There is a wealth of research in multiple species that suggests calorie-restricted diets can extend lifespan and hold back age-related physical decline and age-related diseases, but we don't yet understand the mechanisms that underpin that relationship. “Although health benefits and disease prevention have clearly been observed, the molecular basis for the delayed aging remains unknown,” acknowledges Jean-Pierre Issa, M.D., director of the Fels Institute for Cancer Research at the Lewis Katz School of Medicine (LKSOM) at Temple University.

A team led by Dr. Issa now reports on research in humans, monkeys, and mice that links the average species lifespan with the rate at which DNA undergoes age-related epigenetic changes. Their findings also indicate that calorie restriction (CR) effectively slows down this process of epigenetic drift, which could explain why CR can extend longevity. Reporting in Nature Communications, the researchers suggest their findings warrant further research to determine whether intentionally holding back epigenetic drift might influence how long, and how healthily, we live. “It is worth investigating whether interventions that further slowdown age-related DNA methylation drift may have beneficial effects on longevity and/or preventing the progression of age-related diseases,” they conclude in their paper, which is titled “Caloric Restriction Delays Age-Related Methylation Drift.”

Studies in rats as far back as 1935 indicated that CR increases longevity. Since then, research has found that CR increases lifespan and can prevent age-related disease in mice, as well as in rhesus macaques. Just last month, international researchers reported that CR in mice holds back age-related changes in the natural rhythms of cellular biological clocks that control essential liver and stem cell functioning.

Methylation as an age-related epigenetic change has been observed in normal human tissues, and accelerated age-related epigenetic drift has been linked with age-related diseases including cancers, diabetes, and chronic inflammation. To further investigate epigenetic drift and aging between different species, Dr. Issa’s team used a technique known as digital restriction enzyme analysis of methylation (DREAM) to analyze DNA methylation in whole blood samples from young and aged mice (0.3 to 2.8 years), young and aged monkeys (0.8 to 30 years), and humans aged from 0 to 86 years (cord blood was used to represent age 0). 

The analysis identified distinct patterns in DNA methylation in each species, including increased age-related DNA methylation at sites that weren’t methylated in young animals, and age-related hypomethylation at sites that were highly methylated in young animals. Further analysis suggested that patterns in age-related methylation drift are evolutionarily conserved across species.

To compare the rate of age-related methylation drift between the species, the team focused on 10 genes that showed a high level of sequence conservation across species, and also exhibited age-related hypermethylation in all three species.  When they compared methylation drift in these genes among animals of different ages, they found that the rate of drift was inversely proportional to longevity. This relationship also held true when they looked at all the hypermethylated genes tested, regardless of how conserved they were between species. In effect, the greater the degree of epigenetic drift, and the faster it occurred, the shorter the lifespan of the species. “Our study shows that epigenetic drift, which is characterized by gains and losses in DNA methylation in the genome over time, occurs more rapidly in mice than in monkeys and more rapidly in monkeys than in humans,” Dr. Issa noted.

The researchers then added CR into the mix. They analyzed methylation in middle-aged and old mice that had been exposed to 40% CR from aged 0.3 years, and also in aged rhesus macaques that had been exposed to 30% CR since middle age. In both species, significant reductions in epigenetic drift meant that old animals on calorie-restricted diets exhibited methylation changes that were more similar to those of normal young animals than to old animals fed normal diets. “The impacts of CR on lifespan have been known for decades, but thanks to modern quantitative techniques, we are able to show for the first time a striking slowing down of epigenetic drift as lifespan increases,” Dr. Issa claimed.

Previous research has also indicated that DNA methylation can be used as a predictor of chronological age, so the team next used data from 24 genes in mice and monkeys to calculate a “methylation age” in calorie-restricted animals. The calculations suggested that while the calorie-restricted mice had an average chronologic age of 2.8 years, their average methylation age was just 0.8 years. And while the average chronological age of the calorie-restricted monkeys was 27 years, their predicted methylation age was 20 years. “Thus, in both mice and monkeys, CR was associated with a significantly lower-methylation age, though the effect was much more pronounced in mice (40% CR since early adulthood) than in monkeys (30% CR since middle age),” the authors write.

“Thus we find striking conservation of methylation drift with aging among species and the strong negative correlation between methylation drift and lifespan across several species,” they conclude. “The CR effects on age-related methylation of delaying the drift may be important to the health and life extension seen in CR animals. Thus, we propose that DNA methylation drift is one of the strongest known biomarkers of lifespan.”

The team suggests the findings could have important implications for health research, given that independent studies have recently suggested that greater epigenetic drift increases the risk of age-related diseases, including cancer. “Our lab was the first to propose the idea of modifying epigenetic drift as a way of modifying disease risk,” Dr. Issa commented. “But why epigenetic drift occurs faster in some people and slower in others is still unclear.” The researchers are now working to identify additional factors that impact on epigenetic drift, and which it may be possible to manipulate to slow drift and prevent or slow age-related diseases.

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