular biochemistry to explore, even as clinical development is moving ahead on the blunt and direct approach of clearing senescent cells from the body so as to remove their detrimental effects. This is absolutely the way things should be: taking the fast road to therapies that will effectively treat the causes of aging even in the absence of detailed understanding, and those researchers who can raise funds for more leisurely investigation and mapping can continue their work in the meanwhile. If only this were the case in other fields relevant to aging, but for the most part only the leisurely investigation is taking place there.

Epigenetic clock analyses of cellular senescence and ageing

One model of ageing posits that the failure of tissues to function properly is due to the depletion of stem cells. Stem cells, which are the reservoir cells of tissues, may have finite capacities of proliferation such as being limited by the lengths of their telomeres. Their eventual depletion leads to the deficit of properly functioning cells, causing phenotypic changes that constitute ageing. While this model is plausible and supported by strong circumstantial evidence, it is presently difficult to prove or refute directly, not least because the identification of specific tissue stem cells is difficult. Similarly, the association between telomere length and ageing, although widely reported, is not without inconsistencies.

There is however, another model of ageing which is based on the observation that the number of senescent cells in the body increases in function of organism age. While this could be interpreted to mean that senescent cells cause ageing, it could also equally mean that senescent cells are a consequence of ageing. In this regard, it is noteworthy that there is increasing evidence to demonstrate that senescent cells are not benign. Instead they secrete bio-chemicals that are detrimental to normal functioning of neighbouring cells. The senescence-associated secretory phenotype (SASP) proteins include cytokine, chemokines and proteases and their paracrine activities are very diverse and include oncogenic characteristics that stimulate cellular proliferation and epithelial-mesenchymal transition. Importantly, SASP proteins also promote chronic inflammation, which is the origin of almost all age-related pathologies. As such, SASP proteins, through their different effects on normal and cancer cells, induce deterioration of the tissue. Recently, it was demonstrated that removal of senescent cells in mice delays ageing-associated disorders, providing very strong support for the notion that senescent cells mediate the effects of ageing. Hence it follows that to understand ageing, it is necessary to understand cellular senescence. This model of active induction of ageing (via senescent cells) does not exclude the role of stem cell depletion described above, which could indeed be a result of stem cell senescence.

At present, the causes of cellular senescence in vivo are not known for certain but in vitro, cells can become senescent through (i) telomere shortening via exhaustive replication (replicative senescence), (ii) over-expression of oncogene or (iii) DNA damage. While it is easy to perceive replicative senescence (RS) as part of a bona fide mechanism of ageing, it is more challenging to consider oncogene-induced senescence (OIS) as a significant contributor to natural ageing. Instead OIS has been proposed to function as a tumour suppressor mechanism. The only obvious common factor between RS and OIS is the co-opting of the DNA damage signalling mechanism to usher cells into arrest.

Recently, we developed a multivariate estimator of chronological age, referred to as epigenetic clock, based on methylation levels. The following features of this clock demonstrates that its age estimates capture several aspects of biological age: (a) it can accurately measure the age of cells regardless of tissue types including brain, liver, kidney, breast and lung (b) its accuracy is substantially higher than that of other molecular markers such as telomere length (c) it is able to predict mortality independent of health, life-style or genetic factors (d) its measurements correlate with cognitive and physical fitness amongst the elderly and (e) it is able to detect accelerated ageing induced by various factors including obesity, Down syndrome and HIV infection. Here, we apply this epigenetic clock to study the relationship between ageing and senescence of isogenic cells induced by exhaustive replication, ectopic oncogene over-expression or radiation-induced DNA damage.

We show that induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell. However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway. Collectively, these two sets of observation make an effective case for the uncoupling of senescence from cellular ageing. This however, appears at first sight to be inconsistent with the fact that senescent cells contribute to the physical manifestation of organism ageing, as demonstrated elegantly by studies in which removal of senescent cells slowed down ageing. In the light of our observations however, it is proposed that cellular senescence is a state that cells are forced into as a result of external pressures such as DNA damage, ectopic oncogene expression and exhaustive proliferation of cells to replenish those eliminated by external/environmental factors. These senescent cells, in sufficient numbers, will undoubtedly cause the deterioration of tissues, which is interpreted as organism ageing. However, at the cellular level, ageing, as measured by the epigenetic clock, is distinct from senescence. It is an intrinsic mechanism that exists from the birth of the cell and continues. This implies that if cells are not shunted into senescence by the external pressures described above, they would still continue to age. This is consistent with the fact that mice with naturally long telomeres still age and eventually die even though their telomere lengths are far longer than the critical limit, and they age prematurely when their telomeres are forcibly shortened, due to replicative senescence. Hence senescence is a route by which cells exit prematurely from the natural course of cellular ageing.

Finally, it is necessary to address specifically the role of telomeres as it is easy to confound them with cellular ageing because at first view, they appear to share similar features. Since critical telomere length is attained after many rounds of proliferation, which takes a long time and hence occurs later in life, it is easy to mistake this for a functional link with age even though telomere length has only a modest correlation with chronological age, while cellular ageing as measured by the epigenetic clock has a far higher degree of association with biological ageing. The fact that maintenance of telomere length by telomerase did not prevent cellular ageing defines the singular role of telomeres as that of a means by which cells restrict their proliferation to a certain number; which was the function originally ascribed to it. Cellular ageing on the other hand proceeds regardless of telomere length.

