Fight Aging! Newsletter, May 16th 2016

May 16th 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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  • Help Crowdfund Senescent Cell Clearance as a Therapy for Aging at the Major Mouse Testing Program
  • It is Vital to Accelerate Development of Means to Effectively Treat the Causes of Aging
  • Help to Crowdfund More Progress Towards DRACO Universal Antiviral Therapies
  • Why Do So Few Wealthy, Sick Individuals Fund Medical Research to Treat Their Conditions?
  • Yes, in Principle Aging can be Controlled and Altered to a Large Degree
  • Latest Headlines from Fight Aging!
    • Improving Stem Cell Transplant as a Treatment for Retinal Degeneration
    • Age-Related Inflammation Drives Development of Atherosclerosis
    • Epigenetics and the Programmed Aging View
    • GADD45β in the Mechanisms of Fasting and Calorie Restriction
    • Negligibly Senescent Species in the Context of Longevity Science
    • Towards Stem Cell Medicine that Doesn't Involve Stem Cell Transplants
    • Reporting on a Recent Study of Mitochondrially Targeted Antioxidant SkQ1
    • An Example of Present Attitudes on Treating Aging in the Research Community
    • Autophagy Required for Cancer Metastasis
    • Drawbacks to Healthy Life Extension? What Drawbacks?


The cadence of SENS rejuvenation research fundraising this year will be a little different from that of past years. There will be more groups involved and more smaller initiatives running through existing crowdfunding sites for a start. The first of these fundraisers for 2016 has launched at crowdfunding site, and is definitely worthy of our support. The Major Mouse Testing Program is a new non-profit group of researchers and advocates, who have spent the last six months making connections and laying the groundwork to run more animal studies of SENS-relevant prototype therapies focused on health and life span. This is an important gap in the longevity science community as it exists today: consider the painfully slow progress in organizing animal studies in senescent cell clearance over the past five years, for example. Given more enthusiasm and more funding, that could have happened a lot faster. Consider also that the research mainstream - such as the NIA Interventions Testing Program - carries out very few rigorous health and life span studies of potential interventions for aging in mice, and of those almost none are relevant to the SENS approach of damage repair, the only plausible path to radical life extension within our lifetimes.

Animal studies are vital; not just one or two, here or there, but a systematic approach to generating rigorous supporting data, establishing dosage, and uncovering unexpected outcomes. The Major Mouse Testing Program can do a great deal to fill this gap for our community, and has the potential to be an important supporting organization for the SENS Research Foundation, for startups working on SENS technologies such as Oisin Biotechnologies, and for labs involved in SENS research. The more diversity the better. The only thing that the Major Mouse Testing Program lacks today is the initial funding and support that we can provide to give them a good start on their plans for the future. With clever organization, a non-profit organization allied with established labs can carry out solid animal studies at a cost low enough for people like you and I to fund the work via fundraisers, and that is exactly what we should do.

I have stepped up to donate to this first fundraiser for the Major Mouse Testing Program, and I hope that you will too. This is a useful, needed initiative, the people involved are solid members of the community, doing the right thing, and pulling together the right networks, and they deserve our support. This first crowdfunding initiative is focused on expanding animal studies of drug-based senescent cell clearance approaches, in collaboration with existing groups that are working in this field. Remember, however, that this isn't just about setting up one set of experiments. This is the first step in building out an organization that can help greatly in the years to come, as the field of potential rejuvenation treatments expands, and the need grows for the non-profit groups in our community to specialize and diversify. This is one piece of the larger picture of building a network of research and advocacy at all levels that will shape the next few decades of progress towards effective therapies to treat and control the causes of aging.

Testing a new class of compounds, senolytics, on their ability to extend healthy lifespan by clearing out dysfunctional cells in the body.

According to modern science aging is the accumulation of damage that the body cannot completely eliminate, due to the imperfections of its protection and repair systems. The good news is that the processes that constitute aging are amenable to medical intervention. We can slow down or even reverse some aspects of aging through the application of different therapies, which prevent or block some of these processes. One of these processes of aging is cell senescence. Senescent cells normally self destruct via a process called apoptosis, but unfortunately not all of them do. These "death resistant" senescent cells accumulate in the body with age and secrete toxic signals. This causes inflammation and damage to organs and tissues, increasing risks for cancer and other diseases of old age. This is why these cells are often called "good citizens but bad neighbors". They remain partially functional, but their presence does more harm than good. A new class of drugs known as senolytics have recently demonstrated the ability to remove senescent cells to improve health. However, the potential of senolytics to increase health and lifespan beyond current maximums remains unknown. This is what we at Major Mouse Testing Program want to investigate - with your help!

In our study we have opted to treat already naturally aged mice. These mice will be 16-18 months old (equivalent to a human of approximately 60 years old). This has two advantages: we speed up research, and also demonstrate the feasibility of translating senolytics to already middle aged or older humans. So far senolytics have only been shown to reduce the number of senescent somatic cells, but what effect do they have on stem cells? This has not been closely studied, and is a question we intend to fully answer in addition to the implications this presents for lifespan. It is entirely possible that senolytics taken alone may not extend maximum lifespan, but rather healthspan. Even if this is the case, it is no reason to be discouraged. What we learn in this first phase, paves the way for our next step - combining senolytics with stem cell therapy to encourage tissue regeneration. As part of our commitment to the sharing of scientific research the team plans to publish the results of our research as open access. We believe that knowledge should be shared and this is the level of our contribution to sharing and growing as a community together.

MMTP Campaign Launches to Test New Class of Cell-Clearing Drugs on Healthy Lifespan Extension

As we age our bodies accumulate damage in the form of dysfunctional cells that have entered a state called "senescence", which secrete toxic signals that can lead to chronic inflammation, higher rates of cancer and additional aging-related conditions. Today we proudly announce the launch of a new campaign to test compounds, already known to remove these harmful cells, on their ability to extend healthy lifespan: the Major Mouse Testing Program (MMTP). This program, supported by the International Longevity Alliance (ILA), aims to expedite the identification of compounds which have the potential to increase healthy lifespan in humans via robust testing in mice. By using cohorts of middle-aged mice, the likelihood of discovering promising compounds will be increased in the short term.

The project will be directed by Dr. Alexandra Stolzing at Leipzig University and will involve three compounds already shown to have "senolytic" (senescent cell clearing) properties: dasatinib, quercetin and venetoclax. As such compounds are already FDA approved to treat various cancers, any positive results obtained through the MMTP study would enable a fast-track towards clinical trials. With your support we can help screen these and many more promising senolytic compounds. By donating to the MMTP campaign, your funds can jump start a pipeline towards developing drugs that enhance our healthy life span well into the future. Please check out the campaign, share with your friends, and keep building grassroots support for life extension research!


In the long sweep of human history, there has never been an age in which advocacy could have made as big a difference as advocacy for aging research can make today. The scientific community stands at the gates of rejuvenation, of the effective medical control over the causes of aging. The forms of cell and tissue damage that distinguish old tissues from young tissues are cataloged. The consensus position in the research community is that accumulation of this damage causes aging. Rejuvenation therapies capable of repairing, preventing, or working around the damage of aging are not in the clinic yet, but are at various stages of development, from early clinical trials and development in startup companies, all the way back down the chain to research in progress with years of work left to accomplish. The wave is building up, but despite the promise, despite the goal of controlling the medical condition of aging, a condition that kills more than 100,000 people every day, there is very little interest and very little funding for this branch of medical science.

