Polyamines are organic compounds essential for cell growth and function, possessing two or more amino groups. Alkyl polyamines, both naturally occurring and synthetic, are colorless, hygroscopic, and water-soluble. These low-molecular-weight linear polyamines are found in all forms of life. Principal examples include spermidine (a triamine) and spermine (a tetraamine), both structurally related to putrescine and cadaverine (diamines).
Understanding Polyamines
Polyamines, including putrescine, spermidine, and spermine, are aliphatic hydrocarbons with amino groups at both ends of their molecular structure. Spermidine plays a critical role in activating eukaryotic translation initiation factor 5A (eIF5A), an essential protein for eukaryotic protein synthesis. This activation involves post-translational modifications where a specific eIF5A lysine residue is converted to a hypusine residue via sequential reactions catalyzed by deoxyhypusine synthase, which transfers spermidine to the lysine residue, and deoxyhypusine hydroxylase.
Under physiological pH conditions, polyamines are positively charged and weakly bind to negatively charged intracellular molecules like nucleic acids, phospholipids, and ATP. They most frequently bind to RNA, regulating protein translation by influencing mRNA structure. E. coli has 17 proteins, and eukaryotes have six proteins translationally controlled in this manner, considered members of the "polyamine modulon." These proteins are involved in cell proliferation, biofilm formation, enhanced cell activity, and detoxification.
Sources of Polyamines
Polyamines are sourced from oral intake, intestinal microbiota, and biosynthesis in human cells. The body's ability to biosynthesize polyamines decreases with age, making it difficult to regulate. Therefore, controlling polyamine concentration requires managing intake from food and intestinal bacteria.
Since polyamines are essential for cell proliferation, they are found in high concentrations in actively proliferating cells, such as bacterial cells in the logarithmic growth phase and cancer cells. At the individual level, tissue polyamine concentration is high at a young age and decreases with aging.
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Benefits of Polyamines
Polyamines play a vital role in various biological processes, including maintaining intracellular pH levels and cell membrane potential. They are also central to processes such as aspartate receptor function, cGMP/PKG pathway activation, nitric oxide synthase activity, and cerebral cortex synaptosome activity.
Extending Healthy Lifespans
In 2009, Soda et al. first reported the effects of polyamines on extending healthy lifespans in mice. Mice fed high-polyamine chow (containing spermidine and spermine at 374 nmol/g and 1540 nmol/g, respectively) from 24 weeks of age had higher blood polyamine concentrations than those fed low-polyamine chow (containing spermidine and spermine at 143 nmol/g and 224 nmol/g, respectively). At 88 weeks, the incidence of glomerulosclerosis was lower, and the expression of senescence marker protein-30 (SMP30), which decreases with aging, was increased in the kidneys and liver of mice fed with high-polyamine chow. The survival rate of mice fed with high-polyamine chow was significantly higher than that of mice fed with low-polyamine chow.
Around the same time, Madeo et al. reported that spermidine greatly extended longevity in yeast, flies, worms, and human cells. Spermidine administration inhibited oxidative stress in aging mice and deacetylated histone H3 through the inhibition of histone acetyltransferases in aging yeast. The altered acetylation status of chromatin upregulated the expression of autophagy-related genes and promoted autophagy in yeast, flies, worms, and human cells.
In 2013, Sigrist et al. reported that dietary spermidine supplementation in aging flies suppressed age-induced memory impairment via autophagy mechanisms. They showed that ornithine decarboxylase-1, the rate-limiting enzyme for polyamine synthesis, suppressed olfactory memory loss in aged flies when expressed specifically in Kenyon cells, which are crucial for olfactory memory formation.
Inducing Autophagy
Spermidine is known to trigger autophagy, thought to be the main mechanism by which it slows down aging. It has been demonstrated to induce autophagy in mouse liver cells, worms, yeast, and flies. Defective autophagy and a lack of spermidine are correlated with reduced lifespans, chronic stress, and acute inflammation.
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A 2024 study by Dongmei Jiang and colleagues found that spermidine protects cells from oxidative stress by activating autophagy. The study identified several key genes that spermidine affects, reducing oxidative stress and boosting autophagy in granulosa cells from Sichuan white geese. Blocking the mTOR pathway helps increase the protective effects of spermidine.
