Groundbreaking research elucidates the epigenetic mechanism that may be responsible for why eating fewer calories increases longevity.

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Using deep sequencing DNA analysis, researchers have uncovered an epigenetic mechanism that may explain why restricted calorie intake seems to increase lifespan.

As early as 1935, scientists showed that limiting the intake of calories can drastically increase the lifespan of mammals.

New research brings us closer to understanding why that may be. Researchers from the Lewis Katz School of Medicine (LKSOM) at Temple University in Philadelphia, PA, have uncovered a mechanism that might explain why calorie restriction has such a beneficial effect on longevity.

The mechanism has to do with epigenetics and bears the name of “methylation drift.”

Scientists led by Dr. Jean-Pierre Issa, director of the Fels Institute for Cancer Research at LKSOM, explain what that means and how they have reached their conclusion in a paper published in the journal Nature Communications.

The study also suggests that the epigenetic mechanism may determine why some mammals live longer than others.

DNA methylation is a common epigenetic mechanism. Organisms ranging from fungi to humans use it to regulate their gene expression – that is, to determine which copy of the gene is on and which is off.

“[DNA] methylation patterns drift steadily throughout life, with methylation increasing in some areas of the genome, and decreasing in others,” says Dr. Issa.

Speaking to Medical News Today, Dr. Issa explained the mechanism. “Methylation is a biochemical modification of DNA that creates ‘tags’ on genes and these tags control cell identity (why a cell is a blood cell or a skin cell and why it becomes cancerous).”

“The simplest way to think about these tags is an analogy to ‘bookmarks’ that tell the cell what to do and when to do it,” he added. “If these bookmarks are missing or altered, then the cell loses a bit of its identity. Methylation ‘drift’ is a composite measure of how much these tags have changed.”

Previous research has shown that DNA methylation tends to drift with age.

However, as the study authors report, it was not previously known whether there was a connection between methylation drift and lifespan.

In order to investigate this, Dr. Issa and team studied blood samples from mice, monkeys, and humans at different ages.

The mice were aged between a few months to 3 years, the monkeys’ age ranged from a few months to more than 30 years, and the humans’ age range was between zero and 86 years.

Using deep sequencing techniques, the researchers analyzed the DNA taken from the blood. The analyses revealed “gains and losses of DNA methylation” at certain locations in the genome.

Specifically, older individuals had methylation gains at certain genomic locations where young individuals had losses. The reverse was also true.

The more methylated a genomic site was, the less the genes were expressed, and vice versa. Further DNA analyses revealed an inverse correlation between methylation drift and lifespan. The more and the quicker epigenetic change occurred, the shorter the lifespan of each species was.

“The more the change, the older a person (or animal) is,” Dr. Issa told MNT.

“Our study shows,” he added, “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.”

On average, mice live 2 to 3 years, rhesus monkeys approximately 25 years, and humans around 70.

“Our next question was whether epigenetic drift could be altered to increase lifespan,” explains Dr. Issa. The researchers restricted calorie intake by 40 percent in mice that were 3.4 months old and by 30 percent in monkeys aged between 7 and 14 years.

Their calories were restricted over a long period of time – that is, monkeys were on a low-calorie diet until they were 22 to 30 years old, and mice were on such a diet until they were 2 to 3 years old.

In both species, the effects of calorie restriction were dramatic. Monkeys’ “blood methylation age” seemed to be 7 years younger than their chronologic age. Both species showed methylation changes comparable with those of their younger counterparts.

The findings prompted the team to “propose that epigenetic drift is a determinant of lifespan in mammals.”

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. Jean-Pierre Issa

“Researchers had previously focused on other molecular measures to explain aging and effects of calories (for example telomere length, DNA damage, metabolism etc.) but the strength of the associations suggest that methylation drift could play a central role in aging,” Dr. Issa told us.

The findings may have major implications for age-related diseases, including diabetes, cancer, cardiovascular disease, and some neurodegenerative diseases.