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Aging as Damage versus Aging as Evolved Program from the Viewpoint of a Programmed Aging Theorist

Today I'll point out a view of the divide between theories of programmed aging and non-programmed aging, written by one of the more prominent programmed aging theorists in our community. I think it matters deeply as to whether we are guided by the theory that aging is caused by accumulated damage, or whether we are guided by the theory that aging is caused by an evolved program that is actively selected for. Is aging a matter of damage causing epigenetic change and cell dysfunction or a matter of epigenetic change causing damage and cell dysfunction?

This is an important division in the research community. The strategies for treating aging that must be proposed, agreed upon, and funded in well in advance of any evidence of effectiveness are very different in either case, and there is no reason to believe that the strategies of the wrong camp will prove to be useful. This is because addressing root causes is a powerful way to produce sizable gains, removing many downstream problems. Addressing downstream problems, on the other hand, has very limited utility: it is much harder, the benefits are much smaller, and the root causes will continue to cause a range of other harms. One side of this debate is wrong, and their proposed therapies will largely be a waste of time and energy, producing only marginal benefits at the end of the day.

Why can't we just determine who is right and who is wrong from an inspection of what is known of aging to date? Well, arguably we can, or at least form strong opinions about it, but there is nonetheless sufficient room for debate. The majority consensus is that programmed aging is an incorrect interpretation of the evidence, but the programming aging community is thriving nonetheless. Aging is complex and poorly understood in the details of its progression, and this is because cellular metabolism is complex and poorly understood. There is a great deal of latitude to argue about which correlated metrics in aging are cause and which are effect when it comes to the inner details of cell behavior, molecular damage, tissue function, and so forth. So given the very same data and evidence as a starting point, for much of aging it is still possible for programmed aging theorists to argue that epigenetic changes are the root cause, and for the rest of the field to argue that epigenetic changes are reactions to underlying molecular damage.

This is somewhat threatening from my point of view. While most researchers don't agree with programmed aging, they do undertake research that is more in accordance with programmed aging than with the view of aging as damage. The strategy doesn't match to the vision of aging, for reasons that have a lot to do with the way in which clinical development is regulated. This is a huge problem, and it is why progress is slow and will continue to be slow. Most researchers believe that all that can be done to intervene in aging is to adjust the operation of metabolism into more resilient states - such as by mimicking the calorie restriction response, adjusting the epigenetics of cells in old tissues. They fully understand that the potential upside here is very limited. The programmed aging advocates think that this is great and exactly what we should be doing, and in that the presence of their faction is an additional hindrance. A battle must be fought into order to steer the research community towards effective strategies, those based on repair of damage, and this is already a tall order.

Where a therapy is newly demonstrated to be effective, the side that didn't predict it will adjust their theoretical framework to contain it. That is happening at the moment for senescent cell clearance, predicted by the damage repair advocates of the SENS rejuvenation research community. Programmed aging theorists will now argue that rising levels of senescent cells are a part of the aging program, in some way a consequence of changing epigenetics. Alternatively, both sides might agree that senescent cell accumulation has a lot to do with immune system aging, and then disagree entirely about why it is that the immune system fails with age. Based on progress to date, I'm not optimistic that this debate will be conclusively resolved any time soon, even as we enter the golden age of therapies based on repair of molecular damage, informed by the theoretical view that aging is at root caused by that damage.

Aubrey and Me

I've been in the field of aging research from the late 1990s, just the time when Aubrey de Grey was getting his start. Before others, Aubrey had the vision to realize that cancer, heart disease, and Alzheimer's would never be conquered without addressing their biggest risk factor: aging. From the beginning, I admired Aubrey's successes in communicating with scholars and the public, and I reached out to him. He has always been gracious and supportive of me personally, appreciating the large common ground that we share.

There is, however, one foundational issue on which we disagreed from the start. Aubrey regards aging as an accumulation of damage. Evolution has permitted the damage to accumulate at late ages because (as Medawar theorized in 1952) there is little or no selection against it, since almost no animals live long enough in the wild to die of old age. Aubrey's program is called SENS, where the E stands for "engineering." The idea is to engineer fixes to the 7 major areas where things fall apart with age.

I regard aging as a programmed process, rooted in gene expression. Just as we express growth genes when we are in the womb and ramp up the sex hormones when we reach puberty, so the process continues to a phase of self-destruction. In later life, we over-express genes for inflammation and cell suicide; we under-express genes for antioxidants, autophagy (recycling), and repair of biomolecules. I believe in an approach to anti-aging that works through the body's signaling environment. If we can shift the molecular signals in an old person to look like the profile of a young person, then the person will become young. The body is perfectly capable of doing its own repair, and needs no engineering from us.

Over the years, research findings have accumulated, and both Aubrey and I have learned a thing or two. I'm happy to say that our favored strategies are converging, even as our philosophical underpinnings continue to differ.

Aubrey now finds optimism in the existence of what he calls "cross-talk". If we engineer a fix for one kind of damage, the body may sometimes regain the ability to repair other, seemingly unrelated kinds of damage. Hence, we may not have to engineer solutions to everything-some will come for free. A dramatic example is in the benefit of senolytics. Cells become senescent over time. I see this as a programmed consequence of short telomeres; Aubrey sees it as a response to damage in the cells. But both of us were surprised and delighted to learn, a few years ago, that elimination of senescent cells in mice had 20-30% benefits for lifespan in mice. Even though only a tiny fraction of all cells become senescent, they are a major source of cytokines (signal molecules) that promote inflammation and can cause nearby cells to become senescent in a vicious circle; this apparently accounts for the great benefit that comes from eliminating them. If we find appropriately selective senolytic agents that can eliminate senescent cells without collateral damage, then the signals that up-regulate inflammation will be cut way back, and a great deal of the work needed to repair inflammatory damage is obviated.

Comments

Seeing how the programmed camp appropriated senolytics (formerly a damage camp strategy) as a confirmation of their theory, I think the question will never be settled. Every success of the damage theory will be immediately viewed by them as a success of the programmed theory, and nothing will change.

