Programmed Aging

A couple of items appeared at the Longevity Meme in past days covering the discussion of aging as a genetic program of events versus aging as simple unprogrammed decay:

Over at PubMed Steven Austad provides a good argument for considering aging as unprogrammed decay rather than a programmed process in the body. This sort of high level thinking about processes and purpose - like the reliability theory of aging - is an important part of effectively directing the research community. "Aging, except in exceptional cases such as the rapid decay and death of Pacific salmon, is not design but decay. The decay of senescence is not due to natural selection's designing hand, but to its absence. The empirical difference between programed and nonprogramed senescence becomes evident when comparing the stereotypical steps leading to death in salmon contrasted with the lack of such stereotypy in most organisms such as humans and mice."

...

On the other side of this debate Valter Longo and Paola Fabrizio have authored a paper suggesting that aspects of aging in mammals may indeed be programmed. "Programmed human aging is just a possibility. We don't know whether it's true yet or not. But if aging is programmed in yeast, and the pathway is very similar, then isn't it possible that humans also die earlier than they have to?" This discussion is still at the level of educated hand-waving - much more work is needed to settle it one way or another. My suspicion is that the genetics and biochemistry will turn out to be more complex than a simple yes or no.

The recent Betterhumans article on Longo's work gives a more comprehensive background to the debate in terms of evolutionary explanations for aging and the ramifications of Longo and Austad's positions. Check it out.

In Darwinism, natural selection happens on the individual level. Organisms better suited to their environment survive and reproduce, and beneficial mutations lead species to change over time.

In Longo's theory, however, the majority of a population dies prematurely to provide nutrients for surviving members, who have genetic mutations that increase their chances of reproducing.

"We're not saying Darwin was wrong," says Longo. "We're just saying that there appear to be some big missing pieces in his theory."

As I've said before, I'm always happy to see new theories of aging - it shows that scientists are working on the problem.

Comments

I think Steven Austad is correct that aging is anunprogrammed decay process. I have never accepted the argument that aging is pre-programmed.

I think the engineering approach the De Grey has taken to identify all of the decay mechanisms is essentially corect and that the seven processes he has identified constitute what we know as aging.

It may be that some of these processes are interconnected and that curing one will cure some of the others. It may even be that the whole thing is a cascade effect initiated by the hypothalamus. I know of a biotech company doing research on this assumption. However, until I see more molecular biological evidence to support these theories, the best assumption to work on is that aging is simply an unprogrammed decay process.

Posted by: Kurt at September 29th, 2004 6:29 PM

I think, we've seen several hints that the cellular machinery of life is far more powerful and versatile than most believed, it certainly doesn't seem like something that would just decay, Multi-celled organisms seem quite capable of faithfully preserving their genes(even after going through aging several times, third gen clones) and seems to have vast innate regeneration potential.

It seems few genes are involved in confering regeneration capabilities to an organism, same goes for negligible senescense, as organisms with either of these have closely related species that do not posses such traits.

De-differention of highly complex cells like muscle(mammal muscle IIRC) being shown in the lab.

Succesful cloning from a cancer cell, succesful cloning from old adult organisms, repeated cloning of old adult organisms without compromising health(that is clones from clones from clones, second and third generation clones), and the like have shown, unless I missed some news, that IMHO it seems no permanent or at least significantly impairing damage at a genetic level seems to be occuring with aging. Even some cancers seem to be unable to significantly do damage that permanently impairs genetic function given the healthy clone obtained out of a cancer cell.

I believe the human endogenous viruses seem a bit interesting, I suspect that they may play a role in all of this(but there's just so little data on these, I don't know what to think.). IIRC, some have said that it's possible that they may destabilize genetic regulation, weaken immune system, alter hormonal levels, and lead to auto-immune disorders, cancer and the like.

Posted by: apocalypse at September 29th, 2004 7:58 PM

Apocalypse, I certainly agree with you that aging is purely a somatic cell phenomenon. I also agree with you that there is no damage mechanism that occurs on the genomic level.

