Abstract
The heritability of lifespan is 20-30%, but only a few genes associated with longevity have been identified. To explain this discrepancy, the inheritance of epigenetic features, such as DNA methylation, have been proposed to contribute to the heritability of lifespan.We investigated whether parental lifespan is associated with DNA methylation profile in nonagenarians. A regression model, adjusted for differences in blood cell proportions, identified 659 CpG sites where the level of methylation was associated with paternal lifespan. However, no association was observed between maternal lifespan and DNA methylation. The 659 CpG sites associated with paternal lifespan were enriched outside of CpG islands and were located in genes associated with development and morphogenesis, as well as cell signaling. The largest difference in the level of methylation between the progeny of the shortest-lived and longest-lived fathers was identified for CpG sites mapping to CXXC5. In addition, the level of methylation in three Notch-genes (NOTCH1, NOTCH3 and NOTCH4) was also associated with paternal lifespan.There are implications for the inheritance of acquired traits via epigenetic mechanisms in mammals. Here we describe DNA methylation features that are associated with paternal lifespan, and we speculate that the identified CpG sites may represent intergenerational epigenetic inheritance.
Highlights
The heritability of lifespan has been estimated to be approximately 20-30%, and it has been shown to increase with advancing age
We found that methylation sites that were associated with paternal lifespan were enriched in genes associated with development and morphogenesis
We show that length of paternal lifespan is associated with progeny DNA methylation profiles and that this effect can be identified in nonagenarians
Summary
The heritability of lifespan (age at death) has been estimated to be approximately 20-30%, and it has been shown to increase with advancing age. Healthy aging is heritable, and the offspring of long-lived parents show delayed onset of aging-associated diseases [1, 2, 3, 4]. Much of the research studying the heritability of lifespan has focused on extreme age (nonagenarians, centenarians, supercentenarians), but recently it has been shown that every decade of parental age after the age of 65 reduces the mortality and incidence of cancer of their offspring [5]. Even though the heritability of the lifespan is acknowledged, only one genomic locus (on chromosome 3) and a few genetic variants, such as in APOE and FOXO3, have consistently been shown to be associated with longevity. In addition to disease susceptibility alleles, rare genetic variants and environment-genome interactions, epigenetic mechanisms such as DNA methylation may be mediating the heritability of lifespan
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