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UNITY Biotechnology Raises $116M for Senescent Cell Clearance Development – Article by Reason

UNITY Biotechnology Raises $116M for Senescent Cell Clearance Development – Article by Reason

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The New Renaissance HatReason
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The whispers of late have had it that UNITY Biotechnology was out raising a large round of venture funding, and their latest press release shows that this was indeed the case. The company, as you might recall, is arguably the more mainstream of the current batch of startups targeting the clearance of senescent cells as a rejuvenation therapy. The others include Oisin Biotechnologies, SIWA Therapeutics, and Everon Biosciences, all with different technical approaches to the challenge. UNITY Biotechnology is characterized by a set of high profile relationships with noted laboratories, venture groups, and big names in the field, and, based on the deals they are doing, appear to be focused on building a fairly standard drug development pipeline: repurposing of apoptosis-inducing drug candidates from the cancer research community to clear senescent cells, something that is being demonstrated with various drug classes by a range of research groups of late. Senescent cells are primed to apoptosis, so a nudge in that direction provided to all cells in the body will have little to no effect on normal cells, but tip a fair proportion of senescent cells into self-destruction. Thus the UNITY Biotechnology principals might be said to be following the standard playbook to build the profile of a hot new drug company chasing a hot new opportunity, and clearly they are doing it fairly well so far.

UNITY Biotechnology Announces $116 Million Series B Financing

Quote:

UNITY Biotechnology, Inc. (“UNITY”), a privately held biotechnology company creating therapeutics that prevent, halt, or reverse numerous diseases of aging, today announced the closing of a $116 million Series B financing. The UNITY Series B financing ranks among the largest private financings in biotech history and features new investments from longtime life science investors ARCH Venture Partners, Baillie Gifford, Fidelity Management and Research Company, Partner Fund Management, and Venrock. Other investors include Bezos Expeditions (the investment vehicle of Jeff Bezos) and existing investors WuXi PharmaTech and Mayo Clinic Ventures. Proceeds from this financing will be used to expand ongoing research programs in cellular senescence and advance the first preclinical programs into human trials.

The financing announcement follows the publication of research that further demonstrates the central role of senescent cells in disease. The paper, written by UNITY co-founders Judith Campisi and Jan van Deursen and published today, describes the central role of senescent cells in atherosclerotic disease and demonstrates that the selective elimination of senescent cells holds the promise of treating atherosclerosis in humans. In animal models of both early and late disease, the authors show that selective elimination of senescent cells inhibits the growth of atherosclerotic plaque, reduces inflammation, and alters the structural characteristics of plaque such that higher-risk “unstable” lesions take on the structural features of lower-risk “stable” lesions. “This newly published work adds to the growing body of evidence supporting the role of cellular senescence in aging and demonstrates that the selective elimination of senescent cells is a promising therapeutic paradigm to treat diseases of aging and extend healthspan. We believe that we have line of sight to slow, halt, or even reverse numerous diseases of aging, and we look forward to starting clinical trials with our first drug candidates in the near future.”

So this, I think, bodes very well for the next few years of rejuvenation research. It indicates that at least some of the biotechnology venture community understands the likely true size of the market for rejuvenation therapies, meaning every human being much over the age of 30. It also demonstrates that there is a lot of for-profit money out there for people with credible paths to therapies to treat the causes of aging. It remains frustrating, of course, that it is very challenging to raise sufficient non-profit funds to push existing research in progress to the point at which companies can launch. This is a problem throughout the medical research and development community, but it is especially pronrounced when it comes to aging. The SENS view of damage repair, which has long incorporated senescent cell clearance, is an even tinier and harder sell within the aging research portfolio – but one has to hope that funding events like this will go some way to turn that around.

From the perspective of being an investor in Oisin Biotechnologies, I have to say that this large and very visible flag planted out there by the UNITY team is very welcome. The Oisin team should be able to write their own ticket for their next round of fundraising, given that the gene therapy technology they are working on has every appearance of being a superior option in comparison to the use of apoptosis-inducing drugs: more powerful, more configurable, and more adaptable. When you are competing in a new marketplace, there is no such thing as too much validation. The existence of well-regarded, well-funded competitors is just about the best sort of validation possible. Well-funded competitors who put out peer-reviewed studies on a regular basis to show that the high-level approach you and they are both taking works really well is just icing on the cake. Everyone should have it so easy. So let the games commence! Competition always drives faster progress. Whether or not I had skin in this game, it would still be exciting news. The development of rejuvenation therapies is a game in which we all win together, when new treatments come to the clinic, or we all lose together, because that doesn’t happen fast enough. We can and should all of us be cheering on all of the competitors in this race. The quality and availability of the outcome is all that really matters in the long term. Money comes and goes, but life and health is something to be taken much more seriously.

Now with all of that said, one interesting item to ponder in connection to this round of funding for UNITY is the degree to which it reflects the prospects for cancer therapies rather than the prospects for rejuvenation in the eyes of the funding organizations. In other words, am I being overly optimistic in reading this as a greater understanding of the potential for rejuvenation research in the eyes of the venture community? It might be the case that the portions of the venture community involved here understand the market for working cancer drugs pretty well, and consider that worth investing in, with the possibility of human rejuvenation as an added bonus, but not one that is valued appropriately in their minds. Consider that UNITY Biotechnology has partnered with a noted cancer therapeutics company, and that the use of drugs to inducing apoptosis is a fairly well established approach to building cancer treatments. That is in fact why there even exists a range of apoptosis-inducing drugs and drug candidates for those interested in building senescent cell clearance therapies to pick through. Further, the presence of large numbers of senescent cells does in fact drive cancer, and modulating their effects (or removing them) to temper cancer progress is a topic under exploration in the cancer research community. So a wager on a new vision, or a wager on the present market? It is something to think about.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
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This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Criticizing Programmed Theories of Aging – Article by Reason

Criticizing Programmed Theories of Aging – Article by Reason

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The New Renaissance HatReason
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Today I’ll point out an open-access critique of programmed aging theories by the originator of the disposable soma theory of aging, one of the modern views of aging as accumulated damage rather than programming. The question of how and why we age is wrapped in a lot of competing theory, but of great practical importance. Our biochemistry is enormously complex and incompletely mapped, and thus the processes of aging, which is to how exactly our biochemistry changes over time, and all of the relationships that drive that change, are also enormously complex and incompletely mapped. Nonetheless, there are shortcuts that can be taken in the face of ignorance: the fundamental differences between young and old tissue are in fact well cataloged, and thus we can attempt to reverse aging by treating these changes as damage and repairing them. If you’ve read through the SENS rejuvenation research proposals, well, that is the list. The research community may not yet be able to explain and model how exactly this damage progresses, interacts, and spreads from moment to moment, but that effort isn’t necessary to build repair therapies capable of rejuvenation. You don’t need to build a full model of the way in which paint cracks and peels in order to scrub down and repaint a wall, and building that model is a lot most costly than just forging ahead with the painting equipment.

