The genetic contribution to the variation in human lifespan is ∼25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10⁻⁸). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10⁻³⁶), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

Summary: Genetic variation in FOXO3A has previously been associated with human longevity. Studies published so far have been case–control studies and hence vulnerable to bias introduced by cohort effects. In this study we extended the previous findings in the cohorts of oldest old Danes (the Danish 1905 cohort, N = 1089) and middle‐aged Danes (N = 736), applying a longitudinal study design as well as the case–control study design. Fifteen SNPs were chosen in order to cover the known common variation in FOXO3A. Comparing SNP frequencies in the oldest old with middle‐aged individuals, we found association (after correction for multiple testing) of eight SNPs; 4 (rs13217795, rs2764264, rs479744, and rs9400239) previously reported to be associated with longevity and four novel SNPs (rs12206094, rs13220810, rs7762395, and rs9486902 (corrected P‐values 0.001–0.044). Moreover, we found association of the haplotypes TAC and CAC of rs9486902, rs10499051, and rs12206094 (corrected P‐values: 0.01–0.03) with longevity. Finally, we here present data applying a longitudinal study design; when using follow‐up survival data on the oldest old in a longitudinal analysis, we found no SNPs to remain significant after the correction for multiple testing (Bonferroni correction). Hence, our results support and extent the proposed role of FOXO3A as a candidate longevity gene for survival from younger ages to old age, yet not during old age.

Summary: Telomerase is of key importance for telomere maintenance, and variants of the genes encoding its major subunits, telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), are candidates for interindividual variation in telomere length. Recently, the two SNPs rs3772190 and rs12696304 in the TERC locus were reported to be associated with leukocyte telomere length (LTL) in two genome‐wide association studies, while one haplotype of TERT (rs2853669, rs2736098, rs33954691, and rs2853691) has been reported to be associated with both LTL and longevity in a candidate gene study. In this study, we investigated the two TERC and four TERT SNPs in middle‐aged, old, and oldest‐old Danes (58–100 years) and their association with LTL (n = 864) and longevity (n = 1069). Furthermore, data on 11 TERT tagging SNPs in 1089 oldest‐old and 736 middle‐aged Danes were investigated with respect to longevity. For all SNPs, the association with longevity was investigated using both a cross‐sectional and a longitudinal approach. Applying an additive model, we found association of LTL with the minor TERC alleles of rs3772190 (A) and rs12696304 (G), such that a shorter LTL was seen in rs3772190 A carriers (regression coefficient = −0.08, P = 0.011) and in male rs12696304 G carriers (regression coefficient = −0.13, P = 0.014). No TERT variations showed association. Moreover, the A allele of rs3772190 (TERC) was found to be associated with longevity [hazard rate (AG + AA) = 1.31, P = 0.006]. No associations with longevity were observed for the TERT SNPs or haplotypes. Our study, thus, indicates that TERC is associated with both LTL and longevity in humans.

Oxidative stress is both the cause and consequence of impaired functional homeostasis characterizing human aging. The worsening efficiency of stress response with age represents a health risk and leads to the onset and accrual of major age-related diseases. In contrast, centenarians seem to have evolved conservative stress response mechanisms, probably derived from a combination of a diet rich in natural antioxidants, an active lifestyle and a favorable genetic background, particularly rich in genetic variants able to counteract the stress overload at the level of both nuclear and mitochondrial DNA. The integration of these factors could allow centenarians to maintain moderate levels of free radicals that exert beneficial signaling and modulator effects on cellular metabolism. Considering the hot debate on the efficacy of antioxidant supplementation in promoting healthy aging, in this review we gathered the existing information regarding genetic variability and lifestyle factors which potentially modulate the stress response at old age. Evidence reported here suggests that the integration of lifestyle factors (moderate physical activity and healthy nutrition) and genetic background could shift the balance in favor of the antioxidant cellular machinery by activating appropriate defense mechanisms in response to exceeding external and internal stress levels, and thus possibly achieving the prospect of living a longer life.