J Exp Med. 2026 Oct 05. pii: e20260071. [Epub ahead of print]223(10):
Bingge Zhang,
Ye He,
Ruiming Zhang,
Ting Su,
Ruijuan Liu,
Xiaomei Li,
Xiufen Zhang,
Bocheng Xiong,
Chao Yang,
Xinlei Liu,
Qian Liu,
Qinghua Hou,
Yongmei Xie,
Gongping Liu,
Xifei Yang.
Aging, characterized by progressive physiological decline and systemic dysfunction, represents a major risk factor for age-related diseases such as sarcopenia, which involves fibrosis that disrupts muscle regeneration and function. Effective therapeutic strategies remain limited. Here we report UA-30, a novel compound with a favorable pharmacokinetic and safety profile, that delayed systemic aging in naturally aged mice, as indicated by reduced frailty, slowed epigenetic age, extended lifespan, and improved muscle function. 10-wk UA-30 treatment reduced fibrosis and muscle atrophy in 18.5-mo-old mice. Thermal proteome profiling, surface plasmon resonance, and functional analyses identified Ras-related protein Ral-A (RalA) as a direct molecular target of UA-30. UA-30 suppressed RalA activity, thereby inhibiting the pro-fibrotic JNK-Smad signaling axis and enhancing mitochondrial functions. Overexpression of constitutively active RalA largely abolished the anti-aging and anti-fibrotic effects of UA-30. These findings support UA-30 as a promising therapeutic candidate for aging and sarcopenia, and indicate RalA is a potential target for age-related muscle degeneration.