Some Longevity Mutations Require Civilization and Technology

Loss of the p66(Shc) gene is a canonical example of the rampant complexity of metabolism when it comes to determinants of longevity. If you look back in the Fight Aging! archives, you'll see what I mean: years of work on p66(Shc) mutant mice that piles higher with each new paper, an accumulation of mechanisms, alterations, chains of cause and effect, altered feedback loops, and so forth - all spawned from knocking out this one gene.

It is the height of optimistic hubris to suppose that we'll be safely tinkering with human metabolism in the same way any time soon - which is one of the reasons why efforts to merely slow aging are the slow boat to China. The fast path is to work on ways to repair our existing metabolism; don't change it, just find methods to put it back the way it was when we were young. A great deal more is known about how to go about reversing aging than is known about how to slow aging.

But I digress, as I really did want to talk about p66(Shc). In addition to being a poster child for the complexities of metabolism and genetic determinants of longevity, this gene also turns out to be a good example to draw upon when explaining why it is that there are so many small genetic tweaks capable of extending life in mice. Why didn't evolution select for these small modifications in the first place? See this paper for a starting point:

Deletion of the p66(Shc) gene results in lean and healthy mice, retards aging and protects from aging-associated diseases, raising the question of why p66(Shc) has been selected, and what is its physiological role. We have investigated survival and reproduction of p66(Shc) -/- mice in a population living in a large outdoor enclosure for a year, subjected to food competition and exposed to winter temperatures. Under these conditions deletion of p66(Shc) was strongly counterselected. Laboratory studies revealed that p66(Shc) -/- mice have defects in fat accumulation, thermoregulation and reproduction, suggesting that p66(Shc) has been evolutionarily selected because of its role in energy metabolism. These findings imply that the health impact of targeting aging genes might depend on the specific energetic niche and caution should be exercised against premature conclusions regarding gene functions that have only been observed in protected laboratory conditions.

So in other words, lack of p66(Shc) only extends life and causes the mutants to prosper as individuals if they have the benefits of civilization and technology: secure food supplies, secure heating, protection from the elements, and so forth. If shoved out into the uncaring world, they fare poorly - and would soon enough vanish as a genetic line, out-competed by animals with shorter life spans but a better adapted metabolism. We might expect to see similar results for the range of other longevity genes discovered in small mammals: if there was an evolutionary benefit to their selection for animals in the wild, then we should expect that these longevity mutations would already have been selected.

Is this result anything other than just interesting for those of us following along at home? Well, it might help to further inform out thinking as to the odds of significant human longevity mutations - which I suspect are low, by the way, though I do think there will be many minor longevity genes found in humans, with very limited effects. We are already unusually long-lived for primates, and primates are long-lived in comparison to other similarly sized mammals, and that seems to have squeezed down the range of life span differences that can be created through metabolic tinkering - or at least this is currently the consensus based on what is known of the effects of calorie restriction on metabolism and health in humans.


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