Beijing, March 14, 2025 — A collaborative research team led by Dr. Liu Guanghui from the Institute of Zoology, Chinese Academy of Sciences, and Dr. Wang Si from Xuanwu Hospital Capital Medical University, has made a significant breakthrough in understanding and combating skeletal muscle aging. Their study, published in Nature Metabolism, reveals a novel molecular mechanism and proposes a potential gene therapy strategy to delay age-related skeletal muscle decline.

Skeletal muscle is essential for maintaining physical function and energy metabolism. However, age-related loss of muscle mass and function is linked to reduced mobility, increased risk of falls and fractures, and various chronic diseases. Despite its impact, effective interventions for muscle aging remain limited. Now, researchers have discovered that the "longevity protein" SIRT5 can delay skeletal muscle aging by inhibiting pro-inflammatory pathways through its interaction with the protein kinase TBK1.

Using a primate model of skeletal muscle aging, the team identified key features of muscle aging, including reduced muscle fiber size, transition in fiber types, increased inflammation, and loss of muscle stem cells. They found that downregulation of SIRT5 is a critical molecular change in aged skeletal muscle. Through genetic and biochemical analyses, the researchers showed that SIRT5 desuccinylates TBK1, preventing the activation of downstream inflammatory signals and thereby slowing muscle aging.

Based on these findings, the team developed a gene therapy approach using a lentiviral vector to overexpress SIRT5 in aged mice. After approximately five weeks, treated mice exhibited improved physical performance, increased muscle fiber size, reduced inflammation, and a rejuvenated gene expression profile. These results suggest that SIRT5 overexpression could be a promising strategy to reverse skeletal muscle aging and prevent age-related muscle disorders.

This study not only deciphers the molecular mechanisms underlying skeletal muscle aging but also provides a potential therapeutic target for combating age-related muscle decline. Targeting the SIRT5-TBK1 signaling axis could pave the way for new treatments to enhance muscle health and improve quality of life in the elderly.

This research was a collaborative effort involving Xuanwu Hospital Capital Medical University, the Institute of Zoology, Chinese Academy of Sciences, and Peking University Third Hospital. Dr. Liu Guanghui, Dr. Wang Si, and Dr. Qu Jing are the co-corresponding authors, while Dr. Zhao Qian, Dr. Jing Ying, Ph.D. candidate Jiang Xiaoyu, and Dr. Zhang Xin are the co-first authors.

Fiber-type distribution in aged cynomolgus monkey skeletal muscle (Image by LIU Guanghui's lab)

https://www.nature.com/articles/s42255-025-01235-8