FIGHT AGING! NEWSLETTER
April 25th 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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- High Net Worth Individuals Will Support Medical Research in a Big Way, But Only in Fields Already Mainstream
- Deep Knowledge Ventures to Support BioViva's Human Gene Therapy Development
- The Assumption that Longevity is Valuable and an Early Death is to Be Avoided
- Larger Sources of Funding for Longevity Science are Slowly Awakening
- The Small Molecule View: Searching for Drugs to Slow Aging
- Latest Headlines from Fight Aging!
- Human Longevity Inc. is a Personalized Medicine Company
- A Rise in Rhetoric for Radical Life Extension
- Per2 Deletion Improves Immune Function, Extends Life in Mice
- A Growing Interest in the Potential for Treating Aging
- Senolytic Therapies to Remove Senescent Cells
- An Example of Falling Dementia Rates
- Arguing for Telomerase Therapies to Treat Aging
- Considering the Treatment of Oxidative Stress and Fibrosis in Aging
- BioViva Claims Success in Initial Human Telomerase Gene Therapy
- Arguing for Cryonics Providers to Integrate with the Funerary Industry to Spur Growth
HIGH NET WORTH INDIVIDUALS WILL SUPPORT MEDICAL RESEARCH IN A BIG WAY, BUT ONLY IN FIELDS ALREADY MAINSTREAM
In this day and age, the biggest difference a billionaire can make to the near future is to fund medical research. The costs of that research are falling rapidly with progress across the board in biotechnology, and the foundation for transformative new medicine can be created with a fraction of one billionaire's net worth, if spent wisely. Perhaps a bigger incentive in some cases than making the world a better place is that research can move from start to finish rapidly enough for those who fund it to benefit. We all age and suffer from age-related disease in the same way, no matter what our net worth, and everyone wins or everyone loses together in the game of medical development. Thus there is every incentive for someone with enough money to make a difference to take aim at the medical conditions that he or she will likely suffer in the decades ahead, and in doing so fix the problem for everyone. In a way it is very surprising that so few people do this. That, I think, is changing slowly, however. A realization of the potential for near future medicine to effectively treat aging and age-related disease is spreading, even though most people pay little attention to this sort of thing until they need something done.
Of course while the cost of research in the life sciences has fallen dramatically, the cost of regulatory compliance and commercial development has gone the other way. There remain tremendous problems and costs once at the stage of clinical translation, all the result of the perverse incentives produced by heavy regulation and the consequent regulatory capture, but once a new class of therapy is prototyped and ready there are (a) plenty of groups in the Big Pharma industry willing to take a run at it with their own funds, and (b) other avenues beyond trying to gain FDA approval, such as overseas development and medical tourism. Solving the problem of any specific medical condition, and that includes aging itself, is almost entirely the challenge of producing a working therapy with sufficient animal data to gain the interest of established developers. Once over that hurdle, allies with deep pockets emerge and matters progress.
I'm sure you're all familiar with how some of the wealthier individuals in the English language world have chosen to channel significant resources into medical and life science research. Paul Allen picked understanding the human brain as his first goal and cellular metabolism as his second. Bill Gates aims at the worst of the remaining prevalent infectious diseases, such as malaria. Denny Sanford chose to reinforce later stages of stem cell therapy development. The Google cofounders are focused on aging, though of course everyone and their dog in this community has an opinion on how they are going about it in the wrong way. Aging was also the target for Paul Glenn. There are numerous other examples, and recently Sean Parker picked the growing field of cancer immunotherapy for his new research initiative:
The Parker Institute for Cancer Immunotherapy
The Parker Institute was created through a 250 million grant from the Parker Foundation. The Institute's goal is to accelerate the development of breakthrough immune therapies capable of turning cancer into a curable disease by ensuring the coordination and collaboration of the field's top researchers, and quickly turning their findings into patient treatments.
Over 40 laboratories and more than 300 researchers and immunologists from the country's leading cancer centers are part of the network. Each Parker Institute research center receives comprehensive funding, and access to dedicated research, clinical resources and the key technologies needed to accelerate development in cancer immunotherapy. In a unique agreement, the administration of all intellectual property will be shared, enabling all researchers to have immediate access to a broad swath of core discoveries. A scientific steering committee of the field's leaders will set a research agenda and coordinate world-class research teams focused on the most pressing and promising scientific questions.
The commonality in these initiatives is that they all set forth to reinforce or transform or finalize a field that had already become a part of the research mainstream. Each had gone through a long period of bootstrapping, validation, and development well before the high net work individuals came into the picture. Organizations do not commit nine-figure sums of money to anything other than mainstream, well-supported initiatives, and when thinking about these things, is probably best to consider a billionaire as being the figurehead in a sizable organization. All such large-scale decisions are much more political and collaborative than the naive viewpoint might imagine, no matter who allegedly has the final say over disposition of finances. High levels of risk tend to be ruled out pretty early in any decision process that involves more than three humans, and this is just human nature at work.
Why has no-one stepped in to put a few hundred million in funding into getting SENS rejuvenation therapies to the prototype stage? The answer to that question is that SENS rejuvenation research programs have not yet taken over the aging and broader medical research mainstream, but remain a small faction. They are clearly heading in the right direction, with a growing number of leaders in various field of research and medicine openly providing support for the SENS position of damage repair, and the first classes of therapy are under development in a few startups. Clearly more support, more study data, and more bootstrapping is needed, however. It will be very interesting to see this unfold over the next decade as, for example, senescent cell clearance moves from theory with good backing to "it extends life in mice" to clinical treatment for humans to robust data in humans showing reduced symptoms and risk of age-related disease. Concurrently, other SENS therapies, such as cross-link clearance will be following the same path, a few years behind. Eventually it will be impossible to ignore the fact that the damage repair approach works, and that is when very large donations will start to appear.
To look at the situation for cancer immunotherapy, it has been evident for the past twenty years or more that the next generation of cancer treatment would involve proficient targeting of cancer cells, so as to maximize impact to the cancer and minimize or completely remove side-effects for the patient. Immunotherapy has been a strong contending technology platform for a decade, and in the last five years or so it has been the obvious basis for most of the next generation of targeted cancer therapies. So consider that the Parker Institute arrives something like ten years after the people who mattered in cancer research and related funding institutions became convinced that immunotherapy was something to put serious effort into, the point at which it became mainstream. From this sort of fuzzy and very subjective view of history, I'd judge we are at least ten to twenty years from the similar final avalanche of support for rejuvenation research programs - which will make the time between now and then an era of increasing availability of early rejuvenation therapies after the SENS model, human trials, and a great deal of very interesting data on effectiveness. How long it actually turns out to be is very much up to us. The more we do now, the faster we progress to the point at which large-scale funding arrives to seal the deal.
DEEP KNOWLEDGE VENTURES TO SUPPORT BIOVIVA'S HUMAN GENE THERAPY DEVELOPMENT
Fortes fortuna iuvat, as they say. I'm pleased to see that the BioViva principals have attracted the support of Deep Knowledge Life Sciences as they continue to bootstrap their very intentionally disruptive gene therapy startup:
Deep Knowledge Life Sciences and BioViva announce partnership
"BioViva aims to make gene therapy affordable to everyone. Dmitry Kaminskiy, the founding partner of Deep Knowledge Life Sciences, is enthusiastically funding gene therapy, and is himself an early adopter." said BioViva CEO Elizabeth Parrish, adding "We both want to see a world where investors actually live their legacy instead of just leaving it", alluding to a possible future trend. Parrish made headlines in 2015 when she travelled to an undisclosed location outside the US and personally underwent two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion. It was a gesture intended to prove the safety of the therapies and clear the road ahead for human trials in the US. Months later, BioViva are tracking her results and she has reported no negative side-effects. "I believed the biotech industry had become over-regulated and that the prevailing model was unlikely to bring new therapies to market in our lifetime. What we needed was a company that would treat diseased patients with no other options and then develop these treatments into preventative medicines. And thus was born BioViva in 2015."
For Dmitry Kaminskiy it's not all about the portfolio. He wants to shift the entire industry up a gear, and put an end to the lack of vision he believes has mired biotechnology for decades: "Millions of human lives are affected by diseases with a genetic component. The sooner we can bring affordable gene therapies and other cell therapies to market, the more needless deaths can be avoided."
I regard the shared vision of bypassing excessive regulation in medical development to be somewhat more important than the exact nature of the therapies under development today. Rapid, effective passage to the clinic will be the legacy here, the opening of a door that will see an increasing number of developers in every important field of medicine adopting a fast path to medical tourism and clinical availability outside the US and Europe, transparency of ongoing results, and a sensible degree of safely data. The stem cell field and countless patients benefited greatly from this sort of approach over the past fifteen years, and it really should be the standard, not the exception.