Although the characteristics of cellular ageing are still not well known, the remarkable precision with which the epigenetic clock can measure it and correlate it to biological ageing remove any doubt of its existence, distinctiveness and importance. This inevitably raises the question of what is the nature of this cellular ageing, and what are its eventual physical consequences. Admittedly, the observations above do not purport to provide the answer, but they have however, cleared the path to its discovery by unshackling cellular ageing from senescence, telomeres and DNA damage response, hence inviting fresh perspectives into its possible mechanism. In summary, the results from these experiments, while apparently simple in their presentation, untangles a conceptual knot that hitherto tied senescence, DNA damage signalling, ageing and telomeres together in an incomprehensible way. Here we propose that cellular ageing, as measured by the epigenetic clock, is an intrinsic property of cells, and while independent, its speed can be affected by some factors; a feature that would undoubtedly be exploited to characterise and elucidate its mechanism.


The crew have launched their latest longevity science crowdfunding project in partnership with the Sinclair lab at Harvard: the goal is to raise funds for a novel calorie restriction mimetic mouse life span study based on research published last year. You might recall that David Sinclair was the researcher behind Sirtris, one of the more hyped initiatives in sirtuin research, though far from the only one. Over the past twenty years a lot of work has gone into trying to understand the activities of proteins and pathways thought to be important in the extended longevity produced by calorie restriction in short-lived species, sirtuins among their number, and there was considerable enthusiasm for drug development along these lines a decade ago. A few companies were founded, such as Sirtris, but while some people made a bunch of money, nothing came out of this save for a greater appreciation of the complexities of cellular metabolism and a mountain of new data.

Research on sirtuins didn't halt following the realization that this wasn't a fast path to modestly slowing the aging process. It continues, along with a great many other, similar investigations into the detailed operation of mammalian biochemistry, and how it changes in response to circumstances. In fact much of aging research and longevity science even now is arguably just a thin excuse to bring funds into the grand endeavor of mapping cellular metabolism, in much the same way that Alzheimer's research is used as the rallying banner for fundamental work on understanding the biochemistry of the brain. Decades of work remain to be accomplished in the project of mapping metabolism in the context of aging, even given the advanced tools of modern biotechnology. Actions speak louder than words, and most scientists in the field are doing a lot more mapping than work on potential treatments for aging.

So what are the researchers at the Sinclair lab up to these days? You might recall that they are investigating possible drug candidates to alter the behavior of mitochondria for the better in aged tissues, which is another line of research fairly closely connected to calorie restriction. This particular approach involves manipulating nicotinamide adenine dinucleotide (NAD) levels using compounds such as nicotinamide mononucleotide (NMN) or precursors. NAD levels decline with aging, decline more slowly in calorie restricted individuals, and restoring NAD levels artificially has been shown to produce some benefits in old mice. However there is yet a lot of uncertainty in this; it is a good thing at this point to remember the data on and view of sirtuins and their relevance to aging, and how that changed over time. For my money the research on this to date at the Sinclair lab is much more interesting for the connections it exposes between mitochondria, nutrient sensing, and regulation of cellular maintenance, some of the foundation stones for the operation of hormesis, than as the basis for therapies.

Can NMN Reverse the Effects of Aging in Mice?

One of the best studied anti-aging treatments is a diet reduced in calories, yet high enough in nutrients to avoid malnutrition. Known as calorie restriction (CR), this dietary regimen provides irrefutable evidence of the importance of metabolism in the aging process. While CR has been studied extensively and even tested in human trials, long term adherence to a CR dietary regimen is extremely difficult for most individuals to maintain. One method to achieve the benefits of CR for everyone would be to administer compounds which act as a "CR mimetic." Such compounds are capable of stimulating the cellular signaling cascades that are normally induced during CR. Over the past 20 years, we have made great strides in understanding the key cellular components involved in mediating many of the metabolic changes that contribute to the aging process.

A major metabolic signaling molecule that we and others have shown to exhibit significant declines with increasing age is NAD+. Importantly, CR reverses the age-related decline of bioavailable NAD+. This key metabolite plays a crucial role in regulating the activity of many important signaling molecules involved in age-related diseases. However, feeding or administering NAD+ directly to organisms is not a practical option. The NAD+ molecule cannot readily cross cell membranes and therefore would be unavailable to positively affect metabolism. Instead, precursor molecules to NAD+ must be used to increase bioavailable levels of NAD+.

One such metabolic precursor of NAD+, niacin, is currently used as a medical therapeutic in humans to regulate blood lipid profiles and ward off cardiovascular disease. Niacin, however, has unwanted side-effects and is separated by too many metabolic steps upstream of the final production of cellular NAD+ to substantially impact the magnitude of NAD+ bioavailability. Recently, we have shown that by administering the NAD+ precursor NMN (Nicotinamide Mononucleotide) in normal drinking water, bioavailable NAD+ levels were restored to those normally associated with younger healthy animals. By administering NMN to mice for just one week, our lab demonstrated a robust correction in age-associated metabolic dysfunction and restored muscle function in old mice to levels seen in younger control mice.

