An Interview with a Programmed Aging Theorist

Josh Mittledorf holds an interesting somewhat group selection based view on the evolution of programmed aging, and here is interviewed by the Life Extension Advocacy Foundation volunteers. I have long said that the important divide in the research community is between (a) those who think that aging is programmed, in the sense that evolution selects for epigenetic changes in later life that are a primary cause of damage and dysfunction, and (b) those who see aging as a stochastic process of damage accumulation, that occurs in later life because there is little to no selection pressure for ways to prevent it, and this damage causes epigenetic changes and dysfunction.

This is an important divide because the two views lead to very different strategies for the development of therapies to treat aging. The programmed aging theorist wants to force reversion of epigenetic changes to a youthful pattern, and expects damage and dsyfunction to be reversed as a result. In the damage accumulation view, exemplified by the SENS research programs, repair of damage is the right path, with the expectation that dysfunction and epigenetic changes will revert themselves once the damage is gone. In either case, if the other side is right, the chosen strategy will produce poor results. Now that the research community is earnestly engaged with the idea of treating aging, whether researchers and institutions invest in good or bad strategies is of great importance to the near future of medicine and our own lives.

It seems like the field of aging science has grown remarkably. Are you optimistic that we're on the verge of real breakthroughs in longevity improvements?

I'm not as optimistic as I was a few years ago. The Next Big Thing in the field is likely to be senolytic drugs. These are able to selectively remove the body's worn-out cells that have become toxic, without poisoning our healthy cells. I think they'll add a decade or more to the human lifespan. Calorie restriction mimetic and exercise mimetic drugs will be another boost if they can be made safe. After that, I think the big challenge will require taking control of our epigenetics (heritable changes that don't require changes to the genome itself). Epigenetics, I believe, is in control of aging at a deep level. Epigenetics is so complicated that 20 years into the age of epigenetics, we're still just beginning to understand how it works.

Why are you less optimistic about the potential for major breakthroughs in aging science now in 2018 than you were previously?

Originally, my thinking went like this: The conventional view has been that aging exists despite evolution's best efforts over hundreds of millions of years to eradicate it. Evolution is already trying to make us live as long as possible, and for humans to extend our lifespan, we'll have to do some pretty fancy thinking to come up with something that evolution hasn't already tried. However, this conventional view is wrong. In fact, evolution has preferred defined lifespans to indefinite lifespans. So, we might hope that we can eliminate aging entirely by understanding the mechanisms of self-destruction that evolution has built into our life history and biochemically disabling them. I had thought that this could probably be done by blocking the signals, jamming the works. Pharmaceutical companies are generally quite good at turning off a hormone or a whole biochemical pathway once it's been identified.

The reason I'm less optimistic now is that I believe that the evolved mechanism of self-destruction involves gene expression, which is to say epigenetics. Different genes are turned on at different stages of life (this is a big part of what epigenetics is), and the genes turned on late in life turn the body against itself. Mechanisms like apoptosis (cell death), autoimmunity, and inflammation are all dialed up. The reason my expectations are scaled back now is that epigenetics has turned out to be enormously complicated. We once thought that a few transcription factors controlled a large number of genes, turning them on and off en masse. We now know that there are thousands of different transcription factors, almost as many as there are genes. And there is wide overlap between genes that have transcriptional functions and genes that have metabolic functions.

Could you flesh out a little your contributions to aging science, in terms of the evolutionary theory of programmed death in humans and most other species?

In the modern understanding of evolutionary fitness, evolution is highly motivated to make you live as long as possible, so long as you are still churning out babies. So, where does aging come from? The standard answer is that there are genes that tie fertility directly to deterioration late in life, and evolution has not found a way around this; it has not found a way to have lots of fertility early in life without incurring damage later on, despite hundreds of millions of years of trying to overcome this limitation.

I have described a great mass of evidence against this picture. Much of it is common sense, but there is a lot of technical, genomic evidence as well. The evidence strongly points to the inference that natural selection has preferred shorter lifespans to indefinite (or very long) lifespans. Why might this be? My theory is that it is about ecosystem stability. It's not possible to construct a stable ecosystem out of selfish individuals that are each trying to live as long as possible and produce as many offspring as possible. In order to have stable ecosystems, nature has had to accept limits to fertility and to lifespan.

The reason that the evolutionary community is so resistant to this idea is that it requires natural selection to occur within entire ecosystems. In other words, this ecosystem persisted because it was stable, while that one collapsed because it was way out of balance. For largely historical reasons, evolutionary theory grew up in a way that was committed to the selfish gene. Most evolutionary biologists today believe that the selfish gene is the only mode by which evolution operates, though they could not articulate a reason why, if challenged.