What constitutes a sensible degree of safety data? That should up to companies and patients to decide upon for themselves, but it is certainly far, far less than the FDA presently insists upon. The FDA leadership are not primarily concerned with safety at all, but rather the potential political fallout that might result from approving any any therapy, ever. There is no such thing as a safe medical treatment, but the media can pounce at random on any death, and the defense put up in advance by FDA career bureaucrats is to demand as much expense and data as possible from applicants. Few people seem to care about the potential therapies that never make it through the process, or are never submitted because there is no possible profit - those losses are invisible, but they are measured in lives, not money. These perverse incentives, rife in every government agency, is why the cost of developing drugs is huge, why the process is lengthy and drawn out beyond all common sense, and why the cost has doubled in the past decade. These imposes costs are pointless and unnecessary, and a huge burden on progress. It is long past time to evade the FDA and take the road of medical tourism, transparency from companies, educated customers, and sane levels of testing and development cost.
BioViva has demonstrated prototype follistatin and telomerase gene therapies in the first human volunteer. If successful, and with a enough uptake in cells, the former should provide increased muscle mass and thus compensate partially for the sarcopenia that accompanies aging, while the latter may globally increase stem cell activity, offsetting to some limited degree the decline that occurs with age. To my eyes follistatin and similar myostatin gene therapies are about as low risk as any genetic edit can be before it has been used by thousands of people. Myostatin blockers of various sorts have been trialed in humans with positive results, and scores of animal studies for follistatin and myostatin gene therapies have taken place since the turn of the century. There are natural human and animal myostatin loss of function mutants to study as well, and most seem to do pretty well with their extra muscle tissue. Telomerase gene therapy on the other hand strikes me as being more risky. It clearly extends life and improves health in mice, but mice have very different telomere and telomerase dynamics when compared to humans. There is the strong possibility that telomerase therapies will boost cancer incidence in humans, even though they don't do that in mice. At some point it has to be tried based on the intriguing animal study results, but I wouldn't want to be first in line.
There is no reason for gene therapies to be expensive once they are out of their initial phase of development and early adoption. This is the age of CRISPR, an basis for gene therapy that makes genetic editing so cheap and easy that near every life science laboratory can now undertake this research. A gene therapy treatment to enhance capabilities or compensate somewhat for one or more of the losses of aging, such as myostatin knockout or follistatin overexpression, will trend towards becoming a mass produced infusion, the same for everyone, administered by a bored clinician, and with limited need for followup attention from a physician. All of the complexity is baked into the manufacturing process, and the cost will scale down as the production runs grow large. Unlike drugs for medical conditions, the target market here is every adult human being: the economies of scale and competition will be more like like those for present day childhood vaccinations than other types of medication, and the price will accordingly fall to the same low level.
So, I hope to see BioViva prosper in their effort to shake up clinical translation, and demonstrate that no-one really needs the FDA in order to responsibly place the next generation of therapies in the hands of patients. They have picked a set of treatments likely to attract a lot of interested parties to the clinics that will provide them, and the advent of CRISPR-based gene therapies will make expansion to other very interesting therapies quite plausible. Things should become interesting in the years ahead, I believe.
THE ASSUMPTION THAT LONGEVITY IS VALUABLE AND AN EARLY DEATH IS TO BE AVOIDED
It is fair to say that medicine, like much of our technology, is an expression of the urge to immortality. The rise to civilization is arguably a process of identifying and fixing the problems that kill people, starting with the most pressing and moving on until there are no more problems that kill people. Now that we are in an era in which age-related diseases - and aging itself given that it causes those diseases - collectively form the most pressing problem, it will be worked on. As the authors of the open access paper I'll point out today note, this whole business of medicine, technology, civilization is "based on the assumption that longevity is valuable and that an early death is worse than a late death." That assumption certainly appears to be the basis for the way in which people act when viewing the big picture, but I wish you luck in trying to get any randomly selected room full of people to agree that longevity is valuable and death is a terrible thing, always to be avoided.
A large part of the challenge facing the development of rejuvenation therapies, treatments for aging that can prevent and reverse age-related disease by repairing the cell and tissue damage that causes aging, is that most people don't appear to be particularly enthusiastic when it comes to avoiding natural aging and death. This in turn means that there is little funding, as over the long term and the large scale, public support and interest determines funding for research and development. It is puzzling when compared with the evident, overwhelming support for, say, cancer research or the defeat of other specific age-related disease. You'd be hard pressed to find someone who will say in public that cancer research should be halted, or is pointless, but that is exactly the response from most people regarding research aimed at extending healthy human life by treating aging. The views of the public at large, and many individuals, are incoherent and contradictory on this topic: the fellow who proudly states that he doesn't want to live longer than his parents, and that 80 is long enough for anyone, also thinks that cancer and heart disease should be cured. What is aging without age-related disease? It is youth, because the only way to remove the medical conditions is to remove the damage that causes them, and that damage is one and the same as aging.
The best explanation to date appears to be the widespread mistaken belief that treating aging to extend life would result in ever-increasing decrepitude rather than prolonged youth and health, stemming from all sorts of misunderstandings about what aging actually is under the hood. There are plenty of other theories, however. The modern culture of environmentalism probably has a role, coupled as it is to incorrect Malthusian beliefs about economic development and technology. Also the widespread view that limited funds should be devoted to the young or indeed any cause other than helping old people: in many ways older people are considered less valuable, or to have had their chance. These are pernicious and damaging viewpoints. Certainly, the need for advocacy to support research fundraising efforts is as great as ever.
Can we even all agree that death is bad and something should be done? Not so much, unfortunately, and a sizable fraction of any group of people dissent from that view in one way or another - though when compared with their actions the degree to which they mean what they say is always a question mark. The paper quoted below summarizes some of the philosophical underpinnings of medicine, down at the lower level of asking why we even undertake these efforts to save lives and avoid death, and why there is support for saving some lives but not others, curing some diseases but not treating aging. Like many of these discussions, the authors don't escape the idea that younger lives are worth more. This is unfortunate because it is the basis for a vicious circle: when less work is undertaken to save the lives of the old because they are considered to be worth less than the lives of the young, then there will be slower progress towards rejuvenation biotechnologies capable of granting a long and healthy future to everyone, and therefore equal value to all lives. Everyone loses. So I think it is potentially useful to consider these things occasionally, given the strange and inconsistent behavior and opinions voiced about aging and age-related disease. Somewhere in all of this lies a better way to persuade the world to fund rejuvenation research, and to speed up the slow bootstrapping process of reaching prototype therapies.
The badness of death and priorities in health
The business of saving lives works on the assumption that longevity is valuable and that an early death is worse than a late death. There is a vast literature on health priorities and badness of death, separately. Surprisingly, there has been little cross-fertilisation between the academic fields of priority setting and badness of death. Our primary aim is to connect philosophical discussions on the badness of death to contemporary debates in health priorities. All health care systems share two basic goals: saving lives and improving the quality of life. The first goal gives rise to two essential questions: (i) Why should we save lives? (ii) Which lives should we save first? In the health priorities literature, the second question has received the most attention. We believe (i) and (ii) are closely connected, and that an answer to (ii) presupposes an answer to (i). In order to make claims about which lives to save first, we need an account of why we should save lives in the first place. One justification for saving lives is simply that death is bad. Saving lives entails postponing death, which is justified on the assumption that an early death is worse than a late death. One could, however, argue that we should justify saving lives with reference to considerations of fairness. Although we do not deny this, our aim is a different one, namely that of investigating the reasons we have for saving lives that stem from considerations of the badness of death.
We will briefly clarify the concept of death before we proceed. "Death" can refer to at least four dimensions: "the prospect", "the process", "the incident" and "the loss". The prospect refers to our knowledge of being mortal, which as far as we know is unique to human beings. The process of dying is an event that may be filled with pain, as in some instances of cancer, or it may happen abruptly, as in a traffic accident. The incident of death is when someone goes from existence to non-existence. Finally, there is a permanent loss when death occurs because there is no future for that individual. Although many tend to focus on the process of dying, our focus will be on the loss. Arguably, if dying had not been followed by permanent non-existence, then perhaps dying would not be so bad after all. Interestingly, the loss dimension of death seems to play an important role in current health priorities debates. One example is the estimation of health loss due to both morbidity and mortality in traditional cost-effectiveness analyses; another is the Global Burden of Disease project. If the loss dimension is accepted, the question is for whom death represents a loss. There are two rival theories to this question: Epicureanism and Deprivationism. Epicureanism refers to a contemporary view on the badness of death inspired by the ancient philosopher Epicurus, which states that death is not bad for those who die. Both theories are compatible with the idea that death can represent a loss for others (such as family, friends, and society), but only Deprivationism accepts that death represents a loss for those who die.