Posted by: Antonio at October 10th, 2018 4:26 PM

I think both theories are wrong, or at least moot. Aging is obviously inherited, going back to the earliest homo sapiens. (None of them are still around, to our knowledge.) And genes coding for longevity have shown us diddly squat. (I'm not impressed by old looking centenarians.) So we need to look at the non coding regions of the genome, going back thousands of years of human evolution (200,000 years, or whatever) through bioinformatics. Senescent cells only happen after one is born; those DNA elements have been there for 200,000 years (or whatever). My guess is, senolytic agents will treat disorders like osteoarthritis, but those treated individuals will still age. Telomerase gene therapy may treat Alzheimer's disease, but those treated individuals will also still age. Studies showing treated mice that appear more youthful don't tell us anything about complex molecular pathways that give each one of us unique morphological features, youthful versus aged in appearance. Too complex? We have to look at it.

Posted by: NY2LA at October 10th, 2018 5:28 PM

@NY2LA
You might be right. But how would you define aging if you successfully treat all the age related conditions? If Alzheimer's is cured, arteritis is negotiable the skin is elastic and the internal organs work.

Of course, all this will require more than senolitics alone...

Posted by: Cuberat at October 10th, 2018 6:36 PM

This topic is way over my head, but it would seem to me these concepts aren't really mutually exclusive. It seems plausible that having the gene expression of a young person might significantly improve an older person's ability to remove damage from aging and prolong life and healthspan, although not as well as a fully developed SENS approach.

Is anyone looking at technologies like the Connectivity Map (clue.io/cmap)? I'm a laymen, but as I understand it, the CMAP allows the user to upload a target gene expression profile (what genes are targeted to be upregulated and downregulated) and it will output what drugs/molecules in its database will most effectively achieve that gene expression profile. It has been used to find two molecules (Celastrol and Withaferin A) that are potent leptin sensitizers - something I think that has eluded science until recently.

Couldn't someone look at the gene expression profiles of young people vs old people to identify the genes that should be uregulated/downregulated and use CMAP to identify therapeutics that could get someone closer to that state?

Apologies is I'm way off base - this is not my field.

Posted by: Tim at October 11th, 2018 12:00 AM

"it would seem to me these concepts aren't really mutually exclusive. It seems plausible that having the gene expression of a young person might significantly improve an older person's ability to remove damage from aging and prolong life and healthspan"

Tim, that's not the programmed theory of aging.

Posted by: Antonio at October 11th, 2018 1:36 AM

N2YLA said: "Aging is obviously inherited"

Wow, it's obvious, and scientists debating for decades about it...

Posted by: Antonio at October 11th, 2018 1:43 AM

Antonio - am I misunderstanding the quote from the article?

"I regard aging as a programmed process, rooted in gene expression... If we can shift the molecular signals in an old person to look like the profile of a young person, then the person will become young. The body is perfectly capable of doing its own repair, and needs no engineering from us."

Posted by: Tim at October 11th, 2018 2:29 AM

Tim, to be clear: "Programmers" say that epigenetics is primary and damage accumulation secondary. "Damagers" say the opposite, damage accumulation is primary and epigenetics secondary. So damage accumulation causes epigenetic changes and all the other problems of aging (sarcopenia, etc.). The same can be said from the other side. That doesn't mean that a secondary problem can't cause havoc on its own. None of the camps say that. That also doesn't mean that fixing a secondary problem can't have a beneficial effect. Again, nobody says that. Thus, are both theories converging? Not really. Fixing a secondary problem is worthless? No. It's the better strategy? Nope. The real debate here is about primary causes, and it can have a big impact on how long and how costly the run to LEV is.

Posted by: Antonio at October 11th, 2018 2:31 AM

Sorry my bad English, I'm still sleepy.

Posted by: Antonio at October 11th, 2018 2:42 AM

There is no special program for aging. There is a program of development of the organism, which is not infinite. The development program ends and the epigenetic support (by signals) of the organism main renewal processes ends. Next comes wear. Therefore, large animals whose development is longer live longer. In sharks that live longer, the genome is much larger due to repetitive sequences

Posted by: Dmitry Dzhagarov at October 11th, 2018 5:01 AM

Artificially activating the cell renewal program by minor damages (for example, by senolithics or weak radiation) can prolong life (hormesis).

Posted by: Dmitry Dzhagarov at October 11th, 2018 5:18 AM

I read this fellows web site for a short period, until he "came out" as a 'Lamarckian'. He's a good writer. Clear thinker ?

Posted by: William Voorhies at October 11th, 2018 9:23 AM

@Tim
Thank you for the heads up on the Connectivity Map!!! I ♥ the Broad Institute! I'm even more excited than when I found Phenol Explorer.

Usually I do that sort of thing by rummaging around PubMed, sometimes for hours. Yesterday I read about CAG repeats and how the are implicated in Huntington's Chorea and the other PolyQ diseases (various ataxias), and recently have also been found in Multiple System Atrophy patients. PCNA can repair the type of hairpin loops formed by CAG repeats and can prevent CAG repeat expansion. So I went on to try to find things that (safely) upregulate PCNA and found this (see Table 2):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486016/
These data are specific to skin, though. Resveratrol might be worth a try, keeping in mind the bioavailability issue. Equol's effect on NGF looks very interesting.

Posted by: CD at October 11th, 2018 10:21 AM

I'm fairly convinced of the programmed theory, mainly because the damage theory is so logically flawed in so many ways. Senescent cells are not strictly damage as they provide a function for the body as well, just like ROS. It does seem like the body just stops supporting the maintenance of the body after a certain age, then you coast for a long time because the human body is very fine tuned. And that is the programmed theory of aging. The damage theories are very intuitive, which is why they've been around since the beginning of time, but intuition is very often completely wrong and in biology that is even more the case.

Having said that, I absolutely support both communities going about their business, and don't really care much who is proven correct as long as the job gets done. There is plenty of money to go around if we decide as a society to focus on aging. Aubrey is absolutely right that this thing is solvable in our lifetimes, if we simply decide it's a priority and dedicate enough time and money to it.

Posted by: Alex at October 11th, 2018 11:41 AM

I think the more logical and biological aspect of aging is the combination of damage accumulation and some programmed aspect. Probably each theory on it's own will ultimately benefit us and have some interesting applications for our health and youthfulness

Posted by: Moses at October 11th, 2018 12:25 PM

This is likely a dumb question, but I'll ask anyway: In a hypothetical scenario, if the Programmed Theory of Aging was correct, but SENS developed therapies to completely repair all aging damage, and all people received these therapies, does that mean people would die from aging anyway? If so, by what means exactly would people die from aging, according to the Programmed Theory of Aging?

