UA-30 mitigates systemic aging and motor decline by inhibiting RalA signaling in naturally aged mice

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.