A Matter of the Heart: Spermidine’s Protective Role in Cardiovascular Health

March 27, 2025

A Matter of the Heart:
Spermidine’s Protective Role
in Cardiovascular Health

Spermidine is gaining recognition as a powerful bioactive compound for supporting cardiovascular health and longevity. As cardiovascular disease remains the leading cause of death worldwide, scientists are exploring novel, naturally occurring compounds that can protect the heart and extend lifespan. Spermidine—a polyamine found in many fruits, vegetables, whole grains, and even produced endogenously—is emerging as a promising candidate. Research spanning animal models and human studies has highlighted its role in promoting heart health, reducing inflammation, extending lifespan, and improving overall cardiovascular function through mechanisms such as enhanced autophagy and improved mitochondrial performance. In this review, we bring together findings from several pivotal studies to help you understand the many benefits that spermidine offers for both cardiovascular health and aging.

Extending lifespan and protecting the heart

One of the landmark pieces of research comes from a 2016 study by Eisenberg et al. in Nature Medicine. In this study, researchers demonstrated that oral supplementation with spermidine not only extended the lifespan of mice but also provided significant cardioprotective benefits. Aging is commonly associated with cardiac hypertrophic remodeling, a structural and functional transformation of the heart characterized by an increase in cardiomyocyte (heart muscle cell) size and thickening of the heart walls. This process is often accompanied by a gradual decline in left ventricular diastolic function (how the heart relaxes and fills with blood after it contracts), leading to reduced cardiac efficiency and stiffness.

In this study, spermidine supplementation was shown to reduce cardiac hypertrophy, preserve diastolic function, and enhance key cellular processes such as autophagy, mitophagy, and mitochondrial respiration. It also lowered the age-dependent rise in plasma levels of the pro-inflammatory cytokine tumor necrosis factor-α (TNFα), which contributes to chronic inflammation and is elevated in heart failure patients. Additionally, supplementation led to a decrease in blood pressure and an increase in arginine bioavailability, potentially supporting nitric oxide (NO) production. NO acts as a vasodilator, meaning it relaxes and widens blood vessels, improving blood flow and reducing strain on the heart. NO is synthesized from arginine, which is also a precursor of spermidine. By supplementing with spermidine, arginine thus becomes more bioavailable for NO biosynthesis, likely increasing its production and the observed decrease in hypertension. Spermidine supplementation also increased titin phosphorylation (titin is a large protein that helps muscle cells stretch, like an elastic band in the muscle fibers), which enhances cardiomyocyte elasticity and reduces myocardial stiffness. This effect is likely mediated through increased NO production and activation of PKG, a key kinase that phosphorylates titin. By preserving titin function and reducing TNFα-driven inflammation, spermidine helps maintain diastolic heart properties, which are often impaired in heart failure.

Importantly, the study revealed that these benefits depend on functional autophagy, as autophagy-deficient mice did not experience the same improvements. Similar benefits were observed in hypertension rat models, and human epidemiological data suggested that higher dietary spermidine intake is associated with lower blood pressure and reduced cardiovascular disease (CVD) incidence.

Spermidine’s role in cardioprotection
Spermidine provides overall protection to the heart by reducing oxidative stress, inflammation, and cellular damage.
Spermidine supplementation (i) promotes autophagy and mitophagy in cardiomyocytes; ii) improves mitochondrial volume and function; (iii) reduces chronic inflammation (circulating TNFα levels); (iv) improves systemic arginine bioavailability that may favor the production of the vasodilator nitric oxide (NO), and thus decrease systemic blood pressure; (v) decreases left ventricle hypertrophy; and (vi) increases titin phosphorylation which improves the mechano-elastical properties of cardiomyocytes. Cardiomyocyte: heart muscle cells that contract to pump blood. Blood vessel: includes arteries and veins, which transport blood throughout the body. Titin: a spring-like protein in muscle cells that ensures smooth stretching and contracting when it’s properly phosphorylated. Arginine: an amino acid precursor to NO and spermidine. Adapted from Eisenberg et al., 2017. © 2025 Melissa Cano. All rights reserved.

Dietary polyamines and cardiovascular mortality

Before these cellular insights, a 2012 study published in the Global Journal of Health Science examined the relationship between dietary polyamines (including spermidine and its relative, spermine) and CVD mortality across 48 European and Western countries. Using food supply data and polyamine concentrations in various foods, researchers found that higher dietary intake of these polyamines was linked to lower rates of cardiovascular death. This large-scale analysis also noted that factors like higher GDP and increased consumption of fruits, vegetables, nuts, and beans were associated with better cardiovascular outcomes—while smoking and whole milk consumption had the opposite effect.