Link: https://www.leafscience.org/dr-josh-mitteldorf-are-we-on-the-verge-of-major-breakthroughs-in-anti-aging-science/

Comments

" My theory is that it is about ecosystem stability. It's not possible to construct a stable ecosystem out of selfish individuals that are each trying to live as long as possible and produce as many offspring as possible. In order to have stable ecosystems, nature has had to accept limits to fertility and to lifespan.

The reason that the evolutionary community is so resistant to this idea is that it requires natural selection to occur within entire ecosystems. In other words, this ecosystem persisted because it was stable, while that one collapsed because it was way out of balance. For largely historical reasons, evolutionary theory grew up in a way that was committed to the selfish gene. Most evolutionary biologists today believe that the selfish gene is the only mode by which evolution operates, though they could not articulate a reason why, if challenged."

So Josh basically believes in group selection? I was under the impression that this has long been debunked.

I actually thought that his argument was that there are adaptions that favor animals survival when they are young, but which go on to harm the animal in later life, with the classic example being senescent cells preventing cancer in the short term but causing a host of problems and death in the medium term.

Posted by: Jim at April 18th, 2018 8:03 AM

It starts to sound as if fixing the vascular issues should be the priority - if it can be shown that AGE products actually end up causing cerebral bleeding and death. So, we grow new organs or fix other defects but then what?
Is there any contrarian viewpoint about this? About AGE causing circulatory fragility?

Posted by: Chris Zell at April 18th, 2018 9:43 AM

I read Josh's book. Although I'm a "random damage" aging guy, I nevertheless found it quite good. Josh does a good job at debunking many of the conventional aging theories, most notably genomic DNA damage and antagonistic pleitropy. He also debunks the original mitochondrial DNA theory of aging (MTA). However, he does NOT address the much more nuanced mitochondrial DNA damage theory of aging that makes up the backbone of the SENS strategy.

Josh does indeed believe in group selection, and his epigenetic theory of aging is based on it. Group selection is not necessarily debunked. Its just that there is no plausible molecular biology that has been advanced to explain it.

Posted by: Abelard Lindsey at April 18th, 2018 10:54 AM

"The best senolytic treatment we have now is fasting." -- Josh does not follows progress and do not aware of Oisin's genetic universal framework or SIWA immunotherapy?

Posted by: Ariel at April 18th, 2018 11:58 AM

'epigenetics has turned out to be enormously complicated'

sssiiiiiiigh. of course it did.

you know, it would be super refreshing for some aspect - one tiny little aspect - of the war on ageing to turn out to be simple and easy.

Posted by: TL at April 18th, 2018 12:20 PM

"The best senolytic treatment we have now is fasting." -- Josh does not follows progress and do not aware of Oisin's genetic universal framework or SIWA immunotherapy?

Yes Ariel he is up to date but he is talking about what you, me, and the general public have right now. No Senolytics have been approved for public use, that is what he means.

Posted by: Steve Hill at April 18th, 2018 1:11 PM

or to be more specific, the technologies of SIWA and Oisin etc... are not yet available to Joe Public. Sure there are some approved cancer drugs and Quercetin and a few others around but these are limited and/or have serious side effects. So we are not quite there yet and this is what Josh means, he is optimistic about senescent cell clearance.

Posted by: Steve Hill at April 18th, 2018 1:14 PM

"So, for senolytics to be implemented in humans, we need a really smart poison that only affects senescent cells without harming normal cells. There are several pharmaceutical companies working on this idea. The record-holder so far is FOXO4-DRI, and it is about 10 times more toxic to senescent cells than to normal cells. That factor of 10 isn't enough margin of error for a practical drug. To get rid of all your senescent cells, you'd have to take too many healthy cells as collateral damage.

A combination of dasatinib and quercetin has been suggested for senolytics. Quercetin is found in fruits and berries, but by itself it doesn't extend lifespan (in mice). Dasatinib is a chemotherapy drug that is far too toxic to be a practical life extension medicine."

Ealier I cannot see any sign of up to date info. ;-) Any references for real presision senolitics approach.

Posted by: Ariel at April 18th, 2018 1:22 PM

@Reason, "I have long said that the important divide in the research community is between (a) those who think that aging is programmed, in the sense that evolution selects for epigenetic changes in later life that are a primary cause of damage and dysfunction, and (b) those who see aging as a stochastic process of damage accumulation."

Luckily, the number of 'programmers' is very small to matter. The more important divide in the research community is between (a) those who think that 5 additional years is enough and other proponents of such nonsence like 'healthy ageing', and (b) those who wish real rejuvenation and unlimited healthy life.

