Criticizing Programmed Theories of Aging

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

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?

Comments

"Where was this version of the fellow ten years ago?"

Well, you know, it's the theory of the four stages of acceptance:

(1) this is worthless nonsense
(2) this is an interesting, but perverse, point of view
(3) this is true, but quite unimportant
(4) I always said so

Posted by: Antonio at August 25th, 2016 6:31 AM

to me, both arguments are reductio ad absurdum. To say at this point that it MUST be one or the other is silly. My best guess is that it will be both - in some proportion and episode sequencing.

Posted by: david Gobel at August 25th, 2016 6:46 AM

David Gobel: Can you point out what's wrong with this argument against programmed aging?:

"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."

Posted by: Antonio at August 25th, 2016 7:59 AM

"Where was this version of the fellow ten years ago?"

Ha ! Touché.

Although, if the Thomas Kirkwood clearly acknowledges the mistake of his past stance and openly states his support to the SENS cause, that would be respectable.

Posted by: Spede at August 25th, 2016 8:33 AM

Ah the famous Kirkwood who was frankly very rude about SENS all those years ago. I seriously doubt he would eat humble pie and accept he was wrong.

Posted by: Steve Hill at August 25th, 2016 10:46 AM

Kirkwood does still have a point. A lot of the scientific community still think that DNA damage is important in aging, and eighth class of damage. And if it is, then the SENS approach is sunk for the foreseeable future until each specific piece of DNA damage can be repaired in each individual cell.

Unfortunately the only way to prove or disprove the eighth class of damage is to remove the other 7 classes of damage and see if the animals still die on some form of schedule.

Posted by: Jim at August 25th, 2016 11:14 AM

Jim: It's not the only way. One can measure the rate of (epi)mutation. If it's small enough, it can't influence aging at current lifespans. SRF has funded some research on the topic. For what I can understand from their texts, the matter is mostly settled for mutations (they are only important for cancer and creation of senescent cells, that are already addressed by SENS) but it needs further research for epimutations (currently done by Jan Vijg's lab).

Posted by: Antonio at August 25th, 2016 12:18 PM

Hi there ! Very interesting and the mystery still lingers on which of which is which first.

"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."

I too am of the belief it's not one or the other, it's both that are in motion - in tandem/parallelically and feeding off each other in a complimentary
way. What is certain is that damage is definitely causal, what is less certain is if a 'aging program' is creating that damage as part of its unfolding, which makes us age.
It's both, I think. Studies with iPSCs have shown they can be reprogrammed 'as if new' and their telomeres are relenghtened. They lose their damage, almost like it never happened.
I don't know if they lose their lysosomes lipofuscin mass or if their DNA methylation (epigenetic) pattern is changed. I would wager yes, because
telomerase alters DNA methylation (5-methylcytosine count is increased by telomerase upon telomere size increase) - higher capped telomeres are hypermethylated,
shorter uncapped telomeres are demethylated. Sure telomeres are just a marker of aging rather than a cause, but they do show us that damage is happening (as seen with mice with very long telomeres and they die anyways;
this means that telomeres can be uncoupled from damage and there are more than one 'pathways' to activating p16, p21 and p53 senescence tumor-supressor oncogenes).

Let's transpose that with animals that abuse telomerase : Hydras and Great Basin Bristle Pine Tree. Both these organisms have germ stem cells that are immortal - by virtue of telomerase permanence; and they use it to gain (near) immortality.
Immortality means lipofuscin removal/absence or production with removal (in balance). Studies have shown that when lipofuscin is introduced into cell culture is clogs the proteasome, lysosomes and blocks the autophagy/mitophagy process itself.
Thus, it is not innocent, it hinders proteasome autophagic process by 'loading it' and making it slowed/clogged. In fact, one study demonstrated by FACS scan that fibroblasts accumulate a age-pigment over replicative bouts, until they reach
a maximum and die. Werner Fibroblasts (accelerated aging syndrome/progeria) were cultured for 15 population doublings (until replicative senescence p53 M1 point) while SV-40 infected Werner Fibroblasts were culture for 250 population doublings; meaning that the simian virus had activated telomerase upon infection.
What's more is that, under FACS, Werner Fibroblasts accumulated lipofuscin - from 0 to 100% at 15 population doublings, while SV-40 infected ones, also from 0 to same final 100% quantity - but extremely slowly - in 250 population doublings.
This showed that for extreme replicative lifespan, lysosomal junk must be eliminated - continuously and not accumulate (or else block autophagy/autophagosomes). And death is rapidly actived if autophagy is blocked (it's a crucial element for survival).