In our project, we will test the hypothesis that by restoring bioavailable NAD+, we can reverse the aging process. Starting with mice that are one year old (roughly equivalent to a 30 year old human), longer-term NMN treatments will be applied in order to restore levels of cellular NAD+ to those found in youthful mice. Along with a large cohort of normal mice, a novel genetically engineered mouse, termed the ICE mouse (Induced Change in Epigenetics) will be used during the trial. These ICE mice manifest an accelerated aging phenotype and as a result are short lived. By using ICE mice in our trial, in addition to normal control mice, we will be able to more rapidly test the effectiveness of potential anti-aging treatments, such as NMN, thus obtaining faster experimental results.

Your donations will not only allow us to purchase the materials necessary to perform this experiment, but also open the doors to working together with you in the future eventually leading to human clinical trials aimed at showing, for the first time, that we can actually slow down human aging.

As I'm sure you're all aware by now, I'm really not in favor of traditional drug development with the goal of modestly slowing the aging process. The prime example of this is any attempt to recapture some fraction of the effects of calorie restriction by tinkering with the operation of metabolism. One of the good things to come out of years of sirtuin research is that it now serves as a calibration point to demonstrate (a) just how expensive it is to try to manipulate the operation of metabolism with drugs, even when seeking to recreate a well-studied and easily reproduced natural metabolic state like the calorie restriction response, and (b) just how unlikely it is for this sort of approach to produce useful therapies, even given large investments of time and money. So I'd say that helping to fund this proposed life span study in mice using nicotinamide mononucleotide as a calorie restriction mimetic should be approached with the view that you are assisting fundamental research with the aim of understanding more of the relationships between mitochondria, calorie restriction, and aging, not that you are assisting an approach likely to lead to useful therapies in humans. Clearly life span studies like this are useful fundamental life science research, of the sort undertaken by the Interventions Testing Program and the NIA, who never have enough funding to do as much as they'd like to do, but they are not in the same class of expected value as SENS rejuvenation research projects.


Monday, February 22, 2016

Growth differentiation factor 11 (GDF11) is a protein that appears connected to regulation of stem cell activity in response to rising levels of cell and tissue damage that occur with aging. GDF11 levels fall with aging, as does stem cell activity, and increased GDF11 has been shown to increase stem cell activity in aged mice, producing benefits to health and organ function. There is still some debate over exactly what is going on under the hood in the GDF11 studies carried out to date, and whether researchers are correctly interpreting the results, however. A number of groups are presently exploring the molecular and genetic mechanisms that determine variations in GDF11 levels, with an eye towards the goal of therapies that can compensate for falling levels in aged individuals, and here is news of recent research on this topic:

Previous studies have found that blood levels of this hormone, growth differentiation factor 11, decrease over time. Restoration of GDF11 reverses cardiovascular aging in old mice and leads to muscle and brain rejuvenation. Scientists have now discovered that levels of this hormone are determined by genetics, representing another potential mechanism by which aging is encoded in the genome. Future studies will seek to reveal why GDF11 levels decrease later in life and whether they can be sustained to prevent disease. "Finding that GDF11 levels are under genetic control is of significant interest. Since it is under genetic control, we can find the genes responsible for GDF11 levels and its changes with age."

The study confirmed results from previous experiments showing that GDF11 levels decrease over time and also showed that most of the depletion occurs by middle age. In addition, the study examined the relationship between GDF11 levels and markers of aging such as lifespan in 22 genetically diverse inbred mice strains. Of note, the strains with the highest GDF11 levels tended to live the longest. Using gene mapping, the researchers then identified seven candidate genes that may determine blood GDF11 concentrations at middle age, demonstrating for the first time that GDF11 levels are highly heritable. "Essentially, we found a missing piece of the aging/genetics puzzle. Very generally, we've made an important step toward learning about aging and why we age and what are the pathways that drive it. It's the first step down a long road, but it's an important step."

Monday, February 22, 2016

Over the past twenty years researchers have demonstrated a great many ways to slightly slow aging in short-lived laboratory species: flies, worms, and mice. As a general rule these are largely irrelevant to the future of human longevity, however. They are adjustments to the operation of metabolism, something that is expensive and challenging to understand well enough to do safely in humans, and the beneficial effects are small (and in many cases unreliable and disputed) even when operating over the entire life span. Trying to make human therapies of these results is a dead end in comparison to the approach of repairing age-related cell and tissue damage. Many of the methods of slightly slowing aging through metabolic alterations produce different results in males and females, which is probably to be expected given that there are differences in metabolism between the genders that are at least as large as the changes produced by some of these interventions.

Analyzing years of previous research on dietary and pharmaceutical tests on flies and mice, researchers showed that aging interventions can have opposite effects on mortality rates in males versus females. The findings appear consistent with data gathered on humans as well. Researchers found that treating flies with the steroid hormone mifespristone/RU486 (used in humans for terminating pregnancy) decreased egg production in females while increasing longevity. Similar effects were seen by tweaking the diets of flies and mice, but the effects were sometimes opposite in males versus females.