The engineering point of view described above, simply getting on with the job when there is a good expectation of success, is somewhat antithetical to the ethos and culture of the sciences, which instead guides researchers to the primary goal of obtaining full understanding of the systems they study. In practice, of course, every practical application of the life sciences is created in a state of partial ignorance, but the majority of research groups are nonetheless oriented towards improving the grand map of the biochemistry of metabolism and aging rather than doing what can be done today to create rejuvenation therapies. Knowledge over action. If we had all the time in the world this would be a fine and golden ideal. Unfortunately we do not, which places somewhat more weight on making material progress towards the effective treatment of aging as a medical condition – ideally by repairing its causes.

But what are the causes of aging? The majority view in the research community is that aging is a process of damage accumulation. The normal operation of metabolism produces forms of molecular damage in cells and tissues, a sort of biological wear and tear – though of course the concept of wear and tear is somewhat more nuanced and complex in a self-repairing system. This damage includes such things as resilient cross-links that alter the structural properties of the extracellular matrix and toxic metabolic waste that clutters and harms long-lived cells. As damage accumulates, our cells respond in ways that are a mix of helpful and harmful, secondary and later changes that grow into a long chain of consequences and a dysfunctional metabolism that is a long way removed from the well-cataloged fundamental differences between old and young tissues. An old body is a complicated mess of interacting downstream problems. In recent years, however, a growing minority have suggested and theorized that aging is not caused by damage, but is rather a programmed phenomenon – that some portion of the what I just described as the chain of consequences, in particular epigenetic changes, are in fact the root cause of aging. In the programmed view of aging, epigenetic change causes dysfunction and damage, not the other way around. That these two entirely opposite views can exist is only possible because there is no good map of the detailed progression of aging – only disconnected snapshots and puzzle pieces. There is a lot of room to arrange the pieces in any way that can’t be immediately refuted on the basis of well-known past studies.

There are two ways to settle the debate of aging as damage versus aging as evolved program. The first is to produce that grand map of metabolism and aging, something that I suspect is at the least decades and major advances in life science automation removed from where we stand now. The other is to build therapies that produce large degrees of rejuvenation, enough of a difference to put it far beyond argument that the approach taken is the right one. That is not so far away, I believe, as the first SENS rejuvenation therapies are presently in the early stages of commercial development. I think that, even with the comparative lack of funding for this line of development, ten to twenty years from now the question will be settled beyond reasonable doubt. Meanwhile, the programmed-aging faction has become large enough and their positions coherent enough that the mainstream is beginning to respond substantially to their positions; I expect that this sort of debate will continue all the way up to and well past the advent of the first meaningful rejuvenation therapies, which at this point look to be some form of senescent cell clearance.

Can aging be programmed? A critical literature review – by Axel Kowald and Thomas B. L. Kirkwood

Quote:

Many people, coming new to the question of why and how aging occurs, are attracted naturally to the idea of a genetic programme. Aging is necessary, it is suggested, either as a means to prevent overcrowding of the species’ environment or to promote evolutionary change by accelerating the turnover of generations. Instead of programmed aging, however, the explanation for why aging occurs is thought to be found among three ideas all based on the principle that within iteroparous species (those that reproduce repeatedly, as opposed to semelparous species, where reproduction occurs in a single bout soon followed by death), the force of natural selection declines throughout the adult lifespan. This decline occurs because at progressively older ages, the fraction of the total expected reproductive output that remains in future, on which selection can act to discriminate between fitter and less-fit genotypes, becomes progressively smaller. Natural selection generally favours the elimination of deleterious genes, but if its force is weakened by age, and because fresh mutations are continuously generated, a mutation-selection balance results. The antagonistic pleiotropy theory suggests that a gene that has a benefit early in life, but is detrimental at later stages of the lifespan, can overall have a net positive effect and will be actively selected. The disposable soma theory is concerned with optimizing the allocation of resources between maintenance on the one hand and other processes such as growth and reproduction on the other hand. An organism that invests a larger fraction of its energy budget in preventing accumulation of damage to its proteins, cells and organs will have a slower rate of aging, but it will also have fewer resources available for growth and reproduction, and vice versa. Mathematical models of this concept show that the optimal investment in maintenance (which maximizes fitness) is always below the fraction that is necessary to prevent aging.

In recent years, there have been a number of publications claiming that the aging process is a genetically programmed trait that has some form of benefit in its own right. If this view were correct, it would be possible experimentally to identify the responsible genes and inhibit or block their action. This idea is, however, diametrically opposed to the mainstream view that aging has no benefit by its own and is therefore not genetically programmed. Because experimental strategies to understand and manipulate the aging process are strongly influenced by which of the two opinions is correct, we have undertaken here a comprehensive analysis of the specific proposals of programmed aging. On the principle that any challenge to the current orthodoxy should be taken seriously, our intention has been to see just how far the various hypotheses could go in building a convincing case for programmed aging.

This debate is not only of theoretical interest but has practical implications for the types of experiments that are performed to examine the mechanistic basis of aging. If there is a genetic programme for aging, there would be genes with the specific function to impair the functioning of the organism, that is to make it old. Under those circumstances, experiments could be designed to identify and inhibit these genes, and hence to modify or even abolish the aging process. However, if aging is nonprogrammed, the situation would be different; the search for genes that actively cause aging would be a waste of effort and it would be too easy to misinterpret the changes in gene expression that occur with aging as primary drivers of the senescent phenotype rather than secondary responses (e.g. responses to molecular and cellular defects). It is evident, of course, that genes influence longevity, but the nature of the relevant genes will be very different according to whether aging is itself programmed or not.

