Mitochondria-Targeted Natural-Derived Compounds in Cellular Senescence: Mechanisms, Therapeutic Potential, and Future Directions.

Cellular senescence is a root cause of aging and age-related disease. Senescent cells persist in tissues, secreting inflammatory factors that fuel inflammaging and immune decline. At the subcellular level, mitochondrial dysfunction has become recognized as a central driver of the senescent state: metabolism shifts toward glycolysis, mitophagy stalls while reactive oxygen species production escalates, mitochondrial dynamics tip toward hyperfusion or fragmentation, and damaged mitochondrial DNA leaks into the cytosol to activate the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, amplifying the senescence-associated secretory phenotype. Conventional drugs have struggled to address these layered defects, steering interest toward natural bioactive compounds-polyphenols, flavonoids, saponins-that can simultaneously restore mitophagic flux, boost antioxidant defenses, rebalance fission-fusion, and intercept mitochondrial DNA-driven inflammation. However, the key issue is delivery: these molecules rarely reach mitochondria in meaningful concentrations in vivo due to their poor bioavailability, rapid metabolism, and off-target distribution. Platforms using triphenylphosphonium, mitochondria-penetrating peptides, or biomimetic shells have successfully funneled therapeutic payloads into mitochondria in several models of disease. We contend that the proposed systematic integration of these delivery systems with natural senotherapeutic compounds offers a promising direction for future research.