55 replies to this topic

[maestro949]

Progerias are diseases that accelerate the rate of aging but why not the inverse?

Clearly there's been no selection pressure for longer lived humans but you would think that with the billions of people that have lived and died that perhaps a handful would have had some collection of mutations that significantly adjusted the rate of aging in these individuals. Yet nothing. Why not?

While there are the super centenarians, they really aren't that far from the statistical distribution of elderly people.

Perhaps there have been but something else killed them off before they revealed themselves as having an adjusted rate of aging?

[eternaltraveler]

short answer, metabolism is obscenely complicated. That's why the approach most aging researchers are using is hopeless (i.e. tinkering with metabolism).

Humans already are very long lived mammals.

[DJS]

Progerias are diseases that accelerate the rate of aging but why not the inverse?

Short answer, things can go wrong a lot more easily than they can go right. The key is to recognize that the relationship between negative and positive mutations is rarely inversely proportional.

One deleterious genetic tweek and you can have massively ineffectual M&R mechanismsm, where with the inverse (of improved M&R mechs) you have yourself super centenarians. A number of positive mutations would probably have to happen simultaneously for what your conceptualizing to even be possible, and the chance of such an occurence is exceedingly small, boardering on impossible.

[JonesGuy]

Elrond has made a good point. For our metabolism/weight category, we're remarkably long-lived.

[roidjoe]

There is no increase to fitness for living beyond reproductive age and fitness rapidly decreases after mid twenties.

Mutations that increase the fitness of an organism around reproductive age usually lead to increase prevalence of disease past reproductive age because there is NO selection thereafter.

Trade offs, dawgs. Doesn't seem like any of you took an evolutionary biology course.

Edited by roidjoe, 12 July 2007 - 07:18 AM.

[eternaltraveler]

thanks dawg )

[Live Forever]

Nate dawg and Warren G.

[apoptosos]

Given that the question asked was framed in an evolutionary context, the appropriate short answer was provided by roidjoe:

There is no selective advantage to longer lifespan.

[pyre]

Nonsense! There have been multiple examples of mutations leading to obscenely long lifespans! Noah of the Ark, Moses (I think), Abraham, etc.

Those guys lived a looooong time, so it must be explained by random (or divinely selected) point mutations that gave them exceptional longevity.

[Lazarus Long]

Aside my basic agreement with roidjoe and apoptosis on this there is an added environmental pressure that works against such a longevity mutation, albeit not in a directed selective manner.

Even if such a longevity gene occurred randomly it does not ensure that it will survive the environmental threats of famine, predation, disease, toxicity, natural catastrophe and in a human sense, social competition. It is not even certain such a gene would be a part of a *viable* mutation that occurred in a fertile member of the species in even a recessive mode that could be carried into subsequent generations or that the advantages of greater intelligence would be present. You would still have to survive the learning curve and then be fertile to transmit the advantage in a transmittable fashion and protect the offspring while it could do so.

The irony of natural selection is that there is always more selection pressure against mutation than for it, even when looking backward such mutation is seen from a long term perspective as opportunity. Such an analysis requires the memetics of record keeping and history, something genes do not really do.

Genetic evolution never looks forward in anticipation of change (that happens to be a tenet of ID) it may be selected for in the present by environmental shift through migration into a micro clime, natural disaster or climatic shift but this is simply random chance offering a new opportunity to a characteristic that was already present in a latent form.

Memetic evolution may change that as intelligence offers a shift in strategies for intelligent species but that has still not happened although we see the competition shifting. Memetic evolution through intelligent analysis of predictive modeling of environmental and risk/reward can influence the future through intelligent selection, technological adaption, climate manipulation, and directed opportunism but genetic evolution only looks backward to understand the present. We only discover a future tense through memetics and then can develop a past through future history model.

The past determines most genetic opportunity with the present tense as an unknown variable with severely limited influence. Longevity is not particularly important in that respect, it didn't help dinosaurs and reptiles retain control of the globe for example. Selection for intelligence is far more rewarding in that respect and ironically as I have pointed out before, in an environment of widely variable sudden risk with unforeseeable catastrophe looming on the horizon (when seen from a looking backward perspective) the real challenge is between strategies of larger birth number versus more complex intelligent offspring.

We do see this occurring. Also the short gestation, relatively intelligent, high number of offspring species tend to survive better than highly specialized, even higher intelligent species that are larger with with longer life expectancy and fewer offspring.

