That genetic variation appears to determine little of the variation in life expectancy for the vast majority of people is perhaps the most useful information yet to emerge from the creation of very large databases of genetic and health information, such as the UK Biobank. That this is the case doesn't rule out the existence of rare beneficial mutations with relatively large effects on life expectancy, however. See, for example, the PAI1 loss of function mutants who appear to live seven years longer than near relatives - though one should be wary of small sample sizes when it comes to determining the size of the effect in these circumstances.
In today's open access paper, researchers report on their identification of a rare mutation in cGAS, an important determinant of age-related chronic inflammation. When nuclear DNA or mitochondrial DNA is mislocalized in the cell as a result of age-related damage and dysfunction, cGAS is a part of the maladaptive process by which the STING pathway is triggered to produce an inflammatory response. This pathway evolved to defend against infectious pathogens, so one can't just turn off cGAS-STING signaling because it is essential to normal immune function and health. Too much of it is a bad thing, however, and important in degenerative aging. This newly discovered mutation appears to split the difference, resulting in greater longevity without evidently impaired function.
One might compare this discovery with recent work in the comparative biology of aging, where cGAS and STING are shown to be less inflammatory in response to the molecular damage of aging in long-lived species. For example, researchers have engineered mice to express the less inflammatory naked mole-rat cGAS, and this has the outcome of reducing age-related inflammation to slow degenerative aging. Similarly, another research group engineered mice to expresss the STING gene from bats, which also produced a beneficial reduction in age-related inflammation.
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 at 1q21.1, 6p24.3, 6q14.3, and 19p13.3. Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes (NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2, and SH2D3A) located in longevity-associated loci.
Notably, a missense variant in CGAS (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 CGAS 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.
View the full article at FightAging
