Evolution produces species that exhibit stochastic metabolic variation from individual to individual. Any species or subpopulation of a given species lacking this individual variation might be more successful in a specific ecological niche, but would vanish due to competition the moment that niche changed in any way. And change is a feature of the world we live in. Given a long enough time scale, everything shifts in character. The species we see today are the descendants of the survivors of change, that survival enabled by individual metabolic variation within the species.
This adds to the growing list of complexities faced by any group attempting to find ways to adjust metabolism in order to slow aging. What works in one person may not work in the same way, or anywhere near as well, in another. We can see how this will likely turn out in the long run by looking at the past few decades of preventative clinical practice in cardiovascular disease. Individual variation in cholesterol metabolism has complicated attempts to reduce cardiovascular disease by lowering circulating LDL cholesterol. People exhibit a high degree of variance in the relationship between LDL cholesterol, other circulating atherogenic factors such as Lp(a), the pace at which atherosclerotic plaque grows in blood vessels with age, and the structure of that plaque. Most people presenting with a first heart attack or stroke do not have elevated LDL cholesterol, and it seems likely that only a subset of the population is benefiting meaningfully from LDL lowering drugs.
Today’s open access paper notes that one can take a set of genetically identical nematode worms, raise them in identical ways, and still find that this population naturally produces stochastic differences in metabolism during development. These differences then affect the degree to which age-slowing interventions that attempt to alter metabolism into a more favorable state actually manage to achieve a slowing of aging.
Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using RNAseq analysis of young, isogenic, subpopulations of Caenorhabditis elegans selected solely on the basis of the splicing pattern of an in vivo minigene reporter that is predictive of future life expectancy, we find a strong correlation in young animals between predicted life span and alternative splicing of messenger RNAs related to lipid metabolism.
The activity of two RNA splicing factors, Reversed Polarity-1 (REPO-1) and Splicing Factor 1 (SFA-1), early in life is necessary for C. elegans response to specific longevity interventions and leads to context-specific changes to fat content that is mirrored by knockdown of their direct target POD-2/ACC1. Moreover, POD-2/ACC1 is required for the same longevity interventions as REPO-1/SFA-1. In addition, early inhibition of REPO-1 renders animals refractory to late onset suppression of the TORC1 pathway. Together, we propose that splicing factor activity establishes a cellular landscape early in life that enables responsiveness to specific longevity interventions and may explain variance in efficacy between individuals.
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