Spermidine: Benefits, Uses, and Side Effects

Found in grapefruit, spermidine is one of the more interesting polyamines. Some research suggests that spermidine may slow down aging and promote healthy longevity.

What is spermidine?

Spermidine is a polyamine, meaning that it has two or more primary amino groups. It is naturally occurring and widely encountered in ribosomes and living tissues. It plays a critical role in cellular function and survival.

Spermidine was first discovered in 1678 by Dutch scientist Anton Van Leeuwenhoek in a sample of human semen. Shortly after, spermidine was discovered in human sperm. In the body, spermidine is created from its precursor, putrescine. It is the precursor for another polyamine called spermine, which is also important for cellular function.

There are two pathways in which putrescine is created, and both start with the amino acid arginine.

The first pathway sees arginine converted into agmatine with support from an enzyme known as arginine decarboxylase. In the next step, the agmatine gets converted into N-carbamoyl putrescine by agmatine imino hydroxylase. Finally, N-carbamoyl putrescine is transformed into putrescine, and the transformation is complete.

The second pathway simply converts arginine into ornithine followed by its conversion into putrescine by the enzyme ornithine decarboxylase.

Spermidine and putrescine are known to stimulate autophagy. This is a system that breaks down waste inside cells and recycles cellular components. Autophagy allows damaged or defective mitochondria to be broken down and disposed of. The disposal of mitochondria is a tightly controlled process [1].

Polyamines can bind to many different types of molecules, making them very useful. They support processes such as cellular growth, DNA stability, cellular proliferation, and apoptosis [2]. It also appears that polyamines function in a similar way to growth factors during cell division. This is why putrescine and spermidine are important for healthy tissue growth and function.

What foods are high in spermidine?

There are many dietary sources of spermidine, some of these are shown in the list below:

• Grapefruit 
• Soy products
• Corn
• Whole grain 
• Chickpeas 
• Peas
• Green peppers 
• Broccoli 
• Oranges
• Green tea
• Rice bran
• Fresh green pepper
• Shiitake mushrooms
• Amaranth grain 
• Wheat germ
• Cauliflower, 
• Broccoli
• Mature cheeses
• Durian

Spermidine is also readily available as a dietary supplement.

It is worth noting that much of the Mediterranean diet contains spermidine-rich foods. This may partially explain the phenomena of the “blue zones” and why people there often live longer than elsewhere.

Spermidine benefits

There are some potential health benefits from supplementing or eating enough spermidine in the diet. It may also influence aging and support healthy longevity.

Spermidine plays an important role in the regulation of various biological processes, including levels of intracellular pH and the maintenance of cell membrane potential. 

It also plays a central role in a number of important biological processes. These include aspartate receptors, cGMP/PKG pathway activation, nitric oxide synthase, and cerebral cortex synaptosome activity.

Spermidine interests scientists studying aging. It plays an important role in how long cells and living tissues live [3]. 

Spermidine and autophagy

Spermidine is known to trigger autophagy. It is thought to be the main mechanism by which it appears to slow down aging [4]. 

It has been demonstrated to induce autophagy in mouse liver cells, worms, yeast, and flies. A defective autophagy mechanism and a lack of spermidine are correlated with reduced lifespans, chronic stress, and acute inflammation.

In a 2024 study, Dongmei Jiang and colleagues investigated how spermidine can protect cells from oxidative stress [5]. This is a process that can damage cells and lead to various diseases. They focused on granulosa cells from Sichuan white geese, which are important for the development of eggs in birds.

The team used a model of oxidative stress made with a chemical called 3-nitropropionic acid (3-NPA). They studied how spermidine affects the cell’s response to stress. They found that spermidine activated autophagy.

The study identified several key genes that spermidine affects, which reduce oxidative stress and boost autophagy in these cells. They also found that blocking a pathway called mTOR helps increase the protective effects of spermidine. This pathway usually stops autophagy.

These findings suggest that spermidine may help reduce oxidative stress in cells. It does this by promoting autophagy. This could be beneficial for keeping animal cells healthy.

Spermidine and obesity

In a 2024 study by Yinhua Ni and colleagues, researchers explored how spermidine helps in fighting obesity [6]. They specifically looked at its effects on fat cells in mice, especially in those fed a high-fat diet. Normally, the body can generate heat by burning

fat, a process known as thermogenesis. In lean mice, spermidine didn’t change this heat generation. However, in obese mice, it significantly improved this process, especially under certain conditions like cold exposure.