Combating Obesity
A 2024 study by Yinhua Ni and colleagues explored how spermidine helps fight obesity, particularly its effects on fat cells in mice fed a high-fat diet. Spermidine significantly improved heat generation by burning fat in obese mice, especially under cold exposure.
Spermidine also improved how these fat cells handled sugar and fat by triggering autophagy and increasing a growth factor known as FGF21. Blocking the action of this growth factor eliminated the beneficial effects of spermidine on fat-burning.
Anti-Inflammatory Properties
Spermidine supports health and longevity via autophagy and has anti-inflammatory properties. It is involved in lipid metabolism, cell growth and proliferation, and programmed cell death.
Chronic inflammation prevents healthy tissue regeneration, causes immune cells to become dysfunctional, and accelerates cellular senescence. Spermidine appears to reduce chronic inflammation and may slow down one way in which cells and tissues age.
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Potential for Delaying Aging
Spermidine has been shown to increase lifespan in animal studies and prevents liver fibrosis and hepatocellular carcinoma in mice. A diet rich in polyamines also appears to improve resistance to stress. The age-related decline of spermidine supports the onset of age-related diseases.
However, a November 2023 study by Chisato Nagata and colleagues found no strong link between polyamine intake and the risk of death in Japanese adults. The data suggested high spermidine intake may be linked to a higher risk of cancer death in women, indicating that dietary spermidine may not have beneficial effects on lifespan and requires further research.
Lipid Metabolism
Lipid metabolism is a known regulator of lifespan, and dysfunctional lipid metabolism can have serious ramifications for healthspan and lifespan. Spermidine helps create fat cells (adipocytes) from stem cells and also changes lipid profiles. It facilitates the differentiation of preadipocyte cells into mature adipocyte cells as part of the adipogenesis process.
A study showed that administration of a-difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, could halt adipogenesis entirely. This total disruption of lipid metabolism could be reversed by spermidine administration, restoring the expression of some transcription factors important for preadipocyte differentiation and late adipocyte markers.
Cellular Acylation
A 2024 study by Zhang and others found that when proteins undergo chemical changes, acyl groups attach to spermidine after being taken from proteins in the mitochondria. These new compounds, formed when spermidine gains certain chemical groups, can affect the lifespan of organisms and the growth of cancer cells, providing fresh insights into how cells work and potentially leading to new treatments for different health issues.
Impact on Metabolic Risk Factors
A January 2024 study by Kevser Tari Selcuk and her team examined how dietary polyamines affect health in postmenopausal women. Higher intake of putrescine was linked to lower systolic blood pressure, while increased spermidine intake was connected to a larger waist size, higher blood pressure, and a higher BMI, suggesting that dietary polyamines may affect metabolic risk factors.
Cognitive Function
Research published in 2021 in the journal Cell Reports shows that dietary spermidine can improve thinking and mitochondrial function in flies and mice, with some early data for humans as well.
Cardiovascular Health
A 2016 study found that spermidine can reverse some signs of aging and improve heart function in older mice by improving heart structure and function and restoring mitochondrial structure and function. Two human studies show that spermidine intake may lower the risk of death from all causes, heart disease, and cancer.
Gut Health
A 2024 study examined neoagarooligosaccharides (NAOS) and suggested that spermidine may benefit human gut health. NAOS improved the gut health of chickens by enhancing digestion and nutrient absorption, improving intestinal structure, and increasing the growth of bacteria that make spermidine.
Bone Health
A 2024 study by Amin Cressman and his team researched how polyamines impact bone formation and health. They found that when human bone marrow cells changed into bone cells, a certain enzyme level increased, leading to a decrease in polyamines believed to be crucial for healthy bone development. Adding more polyamines to these cells slowed the growth of bone-like structures, suggesting that treatments targeting these pathways might help in managing bone-related symptoms in people with Snyder-Robinson syndrome.
Safety and Side Effects
Spermidine is a naturally occurring product in the body and part of a group of compounds known as biogenic amines. These amines, including histamine, serotonin, and dopamine, are involved in intercellular communication with multiple effects on human pathophysiology. Histamine and polyamine content should be restricted to patients with H. pylori, as dietary polyamine input has been proposed as one of the major reasons for reducing the effectiveness of anti-tumour strategies based on polyamine deprivation.
General Safety
At the daily recommended dose of about 5 to 10 mg, spermidine supplements are generally considered safe with excellent tolerability and no known adverse effects to date. Spermidine is naturally produced in the human body and occurs in the food we eat, making our bodies well-adapted to these compounds.
