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Although aging and senescence have been extensively studied in the past few decades, however, there is lack of clinical treatment available for anti‐aging. This study presents the effects of berberine (BBR) on the aging process resulting in a promising extension of lifespan in model organisms. BBR extended the replicative lifespan, improved the morphology, and boosted rejuvenation markers of replicative senescence in human fetal lung diploid fibroblasts (2BS and WI38). BBR also rescued senescent cells with late population doubling (PD). Furthermore, the senescence‐associated β‐galactosidase (SA‐β‐gal)‐positive cell rates of late PD cells grown in the BBR‐containing medium were ~72% lower than those of control cells, and its morphology resembled that of young cells. Mechanistically, BBR improved cell growth and proliferation by promoting entry of cell cycles from the G0 or G1 phase to S/G2‐M phase. Most importantly, BBR extended the lifespan of chemotherapy‐treated mice and naturally aged mice by ~52% and ~16.49%, respectively. The residual lifespan of the naturally aged mice was extended by 80%, from 85.5 days to 154 days. The oral administration of BBR in mice resulted in significantly improved health span, fur density, and behavioral activity. Therefore, BBR may be an ideal candidate for the development of an anti‐aging medicine.

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Microcystin-LR (MCLR) is a commonly acting potent hepatotoxin and has been pointed out of potentially causing neurotoxicity, but the exact mechanisms of action still remain unclear. Using proteomic analysis, forty-five proteins were identified to be significantly altered in hippocampal neurons of rats treated with MCLR. Among them, Ca2+-activated phosphatase calcineurin (CaN) and the nuclear factor of activated T-cells isoform c3 (NFATc3) were up-regulated remarkably. Validation of the changes in CaN and NFATc3 expression by Western blotting demonstrated CaN cleavage and subsequent NFATc3 nuclear translocation were generated, suggesting that exposure to MCLR leads to activation of CaN, which in turn activates NFATc3. Activation of CaN signaling has been reported to result in apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. In agreement with this, our results revealed that treatment of neurons with the CaN inhibitor FK506 blocked the reduction in Bad dephosphorylation and cytochrome c (cyt c) release triggered by MCLR. Consistent with these biochemical results, we observed a marked decrease in apoptotic and necrotic cell death after MCLR exposure in the presence of FK506, supporting the hypothesis that MCLR appeared to cause neuronal toxicity by activation of CaN and the CaN-mediated mitochondrial apoptotic pathway.