IS AGING PROGRAMMED? Aubrey de Grey vs. Yuri Deigin debate at Vitalist B...

comment: one thing is that parasites, diseases, germline mutations accumulate with age, fighting all of these is easiest by killing organism, that is in addition to increased evolvability. Also, the exceptions to the free radical theory of aging were explained away with the membrane pacemaker theory of aging, wherein membrane resilience determines rate of damage accumulation. Evolution determines membrane composition, during Calorie Restriction and similar interventions organism even alters membrane composition in a controlled manner increasing lifespan drastically.

In organisms like insects same genome different epigenetic regulation allows 10x--100x lifespan difference between queen and workers. But even here, it was believed queens of some species might be immortal, but for whatever reason it was found that sequential replacement with clones was easier for nature than actual immortality, the longest lasting queens last like 30 years ageless iirc, with extreme reproduction.

Interesting longevity finding regarding astaxanthin.

An Astaxanthin compound has been found to switch on the FOX03 'Longevity Gene' in a study using mice. Researchers measured a nearly 90% increase in the activation of the gene in the animals' heart tissue. Life sciences company Cardax, Inc. looks forward to further confirmation in human clinical trials of Astanxanthin's potential role as an anti-aging therapy. -link

Interesting finding.   The fact that astaxanthin increases lifespan in some species, and also appears to protect cell membranes, make it very promising.

Longevity can be predicted by number of cortical neurons in an animal or so it seems.
https://onlinelibrary.wiley.com/doi/full/10.1002/cne.24564

Crucially, the finding that no correlation between
maximal longevity and metabolic rate remains after accounting for
variation in numbers of cortical neurons argues strongly against
the common notion that damages accumulate at rates that scale
across species depending on metabolism (West et al., 1997).-Herculano Houzel (2018)

Interesting snippet as well as the following

While this new possibility has yet to be investigated, it
leads to one clear prediction: those species with the largest number
of cells in the relevant organ(s) will live longer before succumbing
to physiological breakdown and disintegration and,
consequently, death.-Herculano Houzel (2018)

And yet another related snippet from the news

"The data suggest that warm-blooded species accumulate damages at the same rate as they age. But what curtails life are damages to the cerebral cortex, not the rest of the body; the more cortical neurons you have, the longer you will still have enough to keep your body functional,” said Herculano-Houzel.-source 

But it seems to me that if this were the case you'd see massive lifespan reductions in indivduals with half a brain, which does occur in humans.   Otherwise this would seem to suggest aging may very well be programmed.

Comment on antiaging interventions 2018

We humans had a common ancestor with rodents and later with the other primates. Both likely had far lower lifespan. Yet the genetic differences are minor, but lifespan likely increased 40 fold.

The Brain is one of the highest metabolic activity organs, implying a good chance of metabolic waste production and damage. Yet despite having non-dividing cells there are super agers with minimal cell loss and high function for over 120 years. 50% longer than the average lifespan.

Some whales last for over 200 years with a very metabolically active brain too. What happens to the damage? What about the mitochondria? The damage is exported from the brain through the glymphatic system, it is failure of this system that has been linked to trouble. Mitoptosis, iirc, is able even to remove harmful mutations, that have become common, from the mitochondria population.

We know that cells can be rejuvenated as can tissue generated from such cells. When cells are rejuvenated their epigenetic aging is reset, and the cell repairs itself.

Like the author suggests the aging program likely has several interlocked mechanisms that impede one or two mutations from returning immortality to the organism's lineage. By making each individual mutation on its own harmful without the others, you basically make the immortality trait unevolvable while having all the tools for immortality in your arsenal.

Evolution doesnt increase lifespan by 10 fold or 100 fold with dozens or hundreds of new enzymes solving SENS list. It merely mostly tweaks gene expression and you get up to 10 fold increase. Even with genetically identical members of the same species.

The longer lived a species the closer it is to the immortality genetic program. A trait that requires half a dozen simultaneous mutations might be very difficult to evolve, but a drug cocktail with the right molecules might very well nudge gene expression enough to allow for biological immortality.

Once done. You needn't modify all the cells in the body but merely implant a small population of self regulating cells that generate the appropriate factors.

Post over at kurzweilaiforum

Source http://www.kurzweilai.net/forums/topic/trouble-with-anti-aging-strategies

Paper on research on the evolution of aging, mortality

"..We created such a model to look at the evolution of intrinsic mortality, and were surprised to find the counterintuitive result that lifespan self-limitation is favored even in the absence of other conditions that could intuitively make it favorable – for instance, if animals had to stop reproducing at a certain age, or in a rapidly changing world where you needed new mutations always to be coming along to cope with the changing conditions, it would make sense to clear out old individuals and replace them with new ones." The study's key results show that even without such limiting conditions – that is, if an organism could live and keep reproducing indefinitely, and was just as adapted to the world as its offspring – the lineage would ultimately do better if genes encoded a mechanism that brings about death.

