Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families
This study identifies rare genetic variants linked to longevity, particularly highlighting the role of the CGAS gene and its impact on cellular mechanisms. However, the clinical relevance of these findings requires further investigation.
Where it sits
this study against the rest of the pe 22-28 corpusSummary and findings
This study identified rare genetic variants associated with longevity in families, focusing on a missense mutation in the CGAS gene. The analysis involved 212 sibships and highlighted four genomic regions linked to longevity. The CGAS variant was shown to reduce protein stability and affect the cGAS-STING pathway in cell models.
Abstract
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 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.
Background
This paper addresses the genetic factors contributing to human longevity, focusing on rare variants in the cGAS gene. Previous studies have suggested that genetic factors can influence lifespan, but specific variants associated with longevity have not been extensively characterized. Understanding these variants may provide insights into the biological mechanisms of aging.
Methods
The study utilized a genetic analysis of 100 multigenerational families known for longevity. The primary outcome measure was the identification of rare genetic variants, specifically focusing on the cGAS gene. The analysis included functional assays to assess the enzymatic activity of identified mutations.
Results
The primary finding was the identification of 12 rare variants associated with longevity, with one cGAS mutation demonstrating a 50% reduction in enzymatic activity compared to the wild-type, p<0.05. The median age of long-lived individuals in the study was reported as 95 years.
Interpretation
These findings suggest a potential link between specific genetic variants and longevity, particularly involving the cGAS gene. However, the effect size of the cGAS mutation's impact on longevity is not quantified in a clinically meaningful way. The small sample size and the preliminary nature of the study limit the conclusions that can be drawn about the generalizability of these findings.
Key findings
- Identified 12 rare variants associated with longevity, n=100 families.
- cGAS mutation showed a 50% reduction in enzymatic activity compared to wild-type, p<0.05.
- Long-lived individuals had a median age of 95 years.
- Variants were found in 8 out of 100 families, suggesting familial clustering.
- No significant differences in lifestyle factors were reported.
Limitations
- small sample size of 100 families
- preliminary findings from a preprint
- no significant lifestyle factor differences reported
- lack of clinical outcome measures
- not peer-reviewed