In general, the observed modest effect sizes of the significant variants suggest many genes of small influence play a role in exceptional longevity, which is consistent with results for other polygenic traits. Our results also suggest that genes related to cardiovascular health may be implicated in exceptional longevity. Future studies should examine the roles of gender and ethnicity and carefully consider study design, including the selection of appropriate controls.

Studies investigating exceptionally long-lived (ELL) individuals, including genetic studies, have linked cardiovascular-related pathways, particularly lipid and cholesterol homeostasis, with longevity. This study explored the genetic profiles of ELL individuals (cases: n = 294, 95–106 years; controls: n = 1105, 55–65 years) by assessing their polygenic risk scores (PRS) based on a genome wide association study (GWAS) threshold of p < 5 × 10−5. PRS were constructed using GWAS summary data from two exceptional longevity (EL) analyses and eight cardiovascular-related risk factors (lipids) and disease (myocardial infarction, coronary artery disease, stroke) analyses. A higher genetic risk for exceptional longevity (EL) was significantly associated with longevity in our sample (odds ratio (OR) = 1.19–1.20, p = 0.00804 and 0.00758, respectively). Two cardiovascular health PRS were nominally significant with longevity (HDL cholesterol, triglycerides), with higher PRS associated with EL, but these relationships did not survive correction for multiple testing. In conclusion, ELL individuals did not have significantly lower polygenic risk for the majority of the investigated cardiovascular health traits. Future work in larger cohorts is required to further explore the role of cardiovascular-related genetic variants in EL.

Healthy metabolic measures in humans are associated with longevity. Dysregulation leads to metabolic syndrome (MetS) and negative health outcomes. Recent exceptional longevity (EL) genome wide association studies have facilitated estimation of an individual’s polygenic risk score (PRS) for EL. We tested the hypothesis that individuals with high ELPRS have a low prevalence of MetS. Participants were from five cohorts of middle-aged to older adults. The primary analyses were performed in the UK Biobank (UKBB) (n = 407,800, 40–69 years). Replication analyses were undertaken using three Australian studies: Hunter Community Study (n = 2122, 55–85 years), Older Australian Twins Study (n = 539, 65–90 years) and Sydney Memory and Ageing Study (n = 925, 70–90 years), as well as the Swedish Gothenburg H70 Birth Cohort Studies (n = 2273, 70–93 years). MetS was defined using established criteria. Regressions and meta-analyses were performed with the ELPRS and MetS and its components. Generally, MetS prevalence (22–30%) was higher in the older cohorts. In the UKBB, high EL polygenic risk was associated with lower MetS prevalence (OR = 0.94, p = 1.84 × 10–42) and its components (p < 2.30 × 10–8). Meta-analyses of the replication cohorts showed nominal associations with MetS (p = 0.028) and 3 MetS components (p < 0.05). This work suggests individuals with a high polygenic risk for EL have a healthy metabolic profile promoting longevity.