Read more at: http://phys.org/news/2015-07-death-spatial-natural-favors-genetically-limited.html#jCp

Thing is if there's an aging program, as some suspect, the possibility of radical life extension becomes more likelier, and it is believed probably would require less drastic interventions.

Yet more evidence for programmed aging

Morimoto and Labbadia found the genetic switch occurs between two major tissues in an organism that determine the future of the species: the germline and the soma (the body tissues of the animal, such as muscle cells and neurons). Once the germline has completed its job and produced eggs and sperm -- necessary for the next generation of animals -- it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal...

"In a system where we can actually do the experiments, we discover a switch that is very precise for aging," he said. "All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses."

-link

The germline starts the slow suicide mechanism known as aging.

One of my posts regarding aging on kurzweilai

De Grey talks about garbage accumulation and recycling it in situ as a solution, but usually unless you have energy to spare the intelligent thing to do with garbage is not to recycle it on site, but to throw it out, and for someone or something to pick it up and take it to an appropriate disposal area.(eventually it exits the body and after that it is somebody else's problem, and someone else eventually recycles it.)

The body has the lymphatic system, and the brain has the glymphatic system

[quote]

Throughout most of the body, a complex system of lymphatic vessels is responsible for cleansing the tissues of potentially harmful metabolic waste products, accumulations of soluble proteins and excess interstitial fluid. ...

[In the brain the glymphatic system performs this function... ]
The breakdown of the brain’s innate clearance system may in fact underlie the pathogenesis of neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s disease, in addition to ALS and chronic traumatic encephalopathy. -link

[/quote]


[quote]
Even our brains need to take out the trash.

Researchers from the University of Rochester Medical Center found that a waste-flushing system in the brain, called the glymphatic system, is most active when we sleep -- nearly 10 times more so than during periods of wakefulness, in fact.

Plus, during sleep, brain cells shrink in size by 60 percent to better allow for the removal of waste from the brain.-link
 [/quote]

Despite aging glia and aging vasculature(in part due to the telomere shortening), the oldest human lived for over 122 years, they didn't have dementia when they died, iirc, and died from choking according to some sources.   Those exact same billions of single cell neurons were alive at high metabolism for those entire 122 years without failing, providing mental sanity even till the end of life, even with aging surrounding tissue adversely affecting them(tissue responsible for garbage removal, nutrients, etc). 

[quote]

Using this method, Dr Frisén has shown that most cells in the body are less than 10 years old. -link

[/quote]

  If garbage accumulation was a problem for a cell with an insignificant fraction of that[neural] lifespan, as most of the rest of the cells in the body are, pray tell how did these billions of cells managed to continue working at all decade after decade after decade?

Also to still be able to sustain high metabolic activity even at 122 years of age, the mitochondria must be working to at least some decent degree, probably a bit adversely affected by surrounding aging tissue, but there seem to be mechanisms to preserve mitochondria quality like mitoptosis, there appears to be genetic regulation that keeps mitochondria quality in check, and it is dysfunction of this regulation that may be behind a loss of mitochondria quality.

[quote]

Thus, suggesting that mitochondrial dysfunction is a good enough reason for eliminating mitochondria and as Dr. Skulachev says, mitochondria follow the samurai’s law; “it’s better to die than to be wrong”.-link

[/quote]

As for cancer we have the case of cancer free centenarians who smoked two packs a day for decades, and died cancer free.   Would be very unlikely cancer didn't actually pop up.   The likeliest scenario is it popped up and the immune system handled it, at least this seems the case for some fraction of the population.-link to original thread

Programmed aging article

ABSTRACT
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.-link

Study provides more support for the viability of programmed aging theories.

a response in Josh Mitteldorf's blog

 
Regards Telomeres:
while I'm not sure if the measurements are reflective of increases throughout, say stem cells, it has been claimed that a vegetarian diet combined with even modest low intensity exercise can increase the length of telomeres in humans by a noticeable amount.

Regards Thymus:
I've heard that some doses of melatonin are able to reverse thymic involution in nonhuman animals.

Regards natural substances, we have to remember that some can interact with regulatory proteins and alter gene expression.