The two arguments normally offered in favour of Epicureanism are the experience argument and the time argument. The experience argument is best illustrated by the expression, "What you don't know won't hurt you". One interpretation of this is that in order for something to be good or bad for us, we must experience its goodness or badness. But of course when we are dead, we cannot experience. Therefore, death cannot be good or bad for us. There are at least four views one can adopt in responding to this argument. One view is that death is bad before it occurs, another is that death is bad when it occurs, a third is that death is bad after it occurs, and a fourth is that death is bad at a time which cannot be easily identified. One can successfully object to the time argument on the basis of one of these four views. We believe the fourth view is the best strategy for responding to the time argument. Here are some cases of analogy in support of the fourth view. For example, never having an education, freedom, or children can be bad even if its badness cannot be ascribed to a specific time. Moreover, at times, people may be grateful for not being a victim of accidents or suffering from severe sickness, even if "the evils that they never suffered" cannot be so easily located in time. If one accepts either the experience- or the time argument, it follows that death cannot be bad for those who die. What does this imply with regard to health priorities? If death is no loss for those who die, it matters less whether we suffer a premature or a late death. Consequently, age will play a less significant role (if any role at all) to health priorities. With Epicureanism we are, however, left with the option that death is bad for third parties such as family, friends, and society. This implies a higher emphasis on saving lives for the sake of others. Moreover, this suggests that what matters from a moral point of view are things like the emotional attachments and investments of family, friends, and society. In addition, the death of individuals can be bad by virtue of being a loss of caring relationships, productivity, or simply in terms of the world being deprived of a person.
When it comes to Deprivationism, some things in life can be good or bad in themselves, such as pleasure and pain. Death, on the other hand, is a different kind of evil. Suppose you suffered from paralysis in both your legs as a result of an accident. This accident deprives you of the chance to do a lot of things, like walking or playing tennis. In a similar way, death deprives us of the opportunity to continue with our lives. And assuming that continued life contains value, death is bad for us. Deprivationism explains how we can make judgments concerning the badness of death by comparing at least two different outcomes: (a) how well off individuals would have been if they continued to live and (b) how good it is for individuals not to continue with their lives. As long as (a) is better than (b), death is an evil. Deprivationism is the standard view on the badness of death. We suggest that Deprivationism is relevant to health priorities in at least four areas. First, Deprivationism brings attention to the kinds of values that are lost when death occurs. Secondly, it emphasises that age matters. Thirdly, Deprivationism will favour a person-affecting theory. Fourthly, it may say something new about who the worst off are. Jointly these four areas can provide reasons for saving lives. Though the idea that age matters to health priorities has gained a certain acceptance, there is bound to be disagreement about which age groups to prioritise. This issue is the subject of contemporary debate. Our claim is that in order to prioritise between age groups, it is relevant to consider the question of when it is worst to die. To this end, Deprivationism can provide theoretical support.
LARGER SOURCES OF FUNDING FOR LONGEVITY SCIENCE ARE SLOWLY AWAKENING
Today's news, linked below, comes from the Russian end of the longevity science community. If you've been following the work of the Science for Life Extension Foundation folk over the years, then you'll recognize many of the names involved, but this particular announcement involves a group that I wasn't aware existed. Before diving in, I should say that in comparison to the English language world the Russian public and longevity science community have always been far more enthusiastic and outspoken when it comes to the logical end goal for efforts to treat aging. That means the defeat of aging, the production of a cure for aging, to bring aging under the complete control of medicine, to end aging and thereby produce indefinite healthy life spans. There is probably an interesting anthropological study to be made of this difference between our cultures, but equally perhaps it is simply the consequence of a greater degree of engagement, respect, and support for the sciences one sees in Russia and the surrounding regions.
IVAO to announce plans to invest over 1 billion in aging and longevity projects at a conference in St Petersburg
IVAO is organizing an international conference titled "Biomedical Innovations for Healthy Longevity", where top thought academic thought leaders and industry executives from all over the world will convene for three days to present latest research results, discuss translational and commercialization opportunities, establish valuable collaborations, network and partner. The event features a business forum with one day dedicated to round table discussions on presenting favorably presenting aging research in the press, novel ways to attract funding and classifying aging and many age-associated conditions.
At the conference IVAO plans to announce a roadmap for investing over 1 billion into a broad range of projects, companies and financial instruments linked to longevity research. "After millennia of failed promises, we are finally reaching the point in human evolution, where major breakthroughs contributing to the body of knowledge in aging are happening almost every month in laboratories all over the world. We decided to combine the best features of mutual funds, venture capital firms and analytical companies in one place to build a reasonably conservative investment vehicle to take part in the coming longevity boom," said Andrey Fomenko, founder of IVAO.
"Since 1995 Andrey Fomenko and I monitored research activities in aging and longevity. When in 1996 we established our non-profit Eternal Youth Foundation, most people did not understand. But today these technologies are becoming mainstream and time horizons for many technologies are shrinking," said Lada Fomenko, the head of Eternal Youth Foundation and Director of IVAO. Scientists, industry executive, investors and students are invited to attend the conference and network with the most advanced professionals in aging and longevity to help advance the entire field.
Human organization friction is a very real thing. The larger and less familiar the endeavor, the longer it takes to pull people together, raise funds, and get going. You should assume that any new venture you read about in the press was at least a few years in the making, quietly and behind the scenes. When fields are especially young, it can take years of networking, advocacy, and happenstance for a community to evolve to the point at which formal ventures are even a possibility. So while the regular readers here at Fight Aging! have been involved in this modern rejuvenation research community for a while and are generally pretty bullish on longevity science, the rest of the world is only just opening its eyes.
It has been more than twenty years since the first compelling demonstrations of slowed aging in laboratory animals using modern technologies. Most of the time since then has been a beginning of sorts, the formation of a community, a war of persuasion and debate in the research community, a growing amount of bootstrapped funding, a few major failed projects seeking to find treatments for aging, and advocacy for better ways forward such as the SENS damage repair approach. In the grand scheme of things, the tens of millions in funding devoted to new work on aging by a handful of foundations over the past decade, hard-won victories though they were, are still just faint echoes at the edges of the broader field of medical research. The mainstream is billions in funding for pure research, and hundreds of times that amount for the business of treatments.
Faint echoes are how every new mainstream paradigm begins, however. The end of the beginning was definitively marked by Google's high profile investment in interventional aging research in 2013. It was a sign that the comparatively quiet cultural war that took place in the aging research community over the past few decades was over, and those who favored public discussion and treatment of aging won decisively. Similarly, it was a sign that the overlapping networks of technology, philanthropy, and capital now understood medicine for aging as a promising frontier, something worthy of more than the largely small and faltering experiments in investment that had taken place in the decade prior, the now long-dead startups that suffered largely from being too early, struggling prior to the first wave of significant support for their goals.
Matters are accelerating now. It is rarely the case that more than a few months go by these days without an entirely new significant venture that I had never heard of coming to my notice. People in the philanthropic and investment communities are slowly but surely waking up to the prospects for treating aging and ultimately bringing aging under medical control, and some are becoming quite enthusiastic supporters of radical life extension along the way. Some have been building funds and connections for a few years now, largely isolated from the portions of the advocacy community we're familiar with. The community itself has broadened until its far nodes are well beyond my sight and awareness. This is all very promising, for all that I fully expect most of the new money, like that put in by Google, or that invested in Human Longevity Inc., to go to projects that will do nothing but add knowledge, or only incrementally improve the present inadequate approach to treatments for aging. That means work on therapies that do little or nothing to address the root causes of aging, and are usually only poor patches over the damage. Funding communities build upon themselves, however, and the more interested money in the ecosystem, the easier it will be to advance the state of SENS rejuvenation research - both the work that still must be done in the labs, and the startup companies that are launched or close to launch.
THE SMALL MOLECULE VIEW: SEARCHING FOR DRUGS TO SLOW AGING
Today I thought I'd point out a couple of interesting papers on the work of finding drugs to intervene in the aging process. This is far from a widespread undertaking, even now that more funding is arriving into the field. The majority of researchers focused on aging are not looking to intervene in the aging process at all, and their work is purely investigative. Equally, the majority of research into age-related disease is focused on working backwards from the disarray of a diseased metabolism, tracing molecular links in long chains of cause and effect that hopefully lead closer to causes rather than dead ends. At each new discovery, some groups stop to develop therapies, screening for drugs that can influence the newly uncovered link in a beneficial way, while causing few enough side-effects to be acceptable. Preference is typically given to existing drugs, even if they are much less effective than a theoretical new drug, because it is less expensive to push that through the regulatory system. The nature of this approach means that the resulting therapies largely involve tinkering with an already complex, failed metabolic state, without addressing the root causes of that failure, and are therefore only marginally effective. This is the story of most medical research: expensive drug development, massive regulatory costs, perverse incentives to create less effective treatments, and tiny gains at the end of the day.