For various programmed theories of aging, we re-implemented computational models, developed new computational models, and analysed mathematical equations. The results fall into three classes. Either the ideas did not work because they are mathematically or conceptually wrong, or programmed death did evolve in the models but only because it granted individuals the ability to move, or programmed death did evolve because it shortened the generation time and thus accelerated the spread of beneficial mutations. The last case is the most interesting, but it is, nevertheless, flawed. It only works if an unrealistically fast-changing environment or an unrealistically high number of beneficial mutations are assumed. Furthermore and most importantly, it only works for an asexual mode of reproduction. If sexual reproduction is introduced into the models, the idea that programmed aging speeds up the spread of advantageous mutations by shortening the generation time does not work at all. The reason is that sexual reproduction enables the generation of offspring that combine the nonaging genotype of one parent with the beneficial mutation(s) found in the other parent. The presence of such ‘cheater’ offspring does not allow the evolution of agents with programmed aging.

In summary, all of the studied proposals for the evolution of programmed aging are flawed. Indeed, an even stronger objection to the idea that aging is driven by a genetic programme is the empirical fact that among the many thousands of individual animals that have been subjected to mutational screens in the search for genes that confer increased lifespan, none has yet been found that abolishes aging altogether. If such aging genes existed as would be implied by programmed aging, they would be susceptible to inactivation by mutation. This strengthens the case to put the emphasis firmly on the logically valid explanations for the evolution of aging based on the declining force of natural selection with chronological age, as recognized more than 60 years ago. The three nonprogrammed theories that are based on this insight (mutation accumulation, antagonistic pleiotropy, and disposable soma) are not mutually exclusive. There is much yet to be understood about the details of why and how the diverse life histories of extant species have evolved, and there are plenty of theoretical and experimental challenges to be met. As we observed earlier, there is a natural attraction to the idea that aging is programmed, because developmental programming underpins so much else in life. Yet aging truly is different from development, even though developmental factors can influence the trajectory of events that play out during the aging process. To interpret the full complexity of the molecular regulation of aging via the nonprogrammed theories of its evolution may be difficult, but to do it using demonstrably flawed concepts of programmed aging will be impossible.

Given that the author here has in the past been among those who dismissed the SENS initiative as an approach to treating aging by repairing damage, it is perhaps a little amusing to see him putting forward points such as this one: “despite the cogent arguments that aging is not programmed, efforts continue to be made to establish the case for programmed aging, with apparent backing from quantitative models. It is important to take such claims seriously, because challenge to the existing orthodoxy is the path by which science often makes progress.” Where was this version of the fellow ten years ago?

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries.
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The Immortals Among Us – Article by Reason

The Immortals Among Us – Article by Reason

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The New Renaissance Hat
Reason
November 26, 2015
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Let us define immortality as being a state of agelessness, which seems a common colloquial usage these days. More precisely this means that the risk of death due to intrinsic causes such as wear and tear damage of vital organs remains the same over time, perhaps due to advanced medical interventions. Falling pianos are still going to kill you, and a hypothetical biologically young immortal in a hypothetical environment maintaining today’s first world extrinsic mortality rate would have a half-life of 500 years or so, meaning that at any age, there is a 50% chance of evading a life-ending event for another 500 years. There are no human immortals by this criteria of a static intrinsic mortality rate, it seems, though for a while it looked like very old humans might have essentially flat but very high mortality rates in the same way as very old flies do. Immortality in a state of advanced frailty and coupled with a 90% or higher yearly mortality rate isn’t the sort of circumstance that most people would aspire to, of course. It barely improves on the actual circumstance that the oldest of people find themselves in, all too briefly.

However, let us think beyond the box. Consider the small horde of children that you’ll find playing and running in any junior schoolyard here and now. By the time the survivors of their cohorts reach a century of age, the 2100s will have arrived. If the current very slow trend in increasing adult life expectancy continues, adding a year of remaining life expectancy at 60 for every passing decade, then something like 25% of these present children will live to see that centenary. But I don’t for one moment believe that this trend will continue as it has in the past. Past increases in life expectancy were an incidental side-effect of general improvements in medicine across the board, coupled with increasing wealth and all the benefits that brings. Across all of that time, no-one was seriously trying to intervene in the aging process, to address the causes of aging, or to bring aging under medical control. Times are changing, and now many groups aiming to build some of the foundations needed to create exactly this outcome. You may even have donated to support some of them, such as the SENS Research Foundation. The trend in longevity in an age in which researchers are trying to treat the causes of aging will be very different from the trend in longevity in an age in which no such efforts are taking place.

You don’t have to dig very far into the state of the science to see that the first rejuvenation treatments are very close, their advent limited only by funding. If funding were no issue for senescent cell clearance, for example, it would absolutely, definitively be in clinics a decade from now. Other necessary technologies are more distant, but not that much more distant – the 2030s will be an exciting time for the medical sciences. For the occupants of today’s junior playground, it seems foolish to imagine that by age 60 they will not have access to rejuvenation treatments after the SENS model at various stages of maturity, many having having been refined for more than 30 years, at the height of their technology cycle, and just giving way to whatever radical new improvement happens next.

Take a moment for a sober look at the sweeping differences and expanded technological capabilities that exist between today, the 1960s, and the 1910s. So very much has been achieved, and that pace of progress is accelerating. Those junior playground athletes of today will live to see a world even more radically different and advanced than our present time is in comparison to the First World War era. These are the immortals among us. The majority of them will have the opportunity to attain actuarial escape velocity, to keep on using ever-improving versions of rejuvenation treatments until they are gaining life expectancy at a faster rate than they are aging. Their cellular damage, the wear and tear created by the normal operation of metabolism, will be repaired as fast as it is is generated. It is the rest of us, those of us who are no longer spring chickens, who are faced with much more of a race to the goal. The degree to which we can successfully fund and advocate the necessary research is the determinant of whether we can scrape by into the age of rejuvenation treatments, or whether we will gain modest benefits but still age to death – because we were born too soon, and because the rest of the world didn’t get its collective act together rapidly enough in what is now the very tractable matter of building a cure for aging.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 
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Changing the View of Aging: Are We Winning Yet? – Article by Reason

Changing the View of Aging: Are We Winning Yet? – Article by Reason

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The New Renaissance Hat
Reason
June 28, 2015
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Peter Thiel, who has invested millions into the SENS rejuvenation research programs over the past decade, has of late been talking much more in public on the topic of treating aging. Having wealth gives you a soapbox, and it is good that he is now using it to help the cause of treating aging as a medical condition. One of Thiel’s recent public appearances was a discussion on death and religion in this context.