This is why we live in an age in which advocacy has such power. The science of aging and the plans to build effective treatments stand far, far ahead of the public perception, the funding, and the will to treat aging as a medical condition. Aging is natural, people say - but so is cancer, cancer is caused by aging, and you'd be hard pressed to find someone who thinks that cancer research should be halted. The choice to defeat cancer rather than treating it as set in stone, a part of life not subject to change, is the very same choice that our culture has yet to make regarding aging. Until the average person in the street, when asked about preventing aging so as to live longer in good health, has exactly the same response as is presently the case for cancer research, then progress towards the control of aging will remain slow and uncertain. If the aging research community had the same support and funding as stem cell science or cancer research, both energetic fields as a result of that support, then we would be solidly on our way towards an end to frailty, pain, and suffering in old age - an end to all age-related disease.

This has yet to happen, but it is only a matter of persuasion. The research, the scientists, the biotechnology industry are ready to productively use high levels of funding to finalize prototype rejuvenation therapies and take the results into clinics around the world. That funding and the support it requires are all that is missing. Thus advocacy - simple persuasion - can today change the world, change the very nature of the human condition, can save billions of lives, can rescue the frail and the sick, and prevent the healthy from becoming frail and sick. Progress in the medicine of rejuvenation is limited by funding, and fixing that problem requires nothing more than widespread agreement that these goals are worthwhile and desirable. At the large scale and over the long term of decades research priorities follow the will of the masses, the zeitgeist of the age. We need to change ours for the better.

At present a growing faction within our advocacy community believes that engaging with government and international bodies such as the World Health Organization (WHO) is an effective path to this end. The goal is to sway standards and regulatory bodies to declare aging to be a disease, and thus amplify the views of this community through the megaphones of these large agencies:

If Aging Could Be Stopped, Should It Be? The Need for Accelerated Development of Scientific Methods to Extend Lifespan

100,000 people die every day from age-related diseases - i.e. those deadly diseases (cardiovascular disease, cancer, diabetes, Alzheimer's disease), the risk of which increases with age in geometric progression due to a number of already known biological processes, which are collectively called "aging". Aging transforms active citizens from people who are benefiting society into people requiring state resources to maintain their ailing health. State budget losses include payments for the treatment of age-related diseases, social costs of care for the disabled, budget shortfalls due to tax losses from tax on personal income, etc. The bulk of the costs of medical care falls on the last years of life, therefore, prolonging the health years of citizens will allow to use available funds to address other socially important tasks. It is also hard to overestimate the social benefits from additional healthy years of life of older people, which they can devote to useful social activities or to education and care for their grandchildren.

The latest developments in medical and biological sciences have led to a paradigm shift where aging is now known to be a combination of pathogenic and harmful processes, the intensity of which increases with age. Moreover, recent discoveries show that these processes can be slowed down or even reversed. For example, caloric restriction alone increased maximum lifespan in mice by 40%; pharmacological interventions achieved an increase in lifespan by almost a third. Almost every year science is finding new animals (in 2016 - more than twenty), that exhibit a so-called "phenomenon of negligible senescence", meaning that the probability of death and age-related diseases of these animals, unlike humans, does not increase with age, providing them with healthy longevity and a much longer life expectancy than those of species closest to them. Moreover, scientists have already discovered dozens of drugs and other interventions that are able to extend healthy life expectancy and maximum lifespan in different animals, delaying the onset of age-related diseases and deaths associated with them. The need for a significant increase in aging research and intervention capacity against it to prevent age-related diseases and increase healthy life expectancy is also recognized by the international scientific community and even formed the basis for the signing of the Open Letter on Aging Research by 57 of the world's leading scientists.

An understanding of aging as a disease is gradually entering into the global health discourse. Today, deep old age (senility) is recognized as a disease by the WHO. However, recognizing the above late-stage manifestations of aging does not resolve the underlying problem of aging. Aging as a set of reversible disease processes begins at a relatively early age and requires specific approaches to combat (control, treat, compensate) from the early stages of its development. Aging is a global phenomenon, and the fight against it requires special medical and biological approaches, as well as government support. This corresponds to subjective factors (the degree of scientific understanding of aging processes and the methods of control and control), and objective factors - both of medical and biological nature and those related to the economy and the sociology of healthcare.

We should begin an open dialog on whether age-related pathologies should be formally classified as a disease - and not just recognized nationally, but also internationally within the framework of WHO's ICD-11, as such classification is a prerequisite for substantially increasing worldwide government funding dedicated to finding successful treatments for age-related pathologies - treatments that would greatly increase healthy lifespans. We can start by engaging our governments on where science is today in its understanding of what biological mechanisms cause age-related diseases and how we can fix them, and then hold public debates on whether there is enough scientific evidence to begin the process of classifying aging as a disease. The next step could be an establishment of a National Strategy for Life Extension and a dedicated task force responsible for the coordination of scientific and practical efforts aimed at increasing longevity and fighting aging. The world already knows successful precedents where some countries are mobilizing the international scientific community for the development of therapies for a variety of diseases.

It is an absolute certainty that eventually humanity will conquer aging, just as it had conquered a host of previously terminal diseases thanks to vaccines and antibiotics. But if we want the victory over aging to happen before it is too late for our loved ones, the time to act is now.


A new crowdfunding effort is running to gather funds and support to push forward with DRACO antiviral technology. DRACO stands for double-stranded RNA activated caspase oligomerizer, a class of designer molecules that can selectively destroy cells that are hosting viruses. Viruses hijack cellular machinery in order to replicate, and that process has a distinctive signature: all known viruses produce double-stranded RNA during replication, and that double-stranded RNA is not not otherwise found in our cells. Thus any cell containing these molecules is fair game. Since DRACO therapies don't target any of the other highly varied molecular machinery of the virus itself, but rather prevent the virus from effectively multiplying its numbers, they can be used against near any target virus without much need for specialization or adjustment. It has proven effective against a score of very different viruses in tests in past years.

DRACO is a big deal, a real, potentially truly disruptive medical technology with solid evidence in animal studies to back up the claims. It might be used to up-end the entire field of antiviral therapies, and in principle can effectively treat and defeat near all viruses in near all of the species we care about. Needless to say even in our own species there are plenty of serious viral infections for which there is presently no effective treatment. DRACO could fill all of those gaps. The early development of DRACO is a shining example of how searching for commonalities in an otherwise highly complex field can find ways to turn a very expensive process of addressing thousands of targets individually into a process of addressing one target - a solid, cheap, effective, single path forward.

But of course all good ideas have to be forced on the world. No radical improvement or beneficial departure from the status quo goes unopposed. Just as in our community we are faced with the need to persuade people that we can and should use medical technology to address the root causes of aging and thereby live longer in good health, and we scramble to try to find meaningful levels of funding for rejuvenation research, so too DRACO is stuck in the funding gap that often follows great initial results in animal studies. It is a measure of the madness of the world we live in that such promising technologies can languish for years, or simply never be adopted, and that it requires scores of people to advocate and persuade to keep the work moving forward. Fortunately in this day and age ordinary folk like you can I can band together and do something about this: we can support fundraisers and help to persuade those we know of the value of DRACO. The world is full of people who have presently incurable viral infections, and once we include cytomegalovirus in that list, a cause of age-related immune system degeneration, that is pretty much all of us by the time we are old. People should be beating a path to the door of DRACO's inventor, not living an uncomfortable life without even knowing that this technology exists.

