# Select Small Non‐Coding RNAs Are Determinants of Survival in Older Adults

## TL;DR

This study finds that certain small non-coding RNAs in the blood are linked to longer survival in older adults and could be used as biomarkers or drug targets for longevity.

## Contribution

The study identifies specific piRNAs and miRNAs as novel biomarkers and potential therapeutic targets for human longevity.

## Key findings

- A predictive model using small RNAs and clinical variables achieved high accuracy in predicting 2-year survival in older adults.
- Nine piRNAs were identified as potential therapeutic targets, all reduced in individuals with longer lifespans.
- Reduced piRNA biogenesis has been experimentally linked to increased lifespan in C. elegans, supporting the biological plausibility of the findings.

## Abstract

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 Duke‐EPESE study. Our predictive model incorporating smRNAs, 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 AUCs 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.

Circulating small RNAs were profiled by RNA sequencing in a well‐characterized cohort and evaluated alongside 187 clinical variables to predict survival. Models incorporating circulating small RNAs, including parsimonious subsets, outperformed age and clinical factors alone (AUC), with causal analyses supported by experimental evidence from the literature.