In the struggle to produce meaningful progress in rejuvenation research, the tipping point can come from either a very large amount of money, hundreds of millions of dollars at least, dedicated to something very similar to the SENS research programs, or from a widespread shift in the commonplace view of aging. At the large scale and over the long term, medical research priorities reflect the common wisdom, and it is my view that public support is needed to bring in very large contributions to research. The wealthiest philanthropists and largest institutional funding bodies follow the crowd as a rule; they only rarely lead it. They presently give to cancer and stem-cell research precisely because the average fellow in the street thinks that both of these are a good idea.

So it is very important that we reach a point at which research into treating degenerative aging is regarded as a sensible course of action, not something to be ridiculed and rejected. Over the past decade or two a great deal of work has gone into this goal on the part of a small community advocates and researchers. It is paying off; the culture of science and the media’s output on aging research is a far cry from what it was ten years ago. When ever more authorities and talking heads are soberly discussing the prospects of extended healthy life and research into the medical control of aging, it is to be hoped that the public will follow. Inevitably religion is drawn in as a topic in these discussions once you start moving beyond the scientific community:

Quote [Source: “Peter Thiel, N.T. Wright on Technology, Hope, And The End of Death” by Max Anderson – Forbes/Tech – June 24, 2015]:

The Venn diagram showing the overlap of people who are familiar with both Peter Thiel and N.T. Wright is probably quite small. And I think it is indicative of a broader gap between those doing technology and those doing theology. It is a surprise that a large concert hall in San Francisco would be packed with techies eager to hear a priest and an investor talk about death and Christian faith, even if that investor is Peter Thiel.

Thiel has spoken elsewhere about the source of his optimism about stopping and even reversing aging. The idea is to do what we are doing in every other area of life: apply powerful computers and big data to unlock insights to which, before this era, we’ve never had access. Almost everyone I talk with about these ideas has the same reaction. First there is skepticism  – that can’t really happen, right? Second, there is consideration  – well those Silicon Valley guys are weird, but if anyone has the brains and the money to do it, it’s probably them. Finally comes reflection, which often has two parts – 1. I would like to live longer. 2. But I still feel a little uneasy about the whole idea.

The concept of indefinite life extension feels uncomfortable to people, thinks Thiel, because we have become acculturated to the idea that death, like taxes, is inevitable. But, he says, “it’s not like one day you’ll wake up and be offered a pill that makes you immortal.” What will happen instead is a gradual and increasingly fast march of scientific discovery and progress. Scientists will discover a cure for Alzheimer’s and will say, “Do you want that?” Of course our answer will be “Yes!” They will find a cure for cancer and say, “Do you want that?” And again, of course, our answer will be “Yes!” What seems foreign and frightening in the abstract will likely seem obvious and wonderful in the specific. “It seems,” Thiel said, “that in every particular instance the only moral answer is to be in favor of it.”

One of Wright’s objections was to articulate a skepticism about whether the project of life extension really is all that good, either for the individual or for the world. “If [I] say, okay I’ll live to be 150. I’ll still be a sinner. I’ll still be conflicted. I’ll still have wrong emotions. Do I really want to go on having all that stuff that much longer? Will that be helpful to the world if I do?” This roused Thiel. “I really have to disagree with that last formulation…it strikes me as very Epicurean in a way.” For Peter Thiel, Epicureanism is akin to deep pessimism. It means basically giving up. One gets the sense he finds the philosophy not just disagreeable but offensive to his deepest entrepreneurial instincts and life experience. “We are setting our sights low,” he argued, “if we say everyone is condemned to a life of death and suffering.”

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 
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Why Do We Advocate for Rejuvenation Research? – Article by Reason

Why Do We Advocate for Rejuvenation Research? – Article by Reason

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The New Renaissance Hat
Reason
November 24, 2014
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Yesterday, I had occasion to spend six hours or so in the emergency room of a medical center largely focused on treating serious conditions that are most prevalent in old people. A part of that experience by necessity involved listening to the comings, goings, and conversations of those present. These are not private places: they are typically divided visually by screens but with no way to avoid overhearing the staff and patients. The people there are generally not too concerned about privacy in the immediate sense in any case, having far more pressing matters to focus upon.

So, by proxy, one gets to experience small and somewhat wrenching slices of other people’s lives. It is very easy for even those who follow aging research and speak up for rejuvenation treatments to forget just how hard it is to be very old. It’s one thing to know about the catalog of pain, suffering, and loss of capabilities, the conditions we’d like to find ways to turn back, and another to watch it in action. It is, really, a terrible thing to be frail.

A fellow was brought in a little while after I arrived, a 90-something man who looked a lot better on the exterior than perhaps your mental picture of a 90-something individual might be. Tall, and surprisingly lacking in wrinkles stretched out on the rolling gurney under blankets, a mess of cables, and an oxygen mask. That he had fallen was what I heard from the conversation of the medics, and was in pain. He cried out several times as he was moved from the gurney. It took some time and care to do it without hurting him more, given his weakness.

He seemed confused at first, but that was just my misperception: you try being 90 and in pain some time and see how well you do while you’re being moved around and told to hold this and let go of that. The fellow answered the bevy of questions the receiving staff had for him, but the thing that caught at me was the time he took with the answers, and the questions he just missed. He was coherent, even quite sharp at times, not on any more painkillers than a handful of Tylenol, as I later heard, but he clearly struggled with something that we younger folk all take for granted: parse the question, find the information, form up a reply and speak it. Cognitive ability in all these areas becomes ever less efficient with old age, and there’s something hollowing about hearing what is clearly a capable guy set back for a dozen seconds by a short question about one of the details of his fall. The medic repeated the question a few times and in different ways, which was clearly just making the information overload worse.

It sticks with you to be the observer in this situation and clearly and suddenly realize that one day that faltering older person will be you, trying and often failing to force your mind into the necessary connections rapidly enough for the younger people around you. I know this, but knowing it and having it reinforced by being there are two very different things. An aged person is no less intelligent, far more experienced, wiser and all the rest, but the damage to the structure of the brain that occurs even in those without dementia means that making use of all of that in the way it deserves is near insurmountable.