So, quite separately and aside from the usual focus here on aging research and furthering human longevity, I am happy to be able to put my money where my mouth is for DRACO and contribute to this latest fundraiser. I did so today. I hope that you will consider doing so too.

IndieGoGo: DRACOs May Be An Effective Cure For Viral Diseases

We are now raising funds to test and optimize DRACOs against the herpesvirus family, which contains many major clinical viruses such as Herpes Simplex Virus 1 (HSV-1), Herpes Simplex Virus 2 (HSV-2), Cytomegalovirus (CMV), Varicella Zoster Virus (VZV, chickenpox and shingles virus), Epstein-Barr Virus (EBV), and Kaposi's Sarcoma Herpesvirus (KSHV). If we can raise enough funding, we also hope to test and optimize DRACOs against the family of retroviruses, which includes Human Immunodeficiency Virus (HIV) and Human T-Lymphotropic Virus (HTLV). In principle, the DRACO approach should be effective against virtually all known viruses, or potentially even against new viruses that may appear.

DRACOs could potentially revolutionize the treatment and prevention of viral infections, just as the development of antibiotics revolutionized the treatment and prevention of bacterial infections in the mid-20th century. With your help, we hope that DRACOs may ultimately end suffering and save lives of those struggling with any number of viruses. By the process of efficiently eliminating only virus-infected cells, DRACOs may be able to permanently cure viral infections that can currently only be controlled but not cured by existing antiviral therapeutics. When tested in human and animal cells, DRACOs have been nontoxic and effective against 18 different viruses, including rhinovirus (the common cold) and dengue hemorrhagic fever. For more information on the results of previous DRACO experiments, see the article published in PLOS ONE.

The drug approval process is unfortunately long and complicated. What we know is that 4 years (or potentially less depending on funding and results) should be enough time to test and collect enough data on clinically relevant herpes viruses that should persuade partners to help advance DRACOs toward human clinical trials. We are committed to testing and optimizing DRACOs against clinically relevant viruses as rapidly and as thoroughly as funding will permit, and we hope to see DRACOs advance to human trials as soon as possible. The greatest challenge has been securing funding to help DRACO research progress. It is also important to note that while DRACO is based on sound scientific principles and has yielded promising experimental results thus far, biological systems are very complex and we can offer no guarantee that DRACO research will end with a pill in a bottle for everyone. Without your help, though, we may never find out. If successful, the results of those experiments should persuade pharmaceutical companies and other major sponsors to commit their own resources to advance DRACOs through large-scale animal trials and hopefully human trials. Without your assistance, DRACOs may never progress further, and their potential to revolutionize the treatment of viral infections may remain unfulfilled.


There are a lot of people who have both a medical condition and a lot of wealth - tens of millions or more. In this day and age, a fraction of that wealth is enough to produce a prototype treatment from scratch for many classes of condition, if you are willing to wait the decade or two that low-cost basic science takes to run its course. Alternatively, for a faster result in the five year range, that much money is enough to take a couple of promising potential therapies with initial animal studies and move them to prototype status. Not all conditions are amenable to this sort of approach, but many are. When you have a prototype, you license it freely to maximize the odds that it will be picked up and improved upon, and meanwhile pay a reputable clinic in one of the less regulated portions of the world to set it up for your own use. This is all very possible for a wide range of medical conditions. Why is it that so few wealthy, sick people take this path?

In the longevity science community we tend to ponder a very narrow facet of this question, which is ask why, with very few exceptions, the wealthy of the world are not funding rejuvenation research. They are all aging to death, just like the rest of us. Why are they walking off the cliff when they have a good shot at preventing that outcome? Yet the broader question is also of interest: not just aging research, but all medical research. I was pondering this after donating to the present crowdfunding initiative for DRACO, a universal basis for cheaply creating effective treatments for any and all viral infections, such as those that are poorly controlled and afflicting large numbers of people today. How many individuals are there with both resistant viral hepatitis and enough money to take DRACO to what its inventor considers the finish line of readiness for human trials? The cost of that is a few million at this point. I can think of a couple of individuals from the last celebrity generation alone who are in this demographic. But of course it isn't happening, these people are not jumping in to make waves and build out a prototype therapy that could cure or control their infections. So it seems to me that perhaps our first problem with regard to funding rejuvenation research isn't in fact a matter of convincing the world that treating aging is a viable goal in medicine. That is a challenge, and has to be accomplished, but it isn't the first issue in line. That first problem is that next to no-one with the wealth to have a fair shot at solving their own medical problems through funding research thinks that they can in fact achieve that goal.

We can debate as to just why this is the case. For example, firstly there is simple ignorance of the possibilities. Some people and their supporting networks don't have the framework of ideas that lights the way. I think it isn't unfair to say that most people don't have any great insight into medicine as a system that can be changed and improved. I certainly didn't for half of my life. Engaging with doctors and learning about a specific condition because you happen to have developed it may or may not provide that insight - it strongly depends on the individual. The state of medicine and even the state of waiting for better medicine can be taken as set in stone. You can be good enough at what you do to become very wealthy, and yet lack the ability or patience or drive - or that framework of ideas - to learn the science behind the medicine, see that this science can be influenced, and understand the economics and connections well enough to see how to influence it. That is a tall order for someone who has invested decades in the minutiae of their own business and profession, a hard right turn in life, and a significant investment in time and will.

Secondly, there is a poster child effect here. Consider Michael J. Fox as one example, someone who has given large sums to Parkinson's disease research over the past two decades. Unfortunately, this is a condition in which it will take a long time and enormous funding to establish effective treatments, as is the case for most neurodegenerative diseases at this time. Conditions for which this is true tend to get a lot of the press, since there is more work taking place, and also more philanthropy. Secondly, the span of Fox's philanthropy crosses from a time in which life science work was very expensive and time-consuming into the present in which it is much cheaper and faster. Medical research is very much easier today than it was at the turn of the century: all of the tools are greatly improved, as is knowledge of cellular biochemistry. But people think of this, and similar cases, and see decades of expense and no resulting cure. Subtleties such as the considerable progress achieved in both understanding the condition and building a foundation for treatments yet to come are somewhat lost on the world at large.

Thirdly, it is enormously expensive to move from prototype therapy to clinical availability through the regulatory gauntlet. That is well understood, and it is why most people think of medical research as fantastically expensive. But it is not. Building prototypes is cheap. Early stage research and investigation can be so cheap that it can be crowdfunded by ordinary people like you and I. It is the testing required to prove reasonable safety for clinical translation of a prototype therapy that is merely ordinarily expensive. Then it is the over the top regulatory compliance that is par for the course in the US and Europe that drives the cost through the roof, restricts all meaningful clinical development inside the system to the entrenched Big Pharma interests, and ensures that all too many lines of research are never developed, and never even fully researched, as they cannot be cost-effective.

This is why I point out the strategy of open licensing and medical tourism. Build the prototype, then give it away and undergo the treatment yourself. We live in a world in which the BioViva CEO can be (probably) the first human to undergo a particular gene therapy with good animal data, and get that done for a low six figure cost or less. Regulation and its tremendous costs are not needed to produce a treatment that can be judged safe enough to risk - and that choice of safety should be up to the individual in any case. Again, however, near all of the people with the money to do this sort of thing from scratch, and with a condition that might be treated, don't see things this way. Wealth doesn't magically grant knowledge or wisdom. They, like most people, view medicine as an enormously expensive undertaking, far beyond their ability to move the needle, where they think of it as something that can be influenced at all.


