Spermidine is the polyamine that is the most potent natural trigger of the autophagy — the cellular housekeeping process that removes the damaged proteins, the dysfunctional organelles, and the invasive pathogens from the cell and recycles their components for the new protein synthesis and for the energy production. The spermidine is found in all living organisms — it is synthesised from the putrescine in the mammalian cells, it is taken up from the diet (from the wheat germ, the soybeans, the mushrooms, the cheese, and the meat), and it accumulates in the cells during the fasting and during the caloric restriction. The spermidine concentration in the cells declines with age (from approximately 10-15 nmol/mg protein in the young cells to 3-5 nmol/mg protein in the aged cells), and this decline in the spermidine levels is one of the primary drivers of the age-related decline in the autophagy and of the accumulation of the damaged proteins and the dysfunctional organelles in the aged cells. The supplementation with the spermidine has been shown to induce the autophagy, to reduce the accumulation of the damaged proteins, to improve the mitochondrial function, and to extend the lifespan in multiple animal models of ageing — making it one of the most promising and most evidence-based anti-ageing interventions. The typical dietary spermidine intake is 5-10mg daily (from the normal diet), and the therapeutic doses for the autophagy induction are 1-3mg of spermidine daily (as the spermidine supplement or as the wheat germ extract, which is rich in the spermidine).
Spermidine and the Autophagy Mechanism
The spermidine induces the autophagy primarily through the inhibition of the EP300 (the acetyltransferase that acetylates and inhibits many of the autophagy-related proteins, including the ATG5, the ATG7, and the LC3). By inhibiting the EP300, the spermidine increases the acetylation of the autophagy-related proteins, promotes the assembly of the autophagosome, and enhances the fusion of the autophagosome with the lysosome (to form the autolysosome, where the sequestered material is degraded by the lysosomal enzymes). The spermidine also activates the AMPK (the master regulator of the cellular energy metabolism) and inhibits the mTOR (the master regulator of the cell growth and of the protein synthesis) — both of which are key activators of the autophagy. This multi-target mechanism of the spermidine (EP300 inhibition, AMPK activation, mTOR inhibition) makes it one of the most potent and most comprehensive activators of the autophagy of any natural compound, and it explains why the spermidine supplementation has such broad and powerful anti-ageing effects in the animal models.
The clinical importance of the spermidine for the healthy ageing is underscored by the observation that the spermidine supplementation improves the cognitive function, reduces the blood pressure, and improves the sleep quality in older adults. A study in 8 healthy older adults (aged 60-85) found that the spermidine supplementation at 1mg daily for 3 months significantly improved the cognitive function (as measured by the word recall test and the trail-making test), reduced the systolic blood pressure (by 8-12mmHg), and improved the sleep quality (as measured by the Pittsburgh Sleep Quality Index) — demonstrating the broad anti-ageing effects of the spermidine in humans. A prospective cohort study in over 800 individuals also found that the high dietary spermidine intake was associated with the reduced all-cause mortality (by 30-40%) and with the reduced cardiovascular mortality (by 40-50%) — making the spermidine one of the most protective dietary factors for the longevity.
Practical Application
For general spermidine supplementation for the autophagy support and for the healthy ageing, the evidence-based approach is to supplement with 1-3mg of spermidine daily (as the pure spermidine or as the wheat germ extract, which contains 0.1-0.5mg of spermidine per gram and is the most concentrated natural source of the spermidine). The spermidine should be taken in the morning (to align with the circadian pattern of the autophagy, which is highest during the morning and during the fasting state). The spermidine is generally well-tolerated with no significant adverse effects at doses up to 10mg daily, and it does not cause the gastrointestinal symptoms that are associated with many other autophagy-inducing compounds (such as the high-dose resveratrol or the high-dose curcumin). For comprehensive autophagy and longevity support, spermidine pairs well with the fisetin (which is another natural senolytic that works through a complementary mechanism involving the reduction of the senescent cell burden), with the NR (which increases the NAD+ levels and activates the sirtuins, which regulate the autophagy), with the resveratrol (which activates the NAMPT and enhances the NAD+ synthesis), and with the caloric restriction or the intermittent fasting (which are the most powerful natural triggers of the autophagy and which work synergistically with the spermidine for the cellular housekeeping).
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