Spermidine confers its benefits by inducing a process called autophagy which is Greek for ‘self-eating.’ The ancient Egyptians introduced an enduring concept of self-eating in the form of the Ouroboros, an emblem depicting a dragon devouring its own tail that can symbolize cyclical repetition and restoration. This symbolic process is essentially what autophagy accomplishes in cells. While it may initially invoke images of depraved self-cannibalism, autophagy is a process of cellular renewal by which cells develop increased resistance to oxidative stress and are induced to degrade misfolded proteins, dysfunctional mitochondria, and other disruptive cellular components inside lysosomes. A study of centenarians suggests that these long-lived individuals possess genes that significantly upregulate autophagy-lysosomal pathways, which can be passed on to their offspring.
Autophagy also declines with age, but spermidine intake fans the flames of this restorative process. The benefits of spermidine are autophagy-dependent as demonstrated by the absence of positive health effects in animal models that have had components critical for autophagy regulation genetically disrupted.
Like spermidine, exercise and caloric restriction are also very effective ways of activating autophagy. Fasting and spermidine are referred to as caloric restriction mimetics (CRMs) because they mimic the substantial health-promoting effects that caloric restriction induces. Indeed, they activate similar mechanisms that converge on proteins capable of stimulating autophagy.
Exercise offers a myriad of health benefits not limited to autophagy, so it is practically indispensable for optimal health. Combining exercise and spermidine suggests a possible synergistic effect in preventing and treating skeletal muscle atrophy in aged rats, which could pave the way for human trials to examine combinational therapies.
Even the disappointing CRM resveratrol gets a boost when combined with spermidine at very low doses supporting the possibility of a beneficial synergistic effect of autophagy-promoting agents. Both CRMs induce autophagy via distinct mechanisms that converge on this restorative process. Yet, unlike resveratrol, spermidine shows promising bioavailability thus far.
Mechanism of action
So how does spermidine fuel autophagy? A study in aged, human osteoarthritic cells shows that spermidine can increase the expression of an enzyme called acetyltransferase EP300 which binds to proteins that ignite autophagy to protect against osteoarthritis development. Additionally, it can activate autophagy by promoting the AMPK-FOXO3a (AMP-activated protein kinase-Forkhead box O 3a) signal pathway present in mammals, which promotes health via increased resistance to oxidative stress.