The popular science article I'll point out here is written from a programmed aging point of view, in which - to simplify greatly - epigenetic change is considered to be the root cause of aging, changing the operation of cellular metabolism so as to generate damage, dysfunction, and death. One of the authors maintains a blog, and you'll find much more on his take on programmed aging there. I consider the opposite view to be more plausible, that the root cause of aging is accumulated damage, produced as a side-effect of the normal operation of metabolism, and that where we observe epigenetic changes in aging, they are a response to rising levels of damage. Placing this crucial difference to one side for one moment, the article below does makes an entirely valid point, which is that the enormous evolved variation in life histories in the natural world - in the pace and character of aging and species longevity - indicates that it is in principle possible to engineer a radically different human metabolism in order to create individuals who undergo slower aging, and down the line that sort of approach could be used to produce negligibly senescent or even ageless branches of humanity.

Why Aging Isn't Inevitable

Humans age gradually, but some animals do all their aging in a rush at the end of life, while others don't age at all, and a few can even age backward. The variety of aging patterns in nature should be a caution sign to anyone inclined to generalize - particularly the generalization that aging is inevitable. Life spans range from Methuselans great and small to genetic kamikazes that die of a spring afternoon. Submerged dragonflies live four months, adult mayflies half an hour. We live some 70-odd years; but the meristem of the ginkgo may be millions of years old. This range becomes all the more impressive when we realize that the genetic basis for aging is widely shared across different species, from yeast cells on up to whales. Somehow, the same genetic machinery, inherited from our common ancestors at the dawn of life on Earth, has been molded to generate life spans ranging from hours (yeast cells) to thousands of years (sequoia trees and quaking aspen).

And it is not only the length of life but the pattern of deterioration within that time that varies widely. Aging can occur at a steady pace through the course of an entire lifetime (most lizards and birds), or there can be no aging at all for decades at a time, followed by sudden death (cicadas and century plants). Our own "inner assassin" works with stealth, like an evil empress gradually poisoning her husband; but other species have inner killers that do their deed far more quickly, and still others appear to have no genetic death programs at all. Such variety is a sure signal for a feature molded by active natural selection, not an immutable law of entropy. The great variety of aging styles among plants and animals suggests it can be controlled.

Suppose we were to remove length of life completely from consideration and compare different species based on the shape rather than the duration of their life histories. However long or short the life span, we display it in the same size box for comparison. Rather than asking how long they live, ask instead whether their populations tend to die out gradually, or if many die in infancy and fewer later on, or if all the deaths bunch up at the end of the life cycle. The strange bedfellows that appear as neighbors on the chart are utterly unexpected. For example, at the top of the chart, with low mortality that rises suddenly at the end of life, humans are joined by lab worms and tropical fish (guppies)! In fact, in terms of aging profiles, we humans look more like the lab worm than the chimpanzee.

Styles of aging in nature are just about as diverse as they can be, which suggests that nature is able to turn aging on and off at will. With this in mind, we may be forgiven for regarding theories that explain why aging must exist with extreme skepticism. Whatever our theory of aging turns out to be, it had better make room for plasticity, diversity, and exceptions.

I do not believe that building a variant of human biochemistry to produce negligibly senescent individuals is a near term project in any way, shape, or form. It is certainly possible, and may well be accomplished, but in the same sense as building out human habitats in high Jupiter orbit is possible, and may well be accomplished. Both are projects that could be eclipsed and rendered retro-futures by any number of advances over the decades ahead: why invest in building a negligibly senescent human biochemistry in a world in which we can discard our biology to merge with the machinery of a mature molecular nanotechnology industry, becoming ageless, durable, and repairable, for example? Or why do it if by the time it is plausible the medical community can already comprehensively repair the biological damage that causes aging?

At the present time we stand at least decades from even a comprehensive map of healthy, normal metabolism. Applications of that knowledge will require longer to arrive, and based on existing experience that work will be painfully challenging. Over the past fifteen years, it has required scores of researchers and a few billion in funding to somewhat improve the state of knowledge for one small set of genes and processes involved in calorie restriction, a very well-studied altered state of metabolism that modestly increases health and longevity. The research community is nowhere near a full accounting of how calorie restriction works, or any way to turn it on safely all the time, or even good ways to recreate some of its effects using the standard panoply of drugs and gene therapies. All of that effort could be repeated ten times over between now and 2030 and researchers would still be only a little further along in the process of figuring out how it all works in detail. The molecular biology of life is fantastically complex.

I point this out, as usual, to illustrate why the SENS approach of repairing damage is really the only viable way forward to radical life extension in our lifetimes. The cell and tissue damage that causes aging - that is the signature difference between old and young tissues - is well cataloged, agreed upon in many diverse fields of medical research, and there are plausible ways to repair it either under development or that are planned out in some detail. Given the vast costs and length of time needed to get to the point of being able to defeat aging by creating a new human metabolism, it is vitally important that we have an alternative approach to rejuvenation and agelessness that requires little to none of that effort in order to progress. It really is as simple as periodically fixing the damage and observing the results, a process that is taking place for senescent cell clearance in mice right now, today. This and other similar efforts in the years ahead will help map cause and effect and relative contributions to specific age-related diseases, but much more importantly will also produce the basis for rejuvenation therapies - and produce them soon enough to matter to people alive today.



Researchers have made use of human mesenchymal stem cells to effectively delay retinal degeneration in rats. In this study the authors demonstrate that, as in many other cases, the methodology of delivery matters just as much as the details of the cells used:

Retinal and macular degenerative diseases affect millions of people worldwide. Similar to other neurodegenerative diseases, there are no effective treatments that can stop retinal degeneration or restore degenerative retina. Recent advances in stem cell technology led to development of novel cell-based therapies, some are already in phase I/II clinical trials. Studies from our group and others suggest that human bone marrow-derived mesenchymal stem cells (hBM-MSC) may be a promising source for retinal cell-based therapy.

Currently, one of the major challenges in stem cell-based therapy is how to safely deliver effective doses of cells to the target posterior eye tissues (retina, retinal pigment epithelium (RPE) and choroid), due to the unique anatomy and physiology of the eye. The current subretinal injection method involves three port pars plana, vitrectomy and insertion of a needle that penetrates the retina and, in doing so, detaches the photoreceptor cell layer from the RPE forming subretinal 'blebs'. Limited volumes can be injected and therapeutic effect is restricted to areas proximal to point of injection. Moreover, the subretinal surgery raises a significant safety issue, as the retinal architecture across the entire retina in age-related macular degeneration (AMD) and retinitis pigmentosa (RP) patients is fragile and the surgery can induce mechanical damage, reactive gliosis, and loss of function.

We have recently developed a new cell delivery system that enabled the transplantation of hBM-MSCs as a thin layer across the extravascular spaces of the choroid. We used this system in Royal College of Surgeons (RCS) rats, a widely used model of dry AMD and retinal degeneration. The graft covered most of the area of the back of the eye via a single injection with no retinal detachment or choroidal hemorrhages. Cell transplantation delayed photoreceptor degeneration throughout the whole retina and rescued retinal function for up to 5 months in RCS rats. By contrast, when hBM-MSCs were injected intravitreally, they formed a large cell clamp in the vitreous cavity and retinal function was rescued for a shorter duration, up to 12 weeks following transplantation. These findings suggested that the delivery method significantly affects therapeutic potential of transplanted cells, and that graft location, distance from the retina and graft surface area may be critical parameters for achieving effective treatment.


