A DNA Methylation Signature is Shared Between Calorie Restriction, mTOR Inhibition, and Growth Hormone Inhibition

Calorie restriction, mTOR inhibition, and blockade of growth hormone interaction with its receptor all result in slowed aging and extension of healthy life span in mice. These interventions beneficially alter the operation of metabolism in humans, but do not enhance human life span to anywhere near the same degree; the current consensus suggests that an additional five years is probably the largest effect that could be expected to exist. The mechanisms involved overlap, and nutrient sensing plays an important role. Thus researchers looking for common epigenetic signatures shared by all of these interventions have found such shared signatures.

Long ago, the earliest organisms evolved to better maintain themselves in response to seasonal famine, extending their lives and raising the odds of successful reproduction later. That ability has been passed down over evolutionary time, and is present in near all species tested to date. The shorter the species life span, the greater the relative extension of life needed to pass through a season of famine. Thus mice that live only a couple of years can extend their lives by as much as 40% via stress triggers such as limited nutrient intake, while humans with a life span of decades do not exhibit a significant extension of life in this circumstance. Much of the same cellular machinery exists in both species, however, explaining why humans can obtain health benefits from the practice of calorie restriction.

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, whole-genome, 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.

Link: https://doi.org/10.1371/journal.pgen.1007766

Comments

I guess I've got to wonder about the protocols being followed by these studies and how the mice were treated during these studies. In 2004 I was pretty over-weight and out of shape. I got 6 months of injectable (R-identical Japanese powder to mix into distilled water) Human Growth Hormone. For me, it super-charged my work outs and helped me lose over 40 pounds, taking my resting heart rate down below 40 BPM and peak up to 175 BPM at 44 yo. I don't do it any more because it is expensive and hard (maybe illegal?) to get any longer. I'm also worried about the cancer risk. I wish there was clear research and information about growth hormone, rather than being told (and experiencing) good things and then hearing bad things like the study being presented here.

Posted by: Tom Schaefer at November 29th, 2018 2:18 PM

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