Increasing life span also increased the acceleration of age-dependent mortality rate of the population. That's evidence of a strong Strehler-Mildvan relationship, which is described by the Gompertz equation, a model for mortality named for the British mathematician who first suggested it in 1825. Here's what that means: Suppose you could create a graph of the mortality rate of everyone born in a single year - from birth until the last person died. You'd see two key things: Off the bat, there'd be a small number of individuals dying here and there - typically due to infections and pathogens. That's non-age-driven mortality. Then, as the group aged, you'd see the mortality rate rise exponentially until the last person died. This acceleration is thought to represent true aging - the inexplicable breakdown of the body over time. "We all speculate, but no one has really figured out what the cause of that acceleration is. Our results show that dietary and genetic interventions sometimes have opposite effects on that acceleration in males versus females."

What the Strehler-Mildvan relationship implies is that this equation is affected by the mixture of strong and frail individuals in a population - and that if you tweak the mixture, the mortality rates will adjust accordingly. "There are weaker, low-vitality individuals in the population and if you kill them off, you're left with high-vitality individuals and the population has a slow mortality acceleration with age. The relationship was so striking in how robust it was in the data we analyzed. I've never seen numbers like that. It confirms that this is a very fundamental relationship."

The findings would also seem to support the antagonistic pleiotropy model for aging, proposed in 1957. Pleiotropy refers to a single gene that affects multiple physical characteristics. In part, the model tries to explain why our bodies ultimately break down and die. Natural selection might select for a gene that creates a fatal flaw later in life if it offers some significant benefit earlier -- that is, if it helps individuals reproduce successfully, it's beneficial to the species even if it does ultimately shorten the individual's life span. The mifespristone intervention appears to prevent such a trade-off between life span and reproductive ability - albeit, a sex-dependent one.

Tuesday, February 23, 2016

Autoimmune diseases are caused by a range of malfunctions in the configuration of the immune system that lead it to attack the patient's own tissues, causing chronic inflammation at the least and eventually fatal damage at the worst. Most incidence of autoimmune disease is not very age-related, but aging does bring a rising level of autoimmunity as the immune system becomes increasingly dysfunctional and ineffective, falling into the state known as immunosenescence. One contributing cause of immune aging is a limited and diminishing supply of new immune cells, and one potential approach to treatment is to restore the thymus so as to increase the pace of production of immune cells:

We tend to focus on rejuvenating the aging immune system's specific immunity to pathogens because the loss of this ability is more often acutely life-threatening, as can be seen in the terrifying rise of influenza-associated pneumonia hospitalization and death rates beginning around age 65. But there is also a substantial rise in autoimmunity with age, leading to greater incidence of specific autoimmune diseases such as rheumatoid arthritis and lupus, along with a less specific rise in autoimmune reactivity in the aging immune system, which is seen in the rising frequency of autoantibodies even in people with no overt autoimmune disorder. These may be linked to the rising inflammatory tone with age, and possibly to the increase in cancer, atherosclerosis, and neurodegeneration with age. While their effects are incomplete and not without side-effects, existing models of slow aging already show us that the age-related rise in autoimmunity is modifiable. Both laboratory rodents subjected to calorie restriction (a strong model of slow aging, at least in mice and rats) and human centenarians enjoy rates of autoimmune antibodies and disease that resemble those of controls with much lower calendar ages.

One key to rejuvenating the aging immune system and eliminating the autoimmunity of aging is engineering biologically young thymus tissue to supplement or supplant the shrunken and structurally-damaged ("involuted") aging thymus. The young, healthy thymus prevents autoimmunity in two ways. First, it screens newly-matured T-cells and eliminates any that target "self" proteins in a process known as negative selection. Recently, researchers created mice whose thymuses decayed more rapidly than normal with age by gradually eliminating a gene (FoxN1) that is involved in maturing and maintaining the organ. This accelerated thymic involution resulted in the release of high numbers of autoreactive T-cells from the thymus, which rapidly became activated and began attacking body tissues, leading to increased inflammation. The scientists traced this back to an impairment of the activity of a protein involved in negative selection, and the involuted thymus tissue's inability to recruit the innate immune cells needed to present the thymus with the tissue-specific self-antigens needed to screen out the harmful self-reactive cells. Engineered young thymic tissue grafts would restore the youthful thymus' strong capacity for negative selection.

Additionally, aging people suffer a loss of regulatory T cells (Tregs), also known as suppressor T cells, which help to enforce tolerance to "self" antigens. One possible cause of this is the sheer failure of the involuted thymus to generate sufficient total numbers of T-cells, a subset of which go on to become Tregs. If so, then engineered youthful thymic tissue will reverse that deficit.

But an additional, non-exclusive cause of the loss of Tregs with age is that they may be crowded out by rising clones of dysfunctional T-cells with age. If so, then rejuvenation biotechnology to ablate these "anergic" T-cells might make room to allow the body to restore their numbers, just as it is expected to do for killer T-cells directed at new pathogens. The technology required to eliminate such cells (such as a mature version of the prototype "T-cell scrubber" developed by researchers with SENS Research Foundation and now being adapted as part of Foundation-funded work to rejuvenate the aging systemic environment) could potentially also be turned directly on the self-reactive T-cell clones themselves, purging them from the body even as other aspects of immune aging are reversed by other rejuvenation biotechnologies. Very similar technology could also be applied to clearing out autoreactive B-cell clones, which are essential for autoantibody production and for perpetuation of the autoimmune response. There is, indeed, already proof-of-concept work in ablating aged B-cell clones as rejuvenation biotechnology for humoral immunity. Depending on the full fruits of other rejuvenation therapies, these techniques might need to be periodically reapplied, and could also potentially be used to suppress hereditary and other non-age-related causes of autoimmunity.

