What is spermidine?

Spermidine is a small polyamine molecule found in every living cell, in plants, fungi and bacteria as well as in people. The body makes it from the amino acid ornithine, takes it in from food, and receives some from gut bacteria. In laboratory research it is best known for its link to autophagy, the way cells break down and recycle worn components.

• Spermidine is one of three main polyamines in human cells, alongside putrescine and spermine.
• Wheat germ, soybeans, mushrooms, aged cheese and legumes are among the richest foods measured.
• It has one job no other molecule does: it supplies part of hypusine, an unusual amino acid in the protein eIF5A.
• In yeast, worms, flies and mice, researchers linked spermidine to autophagy and a longer lifespan. These are animal findings.
• In people, a large cohort study found an association between higher dietary intake and lower mortality. The largest randomised trial so far, SmartAge, found no difference in memory compared with placebo after 12 months.

Spermidine is a polyamine: a short chain of carbon atoms carrying three amine groups, which contain nitrogen. Its chemical formula is C7H19N3. Inside cells, those amine groups carry positive charges. That lets spermidine bind to negatively charged molecules such as DNA, RNA, cell membranes and some proteins.

Biologists group it with two close relatives on either side of it in the same pathway:

• Putrescine, with two amine groups, the starting point.
• Spermidine, with three, made from putrescine.
• Spermine, with four, made from spermidine.

Polyamines take part in cell growth, cell division, protein production and the packaging of DNA. Cells keep their levels within a fairly narrow range by balancing production, breakdown and uptake (Pegg, 2016).

The name has an unusual history. In 1678, Antonie van Leeuwenhoek described crystals in human semen that were much later identified as a spermine salt, and the polyamines were named after that source. Despite the name, spermidine is present in essentially all human tissues and in most foods.

The spermidine in your body has three origins: your own cells, your food and the bacteria in your gut (Tofalo et al., 2019).

Made by your cells. Human cells build polyamines in a short chain of reactions. The enzyme ornithine decarboxylase (ODC) turns the amino acid ornithine into putrescine and is usually described as the rate-limiting step. A second enzyme, S-adenosylmethionine decarboxylase, prepares a small chemical group called an aminopropyl group, and spermidine synthase attaches it to putrescine to make spermidine. Spermine synthase adds a second aminopropyl group to make spermine. Other enzymes can run the chain backwards, converting spermine into spermidine and spermidine into putrescine.

Made by gut bacteria. Bacteria in the large intestine produce putrescine and spermidine. A 2019 review reported polyamine concentrations in the colon of 0.5 to 1 millimolar in healthy people and noted that polyamines can pass from the gut into the bloodstream (Tofalo et al., 2019). How much microbial spermidine reaches the body's tissues has not been well quantified.

Plant foods tend to contain more spermidine, while animal foods tend to contain relatively more spermine. Published values vary widely between studies, varieties, countries and lab methods, so treat any figure as indicative (Muñoz-Esparza et al., 2019). Foods that rank high in published surveys include:

• Wheat germ: consistently the richest source measured.
• Soybeans and soy foods, such as natto and tempeh.
• Mushrooms, such as shiitake.
• Aged cheese, such as mature cheddar. Fresh cheese and milk contain very little, and in some aged cheeses putrescine is the main polyamine.
• Green peas and other legumes.
• Whole grains, nuts and some vegetables, such as broccoli and cauliflower, in more moderate amounts.

Preparation matters too. A Spanish study found that boiling and grilling reduced polyamine content by up to 64 percent, mostly because polyamines leached into the cooking water, while microwaving and sous-vide caused little loss (Muñoz-Esparza et al., 2021). Estimates of total daily polyamine intake differ widely between countries (Ali et al., 2011). For a fuller list, see which foods naturally contain the most spermidine.

Most of what spermidine does follows from its positive charge and its place in the polyamine pathway. Three roles stand out in the research.

Binding DNA, RNA and membranes. Positively charged polyamines bind to negatively charged DNA and RNA, which affects how DNA is packed and how RNA folds. They also interact with membranes and with some ion channels. These functions are shared with spermine and putrescine (Pegg, 2016).

Spermidine donates part of its structure to a protein called eIF5A, a translation factor that helps ribosomes make certain proteins. Two enzymes, deoxyhypusine synthase and deoxyhypusine hydroxylase, use spermidine to build an unusual amino acid called hypusine on eIF5A. This modification, known as hypusination, is found only in eIF5A and is required for its activity (Park, 2006).

In 2019, researchers working with immune cells from mice and people reported that spermidine-dependent hypusination of eIF5A was needed to produce TFEB, a protein that controls genes for autophagy and lysosomes (Zhang et al., 2019).

Autophagy, literally "self-eating", is the process cells use to break down and recycle damaged proteins and organelles inside lysosomes. Spermidine is studied mainly for its link to this process. In cell and animal work, researchers have described three routes (Hofer et al., 2022):

• Inhibition of the enzyme EP300, an acetyltransferase, which lowers the acetylation of proteins involved in autophagy (Pietrocola et al., 2015).
• Hypusination of eIF5A, needed in cell studies to produce the autophagy-related proteins TFEB and ATG3.
• Activation of TFEB, a master regulator of lysosome and autophagy genes.

