Fight Aging!

Calorie restriction, reducing the intake of calories while maintaining an optimal intake of micronutrients, slows aging in near all species and lineages tested to date. The effects are much larger in short-lived species, however, despite short-term health benefits observed in calorie restricted humans in studies conducted over the past decade. Protein restriction, in which only dietary protein (or just one type of protein, usually methionine) is reduced, produces similar results to overall calorie restriction. The precise balance of low-level mechanisms involved is somewhat different, however, judging by evaluation of epigenetic and gene expression changes. In the open access paper noted here, researchers investigate some of the metabolic changes brought on by protein restriction in early life in flies, finding once more that the outcomes are similar to calorie restriction or lifelong protein restriction, but the fine details of how those outcomes are achieved are different. Metabolism is complex.

There is now substantial evidence from human and rodent studies that early-life nutrition can have a long-term effect (often termed nutritional programming) upon the risks of coronary heart disease, stroke, hypertension, obesity, type 2 diabetes and osteoporosis during adulthood. Similarly, developmental nutrition has been shown to regulate lifespan, increasing or decreasing it depending upon the particular dietary alteration and when it was experienced. For example, a maternal low protein diet during suckling increases the longevity of male mice.

Drosophila has proved a useful genetic and physiological model for studying nutrition, growth, and metabolism. Developmental nutrition is known to influence several aspects of adult metabolism in Drosophila. Lifespan in Drosophila and in other species can be extended by dietary restriction (DR) during adulthood. In contrast to studies of adult diet, much less is known about how developmental diet regulates Drosophila lifespan. Depriving larvae of dietary yeast, the major protein source, during only the last (third) instar is known to produce adults with a small body size without significantly altering lifespan. It has also been reported that diet or yeast dilution throughout larval development can lead respectively to minor (~7%) or moderate (~25%) increases in lifespan. Hence, there is some evidence that developmental dietary history influences Drosophila lifespan but the regimes tested thus far have only generated modest effects and the underlying mechanisms have not yet been identified.

This study shows that dietary yeast restriction during Drosophila development can induce long-term changes in adult triglyceride storage, xenobiotic resistance, and lifespan. It can also extend lifespan even when adults are switched to a high yeast diet. In contrast, longevity obtained via adult-onset dietary restriction (DR) is largely reversible upon switching to a non-restricted diet. Developmental-diet induced extensions of median lifespan can be as large or larger than those observed with adult DR but this depends strongly upon the adult environment. We found that yeast restricted males reproducibly lived longer than controls, with median lifespan increases ranging from 20% up to a striking 145%, varying with adult diet. Hence, it is the combination of developmental and adult environments that determines survival outcomes, not one or the other.

We explored the possibility that flies themselves might condition the environment with endogenously produced substances detrimental to survival (hereafter called autotoxins). A differential production and/or response to these autotoxins could then contribute to lifespan regulation by developmental diet. A major finding of this study is that male and female flies condition their environment with alkene autotoxins that decrease the survival of both adult sexes. Developmental yeast restriction influences adult oenocytes to synthesise a hydrocarbon blend that contains a lower proportion of alkene autotoxins. In turn, this promotes increased longevity in many adult environments but not those where lifespan is limited by other toxic factors, such as paraquat or a high glucose-to-yeast ratio diet.

Alkenes appear to have a selective mechanism-of-action as physiological amounts of tricosene kill adult flies but not larvae. Their influence upon Drosophila adults is far-reaching and affects not only how survival is regulated by developmental dietary history but also by population density, sex, and insulin signalling. This has important implications for laboratory lifespan studies, with our results suggesting that the autotoxin contribution can be teased apart from other mechanisms by measuring survival curves on a case-by-case basis. During evolution, the selective advantages conferred by alkenes as sex pheromones, barrier lipids, and/or mediators of other beneficial activities are likely to have outweighed any disadvantages due to decreased longevity.

It is surprising that a major class of Drosophila autotoxins corresponds to lipids on the body surface, some of which are known to act as sex pheromones. This link is also emerging in Caenorhabditis elegans, where recent work shows that male pheromone contains ascaroside lipids that mediate the density-dependent mortality of grouped males and that shorten the survival of both sexes. Future studies will be needed to determine whether physiological amounts of skin-derived lipids can influence longevity in mammals, as they do in Drosophila.

Link: https://doi.org/10.1038/s41467-017-01740-9