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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

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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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This work is reproduced here in accord with a Creative Commons Attribution license. It was originally published on FightAging.org.
Another View of Aging Science: That We Don’t Know Enough – Article by Reason

Another View of Aging Science: That We Don’t Know Enough – Article by Reason

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The New Renaissance Hat
Reason
June 27, 2014
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Early this month I pointed out an example of the viewpoint on aging research that focuses on drugs, lifestyle, and metabolic manipulation and sees present work in that area to be a matter of significant and ongoing process. I disagree, for reasons that were explained in that post. Today, I’ll take a glance at a different view of the science of aging and longevity, one that is far more popular in the mainstream research community, and with which I also vehemently disagree.

Researchers in this field might be loosely divided into three camps, which are as follows ordered from largest to smallest: (a) those who study aging as a phenomenon without seeking to produce treatments, (b) those who see to slow aging through development of means to alter the operation of metabolism, such as calorie restriction mimetic drugs, and (c) those who aim to produce rejuvenation biotechnology capable of reversing aging. The vast majority of the aging research community at present consider that too little is known of the details of the progression of aging to make significant inroads in the design of treatments, and that the way forward is fundamental research with little hope of meaningful application for the foreseeable future. This attitude is captured here:

Let me ask you this: ‘Why can’t we cure death yet?’

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We can’t ‘cure death’ because biology is extremely complicated. Without a fundamental understanding of how biological organisms work on a molecular level, we’re left to educated guesses on how to fix things that are breaking in the human body. Trying to cure disease without a full understanding of the underlying principles is like trying to travel to the moon without using Newton’s laws of motion.

The reason we haven’t cured death is because we don’t really understand life.

This is only half true, however. It is true if your goal is to slow down aging by engineering metabolism into a new state of safe operation in which the damage of aging accumulates more slowly. This is an enormous project. It is harder than anything that has been accomplished by humanity to date, measured on any reasonable scale of complexity. The community has only a few footholds in the vast sea of interactions that make up the progression of metabolism and damage through the course of aging, and this is despite the fact that there exists an easily obtained, very well studied altered state of metabolism that does in fact slow aging and extend life. Calorie restriction can be investigated in almost all laboratory species, and has been the subject of intense scrutiny for more than a decade now. Yet that barely constitutes a start on the long road of figuring out how to replicate the effects of calorie restriction on metabolism, let alone how to set off into the unknown to build an even better metabolic state of operation.

Listing these concerns is not even to start in on the fact that even if clinicians could perfectly replicate the benefits of calorie restriction, these effects are still modest in the grand scheme of things. It probably won’t add more than ten years to your life, and it won’t rejuvenate the old, nor restore any of their lost functionality. It is a way of slowing down remaining harm, not repairing the harm that has happened. All in all it seems like a poor use of resources.

People who argue that we don’t understand enough of aging to treat it are conveniently omitting the fact that the research community does in fact have a proven, time-tested consensus list of the causes of aging. These are the fundamental differences between old tissue and young tissue, the list of changes that are not in and of themselves caused by any other process of aging. This is the damage that is the root of aging. There are certainly fierce arguments over which of these are more important and how in detail they actually interact with one another and metabolism to cause frailty, disease, and death. I’ve already said as much: researchers are still in the early days of producing the complete map of how aging progresses at the detail level. The actual list of damage and change is not much debated, however: that is settled science.

Thus if all you want to do is produce good treatments that reverse the effects of aging, you don’t need to know every detail of the progression of aging. You just need to remove the root causes. It doesn’t matter which of them are more or less important, just remove them all, and you’ll find out which were more or less important in the course of doing so – and probably faster than those who are taking the slow and stead scholarly route of investigation. If results are what we want to see then instead of studying ever more esoteric little corners of our biology, researchers might change focus on ways to repair the known forms of damage that cause aging. In this way treatments can be produced that actually rejuvenate patients, and unlike methods of slowing aging will benefit the old by reversing and preventing age-related disease.

This is exactly analogous to the long history of building good bridges prior to the modern age of computer simulation and materials science. With the advent of these tools engineers can now build superb bridges, of a quality and size that would once have been impossible. But the engineers of ancient Rome built good bridges: bridges that allowed people to cross rivers and chasms and some of which still stand today. Victorian engineers built better bridges to facilitate commerce that have stood the test of time, and they worked with little more than did the Romans in comparison to today’s technologies. So the aging research community could begin to build their bridges now, we don’t have to wait for better science. Given that we are talking about aging, and the cost of aging is measured in tens of millions of lives lost and hundreds of millions more left suffering each and every year, it is amazing to me that there are not more initiatives focused on taking what is already known and settled about the causes of aging and using that knowledge to build rejuvenation treatments.

What we see instead is a field largely focused on doing nothing but gathering data, and where there are researchers interesting in producing treatments, they are almost all focused on metabolic engineering to slow aging. The long, hard road to nowhere helpful. Yet repairing the known damage of aging is so very obviously the better course for research and development when compared to the prospect of an endless exploration and cataloging of metabolism. If we want the chance of significant progress towards means of treating aging in our lifetime, only SENS and other repair-based approaches have a shot at delivering. Attempts to slow aging are only a distraction: they will provide a growing flow of new knowledge of our biochemistry and the details of aging, but that knowledge isn’t needed in order to work towards effective treatments for aging today.

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.

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.