Turning back time on muscle stem cells to prevent frailty from aging

(Press-News.org) The population across developed countries is getting older and the associated frailty and debilitation are becoming major health problems. This gradual muscle loss is accelerated by the poor capacity to repair damage and injury, especially after falls or surgeries.

Low muscle mass in the elderly — known as sarcopenia — leads to increased frailty and movement problems. Patients with sarcopenia are more likely to be hospitalized and develop other comorbidities, largely due to falls and fractures that tend to create health declines that quickly spiral out of control.  

“We knew that a major contributor is the muscle stem cells that are needed to repair muscle damage. They become dysfunctional with age. We’ve been trying to understand how aged stem cells are different from young and how to reverse these changes,” said Yu Xin (Will) Wang, PhD, an assistant professor in the Center for Cardiovascular and Muscle Diseases, Center for Data Sciences, and Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys.

Wang and colleagues at Stanford University published findings June 12, 2025, in Cell Stem Cell demonstrating the effectiveness of treating aged mice with a naturally occurring lipid, Prostaglandin E2 (PGE2), which improved regeneration and strength of aged muscle. The research team also detailed how this therapy worked, showing that it counteracts molecular changes that occur with stem cell aging.

The scientists began by examining the effects of PGE2 and its receptor EP4. Their prior research had established that PGE2 signals during muscle injury trigger muscle stem cells to regenerate the muscles of young mice.

In aged mice, the team found that EP4 expression on aged muscle stem cells are either lacking or reduced by half of those found in young stem cells.  

“PGE2 levels in muscle also decline with age, so we see blunted signaling from reductions in both the messenger and receiver,” said Wang. “PGE2 is an alarm clock to wake up the stem cells and repair the damage. Aging essentially reduces the volume of the alarm and the stem cells have also put on ear plugs.”

It is possible, however, to overcome the effects of aging and reset the intensity of this cellular siren. Wang and his collaborators gave a stable form of PGE2 to aged mice after muscle injury and in conjunction with exercise. The treated mice gained more muscle mass and were stronger compared to untreated ones.

“What amazes me most is that a single dose of treatment is sufficient to restore muscle stem cell function, and that the benefit lasts far beyond the duration of the drug,” said Wang. “In addition to making new muscle, the stem cells stay in the tissue, where they sustain the effect of the PGE2 and instill the muscle with further capacity to regenerate.”

The study revealed that PGE2 treatment restores stem cell function by modulating the activity of key transcription factors which reversed many of the age-related changes that the researchers observed.

“The genes that are upregulated during the aging process are downregulated after treatment, and vice versa,” Wang said.

In addition to continuing to uncover how to regenerate muscle and prevent sarcopenia and its associated health risks, Wang and his collaborators plan to widen their scope beyond muscle.

“The evidence suggests that PGE2 is not just acting on one mechanism,” said Wang. “We’ve previously shown that PGE2 can also benefit the muscle fiber, and neurons that innervate the muscle. PGE2 has been implicated in the regenerative process and signaling for the intestine, liver, and several other tissues, potentially opening up an approach that could restore the renewing capacity of other aged tissues.

“The ultimate goal is to improve people’s quality of life by reversing the effects of aging.”

 

Helen Blau, PhD, Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology at Stanford University, is the senior and corresponding author on the study. 

Adelaida Palla, PhD, a principal scientist at Biogen, and Andrew Ho, PhD, head of research and development projects at Sorbonne University’s Myology Institute, share first authorship of the study with Wang.

Additional authors include:

Shiqi Su from Sanford Burnham Prebys Daniel Robinson, Meenakshi Ravichandran, Glenn Markov, Thach Mai, Akshay Balsubramani, Chris Still II, Surag Nair, Colin A. Holbrook, Ann V. Yang, Peggy Kraft, David Burns, Nora Yucel, Lei Qi and Anshul Kundaje from Stanford University The study was supported by the National Institutes of Health, Canadian Institutes of Health Research, Galaxo Smith Kline Sir James Black Program for Drug Discovery, Muscular Dystrophy Association, National Science Foundation, Stanford University, Li Ka Shing Foundation, California Institute for Regenerative Medicine, Baxter Foundation and Milky Way Research Foundation.

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