In its later stages atherosclerosis is a vicious cycle in which oxidized lipids and the remains of dead cells build up into deposits in blood vessel walls, growing because these deposits cause nearby healthy cells to signal for help. That produces an inflammatory response and attracts the immune cells called macrophages that try and fail to clean up the mess, adding their own remains to the disaster area. As a result of this process of ever-widening damage, blood vessels weaken, narrow, and are ultimately blocked, causing incapacity and death.

Inflammation in blood vessel walls is an important driver of atherosclerosis in its early stages as well. Levels of preexisting inflammation contribute to determining the tipping point between successful cleanup of a small deposit of oxidatively damaged lipids and failure of that cleanup, producing a persistent area of damage that will grow over time - the seed of atherosclerosis. An increasing level of chronic inflammation throughout the body is a characteristic feature of aging, caused by a combination of immune system dysfunction and various other factors. Here researchers discuss one of the mechanisms by which chronic inflammation contributes to the development of atherosclerosis:

Atherosclerosis in the aging population has well surpassed other age-associated diseases such as susceptibility to infection, chronic lung disease, and cancer as a cause of morbidity and mortality in older people. The strongest independent risk factor for the development of atherosclerosis is aging. This risk is greater than the additive risk of hypertension, hypercholesterolemia, and genetics accrued over time. Despite the ongoing threat of atherosclerosis in older people, our understanding of the mechanisms by which aging enhances atherosclerosis remains unclear and under investigated especially in relevant experimental disease models.

Aging may affect atherosclerosis through several mechanisms in hematopoietic cells, vascular cells, or both. For example, aging induces cellular senescence, which leads to DNA damage and impaired antioxidant responses resulting in vascular inflammation that contributes to atherosclerosis. In addition, studies in disease-free animals have found that vascular aging induces oxidative stress in endothelial cells, and leads to medial vessel wall thickening, increased collagen, and extracellular matrix deposition. Endothelial cells (ECs) and vascular smooth muscle cells (VSMC) from disease-free animals exhibit enhanced secretion of inflammatory mediators with aging. Hence, these studies indicate that vascular aging may predispose to diseases such as atherosclerosis, yet whether such age-related vascular changes occur during atherosclerosis remains unclear.

Monocytes and their macrophage descendants are critical immune cells for atherosclerosis. Monocyte recruitment into aortas is critical during atherogenesis, whereas macrophage proliferation in the tissue enhances atherosclerotic lesion progression. Monocytes can be categorized into 'inflammatory' monocytes and 'patrolling' monocytes. Inflammatory monocytes are typically the initial cells recruited into inflammatory sites of the aorta that develop atherosclerosis. After recruitment, the cells engulf lipid particles, become 'foam cell' macrophages, and accumulate within atherosclerotic lesions. It is not known, however, whether aging enhances monocyte intrinsic function or whether aging impacts monocytes indirectly via the vasculature during chronic inflammatory diseases such as atherosclerosis.

Here, we examined how aging impacts atherosclerosis using Ldlr-/- mice, an established murine model of atherosclerosis. We found that aged atherosclerotic Ldlr-/- mice exhibited enhanced atherogenesis within the aorta. Aging also led to increased LDL levels, elevated blood pressure on a low-fat diet, and insulin resistance after a high-fat diet. On a high-fat diet, aging increased a monocytosis in the peripheral blood and enhanced macrophage accumulation within the aorta. When we conducted bone marrow transplant experiments, we found that stromal factors contributed to age-enhanced atherosclerosis. To delineate these stromal factors, we determined that the vasculature exhibited an age-enhanced inflammatory response consisting of elevated production of CCL-2, osteopontin, and IL-6 during atherogenesis. In addition, in vitro cultures showed that aging enhanced the production of osteopontin by vascular smooth muscle cells. Functionally, aged atherosclerotic aortas displayed higher monocyte chemotaxis than young aortas. Hence, our study has revealed that aging induces metabolic dysfunction and enhances vascular inflammation to promote a peripheral monocytosis and macrophage accumulation within the atherosclerotic aorta.


The present vocal but minority view in the aging research mainstream is that aging is an evolved program with a strong epigenetic component. In this view, epigenetic changes are keyed to age, occur first, and cause the cell and tissue damage associated with aging. In the majority view of aging as a consequence of damage accumulation, the damage occurs first, and epigenetic changes are then a reaction to this damage, causing secondary and later issues. There is so much work yet to do in mapping out the detailed molecular biology of the progression of aging, and the blank spots on the map so large, that these two entirely opposing viewpoints, each with many variations, can continue to theorize and thrive.

For the damage accumulation view of aging, we fortunately don't need the full map of the molecular details of aging, an explanation of exactly how damage causes each and every age-related disease, in order to make solid progress towards the defeat of aging. All researchers need to do is to repair the root causes of aging, the forms of fundamental damage that distinguish old and young tissues, and these are well known and well cataloged. The fastest way to figure out what they are linked to in terms age-relate decline is to fix them and see what happens - which is also the fastest path to meaningful therapies. So, for example, life extension in mice has been robustly demonstrated in the case of clearing senescent cells, and clearance therapies are on their way to the clinic despite the vast amount of data yet to be gathered on how exactly aging progresses without this contribution.

The programmed aging school does need the molecular map of aging for significant progress, however. In this view, researchers should be working to list and revert epigenetic changes, and that should then either stop further damage or allow damage to be repaired by natural processes. Some such initial reversions, such as increased GDF11 levels, have been shown to produce benefits by restoring stem cell activity in old individuals - but is entirely possible for an epigenetic alteration to produce some level of benefits even if aging is caused by damage, and without addressing underlying damage, by reducing secondary issues or by forcing systems into action where they are normally in decline as a reaction to damage. Perhaps there will be consequences, such as a raised risk of cancer, but so far in the case of stem cells it is all working out better than expected. These results have boosted the confidence of the programmed aging side of the field, but I think they still overstate their case given the varying weights of evidence.

For readers who know me less well, I should introduce my perspective: I believe that aging is an evolved epigenetic program. When we are young and growing, particular genes are turned on and off with exquisite timing to determine the growth and development of bones, muscles, and organs. When we are old, the program continues, more slowly and more diffusely, but inexorably nonetheless. Genes are turned on that destroy us with inflammation and cell senescence and auto-immunity and programmed cell death, while the systems that protect us from pathogens and from free radical damage are gradually shut down. Evolution has left nothing to chance. Epigenetics is a new science in the 21st century. All the cells in one body have the same DNA (pretty much), but different genes are "expressed" (translated into proteins) in different tissues and at different times, and this is what controls the body's metabolism. In fact, only 2% of our DNA is genes, and 98% determines how the DNA is folded and spooled, opened and closed at particular times and places, and this in turn controls gene expression. We are 2% genetic and 98% epigenetic. The part of the epigenetic code on which we have the best handle at present is called "methylation of CpG islands". Long stretches of DNA have CGCGCGCG... on one strand, complemented by GCGCGCGC... on the other. Often the C's in this region get an extra methyl group, turning from cytosine to 5-methylcytosine. Then this stretch becomes a "repressor region," a signal to NOT express the adjacent gene.

