Spermidine is a small polyamine molecule found in every living cell and in many foods. Wheat germ, soybeans and aged cheese are among the richest dietary sources. It is sold as a “longevity” supplement, mostly as a spermidine-rich wheat germ extract, because it switches on autophagy (the cell’s recycling system) and extends lifespan in yeast, worms, flies and mice.
The human evidence is much thinner than the animal data. The best-known human finding, lower mortality with higher dietary spermidine in the Bruneck cohort, is observational and cannot show cause and effect. The largest randomized trial, the 12-month SmartAge study, found no effect on its primary memory outcome. Other trials are small, short or uncontrolled.
This page summarizes what the animal studies, human trials and food regulators report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Class | Natural polyamine; C₇H₁₉N₃, molecular weight 145.25 g/mol (PubChem) |
| Supplement forms | Spermidine-rich wheat germ extract (EU-authorized novel food); spermidine trihydrochloride (used in some trials) |
| Route | Oral (food or capsules) |
| Usual dietary intake | ≈87 µmol/day in EU adults; ≈55 µmol/day in US adults aged 40–80 |
| Doses in cited trials | 0.9–1.2 mg/day (wheat germ extract); 6 mg/day; 15 mg/day; 40 mg/day |
| Half-life | Not established in humans; 15 mg/day did not raise plasma spermidine |
| Key mechanism | Induces autophagy (cell and animal data) |
| EU / GB status | Wheat germ extract authorized for food supplements for adults, up to 6 mg spermidine/day (GB register), excluding pregnant and lactating women |
| US status | Not an approved drug; the GRAS notice for the wheat germ extract (GRN 889) was closed at the notifier’s request in 2020 without an FDA decision |
| WADA status | Not named on the 2026 Prohibited List |
What it is
Spermidine (N’-(3-aminopropyl)butane-1,4-diamine) is one of three main polyamines in the body, together with putrescine and spermine (PubChem). Cells make it from the amino acid ornithine: the enzyme ornithine decarboxylase converts ornithine to putrescine, which is then built up into spermidine and spermine. Cellular synthesis and levels tend to fall with age. Gut bacteria also produce polyamines, mainly in the large intestine (Muñoz-Esparza et al., Front Nutr 2019).
The rest comes from food. Spermidine content varies widely (Muñoz-Esparza et al., Front Nutr 2019):
| Food | Spermidine content |
|---|---|
| Wheat germ | Up to 2,437 nmol/g (highest value in the review) |
| Soybeans | Up to 1,425 nmol/g |
| Vegetables | 6.9–398 nmol/g |
| Cheese | Mostly under 69 nmol/g; one blue cheese 262 nmol/g |
| Fresh meat | 1–92 nmol/g |
Average intake was about 87 µmol/day of spermidine in EU adults and 54.7 µmol/day in US adults aged 40–80. There is no official recommended intake (Muñoz-Esparza et al., Front Nutr 2019).
Autophagy mechanism (cell and animal data)
Autophagy is the process by which cells break down and recycle damaged proteins and organelles. In the founding study, spermidine inhibited histone acetyltransferases in aging yeast. This removed acetyl groups from histone H3 and switched on autophagy-related genes. Autophagy was then triggered in yeast, flies, worms and human cells in culture. Blocking autophagy cancelled the lifespan benefit, so the effect depended on it (Eisenberg et al., Nat Cell Biol 2009).
A 2024 study added a link to fasting. Spermidine levels rose with fasting or caloric restriction in yeast, flies, mice and human volunteers. When the researchers blocked spermidine synthesis, the lifespan and heart benefits of fasting disappeared in the model organisms. The effect ran through autophagy and through hypusination of the translation factor eIF5A (Hofer et al., Nat Cell Biol 2024). For this reason the same research group describes spermidine as a “caloric restriction mimetic” (Madeo et al., Science 2018).
Spermidine is often discussed alongside other “healthy aging” supplements in the library, such as urolithin A (also marketed for mitophagy) and the NAD+ precursors NMN and NR (see also NAD+). They work through different pathways.
How it works in the body
Dietary polyamines are absorbed mainly in the duodenum and the first part of the jejunum. Some are metabolized in the gut wall before reaching the blood (Muñoz-Esparza et al., Front Nutr 2019). A conventional half-life has not been reported for oral spermidine in humans. The small pharmacokinetic studies that exist found that supplements barely change blood spermidine levels:
| Study | Dose and design | Finding |
|---|---|---|
| Senekowitsch et al., Nutrients 2023 | 15 mg/day for 5 days vs placebo, crossover, 12 healthy adults | Plasma spermine rose; plasma spermidine and putrescine did not change. The authors suggest spermidine is converted to spermine before reaching the circulation. |
| Keohane et al., Nutr Res 2024 | 40 mg/day spermidine trihydrochloride for up to 28 days vs placebo, 37 men aged 50–70 | No substantial changes in serum or urine polyamines |
| Schwarz et al., JAMA Netw Open 2022 | 0.9 mg/day (wheat germ extract) for 12 months | Blood polyamine levels not altered |
| Pekar et al., Wien Klin Wochenschr 2021 | Wheat germ rolls, 3.3 mg spermidine per roll, 6 days a week for 3 months | Median serum spermidine rose from 41.65 to 59.40 ng/mL; no rise with the lower-spermidine roll |
The SmartAge authors note that blood levels may not reflect intake, because polyamines may be taken up quickly by tissues. Even so, the lack of a clear rise in blood spermidine makes it hard to know how much of a supplement reaches tissues as spermidine.