However, the most significant damage mechanism proposed (and I think verified) occurs with mitochondrial DNA, since mitochondrial DNA is not in the nucleus with all of the protective enzymes. This does appear to be nothing other than a decay process.the others, like glycation (which has not been verified as a cause of aging) and the accumulation of lysosomal aggregates also appear to be simple decay processes. In terms of actual decay processes, there appears to be four basic processes:

1) Damage to mitochondrial DNA
2) Accumulation of lysosomal aggregates
3) Accumulation of junk outside the cells
4) Glycation

It may be that there are biological mechanisms within the body that can reverse all of these effects, which would make them a form of programmed self-destruction. However, i see very little evidence of this.

The reason why I push the SENS idea is because it is based on the identification of all the decay processes that may or may not cause aging, then focuses on the research to cure all of them, one by one. In my opinion, SENS represents the "most difficult hurtle" in curing aging. If the competing theory of aging of being a programmed self-destruction is indeed correct, it suggests that aging may be much more easily cured than by the SENS project. Thats because pre-programmed theories of aging are based on the notion that a relatively small set of genes are responsible for aging and that be tweeking them, aging can be eliminated and that the tweeking would not involve anything as advanced as gene therapy. I simply do not believe these theories.

In other words, SENS is going to definitely cure aging, but will take alot of work and money. The other more easy approaches may or may not work, but there is no guarrantee that they will work.

My bets are on SENS.

Posted by: Kurt at September 30th, 2004 10:54 AM

One other point. SENS is based on actually bio-chemical reaction mechanisms. Longo's work is not. His group has, so far, failed to identify an actual biochemical reaction mechanism to explain his argument. His work (and indeed 95% of all biological research in the world) is based on descriptive biology, not actual biochemical processes.

A cure for aging will require the identification of the actual biochemical processes that constitute aging and the development of effective therapies to prevent and reverse these processes. The SENS project is the only one I have read of that takes this real world approach to the problem. All others are hand-waving based on descriptive biology only. Hense, they are not likely to be real.

Posted by: Kurt at September 30th, 2004 11:01 AM

Based on a study I saw a while ago, and on the negligible senescence animals having closely related non-negligible senescence species, I think that there may be a mechanism for regulating mitochondrial population fitness and allowing certain types of mutations to spread and certain to not, within the cells.

If this were so, de-regulation of this mechanism, which would probably lie in the nuclear dna, would allow negative mutations to spread, preserving or restoring this mechanism would allow mitochondrial population fitness to increase(as seen in spread of beneficial mutation at later ages in some long lived humans, in some study). This deregulation could be brought about by herv activity arising and going on the rise, it would also probably bring along with it auto-immune reactions, weakening of the immune system against foreign pathogens, increase in cancer rate, genetic de-regulation, and the like, from what I've heard that is.

"SENS represents the "most difficult hurtle" in curing aging. If the competing theory of aging of being a programmed self-destruction is indeed correct, it suggests that aging may be much more easily cured than by the SENS project. Thats because pre-programmed theories of aging are based on the notion that a relatively small set of genes are responsible for aging and that be tweeking them, aging can be eliminated and that the tweeking would not involve anything as advanced as gene therapy. I simply do not believe these theories."

Well, I know it's hopeful, but it's just the strange way in which aging takes place and the plateu that occurs at later ages.

"The Gompertz model, used to predict maximum life spans for different species, is named after 19th-century British actuary Benjamin Gompertz. It predicts that in humans the risk of dying increases 9 percent each year after puberty, or doubles every eight years.

This same relationship holds true for people living under any environmental condition ? a rural farm, a prison camp or a stressful urban setting. Finch and Pike also found that the life span of mice, rats, dogs, hamsters and several birds all fit the same curve. The mortality rate becomes constant and the curve flattens out after 90 percent of the animal or human population has died...