There is a completely different approach to the problem of age-related disease, however, which is to start from the beginning and the known root causes of aging, and try to repair and revert these causes prior to a full understanding of the chain of cause and effect that drives the progression of aging. Don't try to work forward to full understanding of the process, just fix things where there is compelling evidence for their involvement in aging and see what happens. This should be much less challenging than the mainstream approach of working backwards from the disease state, and should produce far better results. It should also answer many questions as to the root causes of specific age-related diseases, and far more efficiently than working backwards through the complexity of late stage disease. How do researchers know what the root causes of aging are with such great reliability? Over the years, many, many research groups have compared old tissue and young tissue, and ruled out everything that has a direct cause other than the operation of normal metabolic processes. What is left is a consensus list of side-effects and molecular damage, the fundamental changes that are produced in the cells of normal, healthy, young individuals, and that slowly turn them into aged, diseased, and ultimately dead individuals. Unfortunately this better approach of repair has yet to gain more than a foothold in the research community. There is a long way to go yet before we can call rejuvenation research a mainstream, well-funded concern.
If you look through the SENS rejuvenation research programs, it is clear that there is a role for traditional or more modern drug discovery and development in a number of areas. There may prove to be good enough drug-based approaches to senescent cell clearance, for example, to compete in the marketplace with the more efficient and directed gene therapy techniques pioneered by Oisin Biotechnologies. Work on breaking down glucosepane cross-links will also no doubt settle down to some form of drug development once an initial class of compounds shows effectiveness. There are other examples, such as the work of Pentraxin Therapeutics or Human Rejuvenation Technologies that are both fairly standard issue drug development and relevant to the SENS vision. So all in all, I think you'll find the open access papers below interesting, even if they have little to say in and of themselves on the topic of rejuvenation research, being more focused on methods of altering metabolism to slightly slow aging.
Finding Ponce de Leon's Pill: Challenges in Screening for Anti-Aging Molecules
Several drugs have demonstrated great promise in the laboratory setting in enhancing the healthspan and lifespan of multiple species, including mice, raising the possibility that efficacious pharmacologic anti-aging therapy in people may be possible. However, screening for novel small molecules with anti-aging effects in mammals in an unbiased fashion represents an enormous, potentially insurmountable challenge. Alternatively, since it is clear that several cellular pathways affect longevity in an evolutionarily conserved manner, invertebrate models may be quite useful for such screening endeavors. However, some known molecular factors with major effects on mammalian lifespan are not well conserved between invertebrates and mammals. Consequently, small molecule screening efforts relying exclusively on the use of invertebrates will likely miss drugs with potent effects on mammalian aging. Moreover, many of the key physiologic features of humans and other mammals are not well modeled in invertebrates, as the latter lack specific tissues like heart and kidney and complex endocrine, nervous, and circulatory systems that are crucial targets of mammalian aging and age-related pathologies. Most invertebrate aging models possess limited regenerative capabilities and incompletely recapitulate processes such as stem cell renewal, which are required for tissue repair mechanisms that maintain tissue homeostasis in mammals, in order to sustain organ function over years and decades.
To date, the discovery of anti-aging compounds has so far been carried out via two basic approaches. One of these is phenotypic, defined as the screening of compounds in cellular or animal models to identify drugs conferring desired biological effects, i.e. lifespan extension. Although this approach has proven enormously valuable in many areas of biochemical research, identifying drugs that can modulate lifespan is more time consuming, complex, and expensive than for many other phenotypes. Moreover, elucidating the mechanism of action of agents identified in such phenotypic, "black box" screens represents a formidable challenge, though the powerful genetic tools available in invertebrate models can facilitate such efforts. A complementary approach involves target-based screening for modulators of pathways known or strongly suspected to modulate the aging rate. However, by definition, such efforts are unlikely to identify novel cellular factors and pathways involved in longevity.
A related challenge in aging research at present is the lack of primate model systems with reasonably short lifespan for preclinical testing of candidate anti-aging drugs. The most commonly used model, the rhesus monkey, lives for three to four decades. In Europe, the marmoset is used as a non-rodent species for drug safety assessment and toxicology. However, their maximal lifespan is ~17 years - shorter than the rhesus monkey, but still highly impractical for testing pharmacological interventions aimed at extending longevity. The development of new mammalian aging models besides the mouse would be extremely helpful to better elucidate the biological processes underlying mammalian aging and to expedite the translation of pharmacological interventions from the laboratory to actual clinical use in humans. One model to consider in this regard is dogs, which share their social environment with humans. Furthermore, dogs are relatively well understood with regard to aging and disease, exhibit great heterogeneity in body size and lifespan, and provide a large pool of genetic diversity. Testing candidate anti-aging compounds in humans represents an enormous challenge. It is highly unlikely that pharmaceutical companies can be persuaded to engage in decades-long clinical trials of candidate anti-aging medicines with lifespan as an endpoint. The evaluation of shorter-term surrogate phenotypes, such as molecular markers or age-associated defects such as impaired responses to vaccination, may permit initial clinical evaluation of candidate anti-aging compounds in a more reasonable timeframe.
Biology of Healthy Aging and Longevity
As a heterogeneous process, aging may occur at different rates across diverse organisms, and even organisms of the same species can age at variable rates. At the biological level, aging is characterized by the accumulation of molecular and cellular damage, which leads to structural and functional aberrancies in cells and tissues, such as loss of mitochondrial homeostasis, impaired intercellular communication, senescence (cell arrest that hampers growth and division), and decreased regenerative capacity. The ability of organisms to overcome stress and respond to external environmental challenges/insults is blunted within aged individuals when compared to younger counterparts. Healthy aging, however, refers to the warding off of molecular and cellular decline for the longest length of the lifespan. Not surprisingly, healthy aging has been associated with increased longevity. This claim is substantiated by the fact that genetic, dietary, and/or pharmacological interventions that promote cellular homoeostasis, stress resistance, and protection against age-related diseases also tend to extend lifespan and vice versa.
Overwhelming scientific evidence supports the claim that there is no single cause of aging. Indeed, notable advancements in the biology of aging, especially during the last few decades, have contributed to the identification of multiple mechanisms that modulate the aging process. Despite this progress, uncovering interventions that can achieve healthy aging in humans is challenging. The conserved molecular and cellular mechanisms that underlie aging, especially how these pathways interplay and how complex lifestyles and environments to which humans are exposed modify them, are not completely understood.
Despite the impressive advancements made towards understanding more about the molecular basis of aging, there is still no definitive intervention for ensuring healthy aging in humans. To uncover new therapeutic avenues, we need to gain deeper knowledge about how different internal and external factors regulate the cellular hallmarks of aging, and how their regulation changes across time and individuals. All molecular pathways exhibit complex communication known as "crosstalk." The genome, epigenome, organelles, proteome, and pathways such as those involving sirtuins, mTOR, AMPK, and insulin/insulin-like growth factor-1 signaling - all integrate and process signals that must act coordinately to promote homeostasis in cells and tissues. It is unclear, however, how these complex molecular networks are affected by diverse environmental challenges and how they become impaired with aging. Lastly, in an effort to find beneficial interventions to delay aging-linked deterioration, the search for small molecules that can mimic calorie restriction - and the dissection of their pharmacological modes of action in vivo - is a growing area of research that merits more attention. Collectively, through all of these scientific efforts, we may someday achieve the longstanding human dream of living a long and healthy life.
LATEST HEADLINES FROM FIGHT AGING!
HUMAN LONGEVITY INC. IS A PERSONALIZED MEDICINE COMPANY
Human Longevity Inc. (HLI) is a young company with a lot of funding that will be using genetics to produce a platform for personalized medicine and investigation of disease mechanisms, with a focus on age-related disease. Unfortunately, as I've noted in the past, this sort of use of genetics in the present research mainstream, which is to say the entirely correct scientific impetus towards building a comprehensive and complete map of human molecular biochemistry, is not the road towards effective extension of human life spans. Some of the Human Longevity principals have in the past talked a good game when it comes to the desire to meaningful extend human life span, but that simply isn't an outcome that is possible or plausible given what they are doing. What is plausible and possible is incremental progress in the expensive and futile approach of patching over age-related disease without addressing root causes, better diagnostics, and a great deal of new information about the details of the overlap of metabolism, genetics, and aging - how and why natural variations in longevity exist.
Understanding natural variations in longevity doesn't give researchers the ability to create radical life extension, people living to 150 and beyond in excellent health. Neither would even perfect diagnostic ability, a complete and transparent view of what is going on in our biochemistry. The only way to control, prevent, and reverse aging to fix the causes of aging, the molecular damage that accumulates to cause dysfunction, damage, and disease. The research community knows how to do this, and classes of potential therapies are outlined in great detail in the SENS research programs and elsewhere. For entirely cultural reasons, however, work on such rejuvenation treatments is a minority field and little funded. We can hope that as it produces results, as is the case for the senescent cell clearance component of SENS at the moment, and as the mainstream approach of tinkering and understanding metabolism continues to fail to produce results, SENS will take over the mainstream. It is a slow and frustrating process, however.
