⫸ Spermidine (8) is the most abundant polyamine in different human tissues, and the concentration of intra- cellular spermidine decreases during the natural aging process of the body [63]. Sperm contains high concentrations of spermidine, which prevents cellular senescence and allows long-term survival of the germ cell line. The homeostasis of spermidine is influenced by nutritional intake, intestinal microflora, endogenous biosynthesis, degradation and intercellular transport systems [64]. High levels of spermidine are found in a wide range of foods, such as fresh peppers, wheat germ, broccoli, cauliflower, and cheeses, while higher levels are found in soy products such as natto, shiitake, and durian [65].

As a mimetic of caloric restriction, spermidine has significant cardioprotective and neuroprotective effects and activates anti-tumor immunosurveillance in rodent models. In addition, polyamines in diet have been associated with reduced cancer-related and cardiovascular mortality in human epidemiological surveys. Spermidine maintains mitochondrial function, shows anti-inflammatory activi- ties, and prevents stem cells from aging. Mechanistically, it follows the same biochemical pathway as other caloric restriction mimics: it induces protein deacetylation and relies on autophagy [66].

Administration of spermidine increased the survival of yeast, nematodes, fruit flies and human immune cells and reduced age-related mortality in mice. In aging flies, spermidine treatment improved memory, an effect asso- ciated with increased autophagy in neuronal tissue [67]. In rats, spermidine treatment (5 and 10 mg/kg) improved motor performance and reduced pro-inflammatory cytokines and oxidative stress in the striatum [68]. In a rodent model of Huntington’s disease, injection of sper- midine into the striatum improved recognition memory for novel objects [69]. Several studies have been con- ducted on spermidine treatment in humans. Long-term spermidine supplementation (1.2 mg/day) is safe and well tolerated in the elderly [70]. Food questionnaires have shown that high dietary intake of spermidine lowers blood pressure and benefits cardiovascular disease, while spermidine supplementation (1.2 mg/day for 3 months) improves memory performance in older adults (60– 80 years) with subjective cognitive decline [71]. As noted above, spermidine administration increases survival in animal models. A study reportedly aimed to test a potential link between dietary spermidine levels and mortality in humans. Their findings provide epidemiological support for the concept of spermidine-rich nutrition and improved human survival [64]. ⫷[1]