Senomorphic agents: Multi-target strategies to tame the senescence-associated secretory phenotype for healthy ageing

Cellular senescence is a central driver of organismal ageing and related pathologies, primarily promoting chronic inflammation and tissue dysfunction through the senescence-associated secretory phenotype (SASP). Unlike senolytics, which aim to eliminate senescent cells, senomorphic agents offer a complementary therapeutic strategy by modulating the SASP without clearing the cells, thereby preserving their potential physiological functions. This review systematically elucidates the multi-target mechanisms of senomorphic agents, including the inhibition of key signaling pathways such as NF-κB, mTOR, JAK/STAT, and cGAS-STING. We classify them into three major categories: "old drugs with new uses" and metabolic modulators (e.g., metformin), natural products and their derivatives (e.g., urolithin A), and designed targeted synthetic inhibitors (e.g., ruxolitinib). Furthermore, we review their translational potential in neurodegenerative diseases, cardiovascular ageing, and osteoarthritis, highlighting the advantages of drug repurposing and synergistic therapy with senolytics. Finally, we discuss current challenges-such as the lack of specific biomarkers and targeted delivery systems-and future directions, including precision senotherapy and integrated intervention strategies. This review demonstrates that by 'taming' the senescent microenvironment rather than eliminating cells, senomorphic agents offer a promising strategy for achieving healthy ageing, yet clinical translation remains hindered by the lack of specific biomarkers, tissue-specific delivery systems, and long-term safety data. Here, we summarize current advances and critically analyze the barriers that must be overcome to move senomorphic agents from preclinical models to clinical practice.