Now that a large funding round for Human Longevity Inc. has been completed, we are seeing more articles on their technology; VCs and founders tend to like to talk up their positions. This is one of the more informative pieces:
So far, HLI has amassed the sequences of around 20,000 whole genomes, says Craig Venter. But, of course, he wants even more. The company has room for more sequencing facilities on its third floor and is considering a second center in Singapore, planning to rapidly scale to sequencing the genomes of 100,000 people per year - whether children, adults or centenarians, and including both those with disease and those who are healthy. By 2020, Venter aims to have sequenced a million genomes. Despite the scale of its ambitions, HLI would be just another company offering DNA sequencing and testing if it were not for the fact that Venter is systematically linking DNA information to a diverse range of other medical data about each patient, gathered in what he calls a Health Nucleus. With this, Venter wants to move from basic genetics to impacting individual lives "very directly," he says. "The most important part of that is nothing to do with the genome directly, but measuring phenotype and physiology and understanding their medical risk. That is what the Health Nucleus is all about."
The Health Nucleus adds yet more data using non-invasive tests. My tour begins with the room where HLI conducts a total body scan to create the avatars that inhabit its app. We pass through a succession of white rooms. There's one where magnetic resonance imaging (MRI) scans are shown, revealing visceral fat (which is linked to type 2 diabetes and cardiovascular disease), muscle volume, grey matter, white matter and more. Venter is happy for his "age-related atrophy" report to be displayed here on a screen, given the good news about how young his brain looks.
So far, Venter and a handful of patients have passed through the Nucleus. Targeted initially at self-insured executives and athletes, a full health scan will be priced at 25,000. "We will be developing the evidence around this to make the case for preventive medicine." Criticisms of such extensive screening stem from the conservative nature of the medical community, notably when it comes to keeping the costs of screening under control. "That is the medical establishment saying: we want to keep doing what we do, we want to see people after they develop symptoms and have something wrong with them. The human longevity approach is the exact opposite."
Ray Kurzweil is one of HLI's advisors. Does Venter buy into his visions for radical life extension? No. Kurzweil's view is interesting but does not change a thing Venter does on a daily basis. Though Venter wants to see the kind of step change in health last witnessed between 1910 and 2010, when improvements in medicine and sanitation increased the average lifespan from around 50 to 75 years, life extension is not the primary objective, he stresses. As his 70th birthday approaches, Venter is only too aware of his own mortality. While his mother, aged 92, is "still pretty bright" despite a stroke, his father only lived to 59 as a result of sudden cardiac death. "I am now ten years beyond that," he says with a chuckle of satisfaction. But if you really want immortality, he adds, "do something meaningful with your life".
A RISE IN RHETORIC FOR RADICAL LIFE EXTENSION
It is interesting to note a growth in discussion of radical life extension as a goal, and this from groups entirely outside the established community of supporters and advocates that came into being a couple of decades ago. Progress in development and advocacy arrives in waves over longer periods of time, and we are in the midst of the start of a new wave. We should expect to see new ventures and new faces, disconnected from prior efforts and coming to this with their own ideas and preconceptions. This is the way in which the patchwork of human endeavor takes shape over the long term.
In connection with the recent funding round for Human Longevity Inc. and resulting coordinated publicity, it is interesting to see the comments below from one of the involved groups, an established incubator-slash-fund focused on healthcare. As I've noted in the past, Human Longevity Inc. is a personalized medicine and genetics company, and not set on a road that can contribute to radical life extension. Other approaches are needed for that, but if people are genuinely interested in the goal of far longer healthy lives - as opposed to merely saying whatever will talk up their positions - then eventually they will gravitate towards the approaches with potential, such as the SENS research and development programs.
StartUp Health, a global organization leading the movement to transform health by building the world's largest community of Healthcare Transformers, today announced the launch of StartUp Health's Longevity Moonshot, a mission to extend and enhance healthy life by 50+ years and change the face of aging. Marked by StartUp Health's recent investment in Human Longevity, Inc (HLI), the genomics-based, technology-driven company led by co-founder and CEO J. Craig Venter, PhD., HLI was selected to be the founding partner of the Longevity Moonshot. "Aging is the biggest risk factor for every significant human disease. We are excited to be launching The Longevity Moonshot with Human Longevity, Inc. as the founding partner because we believe that together we can inspire a global community of Healthcare Transformers to join our mission to extend and enhance a healthy lifespan and ultimately improve the health of billions. By collaborating as a networked community, we can change the face of aging forever."
"Human Longevity, Inc. is honored to partner with StartUp Health and collaborate with their global community of Healthcare Transformers committed to transforming health," said Dr. Venter, co-founder & CEO, Human Longevity, Inc. "Our goal is to solve diseases of aging by changing the way medicine is practiced. Having the opportunity to actively network and engage with other innovators with the same mission will help us all revolutionize healthcare." The StartUp Health Longevity Moonshot is the first moonshot that StartUp Health is organizing for its community of Healthcare Transformers to focus on, with additional moonshots set to be announced throughout the year. StartUp Health is already working to support the White House Cancer Moonshot and The Cancer Moonshot 2020.
PER2 DELETION IMPROVES IMMUNE FUNCTION, EXTENDS LIFE IN MICE
To what degree does the age-related decline of the immune system contribute to mortality and loss of longevity? How important is it in comparison to other aspects of aging? This study offers one useful data point, as the authors describe a genetic alteration that can boost the supply of new immune cells in old mice. The decline in that supply with age is one of the factors leading to poor immune function - and that means more than just vulnerability to infections, as the immune system is also responsible for destroying potentially cancerous and senescent cells, as well as clearing out forms of damaged proteins and unwanted metabolic waste. Various possibilities for increasing the number of new immune cells already exist in principle, such as regenerating the thymus, or cell therapies in which a patient's immune cells are grown outside the body and regularly infused, but this genetic approach is a new discovery.
There's no other age group suffering more from infectious diseases than seniors. With growing age, the risk of chronic and cute infections increases. This is due to the diminishing potential of hematopoietic stem cells (HSC) to build blood and immune cells in an appropriate number. In particular, HSC's capability to build lymphocytes is strongly declining, which leads to imbalances in blood cell composition and, thus, to immune defects limiting overall fitness and organismal survival during aging. There is experimental evidence that the accumulation of DNA damage contributes to these aging-induced immune impairments. Researchers identified gene Per2 as a genetic switch for a better immune system in mice: Per2 gene deletion ameliorates DNA damage responses in HSC leading to stabilization of hematopoietic stem and progenitor cells in aging mice. Hence, mice were less prone to infections and exhibited an elongated lifespan by 15% without increases in cancer.
For their study, in vivo RNA-mediated interference (RNAi) screenings were conducted in mice. 459 putative tumor suppressor genes were targeted to identify genes that limit the self-renewal capacity of HSC in response to DNA damage and aging. This screen identified "period circadian clock 2 (Per2)"-gene - usually one out of various genes regulating sleep-wake cycle - to represent a major factor limiting the maintenance and repopulation capacity of HSC in the context of various types of DNA damage and aging. Interestingly, Per2 deletion was sufficient to maintain a balanced production of lymphocytes, and hence, to improved immune function in aging mice. A similar effect was also found for DNA damages caused by the shortening of telomeres - the protective caps at our chromosomes' ends - a mechanism thought to be relevant for human aging.
"All in all, these results are very promising, but equally surprising. We did not expect such a strong connection between switching off a single gene and improving the immune system so clearly". It will be of future interest to study if the results are transferable to humans. Although humans and mice are genetically quite similar, genes usually regulate myriad of processes in an organism, and possible side-effects of Per2 deletion will have to be elucidated very carefully. Interestingly, Per2 gene mutations in humans have been associated with advanced sleep disorders leading to advanced tiredness of the patients in the early evening hours. "It is not yet clear whether this mutation in humans would have a benefit such as improved immune functions in aging - it is of great interest for us to further investigate this question."
A GROWING INTEREST IN THE POTENTIAL FOR TREATING AGING
In recent years, public and press interest in medicine to treat aging has been growing, and so more popular science and general interest articles - such as the one linked here - have been published. This is a new phase in the bootstrapping of longevity science, in which the media and the public conversation becomes more of a factor. Unfortunately people unfamiliar with the science, which means near all journalists, tend to pick random grab-bags of information for their articles and discussions. You never know just how coherent or correct or reflective of the current state of research any given piece will be, even if accurate within its narrow selection of research topics. There are a lot of differing opinions on how to proceed towards treatments for aging in the research community, and these approaches have enormously divergent expectation values: how much it will cost to get to a prototype treatment, and how many years of healthy life we can expect to gain from successful therapies. All publicity is good publicity when it comes to raising the water level for fundraising in all areas of aging research, but it matters greatly which lines of research gain greater support and funding.
