As the world population ages, chronic diseases such as diabetes, cardiovascular disease, cancer, and neurodegeneration become ever more prevalent. Interventions that favor healthy aging would constitute powerful strategies with which to limit human diseases that have a broad socioeconomic impact. Fasting regimens such as intermittent fasting or dietary adaptations such as caloric restriction are among the few regimens that extend life and beneficially affect health in all tested model organisms, including rodents and nonhuman primates. However, few people seem capable of changing their dietary routines for extended periods. Thus, supplementation with caloric restriction mimetics (CRMs), which would pharmacologically mimic the beneficial effects of caloric restriction or fasting, has gained attention as an attractive and potentially feasible strategy. The naturally occurring polyamine spermidine, the abundance of which declines during the process of aging, has emerged as a well-tolerable CRM targeting various molecular and physiological age-associated adversities.

Conceptually, healthy aging requires the retardation of multiple molecular and cellular alterations that drive the aging process and induce age-associated pathologies. These include genomic instability, epigenetic alterations, loss of protein degradation capacity (leading to neurodegeneration), deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, and chronic inflammation. Spermidine displays pleiotropic effects that include anti-inflammatory properties, antioxidant functions, enhancement of mitochondrial metabolic function and respiration, as well as improved proteostasis and chaperone activity. Many anti-aging effects of spermidine are causally connected to the capacity of this polyamine to induce cytoprotective autophagy. Autophagy ensures general cell homeostasis and proteostasis and is directly involved in the degradation of damaged, potentially toxic organelles and harmful protein aggregates, thus removing and recycling cytoplasmic material that otherwise would accumulate during aging. Consistently, extra supply of spermidine prolongs the life span across species in an autophagy-dependent manner and counteracts age-associated pathologies such as cardiovascular disease, neurodegeneration, and cancer. For instance, dietary spermidine supplementation ameliorates age-induced memory impairment in flies and protects from autoimmune-directed demyelination of neurons in a mouse model for multiple sclerosis. Spermidine also reduces the growth of transplantable tumors, stimulates anticancer immune surveillance in combination with chemotherapy, and suppresses tumorigenesis induced by chemical insults in mice. Moreover, elevated dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.

Although spermidine induces autophagy and autophagy inhibition curtails many of the health-promoting effects of spermidine, additional mechanisms have been proposed to explain the beneficial effects of spermidine on aging. These potentially autophagy-independent mechanisms include direct antioxidant and metabolic effects on arginine bioavailability and nitric oxide (NO) production. However, it has not been formally determined whether these routes act in a completely autophagy-independent manner or are interrelated with autophagy (in an additive or synergistic way) (see the figure), and it …