The point, I'm trying to say is that Hydras and GBBPines are immortal because they don't accumulate lysosomal waste, by a continuing increase in telomerase activity. And we said that lipofuscin cloggs proteasome (which creates senescence). And, for example, in the Hydra's case
this jellyfish has a 'reversal/rejuvenation' where it retracts back from puberty/adult stage to 'child immature' state. This is pure - (epi)genetic rejuvenation. It's not just removal of damages, it's a 'Signal' that removes the damages (lipofuscin for example) - a programmed signal into the Hydras around puberty.
The damage would then be a consequence of that program (the reversal of damage would be a consequence of a 'epigenetic reproductive program' activation around puberty, allowing it to gain infinite lifespan by looping this program).

What else ? Well, programmed aging, yes and no, because for example, IL-6, TNF-a and many 'inflammation' genes are actived with age.
Telomerase replicative end problem creates inflammation even if itself is not a 'true' damage, rather it is 'an imperfection' of the flawed replicating system (telomerase is called upon to add telomeric repeats because polymerase/topoisomerases can't fix the telomere loss during cell division).
Imperfection can then create activation of Genes (programmed aging, it's 'programmed' because there was 'program' 'to it' (aka 'imperfection' program, a 'program' caused by imperfections), which - then - create damages/that damage the DNA. In that case, yes, the program would be first and causal to the appearance of damages.
In any case, it really seems more - both - it's not one or the other. They work, together, at the same time and co(inter)-(In-)dependently of each other.

Posted by: CANanonymity at August 25th, 2016 3:24 PM

I think that there are no special program with the genes that cause aging, but aging is the result of the end of organism development support program. As organism development discontinued - motivate signals damped and the ability to support life weakens.

Posted by: Dmitry Dzhagarov at August 26th, 2016 2:48 PM

The irony in Kirkwood's paper is the ease with which the fundamental premises of his own disposable soma theory can be discredited. In fact, Mitteldorf has done this on more than one occasion (perhaps this is the motivation for the attack from Kowald and Kirkwood?). The absurdity of the idea put forth by the disposable soma theory that aging is a result of "optimizing the allocation of resources between maintenance..and growth and reproduction" should be immediately apparent to most anyone who has a basic grasp of physics.

To illustrate one of the more obvious problems with the theory, consider some arbitrary inanimate object (e.g. car, dishwasher, phone, etc.). Clearly, the rate at which this object degrades is not solely dependent on the investment into maintaining it. It would also very much depend on the environment in which the object is used (exposure to UV, heat, etc.), how often the object is used, and how intense the use is.

Smaller organisms with shorter lives actually spend MORE on protein repair and replacement than larger organisms with longer lives. This is precisely opposite of what the disposable soma theory predicts.

It can also be easily demonstrated that the energetic expenditure required to offset any increase in degradation during aging is miniscule for most organisms (in humans, it would require less than 0.01% of daily energy expenditures by my estimations). For this reason alone it makes absolutely no sense for an organism to allow degradation accumulation so that energy can be redirected for other uses. The negative repercussions of such a strategy would far exceed any benefits.