This article, for example, looks only at classes of research initiative that are capable in principle of doing comparatively little for human longevity, and at great cost. The past fifteen years have demonstrated very well that is it is enormously challenging to alter human metabolism into safe new states in which aging is modestly slowed, even when we have the well-understood and well-studied example of the calorie restriction response to mimic. Billions have been spent on this, and with no result yet that is plausibly going to add more than a couple of years to human life expectancy. For that money, the research community could have completed prototypes for the full toolkit of SENS rejuvenation therapies that actually repair and remove the forms of cell and tissue damage that cause aging, not just slow down their accumulation. Repair can in principle create rejuvenation in the old, and is comparatively cheap. Slowing the pace of damage cannot do this, and is comparatively expensive. So, as I said, the type of research that prospers matters greatly.
"There is such a thing as 'biological age,' and it is distinct from chronological age," said Steve Horvath, a professor of human genetics at UCLA. "There is a huge debate about how to measure it. But everybody would agree 'biological age' should be a better predictor of how long you live than chronological age." Brian K. Kennedy, who heads the Buck Institute for Research on Aging, goes a step further. "I'm a firm believer that there is a 'biological age,' that it is different for different people, and that it can be manipulated," he said. "At least it can be manipulated in animals, and I think we will be able to manipulate it in humans, too." The idea that biological age is measurable and predictive only recently moved out of the mouse lab into human epidemiology.
A study published last year looked at roughly 1,000 New Zealanders who have been followed by researchers since their birth in the city of Dunedin in 1972 and 1973. In the Dunedin study, biological age was calculated for each person when the group was 26, 32 and 38 years old. Because the calculation was done repeatedly over a dozen years, the researchers were also able to estimate a "pace of aging" for each person. The results were startling. Even though all subjects had a chronological age of 38, their biological ages ranged from 28 to 61. There was a similarly wide range in the pace of aging. A few people showed virtually no aging over 12 years, a few showed three years of biological aging per year lived, and the rest fell in between. Cognitive and physical function tracked biological age.
A study last year found that people in their 70s whose biological age is five years greater than their chronological age have a 20 percent higher risk of dying over six years. Biological age appears to be real and able to predict the future, at least to some extent. But what is driving it? For a while it looked like the answer was: "Telomeres." The notion that telomere wear was the engine of aging had many adherents - until research revealed the story was much more complicated. "There's been 20 years of research, and the field has learned that telomere shortening plays a role in aging. But it is not the fundamental cause of aging," Horvath, the genetics professor, said. "We can debate how important it is."
A newer and more informative measure is known as the epigenetic clock. It keeps track of age-related changes in molecules, called methyl groups, that attach to the outside of our strands of DNA, like barnacles on a rope dangling off a dock. "DNA methylation" plays a part in regulating genes; its exact role is still being worked out. A person's methylation pattern is partly inherited and can be altered by lifestyle and environmental exposures. DNA damage, telomere shortening and cell senescence also change methylation patterns. But the biggest driver is the passage of time. "In my opinion, there is a fundamental aging process - the true root cause of aging," Horvath said. "We are currently designing a large human study that will test to what extent epigenetic changes underlie this process." Whatever the answer, it's clear that aging slowly, avoiding disease and living a long time are intertwined phenomena.
SENOLYTIC THERAPIES TO REMOVE SENESCENT CELLS
This is an informative article from one of the Major Mouse Testing Project principals, covering at a high level the development of senolytic therapies, those capable of removing some fraction of the senescent cells that accumulate with age. Since senescent cells are one of the root causes of aging and age-related disease, removing them qualifies as a narrow form of rejuvenation therapy, one of the first to reach the point of clinical development. Work on senolytics reached its tipping point a couple of years ago, and progress has been rapid and promising since then, with the first study to show extension of life in mice via clearance of senescent cells published last year, and startup companies Oisin Biotechnologies and UNITY Biotechnology working on bringing treatments to the clinic.
As your body ages increasing amounts of your cells enter into a state of senescence. Senescent cells do not divide or support the tissue they are a part of, but instead emit a range of potentially harmful chemical signals, these encourage other nearby cells to also enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase levels of chronic inflammation, and can even eventually raise the risk of cancer. Senescent cells normally destroy themselves via a programmed process called apoptosis and they are also removed by the immune system, however the immune system weakens with age and increasing numbers of these senescent cells escape this process and build up. By the time people reach old age significant numbers of these senescent cells have accumulated in the body and cause havoc further driving the aging process.
The health and lifespan of mice have been demonstrated to improve by the removal of senescent cells using a transgenic suicide gene and later experiments showed the same could be achieved using small molecules. Senolytics are a relatively new class of drugs that focuses on the removal of senescent cells. Senescent cells comprise a small number of total cells in the body but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which together form the senescence-associated secretory phenotype or SASP. The resulting SASP is thought to significantly contribute to aging and cancer, and thus senolytics and removal of SASP is a potential strategy for promoting health and longevity.
It was discovered that senescent cells have increased expression of pro-survival genes, consistent with their resistance to apoptosis. Drugs targeting these pro-survival factors selectively killed senescent cells. Two such drugs were dasatinib and quercetin which were both able to remove senescent cells but were better in differing tissue types. However it was discovered that a combination of the two drugs formed a synergy that was significantly more effective at removing some senescent cell types. In other studies whilst only removing thirty percent of senescent cells there were improvements to age related decline. These results suggest the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of aging and promoting healthy longevity.
Even more recently a further study demonstrated the benefits of senolytics for certain aspects of vascular aging. This is the first study to confirm that clearance of senescent cells improves aspects of vascular aging and chronic hypercholesterolemia, and could be a viable therapeutic to reduce morbidity and mortality from cardiovascular diseases. Dasatinib and quercetin are already approved for use by humans too so the application of these drugs or improved drugs based on them could be developed relatively quickly. However to date the combination of dasatinib and quercetin has yet to be tested in relation to its potential to increase maximum healthy lifespan. Current senolytic studies have focused only on health improvements rather than the long term effects (either bad or good) of this type of approach. The Major Mouse Testing Project aims to address this missing and vitally important question, can these senolytics promote healthy longevity?
AN EXAMPLE OF FALLING DEMENTIA RATES
At a given level of medical technology, as the average age of the population rises, the number of people suffering age-related diseases at any given time also tends to rise. The only way to offset that is improved prevention or improved therapies, with the former being more important in the past, and the latter becoming increasingly dominant as technological progress accelerates. The rates of incidence and mortality have fallen over the past few decades for many common age-related conditions, a trend that reflects some combination of prevention and better treatment, especially for cardiovascular disease. Given that there has been a large reduction in cardiovascular disease impact and mortality, and the aging of the cardiovascular system can drive the development of dementia, it isn't terribly surprising to see evidence for similar reductions in dementia incidence:
The UK has seen a 20% fall in the incidence of dementia over the past two decades, according to new research, leading to an estimated 40,000 fewer cases of dementia than previously predicted. Reports in both the media and from governments have suggested that the world is facing a dementia 'tsunami' of ever-increasing numbers, particularly as populations age. However, several recent studies have begun to suggest that the picture is far more complex. Although changing diagnostic methods and criteria are identifying more people as having dementia, societal measures which improve health such as education, early- and mid-life health promotion including smoking reduction and attention to diet and exercise may be driving a reduction in risk in some countries.
As part of the Medical Research Council Cognitive Function and Ageing Study (CFAS), researchers interviewed a baseline of 7,500 people in three regions of the UK (Cambridgeshire, Newcastle and Nottingham) between 1991 and 1994 with repeat interviews at two years to estimate incidence. Then 20 years later a new sample of over 7,500 people from the same localities aged 65 and over was interviewed with a two year repeat interview again. This is the first time that a direct comparison of incidence across time in multiple areas, using identical methodological approaches, has been conducted in the world.
The researchers found that dementia incidence across the two decades has dropped by 20% and that this fall is driven by a reduction in incidence among men at all ages. These findings suggest that in the UK there are just under 210,000 new cases per year: 74,000 men and 135,000 women - this is compared to an anticipated 250,000 new cases based on previous levels. Incidence rates are higher in more deprived areas. Even in the presence of an ageing population, this means that the number of people estimated to develop dementia in any year has remained relatively stable, providing evidence that dementia in whole populations can change. It is not clear why rates among men have declined faster than those among women, though it is possible that it is related to the drop in smoking and vascular health improving in men. The researchers argue that while influential reports continue to promote future scenarios of huge increases of people with dementia across the globe, their study shows that global attention and investment in reducing the risk of dementia can help prevent such increases.
