Yet More Discussion of Programmed Aging

There are many theories of aging, a state of affairs that I would say is really due to past lack of resources put towards building means to treat aging in a targeted way, by addressing specific purported root causes. There has been a great deal of investigation of the biochemistry of aging, and will continue to be given its complexity, and all too little bold experimentation in means to extend healthy life spans. This was in large part cultural for the last generation of researchers, a way to reject any association with the fraud and self-deception of the "anti-aging" marketplace, and thus preserve reputations and the ability to raise funding for legitimate studies of aging. At the same time, however, this meant that greater progress towards longevity enhancement might have happened and did not: talk of treating aging became a threat to careers, an unfortunate state of affairs that has only recently abated.

Ways to increase longevity in laboratory species are the tools by which theories of aging can be winnowed and validated. Unfortunately all of the present means of slowing aging are far too general in their operation to serve as good tools in this sense. Take calorie restriction and its alleged mimetic drugs, for example: these approaches change near every measure of metabolism, to the point at which it remains an enormous puzzle to figure out how and why they act to slow aging. What is needed is a new generation of much more targeted therapies, things like clearance of senescent cells, or clearance of cross-links, or other proposed SENS biotechnologies based on the repair of one single type of tissue damage thought to cause aging. Build the treatment, run the experiment, and a lot will be learned from whether or not it does extend healthy life. If great progress is made by repairing forms of damage thought to cause aging, that tells us that theories painting aging as a process of damage accumulation are more robust and defensible. The types of damage being repaired and the results obtained will help separate out which theories on various types of damage are more robust and defensible.

Ultimately theories of aging matter today because they are used to steer investment in research. This will continue to be important until one group of theories wins out by weight of evidence obtained through extending life in laboratory animals. At the moment the division of greatest importance is between programmed aging theories and stochastic damage theories. Programmed aging theories would have us think that aging is the direct consequence of a set of evolved changes in (say) gene expression and protein levels and cellular operation, and these changes causes damage, dysfunction, and death. The right thing to do if this is true is to work to alter the operation of metabolism, change the gene expression levels, manipulate specific protein levels, to bring them back to a more youthful pattern. In contrast stochastic damage theories of aging tell us that aging is caused by what is effectively biochemical wear and tear, and our bodily systems react to the presence of that damage with altered gene expression and protein levels and cellular operation - but it is the damage that is the root cause of disease and dysfunction. The way forward if this is the case is to repair the damage.

Personally, based on my view of evidence to date, I'm in the latter camp: aging is stochastic damage accumulation. Repairing that damage if following the SENS proposals is very cost-effective, and producing full demonstrations of the various treatments in mice is a $1-2 billion, 10-20 year project at full scale funding. That's less than the cost of developing a single drug candidate in the Big Pharma world these days. Programmed aging on the other hand would direct us into a massive, unending project of trying to fully understand and safely alter swathes of our metabolism. That is a vast project. To give some idea of the scale, about a billion dollars has been swallowed up on research of sirtuins in aging over the past decade or so - just a couple of genes out of thousands worth looking at, and nowhere near a full understanding of their role yet, and no meaningful treatments or ways to alter metabolism resulted from all of that work. So from my perspective, I see programmed aging theories as the road into an endless swamp, a course that might be averted at a low cost by making enough progress on SENS rejuvenation treatments in the laboratory to demonstrate their worth in extending healthy life spans, and thereby showing that aging is mostly likely a process of stochastic damage.

Here is a better than average popular science article that covers many of the aspects of this debate over theories of aging, using a recent paper on programmed aging as a springboard. You should read the whole thing, given that the author took the time to gather opinions from various researchers with different takes on aging, who think that this particular line of research is flawed, and goes on to examine the point I make above, which is that all this theorizing is far from idle and unimportant. It in fact determines the prospects for the near future development of effective means of treatment for degenerative aging, with both sides believing that their road is the more effective one, but only one of them being right:

Are Limited Lifespans An Evolutionary Adaptation?