These are some of the more obvious objections to the disposable soma theory. In a sane world, these (and other) major discrepancies with the disposable soma theory should have resulted in a total and quick dismissal of the theory. But alas that has not been the case and the theory has persevered for nearly 40 years… Instead, what we have been presented with are half-baked attempts to explain these anomalies using special-case exceptions that simply don't work well. An example is Kirkwood's explanation for why caloric restriction (which imposes a limitation on energetic resources) would INCREASE longevity and not reduce it (as one would expect if the disposable soma theory were accurate). (Other manipulations that LOWER metabolism can have similar effects on longevity.) His explanation is that caloric restriction causes an organism to alter its energetic resource proportioning towards increased repair and replacement-despite the fact that there are less resources available. He claims that this is an adapted strategy to help organisms survive famines. While I cannot totally discount the remote possibility that this is accurate, his explanation is illogical and difficult to believe.

Although I do not personally think that programmed theories accurately describe biological aging, the theoretical arguments on which programmed aging has been anchored are certainly no less shaky than those of the disposable soma theory.

People who live in glass houses should not throw stones.

Posted by: BigB at August 26th, 2016 3:02 PM

@BigB: I'd like to see less modeling and more building of possible therapies from both sides of the fence. This is only going to settled with treatments, given that the practice path is now the shortest road to a firm answer.

Posted by: Reason at August 26th, 2016 3:14 PM

@Reason: I'd like to see less money being wasted on approaches that have zero chance of working and instead for resources to be focused towards those approaches that have the best chance of leading to treatments for age-associated pathologies and aging in general. To do this, people are going to have to get on the same page. You can't just tell people to take your word for it and expect them to follow suit (especially when they have their own preconceived notions about aging). The why and how bit needs to be worked out and solidified.

Absent a causal diagram, everyone's just guessing as to what may or may not work. How can you expect anything to be accomplished at a reasonable pace when the field is so fragmented?

The approaches that have shown the best results to date have been non-SENS approaches. Why are a select few PIs receiving enormous sums of money every year from the NIA to administer rapamycin/resveratrol/etc. to nematodes, mice, and now dogs? Because, even though they do very little in higher organisms and are likely already nearly maxed out, they have actually shown *some* results. These are the studies that are currently getting the bulk of the funding. Don't get me wrong-I'm also convinced that these studies are essentially worthless but my opinion, and quite frankly yours or Aubrey's, doesn't mean jack to a NIA/NIH/NSF grant review panel.

You do not need to map out every player in every single molecular pathway related to the aging process or the determination of longevity to formulate a solid aging theory. But you must have a basic idea of what the major factors are, starting with the highest level factors and working down, and understand how these factors interact with one another. This requires using strokes that are not too broad but at the same time, not too fine. If this could be determined, and backed up strongly by empirical findings, then it just may be possible to unite the field towards a common approach. Without this, the field will continue to trudge along as it has. For what it's worth, I don't believe the current mainstream approach is anything at all like what I just described-it is far too tightly focused on particular pathways.

BTW, what you described in the original post is not an "engineering point of view". A good engineer doesn't simply look at what is broken, or make a guess as to what is broken, and then just try to fix everything until things are better. Rather, that is the approach taken by a bad auto mechanic (most people reading this know how effective this strategy is). A good engineer determines the root cause(s) of the problem he is trying to solve and reaches a successful resolution to the problem by addressing those causes. The root causes of a problem are not simply the smallest physical unit displaying a problem. The relationship between root causes and the various degraded components must be defined.

The problem with your cracked paint on a wall analogy is that in that case the underlying root cause is assumed to be already known. Now consider a scenario where the cracked paint on the wall was actually due to a seemingly innocuous water drainage issue that contributed to the swelling and shrinking of the wood in the underlying wall as weather conditions change. You keep sanding the wall down and repainting but eventually the cracks start to appear so quickly that you can't fix them fast enough. Your screwed because you didn't address the true root cause of the problem but mistook addressing the observable end-damage as the "fix". Similarly, it is quite possible that the "damage" found in a particular biomolecule in an aged organism is actually the result of damage in another biomolecule, or that damage to a subset of biomolecules is largely responsible for the damage to most other biomolecules. If true, then the divide and conquer approach of fixing observable damage will be a very round about way of discovering successful therapies.

