15 Jan Duke-NUS Medical School Identifies Signal Explaining Why Aging Muscles Lose Ability to Maintain Mass and Function

Cancer and Stem Cell Biology Duke-NUS Medical School Lab Team Members

MedicalResearch.com Interview with:
Hung-Wen Tang, PhD
Assistant Professor
Cancer and Stem Cell Biology
Duke-NUS Medical School
Singapore

MedicalResearch.com: What is the background for this study?

Response: As we age, we naturally lose muscle strength and function — a condition known as sarcopenia. This makes everyday activities harder and increases the risk of falls, frailty, and loss of independence. Scientists have long known that a growth pathway in muscle cells called mTORC1 becomes overactive with age and contributes to muscle decline. However, the underlying cause of this overactivation remained unclear.

MedicalResearch.com: What are the main findings?

Response:  In our study, we discovered a new transcription factor called DEAF1, that acts as a master switch driving this harmful overactivation. When DEAF1 level rises in aging muscle, it pushes mTORC1 into overdrive, disrupting the muscle’s ability to maintain and repair itself.

Importantly,  we found that exercise can reverse this process. Exercise activates another protein called FOXO, which turns down DEAF1 and restores balance inside muscle cells. This allows muscles to better maintain their strength and health as we age, establishing the FOXO–DEAF1–mTORC1 axis as a central regulatory pathway in muscle aging.

MedicalResearch.com: What should readers take away from your report? Are there some individuals in whom this pathway is less effective?

Response: New target for healthy muscle aging: DEAF1

We have identified a conserved FOXO–DEAF1–mTORC1 signaling axis that explains why aging muscle progressively loses its ability to maintain mass and function. Using cross-species models ranging from fruit flies to aged mice, we showed that DEAF1 plays a central role in this process by switching on a harmful aging pathway inside muscle cells.

The encouraging finding is that exercise naturally turns off DEAF1, helping muscles stay healthier for longer. These findings provide a mechanistic explanation for why long-term exercise is such a powerful intervention for maintaining muscle function with age, positioning DEAF1 as a promising therapeutic target for sarcopenia.

However, not everyone responds to exercise in the same way. People with chronic illness, metabolic problems, or reduced ability to exercise may not activate this protective pathway as strongly, which may help explain why some older adults benefit more from exercise than others.

Our key message is that muscle aging is not just about making less muscle — it’s about losing the ability to maintain healthy muscle. 

MedicalResearch.com: What recommendations do you have for future research as a results of this study?

Response: Our next goal is to confirm these findings in human by analyzing skeletal muscle biopsies from older adults before and after structured endurance or resistance training programs and correlating molecular changes with strength and functional outcomes. We will also investigate how DEAF1 expression is regulated during human aging and in sarcopenic patients.

To enable therapeutic translation and development, we also hope to develop new treatments that could mimic some of the benefits of exercise for people who are unable to exercise due to illness or disability. This includes muscle-targeted delivery strategies and assays to measure DEAF1–mTOR transcriptional status for personalized intervention. We will also define the mechanism in detail through time-course studies and assess potential off-target effects and long-term safety.

To accelerate clinical translation, we will establish partnerships with clinical teams and industry collaborators. Together, these efforts aim to open new therapeutic avenues for treating sarcopenia and other age-related muscle disorders.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Response: Our findings reveal a new biological explanation for why exercise is so effective at keeping muscles strong during aging. Highlighting DEAF1 as a key driver of muscle decline, we have opened the door to new strategies for preventing and treating age-related muscle decline.

Prof. Hong-Wen Tang (corresponding author, Duke-NUS), Priscillia Choy Sze Mun, Wen Xing Lee and Kah Yong Goh (co-first authors)
Collaborators: Dr Kenon Chua, Singapore General Hospital (Orthopaedic Surgery) and Dr Nathan Harmston, Cardiff University.
Funding: Singapore Ministry of Education; Diana Koh Innovative Cancer Research Award; National Academy of Medicine; National Medical Research Council; Khoo Postdoctoral Fellowships.

Citation:

S.M. Choy, K.Y. Goh, W.X. Lee, W. Jiang, Q. Gou, P.D. Gopal Krishnan, S. Chee Ong, K. Chua, N. Harmston, & H. Tang, Exercise suppresses DEAF1 to normalize mTORC1 activity and reverse muscle aging, Proc. Natl. Acad. Sci. U.S.A. 122 (48) e2508893122, https://doi.org/10.1073/pnas.2508893122 (2025).

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Last Updated on January 15, 2026 by Marie Benz MD FAAD