In C. elegans and mammalian cells, D‑pinitol extends lifespan, preserves locomotor healthspan, reduces proteotoxicity in worm models of Parkinson’s (and other neurodegenerative) disease, and activates conserved Nrf2/SKN‑1, HSF‑1 and HLH‑30 autophagy/mitophagy pathways via p38 MAPK.

By engaging antioxidant, proteostasis and mitophagy mechanisms directly implicated in alpha‑synuclein clearance and mitochondrial dysfunction in Parkinson’s, D‑pinitol is a low‑toxicity, repurposing‑friendly candidate that merits mammalian preclinical evaluation for neuroprotective therapy…

Aging is driven in part by progressive deterioration of proteostasis and antioxidant defense, leading to cellular dysfunction and age-associated disease. The naturally occurring methylated inositol D-pinitol (DP) was reported to present metabolic, antioxidant, and anti-inflammatory effects, as well as to extend the lifespan of D. melanogaster and C. elegans through the insulin/IGF-1 signaling pathway. But the mechanism of DP on delay aging remains poorly understand. Here, we showed that 200 μM of DP increased mean lifespan of C. elegans by 28.6%, as well as healthspan phenotypes including preserved locomotor function and delayed lipofuscin accumulation. DP also attenuated proteotoxicity and delays functional decline in C. elegans models of Parkinson's, Huntington's, and Alzheimer's diseases. Moreover, DP suppressed cellular senescence in multiple mammalian cell types. Genetic and reporter analyses show that DP activates conserved stress-response regulators Nrf2/SKN-1 and HSF-1 through the p38 MAPK signaling cascade to improve resistance to oxidative and thermal stress. DP further enhanced HLH-30-dependent autophagy and mitophagy activities, which are essential for lifespan extension. Together, these findings identify DP as a conserved modulator of proteostasis, redox homeostasis, and autophagy, positioning it as a promising, low-toxicity candidate for promoting healthy aging and mitigating age-related neurodegenerative pathology.