Posted by: BigB at August 26th, 2016 10:11 PM

I also think it's both but I nevertheless believe that doesn't mean SENS won't work.

Consider: even if it's programmed, the damage is done by the accumulation of assorted crap that evolution has not provided us with a removal solution for.

Removing that crap will still make the organism function better even if it doesn't completely turn off the aging program.

In such a case we'd need SENS plus genetic/epigentic reprogramming.

I think we actually already have the second piece. CRISPR or systems similar to CRISPR are capable of reprogramming both genetic and epigenetic signatures.

Posted by: xxd at August 27th, 2016 1:16 AM

BigB said:

"Smaller organisms with shorter lives actually spend MORE on protein repair and replacement than larger organisms with longer lives."

Nope. First, not all small organisms live shorter lives (for example, Artic clams, or bats). What is true is that smaller animals from the same clade and a similar environment usually have a higher metabolic rate. Thus, it's no surprise that they have more protein repair and replacement. Also, they usually have a higher reproduction rate, so your point proves nothing.

"It can also be easily demonstrated that the energetic expenditure required to offset any increase in degradation during aging is miniscule for most organisms (in humans, it would require less than 0.01% of daily energy expenditures by my estimations)."

Kirkwood doesn't talk about 'energy' but 'resources'. Before critizicing something, try to know a little about it.

"While I cannot totally discount the remote possibility that this is accurate, his explanation is illogical and difficult to believe."

What is illogical is to reply to that sentence to an argument.

Posted by: Antonio at August 27th, 2016 2:52 AM

Typo: I meant "What is illogical is to reply with that sentence to an argument".

Posted by: Antonio at August 27th, 2016 2:53 AM

BigB also said:

"The approaches that have shown the best results to date have been non-SENS approaches. Why are a select few PIs receiving enormous sums of money every year from the NIA to administer rapamycin/resveratrol/etc. to nematodes, mice, and now dogs? Because, even though they do very little in higher organisms and are likely already nearly maxed out, they have actually shown *some* results."

Doubly wrong. They received big amounts of money because they are "business as usual", i.e., they are mostly oriented to produce knowledge (mapping of metabolism) instead of treatments, and even when they seek for treatments, they don't promise high gains in longevity. Second, SENS didn't show longevity increases UNTIL RECENTLY by a lack of funding, but it DID in recent years: https://www.fightaging.org/archives/2016/02/25-median-life-extension-in-mice-via-senescent-cell-clearance-unity-biotechnology-founded-to-develop-therapies/

"BTW, what you described in the original post is not an "engineering point of view". A good engineer doesn't simply look at what is broken, or make a guess as to what is broken, and then just try to fix everything until things are better."

Nope. That is a very bad engineer. An engineer is paid for getting things done, not for producing a perfect machine. For example, NASA, few weeks after its first manned suborbital trip, decided to go to the Moon and did it in 8 years. Afer that, the next step was to go to Mars, but they decided to gain more knowledge and develop more technologies instead of getting things done (what they called "capability development"). Half a century after that, they are still in low Earth orbit researching how the human body degrades in zero-g. Not only didn't they go to Mars nor have any serious plan to go in the coming years, they didn't even return to the Moon! They are since 1973 in low Earth orbit!

Posted by: Antonio at August 27th, 2016 3:18 AM

@BigB: The basic problem with your argument there is that SENS is a synthesis of the consensus view from the field of what exactly are the causes of aging and age-related disease. It isn't a random set of ideas arriving from outside the field.

Further, engineering looks at cost-benefit outcomes. When you have plausible targets, and the cost to fix them is low, and the potential benefit is high, it is absolutely an engineering approach to go fix them to see if it works. Damage repair is much cheaper as a line of development than attempting to safely adjust metabolism into a new state, especially since the results should be much less marginal.

