Circulating Piwi-Interacting RNA Levels Correlate with Survival in Old People
Researchers here report an association between late life survival and levels of specific piwi-interacting RNAs. This subcategory of non-coding RNAs, meaning RNA molecules that are not translated into proteins, has attracted more interest of late in the context of aging and age-related changes to the regulation of gene expression. The understanding of the role of non-coding RNAs in metabolism lags behind the still incomplete understanding of proteins. The life science community is slowly filling in an enormous map of interactions, a map that will contain many large dark areas for a long time yet. There are only so many researchers, and developing a reasonably complete understanding of how even a single protein or RNA contributes to cell metabolism requires years of work in the best of circumstances.
To investigate the relevance of small RNAs to human longevity, we pursued three goals: (a) to validate epigenetic (small RNA) factors underlying survival of older adults, (b) to develop and validate prediction models of survival for potential clinical application, and (c) to identify plausible druggable targets prolonging longevity. We evaluated 828 small non-coding RNAs - 687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs) - in baseline plasma from 1271 community-dwelling older adults (≥ 71 years) in the EPESE study. Our predictive model incorporating small RNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions) and age achieved strong performance, with cross-validated area under the curve (AUC) values of 0.92 for 2-year survival in Discovery and 0.87 in external Validation.
Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets. Under the assumption of causal sufficiency, these data provide causal evidence linking circulating small RNAs with survival outcomes in humans. While such inference does not replace experimental validation, it complements mechanistic studies by identifying candidate molecular drivers most relevant to human longevity. Supporting biological plausibility, reduced piRNA biogenesis has been shown to double lifespan in C elegans. Together, our findings identify circulating piRNAs and miRNAs as promising biomarkers and potential therapeutic targets to advance human longevity.