Posted by: Tim at October 11th, 2018 12:37 PM

Tim,
That is a great thought experiment. I would answer it by referring back to how the early developmental process, or a salamander limb regeneration is a programmed process. One could intervene in these processes from the outside and, in this case, cause damage to override the program. So you could stunt the growth program with a laminopathy, for example. Or you could impede limb regeneration by damaging some vital component of the process like macrophages. But this doesn't make these processes any less fundamentally programmed. But with this analogy, there will always be a need to address random damages that override the overall programming. But for something like aging, providing a different program through whatever mechanism should do the trick.

I think it in the end both views are important. But there is a practical matter to consider if you find yourself in the camp that says both are legitimate and both may actually be true. Attacking the programmed part of aging should be much easier and more cost effective once all is said and done. The damage theory is often portrayed far too simplistically, especially by sens. According to them, you have one type of damage,like amyloid or lipofuscin, then you clear it, and voila you have a young person. In reality, the science is very much against this. Clearing amyloid doesn't do much, and for that matter neither will clearing other types of damage. That's because, damages being downstream effects are extremely varied and stochastic. It's a game of whack-a-mole with thousands of possible targets. Whereas if aging is programmed, it is one or a few targets, and there's your voila. Epigenetic reprogramming has already shown that this is a much more exciting area of research. One intervention resulted in dozens of improved markers of damage, and probably many more than that which weren't studied.

Posted by: Alex at October 11th, 2018 12:58 PM

Alex said:

"Senescent cells are not strictly damage as they provide a function for the body as well, just like ROS."

That is supposed to be logical flaw?? The logical flaw is in your sentence.

First, damage is any difference between old and young (already grown up) people. So, since old people have a lot more senescent cells, SC are damage. Does that extra amount of SC provide a function? Well, if you consider a function having more inflammation, fibrosis, cancer, ... and in summary more mortality. Yes, they provide a function. Is it a function that we want? Nope. Reducing the amount to young levels would make you young? Yes--by definition, if you remove all differences between you and young people, you are young.

"It does seem like the body just stops supporting the maintenance of the body after a certain age, then you coast for a long time because the human body is very fine tuned."

You have a gross lack of knowledge on the matter. There is no coast at all, there is an exponential growth of mortality from puberty to the end of life.

Posted by: Antonio at October 11th, 2018 12:59 PM

@Tim

It's not a dumb question

To yield true life extension, one must address biological:

1) fitness (the ability to survive in good heath),
2) resilience (the ability to bounce back from pathological events),

and

3) robustness (the ability to prevent negative transitions from happening)

simultaneously.

Damage repair at its best only addresses #1 - great for healtspan; less so for lifespan

Hence, even in a more distant future scenario, where technology could allow the you to snap your fingers and eliminate all damage simultaneously, the body still has the nested biological "architecture" as it pertains to #2 and #3, of a more elderly person

Hence you end up dying of the same stuff but just a little bit later

This is why both approaches need to be merged together

Posted by: Ira S Pastor at October 11th, 2018 1:19 PM

You all forgetting that one of sens therpaies are stem cell replacement. So even if your cells will be old you will replace them by cell therapy to new young ones, and that pretty much converges with the new partial reprogramming method.

Posted by: Moses at October 11th, 2018 1:36 PM

@ Antonio,
Pretty sassy for someone that thinks the Gompertz-Makeham Mortality Law begins at puberty. I don't know anyone who went through puberty at 30....aka when it actually begins.

Just because something can be considered a damage doesn't mean it was the cause of the aging process, and that's what we're trying to establish here.

Posted by: Alex at October 11th, 2018 1:41 PM

@ Ira

Very well said, I never thought of it in those exact terms.

Posted by: Alex at October 11th, 2018 1:43 PM

@Moses

Unfortunately, the long history of "cross-age" transplantation research (here is a great resource with a chapter that delves into it - https://www.elsevier.com/books/principles-of-regenerative-biology/carlson/978-0-12-369439-3) has shown that putting "young stuff" into an "old organism" is not a good solution for reverting the age of an organism - organism micro-environmental architecture trumps cell age

@Antonio

"damage is any difference between old and young (already grown up) people"

This is a flawed part of the "damage centric" thinking in isolation and it violates the unspoken paradox:

That is, why do all of the various aging targets that people study (i.e. inflammation, oxidation, heat shock, microbial burden, toxins, somatic mutations, epigenetic modifications, stem cell exhaustion, senescence, telomere variability, cross-linking, intra / extra-cellular junk, random transcriptional bursting, etc. etc. etc. etc.) show up in both the elderly / decrepit, as well as in developing embryos during ontogenesis? two entirely different states of life, one with decreasing fitness, robustness and resilience, and the other where they are all increasing? For example - The fetal brain has been reported to display a number of amyloidogenic pathways / biochemical similarities to the Alzheimer's brain, namely the presence of Aβ and AβPP, hyperphosphorylated tau , and presenilin-1 expression, as well as Alpha-synuclein, a major target of Parkinson's pathology, but all important in the morphogenesis of neurons of the embryo.

What is important is the context of the damage and the biological architecture it sits within!

Let us not forget all of what sits above damage dynamics in a human system

The "program" in "programmed aging" need not be genetic, but many other physiologic programs

There is a vast "nested architecture" of control systems that sit above our bio-chemical networks, which modulate their function, and more completely represent the integrated causes of disease, degeneration, and aging

These include, but are not limited to:

- bio-mechanical networks - i.e. forces of mechano-transduction, sheer stresses, friction, differential adhesion;

- hydro-dynamic networks - i.e. reaction diffusion dynamics in the intra-cellular space, water / gel transitions, visco-elasticity of interstitial fluids, convection flows, super-molecular ordering, differential sedimentation;

- bio-kinetic networks - i.e. molecular crowding, variability of cellular machinery / unequal partitioning, "bursty" transcription / translation / degradation

- bio-dynamic networks - i.e. geometric morphogenetic flow; cell-tissue movement fields of corrosion, contusion, retension, dilation, detraction, etc.