Building on these findings, the Bruneck Study, a 2018 prospective cohort study in The American Journal of Clinical Nutrition, tracked 829 participants aged 45–84 over 20 years in the town of Bruneck, Italy. The study reported that individuals with higher dietary spermidine intake experienced significantly lower all-cause mortality, suggesting that spermidine-rich diets may contribute to increased longevity. Similarly, a 2022 study published in Frontiers in Public Health analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 23,894 participants) and found that higher dietary spermidine intake was associated with a reduced risk of both CVD and all-cause mortality. Notably, spermidine from vegetables, cereals, legumes, nuts, and cheese demonstrated significant protective effects, reinforcing the role of dietary factors in disease prevention and cardiovascular health.

A 2024 study in Nutrients utilized data from the UK Biobank (184,732 participants) to analyze the association between dietary polyamines and cardiovascular risk. The study found that moderate spermidine intake was linked to lower all-cause mortality and reduced CVD incidence. Another 2024 study in Nutrition used Mendelian randomization (a research method in epidemiology that mimics a randomized controlled trial using genetic data) to confirm a causal relationship between higher spermidine levels and reduced hypertension, reduced blood glucose levels, improved lipid profiles, and lower CVD risk, further supporting spermidine’s potential as a dietary intervention for cardiovascular health.

A closer look in the heart

Spermidine and aortic health

In 2016, a study published in Atherosclerosis investigated spermidine’s effects on atherosclerotic plaque progression (the gradual build up of fats and others substances narrowing arteries and leading to CVD) in mice. The researchers found that while spermidine did not alter the size or cellular composition of plaques, it significantly reduced lipid accumulation and necrotic core formation (the buildup of dead cells, oxidized fats, and cellular debris inside a plaque). These benefits were attributed to spermidine’s ability to induce autophagy in vascular smooth muscle cells (VSMCs, which control the diameter of blood vessels), facilitating cholesterol efflux and stabilizing plaques. This study highlighted spermidine’s potential as a therapeutic agent for preventing CVD by targeting plaque instability. Building on these findings, a 2020 study in Aging Cell demonstrated that spermidine reduces vascular calcification (buildup of calcium leading to stiffness) in both rat and human VSMCs under osteogenic conditions by upregulating SIRT1, a central NAD+-dependent deacetylase that modulates numerous physiological processes by deacetylating target proteins and regulating gene expression. This suggests that spermidine could also help prevent arterial stiffness and vascular calcification, common issues in aging and chronic kidney disease. Together, these studies underscore spermidine’s dual role in combating atherosclerosis and vascular calcification, making it a promising candidate for cardiovascular health.

Peripheral artery disease and autophagy activation

A 2022 pilot study in Antioxidant examined a mixture of autophagy activators, including spermidine, in patients with peripheral artery disease (PAD, a specific type of atherosclerosis which occurs in the legs). After 60 days, patients receiving the mixture experienced a 91% increase in maximal walking distance, alongside improvements in oxidative stress markers and autophagic activity. These results indicate spermidine’s potential in improving vascular function and reducing oxidative stress in PAD patients.

Prevention of aortic aneurysms

A 2020 study in Journal of the American Heart Association investigated spermidine’s effects on experimental abdominal aortic aneurysms (AAAs, bulges in the aorta that can lead to its rupture) in mice. Spermidine treatment preserved aortic structural integrity, reduced inflammation, and increased autophagy-related proteins, suggesting its promise in preventing aneurysm progression.

Spermidine and mitochondrial function

Several studies have explored spermidine’s role in mitochondrial health. A 2020 study in Aging found that spermidine supplementation in aged rats improved mitochondrial biogenesis by activating the SIRT1/PGC-1α signaling pathway (PGC-1α is a master regulator of mitochondrial biogenesis), preserving myocardial structure and function. A 2021 study in Journal of Anatomy similarly demonstrated that spermidine supplementation increased mitochondrial numbers in aged mice and improved their structural alignment, suggesting that spermidine helps maintain mitochondrial integrity in aging hearts.

