There are many mechanisms involved in spermidine’s beneficial health effects. The most researched and major mechanism is spermidine’s ability to induce autophagy.
Spermidine is a compound found in living cells and in foods including soybeans, wheat germ, nuts, fruits such as grapefruit and also in vegetables like broccoli. It is a polyamine, meaning that it is an organic compound with two or more amino groups. Human concentrations of spermidine decline with age and can change depending on nutrition, synthesis of polyamines within the gut microbiome, and disease state. Spermidine plays a crucial role in the survival and function of cells, including supporting cellular growth, DNA health, and apoptosis(33). Increased levels of spermidine have shown to have protective effects for the following: lifespan, cancer, metabolic conditions, cardiovascular conditions and cognitive conditions (24). Spermidine also counteracts 5-6 hallmarks of aging, including epigenetic alterations, impaired proteostasis, mitochondrial dysfunction, stem cell dysfunction, and impaired and intercellular communication(22, 38). The mechanisms for spermidine’s beneficial effects are explored below.
WHAT ARE THE MECHANISMS OF SPERMIDINE?
There are many mechanisms involved in spermidine’s beneficial health effects.
SPERMIDINE INDUCES AUTOPHAGY
The most researched and major mechanism is spermidine’s ability to induce autophagy. It has been shown that spermidine administration induces autophagy, or cellular cleanout, in yeast, mice, flies and worms as well as cell cultures(6, 12, 34, 39). Much of spermidine supplementation’s cardioprotective, anti-cancer, neuroprotective and lifespan-extending effects stem from induction of autophagy, which declines with age(18). Meaning that these health benefits are dependent on autophagy. When autophagy is inhibited, spermidine no longer extends lifespan across organism/animal models (6, 14, 15, 58). In autophagy deficient mice, spermidine does not confer cardioprotective benefits(4, 31). Spermidines’ anticancer properties are also enabled by autophagy. Much of these same effects are also due to an increase in mitophagy, or cleanout of dysfunctional mitochondria, which supports overall mitochondrial health(8, 9, 12, 44).
SPERMIDINE STIMULATES THE DEACETYLATION OF PROTEINS
Induction of autophagy is stimulated by deacetylation of proteins, or removal of acetyl groups from proteins. Spermidine’s ability to induce autophagy is likely enabled by its ability to inhibit E1A-associated protein p300(EP300)(6, 34), which inhibits acetylation of proteins(20, 48) and could be related to acetylCoA levels which when low induce autophagy(7). Spermidine is more active in low acetylCoA environments(39). Spermidine also activates AMPK and inhibits mTORC1 which could also play a role in autophagy and spermidine’s health benefits(27, 39). The exact mechanisms for how spermidine stimulates autophagy need further elucidation.
SPERMIDINES IMPACT ON LONGEVITY-RELATED COMPOUNDS
It is theorized that long-term autophagy effects of spermidine also involve the longevity gene FoxO3(4, 26). In terms of heart health, there is some evidence that spermidine also increases vasodilator nitric oxide(NO), beneficially impacts arginine levels and derails oxidative damage, conferring cardioprotective benefits(8, 18). Spermidine also might be involved in the phosphorylation proteins that would otherwise be damaging.
SPERMIDINE REDUCES INFLAMMATION AND STIMULATES THE IMMUNE SYSTEM
Another mechanism of action is spermidines ability to reduce inflammation and stimulate the immune system, this is of particular interest for spermidines anticancer properties. Autophagy enables the immune system to recognize cancer cells, which leads to improved immunosurveillance(19, 23, 30, 40). Additionally, spermidine is able to improve memory T cell function and response(dependent on autophagy)(42, 43). Spermidine is able to reduce inflammation by preventing the secretion of cytokines which lead to inflammation, in part due to autophagy(8, 17). Expression of lymphocyte function-associated antigen-1(LFA-1)(necessary for immune cell migration) increases with age(52). LFA-1 is suppressed by spermidine supplementation in aged mice(16, 51). This might be of significance due to LFA-1’s potential proaging relationship with DNA methylation of pro-inflammatory factors(16, 51, 57).
Spermidine also modulates facets of brain function. Neuroprotective effects of spermidine are mostly attributed to autophagy and anti-inflammatory effects, but still need further exploration. Spermidine supports proteostasis, protein regulation, in areas of high synaptic activity, which depends on autophagy and is important for neural function(25). Another theory for how spermidine exerts neuroprotective effects is that it acts on inflammation and immune cells, preventing cerebral tissue invasion(13, 57). To better understand these mechanisms, it is critical to understand whether or not spermidine is able to cross the blood-brain barrier in humans, which is widely unknown(5, 49).
WHAT DOES THIS ALL MEAN?
As the aging population grows, rising rates of chronic illness need to be addressed. There are several ways to mediate these rising rates, including lifestyle factors, like diet and exercise, and pharmacological interventions. Currently in the spotlight is the CRM, spermidine, which as an intervention is able to target 5-6 hallmarks of aging, nearly doubling the amount of hallmarks targeted by most other pharmacologic interventions(ie.17alpha-estradiol or senolytic compounds)(38). Spermidine is found naturally in foods and is also created by the bacteria in our guts. As we age, spermidine concentrations decline. In animal and organism models, supplementation of spermidine has been shown to exert longevity benefits from extending lifespan, to preventing age-related diseases such as neurodegeneration and heart disease. In nonagenarians(90-99 y.o) and centenarians, an increase in levels of whole-level spermidine is linked to longevity(41). Epidemiological studies have also suggested that higher polyamine intakes prevent death from certain age-related diseases(8). Spermidine is currently one of the most promising geroprotective agents in the longevity field.
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Author: Jacqueline Seymour
Jacki is a Master’s student at USC, home of Dr. Valter Longo’s Longevity Institute, where she’s studying her passion for life: Gerontology(the science of aging) and Nutrition.
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