- bio-structural - i.e. tensegrity of fascia / extracellular matrices / cytokeleton, crystalochemical structures, desmicity

- bio-electric networks - i.e. membrane potentials of cells, tissues, organs, and body segments

- bio-magnetic networks - i.e. DNA resonance recognition; para-magnetic properties of metal ions / polyanions / electretes; radical pair mechanisms

- microbiome / virome - 100 trillion organisms living on, in or among / symbiogenically as a part of us

- bio-semiotic networks - inter-kingdom signalling; semio-chemical communications; induced phenotypic plasticity

- bio-holon networks - emergent structure hierarchies and related homeotaxic networks - Non-hierarchical, peripheral automaticity - in groups of cells, demonstrating independent dynamics of Sensing/Perception, Valence, Behavior, Memory, Learning, Anticipation, Signal integration / decision making, and Communication

- psycho-biologic - having to do with the increasing amount of evidence in the neuroscience literature on how thoughts, can impact "downstream" physical and chemical manifestations, and the brain, its respective signals, and its connection to the many other systems within the human body (endocrine, lymphatic, etc.) can stimulate alterations to our organs, tissues, cells, and even the level of DNA

This grander architecture of programs dictates all downstream events and should not be ignored of forgotten in the lifespan enhancement plan

Posted by: Ira S. Pastor at October 11th, 2018 2:09 PM

@Ira i know these articles. But more and more studies show that transplanting cells with the right scaffold and signals can make the transplantation much better. And probably doing that after senolytics treatment (to reduce the SASP environment) will raise the success rate.

Anyhow partial reprogramming in vivo might do that even better

Posted by: Moses at October 11th, 2018 2:35 PM

@all For the life of me, I will never understand why Belmonte didn't let his partially reprogrammed mice live to see if there was a lifespan effect. The health effects were nothing less than stunning, so I would be surprised if there wasn't increased longevity. Maybe they were rushing to publish.

If I could run any experiment on mice, it would be to mimic as many of the hallmarks of aging at once with the best known therapy for that hallmark. So for example, Epigenetic reprogramming combined with telomere maintenance and senolytics. Even just the three, which have already shown great promise in mice. The combinations are the next logical step, IMO.

Posted by: Alex at October 11th, 2018 3:23 PM

I recently interviewed Dr Goodwin at the MDI laboratory in Bar Harbor inre to Salamander
being a champion regenerator - Strikingly, the animal becomes sexually mature at 1 year,
but survives till around 35, normally dying of an infection (their lack of immune function being linked to their ability to regenerate) Point is, if humans lived 35 times the age they become sexually mature they would live to 400. This private mechanism suggests that the ability to
regenerate and repair tissues and organs itself has the possibility of greatly extending
health span and lifespan. We have that original blueprint.

Posted by: robert kane pappas at October 11th, 2018 3:55 PM

@moses

It's not an issue about transplant viability of a group of cells - it is about how you dictate the 50 trillion cell integrated organism (tissues, organs, body segments, etc) to become actually younger as a whole

@alex

The issue with partial reprogramming is also this "salt and pepper" dynamic among the integrated tissues which will dictate the success of health span versus lifespan with regard to such tools - but they represent a most promising path

Posted by: Ira S Pastor at October 11th, 2018 3:58 PM

@Moses: There is no reprogramming in RepleniSENS, they simply add more stem cells when there are too few.

@Alex: Please make all us a favour and look at the real data, not your imagination.

Posted by: Antonio at October 11th, 2018 4:03 PM

@antonio that's just what i said...

Posted by: Moses at October 11th, 2018 4:05 PM

@Ira S Pastor:

"That is, why do all of the various aging targets that people study (i.e. inflammation, oxidation, heat shock, microbial burden, toxins, somatic mutations, epigenetic modifications, stem cell exhaustion, senescence, telomere variability, cross-linking, intra / extra-cellular junk, random transcriptional bursting, etc. etc. etc. etc.) show up in both the elderly / decrepit, as well as in developing embryos during ontogenesis?"

I'm surprised that you are really asking that. Damage repair theories don't say that damage suddenly appears in old age. They say that damage accumulates throughout life, some types before birth, some others after birth, until they reach pathological levels and cause some named disease, like Alzheimer's or sarcopenia. Of course, young people also have misfolded proteins, senescent cells, etc. It's the difference in amount what diferentiates them from old people.

"The "program" in "programmed aging" need not be genetic, but many other physiologic programs

There is a vast "nested architecture" of control systems that sit above our bio-chemical networks, which modulate their function, and more completely represent the integrated causes of disease, degeneration, and aging

These include, but are not limited to:

- bio-mechanical networks - i.e. forces of mechano-transduction, sheer stresses, friction, differential adhesion;

- hydro-dynamic networks - i.e. reaction diffusion dynamics in the intra-cellular space, water / gel transitions, visco-elasticity of interstitial fluids, convection flows, super-molecular ordering, differential sedimentation;"

I'm very surprised by this part too. What you are describing is not programmed aging. Programmed aging theories say that there is a program, selected for by evolution, that actively ages the individual. What you are describing is the wear and tear that accumulates in any physical system without perfect repair mechanisms. That is, you are describing damage accumulation theory of aging.

Posted by: Antonio at October 11th, 2018 4:29 PM

@Moses: Ahh, ok, now I understand the "partial reprogramming" part.

Posted by: Antonio at October 11th, 2018 4:33 PM

@Ira
Fair enough. I just want more and more experiments, and eventually the clouds will clear. We're living in very exciting times. Really great studies on mice are coming out at a pace of about once a month now.

Posted by: Alex at October 11th, 2018 4:47 PM

@Antonio

No - I am explaining the complex physiologic dynamics that come before and above damage, which are swept under the rug because they are defined as "too complicated" to even think about

And no, not all of what happens during ontogenesis is "early damage"

If not for those amyloids, the fetal brain would not form

If not for early senescence, tissue pattering would not occur

Don't be blinded by the damage centric view without looking at the bigger picture of how it all fits together at the level of the organism

Posted by: Ira S. Pastor at October 11th, 2018 4:47 PM

@All:

From https://www.ncbi.nlm.nih.gov/pubmed/25902458 (I think fair use applies):

Damage: any change in molecular or cellular structure or composition that can occur to an adult individual and that contributes to a reduction in physiological performance.