DNA methylation can be persistent, turning a gene off for decades at a time. When a cell divides and its DNA is copied, the methylation pattern can be copied with it. This accounts for some of the persistence of epigenetics, and the way gene expression can be inherited across generations. DNA methylation has been appreciated for 30 years, but two recent developments make the subject attractive and accessible to research. (1) There is now a simple lab/computer technique for reading the methylation pattern from DNA. It relies on commercially available, automated machinery for PCR to sequence a full genome before and after chemical modification of the methylated C's. (2) There is now a simple lab/computer technique for changing the methylation state of any chosen target site in the DNA. It is based on CRISPR technology that is taking genetics labs by storm the last two years.

The correlation between aging and epigenetic status is established beyond dispute. But what does it mean? This is the big question. Most researchers think of the body as programmed by evolution to be as strong and healthy as possible. So, when different genes are expressed in old age, they find it natural to assume that the body is protecting itself in response to damage that it has suffered over the years. We express different genes when we are older because we need different genes when we are older. The other possible interpretation is my own, and it has become common among those who are closest to the field of epigenetics. It is that epigenetic changes with age are means of self-destruction. The body is programmed to die, and its suicide plan is laid out in the form of transcribing an unhealthy combination of genes. This idea flies in the face of traditional evolutionary theory. (How could natural selection prefer a genome that destroys itself and cuts off its own reproduction?) Nevertheless, the evidence for this hypothesis is robust. The genes that are turned on don't protect the body - quite the opposite. Genes for inflammation are dialed up. Genes for the body's defense against free radicals are dialed down. Cell turnover is dialed down. DNA repair is dialed down. The mechanisms of programmed cell death (apoptosis) are strengthened in healthy cells, at the same time that they are perversely weakened in cells that are a threat to the body, like infected cells and cancer cells.

In my opinion, the existing evidence heavily favors the hypothesis that aging is caused by epigenetic changes, rather than the other way around. When we look at the kinds of changes that occur, they seem to be pouring fuel on the fire, not putting it out. Protective genes are turned off and inflammatory genes are turned up. I also think that parabiosis experiments provide a strong clue. Three research groups have shown that injecting blood plasma from a young mouse into an old mouse makes the old mouse healthier, and relieves some problems associated with age. The blood plasma contains no cells - only signal molecules that are the product of gene expression. This is powerful evidence that youthful gene expression is supporting a strong and youthful body, and (conversely) that the kind of gene expression that characterizes old age is not doing the body any good. But the ultimate experiment will be to re-program gene expression in an old mouse and see if there is a rejuvenating effect.


Lower calorie intake, while still obtaining required levels of micronutrients, has long been demonstrated to improve near all measures of health, leads to better quality of life, and modestly slows aging. A higher calorie intake leads to visceral fat deposition, metabolic syndrome, type 2 diabetes, fatty liver disease, and a shorter, less healthy life. Separately, fasting appears to have similar influences on health and aging to those produced by a lower calorie intake, but to some degree independently of overall calorie level - though it is worth noting that the body of research here is much smaller than that for calorie restriction without fasting. Since just about every aspect of metabolism is altered by calorie intake, both in the short term and over the long term, researchers attempting to understand how it all works at the detail level have an enormous task ahead of them. They are breaking off pieces of the puzzle one protein at a time, as in the research noted here, and will be doing so for a long time yet:

The growing number of overweight people has long been one of modern society's pressing issues. In particular the resulting metabolic diseases such as type 2 diabetes and corresponding secondary conditions can have serious consequences for health. A reduced intake of calories, such as in the framework of an intermittent fasting diet, can help to whip the metabolism back into shape - but why does this happen? Once we understand how fasting influences our metabolism we can attempt to bring about this effect therapeutically."

In the current study, the scientists looked for liver cell genetic activity differences that were caused by fasting. With the help of transcript arrays, they were able to show that especially the gene for the protein GADD45β was often read differently depending on the diet: the greater the hunger, the more frequently the cells produced the molecule, whose name stands for 'Growth Arrest and DNA Damage-inducible'. As the name says, the molecule was previously associated with the repair of damage to the genetic information and the cell cycle, rather than with metabolic biology. Subsequent simulation tests showed that GADD45β is responsible for controlling the absorption of fatty acids in the liver. Mice who lacked the corresponding gene were more likely to develop fatty liver disease. However when the protein was restored, the fat content of the liver normalized and also sugar metabolism improved.

The scientists were able to confirm the result also in humans: a low GADD45β level was accompanied by increased fat accumulation in the liver and an elevated blood sugar level. "The stress on the liver cells caused by fasting consequently appears to stimulate GADD45β production, which then adjusts the metabolism to the low food intake." The researchers now want to use the new findings for therapeutic intervention in the fat and sugar metabolism so that the positive effects of food deprivation might be translated for treatment.


This popular science article focuses on the study of negligibly senescent species in the context of work aimed at adjusting the course of human aging. There is at least one negligibly senescent mammal, the naked mole-rat, but it seems to me that attempting to mine benefits from other species and port them to humans is just another way to say we should re-engineer human metabolism to age more slowly. The past twenty years have demonstrated that this is enormously expensive and enormously challenging. Billions have been spent on trying to safely change just a few genes and proteins, and to try to better understand the modestly slowed aging of calorie restriction, with no practical result other than to add thin slices to our knowledge of metabolic processes. We should have similar expectations for the results of trying to obtain benefits from the biochemistry of another species - and going far beyond that in scope to produce a whole new human metabolism is very far from being a plausible project today.

The only way today to make practice, cost-effective progress towards very large gains in human longevity is to follow the SENS model of damage repair. The damage that causes aging is very well understood, and we don't need a full explanation of how exactly at the detail level that damage multiplies and interacts to contribute to every facet of aging. We don't need to adjust those facets or integrate them into a new working model of human biochemistry. All we have to do is periodically repair the damage, maintaining the youthful version of human biochemistry that we know works. It is an engineering approach in which we can bypass our ignorance of the details in order to produce working rejuvenation therapies here and now. Repair of the first form of damage is already in the clinical development pipeline: clearance of senescent cells. Others might follow soon, if there was just more support and funding.

The naked mole rat is the superhero of the animal kingdom. Similarly sized rodents usually live for about five years. The naked mole rat lives for 30. Even into their late 20s, they hardly seem to age, remaining fit and healthy with robust heartbeats, strong bones, sharp minds, and high fertility. They don't seem to feel pain and, unlike other mammals, they almost never get cancer. "It's not a ridiculous exaggeration to suggest we can one day manipulate our own biochemical and metabolic pathways with drugs or gene therapies to emulate those that keep the naked mole rat alive and healthy for so long. In fact, the naked mole rat provides us the perfect model for human aging research across the board, from the way it resists cancer to the way its social systems prolong its life."

Over the centuries a long line of optimists, alchemists, hawkers and pop stars have hunted various methods of postponing death, from drinking elixirs of youth to sleeping in hyperbaric chambers. The one thing those people have in common is that all of them are dead. Still, the anti-aging industry is bigger than ever. In 2013, its global market generated more than 216 billion. By 2018 it will hit 311 billion, thanks mostly to huge investment from Silicon Valley billionaires and Russian oligarchs who've realized the only way they could possibly spend all their money is by living forever. Even Google wants in on the action, with Calico, its 1.5 billion life-extension research center whose brief is to reverse-engineer the biology that makes us old or, as Time magazine put it, to "cure death." It's a snowballing market that some are branding "the internet of healthcare." But on whom are these savvy entrepreneurs placing their bets? After all, the race for immortality has a wide field.