The fellow’s 60-something daughter arrived a little later to provide support and fill in more of the details. A story was conveyed in bits and pieces: that he was near blind now, and just about too frail to walk safely, even with a frame. The blindness explained a great deal of what had sounded to my ignorant ears as confusion in the earlier part of the fellow’s arrival: we assume all too many things about those around us, such as the use of sight in an unfamiliar environment, or the ability to walk, or think quickly – and all of this is taken from us by aging. The fellow lived with his wife still, and she was of a similar age to him. His wife was not there because she herself was too frail to be undertaking even a short trip at such short notice. That seemed to me a harsh blow on top of the rest of what old age does to you. At some point you simply cannot do everything you’d want to as a partner. You are on the sidelines and at the point at which your other half is most likely to die, you are most likely unable to be there.

In this case the fellow was in no immediate danger by the sound of it. By good luck this was in no way likely to be a fatal accident, but rather another painful indignity to be endured as a part of the downward spiral of health and ability at the end of life. Once you get to the point at which simply moving from room to room bears a high risk of accident, and this is by no means unusual for a mentally capable person in their 90s, then it really is just a matter of time before you cannot live for yourself with only minimal assistance.

When talking with his daughter while he waited on a doctor and medical assistants to come and go with tests and updates, the fellow was much faster in his responses, though this was interrupted by a series of well-meaning but futile attempts to ease his pain by changing his position, each as much an ordeal as the move from the gurney had been. The conversation between father and daughter had the sense of signposts on well-worn paths, short exchanges that recapitulated the high points of many discussions that had come before. She wanted her father to move into an assisted living facility, and this fall was the latest in a line of examples as to why it was past the time for this – she simply could not provide all of the support needed on her own. She wasn’t even strong enough herself to be able to safely get him back up on his feet after a fall. He was concerned about cost and the difficulties of moving, uncertainties and change. They went back and forth on this for a while. “We have to accept that it’s just going to be more expensive as we get older,” she said at one point, and he replied “I think you’re getting the picture now,” and laughed. There wasn’t much to laugh about, but we can all do it here and there under these circumstances. I believe it helps.

I walked out of there after my six hours of hurry up and wait was done. They were still there, and whenever it is he leaves to go home it is unlikely it will be on his own two feet. But this is a scene I’ll no doubt be revisiting at some point in the future, some decades from now, playing the other role in this small slice of life. What comes around goes around, but I’d like it to be different for me, and more importantly to be different for millions of others a lot sooner than my old age arrives.

Which leads to this: why does Fight Aging! exist? Why do we do this? Why advocate, why raise funds for research programs into ways to treat aging that may take decades to pay off? We do this because we can help to create a future in which there will be no more emergency rooms like the one I visited, no conversations about increasing disability, no pain, and no struggles to answer questions as quickly as one used to. No profound frailty. All these things will be removed by the advent of therapies that can effectively repair the causes of aging, curing and preventing frailty and age-related disease, and the sooner this happens the more people will be spared.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 
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This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

The Slowly Spreading Realization That Aging Can Be Defeated – Article by Reason

The Slowly Spreading Realization That Aging Can Be Defeated – Article by Reason

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The New Renaissance Hat
Reason
May 21, 2014
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At some point in the next ten to twenty years the public at large, consisting of people who pay little attention to the ins and outs of progress in medicine, will start to wake up to realize that much longer healthy lives have become a possibility for the near future. The preliminaries to this grand awakening have been underway for a while, gradually, and will continue that way for a while longer. A few people every day in ordinary walks of life notice that, hey, a lot of scientists are talking about greatly extending human life spans these days, and, oh look, large sums of money are floating around to back this aim. There will be a slow dawning of realization, one floating light bulb at a time, as the concept of radical life extension is shifted in another brain from the “science fiction” bucket to the “science fact” bucket.

Some folk will then go back to what they were doing. Others will catch the fever and become advocates. A tiny few will donate funds in support of research or pressure politicians to do the same. Since we live in an age of pervasive communication, we see this process as it occurs. Many people are all to happy to share their realizations on a regular basis, and in this brave new world everyone can be a publisher in their own right.

Here is an example that I stumbled over today; a fellow with a day-to-day focus in a completely unrelated industry took notice and thought enough of what is going on in aging research to talk about it. He is still skeptical, but not to the point of dismissing the current state and prospects for longevity science out of hand: he can see that this is actionable, important knowledge.

What if de Grey and Kurzweil are half right?

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I think these guys – and the whole movement to conquer aging – is fascinating. I am highly skeptical of the claims, however. Optimism is all well and good, and I have no off-hand holes to poke in their (very) well-articulated arguments. But at the same time, biology is fiendishly complex, the expectations beyond fantastical.

Still though, I have to wonder: What if guys like de Grey and Kurzweil are half right, or even just partially right? What if, 30 years from now, it becomes physically impossible to tell a 30-year-old from a 70-year-old by physical appearance alone? It sounds nutty. But it’s a lot less nuttier, and a lot closer to the realm of possibility, than living to 1,000 – which, again, some very smart people have taken into their heads as an achievable thing.

People who don’t take care of themselves are insane. Ok, not actually “insane.” But seriously, given the potential rewards AND the risks, not taking care of your body and mind – not treating both with the utmost respect and care – seems absolutely nuts. At the poker table I see these young kids whose bodies are already turning to mush, and a part of me just wants to grab them by the shirt collar and say “Dudes! What the hell is WRONG with you!!!”

If it is possible – just realistically possible, mind you – that I could still be kicking ass and taking names at 125 years old, then I want to be working as hard as I can to preserve and maintain my equipment here and now. No matter what miracles medical science will achieve in future, working from the strongest, healthiest base possible will always improve the potential results, perhaps by an order of magnitude. Individuals who go into old age with fit, healthy bodies and sound minds, and longstanding habits to maintain both, may find potential for extended performance at truly high quality of life that was never before imaginable.

