Genetic Determinants of Longevity Are Very Complex

It is becoming clear that genetic contributions to natural variations in longevity are highly complex. In humans the effects discovered to date are almost always very small, and are very few indeed have been replicated between study populations. This points to the relationship between genes and longevity within a species consisting of a network of modest effects, all of which interact with one another and environmental influences. Thus any specific genetic variant might have some small positive effect in one study and no effect or some small negative effect in another, and thus might be true even if the two study populations are recruited from exactly the same city, neighborhood, or well-defined ethnicity. What this suggests to me is that it will take a long time to make any headway in deciphering this web of relationships, and the result at the end of the day, after possibly decades of work, will be no great ability to extend life through genetic alteration. Knowledge will be the primary outcome, which is good for science, but not so good for us as individuals desiring to live longer lives.

Will someone one day turn up a simple human genetic alteration that has effects as impressive as some of the single gene longevity mutations in mice or lower animals? It might still happen, but I think that the odds are tiny and fading as more is discovered of the complex morass of human genes and longevity variations. It is a swamp of thousands of small effects. Like calorie restriction, which has sizable results on mouse longevity and nowhere near the same outcome for human longevity, genetic alterations known to produce large gains in short-lived mammals just don't do the same in humans. You might look at growth hormone receptor mutants: in mice they can live 60% longer. In humans, a similar population are merely somewhat resistant to diabetes and cancer, with no great signs of longevity besides that.

Here is news of research into the relationship between calorie restriction and mitochondrial gene variants that reinforces the points I make above. It is all an intricate web of relationships, with every strand individually making only a small contribution to the whole. This is not an easy path to extending life, and should not be the dominant way forward for longevity science despite the fact that the tools for working with genes are now very cheap. That would be like searching beneath the lamp, simply because it is where it the light falls. There is a lot that can be done in medicine with genetics, but I'm dubious that a fast path to rejuvenation treatments is one of them.

Interactions may matter most for longevity

If studying a single gene or a diet that might extend longevity is like searching for a fountain of youth, then a new study calls for looking at something more like the whole watershed. [Biologists] who experimentally throttled three such factors in fruit flies found that lifespan depended more on interactions among the factors than on the factors themselves. "I think the main lesson is that these interaction effects are as significant or important as the [single] effects, such as diet effects alone or genetic effect alone. Traditionally that's what people have focused on: looking for a gene that extends longevity or a diet that extends longevity."

When researchers have looked at single or even pairs of factors in a wide variety of organisms, they've made many valuable findings about the biology of aging. But sometimes scientists have been unable to replicate each other's findings in seemingly similar experiments. Often this is attributed to mysterious "background effects," presumably other genes that were not properly accounted for. The new study chose to put such background effects into the foreground to examine dietary effects on aging in several panels of different nuclear and mitochondrial genetic pairings.

G×G×E for Lifespan in Drosophila: Mitochondrial, Nuclear, and Dietary Interactions that Modify Longevity

It is widely recognized that mitochondrial function plays an important role in longevity and healthy aging. Considerable attention has been focused on the extension of longevity by caloric or dietary restriction and mutations that alter this process, and these interventions commonly are associated with shifts in mitochondrial function. While the genetic bases of these effects are the focus of much interest, relatively little effort has been directed at understanding the role that mitochondrial DNA (mtDNA) polymorphisms play in the diet restriction response.

This work presents a comprehensive effort to quantify the effects of mtDNA variants, nuclear genetic variants and dietary manipulations on longevity in Drosophila, with a focus on testing for the importance of the interactions among these factors. We found that mitochondrial genotypes can have significant effects on longevity and the diet restriction response but these effects are highly dependent on nuclear genetic (G) background and the specific diet environment (E). For example, a mitochondrial haplotype that shortens lifespan in one nuclear background or diet regime shows no such effect when the genetic background or diet regime is changed.

Our experiments indicate that identifying individual mitochondrial, nuclear or dietary effects on longevity is unlikely to provide general results without quantifying the prevalent mitochondrial × nuclear × diet (G×G×E) interactions.

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