Potential Risks at High Doses
A 1997 study on lab mice revealed that spermidine showed some adverse outcomes at doses of about 600mg/kg body weight, which is extremely high compared to the typical daily dose. At this higher intake, spermidine began to show signs of toxicity, such as a decrease in appetite, weight, and blood levels of calcium and potassium in male rats, and an increase in plasma activity of aspartate aminotransferase and alanine aminotransferase.
Conflicting Information Regarding Health
There is conflicting information regarding the relationship between polyamines and health. Decreased polyamine levels are used to treat cancer, while increased polyamine levels are thought to extend healthy life span. Clinical studies have shown that the simultaneous administration of Sulindac, a known anti-inflammatory agent, and D,L-α-Difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, is effective in the treatment of cancer, thought to be due to the inhibition of the proliferation-promoting effect of polyamines on cancer cells. However, polyamine intake does not seem to induce carcinogenesis in healthy individuals.
Large-scale clinical studies by multiple groups are expected in the future to provide further scientific evidence for the health-promoting effects of polyamines. In ongoing clinical studies in Europe, oral polyamine is administered at concentrations that account for only 4â10% of the estimated average dietary intake, limited by the polyamine concentration in the wheat germ-derived supplements used.
Histamine and Polyamine Interactions
Histamine, serotonin, and dopamine are biogenic amines involved in intercellular communication with multiple effects on human pathophysiology. Polyamines derived from ornithine (putrescine, spermidine, and spermine) are mainly involved in intracellular effects related to cell proliferation and death mechanisms. There are interactions between components of all these amine metabolic and signaling networks (decarboxylases, transporters, oxidases, receptors etc.) at cellular and tissue levels, distinct from nervous and neuroendocrine systems.
Most biogenic amines and polyamines are degraded by flavin-dependent or copper-dependent amino oxidases, such as MAOs, MAO-A and MAO-B, diamine oxidase (DAO)/histaminidase, and polyamine oxidases. Accumulation of some amine degradation products, such as aldehydes and reactive oxygen species (ROS), can become toxic.
Dietary Sources
Polyamines are found in all types of food and in a wide range of concentrations. Spermidine and spermine are naturally present in many foods. The main polyamine in plant-derived foods is spermidine, whereas spermine content is generally higher in animal-derived foods. Turban shell viscera is the food richest in polyamines.
Other dietary sources of spermidine include:
- Grapefruit
- Soy products
- Corn
- Whole grains
- Chickpeas
- Peas
- Green peppers
- Broccoli
- Oranges
- Green tea
- Rice bran
- Shiitake mushrooms
- Amaranth grain
- Wheat germ
- Cauliflower
- Mature cheeses
- Durian
A promising source of polyamines other than food is the commensal bacteria in the gut. Administration of Bifidobacterium animalis subsp. lactis LKM512 in mice increased polyamine levels in the intestine and significantly extended lifespan, associated with the downregulation of inflammation-associated genes and improvement of the intestinal barrier function.
Regulation of Polyamine Levels
The concentration of polyamines in the colonic lumen is determined by the equilibrium between polyamine uptake (utilization) and export (production) by intestinal bacteria. Methods to regulate the levels of polyamines in the colonic lumen, such as increasing the concentration of polyamines by simultaneous administration of bifidobacteria and arginine, are in progress and partially commercialized.
Clinical Trials
In Europe, clinical trials focusing on the ability of polyamines to improve cognitive function began in 2018. Prior to this, the safety and tolerability of wheat germ-derived spermidine used in oral polyamine consumption clinical trials was confirmed.
In a randomized, double-blind, placebo-controlled phase IIa trial reported in 2018, older adults aged 60â80 years (n = 15 in the polyamine and control groups) received 1200 mg spermidine per day for 3 months, with the polyamine group reporting statistically significant improvements in cognition when compared to the control group.
Based on these results, a randomized, double-blind, placebo-controlled phase IIb trial, which began in 2019, will analyze the effects of concurrently administering 200 μg of putrescine, 900 μg of spermidine, and 500 μg of spermine (1600 μg total) per day for 12 months in older adults aged 60 to 90 years (n = 50 in the polyamine and control groups). The amount of polyamines administered in this clinical trial is approximately 4â10% of the estimated dietary intake of polyamines in developed countries.