What is Spermidine? A Summary of Spermidine

This chemical plays many roles in human biology.

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 it has two or more primary amino groups. It is naturally occurring and is widely encountered in ribosomes and living tissues. It plays a critical role in cell 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.

Spermidine and putrescine are known to stimulate autophagy. A system that breaks down waste inside cells and recycles cellular components. It is an important 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 more tightly controlled than was before believed [1].

Polyamines can bind to many different types of molecules making them very useful. They support processes, including cell growth, DNA stability, cell 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, and a variety of mature cheeses, and durian.

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

If you struggle to get enough in your diet you can also get it as a spermidine supplement. The synthetic spermidine used in supplements is identical to the naturally occurring molecule.

What is putrescine?

Before we dive into some of the interesting research behind spermidine and why some researchers think it might be useful in slowing down aging, we should first take a look at how it is created.

There are two pathways in which putrescine is created, though 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 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.

Spermidine benefits 

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

Spermidine and autophagy

As mentioned before, putrescine allows the creation of spermidine as part of a process in which putrescine breaks down decarboxylated S-adenosylmethionine.

It plays an important role in the regulation of various biological processes, including levels of intracellular pH and the maintenance of cell membrane potential. Spermidine 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 for 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 [5].

A defective autophagy mechanism and a lack of spermidine are highly correlated with reduced life spans, chronic stress, and acute inflammation.

Spermidine 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 [6-7] and is involved in lipid metabolism, cell growth and proliferation [8-9], and programmed cell death, which is known as apoptosis [10].

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 and 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 [11-12]. This also appears to be the case with a diet rich in polyamines [13]. 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 [14-15].

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 [16].

A study showed that administration of a-difluoromethylornithine (DFMO), an inhibitor of polyamine synthesis, could halt adipogenesis entirely [17]. 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.

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 [18]. 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 turn back the aging clock and improve cardiovascular function in aged mice [19]. 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 following spermidine supplementation.

In humans there were two population based studies (summarized in the same paper) whose data suggests that spermidine intake is linked to a reduction of all cause, cardiovascular and cancer-related mortality in humans [20].

Based on this data and other studies, some researchers conclude that spermidine delays aging in humans [21]. We should be cautious at this stage as it is still early days for spermidine but the data so far is certainly worthy of further study to see if this anti-aging effect can be confirmed.

Human observational studies also found a link between the intake of dietary spermidine with a reduced risk of colon cancer [22].

Is spermidine safe?

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

Spermidine side effects

There are no known adverse side effects from spermidine supplementation. There have been a number of studies conducted with it, and the results suggest that it is well tolerated. Of course, as with any supplement, if you do experience side effects, cease taking it immediately and consult your 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.

Source: Lifespan.io is a nonprofit advocacy organization and news outlet covering aging and rejuvenation research.

Author: Steve Hill

Literature

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[3] Deeb, F., van der Weele, C. M., & Wolniak, S. M. (2010). Spermidine is a morphogenetic determinant for cell fate specification in the male gametophyte of the water fern Marsilea vestita. The Plant Cell, 22(11), 3678-3691.

[4] Eisenberg, T., Knauer, H., Schauer, A., Büttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., … & Fussi, H. (2009). Induction of autophagy by spermidine promotes longevity. Nature cell biology, 11(11), 1305-1314.

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[8] Landau, G., Ran, A., Bercovich, Z., Feldmesser, E., Horn-Saban, S., Korkotian, E., … & Kahana, C. (2012). Expression profiling and biochemical analysis suggest stress response as a potential mechanism inhibiting proliferation of polyamine-depleted cells. Journal of Biological Chemistry, 287(43), 35825-35837.

[9] Landau, G., Bercovich, Z., Park, M. H., & Kahana, C. (2010). The role of polyamines in supporting growth of mammalian cells is mediated through their requirement for translation initiation and elongation. Journal of Biological Chemistry, 285(17), 12474-12481.

[10] Minois, N., Carmona-Gutierrez, D., & Madeo, F. (2011). Polyamines in aging and disease. Aging (Albany NY), 3(8), 716-732.

[11] Yue, F., Li, W., Zou, J., Jiang, X., Xu, G., Huang, H., & Liu, L. (2017). Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Research, canres-3462.

[12] Eisenberg, T., Abdellatif, M., Schroeder, S., Primessnig, U., Stekovic, S., Pendl, T., … & Tong, M. (2016). Cardioprotection and lifespan extension by the natural polyamine spermidine. Nature medicine.

[13] Soda, K., Dobashi, Y., Kano, Y., Tsujinaka, S., & Konishi, F. (2009). Polyamine-rich food decreases age-associated pathology and mortality in aged mice. Experimental gerontology, 44(11), 727-732.

[14] Minois, N., Carmona-Gutierrez, D., Bauer, M. A., Rockenfeller, P., Eisenberg, T., Brandhorst, S., … & Madeo, F. (2012). Spermidine promotes stress resistance in Drosophila melanogaster through autophagy-dependent and-independent pathways. Cell death & disease, 3(10), e401.

[15] Landau, G., Ran, A., Bercovich, Z., Feldmesser, E., Horn-Saban, S., Korkotian, E., … & Kahana, C. (2012). Expression profiling and biochemical analysis suggest stress response as a potential mechanism inhibiting proliferation of polyamine-depleted cells. Journal of Biological Chemistry, 287(43), 35825-35837.

[16] Vuohelainen, S., Pirinen, E., Cerrada-Gimenez, M., Keinänen, T. A., Uimari, A., Pietilä, M., … & Alhonen, L. (2010). Spermidine is indispensable in differentiation of 3T3-L1 fibroblasts to adipocytes. Journal of cellular and molecular medicine, 14(6b), 1683-1692.

[17] Hyvönen, M. T., Koponen, T., Weisell, J., Pietilä, M., Khomutov, A. R., Vepsäläinen, J., … & Keinänen, T. A. (2013). Spermidine promotes adipogenesis of 3T3-L1 cells by preventing interaction of ANP32 with HuR and PP2A. Biochemical Journal, 453(3), 467-474.

[18] Schroeder, S., Hofer, S.J., Zimmermann, A., Pechlaner, R., Dammbrueck, C., … & Madeo, F. (2021). Dietary spermidine improves cognitive function. Cell Reports, 35(2), 108985. https://doi.org/10.1016/j.celrep.2021.108985

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[21] Madeo, F., Carmona-Gutierrez, D., Kepp, O., & Kroemer, G. (2018). Spermidine delays aging in humans. Aging (Albany NY), 10(8), 2209.

[22] Vargas, A. J., Ashbeck, E. L., Wertheim, B. C., Wallace, R. B., Neuhouser, M. L., Thomson, C. A., & Thompson, P. A. (2015). Dietary polyamine intake and colorectal cancer risk in postmenopausal women. The American journal of clinical nutrition, 102(2), 411-419.

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