A 2024 study reported that fasting raised spermidine levels in several species, including people, and that in yeast, worms, flies and mice the autophagy response to fasting depended on spermidine synthesis and eIF5A hypusination (Hofer et al., 2024). Read more in our explainer on what autophagy is.

Laboratory and animal studies. In 2009, Eisenberg and colleagues reported that adding spermidine extended the lifespan of yeast, fruit flies and nematode worms and reduced cell death in cultured human immune cells. In yeast, spermidine inhibited histone acetyltransferases and increased the activity of autophagy genes, and the lifespan effect required autophagy (Eisenberg et al., 2009).

In 2016, the same group reported that oral spermidine extended lifespan in mice, including when it was started late in life, and that aged treated mice showed differences in heart structure and function together with higher markers of autophagy in heart tissue. These heart findings were absent in mice lacking the autophagy gene Atg5 in heart muscle cells (Eisenberg et al., 2016).

These are results in laboratory models. They describe biology in those organisms and do not show what happens when a person eats or takes more spermidine (Madeo et al., 2018).

The Bruneck Study follows a population in South Tyrol, Italy. An analysis published in 2018 included 829 participants aged 45 to 84, with diet assessed by repeated food questionnaires between 1995 and 2010 and follow-up until 2015. People with higher estimated spermidine intake had lower all-cause mortality over the follow-up period (Kiechl et al., 2018).

This is an association, not proof of cause. Spermidine intake goes together with whole grains, legumes, vegetables and other features of diet and lifestyle. Questionnaire estimates are imprecise, and other factors may explain the link. The study generated a hypothesis. It did not test one.

SmartAge is the largest and longest published randomised controlled trial of spermidine supplementation so far (Schwarz et al., 2022, JAMA Network Open).

• Who: 100 older adults in Germany, mean age around 69, with subjective cognitive decline.
• What: a spermidine-rich wheat germ extract providing 0.9 mg of spermidine a day, or a placebo.
• How long: 12 months.
• Main outcome: memory performance, measured as mnemonic discrimination.
• Result: no difference between the spermidine and placebo groups. Secondary outcomes showed no substantial effects in the main analysis. Adverse events were similar in both groups.

The authors noted that higher amounts could be tested in future trials. At the amount tested, the result was null.

A small 2023 crossover trial gave 12 healthy adults 15 mg of spermidine a day for five days. Plasma spermidine did not rise compared with placebo, but plasma spermine did. The authors suggested that spermidine taken by mouth may be converted into spermine before it reaches the circulation (Senekowitsch et al., 2023).

What is missing. No randomised trial has shown that spermidine supplementation changes a hard clinical outcome in people. Most human data are observational or come from small, short studies that measured biomarkers. That describes the current evidence, not a prediction about future studies.

Spermidine reaches people in three ways, and the research behind each is different.

Spermidine and NAD+ are unrelated molecules that often appear side by side in research on how cells age. NAD+ is a coenzyme at the centre of energy metabolism and a raw material for sirtuins and PARPs. Spermidine is a polyamine studied mainly for its link to autophagy.

Their research paths cross at protein acetylation. The sirtuin SIRT1 removes acetyl groups from proteins and needs NAD+ to do so. Spermidine has been studied for inhibiting EP300, an enzyme that adds them. In cell studies comparing spermidine with resveratrol, a compound that activates SIRT1, researchers described distinct pathways that converge on the same set of acetylated proteins (Morselli et al., 2011). These are laboratory findings and say nothing about combining the two in people.

See how both fit into the wider picture on our page about cellular health.

Spermidine is an ordinary part of food, but a supplement or an injectable is a different matter. Useful points to raise with a doctor:

• Your medical history. Polyamines are involved in cell growth and division, and researchers have discussed their role in cancer biology. Mention any history of cancer and any current conditions.
• Medicines and supplements you already take.
• Pregnancy and breastfeeding. Data in these groups are lacking.
• Wheat allergy or coeliac disease, if you are considering a wheat germ extract.
• The route. Injecting under the skin involves technique, hygiene and possible skin reactions at the injection site that food and oral products do not.
• The dose, which is a decision for your doctor, not for a website.

For more on daily use, read is it safe to take spermidine every day? and our guide to using the Longevity Pen.

• Polyamine: a small molecule with two or more amine groups. Putrescine, spermidine and spermine are the main ones in human cells.
• Autophagy: the process cells use to break down and recycle their own components inside lysosomes.
• Lysosome: a compartment in the cell filled with enzymes that break down proteins, fats and other molecules.
• eIF5A: a translation factor that helps ribosomes make certain proteins.
• Hypusination: the spermidine-dependent change that turns one amino acid in eIF5A into hypusine.
• Acetylation: the addition of an acetyl group to a protein, which can change how the protein behaves.
• Observational study: research that follows people without assigning a treatment. It can show associations, not cause and effect.
• Randomised controlled trial: research in which participants are assigned by chance to a treatment or a comparison, such as a placebo.

Longevity Pen makes the S-Core 200, a pre-filled cartridge with 200 mg of spermidine for subcutaneous use with the Longevity Pen. The Spermidine Starter Kit combines the pen, an S-Core 200 cartridge and a travel case. The Longevity Protocol Starter Kit includes cartridges for both spermidine and NAD+.

Your doctor sets the dose. Certificates of analysis are published on our lab reports page. For handling, storage and injection technique, see how to use the Longevity Pen.

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