Genetic influence on human lifespan and longevity

Abstract

There is an intense search for longevity genes in both animal models and humans. Human family studies have indicated that a modest amount of the overall variation in adult lifespan (approximately 20-30%) is accounted for by genetic factors. But it is not known if genetic factors become increasingly important for survival at the oldest ages. We study the genetic influence on human lifespan and how it varies with age using the almost extinct cohorts of Danish, Finnish and Swedish twins born between 1870 and 1910 comprising 20,502 individuals followed until 2003-2004. We first estimate mean lifespan of twins by lifespan of co-twin and then turn to the relative recurrence risk of surviving to a given age. Mean lifespan for male monozygotic (MZ) twins increases 0.39 [95% CI (0.28, 0.50)] years for every year his co-twin survives past age 60 years. This rate is significantly greater than the rate of 0.21 (0.11, 0.30) for dizygotic (DZ) males. Females and males have similar rates and these are negligible before age 60 for both MZ and DZ pairs. We moreover find that having a co-twin surviving to old ages substantially and significantly increases the chance of reaching the same old age and this chance is higher for MZ than for DZ twins. The relative recurrence risk of reaching age 92 is 4.8 (2.2, 7.5) for MZ males, which is significantly greater than the 1.8 (0.10, 3.4) for DZ males. The patterns for females and males are very similar, but with a shift of the female pattern with age that corresponds to the better female survival. Similar results arise when considering only those Nordic twins that survived past 75 years of age. The present large population based study shows genetic influence on human lifespan. While the estimated overall strength of genetic influence is compatible with previous studies, we find that genetic influences on lifespan are minimal prior to age 60 but increase thereafter. These findings provide a support for the search for genes affecting longevity in humans, especially at advanced ages.

Genomics of ageing in twins

“…In other words, one quarter of the human longevity variation is due to genetic factors. A further study based on a larger twin dataset of North European descent not only confirmed the previous results but also highlighted that the genetic influences are minimal prior to age 60 years and increase thereafter (12) . In 1994, Marenberg et al (13) studied the concordance on 10 502 Swedish twin pairs to investigate the genetic basis of coronary artery disease (CAD) and myocardial infarct mortality.…”

“…In particular, twin studies defined the genetic component of longevity (11,12) , CVD (13) , Alzheimer's disease (14) and cancer (15) as well as the influence on dietary intake (16,17) (Table 1).…”

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

“…This means that while Kuningas and colleagues focus on mortality from middle age to old age, our study investigates mortality at very advanced ages. Thus, we explore the possible significance of CNVs in individuals belonging to the age group where the genetic component of longevity has been suggested to be most profound and hence more profound that at younger ages (Hjelmborg et al ., 2006). In agreement with this, it has previously been shown that the association between the APOE ε4 risk allele and mortality increases with higher ages, even after the age of 100 (Jacobsen et al ., 2010).…”

“…Here, we explored this by analyzing the association between the CNV burden of each individual and prospective mortality, as well as between specific deletions and duplications and prospective mortality in long‐lived individuals of Danish descent (DKLS, mean age 96.9 years, range 90.0–102.5 years). The long‐lived individuals are all older than 90 years, and they thus represent the age group where the influence of genetic factors on survival is likely to be most profound (Hjelmborg et al ., 2006). Suggestive findings were replicated in a second population of long‐lived individuals from the Leiden Longevity Study (LLS, mean age 93.2 years, range 88.9–103.4 years), and, in addition, a joint analysis of these findings was performed.…”

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…The understanding that the genetic contribution to lifespan strongly increases with greater age provides basis for research on which genetic differences distinguish centenarians from average‐lived individuals (Herskind et al ., 1996; Hjelmborg et al ., 2006; Murabito et al ., 2012; Sebastiani & Perls, 2012; Brooks‐Wilson, 2013). Accordingly, longevity clusters within families as parents and siblings of centenarians present an increased probability of reaching advanced age (Perls et al ., 2000, 2002; Atzmon et al ., 2004; Willcox et al ., 2006).…”