British biomedical gerontologist Aubrey de Grey is enjoying the growing clamor about conquering aging, or "senescence," as he calls it. His charity, the SENS Research Foundation, has enjoyed a bumper few years thanks to a 600,000-a-year investment from Peter Thiel ("Probably the most extreme form of inequality is between people who are alive and people who are dead"). Though he says the foundation's 5.75 million annual budget can still "struggle" to support its growing workload. According to de Grey, the fundamental knowledge needed to develop effective anti-aging therapies already exists. He argues that the seven biochemical processes that cause the damage which accumulates during old age have been discovered, and if we can counter them we can, in theory, halt the ageing process. He says traditional medicines won't wind back the hands of our body clocks - we need to manipulate our makeup on a cellular level, like using bacterial enzymes to flush out molecular "garbage" that accumulates in the body, or tinkering with our genetic coding to prevent the growth of cancers, or any other disease. "If you look at the maths it is very straightforward. All we are saying here is that it's quite likely that within the next 20 or 30 years, we will develop medicines that can rejuvenate people faster than time is passing. It's not perfect yet, but soon we'll take someone aged 60 and fix them up well enough that they won't be 60 again, biologically, for another 30 years. In that period, therapies will improve such that we'll be able to rejuvenate them again so they won't be 60 for a third time until they are chronologically 150, and so on. If we can stay one step ahead of the problem, people won't die of aging anymore."

Of course, the naked mole rat isn't the only animal scientists are probing to pick the lock of long life. With a heart rate of 1,000 beats a minute, the tiny hummingbird should be riddled with rogue free radicals, the oxygen-based chemicals that contribute to aging by gradually destroying DNA, proteins, and fat molecules... but it's not. Then there are pearl mussel larvae that live in the gills of Atlantic salmon and mop up free radicals, and lobsters, which seem to have evolved to have more of a protein which repairs the tips of DNA, allowing for more cell divisions than most animals are capable of. And we mustn't forget the 2mm-long C. elegans roundworm. Within these 2mm-long nematodes are genetic mechanisms that can be picked apart like cogs and springs in an attempt to better understand the causes of aging and ultimately death.


In all but the most aged and damaged individuals, the beneficial effects of much of the present generation of stem cell transplant therapies could in principle be produced by stem cell populations already present in the body. These cells just need the right signals and instructions to be put to work. Gaining a sufficient understanding of those signals is a work in progress, and the existing approach of stem cell culturing and transplantation has been an important part of that work to date - a necessary step on the road. It is still the early days in this field when considering the bigger picture, but it is interesting to see that factions within the research and development community are already forging ahead towards a stem cell medicine that doesn't involve transplantation:

OxStem has closed a 24.4million fundraising round to design stem cell drugs that treat age-related diseases. The raise - the highest ever for a UK academic spinout - will go toward developing small molecule drugs that can activate repair mechanisms that already exist within the body. The biotech was first founded back in 2014. Building on decades of experience in medicinal chemistry, OxStem will design drugs that can programme resident stem and stem-like cells in situ to treat currently untreatable age-related conditions. This follows in-line with other biotechs looking to "cure old age."

Just last month, U.S. biotechs Ascentage Pharma and Unity Biotechnology signed a research pact to help reverse aging, using preclinical data focusing on senescent cells. Google is also attempting to make a splash in the expanded lifespan field with its upstart Calico, although this very early-stage and the tech giant is a little thin on the details. Others are looking to older meds that may contain previously unknown qualities - the top among which is the off-patent type II diabetes drug metformin. Studies are planned from U.S. academic and government centers in the next year to see if the drug can delay or prevent some of the most devastating diseases of advanced age, from heart ailments to cognitive decline to cancer.

OxStem is focusing on stem cell science, and in essence aims to switch on the body's natural regeneration and repair systems. Current stem cell treatments mostly focus on injection of cells into the body and are available only in hospitals with access to the specialist laboratory facilities needed to harvest, isolate and multiply stem cells. The biotech said it however plans to reprogram stem and stem-like progenitor cells that already exist in the body with no need for cell transplantation procedures. "We will identify small molecule drug candidates, which can programme adult stem and stem-like cells to repair and replace tissues affected by disease or injury. We are tackling many of the worst conditions associated with ageing: dementia, heart failure, cancer and macular degeneration, which is the leading cause of blindness in the developed world."


Here, researchers report on a recent study of the ability of mitochondrially targeted antioxidants to modestly increase healthy life span in lower animals such as the flies used here. Mitochondria are important in the progression of aging for a number of reasons, all of which seem to be very connected to the reactive oxygen species (ROS) they produce in the course of generating chemical energy stores to power the cell. ROS can damage mitochondrial structures, and that can lead to mutant mitochondria that take over and cripple cells, causing harm to surrounding tissues. ROS are also used as signals in many fundamental cellular processes, such as the response to exercise and triggering of cellular maintenance in response to stresses. Thus antioxidants targeted specifically to the interior of mitochondria have the ability to influence these processes, where other types of antioxidant cannot:

Mitochondria play an important role in aging. Strongly reduced function of the mitochondria shortens life span, whereas moderate reduction prolongs life span, with reactive oxygen species production being the major factor contributing to life span changes. Previously, picomolar concentrations of the mitochondria-targeted antioxidant SkQ1 were shown to increase the life span of Drosophila by approximately 10%. In this article, we demonstrate that SkQ1 elevates locomotion, which is often considered a marker of health and age. We also show that mating frequency and fecundity may be slightly increased in SkQ1-treated flies. These results indicate that SkQ1 not only prolongs life span but also improves health and vigor.

An important property of any potential therapeutic is the stability of its effects in an uncontrolled and changing environment as well as on individuals with various genetic constitutions. In this article, we present data on SkQ1 effects on Drosophila longevity in extreme environments (low temperatures and starvation) and on individuals with severe genetic alterations in the mitochondrial systems responsible for production and detoxification of reactive oxygen species. We hypothesize that in vivo SkQ1 is capable of alleviating the probable negative effects of increased mitochondrial reactive oxygen species production on longevity but is not effective when reactive oxygen species production is already reduced by other means.


This open access paper is quite representative of attitudes in much of the aging research community. Scientists are excited by the obvious burst of progress and possibilities, and changing attitudes in the research community let them openly express the desire to intervene in the aging process without risk to their careers - a concern that significantly suppressed dialog on treating aging as recently as a decade ago. Yet at the same time, very few people look past the established approach of drug development to tinker with metabolism in the hope of slightly slowing the aging process, and that is certainly the case here. The SENS rejuvenation research approach of repairing the cell and tissue damage that causes aging in order to reverse the aging process still has a long way to go in order to capture even a sizable fraction of the mainstream and its funding. This is why advocacy and philanthropic fundraising remain very important.

We are at a tipping point in the biology of aging-from lifespan extension per se to maintaining and extending health in late life. Since the early 1980s, there have been serious efforts to use genetic approaches to extend lifespan in model systems such as Caenorhabditis elegans, Drosophila, and, increasingly, mice. Collectively, such efforts fall under the catch-all term "geroscience", which describes interdisciplinary efforts to better understand the biology of aging with a view towards improving healthcare in the elderly. Recently, the tried and true genetic approaches of the 1990s and early 2000s in geroscience research have been increasingly giving way to a plethora of pharmacological approaches to extend lifespan. This has been in conjunction with efforts to simultaneously increase healthspan, thereby providing a preclinical rationale for similar studies in human beings.

