SIRT6 Variants Found in Centenarians Produce a Lower Burden of Cellular Senescence
The point of studying the biochemistry of very long-lived humans is to try to better understand which of the many underlying mechanisms of damage and dysfunction that drive degenerative aging are the most important and thus should be prioritized for the development of therapies. One can look at the differences in the sequences of proteins, expression of proteins, and the operation of metabolism and try to infer why those differences tend to exist more often in long-lived individuals, try to make a link to a known form of damage. The point is not to to try to emulate the specific biochemistry of long-lived individuals: all that will happen as a result of that is a modest decrease in pace of aging, while one will still wind up frail, greatly impacted by degeneration, and with a very high mortality rate. It is a small gain. We would like to engineer larger gains.
In today's open access paper, researchers find that SIRT6 variants that are more common in centenarians are protective because they reduce the burden of senescent cells in aged tissues. The response to that finding should be to ramp up development of more and better senotherapeutic research programs with the goal of selectively removing senescent cells from the aging body on an ongoing basis, or at the very least halting the harmful signaling that is the primary mechanism by which lingering senescent cells are disruptive to structure and function in surrounding tissues. The response should not be to deliver better versions of SIRT6 into patients via gene therapy, as this will be far less beneficial.
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.