As the foundations of rejuvenation biotechnology are assembled and institutions like the SENS Research Foundation continue to win allies in the research community and beyond, the number of people experiencing this sort of epiphany will grow. The more the better and the sooner the better, as widespread support for the cause of defeating aging through medical science is necessary for more rapid progress: large scale funding always arrives late to the game, attracted by popular sentiment. The faster we get to that point, the greater our chances of living to benefit from the first working rejuvenation treatments.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 
***

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To Accept Aging and Death is to Choose Aging and Death – Article by Reason

To Accept Aging and Death is to Choose Aging and Death – Article by Reason

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The New Renaissance Hat
Reason
April 1, 2014
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It is in the nature of things for people to become more accepting of the imperfect state of the world and the flawed human condition with advancing age, to lose that youthful indignation and urge to change all that causes suffering and injustice. We can blame a range of things for this, but I suspect that it has a lot to do with the growth in wealth and connections that occurs over the years for most individuals. Whatever your starting level, on average the 50-year-old you will be in a better place than the 20-year-old you. The gains you have amassed merge with nostalgia in a slow erosion of the desire to tear down walls and shake up your neighbors: things are better for you, and isn’t that a good thing? Not everyone is this way, of course, but it is a dynamic to be aware of in your relationship with the world. It is human nature to measure today against yesterday, and feel good about gains that are relatively large but absolutely small.

Acceptance of death and aging is the mindset I am thinking in particular here. The unpleasant ends of life are dim and distant myths when you are young and vigorous in your search for world-changing causes. It is the rare young individual who is willing to devote his or her life in preparation for a time half a century down the road. The older folk who feel the pressures of time and encroaching frailty are those who have become more accepting, however. To fight aging and work on rejuvenation treatments is an intrinsically hard sell in comparison to many other ventures. The youth think they have time to focus on other matters first, and the old have come to terms.

Nonetheless, with rapid progress in biotechnology year after year the number of people needed to get the job done is falling rapidly. Ten million supporters willing to put in a little time or money (rather than just a wave and a good word) and the careers of a few thousand scientists and biotechnicians is probably more than is needed at this point, a level of support that lies in a similar ballpark to that of the cancer or stem-cell research communities. We are not there yet, though support for scientific, medical approaches to the treatment and prevention of aging has grown in a very encouraging fashion over the past decade. At any time in the next year or so you might see mainstream press articles in noted publications favorably mention the SENS Research Foundation, regenerative medicine, Google’s Calico initiative, and progress in genetic science all in the same few paragraphs.

We are here, where we are, precisely because numerous people retained a youthful fire and verve, and indignation and horror of aging and death. Despite the ever-present opposition from a mainstream that once mocked aging research, these iconoclasts put in the work that has raised funds, created organizations, and changed minds: all seeds for tomorrow’s grand rejuvenation research community. This is a work in progress. But let us take a moment to admire some of the fire from those driving things along at the grassroots level:

Those Critical of Indefinite Life Extension Fear Life

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Accepting death is in fact choosing it. In the face of recent discoveries and progress in science, medicine, technology – it is a matter of choice. Pretending to be fearless in the face of death isn’t some form of heroism. It isn’t reasonable or courageous. It is quite the opposite. It is taking the easy way out. Let’s repeat it – death really is the easy way out. You fall asleep; you get a bullet; cancer kills you; some choose suicide; some accept aging and its effects as an inexorable given. The hard truth here that we should be prepared to acknowledge is: accepting death is the true cowardice, no matter the circumstances. Fighting it and choosing life is the true courage.

Critics of indefinite life extension, don’t put on a snide, condescending face and tell me that you aren’t afraid of death, because you are, too.

By your own knee-jerk flippancy, reactionary admission, you are also afraid of life. You’re afraid of death, and you’re afraid of life. You say, right to us, all the time, that you don’t want to bear to deal with the drastic changes, you don’t want to live without all your friends and family around, you don’t want to live with war still being a reality anywhere. You can’t stand all the jerks and the dangerous people, and rich people, or tyrants, controlling you for one decade longer than a traditional lifespan. The thought of it makes you want to jump into your grave right now to get away from this big, bad, scary life.

You, my friend, are afraid of life. Living scares you. You think of life and you cower. You see the challenges of life and you’re too scared to face them. You wouldn’t dare form and join teams and initiatives to meet those challenges on the intellectual combat fields of dialectics and action. You don’t have what it takes. Life isn’t for you. It’s not your thing. So love your death, fear your life. Do that if that’s what you want.

I am afraid of death. It scares me to think of losing my life. I value my life. I have no shame in that. That is the reasonable thing to do. What I have shame for is that anybody would think that being afraid of death might possibly be something to mock.

You mock us for being afraid of death. We are afraid of death; it’s a logical and positive thing to be afraid in the face of it. It reminds a person to take action against danger. It’s your being afraid of life that is to be mocked. So stand up and tell us how afraid you are of living. We promise not to look upon you with too much shame, and we promise to lend you a hand if you need help crossing over to the land of reason.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

Theorizing That Some Change in the Aging Brain is Optimization, Not Degeneration – Article by Reason

Theorizing That Some Change in the Aging Brain is Optimization, Not Degeneration – Article by Reason

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The New Renaissance Hat
Reason
February 9, 2014
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The nature of neural networks is perhaps better understood by more people nowadays than used to the be the case. Forms of neural network are used for a range of computational purposes, where they have proved useful as a way to economically discover solutions to difficult problems in pattern recognition, optimization, and other fields. How a particular solution works isn’t always clear, especially when using larger networks, but if it can be proven to work well then why worry?

We ourselves are neural networks: the complex adaptive phenomena that we choose to call the self arises from comparatively simple exchanges between many, many neurons. The machine is the connections and the state of its neurons, constantly altering itself in response to circumstances and its own operation.

The brain, like all tissues, suffers due to the accumulation of cellular and molecular damage that drives aging. But which of the characteristic differences between a young brain and an old brain are aging, and which are the expected operation of the neural network as it processes and reprocesses the data gathered throughout life? In some cases the classification is obvious: broken blood vessels and white matter hyperintensities are damage, as is the amyloid that accumulates in Alzheimer’s disease. We would be better off without them, and they harm us by destroying physical structures needed for operation of the brain. Once researchers start looking at the structure of neural connections, or activity in response to stimulus, or gene expression maps in various portions of the brain things become a little less clear, however:

The Brain Ages Optimally to Model Its Environment: Evidence from Sensory Learning over the Adult Lifespan

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The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses – including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline.

Theoretical neurobiology offers a simpler explanation for all of these effects – from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning.

Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world.

My suspicion is that it would be faster to implement rejuvenation biotechnologies and then assess what happens to an aging brain that remains physiologically young than to fully pick apart and understand present contributions to changes over time in the brain.

This line of research is of interest because of a potential threat to extreme longevity, past the present limits of human life span, once we have build the necessary medical technologies. The threat is this: it is possible that the brain is like the immune system, in that it is poorly structured for long term use, and will fail for reasons inherent to that structure, even in the absence of damage. We have no reason to suspect that this is the case, but equally there is no good reason to rule this out – the scientific community simply doesn’t understand enough about the detailed operation of the brain to say either way with confidence.

On the plus side, this is a comparatively remote potential threat, something that lies decades past all the other fatal forms of damage and age-related disease that we have to deal with. Old people with little physical damage to their brains are sharp and on the ball, to the degree allowed by their failing bodies and decades of increasing caution required in their interaction with the world. Further, by the time we are at the point of worrying about this, biotechnology will be far more advanced. So it is, I think, worth considering, but not worth panicking over.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

More Recent Coverage of SENS Research – Article by Reason

More Recent Coverage of SENS Research – Article by Reason

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The New Renaissance Hat
Reason
January 31, 2014
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SENS stands for the Strategies for Engineered Negligible Senescence, a research and development plan first assembled more than a decade ago by biomedical gerontologist Aubrey de Grey. This was a work of vision and synthesis: taking decades of research results from many diverse fields of medical research whose scientists had comparatively little contact with one another, and little interest in working on ways to treat aging, and pulling these results together into a convincing argument as to (a) which forms of cellular and molecular damage cause aging, and (b) how to go about developing the means of repair for this damage.

Aging is damage, and repair is rejuvenation. Sufficiently comprehensive implementations of SENS should not only prevent aging and age-related disease, but also reverse the effects of aging in the old. This isn’t a matter of hand-waving: the capabilities in molecular biology and research plans to build therapies are outlined in considerable detail at the SENS Research Foundation website and in related scientific papers. You should take a look if you haven’t recently. The estimated cost of developing this to the point of demonstration in mice is on a par with the total cost of development of a single drug: perhaps $1-2 billion over 10-20 years.

It is pleasing to chart the changing character of press coverage over the years for SENS rejuvenation research and its figurehead advocate and organizer Aubrey de Grey. In the past ten years of increasing support within the scientific community and an influx of millions of dollars in philanthropic funding for research, it has become ever harder for journalists to stick their heads in the sand and pretend that SENS is either fringe or not real science. The gatekeepers of the establishment are never kind to any form of change or progress in the early days.

Measured by budget the SENS Research Foundation is a presently a tenth of the size of the well-established and mainstream Buck Institute for Aging Research. This is still larger than a good many labs in the field, and funding for SENS research has grown considerably over the past few years. Skilled molecular biologists in numerous laboratories are working on aspects of the SENS program of development for rejuvenation therapies. This work is still at the level of building tools and foundations for later progress, but it is very much real, tangible medical research. This is a new and upcoming field, the future of medical science and aging.

Aubrey de Grey: Out to Defy Death

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Spend a moment asking yourself, “What is the world’s worst problem?”

Biomedical gerontologist Aubrey de Grey, Ph.D., has an answer that may be radically different from yours. For him, it’s aging, and he not only makes a convincing case for why this is so, but he’s devoting his life to doing something about it. Dr. de Grey is the founder of SENS, a research foundation that aims to help build the regenerative medicine industry, an industry that arguably has the best chance for curing the diseases of aging. Surprisingly, he’s having more success than the people who were calling him a maverick and a heretic five years ago ever imagined.

First they ignore you, then they laugh at you, then they fight you, then you win. To my eyes, things have made it to the early stages of the winning part of that saying these days, certainly insofar as the scientific community is concerned. (Much more remains to be done in order to sell the public on the idea that radical life extension is a real possibility and that the relevant research is important and should be supported.) SENS is far more than Aubrey de Grey nowadays: it’s his vision, but has grown to be shared quite widely. There are dozens of influential allied scientists and laboratories, a number of high-net-worth philanthropists providing support, many advocates, a SENS Research Foundation staff, fundraisers, and, of course, the numerous researchers working to build the tools needed for future rejuvenation treatments.

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The SENS Foundation is a public charity based in California, and its purpose is to fill a niche in the research funding chain. Private sector research, particularly in the drug industry, has funds to drive important research, but only after it’s clear that the odds of success are good, the time frame is reasonably short, and the potential for profit large. At the other end of the research spectrum, public sector research funding is available for basic research that doesn’t have an immediate commercial purpose.

However, in Dr. de Grey’s view, and his colleagues’ as well, there’s a midway point between the private sector funding and the public sector, and this midpoint is often neglected. Research that may yield incalculable commercial success (and public benefit as well), may be at such an early stage of development that it doesn’t yet attract commercial funders. “We exist to make sure that this kind of intermediate research is not neglected,” he says.

People no longer refer to Aubrey de Grey as a “maverick” or “heretic.” “These days, I’m more often called ‘controversial,'” he says, sounding pleased with this new characterization.

“Controversial,” after all can be translated as, “might be right.”

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.

Why Prioritize SENS Research for Human Longevity? – Article by Reason

Why Prioritize SENS Research for Human Longevity? – Article by Reason

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The New Renaissance Hat
Reason
December 29, 2013
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Why do I vocally support rejuvenation research based on the Strategies for Engineered Negligible Senescence (SENS) over other forms of longevity science? Why do I hold the view that SENS and SENS-like research should be prioritized and massively funded? The short answer to this question is that SENS-derived medical biotechnology has a much greater expected utility – it will most likely produce far better outcomes, and at a lower cost – than other presently ongoing lines of research into creating greater human longevity.

What is SENS?

But firstly, what is SENS? It is more an umbrella collection of categories than a specific program, though it is the case that narrowly focused SENS research initiatives run under the auspices of the SENS Research Foundation. On the science side of the house, SENS is a synthesis of existing knowledge from the broad mainstream position regarding aging and the diseases of aging: that aging is caused by a stochastic accumulation of damage at the level of cells and protein machinery in and around these cells. SENS is a proposal, based on recent decades of research, as to which of the identified forms of damage and change in old tissues are fundamental – i.e. which are direct byproducts of metabolic operation rather than cascading effects of other fundamental damage. On the development side of the house, SENS pulls together work from many subfields of medical research to show that there are clear and well-defined ways to produce therapies that can repair, reverse, or make irrelevant these fundamental forms of biological damage associated with aging.