Tuesday, February 23, 2016

A team funded by the SENS Research Foundation has developed an improved system for evaluating methods of lipofuscin removal in cells. Lipofuscin, a mix of many different forms of hardy metabolic waste, builds up in tissues with age. It clogs up lysosomes, the cellular recycling units, causing them to become bloated and dysfunctional. As all forms of cellular garbage accumulate due to this issue, cells themselves become dysfunctional or die. This is a significant and damaging problem in long-lived cell populations, such as those of the central nervous system. The compounds involved in the lipofuscin mix found in the retina, for example, directly contribute to the progressive age-related blindness caused by macular degeneration. Elsewhere in the body lipofuscin accumulation is implicated in the pathology of a range of age-related diseases. Clearing these waste compounds is an important goal in the development of rejuvenation therapies to treat aging by addressing its root causes.

Lipofuscin accumulation has an inverse relationship with lifespan and is a well-documented hallmark of aging. Many age-related disease states including Alzheimer's, Parkinson's, and age-related macular degeneration show increased lipofuscin accumulation. Some organisms accumulate lipofuscin in a nearly linear manner over time, and therefore their age is determined using methods that quantify lipofuscin levels. Two primary theories have been proposed for lipofuscin formation: the mitochondrial-lysosomal axis theory of aging and the protease inhibitor model of aging. The former focuses on irreparable oxidative damage caused by oxygen-driven Fenton reactions associated with mitochondrial processes, while the latter espouses inadequate lysosomal proteolysis as a cause of aging. Both theories have significant merit and lend credence to the 'garbage catastrophe' theory of aging, which states that the buildup of recalcitrant nondegradable material within the cell eventually leads to cell senescence or inhibited function.

Since lipofuscin accumulation impairs proteosome and lysosome pathways critical to cell health and homeostasis, the ability to quickly generate lipofuscin in vitro, and identify drugs that mitigate the accumulation or clear lipofuscin would be of great benefit to aging research. Here, we present a platform to quickly create lipofuscin-loaded but otherwise healthy cells and screen drugs for efficacy in lipofuscin removal. The combination of leupeptin, iron (III) chloride and hydrogen peroxide generates significant amounts of lipofuscin within cells while eliminating the need for a 40% hyperoxic chamber required by another existing protocol for lipofuscin generation. Alternative methods which load fibroblasts with "artificial" lipofuscin obtained via UV-peroxidation of mitochondrial fragments are much more labor-intensive. This method is faster (≤10 days) than most protocols to generate lipofuscin and assess its removal, which typically require 2 to 4 weeks or longer to complete.

Wednesday, February 24, 2016

Researchers have discovered that an existing drug can slow the progression of rare forms of transthyretin amyloidosis caused by mutation by interfering in the formation of this type of amyloid. It is unclear as to how useful this would be in practice for the age-related accumulation of transthyretin amyloid known as senile systemic amyloidosis that occurs in every individual, however, as that happens at a much slower pace over a greater span of time. The growing presence of this amyloid is implicated in a range of age-related conditions, particular cardiovascular disease. The ideal approach to amyloidosis, whether age-related or not, is clearance of amyloid rather than slowing its formation, however. Clearance can be applied at any point in the progression of the amyloidosis to obtain benefits, and applied repeated as needed, at a much lower cost. Slowing progression requires constant treatment at a much higher cost, and produces smaller and diminishing benefits. Fortunately a therapy capable of transthyretin amyloid has already been successful in a small trial, though the pace of clinical development in this field is, as ever, glacial.

Researchers have published the results of a drug repositioning study in which they describe a powerful drug, SOM0226 (tolcapone) that could significantly improve the pharmacological treatment of familial transthyretin amyloidosis (ATTR). ATTR is a rare degenerative disease that mainly affects the nervous system and heart muscle tissue (myocardium), and which is usually passed on from parents to children. It originates when the liver and other areas of the organism produce mutations of the protein transthyretin (TTR), which lose their functional structure. This causes toxic aggregates of amyloid fibres to build up, which, depending on the mutation involved, are deposited in different organs, such as the brain, the kidneys, the nerves, the eyes, or the myocardium, causing them to malfunction and bringing on the various forms of the disease. To prevent the disease from progressing, a liver transplant or liver and heart transplant is needed.

The researchers conducted trials in vitro in cell cultures and ex vivo in human plasma and in mouse models of the disease to show that tolcapone is a powerful inhibitor of the aggregation of amyloid fibres by TTR. Tolcapone acts by imitating the process by which the thyroid hormone - T4 or thyroxine - binds to TTR in the bloodstream. Just like the hormone, the drug binds closely to the protein, tying together the four protein sub-units that form the protein's structure. This binding has been proven to stabilise the protein, preventing the sub-units from separating and then forming aggregates. This is a hitherto unknown property of the drug, which is used to treat Parkinson's disease. The compound turns out to be four times more effective than the only medicine currently available for treating the polyneuropathic variant of ATTR. The results were positive for all variants of the disease that were studied: familial amyloid polyneuropathy and cardiomyopathy (which affects the peripheral nerves and the myocardium, respectively) and senile systemic amyloidosis, a sporadic form that appears in a very high percentage of men over 60 years of age (and also affects the myocardium). In addition, the treatment was shown to cross the blood-brain barrier, making it the first to tackle the variants that affect the central nervous system.

