With age comes wisdom, and also a changing methylation landscape. These changes in methylation can predict life expectancy, with a subset referred to as the ‘epigenetic clock’. For those of us looking to add more time, caloric restriction has been shown to increase life expectancy and reduce the incidence of age-related diseases. Despite three decades of research on caloric restriction, the link to longevity has remained elusive. But now, the lab of Jean-Pierre Issa at the Fels Institute for Cancer Research & Molecular Biology (Pennsylvania) has identified an epigenetic component of caloric restriction that correlated with increased lifespan.
As we age, there are aberrant, cumulative changes to the methylation of our genomes in a process called methylation drift. Methylation drift results in random hypomethylation or hypermethylation at CpG sites within genes, as well as CpG islands near transcription start sites. As we get older, our DNA shows increasing amount of errant methylation.
The authors propose that methylation drift is a determinant of lifespan, which can be altered via caloric restriction. Here’s what they found:
- A quantitative deep sequencing-based method known as ‘Digital Restriction Enzyme Analysis of Methylation’ (DREAM) sequencing was used to identify genome-wide methylation sites
- Whole blood samples from mice, rhesus monkeys, and humans revealed that age-related methylation drift is conserved across these species, and that drift rate is inversely related to longevity
- Errant hypomethylation or hypermethylation of gene promoters results in increased or decreased gene expression accordingly
- Hypermethylated genes tend to be involved in key cellular functions like growth, signaling, and development, as well as genes involved in tumorigenesis and cardiovascular disease
- Caloric restriction can slow methylation drift!
- Mice and monkeys on a calorie restricted diet have a “younger” methylation pattern compared with their chronological age; most noticeably there is decreased methylation of CpG islands, which mimics the younger population
- Caloric restriction may counteract methylation drift, but does not alter the global methylation pattern
- The inhibition of methylation drift caused by caloric restriction correlates with changes in gene expression analogous to the methylation age
- Caloric restriction has no effect on telomere shortening—another oft-cited marker of aging
The authors propose that methylation drift is caused by the accumulation of errors during reproduction of adult stem cells, which are then passed along to progenitor cells. Caloric restriction may decrease cell turnover, thereby resulting in fewer methylation errors, and ultimately leading to a longer lifespan. The dampened incidence of cancer in calorie restricted animals may function through the same mechanism. Conversely, any process that increases cell turnover (such as chronic inflammation, as reported ) will correspondingly increase the rate of methylation drift, and decrease lifespan.
Hungry for more? Go take a bite out of the rest over at Nature Communications, September 2017