Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational...

Area of Science:

• Genetics and Aging Research
• Molecular Biology
• Human Longevity Studies

Background:

• Human life expectancy has increased, but healthspan has not kept pace.
• Familial clustering of extreme longevity suggests a genetic component.
• Mechanisms of genetic protection against age-related diseases are largely unknown.

Purpose of the Study:

• To identify genetic factors contributing to familial longevity.
• To investigate the role of rare variants in longevity.
• To explore the cGAS-STING pathway's involvement in aging and survival.

Main Methods:

• Affected sib-pair linkage analysis in 212 families enriched for longevity.
• Prioritization of rare protein-altering variants in candidate longevity genes.
• Functional studies using human and mouse cell models to assess variant impact on the cGAS-STING pathway.

Main Results:

• Four significant genomic regions associated with longevity were identified.
• Twelve rare variants in seven candidate genes, including CGAS, were prioritized.
• A specific CGAS variant (rs200818241) reduced protein stability, attenuated cGAS-STING pathway activation, mitigated inflammation, and delayed cellular senescence.

Conclusions:

• Novel rare variants and candidate genes linked to familial longevity were discovered.
• The cGAS-STING pathway is implicated as a potential mechanism in human longevity.
• The identified CGAS variant may confer a survival advantage by reducing inflammation and delaying aging.