Reverse the clock – How exercise can mimic the effects of youthful cells

Reverse the clock – How exercise can mimic the effects of youthful cells

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Exercise has the ability to mimic the molecular profile of muscles that have been subjected to Yamanaka factors, resulting in molecular expression similar to that of younger cells.

Evidence suggests that exercise creates a molecular profile in muscle that is consistent with the expression of youth-promoting Yamanaka factors.

A recent study published in the Journal of Physiology further supported the idea that exercise can help maintain youthful qualities in aging organisms. This research builds on previous experiments with lab mice that were near the end of their lives and had access to a weighted exercise wheel.

The lead author of the article is Kevin Murach, an assistant professor at the University of Arkansas in the Department of Health, Human Performance, and Recreation. The first author is Ronald G. Jones III, Ph.D. student at the Molecular Regulation of Muscle Mass Laboratory at Murach.

For this paper, the researchers compared aging mice that had access to a weighted exercise wheel with mice that had undergone epigenetic reprogramming through the expression of Yamanaka factors.

Kevin Murach

Kevin Murach. Credit: University of Arkansas

The Yamanaka factors are four protein transcription factors (identified as October 3/4, Sox2, Klf4, And c-Myc, often abbreviated to TOC) that can transform highly specific cells (such as a skin cell) into a stem cell, which is a younger and more adaptable state. The Nobel Prize in Physiology or Medicine was awarded to Dr. Shinya Yamanaka for this discovery in 2012. At the correct doses, induction of Yamanaka factors throughout the body in rodents can improve characteristics of aging by mimicking the adaptability that is common to younger people. cells.

Of the four factors, Myc is induced by exercising skeletal muscle. Myc may serve as a naturally induced reprogramming stimulus in muscle, making it a useful point of comparison between cells that have been reprogrammed via overexpression of Yamanaka factors and cells that have been reprogrammed through exercise – “reprogramming” in the latter case reflecting how an environmental stimulus can alter gene accessibility and expression.

The researchers compared the skeletal muscle of mice that had been allowed to exercise late in life to the skeletal muscle of mice that overexpressed OKSM in their muscles, as well as genetically modified mice restricted to overexpressing OKSM. Myc only in their muscles.

Ultimately, the team determined that exercise promotes a molecular profile consistent with partial epigenetic programming. That is, exercise can mimic aspects of the molecular profile of muscles that have been exposed to Yamanaka factors (thereby displaying the molecular characteristics of younger cells). This beneficial effect of exercise can in part be attributed to the specific actions of Myc in the muscle.

While it’s easy to assume that one day we could manipulate Myc into muscle to achieve the effects of exercise, thus sparing ourselves the hard work, Murach warns that would be the wrong conclusion to draw.

First, Myc would never be able to replicate all of the downstream effects of full-body exercise. It is also the cause of tumors and cancers, so there are inherent dangers in manipulating its expression. Instead, Murach thinks that manipulating Myc might be better used as an experimental strategy to figure out how to restore exercise adaptation to old muscles showing declining responsiveness. It could also be a way to supercharge the exercise response of weightless astronauts or people confined to bed rest who have only limited exercise capacity. Myc has many effects, both good and bad, so defining beneficial effects could lead to safe therapeutics that may be effective for humans later.

Murach sees their research as further validation of exercise as a polypill. “Exercise is the most powerful medicine we have,” he says, and should be considered a health-enhancing – and potentially life-prolonging – treatment along with medications and a healthy diet.

Reference: “A molecular signature defining adaptation to exercise with aging and live partial reprogramming in skeletal muscle” by Ronald G. Jones III, Andrea Dimet-Wiley, Amin Haghani, Francielly Morena da Silva, Camille R. Brightwell, Seongkyun Lim, Sabin Khadgi, Yuan Wen, Cory M. Dungan, Robert T. Brooke , Nicholas P. Greene, Charlotte A. Peterson, John J. McCarthy, Steve Horvath, Stanley J. Watowich, Christopher S. Fry, and Kevin A. Murach; The Journal of Physiology.
DOI: 10.1113/JP283836

The study was funded by the National Institute of Health.

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