Aging: the progressive accumulation of damage in an individual, occurring as an intrinsic consequence (selected or otherwise) of the body's normal operation, which progressively (though perhaps only late in life) diminishes physiological performance.

Programmed aging theory (PA): the contention that aging in most metazoans occurs mainly due to the action of genetic pathways whose selected function is to accelerate that accumulation and thereby hasten decline and death, without any compensating individual evolutionary fitness benefit, only non-individual benefit, and that species differences in the rate of aging arise mainly from differences in the strength of these "pro-aging" pathways.

Non-programmed aging theory (NPA): the contention that aging in most metazoans occurs entirely due to imperfections (gaps) in the organism's genetically-programmed pro-homeostatic arsenal persists because selection exerts insufficient pressure to drive the evolution of greater comprehensiveness of that arsenal, and that species differences in the rate of aging arise solely from differences in that selective pressure, which arise in turn from differences in risk of death from extrinsic causes such as predation.

Posted by: Antonio at October 11th, 2018 4:48 PM

The damage theory folks are in a very dangerous theoretical place. What happens when we can clear senescent cells, lipofuscin, amyloid, and whatever else is listed in SENS, and yet there is only healthspan and still marginal lifespan gains?

To me that is a critical point that we could reach fairly soon. The nature of damage theories is that there are always more damages to pursue, potentially thousands of them. It's possible that at that point it is still the main cause of aging and we just have to trudge on and clear every possible damage. But I would hope that the programmed aging theory would at least be taken more seriously by then, lest we potentially waste a lot of money, and even more importantly time.

I'd be happy if both theories were taken at an equal level of seriousness because programmed aging very much deserves that. Then the science can determine the rest.

Posted by: Alex at October 11th, 2018 5:02 PM

@Ira
I didn't know amyloid plays that role as well, even though I knew it plays a functional role in the brain, so that's very interesting. It can be placed alongside senescent cells and ROS, and probably others as things that are not so much damages as they are out of control processes.

The lack of the use of the very accurate term "process" is yet another reason I don't favor the damage theory. Processes are very important for biological systems, possibly more important overall than "things" which can always be rearranged assuming an open loop process is governing things. But as you said, such things are very complicated. The good news is that although they are much more complicated, once you crack it and hack it, they then become much easier to manipulate and powerful.

Posted by: Alex at October 11th, 2018 5:09 PM

I have three issues with programmed aging:

1) Whether or not programmed aging is true doesn't really matter; if the damage is removed, aging has no way to kill.
2) Despite tons of research looking at the genetics of aging and age-related disease, no simple death genes have been found.
3) Programmed aging might turn out to be so complicated that any intervention would not be effective.

Posted by: Florin Clapa at October 11th, 2018 8:39 PM

@robert kane pappas

Hi Robert ! Just a 2 cents.

I think being sexually reproductive in one year, is the outlier/exception to the rule, or is exaggerated :

As you said, there is a clear correlation between longevity and time at puberty. Animals (except maybe insects where it is not always so evident) that live the longest post-pone, the longest possible, the time
of entry to sexual reproduction capability (puberty/teen/adult entry). This not only visible in mammals but in these salamander, and even in naked mole rats or
little brown bats too. There are different types of salamander and not all live the same length (large differences between each other).
Salamander (can live 10-30 years roughly, average 20 or so; with entry into sexual reproduction at 3-5 years - the longer the living - the later that period arrives)
Axolotl
Newt/Eft (can live 30 years or so, same thing as salamander, it is a salamander but a sub specie)
Olm (Proteus anguinus) (can live 100 years, this is a rare one where they stay they stay in immature state (in folklore'baby dragons'/larval state) which means they Extremely Delay the entry into sexual reproduction (up to 15 years old, roughly like humans; they thus live roughly as long as humans.
They share the same neotenous properties of humans, naked mole rats; by maintaining juvenility/immaturiy state Neoteny they push back sexual entry; when these animals are 'forced' into 'developing' (by hormones/nutrient/mTOR activation which activate IGF cascade and SIR loss) they can die quickly after becoming sexually capable 'adults')

Late bloomers = long life. But, there is hope though, quahogs clams like Icelandic A.Islandica are extremely slow growth and have late puberty onset (about 15-30 years; most likely the 30 years one sexual-entry is the one that lives the longest); these animals reach 500 years old. Same thing for Greenland sharks extremely slow entry to puberty, they live 500.

1. https://link.springer.com/article/10.1134/S1067413618020029
2. https://phys.org/news/2010-07-scientists-salamander.html
3. https://www.reddit.com/r/Awwducational/comments/7noctr/it_takes_the_olm_proteus_anguinus_fourteen_years/

Just a 2 cents.

PS: Both are important, programmed aging and damage accrual causing aging. Programmed aging is a bit an error said that way, rather what it is
is a 'self-regulating' 'self-fulfulling (prophecy?)' stocastic 'non' program if you will. Analogically it is like a computer AI whom 'acts on itself'
in a self-balancing/homeostatic way; the very fact 'it is' makes it 'act on itself'. There was an analogy I had seen that showed what it is,
programmed aging is like these epigenetic valleys 'a landscape' if you will; in it there are small and tall valleys/mounts/mountains.
Not everyone has the same landscape - but everyone has a 'self-fulling' 'happening' in it - where methylation acts on DNA decorum 'landscape';
like a needle that will 'gauge' the valleys and will 'randomly' oscillate between small or tall valleys - and 'give a result' - the sum 'program'.
It was kind of called 'the tug-n-pull' (invisible forces at work, that program which we can also add damages in that; since both feed off of each other in a vicious circle of stocastic change/loss of function as the 'system' tries to continuously (and futily) 'rebalance' itself to amend the 'new changes/alterations', a compensatory rebalancing which of course means many epigenetic gene changes),
with age it creates epigenetic transcriptional drifting (the epigenome has also been analogically compared
to an elastic, it can bounce back, only so many times when you 'strech it' so much - it breaks and then changes are irreversible (supposedly)).