Finch and Thomas Kirkwood of the University of Newcastle, in England, had the notion that chance variation, while clearly recognized for years, has never been properly observed. How else to explain genetically identical worms, raised under the same laboratory conditions, dying over a three-fold range of ages? Or inbred mice, born of the same mother and reared in the same environment, dying over a similarly wide variation? Human twin studies also exhibit unusual differences in life spans.
"

There are many things suggesting that this may be the case, as it is so in other species, and if it turned out to be so in ours too, as you've said aging could be as good as gone quite quickly maybe even in less than 30yrs. Also, we've to consider that increases in herv activity increases may also be important thus it should be considered as something to take care of too, unless information has been provided to the contrary.

Here's an example of what I mean:

"Genes and Cells that Regulate the Lifespan of C. elegans

Our laboratory studies the regulation of aging. Not very long ago, most people thought that aging was something that just happened. We just wear out, like cars. Not true! Several years ago, we discovered that mutations in the gene daf-2, which encodes an insulin/IGF-1-like receptor, double the lifespan of the nematode C. elegans. Since then, insulin/IGF-1 endocrine systems have been shown to regulate the longevity of flies and mice as well. We have found that this system is regulated by sensory neurons in C. elegans, and that signals from the reproductive system also regulate aging. Amazingly, if we perturb insulin/IGF-1 signaling and reproductive cells in the same animal, we end up with animals that live SIX times as normal! What?s more, they stay vibrant and healthy until the very end. We have also discovered that a different regulatory system involving mitochondria functions during development to set the rates of behavior and aging. We are now trying to understand how the insulin/IGF-1, reproductive and mitochondrial pathways, as well as another perturbation, caloric restriction, influence lifespan at the molecular level."
http://www.ucsf.edu/pibs/faculty/kenyon.html

Another example is the cancer resistant mice, why is a mutation that seems to confer resistance to even aggresive malignant cancers not widespread why is it rare if it does not compromise lifespan, health, reproduction or the like?

Now as for the accumulating stuff all around, I'd have to see how things fare once you enable full-blown regeneration. For example, It was said that maybe some of the more complex cells like muscle would be unable to de-differentiate, and that such might be a reason for higher organisms lacking it, but this was shown to be not so. Mammalian muscle, IIRC human, was de-differentiated when exposed to a chem. from a species with regeneration capabilities. The question is what are the negligible senescent species doing about it.

Posted by: apocalypse at September 30th, 2004 9:30 PM

I'm not sure that you are correct in the last part of your posting, but I certainly hope that you are.

Posted by: Kurt at October 1st, 2004 1:00 PM

The info on regeneration from my last paragraph was posted on imminst forums, it's from an article in wired, though mammalian it seems I recalled incorrectly it was done with cells from the muscle of mice not men:
"It's an elegant system, but the hitch was that no one had been able to get the same thing to happen in mammals. Until the fall of 1998, when, on something of a lark, Keating and his colleagues, postdoc Shannon Odelberg and researcher Chris McGann, decided to treat mouse muscle cells in a petri dish with a liquefied extract made from a newt's regenerating leg cap. Unlike newt cells, mammalian muscle cells change dramatically as they mature, growing fat bundles of ropelike fibers and merging their cytoplasms en masse, like eggs whose whites have run together. Believing that this elaborate structure could be reversed was, researchers thought, like expecting a Ming vase to morph back into a lump of raw clay and powdered pigments.

And yet, under the influence of the newt extract, that was exactly what happened. "Nobody expected it to work," admits Odelberg, still sounding baffled. In a follow-up experiment, the researchers were able to apply growth factors to dedifferentiated cells, making the stem cells mature again to resemble muscle, bone, or fat cells.

It was a staggering discovery. "People had been studying regeneration for years and had zero evidence it could happen in mammals," Li says. "It wasn't until Mark and Shannon debunked the myth of terminal differentiation that anyone believed this could work."
http://www.wired.com/wired/archive/11.11/regeneration.html?pg=2&topic=&topic_set=

My hypothesis is that maybe the regeneration path may be in some way connected with aging, maybe altering cells from one type to another may make it easier for mutants of such species to develop the means to keep a younger gene expression pattern(due to the changes taking place, the epigenetic reprogramming of such cells, may seal things like hervs, and may be able to restore a youthful gene expression pattern) . This may be the real reason why it was selected out in more complex organism, because aging was a necessary adaptation to increase the evolvability of the species given the more prolonged development time and generation transition time.