So here we have come back to the checks and balances issues. Yes there is some pressure to develop longer lived higher intelligent species but there is seven greater selection pressure preventing that from occurring and the environment occasionally intervenes to level the playing field in a catastrophic manner on an evolutionary scale and this defaults to the advantages of the smaller, shorter lived species with faster gestation, less resource demand, broader climactic and food adaptability and larger number of offspring.

We have seen this formula a number of times play out and the last KT event was the most recent and significant but there are numerous examples of it playing our regionally in smaller versions since. Mammals (and us in particular) are dominant exactly because our ancestors possessed the advantages of short lives, short gestation periods, with high environmental adaptability and large numbers off offspring and to a certain extent as a species we are still paying that piper.

[bgwowk]

There are no doubt mutations that incrementally increase lifespan all the time, but until very recently there has been no selection pressure for them because people got eaten by other animals or bacteria before they could benefit from slower aging. Not having lived through those times, most people don't intuitively realize that only a few generations ago there were scarcely any old people around at all.

There are now selection pressures for longer lifespans, especially with women postponing attempts to have children to later ages because of training and career requirements of the modern world. Even without further technological intervention, natural lifespans would probably increase significantly within a few dozen generations.

If you are asking why there aren't just a few 200-year-old outliers around by genetic accident, that's most likely because big changes in aging would require changes in more than just a few genes.

[JonesGuy]

There is no increase to fitness for living beyond reproductive age and fitness rapidly decreases after mid twenties.

Mutations that increase the fitness of an organism around reproductive age usually lead to increase prevalence of disease past reproductive age because there is NO selection thereafter.

Trade offs, dawgs.  Doesn't seem like any of you took an evolutionary biology course.

It's a bit more complicated than that. Given the huge number of grandparents who take care of children (because the parents aren't capable/available), there's certainly a competitive advantage to longevity mutations. Remember, it's not just the number of offspring that's selected for, but also the robustness of the future generations.

If a grandma can still chase tykes around when she's in her sixties, her family will do better than the ones where the grandma's are needing to be taken care of in their sixties.

This, in fact, could be why humans are already so long-lived.

[John Schloendorn]

If such mutations occurred randomly (by drift, not by selection), I don't see how we could know about them at this time. Efforts to investigate the genetics of extreme human longevity are in their infancy at the Supercentenarian Research Foundation. Unfortunately, this is really really hard, for reasons explained on their website.

[roidjoe]

There is no increase to fitness for living beyond reproductive age and fitness rapidly decreases after mid twenties.

Mutations that increase the fitness of an organism around reproductive age usually lead to increase prevalence of disease past reproductive age because there is NO selection thereafter.

Trade offs, dawgs.  Doesn't seem like any of you took an evolutionary biology course.

It's a bit more complicated than that. Given the huge number of grandparents who take care of children (because the parents aren't capable/available), there's certainly a competitive advantage to longevity mutations. Remember, it's not just the number of offspring that's selected for, but also the robustness of the future generations.

If a grandma can still chase tykes around when she's in her sixties, her family will do better than the ones where the grandma's are needing to be taken care of in their sixties.

This, in fact, could be why humans are already so long-lived.

HOW IS THERE ANY SELECTION FOR OLD AGE WHEN THERE IS NO SELECTION PAST REPRODUCTIVE AGE?

YOU CANNOT REPRODUCE. Fitness = offspring. Reproduction past reproductive age is impossible therefore there is no selection for it. Genes that increase the age of an organism will be lost.

How is a gene that makes grandmother live longer selected for?

Ok. So your theory is that grandmother raises and nurtures the children, and that is a given without mutations that would lengthen the lifespan of the organism - but it comes down to the question of when does age become a liability to the family instead of an asset? I would wager that shortly after reproductive age, when the organism starts to fail the individual becomes a huge liability and this is why it is natural for the organism to die around that time.

[bgwowk]

But why is the reproductive age what it is? The reproductive period in humans is optimized for the living conditions of our ancestors, in which people were killed by external causes two to three decades after being born. If you remove external causes of death, evolution expands the reproductive period and delays senescence because then there is benefit for doing so.

Animals with few predators age slower than animals with short extrinsic lifespans. There are stunning natural examples. Consider naked mole rats that live safely underground, with lifespans ten times as long as field mice. They are almost biologically immortal. There are also eagles, large turtles, and whales that live for hundreds of years. There even appear to be instances of the same species being translocated to safer environments and evolving slower aging and longer lifespans than their cohort that remained exposed to predators, which is what evolution would predict.

