Extending Life by Manipulating Metabolism Only Produces Dramatic Results in Short-Lived Species
Permalink | View Comments (0) | Post Comment | | Posted by Reason

I'm sure that you noticed recent research results demonstrating a five-fold increase in life span in nematode worms. That's actually only half as long as the present record for that species, but both approaches involved tinkering with genes associated with insulin-like signaling, one of the better studied areas of intersection between metabolism, genetics, and aging. The press picks up on this sort of thing and uses it to wave around wild comparisons with hypothetical 500-year human life spans; wild comparisons in the headline attract attention regardless of merit, and the press is in the attention business, not the truth, sense, and accuracy business. There isn't any merit of course: one thing that is pretty clear from the data of the past couple of decades is that ways of manipulating metabolism to slow aging only have dramatic outcomes in very short-lived species.

A good example is manipulation of growth hormone metabolism, such as by removing the growth hormone gene, or interfering with gene expression of growth hormone, or by blocking or removing growth hormone receptor. In mice the best of these methods extends life by 60-70%. There is, however, an analogous natural mutation in the human growth hormone receptor that leads to Laron dwarfism. Those with the condition do not appear to live any longer than the rest of us, but may be resistant to some age-related disease. That is quite a climb-down in comparison to the results in mice.

But we can see the same sort of trend when comparing effects in worms with effects in mice: the best of the methods of slowing aging explored to date produce much greater results in nematodes, which of course normally live for a fraction of a mouse life span.

This should all make sense if considered from the perspective of evolution. Why would species evolve the ability to extend life in response to circumstances, or evolve a toolkit that allows for easier subsequent evolution of altered life span, or evolve a general adaptability of life span? The usual answer stems from consideration of the metabolic response to calorie restriction: for a short-lived species surviving a famine to reproduce later requires a great lengthening of life. For a long-lived species that survival doesn't require any lengthening of life, but it does require other types of short-term resistance to privation. So the evolutionary pressures that emerge from environmental changes that proceed on a timescale of seasons are very different for short-lived species, but they are sufficiently ubiquitous across all of evolutionary time to have very deep roots in our ancestry.

The evidence to date obtained from myriad ways of slowing aging in mice, flies, and worms suggest that we shouldn't be terribly excited by even a tenfold extension of healthy life through present genetic engineering or similar approaches when it occurs in very short-lived animals. There is no good reason at this time to expect any of these strategies to achieve results of great consequence in humans. Researchers may find therapies that improve upon present-day marginal treatments for age-related conditions, but that is about it - a very poor showing in the grand scheme of things.

The future of human life extension is very different from this work: it will be based on direct repair of damage rather than altering metabolism to slow the accumulation of damage. Aging is damage, and removing that damage should constitute a reversal of aging. However, we have at this point very little data to use to understand how damage repair will differ in its outcome between short-lived and long-lived species. It wouldn't be unreasonable to expect partial repair - such as, say, partial clearance of AGEs or replacement of mitochondrial DNA or removal of some fraction of senescent cells - to have more of an effect on mouse life span than on human life span. But more data is needed: clearly it is the case that ongoing perfect damage repair should have exactly the same effect in mice and people, the result being agelessness and indefinite healthy life span.

Comments
Post a comment; thoughtful, considered opinions are valued. Please note that comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.









Remember personal info?