Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families

Life expectancy has steadily increased in the last two centuries, while healthspan has been lagging behind. Survival into extreme ages strongly clusters within families which often exhibit a delayed onset of (multi)morbidity, yet the underlying protective genetic mechanisms are still largely undefined. We performed affected sib-pair linkage analysis in 212 sibships enriched for ancestral longevity and identified four genomic regions (LOD_max ≥3.0) at <i>1q21</i>.<i>1</i>, <i>6p24.3, 6q14.3,</i> and <i>19p13.3</i>. Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes (<i>NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2,</i> and <i>SH2D3A</i>) located in longevity-associated loci. Notably, a missense variant in <i>CGAS</i> (rs200818241), was present in two sibships. Using human- and mouse-based cell models, we showed that rs200818241 reduced protein stability and attenuated activation of the canonical cGAS-STING pathway in a cell-type specific manner. This dampened signalling mitigated inflammation and delayed cellular senescence, mechanisms that may contribute to the survival advantage of <i>CGAS</i> variant carriers. Our findings indicate novel rare variants and candidate genes linked to familial longevity and highlight the cGAS-STING pathway as a potential contributor to the protective mechanisms underlying human longevity.