Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment

Abstract

BackgroundGlobal but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans.ResultsWe first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls.ConclusionsThis study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1186-2) contains supplementary material, which is available to authorized users.

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

“…Previous studies revealed increased entropy in human DNA methylation (Hannum et al., 2013) and in mouse livers aged 0.2 to 7.1 months old (Wang et al., 2017). We were able to examine changes in entropy across the whole mouse and human lifespan at a high resolution.…”

“…Previous mouse studies revealed age‐related changes in promoters and increasing methylation of development‐ and differentiation‐related pathways (Maegawa et al., 2010). A global age‐related increase in entropy was also shown (Wang et al., 2017), and dietary restriction was found to influence hepatic genes involved in lipid metabolism‐related pathways (Hahn et al., 2017). Another advantage of mouse studies is that they allow investigating evolutionarily conserved and species‐specific changes during aging and examining the effects of interventions that extend lifespan.…”

Analysis of DNA modifications in aging research

“…For genomic features, this often takes the form of determining if changes are more or less likely than chance to occur in a certain feature such as a promoter, intron, and CG island. A number of examples exist from recent studies (Cole et al 2017;Dozmorov 2017;Hadad et al 2017b;Masser et al 2017a;Wang et al 2017). For integration with other epigenomic data, the process is similar but the comparison is with other epigenomic data such as ChIP-Seq.…”

Chromatin modifications in metabolic disease: Potential mediators of long‐term disease risk

“…DNA methylation profiles have even been used to define an “epigenetic clock” (Horvath, 2013; Stubbs et al, 2017b). Epigenetic alterations associated with aging have been found to be accelerated or slowed as a result of high fat diet and caloric restriction, respectively (Cole et al, 2017; Stubbs et al, 2017b; Wang et al, 2017). Recent work profiling transcription in livers of mice found that, while protein coding genes can be activated or repressed with no particular bias in one direction or the other, non-coding RNAs (sRNAs and lncRNAs) and transposable elements were largely activated and this trend could be reversed by lifespan extending interventions such as caloric restriction (Green et al, 2017).…”