Effect of longevity genetic variants on the molecular aging rate

Geroscience. 2021 Jun;43(3):1237-1251. doi: 10.1007/s11357-021-00376-4. Epub 2021 May 4.


We conducted a genome-wide association study of 1320 centenarians from the New England Centenarian Study (median age = 104 years) and 2899 unrelated controls using >9 M genetic variants imputed to the HRC panel of ~65,000 haplotypes. The genetic variants with the most significant associations were correlated to 4131 proteins that were profiled in the serum of a subset of 224 study participants using a SOMAscan array. The genetic associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazi Jewish descent. The proteomic associations were replicated in a proteomic scan of approximately 1000 Ashkenazi Jewish participants from a third cohort. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and under-expression of APOB in carriers of the APOE2 allele (p < 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2A/CDKN2B in chromosome 9) that suggests a genetic regulation of GDF15. The analyses showed that longevity variants correlate with proteome signatures that could be manipulated to discover healthy-aging targets.

Keywords: Extreme human longevity; Genetic variants; Molecular aging rate; SOMAscan array.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged, 80 and over
  • Aging / genetics
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Longevity* / genetics
  • Proteomics