That aging is a deliberate function of our genetics remains a controversial idea, but it's an idea that's steadily acquiring adherents. One of these adherents is NECSI president Yaneer Bar-Yam, who contends that popular approaches to the aging problem fail to address a very important constraint, namely the ways lifespans are genetically controlled according to the resource limitations of a given environment. Without genetically programmed aging, he argues, animals wouldn't be able to leave sufficient resources for their offspring. And this holds true for all animals, whether they be rabbits, dolphins, or humans.

Bar-Yam and his team reached this conclusion by developing a simple model that analyzed how the lifespans of simulated organisms would change and evolve over time under spatially constrained conditions. Fascinatingly, group selection -- the idea that natural selection acts at the group level -- was never a consideration in the model. Yet the simulations consistently showed that a built-in life expectancy emerged among the simulated organisms to preserve the integrity of their species over time. This is surprising because a pro-group result was produced via an individualized selectional process.

"Beyond a certain point of living longer, you over-exploit local resources and leave reduced resources for your offspring that inhabit the same area," Bar-Yam said. "And because of that, it turns out that it's better to have a specific lifespan than a lifespan of arbitrary length. So, when it comes to the evolution of lifespans, the longest possible lifespans are not selected for."

Programed Death is Favored by Natural Selection in Spatial Systems

Standard evolutionary theories of aging and mortality, implicitly based on mean-field assumptions, hold that programed mortality is untenable, as it opposes direct individual benefit. We show that in spatial models with local reproduction, programed deaths instead robustly result in long-term benefit to a lineage, by reducing local environmental resource depletion via spatiotemporal patterns causing feedback over many generations. Results are robust to model variations, implying that direct selection for shorter life span may be quite widespread in nature.

Oh look, a bunch of people in the comments section talking about resources, people being stuck in their ways, and overpopulation. Shocking. I wish more people's attitudes on this would change a bit...

Posted by: Ham at June 12th, 2015 8:07 PM

I believe Aubrey said somewhere that he would prefer that aging was programmed, that that likely would be easier for change. He just doesn't think that's the case.

Posted by: Northus at June 12th, 2015 9:51 PM

From the article:

"The neo-Darwinian synthesis, with its declaration of the gene as the basic unit of evolution"

Totally false, that is the declaration of Dawkins' selfish gene theory, that come much later. For neodarwinism, the unit of evolution is the organism, nor the gene nor the group (group selection).

"Without genetically programmed aging, he argues, animals wouldn’t be able to leave sufficient resources for their offspring."

Actually, in nature, most animals die (by predators, diseases, etc.) before they are aged.

“The idea that short lifespans can be extended, but long lifespans cannot, is an idea without a lot of phenomenological support.”

Actually, the life extension experiments on different species systematically show the contrary. For example, CR extends life more in worms than flies, more in flies than fish, more in fish than in mouse and more in mouse than in monkeys.

Posted by: Antonio at June 13th, 2015 12:44 AM

If aging is programmed by evolution, how would that make the job of stopping or reversing the aging process any easier? If humans have evolved to live only for a certain amount of years, how can it be possible to extend this by 5 or 10-fold? Because from the sound of it, anti-aging would be even harder if we found out that we were genetically programmed to live for only so long.

Posted by: InternetStranger at June 13th, 2015 3:58 AM

InternetStranger. If it's programmed we'll change, destroy or suppress the programming, or perhaps still go on to fix the damage it's causing, depending on the specifics. Whether aging is programming or a sideffect there has to be a biochemical mechanism we can interfere with.

Posted by: Northus at June 13th, 2015 10:38 PM

Wear and Tear damage can also be repaired by upregulating the bodies own systems too. One can use key pathways to reduce the work SENS has to do as ADG himself stated.

There have been a number of recent experiments demonstrating rejuvenation occurring from single pathways eg, TERT, TIF-1A, Oxytocin and so on. These could substantially restore function to tissue making the SENS proposition considerably easier and more likely to happen in a useful time frame.

Posted by: Steve H at June 14th, 2015 9:41 AM

Steve H, does any of those recent rejuvenation experiments repair any of the root damage as described by SENS, or are they more dealing with some of the downstream effects of that damage (also useful if it buys time) or something else? I'm trying put all of this together in my mind.

