Centenarian SIRT6 variants elevate SIRT6 protein and enhance cellular senescence resistance

Centenarians represent a natural model of delayed human aging, offering a unique opportunity to uncover genetic mechanisms that promote longevity. However, the functional consequences of the genetics variants carried by these long-lived individuals remain poorly characterized in physiologically relevant systems. Here, we introduced two linked missense variants in SIRT6 enriched in Ashkenazi Jewish centenarians into the endogenous SIRT6 locus of human embryonic stem cells and differentiated them into somatic lineages to define their effects in a native genomic context. We revealed that centenarian variants elevated endogenous SIRT6 protein abundance through weakened interaction with vimentin, and altered endogenous SIRT6 enzymatic activities, including enhanced mono-ADP-ribosyltransferase activity and reduced deacetylase activity. Functionally, these variants delayed replicative senescence and conferred resistance to progerin-induced stress, accompanied by preservation of DNA repair gene expression programs and suppression of transposable element derepression. Guided by these findings, we evaluated the translational potential of both genetic and pharmacological interventions, demonstrating that adeno-associated virus (AAV)-mediated delivery of centenarian SIRT6 or pharmacological activation of SIRT6 using fucoidan from Fucus vesiculosus (Fucoidan-FV) partially attenuated aging-associated molecular defects, including genome instability and LINE1 derepression, in progeria fibroblasts. Together, these findings demonstrate that centenarian variants exert multifaceted effects on SIRT6 function to enhance cellular stress resistance, and providing a framework for translating genetic discoveries from long-lived individuals into mechanistic insight and potential gerotherapeutic strategies for healthy aging.