ARGUING FOR TELOMERASE THERAPIES TO TREAT AGING
At the high level, the arguments for deploying telomerase-based therapies to lengthen average telomere length in various tissues and cell populations as a treatment for aging have not changed much over the past decade. The data and details have evolved with progress in investigative research, but the digest of the views held by the faction who think this way remains this: that average telomere length is enough of a cause of issues in aging, as opposed to being a reflection of other processes with few secondary effects of its own, to merit addressing. My view of the state of research is still that average telomere length looks very much like a signature of aging, not a cause of aging. It is a measure of some combination of stem cell activity, meaning the pace of delivery of new cells with long telomeres, and rates of cell division, as telomeres shorten a bit every time a cell divides. Since stem cell activity declines with age, so too does average telomere length - and the problem here is the loss of tissue maintenance by stem cells, not the length of telomeres per se.
Researchers have demonstrated that telomerase therapy can extend life in mice, most likely by improving stem cell activity in old age, one of the many ways in which it is possible to force old stem cells do more work than they have evolved to undertake at that stage in life. This approach to treating issues of old age is heading in the direction of human medicine, at the usual glacial pace of later stage research moving through the regulatory pipeline, barring a few brave outliers. There are concerns about cancer risk, given that the present consensus is that loss of stem cell activity with age most likely serves to reduce cancer incidence, extending life at the cost of frailty. In mice telomerase therapy has not shown increased cancer rates, which is a challenge to the consensus view, but mice have very different telomere dynamics in comparison to we humans. In any case, this paper is authored by one of the more prominent groups involved in this work, arguing for more of a focus on the field of telomerase therapies to treat aging:
Telomerase is a DNA reverse transcriptase polymerase (telomerase reverse transcriptase, TERT) which uses an RNA template (telomerase RNA component, TERC) for de novo addition of telomeric DNA onto telomeres, thus compensating for the telomere erosion caused by cell divisions. Indeed, overexpression of telomerase is sufficient to counteract telomere attrition and to indefinitely extend the replicative lifespan of primary cells in culture in the absence of genomic instability, transforming them into cancerous cells. However, high telomerase expression is normally restricted to early stages of embryonic development (i.e. the blastocyst stage in mice and humans) and to pluripotent embryonic stem cells. Thus, adult mammalian tissues including adult stem cell compartments do not express sufficient amounts of telomerase to maintain telomere length throughout organismal lifespan. Consequently, telomere shortening occurs along with physiological aging in humans and mice and this process is proposed to underlie aging and age-associated diseases as well as organismal longevity.
During recent years, a number of molecular pathways have been identified as main molecular causes of aging, including telomere attrition, cellular senescence, genomic instability, stem cell exhaustion, mitochondrial dysfunction, and epigenetic alterations, among others. Interestingly, telomere attrition is considered a primary cause of aging, as it can trigger all the above-mentioned hallmarks of aging, although the degree to which it is a principal cause of aging is under active investigation. Critical telomere shortening elicits the induction of cellular senescence or the permanent inability of cells to further divide, which in turn has been proposed to be at the origin of different disease states. In addition, telomere attrition in the stem cell compartments results in the exhaustion of their tissue- and self-renewal capacity, thus also leading to age-related pathologies.
A substantial number of companies are now aiming to harness the knowledge that has been generated, unveiling the molecular mechanisms of aging in order to develop a new class of drugs to prevent and treat the major age-related diseases. In this regard, telomerase overexpression studies in mice have been proof of principle that just modifying a single hallmark of aging, i.e. telomere shortening, this was sufficient to delay not one but many different age-associated pathologies in mice, including cognitive decline. Indeed, the use of telomerase activation in delaying aging-associated conditions has spurred the interest of commercial enterprises. However, potential off-target effects of compounds that activate TERT at a transcriptional level should be a concern. Such off-target effects may be circumvented through direct delivery of TERT, such as by means of systemic gene therapy using non-integrative AAV vectors, which showed a significant delay of age-related pathologies in mice and increased longevity. However, it should be mentioned that strategies for telomerase activation, indirect or direct, have raised safety concerns due to the close correlation of most cancers and constitutive reactivation of endogenous telomerase. This highlights that, in addition to proof-of-concept studies in mice, the development of safe strategies for transient and controllable telomerase activation in humans should be a future goal.
In this regard, TERT gene therapy with AAVs is particularly attractive for TERT activation, since the non-integrative and replication-incompetent properties of AAVs allow for cell division-associated telomere elongation and subsequent loss of TERT expression as cells divide, thus restricting TERT expression to a few cell divisions. It is likely that the first clinical use of a TERT-based therapy, such as the TERT gene therapy approach developed by us, will be for the treatment of the human telomere syndromes, including aplastic anemia and pulmonary fibrosis. However, this requires the development of appropriate preclinical models and the subsequent clinical trials in humans. Given that physiological aging is provoked, at least in part, by telomere shortening, a TERT gene therapy may be used not only for the prevention and treatment of telomere syndromes but also for the treatment of multiple age-related diseases. In this regard, short telomeres have been extensively associated with a higher risk for cardiovascular disease. In support of a potential use of TERT activation in the treatment of age-related diseases, we demonstrated that TERT gene therapy can efficiently rescue mouse survival and heart scarring in a preclinical mouse model for heart failure upon induction of acute myocardial infarction. Collectively, experiments in cell and animal models provide proof of concept for the feasibility of telomerase activation approaches to counteract telomere shortening and its consequences. In particular, the successful use of telomerase gene therapy in animal models of aging and short telomere-related diseases paves the way for the development of therapeutic telomerase treatments in human aging and associated disease.
CONSIDERING THE TREATMENT OF OXIDATIVE STRESS AND FIBROSIS IN AGING
The presence of reactive oxidizing molecules in our tissues increases with age. These cause damage by reacting with proteins, all of which are important parts of the biological machinery in some portion of a cell. An oxidized protein has a different chemical structure and thus cannot perform its normal tasks. This contributes to disarray and dysfunction in a cell until the damaged protein is removed by quality control processes. High levels of oxidation are referred to as "oxidative stress," and this plays an important role in aging. It is, however, far from straightforward as to how this stress arises and then interacts with metabolic operations and damage repair systems, though mitochondria appear to play a number of important roles. It appears that oxidative stress is a later condition of aging, a fair way removed from primary causes, but a lot of researchers start at this point and consider how to intervene at this level:
Improved therapies for the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrotic diseases are needed. It has been suggested that core pathways that mediate fibrosis in multiple organ systems may serve as targets for anti-fibrotic drug development, such as redox imbalance in the context of aging. Aging results in decreased resistance to multiple forms of stress, as well as increased susceptibility to numerous diseases. Progressive fibrosis is a hallmark of aging in various organ systems, including the liver, kidney, pancreas and lung. IPF, the most fatal and progressive fibrotic lung disease, disproportionately affects the elderly population and is now widely regarded as a disease of aging. The incidence and prevalence of IPF increase with age; two-thirds of IPF patients are older than 60 years at the time of presentation with a mean age of 66 years at the time of diagnosis. Further, the survival rate for IPF patients markedly decreases with age. Although the roles of specific aging hallmarks in the pathogenesis of IPF have not been fully elucidated, numerous studies implicate age-related alterations in cellular function in the pathogenesis of IPF.
Aging and fibrotic disease are both associated with cumulative oxidant burden, and lung tissue from IPF patients demonstrate "signatures" of chronic oxidative damage. The "oxidative stress theory" posits that a progressive and irreversible accumulation of oxidative damage caused by reactive oxygen species (ROS) impacts critical aspects of the aging process by contributing to impaired physiological function, increased incidence of disease, and a reduction in life span. Oxidative stress can lead to extensive modifications or damage to macromolecules including DNA, lipids and proteins and can also lead to increased production of cytokines. The lungs are particularly prone to insult and injury by oxygen free radicals given their direct exposure to the environment via inspired air. Further, environmental insults to lung may serve as a "second hit" which accelerate the aging process by promoting persistently elevated oxidative stress levels leading to increased susceptibility to disease. Oxidative stress may represent a core pathway by which other "damage" theories of aging are based. Examples include genomic instability as a result of DNA damage, and accumulation of glycated crosslinks during protein damage that can result in pathogenesis associated with cardiovascular and neurodegenerative disease. Recent studies of familial and sporadic cases of IPF have been associated with telomere shortening, further supporting the concept that IPF may represent an age-related degenerative disease process. The causes for the shortened telomeres in IPF patients without mutations in telomerase is currently unknown; however, oxidative stress represents one potential mechanism. A better understanding of the mechanisms that mediate oxidant-antioxidant imbalance in aging may be critical to the development of more effective therapeutic strategies.
Despite the well-recognized role of oxidative stress in fibrosis and aging, the ability to precisely target key mediators of this process has proved difficult. By definition, oxidative stress occurs when cellular ROS levels overwhelm the cellular antioxidant capacities, thus therapeutic strategies have been directed inhibiting oxidant generation as well as stimulating antioxidant capacity. A number of antioxidant therapeutic strategies have shown promise in various preclinical models, however, they have failed to demonstrate efficacy in the clinic. Although there may be several potential reasons for this observed lack of efficacy of anti-oxidants, one important consideration is the potential for ROS to function as redox signaling molecules for physiologic cell signaling. In fact, ROS may be viewed as "antagonistically pleiotropic" by mediating detrimental effects in the context of aging or an age-related disease. Based on its pleiotropic functions, it can be argued that targeting the primary enzymatic source of ROS (rather than anti-oxidant approaches) may offer a more promising strategy.
