Looking Back at the Discovery of a Genetic Pathway of Longevity

It is sometimes easy to forget just how recently the more important discoveries in the genetics of longevity occurred. The concept that aging is very plastic, regulated by metabolic signaling pathways, sped and slowed by environmental circumstances, and considerably slowed by specific mutations in a few genes, has only really taken hold over the past fifteen years. This is a time of great change in the science of aging, even if progress seems glacial to those of us waiting on the practical applications of research: enhanced human longevity.

Today I'll point out a look back at the discovery of the importance of the insulin / insulin-like growth factor-1 (IGF-1) pathway in the regulation of aging. If you have an interest in how the mainstream of aging research moves forward behind the scenes, you should find this an entertaining read.

The first long-lived mutants: discovery of the insulin/IGF-1 pathway for ageing

This article describes the discovery of a genetic pathway that regulates ageing. In spite of the fascinating qualities of the ageing process, such as its remarkably different pace in different species, until the last few decades ageing was not thought to be subject to any active regulation. Now we know that the rate of ageing is indeed subject to regulation, by classical signalling pathways. These pathways link the ageing rate to environmental and physiological cues, and may even underlie its diversification during evolution. At the heart of these pathways are stress and metabolic sensors such as insulin and IGF-1 hormones

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At the time, ageing was generally thought to be a hopelessly intractable, even futile, problem to study. We just wear out; that's it. Fortunately, because of my experience I had come to expect that biological phenomena that seemed to happen haphazardly might well turn out to be controlled by the genes. ... Not only was ageing thought to be merely a passive, entropic process, evolutionary biologists had argued forcefully that ageing could not be regulated. For example, they felt that mechanisms for regulating ageing would have no way to evolve, as ageing takes place after reproduction. These theories were thought provoking, but to my mind, they had the effect of discouraging searches for regulatory genes. It seemed to me, a molecular geneticist from the outside, that one should keep an open mind and just have a look. So I saw the analysis of ageing as a fantastic opportunity to explore the unknown and perhaps discover something new and important.

It is an interesting account, all told. But the more things change, the more they stay the same: the "aging is plastic and regulated" camp back then were the heretics in the research community. Now that they have overturned the old guard and are at the head of the field, from the point of view of the success of their theories and supporting evidence, they have become the new old guard. They are focused on metabolic alteration and slowing aging as the only viable path forward: from their point of view it is self-evident that since aging is regulated, we must change the regulation, and since it is a matter of regulation, all we can do is slow things down.

The new heretics are people like Aubrey de Grey and other folk who advocate that (a) gerontologists should stop denying the moral imperative to work towards therapies for aging, and act more like the cancer research community and less like people who look but don't touch, and (b) repair-based approaches to engineered longevity are far superior: capable of reversing aging and helping people who are already old, and also easier to develop based on our present state of knowledge.

It is in all our interests for the new heretics to overturn the dominance of metabolic manipulation and for their repair-based approach to ascend to the head of the field as soon as possible. It's the only way we're likely to see radical extension of the healthy human life span within our lifetimes, and it's the only way we're going to see our frailties and ill-health reversed by rejuvenation medicine when we are old.

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