Hepatic gene body hypermethylation is a shared epigenetic signature of murine longevity

Abstract

Dietary, pharmacological and genetic interventions can extend health-and lifespan in diverse mammalian species. DNA methylation has been implicated in mediating the beneficial effects of these interventions; methylation patterns deteriorate during ageing, and this is prevented by lifespan-extending interventions. However, whether these interventions also actively shape the epigenome, and whether such epigenetic reprogramming contributes to improved health at old age, remains underexplored. We analysed published, wholegenome, BS-seq data sets from mouse liver to explore DNA methylation patterns in aged mice in response to three lifespan-extending interventions: dietary restriction (DR), reduced TOR signaling (rapamycin), and reduced growth (Ames dwarf mice). Dwarf mice show enhanced DNA hypermethylation in the body of key genes in lipid biosynthesis, cell proliferation and somatotropic signaling, which strongly correlates with the pattern of transcriptional repression. Remarkably, DR causes a similar hypermethylation in lipid biosynthesis genes, while rapamycin treatment increases methylation signatures in genes coding for growth factor and growth hormone receptors. Shared changes of DNA methylation were restricted to hypermethylated regions, and they were not merely a consequence of slowed ageing, thus suggesting an active mechanism driving their formation. By comparing the overlap in ageing-independent hypermethylated patterns between all three interventions, we identified four regions, which, independent of genetic background or gender, may serve as novel biomarkers for longevity-extending interventions. In summary, we identified gene body hypermethylation as a novel and partly conserved signature of lifespan-extending interventions in mouse, highlighting epigenetic reprogramming as a possible intervention to improve health at old age.

Sestrin is a key regulator of stem cell function and lifespan in response to dietary amino acids

“…Our results establish Sestrin as an important mediator of DR benefits; however, loss of Sestrin did not fully block the beneficial effects of DR on longevity and the combination of DR and the Sesn R407A mutation resulted in a greater extension of lifespan than each treatment individually, indicating that DR and TOR might also work via independent mechanisms. This hypothesis is consistent with recent gene expression studies in flies and mammals, which suggest both shared and independent mechanisms of DR and reduced TOR signalling [52][53][54] .…”

Hallmarks of Aging in the Liver

“…Interventions that delay aging such as CR and rapamycin also influence epigenetic changes in the liver [88]. Specifically, CR acts on lipid biosynthesis genes and rapamycin on genes coding for growth factors and growth hormone receptors [89].…”

Environment, Epigenetics, and the Pace of Human Aging

“…While BS-seq data are more flexible and applicable to a wider variety of questions compared with data produced on the microarray, sequencing data require substantially more preprocessing and a higher level of technical skill to build a working epigenetic clock model. Largely successful experimental applications of BS-seq-based models have included testing hypotheses related to aging and antiaging intervention in rodents in closely monitored laboratory conditions (see Cole et al 2017;Hahn et al 2017Hahn et al , 2018Levine et al 2020;Petkovich et al 2017;Wang et al 2017). While enforcing this level of environmental homogeneity is typically not feasible for other species, it has provided some unique insight into facets of molecular aging in the DNA methylome.…”