The role of spermidine in arterial aging and endothelial function

A 2013 study in Mechanism of Ageing and Development showed that spermidine supplementation reduced arterial stiffness in aged mice (the loss of elasticity in the arteries leading to CVD, primarily caused by aging). It also improved endothelial function (the ability of the thin layer of cells lining the blood vessels to properly control blood flow) by enhancing autophagy and increasing NO production. A 2023 study in Scientific Reports further supported these findings, showing that spermidine improved angiogenesis (the development of new blood vessels) and neovascularization in ischemic limbs (the development of small blood vessels to compensate for impaired blood flow) of aged mice by enhancing autophagy and mitochondrial function. Similarly, a 2017 study in Oncotarget reported that both spermidine and its relative spermine reversed age-related myocardial alterations in rats, reduced fibrosis (the overgrowth of scar tissue that can affect organ function), and decreased apoptosis (cell death), further suggesting that polyamines can modulate key pathways involved in cardiac deterioration.

The gut-heart connection

Beyond direct cardiac effects, spermidine appears to influence cardiovascular health via the gut microbiota. A 2020 study in Biological & Pharmaceutical Bulletin developed an innovative hybrid putrescine biosynthesis system using Bifidobacterium animalis ssp. lactis and arginine to boost polyamine production in the gut. A clinical trial involving a specially formulated yogurt showed improved vascular endothelial function and elevated blood spermidine levels, indicating a reduced risk of atherosclerosis. Additionally, a 2019 review in the Journal of Molecular and Cellular Cardiology highlighted how polyamines synthesized by both our cells and gut bacteria contribute to improved cardiomyocyte function, enhanced NO bioavailability, and reduced systemic inflammation—factors critical in preventing aortopathy in patients with bicuspid and tricuspid aortic valves. Further supporting this gut-heart axis, a 2021 study in Frontiers in Cardiovascular Medicine demonstrated that spermidine supplementation improved cardiac function in heart failure mice while modulating gut microbiota composition, suggesting a potential mechanistic link between gut-derived polyamines and cardiovascular health.

Mechanisms underlying spermidine’s cardioprotective effects

Across these studies, several recurring mechanisms emerge:

Enhanced autophagy and mitophagy: Spermidine consistently stimulates cellular recycling processes, which help clear damaged organelles and proteins, leading to improved cell survival and function.
Improved mitochondrial function: Many studies show that spermidine restores mitochondrial biogenesis and quality, ensuring that cardiomyocytes maintain their energy supply and structural integrity.
Anti-inflammatory and antioxidant effects: By reducing oxidative stress and systemic inflammation, spermidine contributes to healthier blood vessels and less plaque instability.
Gut microbiota interactions: The modulation of gut bacterial metabolism can increase endogenous spermidine production, offering an additional layer of cardiovascular protection.

Conclusion : you can protect your heart with spermidine

Spermidine has emerged as a powerful and versatile nutraceutical with significant potential to support cardiovascular health and promote longevity. Through its ability to enhance autophagy, improve mitochondrial function, reduce oxidative stress, and modulate inflammation, spermidine addresses multiple hallmarks of CVD. Studies spanning animal models and human populations have demonstrated its cardioprotective effects, including reducing cardiac hypertrophy, stabilizing atherosclerotic plaques, preventing vascular calcification, and improving endothelial function. Furthermore, spermidine’s interaction with the gut microbiota adds another layer of complexity to its benefits, suggesting a holistic approach to cardiovascular health.

The evidence is compelling: spermidine-rich diets are associated with lower blood pressure, reduced cardiovascular mortality, and increased lifespan. Clinical trials and mechanistic studies continue to uncover new ways in which spermidine can protect the heart, from improving peripheral artery disease symptoms to preventing aortic aneurysms. As research progresses, spermidine’s role as a dietary intervention for cardiovascular health becomes increasingly clear.

For those looking to support their heart health naturally, incorporating spermidine-rich foods—such as whole grains, legumes, aged cheeses, and mushrooms—into the diet may offer a simple yet effective strategy. Additionally, spermidine supplementation could provide a targeted approach for individuals at risk of CVD or those seeking to optimize their longevity. While further clinical trials are needed to fully establish its therapeutic potential, the current body of evidence positions spermidine as a promising candidate for the prevention and management of CVD.

Tackling this global health challenge demands a multifaceted approach, including public health interventions, lifestyle changes, and improved healthcare access. In this context, spermidine emerges as a natural, science-backed ally, offering a promising strategy to support heart health and enhance both lifespan and healthspan, helping to combat the growing threat of heart disease.

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