Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring

Abstract

The role of epigenetics in the modulation of longevity has not been studied in humans. To this aim, (1) we evaluated the DNA methylation from peripheral leukocytes of 21 female centenarians, their 21 female offspring, 21 offspring of both non-long-lived parents, and 21 young women through ELISA assay, pyrosequencing analysis of Alu sequences, and quantification of methylation in CpG repeats outside CpG AGE (2013) 35:1961-1973 DOI 10.1007 islands; (2) we compared the DNA methylation profiles of these populations through Infinium array for genome-wide CpG methylation analysis. We observed an age-related decrease in global DNA methylation and a delay of this process in centenarians' offspring. Interestingly, literature data suggest a link between the loss of DNA methylation observed during aging and the development of age-associated diseases. Genomewide methylation analysis evidenced DNA methylation profiles specific for aging and longevity: (1) aging-associated DNA hypermethylation occurs predominantly in genes involved in the development of anatomical structures, organs, and multicellular organisms and in the regulation of transcription; (2) genes involved in nucleotide biosynthesis, metabolism, and control of signal transmission are differently methylated between centenarians' offspring and offspring of both non-long-lived parents, hypothesizing a role for these genes in human longevity. Our results suggest that a better preservation of DNA methylation status, a slower cell growing/metabolism, and a better control in signal transmission through epigenetic mechanisms may be involved in the process of human longevity. These data fit well with the observations related to the beneficial effects of mild hypothyroidism and insulinlike growth factor I system impairment on the modulation of human lifespan.

DNA methylation and healthy human aging

“…They differ in two major ways: (i) the rate of change is much higher in early life than later life, and (ii) the genomic locations of the changes are quite different. In early life, DNA methylation is gained globally, but more at island shores and intergenic regions, while in later life, DNA methylation is lost globally, but still gained at islands and shores (Alisch et al ., 2012; Gentilini et al ., 2013; McClay et al ., 2014). …”

“…However, some individuals would likely be in the ‘off‐diagonal’ region of this comparison, with an epigenetic age that is higher (‘epigenetically old’) or lower (‘epigenetically young’) than their chronological age. This trend has already been observed using the age predictors described in many of the studies described in Table 1, one study in particular found that centenarians had an unusually young epigenetic age (Gentilini et al ., 2013). An intriguing possibility is to predict health outcomes for those in the epigenetically old or epigenetically young groups relative to those who display concordant epigenetic and chronological ages, supported by a very recent study which associated accelerated epigenetic age with increased mortality (Marioni et al ., 2015) (Fig.…”

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

“…In the human aging process, alterations of DNA methylation indicate a loss of epigenetic control and relate to pathological phenotypes [2,3]. Today, epigenome-wide association studies (EWAS) have established general knowledge on age-related methylation patterns in humans [4-8].…”

Distinctive topology of age-associated epigenetic drift in the human interactome

“…However, such human longevity-associated genes (LAGs) seem to be very rare, and although a few have been confirmed in independent studies (2,3), their existence remains controversial. More recently, epigenetic changes associated with human longevity have also been documented (7).…”