(You can read about the various forms of low-level damage that cause aging at the SENS Research Foundation website and elsewhere. This list includes: mitochondrial DNA mutations; buildup of resilient waste products inside and around cells; growing numbers of senescent and other malfunctioning cells; loss of stem cells; and a few others).

Present arguments within the mainstream of aging research are largely over the relative importance of damage type A versus damage type B, and how exactly the extremely complex interaction of damage with metabolism progresses – but not what that damage actually is. A large fraction of modern funding for aging research goes towards building a greater understanding this progression; certainly more than goes towards actually doing anything about it. Here is the thing, however: while understanding the dynamics of damage in aging is very much a work in progress, the damage itself is well known. The research community can accurately enumerate the differences between old tissue and young tissue, or an old cell and a young cell – and it has been a good number of years since anything new was added to that list.

If you can repair the cellular damage that causes aging, it doesn’t matter how it happens or how it affects the organism when it’s there. This is the important realization for SENS – that much of the ongoing work of the aging research community is largely irrelevant if the goal is to get to human rejuvenation as rapidly as possible. Enough is already known of the likely causes of aging to have a reasonable expectation of being able to produce laboratory demonstrations of rejuvenation in animal models within a decade or two, given large-scale funding.

Comparing Expected Values

Expected value drives human endeavor. What path ahead do we expect to produce the greatest gain? In longevity science the investment is concretely measured in money and time, and we might think of the expected value in terms of years of healthy life added by the resulting therapies. The cost of these therapies really isn’t much of a factor – all major medical procedures and other therapies tend to converge to similar costs over time, based on their category: consider a surgery versus an infusion versus a course of pills, for example, where it’s fairly obvious that the pricing derives from how much skilled labor is involved and how much care the patient requires as a direct result of the process.

On the input side, there are estimates for the cost in time and money to implement SENS therapies for laboratory mice. For the sake of keeping things simple, I’ll note that these oscillate around the figures of a billion dollars and ten years for the crash program of fully-funded research. A billion dollars is about the yearly budget of the NIA these days, give or take, which might be a third of all research funding directed towards aging – by some estimates, anyway, though this is a very hard figure to verify in any way. It’s by no means certain the that the general one-third/two-thirds split between government and private research funding extends to aging research.

On the output side, early SENS implementations would be expected to take an old mouse and double its remaining life expectancy – e.g. produce actual rejuvenation, actual repair, and reversal of the low-level damage that causes aging, with repeated applications at intervals producing diminishing but still measurable further gains. This is the thing about a rejuvenation therapy that works; you can keep on applying it to sweep up newly accruing damage.

So what other longevity science do we have to compare against? The only large running programs are those that have grown out of the search for calorie-restriction mimetic drugs. So there is the past decade or so of research into sirtuins, and there is growing interest in mTOR and rapamycin analogs that looks to be more of the same, but slightly better (though that is a low bar to clear).

In the case of sirtuins, money has certainly flowed. Sirtris itself sold for ~$700 million, and it’s probably not unreasonable to suggest that a billion dollars have gone into broader sirtuin-related research and development over the past decade. What does the research community have to show for that? Basically nothing other than an increased understanding of some aspects of metabolism relating to calorie restriction and other adaptations that alter lifespan in response to environmental circumstances. Certainly no mice living longer in widely replicated studies as is the case for mTOR and rapamycin – the sirtuin results and underlying science are still much debated, much in dispute.

The historical ratio of dollars to results for any sort of way to manipulate our metabolism to slow aging is exceedingly poor. The thing is, this ratio shouldn’t be expected to get all that much better. Even if marvelously successful, the best possible realistic end result of a drug that slows aging based on what is known today – say something that extracts the best side of mTOR manipulation with none of the side-effects of rapamycin – is a very modest gain in human longevity. It can’t greatly repair or reverse existing damage, it can’t much help those who are already old become less damaged, it will likely not even be as effective as actual, old-fashioned calorie restriction. The current consensus is that calorie restriction itself is not going to add more than a few years to a human life – though it certainly has impressive health benefits.

(A sidebar: we can hope that one thing that ultimately emerges from all this research is an explanation as to how humans can enjoy such large health benefits from calorie restriction, commensurate with those seen in animals such as mice, without also gaining longer lives to match. But if just eating fewer calories while obtaining good nutrition could make humans reliably live 40% longer, I think that would have been noted at some point in the last few thousand years, or at least certainly in the last few hundred).

From this perspective, traditional drug research turned into longevity science looks like a long, slow slog to nowhere. It keeps people working, but to what end? Not producing significant results in extending human longevity, that’s for sure.

Ergo…

The cost of demonstrating that SENS is the right path or the wrong path – i.e. that aging is simply an accumulation of damage, and the many disparate research results making up the SENS vision are largely correct about which forms of change in aged tissue are the fundamental forms of damage that cause aging – is tiny compared to the cost of trying to safely eke out modest reductions in the pace of aging by manipulating metabolism via sirtuins or mTOR.

The end result of implementing SENS is true rejuvenation if aging is caused by damage: actual repair, actual reversal of aging. The end result of spending the same money and time on trying to manipulate metabolism to slow aging can already be observed in sirtuin research, and can reasonably be expected to be much the same the next time around the block with mTOR – it produces new knowledge and little else of concrete use, and even when it does eventually produce a drug candidate, it will likely be the case that you could do better yourself by simply practicing calorie restriction.

The expectation value of SENS is much greater than that of trying to slow aging via the traditional drug-discovery and development industry. Ergo the research and development community should be implementing SENS. It conforms to the consensus position on what causes aging, it costs far less than all other proposed interventions into the aging process, and the potential payoff is much greater.

Reason is the founder of The Longevity Meme (now Fight Aging!). He saw the need for The Longevity Meme in late 2000, after spending a number of years searching for the most useful contribution he could make to the future of healthy life extension. When not advancing the Longevity Meme or Fight Aging!, Reason works as a technologist in a variety of industries. 

This work is reproduced here in accord with a Creative Commons Attribution license.  It was originally published on FightAging.org.