Abstract Aging is characterized by the progressive loss of physiological integrity, leading to impaired tissue function and increased vulnerability to chronic diseases. Although the Hedgehog (Hh) signaling pathway is well established as a key regulator of embryonic development and tumorigenesis, emerging evidence suggests it also plays vital roles in adult tissue maintenance, regeneration and immune modulation—processes that are intimately linked to aging. Here we synthesize recent findings demonstrating that the controlled activation of Hh signaling across diverse tissues, including the brain, liver, heart, lung, bone, skin and adipose tissue, can counteract hallmark features of aging such as stem cell exhaustion, mitochondrial dysfunction and chronic inflammation. In preclinical models, Hh pathway modulation enhances tissue regeneration, supports progenitor cell function and suppresses senescence-associated secretory phenotypes. Promising therapeutic strategies—ranging from gene delivery to pharmacological agonists—have shown efficacy in mitigating age-related decline, though challenges remain regarding tissue specificity, long-term safety and tumorigenic risk. By integrating insights from developmental biology, regenerative medicine and geroscience, this Review positions Hh signaling as a compelling target for anti-aging interventions aimed at preserving organ function and extending healthspan.
Kim et al. (Thu,) studied this question.