Lesson 31: Spermadine

Spermadine is one of many compounds identified to date that trigger some of the same beneficial stress response mechanisms that are upregulated by calorie restriction. For example, spermadine is known to boost the operation of autophagy, a collection of cellular maintenance processes responsible for recycling damaged structures and unwanted proteins. Keeping the level of damage lower means a lesser a chance of generating further detrimental consequences. The outcome, at least in short-lived species, is a longer healthy life span.

Spermidine—a compound found in foods like tempeh, mushrooms, , legumes, corn and whole grains—seems to prevent (at least in animal models) liver fibrosis and hepatocellular carcinoma, which is the most common type of liver cancer. the highest source of spermidine is from Natto.

Polyamines including spermidine play an essential role in intermediate metabolism. Since they are synthesized by higher eukaryotic cells, they are not vitamins. However, the levels of polyamines are profoundly influenced by their external supply. Research has shown over the past decade that supplementing spermidine by adding it to culture media is sufficient to extend longevity and to improve health span at multiple levels. Thus, supplementation was able to suppress the age-related decline in cardiovascular function and increased overall longevity by approximately 10%.

The molecular and cellular mechanisms through which spermidine delays age-related disease and death have been elucidated to some extent. Spermidine can act as an inhibitor of EP300. EP300 acts as an inhibitor of autophagy by acetylating lysine residues within multiple proteins that are involved in autophagy-regulatory or autophagy-executing circuitries. As a result, the inhibition of EP300 by spermidine stimulates autophagy. Autophagy is required for the anti-aging effect of spermidine as indicated by the fact that genetic inhibition of autophagy abolishes the longevity-extending effects of spermidine.

Until now the literature on the longevity-enhancing effects of spermidine has been limited to model organisms. Now, two prospective population-based studies report for the first time that nutritional spermidine uptake is also linked to reduced overall, cardiovascular and cancer-related mortality in humans. Both studies were based on the use of food questionnaires that allowed to calculate for each individual the nutritional uptake of polyamines including spermidine. Importantly, high spermidine uptake constituted an independent favourable prognostic parameter for reduced mortality, meaning that this variable predicted a reduced incidence of death even after correction for possible confounding factors.

In addition to the aforementioned epidemiological results, there are further, though admittedly indirect arguments in favour of a health-improving role for spermidine in human health. Thus, spermidine has been classified as a “caloric restriction mimetic” that has broad health-promoting effects due to its capacity to induce similar biochemical changes as does caloric restriction. Second, the proximal pharmacological target of spermidine is the same as that of salicylic acid, the active metabolite of aspirin (both inhibit EP300). The health-improving effects of aspirin have been initially attributed to act as an anti-coagulant. Since spermidine has not been reported to have similar anti-coagulant activity, we prefer the hypothesis that aspirin may mediate its broad pro-health effects via the inhibition of EP300.

Spermidine is a type of compound called a polyamine and was first isolated from semen, which explains its name. It likely works to prevent cancer by enhancing MAP1S-activated autophagy, or the cells’ self-eating behavior: The benefits of spermidine disappear when MAP1S isn’t available. A proposal is that autophagy — or the lack thereof — plays a role in cancer and premature aging. Damaged cells due to defective autophagy can go on to replicate and become tumors or cause other problems. Spermidine can prevent this process. There is also some evidence that it might improve cardiovascular health.