The so-called "evolutionary theory of aging" may not be the whole story, but it seems to be an important part of understanding why many animals age at the rates they do.

http://www.senescenc.../evolution.html

The most important reason that fertility and longevity of human grandparents hasn't been selected for is probably that until very recently few humans survived disease and predation long enough to become grandparents.

[JonesGuy]

How is a gene that makes grandmother live longer selected for?

Her grandchildren will receive more care, ensuring that her grandchildren outcompete other children.

The more 'parental' type caregiving you can give to children, the better the children thrive. Grandparents can take care of the toddlers too. Thriving children is a reproductive selective advantage.

[apoptosos]

Her grandchildren will receive more care, ensuring that her grandchildren outcompete other children.

There are at least 2 issues with this assumption that stand to repudiate the notion of positive selection of longevity genes based on grandparent caring: a) caring can, and is often provided by non-genetically linked caregivers, and b) it does not follow that grandparents with longevity genes will always choose to be involved in raising their grandchildren in such a way as to provide a significant advantage over children with nil or "ordinary" grandparent caring..

it comes down to the question of when does age become a liability to the family instead of an asset?

As an aged person becomes increasingly infirm the investment in caring becomes greater yet provides no return to the caregiver. Compare this with the investment made in caring for a very young child. Given the burden that such caring could place on limited resources it would not be disingenuous to propose that selection pressure for shorter lifespans may be operating.

[bgwowk]

How is a gene that makes grandmother live longer selected for?

Her grandchildren will receive more care, ensuring that her grandchildren outcompete other children.

Academic. For genes of post-reproductive grandparents to experience selection pressure, there have to *be* living post-reproductive humans, which has not been the case for almost all of human evolution. Extrinsic lifespan (lifespan in the presence of external causes of death) prevents evolution of longer instrinsic lifespans until external causes of death are removed.

[John Schloendorn]

there have to *be* living post-reproductive humans, which has not been the case for almost all of human evolution.

Under conditions were there are *no* living post-reproductive humans due to exogenous causes, longevity genes should drift out of the gene-pool due to lack of pressure to maintain them. This would accelerate aging, until we have enough post-reproductive humans for the pressure to kick in to maintain aging at that rate. If this happened in the past, then our current "rate of aging" was the result. This mechanism would provide an adjustable "longevity-stat" as a function of exogenous causes of death It also predicts that non-negligible numbers of post-reproductive people should be around in primitive societies. For contemporary hunter-gatherers this indeed appears to be indeed the case. Interestingly, this would also predict a natural increase of longevity in civilizations that reduce exogenous causes of death. This too may be consistent with the data. Thus, grandma's contribution to childcare may not have been as important as mom's, but based on the available data (grandmas exist), it seems non-negligible.

But all this is really off-topic, as the original question was about "random" mutations, not about selected ones.

[Brainbox]

Probably OT and naive question:
Aren't mutations always random before evolution "decides" to select certain mutations to be more favourable than others?

[caston]

Isn't evolution enabled by sloppy DNA repair and ageing a consequence of sloppy DNA repair? Maybe we should turn the question on its head. It's not that evolution selects for longevity its that evolutionary mutations undermine the individual. Organisms capable of cellular sex and death are vibrant and dynamic they select for sex and pass on random mutations in their code. Immortal organisms never evolve.

[bgwowk]

Isn't evolution enabled by sloppy DNA repair and ageing a consequence of sloppy DNA repair?

No. DNA damage is a negligible part of aging.

Organisms capable of cellular sex and death are vibrant and dynamic they select for sex and pass on random mutations in their code. Immortal organisms never evolve.

Biologically immortal organisms still evolve because individuals still succumb to exogenous causes of death.

However you do touch on "group selection", the idea that groups can experience positive selective pressure for traits that are detrimental to individuals. I think this idea is still controversial in evolutionary biology. I don't believe the idea that aging of individuals evolved for the sake of evolution of species is strongly supported because there is so little aging in the wild.

[Lazarus Long]

There is also a correlation that is coincident at worst and directly related at best, which reflects a form of genetic selection for longevity and that can be inferred from the selection process for intelligence.

In every species where we observe increasing intelligence over the fossil record we also seem to seem a correlation of increased brain mass to body weight that corresponds with a longer gestation period, and longer rearing period from potentially older parents, which often are in social groups.

