Age-Associated Splicing Events in the Integrative Longevity Omics (ILO) Cohort

TL;DR

This study explores how alternative splicing changes with age in centenarians and older adults, identifying splicing events linked to exceptional longevity.

Contribution

The study identifies age-associated splicing events in centenarians and suggests a reversal of typical aging splicing patterns.

Findings

731 significant age-associated splicing events were identified, mostly skipped exons and mutually exclusive exons.

A skipped exon in NFYC showed reversed splicing trends in centenarians compared to controls.

Centenarians deviate from normal aging splicing patterns according to residual analysis.

Abstract

Alternative splicing regulates transcript diversity and is increasingly recognized as a key mechanism in aging and age-related disease, yet little is known about how splicing contributes to human exceptional longevity. We analyzed RNA-seq data from the Integrative Longevity Omics (ILO) cohort, which includes centenarians (the oldest-old, age ≥100) and older adult controls (ages 60–89), to identify age-associated splicing events. Splicing was quantified with rMATS to estimate percent-spliced-in (PSI) values across five event categories, and quasi-binomial regression was used to model splicing changes with age. This analysis identified 731 significant age-associated events (false discovery rate < 0.05), the majority of which were mutually exclusive exons and skipped exons. A strong example is a skipped exon in Nuclear Transcription Factor Y subunit C (NFYC), a regulator of senescence-associated pathways. In controls, NFYC PSI trended downward with age, whereas in centenarians, PSI increased significantly with age, suggesting a reversal of midlife splicing trajectories. Residual analysis comparing observed PSI to predictions from a spline model of normal aging further suggests that centenarians deviate from normal aging patterns. This work describes age-associated splicing events in a population enriched for centenarians and provides preliminary evidence for a candidate splicing signature of exceptional longevity. Ongoing analyses will evaluate functional pathways and clinical relevance in independent cohorts.