Posted by: Ariel at April 18th, 2018 1:30 PM

"The standard answer is that there are genes that tie fertility directly to deterioration late in life, and evolution has not found a way around this; it has not found a way to have lots of fertility early in life without incurring damage later on, despite hundreds of millions of years of trying to overcome this limitation."

AFAIK, that's not the standard answer. The standard answer is that lifespan is mostly determined by predatory pressure, and both reproduction strategy and repair comprehensiveness are influenced by it. If you are eaten before you age, there is low evolutionary pressure to maintain those antiaging repair mechanisms. Also, there is no point in reaching reproductive age after you are eaten.

"For largely historical reasons, evolutionary theory grew up in a way that was committed to the selfish gene."

What??? The selfish gene is a quite modern theory, from the 1970's. The idea that individuals are the unit of selection comes directly from Darwin, even before genes were known or defined. Individual selection is a century older than the selfish gene.

Posted by: Antonio at April 18th, 2018 1:53 PM

If the aging was programmed then probably the trigger would depend on just a handful of pathways. There would be people with rate sets of mutations that don't age. And to paraphrase Fermi's paradox: Where are they? And those few clock systems would be somewhat easy target...

The group selection is an elegant but not very likely theory. After all, biologically we humans are short lived species, because we had such high early life mortality that a long lived yet slightly damaged individual would have no competitive advantage over the fresh arrivals. Therefore, there are no shortcuts we will have to address all possible damages and outgrowths.

Posted by: cuberat at April 18th, 2018 2:09 PM

"Ealier I cannot see any sign of up to date info. ;-) Any references for real presision senolitics approach."

That is pretty much the current situation Ariel, selective senolytics are NOT available to the public now. That is all he is saying, I don't know why you are struggling with this.

Posted by: Steve Hill at April 18th, 2018 2:27 PM

Why does this group selection theory imply programmed aging wouldn't it just imply no evolutionary selection of better inate repair mechanisms. If so even if true it does not count as argument against sens damage repair.

Posted by: David at April 18th, 2018 2:28 PM

Evolution itself is dependent upon the turnover of cells and life so as to easily adapt to changes over time. Were we to finally have children at 628 years old, and were the environment changed significantly before then, we'd be bringing old genes into a new world. That said, humans have been the same for well over a million years. Bring any child from 1myo to the modern era and you will see nothing different than you do now. Go back in a time machine to the paleolithic or earlier, and you may survive just fine, if you're not eaten by predators or don't take modern medicine with you.

So I'm more inclined to accept the theory that the SENS model rests on, but why couldn't it be both, or some combination of the two?

With CRISPR technology on the horizon, I'm more optimistic about things.

Posted by: Nathan at April 18th, 2018 2:31 PM

"I'm not as optimistic as I was a few years ago...Calorie restriction mimetic and exercise mimetic drugs will be another boost if they can be made safe. "

All the more reason to do what you can RIGHT NOW instead of waiting for the easy pill.
Practice calorie restriction
Exercise

Also, what I don't think is being considered is the problem solving boost that AI will provide. As more and more machine learning comes on-line these puzzles will be solved more quickly.

Posted by: Lee at April 18th, 2018 2:53 PM

Wait, Foxo4-dei isn't useful?

Posted by: Jim at April 18th, 2018 5:19 PM

@Jim: As far as I can tell, he pulls the 10:1 toxicity ratio out of nowhere. I don't believe it is in the mouse study-FOXO4-DRI showed very high selectivity for senescent cells.

Generally I don't see why a middle approach couldn't be true. For instance, maybe there is an epigenetic pro-aging program, but it works by allowing damage to accumulate. So SENS would still be effective, even if the evolutionary programming explanation is right. Alternately, maybe cellular damage triggers some sort of epigenetic feedback loop, leading to signals that exacerbate or speed along damage accumulation. Then epigenetics would likely have to be fixed along with damage for robust rejuvenation.

I'm not saying a middle view is right, though it would explain data like parabiosis research that supports the programmed view, along with data that supports the damage accumulation view. Just saying this is not an either/or situation, and drawing a line in the sand is silly.

Posted by: gheme at April 18th, 2018 11:18 PM

@gheme the middle view is possibly right. This is why I favor Hallmarks of aging as it incorporates damage and programmed elements.

Anyway, I am glad the interview sparked some interesting discussion here, it is good to include differing viewpoints and ideas in science least we become too entrenched in one idea.

Posted by: Steve Hill at April 19th, 2018 3:02 AM

Hi there, just a 2 cent.