There is, as others have pointed out, a huge alignment problem in the field in that people don't work on what they actually think are the causes of aging. They work on mapping and altering the operation of metabolism, because that is what they can get grants to do - even when the cost-benefit expectation for results beyond keeping your lab in operation happen to be terrible. The causes of this are regulatory, in that treating aging isn't going to be approved by the FDA without a fight, and cultural, in that for the past three decades the research community has been suppressing any talk of treating aging, and in that the scientific motivation is to produce knowledge, not to create treatments.

The shift towards more productive directions is unfortunately glacial, as demonstrated by the lapse of time between SENS first being proposed and the Hallmarks of Aging paper. But to say that it isn't known that damage causes aging, or which forms of damage are high-expectation targets, is just outright wrong.

Posted by: Reason at August 27th, 2016 9:20 AM

@Antonio:

"Smaller organisms with shorter lives actually spend MORE on protein repair and replacement than larger organisms with longer lives."

Nope. First, not all small organisms live shorter lives (for example, Artic clams, or bats).

I thought it should have been fairly obvious that I am describing a species trend, in this case a very strong trend, not an absolute rule. These are comments on a blog, not a thesis. Sometimes you may need to read between the lines.

Kirkwood doesn't talk about 'energy' but 'resources'. Before critizicing something, try to know a little about it.

..Sigh...

"The crux of the matter is whether enough energy can be diverted from reproduction to maintenance to make a physiologically important difference and whether, in a world where mortality pressure is high anyway, it actually boosts darwinian fitness." - Kirkwood, 2008. A systematic look at an old problem.

"The mouse will therefore benefit by investing any spare energy into thermogenesis or reproduction, rather than into better capacity for somatic maintenance and repair, even though this means that damage will eventually accumulate to cause aging." - Kirkwood, 2005. Understanding the odd science of aging.

"It may be selectively advantageous for higher organisms to adopt an energy saving strategy of reduced accuracy in somatic cells to accelerate development and reproduction, but the consequence will be eventual deterioration and death. This 'disposable soma' theory of the evolution of ageing also proposes that a high level of accuracy is maintained in immortal germ line cells, or alternatively, that any defective germ cells are eliminated." - Kirwood and Holliday, 1979. The evolution of ageing and longevity.

I'm getting bored of going through my library of papers for these examples, but I'll end with a quotation from the very same paper that initiated this blog post:

"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." - Kowald and Kirkwood, 2016. Can aging be programmed? A critical literature review.

Antonio said:

Kirkwood doesn't talk about 'energy' but 'resources'. Before critizicing something, try to know a little about it.

Sorry Antonio but I just had to quote you on this again. You were saying?

As for your comment to my remark about non-SENS approaches, I think we are more or less saying the same thing. I'm not going to argue semantics.

My remark about engineering was from the context as if a engineer were tasked with improving the reliability, or usable lifespan, of a system (in this example, an organism). That approach is totally different then what one would take with a new design. I did like the fact that you used the space analogy in your engineering argument. One of my dad's first jobs out of college was as an engineer working on the thrust vectoring system of the Saturn V rocket.

Posted by: BigB at August 27th, 2016 9:59 AM

@Reason: What precisely is the "consensus view from the field of what exactly are the causes of aging and age-related diseases"? I would be very interested to hear your answer to this as I don't see any consensus at all.

The disposable soma theory is focused on energy balance and suggests that a reproportioning of energy towards repair and maintenance will extend longevity. Don't you think that some of the focus on metabolism is a result of this thinking? If scientists believe that they can modulate metabolism and slow/stop/reverse aging, then why would they bother with damage repair? I have put a good deal of effort into showing why this idea won't work and why the disposable soma theory is wrong. Do you not appreciate the potential benefits of moving the field away from metabolic approaches and towards those that could actually deliver significant results?

Further, engineering looks at cost-benefit outcomes. When you have plausible targets, and the cost to fix them is low, and the potential benefit is high, it is absolutely an engineering approach to go fix them to see if it works.

The problem with this argument is the assumption that "the potential benefit is high". Without a solid understanding of the etiology, you cannot state this as fact and you can't know which targets are the best. That, my friend, is why I think that a primary objective of the field should be to develop a solid theoretical framework of the aging process. The field is fragmented and needs to be aligned.