Spermidine also improved how these fat cells handled sugar and fat. This improvement was due to two factors. First, it triggered autophagy in cells. Second, it increased a growth factor known as FGF21, which in turn, affected other pathways in the cells. 

When researchers blocked the action of this growth factor, the beneficial effects of spermidine on fat-burning were lost. This study suggests spermidine could be a useful tool in managing obesity and its related health issues.

Anti-inflammatory properties

The primary way in which spermidine appears to support longevity is via autophagy. But there is also evidence that it supports health and longevity in other ways. Some studies suggest that it has anti-inflammatory properties [7-8]. It is also involved in lipid metabolism, cell growth and proliferation, and programmed cell death [9-11].

It is widely accepted that inflammation helps with wound healing and fighting off germs. However, persistent inflammation from aging, known as inflammaging, can be harmful.

Chronic inflammation prevents healthy tissue regeneration, causes immune cells to become dysfunctional, and can even accelerate cellular senescence. Spermidine appears to reduce this chronic inflammation and may slow down one way in which cells and tissues age.

Spermidine may delay aging

Spermidine has been shown to increase lifespan in a number of animal studies. It also prevents liver fibrosis and hepatocellular carcinoma in mice [12-13]. This also appears to be the case with a diet rich in polyamines [14]. 

There is also some evidence to suggest that it improves resistance to stress. And the age-related decline of spermidine supports the onset of age-related diseases [15-16]. However, not all studies agree with this.

In a November 2023 study by Chisato Nagata and colleagues, the team investigated the relationship between dietary polyamines and mortality in Japanese adults [17]. Polyamines are substances like putrescine, spermidine, and spermine. They are found in many foods and may affect health.

The study involved over 29,000 Japanese men and women aged 35 and older. The researchers used food frequency questionnaires from 1992 to estimate the participants’ intake of polyamines. They tracked the participants for 16 years to see how their diet might relate to their risk of death.

The study looked at other factors that could affect health. It found no strong link between polyamine intake and the risk of death. This was true for both men and women. The data suggested high spermidine intake may be linked to a higher risk of cancer death in women.

This study suggests that dietary spermidine may not have beneficial effects on lifespan. More research is needed to understand how dietary polyamines affect health and disease in different populations with varying diets.

Fat and blood pressure

Lipid metabolism is a known regulator of lifespan. When lipid metabolism is dysfunctional it can have serious ramifications for both healthspan and lifespan. Spermidine helps create fat cells (adipocytes) from stem cells and also changes lipid profiles. Spermidine facilitates the differentiation of preadipocyte cells into mature adipocyte cells as part of the adipogenesis process [18].

This suggests lipid metabolism is another way spermidine may affect lifespan.

A study showed that administration of a-difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, could halt adipogenesis entirely [19]. This total disruption of lipid metabolism could be reversed by the administration of spermidine despite DFMO still being present. The researchers found that spermidine helped restore the expression of some transcription factors. These particular factors are important for preadipocyte differentiation and late adipocyte markers.

If these compounds are taken together, they may help support healthy aging. This is due to better autophagy, less inflammation, lower oxidative stress, improved cell growth, and better lipid metabolism.

In a 2024 study by Zhang and others, researchers looked at how proteins in our cells deal with chemical changes. They focused on a process where small chemical groups, called acyl groups, are added to and removed from proteins. This study showed that these chemical groups, after being taken from proteins in the mitochondria, attach to spermidine. 

Normally, when proteins undergo these chemical changes, it can affect their function and the overall balance within the cell. Understanding how these changes occur and are reversed is essential for grasping how cells work. The team found new compounds, formed when spermidine gains certain chemical groups. They studied the effects of these compounds in worms and mammalian cells.

They found that these new compounds can affect the lifespan of organisms and the growth of cancer cells. This surprising finding about spermidine and new compounds gives us fresh insights into how our cells work. It may lead to new treatments for different health issues, like ways to extend lifespan and fight cancer [20].

In a January 2024 study by Kevser Tari Selcuk and her team, researchers examined how dietary polyamines affect health. These nutrients are found in many foods. They looked at health risk factors and body measurements in postmenopausal women.

