Murine studies headed by a team at the University of Arkansas (U of A) have found that exercising, even when started later in life, can help to keep skeletal muscles more youthful, by holding back epigenetic aging.

The research, reported in Aging Cell, showed that in mice, late-life, voluntary endurance and resistance exercise training significantly held back age-associated shifts in epigenetic aging in skeletal muscle. The epigenetic age of muscle from older mice that trained for eight weeks was about eight weeks younger than that of their sedentary peers, which equates to about 8% of expected mouse lifespan.

Describing their studies in a paper titled, “Late-life exercise mitigates skeletal muscle epigenetic aging,” Kevin Murach, PhD, an assistant professor in the department of health, human performance and recreation at the U of A, and colleagues, concluded, “… the attenuation of muscle epigenetic aging by exercise supports recent targeted observations in humans and adds to the growing body of evidence touting exercise as a strategy to extend healthspan.”

Body aging is associated with increased DNA methylation, or even hypermethylation, at promoter sites on genes in muscle. “DNA methylation changes in a lifespan tend to happen in a somewhat systematic fashion,” Murach explained, “to the point you can look at someone’s DNA from a given tissue sample and with a fair degree of accuracy predict their chronological age.” This allows researchers to use one of a number of “methylation clocks” to determine the age of a DNA sample.

All tissues, including skeletal muscle, undergo changes to DNA methylation as they age, and this may contribute to structural and functional decline with aging, the authors noted. While its been shown that there are functional benefits of exercising to muscles, even when performed later in life, the contributions of epigenetic factors to late-life exercise are not well understood. “Exercise training alters muscle DNA methylation, but whether it causes the aged mouse skeletal muscle methylome to more closely resemble that of a younger mouse remains unclear,” the team noted.

To investigate this further, Murach and colleagues from the U of A, the University of Kentucky, and the University of Texas, carried out an exercise study in laboratory mice. “We hypothesized that late-life combined resistance/endurance exercise would reduce aging-associated hypermethylation and DNAge™ in skeletal muscle,” they suggested. Animals nearing the end of their natural lifespan, at 22 months of age, were allowed access to a weighted exercise wheel. Mice generally require no coercion to run and will do so voluntarily. In fact, older mice will run anywhere from six to eight kilometers a day, mostly in spurts, the research teams noted, while younger mice may run up to 10–12 kilometers. Giving the test animals a weighted wheel for exercise ensured that they built muscle. While there isn’t a direct analogue to most human exercise routines, Murach likened this to “a soldier carrying a heavy backpack many miles.”

The animals were then studied after two months of progressive weighted wheel running, (known as voluntary murine endurance/resistance exercise training, or progressive weighted wheel running, PoWeR). Using methods for methylation analysis, the researchers found that these exercising mice were the epigenetic age of mice eight weeks younger than sedentary mice of the same age, 24 months. Murach noted that while the specific strain of mice and their housing conditions can impact lifespans, “historically, they start dropping off after 24 months at a significant rate.” Needless to say, when lifespan is measured in months, an extra eight weeks—roughly 10% of that lifespan—is a noteworthy gain.

While the paper strengthens the case for exercise, there is still much that needs to be learned. Though the connection between methylation and aging is clear, the connection between methylation and muscle function is less clear. Murach is not yet prepared to say that the reversal of methylation with exercise is causative for improved muscle health. “That’s not what the study was set up to do,” he explained. However, he intends to pursue future studies to determine if “changes in methylation result in altered muscle function.”

“If so, what are the consequences of this?” he continued. “Do changes on these very specific methylation sites have an actual phenotype that emerges from that? Is it what’s causing aging or is it just associated with it? Is it just something that happens in concert with a variety of other things that are happening during the aging process? So that’s what we don’t know.”

And as the authors concluded in their paper, “Our work provides potentially modifiable epigenetic markers for improving muscle health with age once the mechanistic bases of dynamic DNA methylation alterations in muscle fibers are more clearly define.”

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