Posted by: BigB at August 27th, 2016 10:43 AM

@BigB: Well, clearly we disagree on how to get to the endpoint. From my perspective, the tremendous benefit from damage repair is that either it works, as seems likely based on everything established to date about the relationship between these forms of damage and specific age-related diseases, or it fails and thereby demonstrates that aging is not caused by damage, and thus most of the research community is absolutely wrong in the theoretical underpinnings of their work. At the cost of what might now be half a billion dollars and ten years of work, were it funded as a large-scale program, that's a tremendously valuable outcome either way. When you look at the cost to create the full map of how exactly aging progresses, it will take a lot longer and much more money than that. More than a billion dollars went to sirtuin research alone, and that is a tiny slice of a tiny slice of the full biochemistry of aging. It will take decades, major advances in automation, and some large number of billions of dollars to complete that work.

For the underpinnings of the consensus on damage and aging, you want to be looking more at the research of people working directly with specific age-related diseases, and less at the theorists concerned with the evolution of aging.

Posted by: Reason at August 27th, 2016 11:12 AM

Hi there ! Interesting where this is going.

Hi ! I will try to make sense of this (also let's not forget SENS means Strategies for *Engineered* Neglive Senescence, Engineering there...)..a bit long.

I am somewhat in between on this dilemma but I believe there is 'some' truth to the
assertion that there is a certain tugg/trade-off between lifespan and reproduction :
that Short-lived species individuals relocate DNA longevity genes maintenance resources
towards sexual reproduction resources. Vice versa, Long-lived species individuals relocate
sexual resources (become infertile) towards DNA longevity maintenance. Long-lived ones live long lives
there is no need for immediate reproduction/offspring replacement by population mortality, there loss
is that they are infertile/no offspring output. While, short-lived ones, need to maintain specie population
to offset extreme mortality (keep the population count for specie survival) by short-living individual.
Their loss is lifespan, but they are highly reproductive/high offspring output. This is a tradeoff
between lifespan (DNA longetive genes) vs sexual reproduction (hormones/endocrinal/sexual maturation/sexual organ hyperfunction).
It makes me think a lot of IGF growth and growth endocrinal pathways (hormones, sex steroids, sex estrogen/androgen, that regulate developmental growth
and sexual capacity). It also makes me think of that famous example of the salmon who has reproductive senescence at 3-4 years old and dies there too,
while the parasited-one reaches 13 years lifespan, and is sexual reproductive for all that time. Showing that sexual senescence is costly
(women and men experience that with menopause and andropause, respectively. Women die of heart attack after menopause onset, because
estrogen is low in them, this means lower activation of hTERT telomerase estrogenic receptors in them (a protection that increases women's life by telomerase,
in fact one study showed that for mammary growth hTERT is necessary) male same thing, andropause is costly, by having lower testosterone (thus lowered fitness/fragility/skeletal muscle loss, osteo/sarcopenia, infertility, lowered IGF) there is less in the body for conversion to estrogen
(aromatase converts testosterone to estrogen in men, thus activates hTERT estrogenic receptors in men too, a protection. You don't have to wonder
why men who are 'effeminate/feminized' harbor biological slowed aging, they have increased hTERT activity in non-somatic cell tissues - a gift from women).

Centenarian women (age-reaching 100 years) on average had no children (childless) in their lifetime or had 1 child (plus were much more oftenly single for their entire life/avoided men) - vs - 1.5 children or more for non-centenarian reaching women (died younger). Those of high gravidity/above 4 children (like in the old days women making 10, 15 kids) have reduction in lifespan and will not reach the age of 100 years old (die much younger, they may attain 81 years old life expectancy but the chances are smaller/they are a small percentage, because the oxidative damage-to-reproduction cost was done during the consecutive reproductions).
It does not mean, it is impossible, there are certain women whom, almost as an anomaly defeating natural biological selection pressures, had many children and reached around 90, but you can count them in the very low percentage as outliers (these women had a biological and DNA methylation epigenetic clock that was delayed/biologically younger than their chronological 'real time' age), they are not the norm, the rest, the large percentage remaining die quite younger.
This has also been verified in a study on various reptiles, lizards of varying ages. The longest living reptiles were those abstained from sexual reproduction, those who were making children had shortened lifespan.
It tells us that there is a trade off between 'fitness' 'sexual reproduction' and 'longevity' at large 'pattern'. But it can be uncoupled.

