Abstract 13491: Spermidine Improves Angiogenic Capacity in Senescent Endothelial Cells and Enhances Ischemia Induced Neovascularization in Aged Mice

Abstract

Aging is closely associated with high morbidity and mortality of various diseasesincluding cardiovascular disease. Cellular senescence has been cruciallyinvolved in the mechanisms underlying age-related diseases, and vascularendothelial cells <ECs> become senescent during aging. Spermidine, a naturallyoccurring polyamine, is an emerging organic compound that shows various anti-aging effects. Serum spermidine concentration decreases during aging inhuman, and dietary spermidine has been reported to extend healthy lifespanand delay the age-related decline in cognitive and physical performance inmany species such as yeast, worms, flies, and mice. Here, we explored aneffect of spermidine on age-associated decline in angiogenesis. Replicativesenescent ECs were prepared by culturing human ECs for an extended perioduntil passage 18-20, and cellular senescence was confirmed by loss ofproliferation capacity, increased CDK inhibitors expression, and senescence-associated beta-Gal activity. Intracellular polyamine contents were significantlyreduced in replicative senescent ECs, which was recovered by spermidinesupplementation. Spermidine supplementation improved the declinedangiogenic capacities including tube-formation on Matrigel in senescent ECs,while senescence features such as reduced proliferation and senescence-associated beta-Gal activity were not affected. Mechanistically, spermidinesupplementation accelerated the static autophagy flux, and improvedmitochondrial quality, e.g. reduced mitochondrial ROS and preservedmitochondrial membrane potential, in senescent ECs. Ischemia-inducedneovascularization was assessed using the hind-limb ischemia model in youngand aged mice. Blood flow recovery and neovascularization in ischemic musclewere considerably impaired in aged mice comparing to those in young mice. Ofnote, dietary spermidine significantly enhanced ischemia-induced angiogenesis,and improved the blood flow recovery in the ischemic limb, especially in agedmice. Our results reveal new mechanistic insights in anti-aging property ofspermidine, and suggest its therapeutic potential against ischemiccardiovascular disease, particularly in elderly population.