Spermidine Prolongs Lifespan and Prevents Liver Fibrosis and Hepatocellular Carcinoma by Activating MAP1S-Mediated Autophagy

Abstract

Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy which trigger oxidative stress-induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan.

Spermidine promotes nucleus pulposus autophagy as a protective mechanism against apoptosis and ameliorates disc degeneration

“…Moreover, re‐activation of basal autophagy by spermidine has recently been reported to maintain the regenerative function of skeletal muscle stem cells in ageing mice 27. It has also been shown to induce autophagy in various tissues, including the heart,16 brain17 and cancer cells 37. In this study, we found that spermidine may activate autophagy in NP cells.…”

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline

“…However, tumor frequencies of physiologically aging C57BL6 wild type mice remained unchanged even after life-long dietary supplementation of spermidine [12]. A recent study further demonstrated that oral spermidine administration reduced the incidence of chemically-induced hepatocellular carcinoma and liver fibrosis in mice and caused a life span extension of 25% [13]. In addition, spermidine and other caloric restriction mimetics were shown to induce anticancer immune-surveillance in mice [14], which supports previous observation that higher polyamine intake inhibits the emergence of tumors in rodents, while promoting growth of existing ones [15].…”

Metastatic prostate cancer‐associated P62 inhibits autophagy flux and promotes epithelial to mesenchymal transition by sustaining the level of HDAC6

“…Autophagosomes migrate along acetylated microtubules to fuse with lysosomes to form autolysosomes, in which substrates are degraded . Microtubule‐associated protein MAP1S interacts with LC3 and acts as an activator of autophagy . Another interactive protein of MAP1S, a mitochondrion‐associated protein LRPPRC suppresses both autophagy and mitophagy …”