Posted by: Northus at June 15th, 2015 7:21 AM

Cal Harley demonstrated in 2000 that Telomerase for example restored in Human skin cells restoration of the aged phenotype, restoration of collagen levels to more youthful ones, repair of the Dermal Matrix (ECM), restoration of function and no increase of cancer observed. So that single pathway alone has rejuvenated tissues and cells.

I could cite dozens of papers supporting Telomerase as a therapy and why it is a good and common intervention point. It also known to repair at least one form of DNA damage making it repair at least some of the damage SENS talks about. As to if Telomeres are a down up upstream effect is unknown but they do seem like a poitn of intervention that rescues the aged phenotype somewhat. Restoration of youthful function could hardly be considered a bad thing. However SENS WILT is in favor of removing Telomerase which is in conflict with its regenerative properties.

The other pathways seem to cover some damage types detailed in SENS too so they could be incorporated into the approach.I will investigate further and post citations supporting this.

Posted by: Steve H at June 15th, 2015 9:37 AM

To clarify the Cal Harley study linked previously addresses GlycoSENS as it shows Telomerase repairs the dermal matrix which is part of the ECM and restores collagen production.

TGF-Beta also restores bone tissue matrix and can regulate mineralisation. This is also Follistatin of which a gene therapy has recently been used in Children at the Nationwide Childrens Hospital to treat Beckers MD so is already safety proven and the results were impressive on muscle wastage. This comes under GlycoSENS and I believe Oxytocin has similar effects on bone though I would need to investigate that further.

The work of Dr Fossel and the aim of his Telocyte project is to clear plaque by targetting the Glial cells thought to be important in AL. He will do this by using Telomerase to restore function and gene expression. This covers AmyloSENS if succesful. A number of papers highlight Glial cells in AL and how it might benefit from intervention.

and this very important paper demonstrating TERT is beneficial against AL

If you are interested read the work of Dr Michael Fossel who elaborates on why Telomerase/TERT therapy may well mitigate a lot of aging consequences and is an upstream intervention point common to many of the systems in the body.

Ok so LysoSENS there is a gene therapy which has the side effect of clearing plaque from the body thus potentially mitigating atherosclerosis. Follistatin which i mentioned earlier also has the possible side effect of plaque ablation due to its ability to regulate Minerilisation. Follistatin gene therapy as previously mentioned also helps muscle wastage and could be combined with TERT for example for potentially further benefits.

Follistatin is also a Myostatin inhibitor and that can help mitigate build up of plaque. There are a number of studies showing promising results and allegedly a person has tested this therapy on themselves to good effect. I shall remain skeptical until I see the CT scans and data however.

This is not an exhaustive list but it shows how Gene therapy can compliament SENS and in fact is talked about under delivery methods in the SENS RF page here:

Posted by: Steve H at June 16th, 2015 5:57 AM

Steve, thanks. I'll need some time to melt all that info.

Posted by: Northus at June 16th, 2015 7:41 AM

To be fair it is only a very quick overview and I dare say a lot more gene therapies could be linked to SENS. I have heard there might be a gene therapy floating about that clears Senescent cells though I am not sure what it is as yet. If this is true that would cover ApotoSENS but I need to find out more about that first.

The bottom line is I see a number of gene therapies that could compliment the SENS approach and do address the kinds of damage ADG is talking about. WILT is about the only SENS approach I flatly disagree with as frankly there are far too many signs and studies showing the benefits of TERT/Telomerase.

There are also promising approaches to Cancer like Maria Blasco's recent one here that simply removes immortality from Cancer by attacking the Shelterin TRF-1.

This effectively ends the cancers ability to multiply and is a common mechanism in all Cancers. They used a drug to inhibit but a gene therapy could probably be created to do the same. This fits into OncoSENS.

CD47 is another promising approach to Cancer which targets the Cancer which is transmitting a "do not eat me" signal. Switching it off allows the immune system to attack it as it correctly identifies the cell as an enemy and removes it.

Again could be used for OncoSENS and produced as a Gene therapy.

