Nearly a century ago, researchers discovered that cutting calorie intake was actually able to extend lifespan in various animal species. Although numerous studies have been conducted since to find out exactly why reducing calories can extend lifespan, scientists have been unable to pinpoint the answer. Now, a group of investigators at the Lewis Katz School of Medicine at Temple University (LKSOM) have uncovered an explanation to the longevity conundrum, something they call “age-related methylation drift.”
The senior investigator, Jean-Pierre Issa, MD, Director of the Fels Institute for Cancer Research at LKSOM, explained, “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.”
These findings may explain why certain animals live for shorter or longer periods of time. For instance, on average, mice live for two to three years, whereas rhesus monkeys live for 25 years and humans live to around 70-80 years.
DNA methylation is the epigenetic mechanism characterized by suppressing gene expression as a result of adding methyl groups onto DNA. This mark serves as a molecular bookmark in order to control mammalian genes, indicating when they should be used.
“Methylation patterns drift steadily throughout life, with methylation increasing in some areas of the genome, and decreasing in others,” said Dr. Issa. These epigenetic changes have previously been linked to age, but their connection to lifespan was uncertain.
The team first examined DNA methylation patterns in blood from three different species – mouse, human, and monkey. The samples were from animals at different ages – the mice ranged from a couple months to nearly three years old, the monkeys ranged from under one year to 30 years old, and the humans ranged from 0 to 86 years old. The researchers used cord blood to measure epigenetic patterns at age zero.
Variations in DNA methylation related to age were analyzed by deep sequencing technology. The results revealed unique patterns, specifically showing that there were increases in methylation in older individuals at certain sites compared to unmethylated sites in young individuals at the same genomic sites, and vice versa.
“Epigenetic drift is conserved across species and the rate of drift correlates with lifespan when comparing mice, rhesus monkeys, and humans,” reported the researchers.
In genomic areas that had increased methylation as the animals got older, there were dramatic losses in gene expression. Conversely, certain genes with reduced methylation showed increases in gene expression. Further analysis of a subset of genes impacted by age-related adjustments in methylation levels demonstrated an inverse relationship between longevity and methylation drift.
Essentially, the more epigenetic change there was, and the faster it occurred, the shorter the animals’ lifespan. “We propose that epigenetic drift is a determinant of lifespan in mammals,” they said.
They were also curious about whether they could increase lifespan by altering epigenetic drift. Calorie restriction has been known to be one of the most powerful factors for increasing lifespan in animals. This occurs by reducing calories while also maintaining a healthy intake of essential nutrients. In our article 3 Pioneering Epigenetic Labs: Exploring the People and Discoveries that Transcend the Lab Walls, Dr. Tollefsbol shared with us his findings on glucose restriction and longevity.
In young mice, researchers cut calorie intake by 40 percent. For middle-aged monkeys, they cut calorie intake by 30 percent. Significant decreases in epigenetic drift were observed in both species. Age-related changes in DNA methylation in older, calorie-restricted animals were comparable to those of young animals.
“The impacts of calorie restriction 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 said.
Fully understanding DNA methylation drift and how it determines lifespan in mammals will be an interesting development to follow. There is still much more that has yet to be answered now that the researchers proposed that slowing epigenetic drift might be used to extend life. The complexity of this mechanism has vast implications in health research, especially because the risk of age-related diseases such as cancer is heightened when there is a greater amount of epigenetic drift.
The group of researchers hopes to pinpoint more factors that influence the changes in methylation over time. If these factors could be changed to slow drift, we might be able to help prevent age-related diseases and extend the human lifespan.
Source: Maegawa, S. et al. (2017). Caloric restriction delays age-related methylation drift. Nature Communications, 8(1).
Reference: Temple Health. Temple Researchers Uncover Mechanism Behind Calorie Restriction and Lengthened Lifespan. Temple Health News & Announcements. 14 Sep 2017. Web.