The study involved 562 women between the ages of 45 and 64 who visited a Family Health Center. The researchers used questionnaires to collect information about the women’s diets. They searched for connections between certain polyamines and health indicators. These indicators included blood pressure, waist circumference, and body mass index (BMI).

They found that higher intake of putrescine was linked to lower systolic blood pressure. On the other hand, increased spermidine intake is connected to several health issues. These include a larger waist size, higher blood pressure, and a higher BMI. It also relates to a bigger waist-to-height ratio.

The study suggests that dietary polyamines may affect health, especially in postmenopausal women. This needs more research due to their potential impact on metabolic risk factors. Also the study’s design means it cannot definitively prove cause and effect. There are some limits, like relying on self-reported food intake and not considering seasonal changes in diet [21].

Spermidine and cognitive decline

Research published in 2021 in the journal Cell Reports shows that dietary spermidine can improve thinking and mitochondrial function. This was found in flies and mice, and there is some early data for humans as well [22]. 

This study was interesting, but it had some limitations. We need more dose-response data before we can make a strong conclusion about the benefits to human thinking.

Spermidine for cancer and cardiovascular health

There is also some evidence that it might reduce the risk of cardiovascular disease. In a 2016 study, researchers found that spermidine can reverse some signs of aging. It also helps improve heart function in older mice [23]. 

At the organ level, heart structure and function were improved in the aged mice given spermidine. The same mice also saw improvements to their metabolism due to restoration of mitochondrial structure and function.

In humans, two studies show that taking spermidine may lower the risk of death from all causes, heart disease, and cancer [24]. Based on this data and other studies, some researchers conclude that spermidine delays aging in humans [25]. This data is not yet completely conclusive but is certainly worthy of further study.

Studies also found a link between the intake of dietary spermidine with a reduced risk of colon cancer [26].

Spermidine and gut health

In a study from 2024, researchers examined a sugar called neoagarooligosaccharides (NAOS). This sugar may improve the gut health of chickens [27]. This research focused on antibiotics in livestock feed. However, there was an underlying suggestion that spermidine may also benefit human gut health.

When they added NAOS to the diet of chickens, the results were promising. The chickens grew better, and their gut health improved significantly. This included better digestion and nutrient absorption, and a healthier intestinal structure. 

The researchers also found that NAOS improved the gut bacteria in these birds. In particular, it increased the growth of bacteria that make spermidine.

This study shows that NAOS may be a safe alternative to antibiotics in animal farming. It also highlights how NAOS can improve gut health in humans by increasing the production of spermidine.

More research is needed to determine if the results of this work are transferable to humans.

Spermidine may improve bone health in Snyder-Robinson syndrome

Snyder-Robinson syndrome is a condition linked to issues in polyamine production. In a study from 2024, Amin Cressman and his team researched polyamines [28]. They explored how these substances impact bone formation and health. They focused on human bone marrow cells capable of turning into various types of cells, including bone cells.

The researchers noticed that when these cells changed into bone cells, a certain enzyme level increased. The enzyme specifically helps to break down polyamines. This led to a decrease in polyamines believed to be crucial for healthy bone development. When they added more polyamines to these cells, they found it slowed the growth of bone-like structures.

Next they used a chemical to block the production of the polyamine, spermine. This also prevented bone-like structures from forming. However, using another inhibitor that acts earlier in the polyamine production process reversed these negative effects.

These findings could be significant for people with Snyder-Robinson syndrome. It suggests that treatments targeting these pathways might help in managing their bone-related symptoms.

Is spermidine safe?

Spermidine is a naturally occurring product in the body and part of the natural diet. The data suggests that spermidine supplementation using a spermidine supplement is safe and well-tolerated.

There are no known adverse side effects from spermidine supplementation. There have been several studies conducted with it, and the results suggest that it is well tolerated. Of course, as with any supplement, anyone experiencing side effects should immediately cease taking it and consult a doctor.

Disclaimer

This article is only a brief summary and is not intended as an exhaustive guide. It is based on the interpretation of research data, which is speculative by nature. This article is not a substitute for consulting your physician about which supplements may or may not be right for you. We do not endorse supplement use or any product or supplement vendor.

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