However SENS has enough common ground IMO to unite the community and the best way to see if something is going to work is test it. If TERT turns out to be useless as a therapy after testing then ditch it and move onto other ideas. Somehow I doubt it will be knowing what I do about Telomere biology.

Posted by: Steve H at June 16th, 2015 8:36 AM

One thing that doesn't make sense to me is that in the iterative computer simulation they put in a bunch of parameters (food supply, predation etc) and see how they impact on optimal lifespan, then somehow conclude that because this isn't indefinite all animals are programmed to die, and that differing lifespans between species are a result of each facing different parameters.

They don't seem to consider that differences in food supply, predation etc might affect the optimal development time of each species, which then goes on to create differing lifespans as each species now has a differing amount of redundancy for damage tolerance before it begins to have negative effects. Also that if species have differing optimal development timeframes, then species with longer development timeframes will probably have better self repair capabilities further diverging different species lifespans.

Posted by: Jim at June 16th, 2015 9:13 AM

Too much here to address, but a couple of serious ones:

Steve H: To clarify the Cal Harley study linked previously addresses GlycoSENS as it shows Telomerase repairs the dermal matrix which is part of the ECM and restores collagen production.

The study you linked shows how in a culture model, ectopic telomerase changes fibroblast function in various ways, including increasing collagen production; but (a) this isn't representative of what actually goes wrong in aging fibroblasts to begin with (replicative aging of fibroblasts in vivo is actually quite rare), and (b) it really doesn't show much of anything about GlycoSENS, which is about the accumulating damage in the ECM itself: producing more collagen won't break the crosslinks in the existing collagen, nor re-knit or replace frayed elastin lamellae in arteries; it's also not clear to me that it would restore fibroblast attachment, though that seems at least plausible.

Steve H: TGF-Beta also restores bone tissue matrix and can regulate mineralisation.

Indeed. It also contributes to tissue fibrosis, and is the major factor identified by Irina Conboy in impairing muscle satellite cell regenerative response in response to injury in her parabiosis experiments; as featured here on FA!, she just recently reported that "Systemic attenuation of the TGF-β pathway by a single drug simultaneously rejuvenates hippocampal neurogenesis and myogenesis in the same old mammal". I.e., this is another illustration of why trying to outsmart metabolism is a mug's game.

Steve H: This is also Follistatin of which a gene therapy has recently been used in Children at the Nationwide Childrens Hospital to treat Beckers MD so is already safety proven and the results were impressive on muscle wastage.

To be clear, (a) follistatin is not TGF-β, although it (and GDF-11, and a lot of other things) are in the same family; (b) the evidence that follistatin is effective in Becker's in humans is still highly preliminary; (c) aging humans are not Becker's patients, as an illustration of which (i) follistatin inhibits GDF-11, which up until weeks ago everyone thought was the secret sauce behind the parabiosis effect in rejuvenating the heart, brain, and skeletal muscle — so at minimum, we need to sort the role of GDF-11 in the young systemic milieu before even considering using either it or follistatin in aging humans.

In this context, Steve, I think you've pretty seriously misunderstood some recent comments by Dr. de Grey about parabiosis. He is emphatically not now saying that we should take the results of parabiosis experiments as a route to developing ways to outwit metabolism by replacing what declines with age and inhibiting what rises. He is saying that the parabiosis experiments give us clues as to what we need to focus on in terms of repairing the primary damage underlying those changes, as they tell us the effects we will get "for free" once the original damage is repaired.

Posted by: Michael at June 16th, 2015 11:20 AM

Second paper was "Received 18 April 2013" and "Published 12 June 2015" - not a very important side note, but still something to keep in mind, as there were new developments meanwhile.

Posted by: Adrian Crisan at June 16th, 2015 12:18 PM

Fair enough Michael I see what you folks are driving at, still think you need to revisit Telomerase as its role is becoming more varied and integral to so many things.

Follistatin you agree is a possible avenue of interest which is nice.

It talks about gene therapy as a delivery method in SENS is this something you still see value in at all? eg, identify some beneficial changes to make that might compliment SENS?