I'm also hoping that if this path is flexible and powerful enough to revert a complex cell such as a muscle cell, than maybe it can do something about all the junk.

Though, as you say this may or may not be. But I'm an optimist, and If this turned out to be the case, it would mean in at the most a few decades the world may be an entirely different place.

"Under the circumstances, one might expect animals that regenerate regularly to get cancer more often, but oddly enough the opposite is true: salamanders are one of a very small number of species that don't get cancer at all."

That's another way in which regeneration may interfere with the aging/self-destruction adaptation, by requiring immunity from cancer, as occured in the mutant mice strain. Maybe it's necessary that cancer be there, to ensure that mutants hardy-enough to withstand the aging assault for a prolonged period, do not compromise and take resources from the new generations. That would explain why cancer immune resistance is such a rare mutation despite not having any apparent negative side-effects.

"abstract from publication
This powerful resistance segregates as a single-locus dominant trait, is independent of tumor burden, and is effective against cell lines from multiple types of cancer. During spontaneous regression or immediately after exposure, cancer cells provoke a massive infiltration of host leukocytes, which form aggregates and rosettes with tumor cells. The cytolytic destruction of cancer cells by innate leukocytes is rapid and specific without apparent damage to normal cells. The mice are healthy and cancer-free and have a normal life span. These observations suggest a previously unrecognized mechanism of immune surveillance, which may have potential for therapy or prevention of cancer."
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=Pubmed&list_uids=12724523&dopt=Abstract

"Several intriguing implications derive from the properties of the SR/CR mouse. First, this model demonstrates the existence of a host resistance gene that can prevent the growth of advanced, MHC-negative cancers. The existence of host cancer resistance genes has been postulated to be one explanation for the existence of individuals in the human population who fail to develop cancers, despite prolonged and intense exposure to carcinogens. The gene(s) responsible for the SR/CR phenotype may well be an example of such a resistance gene that might have a direct human ortholog. Second, the concept of immune surveillance has been debated for decades and has been difficult to prove, although recent studies have lent support to this concept. The SR/CR mouse may also provide a potential example of such a surveillance mechanism. Third, the alteration in the type of response seen with age in these mice suggests an intriguing possibility. The appearance of cancer in older individuals at a much higher frequency may not solely be caused by the accumulation of mutations in individual preneoplastic cells. This mouse model suggests that there may also be host resistance mechanisms that decline with age. Fourth, the rare phenomenon of SR of cancers has been documented in humans, but has been difficult to study because of a lack of an appropriate animal model. The SR/CR mouse may provide such a model and allow identification of the cellular and genetic machinery necessary to reject a fully developed malignancy. The ability of adoptively transferred infiltrating leukocytes from SR/CR mice to protect control mice from S180 cells may suggest a potentially feasible strategy for treatment of advanced cancers that could be translatable into human patients."
http://www.innovitaresearch.org/news/03090501.html

Not only simple malignant cancers, but some of the most aggressive ones that killed all other strains. Even large grafts that could make up to 10% of the organism were withstood.

Some select quotes from my post in the aging theories thread in imminst forums:

"We did see changes that look like the changes that you see in the development of age-related diseases. This has been found by other workers conducting micro-array gene expression studies in other tissues as well. I think our results are very consistent with theirs in showing that gene expression profiles in tissues begin to resemble profiles of tissues that have age related disease processes going on in them. Our tissues looked healthy-we could slice them and look at them under the microscope and see no signs of liver fibrosis for instance. But when we looked at gene expression in these tissues with age, we found changes that more and more resemble those that you see in diseased tissues. So, I think that's part of the development of age-related diseases-a drift towards gene expression that resembles the gene expression of diseased tissues. Calorie restriction reverses much of that, short and long-term."

"Even telomerase expression, the hallmark of immortal cells, has been found at extraordinary high levels in all the cells of
negligibly aging animals )(Klapper, et al, 1998a, 1998b)."

