Abstract
Neither genetic nor environmental factors fully account for variability in individual longevity: genetically identical invertebrates in homogenous environments often experience no less variability in lifespan than outbred human populations. Such variability is often assumed to result from stochasticity in damage accumulation over time; however, the identification of early-life gene expression states that predict future longevity would suggest that lifespan is least in part epigenetically determined. Such “biomarkers of aging,” genetic or otherwise, nevertheless remain rare. In this work, we sought early-life differences in organismal robustness in unperturbed individuals and examined the utility of microRNAs, known regulators of lifespan, development, and robustness, as aging biomarkers. We quantitatively examined Caenorhabditis elegans reared individually in a novel apparatus and observed throughout their lives. Early-to-mid–adulthood measures of homeostatic ability jointly predict 62% of longevity variability. Though correlated, markers of growth/muscle maintenance and of metabolic by-products (“age pigments”) report independently on lifespan, suggesting that graceful aging is not a single process. We further identified three microRNAs in which early-adulthood expression patterns individually predict up to 47% of lifespan differences. Though expression of each increases throughout this time, mir-71 and mir-246 correlate with lifespan, while mir-239 anti-correlates. Two of these three microRNA “biomarkers of aging” act upstream in insulin/IGF-1–like signaling (IIS) and other known longevity pathways, thus we infer that these microRNAs not only report on but also likely determine longevity. Thus, fluctuations in early-life IIS, due to variation in these microRNAs and from other causes, may determine individual lifespan.
Highlights
Inter-individual variation in human longevity has not been found to be under substantial genetic control, with heritability generally between 15% and 30% [1,2]
Lipofuscin accumulation correlates with the qualitative movement classes defined in Herndon et al [19], though such accumulation has not been directly shown to predict an individual’s future longevity, and in one recent work was not found be predictive of longevity [20]. (This last observation was made of greenwavelength autofluorescence, which is more specific for flavin compounds, while lipofuscin per se fluoresces most strongly in blue wavelengths [19,21].) Lastly, animals that reach their final adult size more rapidly have shorter lifespans [14]
Using fluorescent markers to examine the level of activation of several genes, we found three regulatory microRNA genes that vary in activity between individuals in a manner that predicts future lifespan
Summary
Inter-individual variation in human longevity has not been found to be under substantial genetic control, with heritability generally between 15% and 30% [1,2]. The identification of ‘‘biomarkers of longevity’’ – measurable parameters that predict individual longevity better than chronological age [9] – will help pinpoint genetic and physiological processes that promote or defer senescent decline. Such biomarkers may help clarify whether lifespan differences are the result of variable accumulation of damage over time, or whether they may result from gene-regulatory states, potentially set early in life, that determine individual robustness [10].
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