And, let's remember, it does not necessarily need to be a requirement that the animal is 'small' or 'big' (in size or mass),
size, mass, growth size, energy, and speed/developmental growth can - all be decoupled (it has been shown time
and again with 'anomalies/outliers' who seem to defy the general trend of the population (for example,
Naked Mole Rats (35 years), Queen Bees (3 years), Hydras Jellyfish (immortal), A.Islandica Icelandic Quahog Clam (528 years), Queen Ants (35 years), Little Brown Bats (40 years), Red Lobster (160 years), Carp (160 years), Yellow Rougheyed rockfish (205 years), etc).
Most of these 'small' animals can - either - have slow - or faster - metabolism; but they all share
important traits; they maintain Redox homeostasis and most have delayed Developmental growth (for example one study in the
naked mole rat showed that its brain was replasticizing/remodelling continuously up until its puberty (just like humans);
meaning it has slowed Developmental growth). And what's even more ironic, is these same traits are in BIG animals : Bowhead whales (211 years),
Giant Sea Galapagos tortoise (255 years), Greenland shark (250-500 years). What does this all mean, it means that evolution
found ways to 'rig' the game and alter metabolism, sexual resources, DNA maintenance genes, DNA maintenance resources, etc...in
very precises balances that defy odds. Why would a tiny clam live 500 years while a huge whale or shark live 211 or 500 years, yet
they are so far from one another in terms of size, mass, order, etc ? Because developmental growth can be uncoupled from
all of these factors. As such, yes, you can see a tiny clam live half a millenium or humongous shark live nearly half a millenium too.
And you know what else, you can see a tiny mouse - live 3 years barely, a tiny fly live about 60 days, a tiny ant live a couple of months, an - another - little same A.Islandica clam - not in Iceland live barely 10 years (in Kategat waters) - while the one in Iceland waters lives 500 years - same specie - different individual/different environment/different lifespan).
a tiny nematod live 20 days normally - or 250 days, nearly a year (10-FOLD extension) when its mitochondrial membrane lipidome composition is remodeled (no genetic intervention has this power). A huge whale live barely 30 years (mostly in temperate waters or because of predation), a big turtle who lives just 50 years, big animals who don't live all that long, while us humans we live 122 MLSP, etc .

If that's not mixed up enough for you, then I don't know what to say. It shows us that there is no 'perfect' theory for explaining it all,
it is a combination of different theories that make aging, not one is so much more important than an another they all chime in to give us a ''overal portrait'' of aging (ie membrane pacemaker theory, disposable soma theory, homeoviscous membrane theory, programmed aging theory, epigenetic external/by environment factor acting on genes aging theory, CR/mTOR/IGF growth endocrinal hypopituitary/pineal/adrenal-axis theory, immunosenescence theory, inflammation aging theory, telomere loss aging theory, damage causing aging theory, redox homeostasis theory, live fast/live slow metabolism spend/conserver energy for repair/sex offset,,theory...etc)

Posted by: CANanonymity at August 27th, 2016 12:10 PM

PS: I too am of the belief that (despite CR/metformin/rapamycin/metabolism tinkering works with tangible 'results' and shows some benefit hence get all the money') there are way too much studies that show us that indeed damage is causal and a large part of aging. As such we shouldn't continue spending money in a mostly dead-end avenue like CR or other rehashed stuff. It is just self-defeating, as an Engineer, like said, you have to engineer the method of Defeating Aging, - not just slowing it a little and then we die. The whole goal is to Cure aging and Cure Death Itself, not slow it a tiny bit or just post-pone it.