More info on one of the C-elegans experiments mentioned in my prior post:
"When the tiny worm Caenorhabditis elegans cannot sense what is going on in its immediate surroundings, there is a surprising payoff. It lives up to twice as long as normal, according to Javier Apted and Cynthia Kenyon of the University of California at San Francisco. They have found that 'nematode' worms that have defective sensory organs can double their lifespan, without any apparent change in behaviour. This suggests that, in nematodes at least, longevity is not simply programmed into the genes but can be altered by feedback through the nervous system. The role of nervous system in aging could not be remarked upon*."

NOTE THIS PECULIAR STIMULATION:
"It is known that senescent human fibroblasts stimulated hyperproliferation and progression of preneoplastic epithelial cells and accelerated tumorigenesis by neoplastic epithelial cells. These results may seem at odds with the tumor suppression function of cellular senescence."

"Senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and form tumors in mice. In culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14ARF, or hydrogen peroxide. Moreover, it was due at least in part to soluble and insoluble factors secreted by senescent cells. In mice, senescent, much more than presenescent, fibroblasts caused premalignant and malignant epithelial cells to form tumors. It could be suggested that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms...."
http://www.innovitaresearch.org/news/03082001.html

This is a quote from the mitochondria study I mentioned, maybe I misinterpreted it, but in any case here it is:
"The aging-related increase in discordance, as concerns the presence and/or level of the C150T transition between lympho-monocytes and granulocytes from the same individuals, has clearly indicated that the observed accumulation of the mutation in centenarians has a somatic contribution. Furthermore, a nuclear genetic control of this somatic contribution is strongly suggested by the striking nucleotide selectivity of the mutation...

Strong support for the conclusion of a contribution of somatic events to the phenomenon investigated here has come from the longitudinal studies of fibroblasts, which have provided convincing evidence that the mutation can arise during life or change level in the same individual during aging. Furthermore, in these cells as well, the nucleotide selectivity of the mutation has reinforced the suggestion that the postulated somatic event(s), induced by an environmental or internal stimulus, is under nuclear genetic control...

An interesting possibility is that the somatic event(s) at or near position 150 leading to the appearance and/or amplification of the C150T transition may be a part of a general remodeling of the mtDNA replication machinery, probably nuclearly controlled. This remodeling could accelerate mtDNA replication and compensate for the oxidative damage of mtDNA and its functional deterioration occurring in old age and, possibly, during or after twin gestations. The aging-dependent accumulation of tissue-specific point mutations, which we have previously identified in fibroblasts and skeletal muscle at critical control sites for mtDNA replication (1, 2), is conceivably also a part of this remodeling."
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=298736

On regeneration and aging:
"Extreme longevity seems to be related not only to the low metabolic rate in the cold climate, but the species can reduce energy expenditure for growth, and can rapidly increase metabolic rate up to 130x the normal level, to regenerate damaged shell or tissue. The physiology of this species may provide valuable clues to understanding the mechanisms that sustain longevity and retard senescence."
http://www.bioone.org/bioone/?request=get-document&issn=0044-7447&volume=029&issue=02&page=0102

"In any case, this general (and speculative) line of

thinking leads us to conjecture that biological age may

be better captured by the ??average age?? of an

individual?i.e., by some appropriate measure of the

average age of the organs, body parts or cells of an

individual?than by the chronological age of the

individual...

Furthermore, organisms that can repair,

replace or rejuvenate body parts may show, over

chronological time, slow increases or even decreases in

average age...

For some species of plants and animals, there

can be a complete turnover of body parts over a time

interval: for these species, average individual age can be

much lower than chronological age and can decline over

time if the individual grows and its component parts

continue to turnover with time."
http://www.demogr.mpg.de/publications/files/1685_1088431236_1_NegSenTPB.pdf

Posted by: apocalypse at October 1st, 2004 7:07 PM

People interested in aging may want visit the web page http://www.agingtheory.com . A powerful convincing hypothesis, yet unrelated to other aging theories, is presented there. It also resolves Darwin's Dilemma.

Basie

Posted by: Basie at May 28th, 2005 7:22 PM

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