Posted by: Steve H at June 16th, 2015 12:36 PM

Steve. All very interesting. When telomerase repairs the dermal matrix, is the exact nature of that repair known? I mean, does it actually break the crosslinking, or does it do something else? And why does that happen, what is the causal connection between telomerase (and/or telomeres) and AGEs?

All for now, but I have more thinking to do. Brain is a bit slow right now, trying out fasting.

Posted by: Northus at June 17th, 2015 5:34 AM

To be fair Michael's point above is probably right:

"The study you linked shows how in a culture model, ectopic telomerase changes fibroblast function in various ways, including increasing collagen production; but (a) this isn't representative of what actually goes wrong in aging fibroblasts to begin with (replicative aging of fibroblasts in vivo is actually quite rare), and (b) it really doesn't show much of anything about GlycoSENS, which is about the accumulating damage in the ECM itself: producing more collagen won't break the crosslinks in the existing collagen, nor re-knit or replace frayed elastin lamellae in arteries; it's also not clear to me that it would restore fibroblast attachment, though that seems at least plausible."

The fact is we will not really know exactly what it will do until we test this in a person and see what it does in the systemic environment. Michael's point a) is true as it was an artificial situation and therefore not representative of cells in situ, though the results are fairly interesting if they are replicated in situ. His point b) while probably right still is interesting if some level of repair to the ECM occurs.

We wont know unless it is tested anyway and SENS is unlikely to try that because as Michael has clarified above it is not the approach they are taking.

Posted by: Steve H at June 17th, 2015 7:21 AM

"To be fair Michael's point above is probably right:"

Ah, hadn't even read that comment yet. More to read and absorb and learn from, good.

Posted by: Northus at June 17th, 2015 9:38 AM

It does not change the fact that some of the linked studies are interesting like the Cancer therapy from Blasco and the other one that removes the "Do not eat me" signal Cancer cells transmit. These could all be very powerful therapies, potentially they could be part of OncoSENS be they drug or gene therapy delivered. It does go to show just how much progress we are making in Science and even if SENS is not the full answer that progress is moving forward rapidly in some areas.

Stem Cell research aka repleniSENS is something that seems to be belting along at a fast pace and that holds a lot of power for therapies and could work perfectly for restoring lost stem cells just as SENS and others have described.

I am also very confident in the theory behind Dr Fossels Telocyte project and using Telomerase to rescue the aged phenotype in cells. I would urge you to check out his work and some of his talks if you are interested in the rejuvenation potential of Telomerase/Telomeres. They are not the simple replicative clocks some people dismiss them as and in fact as Wright and Shay have explained are in fact far more complex and important. However this last bit does not fit with SENS but still I would suggest reading up on the work as it's very interesting.

Posted by: Steve H at June 17th, 2015 3:29 PM

I've seen a couple of interviews with Dr. Fossel but was unable to make out how exactly his method relates to SENS, whether it would repair root damage or something above that level or slow down aging or what, but those were just interviews and it sounds from your description that it is actual repair (at some level), even aside from the obvious repair of the telomeres. I have to say that of all interviews and speeches I've seen from various researchers in the field it's always Aubrey that makes the most sense, but I'm glad a lot of smart people are working on this and there might be some value on having a diversity of approaches as long as they're reasonably reasonable and as long as SENS gets more funding than now...

SENS WILT does sound very invasive and potentially risky. It seems to rely on telomerase only having the function of rejuvenating telomeres (though if that isn't the case we'll find out long before it becomes part of any whole-body treatment for humans) and it would also mean we'd become dependent on stem cell therapy every ten years or less or we'll start to die as we run out of telomeres. If I understand everything correctly, if not I'd be happy to be corrected.

It's a drastic measure, but then cancer is a very drastic and deadly and common condition. Let's see what solutions other can come up with. If only accelerating return could accelerate a little more so as to quickly make versatile medical nanobots available as soon as possible.

Posted by: Northus at June 19th, 2015 9:23 AM


The vast majority of cells don't use telomerase at all. Only stem cells use it. So it can't have an important role apart from enlarging telomeres (that is, a role that will get you sick if eliminated).

Posted by: Antonio at June 24th, 2015 3:43 AM
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