Mice and short-lived dogs have much faster rate of methylation changes than long-lived dogs and naked mole rats (whom can live 20 to 35 years),
demonstrating that epigenetic element is underestimated in the equation to aging; and that much later puberty Correlates with Gene Silencing/Less alteration of the epigenome,
and thus reduces metabolism (not always although such as bats or birds whom may display accelerated metabolism but lengtened lifespan; are exception to the rule; but quahogs or greenland sharks Do Not have accelated metabolism, they are Slowmo metabolism/Very late sexual reproduction (ultra-neotenous Immature juveniles) and they live many times longer than these long-lived mammals);

What's more is that it has been shown that epigenetic show strong changes with menopause/andropause/menarch entry; demonstrating epigenetic program is Absolutely there and in part responasble for these 'aging' events (such as become menopaused/andropaused with older adult age (by reducing estrogenic/testosterogenic endrocrinal capacity); a sign of aging and death later).
Sex is costly, there is a trade-off and metabolism/developmental growth, and precisely, epigenenetic changes (that acceleate DNA methyl clock and cell passaging thus your 'cell age' (its memory of its age)). Evolution chose puberty as the moment you 'purpose' is done, after that your purpose is not as strong because you completed the most important point of making the specie survive through reproducing (you are then 'disposable').
Animals that PUSH BACK the latest are effectively pushing that 'you are expired soon (and then will decripit)' period (when becoming sexual capable/adult/puberty). They stay in a phenotypitic state of 'youth' - their DNA methyl clock 'signature' is that of Much Younger (they are neotenous/in immature juvenile state or as children like body; thus much farther from their death that is assured (rejuvenation is all about getting back to your 'Young body' phenotype/signature or in essence being neotenous again). It's their that I fear we may have much difficulty (because now we know that cells 'remember' their age even after Yamanaka (OCTSOXNANGO) reprogramming, they are 'fake' immature juveniles in disguise (still adult); but, who cares, if it slows aging dramatically (with defects) it'S been than death.

Posted by: CANanonymity at October 11th, 2018 8:45 PM

Alex said:

"The damage theory folks are in a very dangerous theoretical place. What happens when we can clear senescent cells, lipofuscin, amyloid, and whatever else is listed in SENS, and yet there is only healthspan and still marginal lifespan gains?"

LOL. You make a prediction with no proof whatsoever and, based on that, say that the theory of others is in a very dangerous place. LOL.

"I'd be happy if both theories were taken at an equal level of seriousness"

Sorry, no. Science doesn't work that way. Respect must be gained with evidences and consistency.

Posted by: Antonio at October 12th, 2018 12:09 AM

I suspect the programmed aging theory arises from the old human instinct of putting together patterns and then attributing said patterns to a first cause. Call it the religious instinct. I feel the selfish gene kicks that theory out of the door.

Posted by: Neal Asher at October 12th, 2018 3:07 AM

@Antonio
I would love for you to explain to me what would happen if that scenario I proposed comes to pass, as it might in the next 5-10 years. The reason we are debating this is because we know very little about the cause of aging, so don't dare try to claim there is more evidence for the damage theory. You sound like you've already made up your mind, and so just like in the case of a political ideologue or religious zealout, it doesn't make much sense for me to try to convince you of anything.

@Florin
1) "Whether or not programmed aging is true doesn't really matter; if the damage is removed, aging has no way to kill."
One could claim the exact opposite, and it would be no less true. If you were to phrase this as, it doesn't matter which is true, lets get on with the science, I'd mostly agree with you.
2) "Despite tons of research looking at the genetics of aging and age-related disease, no simple death genes have been found."
As Ira has already stated, programmed aging does not have to be genes, but even if it were, you are characterizing it as "we haven't found a gene", which we know very well now is not the way genes work. Nevertheless, it could just as easily be gene expression or epigenetics, or whatever, as long as it can be characterized as programmatic.
3) "Programmed aging might turn out to be so complicated that any intervention would not be effective."
This is a good point. That's why I don't want to give up on damage interventions. There is plenty enough time and money to put some toward programmed aging as well. I don't think it is too complicated to tackle at all, but it may be complicated enough that it would take 100 years, whereas clearing damages takes 50 years. Having said that, we just don't know do we. Programmed aging could just as easily be figured out in 10 years, and damaged aging could be stuck tackling the thousands of potential damages for 100 years. We.....just.....don't...... know, so we need to do the science!!

@ Neal
We have already discussed this. The damage theory has been around for thousands of years. If you ask a child why people age, they will surely come up with a damage theory not a program theory. The damage theory is mundane and obvious in the worst sense. The reality is precisely the opposite of that which you are claiming.

Posted by: Alex at October 12th, 2018 6:57 AM

@CANanonymity you sure you know what you talking about? That's one of many examples i found.

A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation.
Sheng C, et al. Nat Commun. 2018.
Show full citation
Abstract
Recent reports suggest that induced neurons (iNs), but not induced pluripotent stem cell (iPSC)-derived neurons, largely preserve age-associated traits. Here, we report on the extent of preserved epigenetic and transcriptional aging signatures in directly converted induced neural stem cells (iNSCs). Employing restricted and integration-free expression of SOX2 and c-MYC, we generated a fully functional, bona fide NSC population from adult blood cells that remains highly responsive to regional patterning cues. Upon conversion, low passage iNSCs display a profound loss of age-related DNA methylation signatures, which further erode across extended passaging, thereby approximating the DNA methylation age of isogenic iPSC-derived neural precursors. This epigenetic rejuvenation is accompanied by a lack of age-associated transcriptional signatures and absence of cellular aging hallmarks. We find iNSCs to be competent for modeling pathological protein aggregation and for neurotransplantation, depicting blood-to-NSC conversion as a rapid alternative route for both disease modeling and neuroregeneration

Posted by: Moses at October 12th, 2018 1:24 PM

1) The science is completely clear--aging kills only by damage, as far as we know. What produces this damage is an entirely separate issue. It could be PA, entropy, or whatever.
2) You can substitute genes with anything you want. If it's so simple, it should be simple to find. But nothing has been found.
3) Well, we know that PA is probably not simple and will probably involve messing with metabolism. And everyone knows how spectacularly successful MWM is, right? Also, damage is not that complicated (there aren't thousands of damage targets, just a handful according to SENS) and can be repaired cleanly, without MWM.
4) Interventions for PA are not even hypothetical, since it's not even known what PA is, whereas damage repair is a proven strategy.
5) PA can completely fail, while damage repair can't by definition (see #1). The only conceivable advantage that PA could have is that it might be easier to implement, but #2 and #3 makes this idea unlikely.
6) After SENS/DR is fully funded, I'd have no objection to funding PA or anything else. But depending on how you define it, PA has a gigantic amount of funding right now from the latest buzz-wordy, MWM research like omics, big data, and all mixed in with AI and deep learning.

