Caloric restriction delays age-related methylation drift

Abstract

In mammals, caloric restriction consistently results in extended lifespan. Epigenetic information encoded by DNA methylation is tightly regulated, but shows a striking drift associated with age that includes both gains and losses of DNA methylation at various sites. Here, we report that epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans. Twenty-two to 30-year-old rhesus monkeys exposed to 30% caloric restriction since 7–14 years of age showed attenuation of age-related methylation drift compared to ad libitum-fed controls such that their blood methylation age appeared 7 years younger than their chronologic age. Even more pronounced effects were seen in 2.7–3.2-year-old mice exposed to 40% caloric restriction starting at 0.3 years of age. The effects of caloric restriction on DNA methylation were detectable across different tissues and correlated with gene expression. We propose that epigenetic drift is a determinant of lifespan in mammals.

Dietary Intervention Modifies DNA Methylation Age Assessed by the Epigenetic Clock

“…However, the changes in DNA methylation at the loci incorporated into these models are predominantly small in effect size. Furthermore, a recent study by Maegawa et al . reported that the rate of epigenetic drift is correlated with lifespan.…”

Age estimation in a long‐lived seabird (Ardenna tenuirostris) using DNA methylation‐based biomarkers

“…Improvements in bioinformatics will also help to validate DNAm markers and predict age in large data sets (Vidaki, Ballard, Aliferi, Miller, & Barron, ). The DREAM technique has been used previously to identify DNAm changes following compound exposure in zebrafish embryos (Bouwmeester et al, ) and caloric restriction in mice (Maegawa et al, ). A similar method, EpiRADSeq, also uses a methylation‐sensitive restriction enzyme ( HpaII ) and NGS to quantify DNAm in CpG sites (Schield et al, ).…”

“…Molecular biomarkers of age have recently been the focus of an increasing number of studies (Ito, Udono, Hirata, & Inoue‐Murayama, ; Maegawa et al, ; Wright et al, ). Neither telomere length nor DNA damage markers have been successfully used for chronological age estimation in a wild animal population, so there is interest in developing alternative molecular age biomarkers (Dunshea et al, ; Jarman et al, ).…”

Global remodeling of the mouse DNA methylome during aging and in response to calorie restriction

“…Many immunological and inflammation‐related pathways were also enriched, in agreement with the known increase in inflammation in late life (Lopez‐Otin et al., 2013). The most dominant pathways of genes and promoters gaining methylation during aging were developmental genes (Maegawa et al., 2017), which may indicate the decreasing expression of at least a subset of developmental genes during aging. There were also pathways in this group of promoters known to contribute to aging and lifespan‐extending interventions, such as regulation of cell response to growth factor stimulus (Lopez‐Otin et al., 2013), regulation of stem cell proliferation and differentiation (Heilbronn & Ravussin, 2003), insulin‐like growth factor and response to insulin‐related pathways (van Heemst, 2010), response to estradiol (Harrison et al., 2014), and ubiquitin‐mediated proteolysis (Ott & Grune, 2014).…”

“…Another study revealed that different sites change in response to CR in young and old mice (Hahn et al., 2017). A negative correlation was also shown between the methylation drift during aging and methylation changes following long‐term CR in mice and monkeys (Maegawa et al., 2017), and the severity and duration of CR may have influenced the resulting methylation patterns. Based on these findings, the cumulative effect of CR seems to slow down the aging pattern of the methylome and it may have a more important role for lifespan extension, compared to the transient initial shift.…”