According to the researchers, this molecule has the potential to become an effective drug for preventing the protein depositions that cause the disease and slowing down its progress, one that could be on the market within five years, as it has already been tested in a clinical trial with persons affected by the neuropathic variant.

Wednesday, February 24, 2016

I wasn't aware that some objectivists use Ayn Rand's thought experiments to support an opposition to extended human longevity. The essay linked here refutes that interpretation, but this is only one facet of a much broader set of arguments - found in or arising from adherents of near every philosophy - made to suggest that aging and death gives human life value, or moral or ethical standing. From this perspective the medical control of aging, and the elimination of pain, suffering and death caused by age-related disease, achieved through technologies such as SENS rejuvenation treatments, would somehow make us all worse off. This is one of many reasons why most philosophical positioning, like the theology it evolved from, isn't worth the paper it is printed on, or the time taken to understand its errors. It is self-evidently ridiculous to argue that less age-related disease and more healthy life diminishes us, and I don't see any of the people making that argument rushing to give up the advantages of present day medicine when it comes to treating age-related disease. Hypocrites, the lot of them. Nonetheless, that is is exactly the position regularly deployed against advocates of greater research and development in longevity science. It is both irrational and, to the extent it harms progress, dangerous for all of us.

Some advocates of Ayn Rand's philosophy believe that indefinite life would turn human beings into "immortal, indestructible robots" that, according to Ayn Rand, would have no genuine values. Both of these claims are false. Indefinite life would not turn humans into indestructible robots, nor would an indestructible robot with human abilities lack values or motivation for doing great things. Rand's "immortal robot" argument is found in "The Objectivist Ethics": "To make this point fully clear, try to imagine an immortal, indestructible robot, an entity which moves and acts, but which cannot be affected by anything, which cannot be changed in any respect, which cannot be damaged, injured or destroyed. Such an entity would not be able to have any values; it would have nothing to gain or to lose; it could not regard anything as for or against it, as serving or threatening its welfare, as fulfilling or frustrating its interests. It could have no interests and no goals."

First, at no point in time will human beings become "immortal, indestructible robots". The simple reason for this is that our existence is physical and contingent on certain physical prerequisites being fulfilled. The moment one of these physical prerequisites is lacking, our existence ceases. This will always be the case, even if we no longer have a necessary upper limit on our lifespans. For instance, biomedical advances that would greatly expand human lifespans - allowing periodic reversions to a more youthful biological state and therefore the possibility of an indefinite existence - would not turn humans into indestructible robots. There would still be the need to actively turn back biological processes of decay, and the active choice to pursue such treatments or not. People who live longer by successfully combating senescence could still get run over by a car or experience a plane crash.

Moreover, the need to reject the "immortal robot" argument when discussing indefinite life extension does not stem solely from a desire to achieve philosophical correctness. Rather, we should recognize the potential for actually achieving meaningful, unprecedented longevity increases within our own lifetimes. Thus, it is premature to conclude that death is a certainty for those who are alive today. Medical advances on the horizon could indeed turn many humans into beings who are still potentially vulnerable to death, but no longer subject to any upper limit on their lifespans.

It is therefore ill-advised to pin any ethical justifications for the ultimate value of human life to the current contingent situation, where it just so happens that human lifespans are finite because we have not achieved the level of technological advancement to overcome senescence yet. If such advances are achieved, common interpretations of the "immortal robot" argument and its derivative claims would suggest that life for human beings would transform from an ultimate value to some lesser value or to no value at all. This implication reveals a flaw in arguments that rely on the finitude of life and the inevitability of death. How is it that, by making life longer, healthier, and of higher quality (with less suffering due to the diseases of old age), humans would, in so doing, deprive life of its status as an ultimate value? If life is improved, it does not thereby lose a moral status that it previously possessed.

But suppose that a true immortal, indestructible robot could exist and be identical to human beings in every other respect. Even if death were not a possibility for such a being, it could still pursue and enjoy art, music, inventions, games - any activity that is appealing from the perspective of the senses, the intellect, or the general civilizing project of transforming chaos into order and transforming simpler orders into more complex ones.

The fear of death is not the sole motivator for human actions by far. Indeed, most great human accomplishments are a result of positive, not negative motivations. I concur fully with the goal of a full life, of flourishing, and recognize the existence of numerous positive motivations besides mere survival. For example, the desire to see oneself create something, to witness a product of one's mind become embodied in the physical reality, is a powerful motivation indeed. One can furthermore seek to take aesthetic pleasure from a particular object or activity. This does not require even a thought of death. Creating art and music, undertaking scientific discoveries, envisioning new worlds - actual and fictional - does not rely on having to die in the future. None of these activities even rely on the threat of death. Life is not merely about survival and should be about the pursuit of individual flourishing as well. Survival is a necessary prerequisite, but, once it is achieved, an individual is free to pursue higher-order values, such as self-actualization. The individual would only be further empowered in the quest for flourishing and self-actualization in a hypothetical environment where no threats to survival existed.

