Spermidine: Benefits, Research, 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.
Spermidinewas 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.
Spermidine and putrescine are known to stimulate autophagy, a system that breaks down waste inside cells and recycles cellular components. This is a quality control mechanism for the mitochondria, the powerhouses of our cells. 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, including grapefruit, soy products, legumes, corn, whole grain, chickpeas, peas, green peppers, broccoli, oranges, green tea, rice bran, and fresh green pepper.
It can also be found in shitake mushrooms, amaranth grain, wheat germ, cauliflower, broccoli, a variety of mature cheeses, and durian. 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.
People who do not get enough spermidine in the diet can also get it as spermidine supplements, which are identical to the naturally occurring molecule.
What is putrescine?
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.
What is spermidine used for?
Some research suggests that it may prevent liver fibrosis and hepatocellular carcinoma, common causes of liver cancer. Some people take it as a supplement believing that it may have an impact on aging and promote longevity.
It is most well-known for its ability to boost autophagy, a cellular recycling routine that can help cells remove waste and unwanted components, which is also the most likely reason it may influence aging.
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, including aspartate receptors, cGMP/PKG pathway activation, nitric oxide synthase, and cerebral cortex synaptosome activity.
Spermidine is of interest to scientists in the context of aging because it is a key morphogenetic determinant of the lifespan of cells and living tissues [3]. The ability of spermidine to trigger autophagy is thought to be the main mechanism by which it appears to slow down aging and support longevity [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 highly correlated with reduced lifespans, chronic stress, and acute inflammation.
In a study released in February 2024 by Dongmei Jiang and colleagues, researchers investigated how spermidine, a naturally occurring substance, can protect cells from oxidative stress, a condition 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.
Using a model of oxidative stress created by a chemical called 3-nitropropionic acid (3-NPA), the team studied how spermidine influences 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. Additionally, they discovered that blocking a pathway known as mTOR, which is usually involved in suppressing autophagy, further enhances the protective effects of spermidine.
These findings suggest that spermidine could be a valuable tool in reducing oxidative stress in cells by promoting autophagy, offering potential benefits for maintaining the health of animal cells [5].
Spermidine is believed to combat obesity
In a 2024 study by Yinhua Ni and colleagues, researchers explored how spermidine helps in fighting obesity. 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 linked to two things: the activation of a cellular cleanup process (autophagy) and an increase in a specific growth factor (FGF21). This growth factor, 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 [6].
Anti-inflammatory properties
Although the primary way in which spermidine appears to support longevity is via autophagy, there is also evidence that it supports health and longevity in other ways. Some studies suggest that it has anti-inflammatory properties [7, 8] and is involved in lipid metabolism, cell growth and proliferation [9, 10], and programmed cell death, which is known as apoptosis [11].
It is widely accepted that while inflammation plays a helpful role in wound healing and repelling invading pathogens, the persistent inflammation associated with aging, often called inflammaging, is harmful. Chronic inflammation prevents healthy tissue regeneration, causes immune cells to become dysfunctional, and can even accelerate the speed at which healthy cells become senescent. Spermidine appears to reduce this chronic inflammation and may slow down one way in which cells and tissues age.
Spermidine may delay aging
On the longevity front, the administration of spermidine has been shown to increase lifespan in a number of animal studies and prevents liver fibrosis and hepatocellular carcinoma [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 that the age-related decline of spermidine supports the onset of age-related diseases [15, 16].
Not all studies have confirmed these findings however, In a November 2023 study by Chisato Nagata and colleagues, the team investigated the relationship between dietary polyamines and mortality in Japanese adults. Polyamines, which include substances like putrescine, spermidine, and spermine, are found in various foods and are thought to impact 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 then tracked the participants for 16 years to see how their diet might relate to their risk of death, whether from any cause or specific causes like cancer.
After considering other factors that could affect health, the study found no significant link between the intake of polyamines and the risk of death from any cause or specific diseases in both men and women. However, there was a slight indication that high spermidine intake might be associated with an increased 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 the impact of dietary polyamines on health and disease in different populations with varying diets [17].