In summary:

PA can't kill without damage.
PA is probably not simple.
PA will probably involve MWM, and MWM is a Bad Idea.
Damage is not that complicated, and damage repair is proven.
PA could fail but damage repair can't.
De facto PA funding dwarfs SENS/DR funding.

Posted by: Florin Clapa at October 12th, 2018 1:44 PM

@Florin

"according to SENS"
"After SENS"
blah blah blah.

Aubrey himself takes better criticism of his ideas than some of his acolytes. Look, if I want to familiarize myself with the SENS program, I know exactly where the website is. In fact, I've donated quite a bit to SENS over the years.

But you are acting like the science is settled. It simply isn't and what you are saying is not backed up by the science. The science as it stands now, does not know what causes aging, and it does not know what will cure it. There are many successful interventions in mice that prolong aging, none of which so far that can be characterized as providing KO evidence for either side of this debate. The records for longevity in mice are all over the place with things like Klotho, Telomeres and Senolytics. But very little max lifespan increases among them which means we are still very early in the game. If I had to guess the first single intervention that will smash through that barrier, it would have to be OSKM reprogramming. Closely recapitulating elements of the early developmental program is the best way forward IMO.

No one will be happier than me to come back here and say how wrong I was if and when we beat this thing. I hope it would be the same if it goes the other way, but I'm not gonna hold my breath.

Posted by: Alex at October 12th, 2018 4:00 PM

@Moses

Hi Moses ! Thank you for that. Just a 2 cents, that is what puzzles me, if certain cells can epigenetically reverted back to near DNAm age 0 but certain can't how does this plays out ?
In that example, they use induced neural stem cells, while certain studies failed to get back to age 0 with iPSC (induced pluripotent stem cells). I guess it is a light of hope that certain cells can lose their DNA methylation signature as you passage them and more and at normal body temperature (37oC), but it has to be reproducible in most cells; or in the stem cells which have the highest differentiation potential (differentiating in all types of other cells). In any case, the study concludes this has regenerative medecine potential and disease modeling; I like that but the sound of it seems almost therapeutic only (where the 'regenerative' means just regenerating certain cells you have that may be diseased, not necesseraly reverting the DNAm age of all our cells; thus, like 'patching' work with stem cells (stem cells injection always give 20% lifespan extension or so in mice; certainly not true rejuvenation/age reversal). In my mind, the only way to revert this DNAm age is making sure that it affects all the cells, not just some (just neural ones, not enough, you need to affect the pluripotent or mesenchymal ones too since all of them 'age' (except primordial gonadal stem cell that depend on telomerase (even then, they may age despite being immortal potential for replication (since DNAm clock and telomeres can be uncoupled, are independent predictors of aging). Just a 2 cents.

Posted by: CANanonymity at October 12th, 2018 4:24 PM

Alex, can you name any fatal age-related disease or condition that's not a direct result of the accumulation of damage?

Posted by: Florin Clapa at October 12th, 2018 5:08 PM

@Florin

Are you now claiming you know what any fatal age-related disease is a direct result of?

Lets see, you must think:
Amyloid/Tau > Alzheimer's
Oxidized cholesterol/foam cells/etc. > Heart disease
Everything/DNA Damage > Cancer

Those are the big three, and we've gotten no closer to curing those diseases with those hypotheses. Remember, I'm not the one making claims here, you are. I used to think science will just go wherever the evidence leads, but it's a much rougher path than that and minority views have to fight for their right to be heard.

How many more Amyloid studies do you think we need before Alzheimer's is cured? Oh but it's Tau you will say. Well, how many years of clearing Tau will we have before that is not considered a cause. Science moves too slow for me, and medicine even slower, because they will keep tweaking and trying minor variations on the same theme for decades without thinking outside the box. And that is precisely what I said is the danger of the damage hypothesis. That we will keep after the myriad damages for many years to come, make only marginal gains, and never even get close to touching aging itself. And all because people are unwilling to question their beliefs or try something else.

Posted by: Alex at October 12th, 2018 5:32 PM

I'm merely repeating what nearly all experts agree about. Generally, scientists are good at finding the causes of things, so I have no reason to doubt them. If you don't agree with them, the burden of proof falls on you.

But assuming that everyone else is wrong, how would PA kill without damage anyway? If atheromas are eliminated, how would PA cause a fatal heart attack, for instance?

And why would you expect Alzheimer's disease to be cured when no one has even tried to get rid of beta amyloid and tau at the same time? There's also evidence that more kinds of damage play a role in the development of AD such as senescent cells. Getting rid of only one cause of AD would, at best, slow it down.

To provide cures, knowing that damage causes disease is not enough—ways of getting rid of that damage have to be developed as well. And sometimes, multiple damage targets need to be hit at the same time. But for most of the history of modern medicine, messing with metabolism has dominated research approaches. While scientists are good at finding out how stuff works, they aren't necessarily good at providing solutions to problems, especially when multiple kinds of damage is involved. This is a why almost nothing has been cured. The little that has been cured (stuff like cataracts and knee degeneration) depends entirely on damage repair approaches.

Posted by: Florin Clapa at October 12th, 2018 10:16 PM

Is there any way that evolution could have selected for a way of programmed death? At the moment that process started how could that program be inherited to the next generation if the organism is dead? Something is not black and white here.