LEV is a SENS Engineering. 'Treat the source/root cause of aging' 'instead of patching it with band-aids (rapamycin/metformin/CR)'. Do you stop the bleeding woud by putting band-aids continuously or do you go to the cause of the bleeding. Exactly, you solve this by closing the wound (heal it/repair damages/macrogranulation/coagulation/clotting) not putting a band-aid over a continuously bleeding wound and thinking 'it stops the bleeding' - it doesn't, it just slows the inevitable (bleed yourself to death if coagulation/clotting and wound closure was impossible like in certain people with low or no blood platelets).

Posted by: CANanoymity at August 27th, 2016 1:19 PM

PPS:

You know what's hurtful is that these researchers keep on 'researching on theory and theorizing' instead
'of trying' something new (like SENS), to cure aging. They have 'nothing' - they oftenly end their studies with:
''this could help, we learned this and that...someone else try to 'do something about it'''. THey don't Act on what
they found, it ends up as 'more info' piling in the 'research' database. But is there 'creation' of methods to
counter aging - from these new infos - No. Only SENS and a few others, acted upon a specific plan that aims
to solve aging. The rest they keep on researching/theorizing and using up moneys for that, or supporting
Calorie Restriction/Rapamycin BullSh... I specified some reasons why, but I think one of the deepest one,
is not that they don't 'believe in' SENS or think it has no merit, No, they do realize the power of it and
that it attacks aging at the CORE. But - there is a big but, in pratice and reality, there are no 'Tangible' results
(like a mouse that was rejuvenated for example,that senescence reversal by senolytics in mouse doesn't convince them),
they don't believe it's so feasible with the Means (Financial, Logistics, Societal...), Technology and Capabilities of Today
and in Our Lifetime. So they give up on the SENS LEV 'Dream'. It's sad, all this cash should be transfered to SENS, ASAP,
because it's the only remote thing that can claim to make LEV if things pan out correctly with all SENS therapies, nothing else can.
IF I were them, I would be jumping of you (maybe a bit overoptimistic/fooling myself) to defeat aging, damage repair is the
solution, they are too vain/stupid/full of themselves/not wanting to lose their cash (doctors prescribing pills for your ills pharma bs),
It's so sad. Thank goodness Reason for your website and other iniatives that really hold on and make hope that it is not some utopia.

Posted by: CANanonymity at August 27th, 2016 1:41 PM

@BigB:

Why don't you quote complete descriptions instead of cherry-picking what you like? I will complete what you cited from the paper in the post:

"The disposable soma theory (Kirkwood, 1977; Kirkwood & Rose, 1991) 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."
Kowald and Kirkwood, 2016. Can aging be programmed? A critical literature review.

Most of the time, he talks about resources. Clearly, energy is only part of them. He is even more clear in one of the papers you cite:

"The likely physiological basis for such trade-offs has been most explicitly developed within the "disposable soma" theory (Kirkwood 1977, Kirkwood and Holliday 1979, Kirkwood and Rose 1991). The disposable soma theory was based on asking HOW THE ORGANISM SHOULD OPTIMALLY ALLOCATE ITS METABOLIC RESOURCES, CHIEFLY ENERGY, between the maintenance and repair of its soma and the other functions that it must carry out in order to maximise its Darwinian fitness (Figure 1). The necessity for trade-off arises because resources allocated to one function are unavailable to another."
Kirkwood, 2005. Understanding the odd science of aging.

What did you say about reading between the lines?

Posted by: Antonio at August 27th, 2016 4:13 PM

@Antonio

That's an incredibly weak response. There are times when it's best to simply admit you were wrong. This would be one of those time for you Antonio. Your comprehension skills are nonexistent.

Posted by: BigB at August 27th, 2016 4:28 PM

@BigB: See the note on ad hominem. Address the argument, not the individual.

Posted by: Reason at August 27th, 2016 4:32 PM

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