BIOVIVA CLAIMS SUCCESS IN INITIAL HUMAN TELOMERASE GENE THERAPY
Initial data appears to show success for the telomerase gene therapy undergone by the BioViva CEO last year. Similar gene therapies extend life in mice, most likely though increased stem cell activity and thus improved tissue maintenance. It doesn't seem to raise cancer risk in mice, but there is a concern that this may still be an issue in humans, with our quite different telomere and telomerase dynamics. Measuring the length of telomeres as presently accomplished in white blood cells is a proxy metric of dubious value for the endpoint of improved stem cell function, unfortunately, but it is the technique presently available at reasonable cost and reliability. Average telomere length in immune cells is only tenuously related to age, statistically over large populations, and does tend to change over time in both directions in individuals due to changing health and other circumstances. The alteration here is large enough and rapid enough, however, to indicate that the gene therapy worked in the sense of delivering telomerase. Finding out whether it worked in other senses, producing a more youthful tissue environment, would require a biomarker of biological age, such as the DNA methylation measures presently under development.
In September 2015, then 44 year-old CEO of BioViva USA Inc. Elizabeth Parrish received two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion responsible for diverse age-related diseases and infirmities. The treatment was originally intended to demonstrate the safety of the latest generation of the therapies. But if early data is accurate, it is already the world's first successful example of telomere lengthening via gene therapy in a human individual. Gene therapy has been used to lengthen telomeres before in cultured cells and in mice, but never in a human patient. Telomeres are short segments of DNA which cap the ends of every chromosome, acting as 'buffers' against wear and tear. They shorten with every cell division, eventually getting too short to protect the chromosome, causing the cell to malfunction and the body to age.
In September 2015, telomere data taken from Parrish's white blood cells by SpectraCell's specialised clinical testing laboratory in Houston, Texas, immediately before therapies were administered, revealed that Parrish's telomeres were unusually short for her age, leaving her vulnerable to age-associated diseases earlier in life. In March 2016, the same tests were taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb. This implies that Parrish's white blood cells (leukocytes) have become biologically younger. These findings were independently verified by the Brussels-based non-profit HEALES (HEalthy Life Extension Company), and the Biogerontology Research Foundation, a UK-based charity committed to combating age-related diseases.
"Current therapeutics offer only marginal benefits for people suffering from diseases of aging. Additionally, lifestyle modification has limited impact for treating these diseases. Advances in biotechnology is the best solution, and if these results are anywhere near accurate, we've made history.". Bioviva will continue to monitor Parrish's blood for months and years to come. Meanwhile, BioViva will be testing new gene therapies and combination gene therapies to restore age related damage. It remains to be seen whether the success in leukocytes can expanded to other tissues and organs, and repeated in future patients. For now all the answers lie in the cells of Elizabeth Parrish, 'patient zero' of restorative gene therapy.
ARGUING FOR CRYONICS PROVIDERS TO INTEGRATE WITH THE FUNERARY INDUSTRY TO SPUR GROWTH
Cryonics is the low-temperature vitrified storage of at least the brain on clinical death, with good evidence for it to preserve the fine structures that store the data of the mind. For so long as the mind is maintained, there is a chance that future technologies and societies will become capable of restoration. A small non-profit industry offers cryopreservation services for the few people who choose to avoid the certain oblivion of the grave, but growth into a sizable competitive market has proven elusive. This is important because growth is largely agreed to be necessary for longer-term survival of cryonics organizations, and thus the preserved minds, into a future period in which restoration is plausible. A lot of people interested in cryonics have their opinions on what should be done, which strategies should be pursued for growth, and the open access paper linked here is one such, suggesting integration with the funerary industry.
A significant merger of cryonics with the funerary industry has not happened and will likely never happen on the part of present organizations, as the essence of cryonics and the culture of its community is predicated on the fact that preserved individuals are patients, and clinical death is distinct from final information theoretic death. Cryonics is an emergency medical service, not a funeral arrangement, and this distinction is vital to the community. The path presently taken by the cryonics industry to grow and gather more acceptance is through integration with the medical development community, such as via the development of reversible vitrification for use in the organ transplant field, a line of research that is gaining more interest and appears to be nearing realization.
Cryonics service providers offer their customers perpetual care. This care is meant to continue until medical technology has advanced to the point that their reanimation can be performed safely. While the most optimistic estimates are that reanimation may be possible in as little as fifty years, the time frame is normally considered to be hundreds of years. The poor quality of suspensions received by most persons, however, suggests that many will be reanimated only in the distant future, if at all. One of the greatest unknowns is whether these companies will be able to operate continuously over this period. The cryonics industry's offer of perpetual care is organizationally similar to the offer of perpetual care provided by the Catholic Church in England in the Middle Ages in the form of chantries. The first perpetual Mass was established by royalty in the 1180s. Most institutions providing this service were suppressed in 1547 as part of the Reformation. Therefore, the "perpetual" care lasted for less than 400 years. The chantries were established as part of the Roman Catholic Church or as institutions under its direction and control. During this period, the Roman Catholic Church was as powerful as a state and was considered by many to be the governing body of Europe. In contrast, cryonics organizations are very small businesses with extremely limited resources, and are subject to regulation by both State and Federal governments. The key question addressed here is whether and how such organizationally inferior institutions can achieve the longevity that the most powerful organization in Europe only barely achieved in earlier times.
According to the monthly data on the Cryonics Institute (CI) website, CI membership will not continue to increase indefinitely with the current strategy. Those figures show that paid-up memberships will never pass 2,200. At that point, members going into suspension will equal new signups. The Alcor Life Extension Foundation membership appears to be following a similar pattern, i.e. a fixed number of new members per month, which is a declining growth rate. This is in sharp contrast to the earlier growth rates seen at CI, which indicated a doubling in membership every three to five years. If this trend continues, then CI will reach its peak size in about 50 years. We can expect a long decline to follow, since long-term stability is an unknown phenomenon for organizations. CI would then be expected to disappear in less than a hundred years after this peak, about 150 years from now. Since about half of prearranged suspensions can be considered poor, due to delays in cooling, it is unlikely those cryonicists will be reanimated within this time frame. In fact, there is significant doubt that anyone cryopreserved with today's technology could be reanimated within the next 150 years. A hundred and fifty years would be an unusually long lifetime for a business organization, so this estimate is likely overoptimistic.
The mainstream view of cryonics is that it is an unusual interment practice. In fact, CI was, for a time, officially registered as a cemetery. Under the Uniform Anatomical Gift Act employed, persons must be declared dead prior to being processed for suspension. About half of all cases at CI are postmortems. Since no marketing is directed toward the funeral industry, we can conclude that marketing efforts are having no effect or that there is an unmet demand that is being made apparent. In fact, a cooperating funeral director recently requested that he be allowed to offer cryonics as a standard product. Therefore, we can conclude that both mainstream opinion - government - and the market are signaling the need for a strategy employing the funeral industry as a sales channel. Failure of the medical model has been attributed to the inability to demonstrate revival from the suspended state. However, survey data shows that attitudes would hardly be affected by such a demonstration. A majority of the public simply doesn't view aging as a disease and doesn't see death as a medical problem. Some funeral directors see cryonics as an option, suggesting the funeral industry as an appropriate sales channel.
There is no physical difference necessary between facilities for cryonic suspension and cryogenic interment, which could be considered an esoteric burial practice similar to having one's ashes launched into space. The difference amounts to an intent to revive. The major barrier to implementation of this new sales channel is the self-perception of the leadership of the cryonics organizations. They would have to accept that they were participants in the funeral industry. The entire future of the cryonics industry, of those in storage, and of the many that will never be suspended because suspension is not marketed via the funeral industry is being jeopardized to maintain this self-perception by the leadership of the cryonics organizations. From the standpoint of social movement theory, the industry is maintaining its isolation from the mainstream at a time when it is technically mature enough to become a mass movement. If local funeral directors acted as sales agents, a rapid response would be likely. This arrangement could lead to better suspensions and increased sales. The major barrier appears to be the self-perception of leaders in the cryonics organizations.
Knowledge of and acceptance of cryonics, as an interment practice, has become widespread. The discrepancy between the acceptability of cryonics and its adoption suggests that a new approach based upon existing social models is needed. One such model is conventional funeral provision. The key to survival of the cryonics industry appears to be a successful transition to the mainstream. However, continued isolationism appears to be essential to the maintenance of a preferred self-image by insiders. While insiders see themselves as "saving lives" by performing an advanced form of medicine, the isolationism of the industry is actually resulting in the "loss" of many lives that could be "saved."