Enhanced Selenium Supplement Extends Lifespan and Delays Multi‐Organs Aging by Regulating the Sik1 Pathway Through Maintaining Calcium Homeostasis

Selenium supplementation has potential in treating aging-related disorders like neurodegenerative and cardiovascular diseases, but its use is limited by poor bioavailability, a narrow therapeutic window, and unclear mechanisms. To overcome this, redox-dual-responsive diselenide-bridged mesoporous silica nanoparticles (SeMSNs) are developed. SeMSNs effectively reduce oxidative stress and downregulate senescence markers (p16, p21), suppressing senescence in both naturally aged primary mouse embryonic fibroblasts (MEFs) and H₂O₂-induced HEK-293T cells. They show prolonged antioxidant effects (p < 0.05) and lower cytotoxicity (p < 0.01) than commercial selenomethionine. In aged mice, SeMSNs extend lifespan, reduce frailty, and improve age-related conditions, including muscle atrophy, renal dysfunction, cognitive decline, and hepatic steatosis, while restoring metabolic balance. They outperform conventional organically-bridged mesoporous silica nanoparticles (MSNs) and disulfide-bridged MSNs (SMSNs) (p < 0.01). Mechanistically, SeMSNs upregulate selenoproteins (GPx1, SelK), suppress endoplasmic reticulum (ER) stress-mediated calcium release, maintain calcium homeostasis, and inhibit NFATc2-driven Sik1 transcription, reducing p21/p16. Clinical data confirm an inverse correlation between selenium levels and aging biomarkers (p < 0.0001). SeMSNs also restore adipogenic differentiation in human adipose progenitor cells via calcium-NFATc2-Sik1 signaling. These results demonstrate the superiority of SeMSNs over traditional selenium forms, providing a nanotherapeutic strategy to combat multi-organ aging and promote healthy longevity.