It has been reported that lifespan and healthspan can be extended in invertebrates using a variety of pharmacological approaches, including single antioxidants through small molecule screens and natural compounds as well as some anticonvulsants. Not to be outdone, there are also supporting data for lifespan/healthspan extension in mice using repurposed US Food and Drug Administration (FDA)-approved drugs, novel chemical compounds, and biologicals. Before examining key concepts in geroscience that drive a lot of the excitement in the pharmacology of lifespan/healthspan extension, it is necessary to first of all define what we mean by aging and healthspan. This is particularly germane in the model systems most commonly used in the biology of aging. By no means is the definition of such terms straightforward, and eminent figures in the field have spent considerable effort clarifying such apparently simple concepts. For the purposes of this article, the term "aging" refers to post-reproductive changes that adversely affect lifespan. However, to define healthspan in the context of geroscience is perhaps even more difficult.

Healthspan is commonly interpreted to mean "maintenance of functional health with increasing age". By necessity, this means one has to understand what it is to be healthy for multiple different systems and tissues. In human beings, this is perhaps non-controversial-one can access high-quality data collected from many thousands of individuals of both sexes as well as differing ethnicities while controlling for multiple lifestyles. One can then establish age-dependent measures for many different aspects of human biology. These include measures of cardiovascular and cognitive function, movement (walking speed), renal function, and hemodynamic function, to name a few. Typically, such functional measures peak in early adulthood, then decline at different trajectories as the individual ages. There are many factors that can modulate the slope of such a functional decline with age, including exercise, diet, and lifestyle. Maintaining function and independence with age using selective and specific interventions is arguably the single biggest challenge currently facing geroscience. For the model systems commonly employed in the study of aging biology, identifying functional measures that are relevant to human healthspan is quite difficult. In nearly all model systems used in the biology of aging, healthspan measures have been collected from aging animals not necessarily because of their relevance to human aging but because methods exist that allow one to measure the metric in question over time. Amongst these metrics, there is one clear measure that is very well established as being a robust biomarker of healthspan in human aging, and that is the measurement of movement with age. A sound argument can be made for measuring this parameter in model systems of aging to ensure potential translational relevance.


If researchers can shut down metastasis by targeting a fundamental mechanism common to all or even many cancers, then cancer becomes much more manageable and much less threatening. That is why it is worth paying attention to research that might produce useful results along those lines. This link between metastasis and the cellular maintenance process of autophagy is intriguing:

Researchers have shown that inhibiting autophagy, a self-devouring process used by cells to degrade large intra-cellular cargo, effectively blocks tumor cell migration and breast cancer metastasis in tumor models. "Using genetic and chemical means, we showed that autophagy is required for the motility and invasion of highly metastatic tumor cells. Our work suggests that inhibiting autophagy in the clinical setting may be an effective approach to block metastatic dissemination."

Metastasis is responsible for 90 percent of cancer deaths. Rapidly growing tumor cells are tightly packed. They quickly exhaust their available supplies of oxygen and nutrients. By breaking away from the original tumor, migrating cancer cells have a chance to escape starvation and wind up in a less crowded environment with more nutrients. "We began by asking, what would happen if we shut down autophagy in metastatic cancer cells." The researchers noticed that when they placed metastatic breast cancer cells on a dish and monitored them with time-lapse microscopy, the control cells were "active, constantly moving around the dish." But cancer cells that the team had altered, by knocking down autophagy-related genes Atg5 and Atg7, "didn't move at all. They appeared to be stuck."

When they injected these gene-altered cancer cells into the mammary fat pad of female mice, the cells multiplied, forming large primary breast tumors, but these cancer cells were unable to metastasize to the usual distant sites, the lungs, liver or bone. A closer look showed that these cells were morphologically very different. Their focal adhesions, large structures at the edge of the cell that are crucial for cell movement, were more numerous and abnormally large. As the cell travels forward, focal adhesions form at the front of the cell and establish dynamic connections to the extracellular matrix. As the cell passes over them, these adhesions drift back to the trailing edge of the cell. Then autophagy intervenes, disassembling the focal adhesion, breaking down its contents and allowing the back edge of the cell to disengage from the extracellular matrix and be pulled forward by traction from the front end. The researchers have now shown that if autophagy is inhibited, these metastatic tumor cells cannot move. Adhesions that don't get turned over grow larger and larger. They anchor the cell in place. "They literally just get stuck. Through the microscope, you can see the cell wobbling, trying to move, to put out new protrusions, to migrate. But it can't, because it is stuck, unable to dissolve the adhesions at the back end of the cell."


Gaining more years of healthy life through progress in medicine is a change with no downside, to my eyes. That many people strive to find problems, and that many more people seem disinterested in gaining more years, disinterested in eliminating age-related suffering and frailty, is a mystery to me:

The greatest benefit of life extension is the continued existence of the individual who remains alive. Each individual - apart from the worst criminals - has incalculable moral value and is a universe of ideas, experiences, emotions, and memories. When a person dies, that entire universe is extinguished, and, to the person who dies, everything is lost and not even a memory remains. It is as if the individual never existed at all. This is the greatest possible loss and should be averted if at all possible. The rest of us, of course, also lose the possible benefits and opportunities of interacting with that individual.

People would be able to accomplish far more with longer lifespans. They could pursue multiple careers and multi-year personal projects and could reliably accumulate enough resources to sustainably enjoy life. They could develop their intellectual, physical, and relational capabilities to the fullest. Furthermore, they would exhibit longer-term orientations, since they could expect to remain to live with the consequences of decisions many decades and centuries from now. I expect that a world of longer-lived individuals would involve far less pollution, corruption, fraud, hierarchical oppression, destruction of other species, and short-term exploitation of other humans. Prudence, foresight, and pursuit of respectful, symbiotic interactions would prevail. People would tend to live in more reflective, measured, and temperate ways instead of seeking to haphazardly cram enjoyment and activity into the tiny slivers of life they have now. At the same time, they would also be more open to experimentation with new projects and ideas, since they would have more time to devote to such exploratory behaviors.

Major savings to health-care systems, both private and governmental, would result if the largest expenses - which occur in the last years of life today, in the attempt to fight a losing battle against the diseases of old age - are replaced by periodic and relatively inexpensive rejuvenation and maintenance treatments to forestall the advent of biological senescence altogether. Health care could truly become about the pursuit of sustainable good health instead of a last-ditch effort against the onslaught of diseases that accompanies old age today. Furthermore, the strain on public pensions would be alleviated as advanced age would cease to be a barrier to work.

I do not see true drawbacks to life extension. Certainly, the world and all human societies would change significantly, and there would be some upheaval as old business models and ways of living are replaced by new ones. However, this has happened with every major technological advance in history, and in the end the benefits far outweigh any transitional costs. For the people who remain alive, the avoidance of the greatest loss of all will be well worth it, and the human capacity for adaptation and growth in the face of new circumstances is and has always been remarkable. Furthermore, the continued presence of individuals from older generations would render this transition far more humane than any other throughout history. After all, entire generations would no longer be swept away by the ravages of time. They could persist and preserve their knowledge and experience as anchors during times of change.

Every day, approximately 150,000 people die, and approximately 100,000 of them die from causes related to senescence. If those deaths can be averted and the advent of indefinite life extension accelerated by even a few days, hundreds of thousands of irreplaceable individual universes would be preserved. This is worth paying even substantial costs in my view, but, fortunately, I think the other - economic and societal - effects that accompany life extension would be overwhelmingly positive as well.


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