These longer gestation/growth periods also appear to correspond to longer developmental biologies that correspond to longer lived species. This is certainly true in large mammals and not just the case of the naked mole rat. Elephants and large whales also have very long life expectancies relative to their forebears and they also represent species that dominate their food chains often through intelligent social behavior and have life expectancies that increased with their brain/body mass ratios.

There is some logic to the idea that evolving intelligence requires a longer life expectancy to expand its learning curve and develop the opportunities of intelligence that express its advantages in terms of environmental competition for resources.

Short lived species do not need the advantage of intelligence nor would they acquire much benefit from being intelligent as they would lack as much opportunity to put it to use or share it socially.

[caston]

No.  DNA damage is a negligible part of aging.

I disagree with that. Specifically with your use of the word "negligible". What would happen to me if all my DNA repair was suddenly switched off? The cause of death might not be called "ageing" because it would happen so
quickly but I would mutate so fast that I wouldn't have a chance to pass on these mutations (and any of their potential benefits) to offspring. Although I'd probably for these mutations to be valid they'd have to be from using error-prone repair mechanisms instead of more accurate ones so rather than giving an example of turning off DNA repair instead it probably better to give an example of using a different mechanism of DNA repair.


Here is an article that came up when I googled for dna repair and progeria.
http://www.pubmedcen...gi?artid=433405

Biologically immortal organisms still evolve because individuals still succumb to exogenous causes of death.

Lets compare the immortal individual organism to feudal or Stalinist dictatorship and the rapidly ageing individual organism to a thriving free open market (perhaps even slightly anarchist) nation . There is little or no innovation (evolutionary changes) in the immortal organism because every cell is kept in check like a police state. Cells that change to much due to mutations in their DNA are at danger of becoming cancerous so the mitochondria has changed its sex machinery into the machinery to induce apoptosis. Organisms with mitochondria that does this survive cancer long enough to pass on their genes to future offspring. In the "thriving open market" cells rapidly change and are not punished for this but they no longer seamlessly form the individual and these cells have no reason to be clumped together in the first place. They are in just as much danger from each other as they are from the surrounding (and very deadly) oxygen.

So we are most likely something in the middle like a mixed economy. Mitochondria that allows just enough evolutionary mutations to go unrepaired are able to pass their genes on inside "new hardware" ie passed down through the maternal line into a new individual that has slight changed which might confer it advantages in rapidly changing conditions.

However you do touch on "group selection", the idea that groups can experience positive selective pressure for traits that are detrimental to individuals.  I think this idea is still controversial in evolutionary biology.  I don't believe the idea that aging of individuals evolved for the sake of evolution of species is strongly supported because there is so little aging in the wild.

Well I think we would never be complex organisms in the first place if it so so easy for us to live as simple ones. There is ageing in the wild just not many organisms failing due to near total senescence.

Edited by caston, 14 July 2007 - 03:24 AM.

[bgwowk]

No.  DNA damage is a negligible part of aging.

I disagree with that. Specifically with your use of the word "negligible". What would happen to me if all my DNA repair was suddenly switched off?

Aubrey de Grey would predict you'd die of cancer. That is the essence of his argument for why mutations are not a big part of aging: Highly effective DNA repair exists because cancerous mutations in just a single cell can kill the whole organism.

Allow me to propose a slight variation of your thought experiment: What would happen to you if we suddenly added a bunch of random mutations to your body? We can do exactly that by irradiating you with a near lethal dose of radiation. What happens? The primary chronic effect is an increased incidence of cancer. You are not suddenly glycosylated, atherosclerosed, and wrinkled with systemic amyloidosis, if you see what I mean.

Take care that your thinking doesn't become circular. While germline mutation is necessary for adding true new genes to a species gene pool, it does not follow that the rate of somatic mutation must be so high as to make mutations a dominant cause of aging, unless you believe that mutations are the cause of aging, which is where the circularity comes in. There is much more to aging than just mutation. Aging is better thought of as an absence of sufficient housekeeping mechanisms for indefinite survival past reproductive age.

[caston]

Thanks bgwowk.

Aubrey de Grey would predict you'd die of cancer.  That is the essence of his argument for why mutations are not a big part of aging: Highly effective DNA repair exists because cancerous mutations in just a single cell can kill the whole organism.