Fat and blood pressure
Lipid metabolism is a known regulator of lifespan, and dysfunctional lipid metabolism can have serious ramifications for both healthspan and lifespan. The role that spermidine plays in the process of adipogenesis, the creation of adipocytes (fat cells) from stem cells, and its ability to modify lipid profiles could suggest another way in which spermidine influences lifespan. Spermidine facilitates the differentiation of preadipocyte cells into mature adipocyte cells as part of the adipogenesis process [18].
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 observed that spermidine also restored the expression of transcription factors needed for preadipocyte differentiation as well as those associated with late adipocyte markers.
If these compounds are taken together, the combination of effective autophagy, reduction of inflammation, lower oxidative stress levels in the cell, improved cell growth, and improved lipid metabolism may potentially support healthy longevity.
In a 2024 study by Zhang and colleagues, the researchers investigated how proteins in our cells handle certain chemical changes, specifically focusing on a process in which small chemical groups (acyl groups) are added and removed from proteins. This study revealed that these chemical groups, after being removed from proteins in the mitochondria (the energy-producing parts of the cell), unexpectedly attach themselves 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 discovered new compounds, formed when spermidine acquires these chemical groups, and studied their effects 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 discovery about spermidine and these new compounds offers new insights into the intricate workings of our cells and could lead to potential treatments for various health conditions, including strategies for extending lifespan and fighting cancer [20].
In a January 2024 study by Kevser Tari Selcuk and colleagues, the researchers looked at how different levels of dietary polyamines (nutrients found in various foods) are related to 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 gather information about the women’s diets and then analyzed the data to see if there were any connections between the intake of specific polyamines and various health indicators like 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 consumption of spermidine was associated with higher waist circumference, blood pressure, BMI, and waist-to-height ratio. In contrast, a higher intake of spermine was connected to lower waist circumference, systolic blood pressure, BMI, and waist-to-height ratio.
The study suggests that the role of dietary polyamines in health, especially in postmenopausal women, warrants further investigation due to their potential impact on metabolic risk factors. However, the study’s design means it can’t definitively prove cause and effect, and there are some limitations, like relying on self-reported food intake and not accounting for seasonal diet variations [21].
Spermidine may reduce cognitive decline
Research published in 2021 in the journal Cell Reports provides a detailed account of dietary spermidine improving cognition and mitochondrial function in flies and mice, with some prospective human data to top it off [22]. While this study was interesting, it had some limitations, and additional dose-response data is needed before a firm conclusion can be made about benefits to human cognition.
Spermidine for cancer and cardiovascular health
There is also some evidence that it might reduce the risk of cardiovascular disease. In a 2016 study, spermidine was found to reverse some aspects of aging and improve cardiovascular function in aged 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, there were two population-based studies whose data suggests that spermidine intake is linked to a reduction of all-cause, cardiovascular and cancer-related mortality in humans [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.
Human observational 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 2024 study by A La Teng Zhu and colleagues, researchers explored how a certain type of sugar, neoagarooligosaccharides (NAOS), can improve the gut health of chickens. Although the aim of this study was centered on antibiotics in animal feed, the potential for spermidine as a means for improving human gut health is implicit.
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 discovered that NAOS positively changed the gut bacteria in these birds, particularly increasing the growth of bacteria that produce spermidine. They further confirmed that these beneficial bacteria could use NAOS to grow and produce more spermidine.
This study not only provides a solid foundation for using NAOS as a safe alternative to antibiotics in animal farming, it also highlights its role in enhancing gut health in humans through the consumption of NAOS to rev up the production of spermidine [27]. 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 2024 study by Amin Cressman and colleagues from the University of California, Davis, the team investigated how certain compounds called polyamines affect bone formation and bone health. They focused on human bone marrow cells capable of turning into various types of cells, including bone cells.
The researchers observed that during the transformation of these cells into bone cells, the levels of a specific enzyme involved in breaking down polyamines increased. This change led to a decrease in certain polyamines, which are believed to be crucial for healthy bone development. When they added extra polyamines to these cells, they found that it actually hindered the development of bone-like structures.
Interestingly, when they used a chemical to block the production of one particular polyamine, spermine, it 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, suggesting that treatments targeting these pathways might help in managing their bone-related symptoms [28].
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 very brief summary, is not intended as an exhaustive guide, and 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, and all discussion here is for scientific interest.
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