Preprint reports rare IIS/mTOR pathway variants in long-lived individuals show cross-species functional signatures

A preprint posted to bioRxiv describes a targeted pathway analysis of rare genetic variants in the insulin/insulin-like growth factor 1 signalling and mechanistic target of rapamycin (IIS/mTOR) pathway, identified in exceptionally long-lived individuals and members of long-lived families.

The IIS/mTOR signalling network is one of the most consistently implicated pathways in the biology of ageing across model organisms. Using a targeted approach, the authors identified rare protein-altering variants in pathway components among study participants and characterised their functional properties in vitro. They report that the identified variants show effects in cell-based assays that are directionally consistent with lifespan-extending perturbations documented in organisms from yeast to mammals.

The findings contribute to an active area of human longevity genetics that seeks to move beyond polygenic risk scores to identify rare, high-impact variants in specific biological pathways. The authors note that exceptionally long-lived individuals and long-lived family members tend to show compression of multi-morbidity — that is, a shorter period of serious illness at the end of life — and suggest that understanding the genetics of this group could inform research into healthspan extension.

The preprint has not yet undergone peer review. Readers should note that this work is of research interest and does not constitute a basis for any individual inference about longevity.