Select Small Non-Coding RNAs Are Determinants of Survival in Older Adults.

A predictive model incorporating small RNAs, clinical variables, and age achieved strong performance for 2-year survival prediction in older adults.

• Cross-validated AUC of 0.92 for 2-year survival in the Discovery cohort
• Cross-validated AUC of 0.87 for 2-year survival in the external Validation cohort
• Model incorporated smRNAs, clinical variables (demographics, lifestyle, mood, physical function, standard clinical laboratory tests, NMR-derived lipids and metabolites, and medical conditions), and age
• Study population consisted of 1271 community-dwelling older adults aged ≥71 years from the Duke-EPESE study

Nine piRNAs, all reduced in longer-lived individuals, were identified as potential therapeutic targets for prolonging longevity.

• All nine identified piRNAs were reduced in longer-lived individuals
• These piRNAs were identified as potential druggable targets
• Findings were derived from evaluation of 828 small non-coding RNAs in baseline plasma samples
• The 828 small RNAs included 687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs)

The study evaluated 828 small non-coding RNAs in baseline plasma from community-dwelling older adults.

• 687 microRNAs (miRNAs) and 141 piwi-interacting RNAs (piRNAs) were evaluated
• Samples were drawn from 1271 community-dwelling older adults aged ≥71 years
• Samples were baseline plasma from the Duke-EPESE study
• Both a Discovery cohort and an external Validation cohort were used

Under the assumption of causal sufficiency, the data provide causal evidence linking circulating small RNAs with survival outcomes in humans.

• Authors note this causal inference does not replace experimental validation but complements mechanistic studies
• The findings identify candidate molecular drivers most relevant to human longevity
• Causal sufficiency was a stated assumption underlying this inference

Reduced piRNA biogenesis has been shown to double lifespan in C. elegans, supporting biological plausibility of the human findings.

• This finding in C. elegans is cited as supporting biological plausibility for the role of piRNAs in longevity
• The direction of effect in C. elegans (reduced piRNA biogenesis extending lifespan) is consistent with the human finding that piRNAs are reduced in longer-lived individuals
• This cross-species evidence is presented as corroborating the clinical findings

Circulating piRNAs and miRNAs were identified as promising biomarkers and potential therapeutic targets to advance human longevity.

• Three goals were pursued: validating epigenetic (small RNA) factors underlying survival, developing and validating prediction models, and identifying plausible druggable targets
• Both piRNAs and miRNAs were implicated as relevant to survival outcomes
• The study population was community-dwelling older adults, supporting potential clinical application of these biomarkers