For example I believe that CR is at least in  part  probably an artefact of metabolic regulatory networks and not a primarily evolved survival mechanism, it works up to around 65% restriction in some animals but requires optimal nutrition unlikely in any natural environment at that level of restriction.   If you can mess directly with the signaling pathways there's no telling what the limits are, as you wouldn't be bound by minimum survival necessary caloric intake limits, and multiple substances are emerging that appear to affect the signalling directly such as nicotinamide riboside, and the various partial cr-mimetics(resveratrol, fisetin, pterostilbene,etc).  There's also probable dietary means of also activating these signaling pathways such as low methionine diets, which can be combined with the substances and probably yield additive effect.

update:
The telomere study wasn't large but iirc, it took measures after five years, which should give time for changes to accumulate,  between comparison groups and had noticeable differences

"The group that made the lifestyle changes experienced a “significant” increase in telomere length of approximately 10 percent. Further, the more people changed their behavior by adhering to the recommended lifestyle program, the more dramatic their improvements in telomere length, the scientists learned.

By contrast, the men in the control group who were not asked to alter their lifestyle had measurably shorter telomeres – nearly 3 percent shorter – when the five-year study ended. Telomere length usually decreases over time."-http://www.ucsf.edu/news/2013/09/108886/lifestyle-changes-may-lengthen-telomeres-measure-cell-aging

"I believe CR is an evolved mechanism for population regulation. Think of it as aging extra fast when there is a temporary plentitude of food, so overpopulation is a risk. The idea that CR life extension only works with optimal nutrition has become part of the biological lore, but it has never really been tested. At the very least, there are big exceptions, as when insufficient protein and methionine help to ENHANCE life extension from CR."

While I don't remember the source I've also heard it must be gradually undertaken or else no lifespan benefits are seen if it is  introduced all of a sudden in adult organisms, in nature it seems sudden famine is more likely.  Also it seems to work up to about 65% in some animals, even if we were to assume no supplementation is necessary in more mild calorie restriction, it is unlikely there wouldn't be serious malnutrition at such extreme levels, yet it keeps on working past what would seem like natural environment nutrient limits.  
Regards methionine, iirc, it's believed to be one of the key signals of nutrient availability which is used by the mechanisms of cr, but it cannot be reduced beyond a certain point without severe side effects.

As for testing malnutrition CR I would imagine you consider CR not effective in humans or else some of the poorest on earth would be breaking records, which they're not and would serve as a test if it is effective in humans.

CR an artifact?

The most widely accepted theory is that this effect evolved to improve survival during times of famine. "But we think that lifespan extension from dietary restriction is more likely to be a laboratory artefact,"
  says Dr Adler.

Lifespan extension is unlikely to occur in the wild, because dietary restriction compromises the immune system's ability to fight off disease and reduces the muscle strength necessary to flee a predator.-link 

I would also add that since the calorie restriction is done with dense nutrient enriched optimal nutrition, this is unlikely to occur in the wild.  Without optimal nutrition calorie restriction is said to fail to extend life, small amounts of nonenriched foodsource as found in the wild is in my opinion unlikely to provide optimal nutrition required for extension. edit: especially at levels that cr can work in some animals like 60+%, at 60% deprivation not only would the nutrient density likely be insufficient, but in an environment lacking resources the small amount of calories would be insufficient for exploration, cr appears to work and extend life even in calorie amounts beyond what would be sustainable in the wild.

Comment on fightaging telomerase article

"Contrast that with the SENS hypothesis that aging is molecular and cellular damage that the body cannot repair at any reasonable cost."

If that were the case, we should see SENS like approaches being implemented by nature in negligible Senescence species. If all they've is mostly the same genes and differing expression patterns, then existing mechanisms are sufficient if ramped up. We have over 98% genetic similarity with our closest relative yet over twice the lifespan.

What approach doubled species lifespan?

If we were bonobos with 40year lifespans and we asked SENS proponents. They'd say most of the [easy] longevity changes were already implemented by nature in achieving this lifespan and they'd propose the SENS solutions as a way to lengthen lifespan.

If like me you believed existing mechanisms are mostly sufficient for vast lifespan increase, then you'd suggest mostly gene expression changes with high conservation of the genome. What did nature do? AFAIK, it simply mostly tweaked gene expression and presto triple lifespan.

If you ask me, it is likely that similar tweaks could very likely carry us all the way up to negligible senescence.

 Let's see what we find from the genetic sequences of negligible senescence organisms.

"Indeed; it's not like there aren't plenty of species whose telomeres don't shorten with age, in fact there's a species of bird whose telomeres get -longer- with increasing age, and it ages quite normally."

I've not looked into it deeply, but according to Dr. Bill Andrews, it is only a few species who have significant aging contribution from short telomeres.

"The same thing should happen if you were to repair all the cellular and molecular damage of aging that suppresses stem cell activity."

And it also as mentioned seems to slightly begin to occur with lifestyle changes that increase telomeres.-Darian S in Fightaging