Protective effects of lifelong consumption of spermidine on accelerated aging through modulation of NAD-related metabolic pathways

Background: Physiological polyamines putrescine, spermidine and spermine are a class of polycations involved in important biological processes, like cell growth and proliferations. They can be formed endogenously or taken from diet, and even though their biosynthesis and catabolism is efficiently controlled through finely regulated rate-limiting enzymes, aging impairs polyamine homeostasis leading to a decrease of their intracellular levels. Among polyamines, spermidine plays an important role in delaying aging: exogenous administration of spermidine markedly extended the lifespan of yeast, flies and worms, and human immune cells. Purpose: This work aimed to assess the effect of spermidine as a neuroprotector and its relative influence on nicotinamide adenine dinucleotide (NAD) metabolism, and ATP metabolism in the senescence accelerated mouse prone model (SAMP8) and in parallel in the senescence-accelerated mice resistant (SAMR1) strain. Methodology: Spermidine was daily administered to both SAMP8 and SAMR1 mice in drinking water at a concentration mimicking a spermidine rich diet for 32 weeks. The multifactorial aspects of aging have been analyzed by assessing the impact of longterm administration of spermidine on the levels of NAD and ATP related metabolites, on oxidative stress response through the evaluation of the coenzyme Q10 levels, on neuroinflammation and NMAD receptor expression in the brain using immunohistochemical analysis, and on cognitive impairment through Novel Object Recognition test. Results and Conclusions: The obtained results have evidenced a marked effect on the oxidative stress response, NAD synthesis and energetic metabolism in SAMP8 mice consuming a spermidine rich diet, accompanied by an amelioration of the cognitiveperformance.