Thursday, February 25, 2016

There are a growing number of theories on the mechanisms of Alzheimer's disease. The biochemistry of the brain is very complex and still incompletely mapped, and it is cheaper to theorize than it is to build therapies and test them, so the theorizing is always going to be far more extensive and diverse than ongoing efforts to treat the condition. This is especially true since the consensus efforts based on clearing amyloid from the brain have yet to produce compelling results in trials. It is unclear as to whether this is because it is a difficult challenge, even for the present state of biotechnology, or because it isn't yet the right direction.

This theory focuses on rising levels of oxidative damage to lipids and cholesterols, a process that plays an important role in other age-related disease, such as atherosclerosis. These oxidized molecules can spread throughout the body via the bloodstream, allowing inflammation and generation of reactive oxidizing molecules caused by scattered damaged or senescent cells to contribute to aging everywhere.

Alzheimer's disease (AD), the most common neurodegenerative disorder associated with dementia, is typified by the pathological accumulation of amyloid Aβ peptides and neurofibrillary tangles (NFT) within the brain. Considerable evidence indicates that many events contribute to AD progression, including oxidative stress, inflammation, and altered cholesterol metabolism. The brain's high lipid content makes it particularly vulnerable to oxidative species, with the consequent enhancement of lipid peroxidation and cholesterol oxidation, and the subsequent formation of end products, mainly 4-hydroxynonenal and oxysterols, respectively from the two processes.

The chronic inflammatory events observed in the AD brain include activation of microglia and astrocytes, together with enhancement of inflammatory molecule and free radical release. Along with glial cells, neurons themselves have been found to contribute to neuroinflammation in the AD brain, by serving as sources of inflammatory mediators. Oxidative stress is intimately associated with neuroinflammation, and a vicious circle has been found to connect oxidative stress and inflammation in AD. Alongside oxidative stress and inflammation, altered cholesterol metabolism and hypercholesterolemia also significantly contribute to neuronal damage and to progression of AD. Increasing evidence is now consolidating the hypothesis that oxidized cholesterol is the driving force behind the development of AD, and that oxysterols are the link connecting the disease to altered cholesterol metabolism in the brain and hypercholesterolemia; this is because of the ability of oxysterols, unlike cholesterol, to cross the blood brain barrier. The key role of oxysterols in AD pathogenesis has been strongly supported by research pointing to their involvement in modulating neuroinflammation, Aβ accumulation, and cell death.

Thursday, February 25, 2016

Last year, researchers demonstrated a link between mitochondrial dysfunction and cellular senescence, both implicated as mechanisms of aging. It isn't clear at this stage whether the link demonstrated is relevant in normal aging, as the senescent state produced through induced mitochondrial dysfunction doesn't appear to be the same as that observed in naturally aged tissues, but it is nonetheless quite intriguing. Here is a commentary on that research from one of the scientists involved:

Mitochondria are the primary source of energy (largely in the form of ATP) for most of our cells. They also more closely resemble bacteria than they do other parts of the cell. In fact, they have their own unique genome that, much like bacteria, is circular. Moreover, our mitochondrial DNA acquires mutations much more rapidly than our nuclear genome - due to a combination of weaker DNA repair and close proximity to reactive oxygen species (ROS) produced by respiration. These and other factors result in a state in which mitochondria become less and less functional as we age, a term generically called "mitochondrial dysfunction".

We show that cells with mitochondrial dysfunction undergo cellular senescence - a tumor-suppressive process that permanently halts cell division. However, these senescent cells lack many of the secretory features of the other types of senescence that we and others have studied. Cells that undergo mitochondrial dysfunction-associated senescence (MiDAS) secrete many biologically active factors, but they don't produce many of the typical inflammatory molecules produced by other forms of senescence. Instead, these cells secrete their own unique blend of biologically active factors that prevent adipogenesis and promote skin cell differentiation. In a model of mice that age prematurely due to mitochondrial mutations, MiDAS cells accumulate in fat deposits and skin, causing the mice to lose fat, lose hair, and develop very thin skin as they age.

Mechanistically, MiDAS occurred due to decreased cytosolic NAD+/NADH ratios. Mitochondria oxidize NADH to NAD+ as part of normal respiration, so when mitochondria are compromised NADH levels rise in the cell. As a consequence of lower NAD+/NADH ratios, AMP and ADP rise, leading to activation of AMP-activated protein kinase (AMPK), which then phosphorylates and activates p53 - a major mediator of senescence. Therefore, senescence is a natural outcome of metabolic stress following mitochondrial compromise. NADH can be oxidized by alterative means - and addition of factors such as pyruvate to the culture media allowed mitochondria-independent enzymes to oxidize NADH, restoring the NAD+/NADH ratio. When cultured in the presence of these compounds, cells with mitochondrial dysfunction grew normally and did not senesce. Surprisingly, these non-senescent cells had a secretome that largely resembled the canonical senescence-associated secretory phenotype (SASP)! Upon pyruvate withdrawal, these cells underwent senescence and lost their SASP-like secretome.

Many questions are still unanswered. Do MiDAS cells accumulate during normal aging? If so, where and when do they do so? Are NAD-targeted therapeutics still beneficial if they allow secretion of inflammatory factors? More importantly, can we target these cells to prevent or even cure some of the disorders associated with aging? Now that we know that MiDAS exists, we are positioned to answer these important questions.