Posted by: Moses at October 13th, 2018 1:46 AM

I have no doubt that there will be beneficial pharmaco-therapeutic interventions that emerge from SENS type projects

Will they improve health-span? Sure

Will all of them translate successfully in humans? The bio-pharma odds are clearly against that - and early clinical failures in amyloid scavenging, stem cells as mono-therapies, etc. continue to highlight that this is not a short term game

Will they have a meaningful effect on human lifespan? - Unanswerable at this time

Pure "damage centric" strategies. as they pertain to life-span / life extension, rely on a core hypothesis that one can continually "stay ahead" of damage , and not have to worry about the dynamics "behind the curtain", whether we are trying to rejuvenate a 50 year old, or an 80 year old - kind of the way few people care or want to understand the complexity of what is behind the apps on our smart phone screens

This idea is promulgated by the often used "classic car" analogy

Namely: Modern Car

- 25,000 parts,

- mainly non-integrated systems, with horizontal control hierarchy,

- designed by a human designer, over the course of 100+ years, in a bottom up fashion,

- no self-repair mechanisms,

- few redundancies,

- no decoupling of effects, or compartmentalization of functions,

- no peripheral automaticity

- can "die" and enter a stage of suspended animation, over a long period of time, where damaged can be corrected / removed

All great

But as much as some folks may see us as just a more complex machine, that's still very far away from what we are dealing with

Namely: Human Organism

- 50 trillion parts (cells), each containing 25,000 protein coding genes, in an endless array of expression, across 210+ lineages (not to mention 000s of organelles per cell, and a literally infinite array of cystoskeletal arrangements, glycome structures, water-gel transitions, etc. etc.)

- mainly integrated bio-systems (endocrine / PNS; lymphatic / CNS, etc.) with vertical / nested control hierarchies,

- designed by the forces of evolution, over the course of 3.5+ billion years, in a bottom up / top down / and lateral design fashion,

- many self-repair mechanisms,

- many redundancies,

- decoupling and compartmentalization of functions,

- peripheral automaticity

- even in a state of death of the whole organism, can keep on "living" at the cellular level

We have made some progress against this "beast" over the last 100 years, but still have a very long way to go

So let's all stop arguing the unanswerable and get back to work :)

Posted by: Ira S. Pastor at October 13th, 2018 3:59 AM

instead of engaging in pointless slap fights why dont we just test it all and see what happens

arguing gets us nowhere.

Posted by: scott emptage at October 13th, 2018 6:31 AM

@Scott
Absolutely, I agree with the "shut up and experiment" POV to a large extent. As long as we don't get bogged down in some orthodoxy.

@Ira
Well said. There can't be many Ira Pastor's around, so thanks to you and your team @ Bioquark.

Posted by: Alex at October 13th, 2018 8:15 AM

@Ira s. Pastor i was looking at your company website and you mention something called bioquantines. do these have any age reversal effects?

Posted by: scott emptage at October 13th, 2018 8:48 AM

@Alex yes thats true. although i am swayed more to the damage accumilation hypothesis/hallmarks of aging. now i am not saying i turn my back on other theories, i like to mkeep an open mind to all avenues of research and intervention. i just think when people say "this is not likely to work" or "SENS has no chance of success" is quite silly given we havent been able to find out yet. i do believe that senolytics will help a lot in the "healthspan" arena, plus NAD repletion, but in terms of lifespan extension, the answer is........well we dont know. lets just wait and see and keep fighting forward. the more we fight for it, the sooner we have a chance of solving the problem.

Posted by: scott emptage at October 13th, 2018 8:54 AM

@scott emptage:

It isn't pointless, it isn't slap fight and we can't test all. As I said above, there is a big difference in time and cost depending on which branch you decide to pursue.

Posted by: Antonio at October 13th, 2018 11:54 AM

@Florin

There is a reason big pharma is packing up and walking away from these approaches

Not that I believe they have exclusivity on good insight, but after billions of $$$ in this graveyard, the signals are still hotly debated

http://fortune.com/2018/07/30/alzheimers-biogen-eisai-ban2401/

Posted by: Ira S. Pastor at October 14th, 2018 5:43 AM

Many of the issues discussed here are also considered in a paper that I published just this month in Medical Hypotheses:

https://doi.org/10.1016/j.mehy.2018.07.020

Anthonie Muller

Posted by: Anthonie Muller at October 14th, 2018 12:17 PM

The main message of this paper in Medical Hypotheses, titled 'aging is an adaptation that selects in animals against disruption of homeostasis' is a mechanism for a selection by aging: the common assumption is that aging cannot select since it occurs after the individual has propagated. But even after it has been born, the offspring may still depend on parental care. The selection by aging would occur through diminished parental care, which enhances mortality. Aging would select against germline genes that disrupt homeostasis, whereas cancer would select against germline genes that enhance energy dissipation (https://doi.org/10.1016/j.mehy.2017.05.030).

Anthonie Muller

Posted by: Anthonie Muller at October 14th, 2018 4:05 PM

The theory of programmed aging has been devised to discourage long-life prospects from protection from harm.
Everything is invented. By slowing down the damage you can extend your life three times. The problem is that a three-fold extension is calculated from the time you take these supplements.
You can stop eating aging foods, but you will also experience mitochondrial damage.

You can have transplanted new mitochondria, but you will not be able to reverse diseases caused by stress and excess food.
You can start taking medications against stress and hunger. But you are not normally in pharmacies. Still, you will grow older, slower and you will experience cumulative cadmium poisoning.

You can use a two-phase treatment for cadmium poisoning that is not commonly available to doctors. But there is another problem. Each treatment has its negatives. Supplementation with testosterone causes increased levels of estradiol, which acts on the body as a poison and precipitates wasting.

Posted by: Jan Omasta at October 14th, 2018 8:38 PM

Estradiol 'acts as a poison'? Estradiol is a necessary hormone for both females and males. In excessive amounts and in some disease contexts [e.g., some cancers (but note that it is also protective against certain types of cancer)] it can have harmful effects.

Posted by: CD at October 15th, 2018 11:10 AM

A bit late to the party, but a question I've always had about the programmed ageing theory: given that damage accumulation already causes many of the things we call 'ageing', especially because the repair mechanisms themselves get damaged, is there anything left for a program to do?

It feels a bit like the valid criticism that is sometimes made of the argument that God is necessary to explain the existence of life: all God had to do was start the universe with a bang; the subsequent appearance of life can be reasonably explained without a God. (Which, I would like to emphasize, is not an argument against God)

All the program has to do is ensure the repair mechanisms are not good enough to reliably repair themselves as well, so deterioration is inevitable?

Posted by: Ivo at November 3rd, 2018 11:04 AM

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