I believe the more accurate definition would be self-programming aging/self-feedback loop programming/state-dependent self-deterministic 'transparent' program. Self-deterministic because auto-regulatory/auto<compensatory feedback acting on self.= a 'program' 'happening' - that is 'started' from a universal code of valleys, states and mountains on DNA decorum; methylation and acetylation being code silencers and unsilencers, why DNA landscape the genetic blueprint.
The Program TM his happening for real ever so surreptitiously deep in methylome, transcriptome, retranslation/retransposome etc. This, silent 'in the very background' process is the sum of itself (and its parts and states/autodeterministic) and transient like a ghost. Yet, despite this mysterious self-manifesting 'acting on self/inhibiting self' orchestration, there is definitive {in)dependent cooperation and dual-acting on each other between programmed aging and damage cumul aging. They feed off each other while Self-feeding themselves (feedback loop on self).
As others said, there is no one or the other, but both, an autobalancing act, they compliment/complete each other and create the lifespan (self-tracing) trajectory.

As for the article saying evolution cannot work out eternal life out competing selfish individuals, selfish genes, because of a need for environmental ecosystem stability and survival; it supposes these individuals will run of earth resources through depleting as they live eternally, never dying and making an infinite amount of eternally living offspring. The Universe is BIG and expanding, there would never be a lack even we sourced the entire universe, which is composed of a near infinite amount of galaxies, planets, matter, and energy; resources were never a problem to begin with once one looked farther than their backyard. Because of dual parallelism, the chances of a 'twin' clone Earth somewhere in this world would bw high. Now, we just have to reach there and evolution will follow along our travelling as it adapts us (or rather We adapt it, just like in a lab - evolution chose specific masterplans for specie individual survival; depending on their env/predatory prey degree/resource abundance. But, inlab, evolution is at our mercy as we discover its tricks of the trades and use them on it. Outwitting it by turning it on its head, thus we tame it and it gives much more predictable results. I second having ultra-advanced neural AI to decipher it and thus tame the bull to go where we wish it to. We're not there yet but ever closer, there won't be anymore secrets or surprises.).

Just a 2 cent.

Posted by: CANanonymity at April 19th, 2018 3:37 AM

Suppose they find a good senolytic but then death happens from a brain bleed? Or a similar circumstance with regrown organs? I think glucosepane and AGE products need priority.

Posted by: Christopher Zell at April 19th, 2018 7:28 AM

@Christopher Zell
If the death is delayed and you have otherwise healthier live even without increasing the lifespan then it still would be a win. And after that the next step would be to make the therapies very targeted to a specific organ.

So if in your example if you have the heart-related senolithycs case brain damage then they will have to be applied by a surgically injected patch that limits the impact to the heart. Or find antibody targets to bind the chemicals only to few cell types. That would take a decade more over the simple whole-body exposure.

Posted by: cuberat at April 19th, 2018 2:25 PM

I don't think you get what I'm saying. I can easily foresee being able to replace all organs in a decade or so - leaving the brain remaining. You might even be able to replace the whole body from the neck down. However, if blood vessels in the brain are old and weak, you'll die of hemmorhage anyway. So, I think fixing the AGE/Glucosepane problem needs the most attention, as the rest is due to arrive soon.

Generally, I think we already have opportunity to live a healthy life into 80's or so - but only if diet is strictly controlled and most people can't do that.

Posted by: Chris Zell at April 19th, 2018 2:52 PM

About FOXO: yes, dr. de Keizer himself is not satisfied about it: it takes out 1 healthy cell for every 10 senescent cells. He has since moved to another lab at another university to pursue the search for a molecule with more precision.

Posted by: PeterB at April 20th, 2018 4:09 AM

Hi Chris Zell,
Of course eventually even the brain will have to be repaired or even replaced. But if you have youthful organs, blood without elevated lipoproteins and sugar and if that blood has the right stem cells like in the cord blood, then probably it could reverse some cross-linking and plaque accumulation in the brain. For some it was mean healthy nineties but for others cold be 30-40 years more. This gives a good boost to LEV

Posted by: Cuberat at April 20th, 2018 5:40 AM

@Chris Zell & @Lee
Good points.

~~~
Group selection is not necessary to explain various aspects of life history evolution, including lifespan evolution. Stephen Stearns has some good lectures on YouTube on the subject - though IIRC he has some negative attitudes to life extension research.

For a *very* succinct explanation of the basics of lifespan evolution in vertebrates:
Steve Horvath | 2017 Allen Frontiers Symposium
https://youtu.be/Tjq6oVl3k7A?t=10m02s

Hovarth seems rather optimistic about anti-aging therapies based on epigenetic modification, though I suppose optimism is a relative thing.

Posted by: CD at April 20th, 2018 10:49 AM

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