Friday, February 26, 2016

Even small changes in the trajectory of aging bring enormous economic gains, and here I'll point out an interview with one of the few economists to have modeled these gains, albeit for small increases in healthy life span after the Longevity Dividend view of slightly slowing the progression of aging via calorie restriction mimetic drugs and the like. Most expenditure on healthcare occurs due to aging, and increases greatly in the final stages of life. Care of those disabled by aging and the provision of largely palliative therapies for late stage age-related disease are both expensive undertakings, and because existing treatments don't target the causes of aging and age-related disease they are also unreliable and of only marginal benefit. This situation will change radically in the years ahead as the first therapies following the SENS vision for rejuvenation biotechnology arrive in the clinic, capable of repairing the cell and tissue damage that causes aging, with senescent cell clearance and transthyretin amyloid clearance first out of the gate. The deployment of the full spectrum of SENS treatments will do far more than add just a couple of years to life.

ResearchGate: What are the economic benefits of delayed aging?

Dana Goldman: We need to think about benefits more broadly than just traditional measures like Gross Domestic Product (GDP). Now that people are living longer, we need to make decisions about a whole host of treatments for diseases like cancer and Alzheimer's that are much more prevalent post-retirement. Thus, economists have developed ways to think about - and measure - the benefits of a healthy, productive life using the concept of a quality-adjusted life year. Thus, the 'economic' benefits come from better functioning, improved cognition, and a life free of comorbidities as much as possible. The key benefit of delayed aging is not just to extend life, but to also reduce the amount of time we spend with disability and disease - all of which can be measured and valued.

RG: How do the projected benefits compare with the costs?

DG: Once we do a good job valuing the health gains - both in terms of life expectancy and quality of life - it is clear that the benefits likely outweigh the costs by a factor of ten or more. This does not mean that delayed aging will pay for itself in reduced health care spending - quite the contrary. However, it is a very different question to ask if the medical spending is less or more than to ask if the benefits outweigh the costs. That is because the benefits include all the value we place on healthier, longer life. For example, we find that if the promise of delayed aging is fully realized - based on the best animal models - we could increase life expectancy by an additional 2.2 years, most of which would be spent in good health. The economic value of would be about 7.1 trillion over fifty years - with little additional government costs if we index Medicare and Social Security to the life expectancy increases.

RG: Research has shown that delayed aging simultaneously lowers the risk of all fatal and disabling diseases. What changes to healthcare systems and related costs do you foresee?

DG: This makes delayed aging a lot like other important interventions we know about, like reduced smoking, more physical activity, or a better diet. All of those 'treatments' have benefits for a constellation of illnesses. The big change we need is to make sure the health care system is rewarded for keeping people free of disease, rather than getting paid only when people get sick.

Friday, February 26, 2016β-secretase-inhibitors-as-a-therapy-for-alzheimers-disease.php

One approach to the treatment of Alzheimer's disease is to interfere in the production of β-amyloid rather than trying to clear it after it has been produced. Insofar as Alzheimer's is a disease of amyloid accumulation, the evidence suggests it results from a gradual failure of clearance and filtration mechanisms operating on cerebrospinal fluid, and amyloid levels are fairly dynamic on a short time frame. This makes blocking production more viable here than in age-related conditions where the causative metabolic waste accumulates and clears only slowly. One possible way to block production is to interfere with the proteins that produce β-amyloid from amyloid precursor protein, but as this article points out, that has proven to be challenging:

Protein deposits in the brain are hallmarks of Alzheimer's disease and partly responsible for the chronically progressive necrosis of the brain cells. Nowadays, these plaques can be detected at very early stages, long before the first symptoms of dementia appear. The protein clumps mainly consist of the β amyloid peptide (Aβ), a protein fragment that forms when two enzymes, β and γ secretase, cleave the amyloid precursor protein (APP) into three parts, including Aβ, which is toxic. If β or γ secretase is blocked, this also inhibits the production of any more harmful β amyloid peptide. Consequently, for many years biomedical research has concentrated on these two enzymes as therapeutic points of attack. To date, however, the results of clinical studies using substances that block γ secretase have been sobering. The problem is that the enzyme is also involved in other key cell processes. Inhibiting the enzymes in patients therefore triggered severe side effects, such as gastrointestinal hemorrhaging or skin cancer.

For a number of years researchers have also been focusing their efforts on β secretase. A large number of substances have been developed, including some highly promising ones that reduced the amount of Aβ in mouse models effectively. Nevertheless this presents the same challenge: "The current β secretase inhibitors don't just block the enzyme function that drives the course of Alzheimer's, but also physiologically important cell processes. Therefore, the substances currently being tested in clinical studies may also trigger nasty side effects - and thus fail." To address this, researchers studied how β secretase might be inhibited selectively - in other words, the harmful property blocked without affecting any useful functions. In a series of experiments, the scientists were able to demonstrate that the Alzheimer's protein APP is cleft by β secretase in endosomes, special areas of the cells that are separated by membrane envelopes, while the other vital proteins are processed in other areas of the cell. The researchers exploited this spatial separation of the protein processing within the cell.

"We managed to develop a substance that only inhibits β secretase in the endosomes where the β amyloid peptide forms. The specific efficacy of our inhibitor opens up a promising way to treat Alzheimer's effectively in future, without causing the patients any serious side effects." The researchers' next goal is to hone their drug candidate so that it can initially be tested in mice and ultimately in clinical studies on Alzheimer's patients.


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