The damage needs to occur and be improperly or unrepairered in certain tumour suppressor or oncogenes. But what if you had good DNA repair in for these genes but shoddy DNA repair in others would you age faster?
I suspects there would be a much higher rate of apoptosis.

Allow me to propose a slight variation of your thought experiment: What would happen to you if we suddenly added a bunch of random mutations to your body?  We can do exactly that by irradiating you with a near lethal dose of radiation.  What happens?  The primary chronic effect is an increased incidence of cancer.  You are not suddenly glycosylated, atherosclerosed, and wrinkled with systemic amyloidosis, if you see what I mean.

Well I believe it was the radiation from the sun that got the evolutionary ball rolling in the first place. Some organisms that survived actually used the suns deadly radiation to produce energy via photosynthesis. My question is do organisms purposely speed up their rate of mutation in order to evolve even faster than other organisms just responding to normal damage such as from oxygen and solar radiation?

Does this program lead to greater cell death past reproductive age?

Take care that your thinking doesn't become circular.  While germline mutation is necessary for adding true new genes to a species gene pool, it does not follow that the rate of somatic mutation must be so high as to make mutations a dominant cause of aging, unless you believe that mutations are the cause of aging, which is where the circularity comes in.  There is much more to aging than just mutation.  Aging is better thought of as an absence of sufficient housekeeping mechanisms for indefinite survival past reproductive age.

Of course i'll be careful not to ignore contradictory evidence and keep an open mind. Have there been specific experiments on up regulating DNA repair and recording the effect on longevity? What about the effect of mitchondrial binary nuclear fusion or the introduction (such as to a zygote) of genetically modified (even given genes taken from longer lived species) mitochondria on longevity?

Edited by caston, 14 July 2007 - 08:10 AM.

[bgwowk]

My question is do organisms purposely speed up their rate of mutation in order to evolve even faster than other organisms just responding to normal damage such as from oxygen and solar radiation?

I'm not an evolutionary biologist, but I'm not aware of evidence for positive selection pressure for poorer repair of random damage (mutation). That's not to say that other mechanisms of genetic variation, such as gene shuffling by sexual reproduction, haven't been selected for. However pure random damage is much more... damaging.

Does this program lead to greater cell death past reproductive age?

We can be more certain that the answer to this is "no", because mutation is only a small part of aging. There is another way to look at this question that may be helpful. What if we put nanomachines inside you right now that performed perfect DNA repair? Would you still age? Absolutely. Visit Aubrey's SENS pages to see all the bad things that happen with aging that are not caused by mutations.

[apoptosos]

It is difficult to find a flaw with Caston's argument that damaged DNA contributes to aging. Recent work reported by Nijnik et al in Nature (2007 Jun 7;447(7145):686-90) support the hypothesis that DNA damage accumulation leads to adult stem cell exhaustion. There is a consensus in the scientific community for a positive correlation between aging and DNA damage accumulation than not. What I have difficultly with is following Caston's reasoning that aging is a consequence of the positive selection of sloppy DNA repair.

[bgwowk]

It is difficult to find a flaw with Caston's argument that damaged DNA contributes to aging.

Contributes to aging, or is *the* cause of aging?

The original question was:

Isn't evolution enabled by sloppy DNA repair and ageing a consequence of sloppy DNA repair?

While some aspects of aging result from DNA damage, aging is not just a consequence of DNA damage.

Looking back, there has also been confusion in the discussion between mutation and damage. It is possible for aspects of aging to be driven by damage such as double stranded breaks while still being influenced negligibly by heritable mutations. I should not have said that "DNA damage is a negligible part of aging" when what was really going through my head was mutations, not the more general case of damage, which per your references does contribute significantly to aging even if it is not the primary cause of aging.

Edited by bgwowk, 15 July 2007 - 07:21 AM.

[maestro949]

Lots of good points.

I keep thinking of this from a survival rate perspective and keep coming back to why the curve doesn't taper off more smoothly. Could it be that it boils down to the fact that the numbers are still not there to really determine whether or not the mortality curve truly tapers off to zero near 120? Despite a mortality plateau the chance of death of supers is still quite high. Perhaps the multivariate nature of the data is the issue rather than simply a lack of mutations. Something along the lines of :

proliferation of centenarians x mortality plateau x nbr mutations required

The first is a recent phenomenon so the population may still be statistically insignificant and the 3rd requires many generations. It'll be interesting to see the boomer generation stress these curves but who wants to wait.