Regulatory status
Spermidine is not an approved drug anywhere.
- European Union. TLL The Longevity Labs GmbH notified the European Commission on December 6, 2017 that it intended to market a spermidine-rich wheat germ extract (Triticum aestivum) as a novel food, and the extract was added to the Union list of novel foods. The specification requires 0.8–2.4 mg spermidine per gram of extract. A 2020 regulation raised the permitted cadaverine level (another polyamine) after the company explained that the original limit had been entered by mistake (Commission Implementing Regulation (EU) 2020/443). The authorization is specific to this wheat germ extract.
- Great Britain. The carried-over authorization (NOVEL-130) allows the extract in food supplements for adults, excluding pregnant and lactating women, up to the equivalent of 6 mg spermidine per day. The label must say “spermidine-rich wheat germ extract” (Food Standards Agency register).
- United States. TLL submitted a GRAS (generally recognized as safe) notice, GRN 889, for the wheat germ extract in food bars and yogurt at up to 2.7 g per serving. At the notifier’s request, FDA stopped evaluating it, and the notice was closed on March 20, 2020 (FDA GRAS Notice Inventory).
- Sport. Spermidine is not named on the WADA 2026 Prohibited List.
What the research shows
Lifespan in animals (not human data)
| Model | Finding | Source |
|---|---|---|
| Yeast, worms, flies | Spermidine markedly extended lifespan; the effect required autophagy | Eisenberg et al., Nat Cell Biol 2009 |
| Human immune cells in culture | Longer survival | Eisenberg et al., Nat Cell Biol 2009 |
| Female mice, lifelong spermidine in drinking water | Significantly longer median lifespan than controls | Eisenberg et al., Nat Med 2016 |
| Male and female mice, started late in life | Median lifespan ≈10% longer; less age-related cardiac hypertrophy and better diastolic function | Eisenberg et al., Nat Med 2016 |
| Mice lacking the autophagy gene Atg5 in heart muscle | No heart protection, showing the effect depends on autophagy | Eisenberg et al., Nat Med 2016 |
| Salt-sensitive rats on a high-salt diet | Lower blood pressure and slower progression to heart failure | Eisenberg et al., Nat Med 2016 |
In the mouse study, food and water intake, body weight and body composition did not differ between groups, so the authors argue the lifespan effect was not simply caused by eating less. These results come from animals and cell cultures. No study has shown that spermidine extends human lifespan.
Observational studies in people
The Bruneck Study is a prospective, community-based population cohort. Kiechl and colleagues followed 829 people aged 45–84 from 1995 to 2015. Diet was assessed four times with dietitian-administered food-frequency questionnaires, and 341 people died during follow-up (Kiechl et al., Am J Clin Nutr 2018):
| Measure | Result |
|---|---|
| All-cause deaths per 1,000 person-years, lowest to highest third of intake | 40.5 → 23.7 → 15.1 |
| Hazard ratio per 1 SD higher intake (age-, sex-, calorie-adjusted) | 0.74 (95% CI 0.66–0.83) |
| Hazard ratio after further adjustment for lifestyle, risk factors and diet | 0.76 (95% CI 0.67–0.86) |
| Replication in the SAPHIR cohort | 0.71 (95% CI 0.53–0.95) |
| Top vs bottom third, expressed as age | Similar to being 5.7 years younger |
This is an observational association, not proof of effect. People who eat more spermidine-rich foods (whole grains, legumes, vegetables) may differ in many other ways, and food questionnaires measure intake imprecisely. Several of the study’s coauthors (including Madeo and Eisenberg) also led the animal studies and disclosed equity in The Longevity Labs, which makes the wheat germ extract (Eisenberg et al., Nat Med 2016).
An independent analysis of 23,894 US adults in NHANES (2003–2014) found a similar pattern. The highest quartile of dietary spermidine had lower all-cause mortality (HR 0.70, 95% CI 0.60–0.82) and cardiovascular mortality (HR 0.68, 95% CI 0.51–0.91) than the lowest quartile (Wu et al., Front Public Health 2022). It shares the same observational limits.
Memory and cognition trials
Most human trials tested memory in older adults, using the wheat germ extract.
| Trial | Participants | Intervention | Main result |
|---|---|---|---|
| Wirth et al., Cortex 2018 (phase 2a pilot) | 30 adults aged 60–80 with subjective cognitive decline | Wheat germ extract vs placebo, 3 months | Moderate improvement in mnemonic discrimination; Cohen’s d 0.77 (95% CI 0–1.53) |
| Schwarz et al., JAMA Netw Open 2022 (SmartAge, phase 2b) | 100 adults aged 60–90 with subjective cognitive decline | 750 mg/day extract (≈0.9 mg spermidine) vs placebo, 12 months | Null primary outcome: difference −0.03 (95% CI −0.11 to 0.05; P = .47); no effect on secondary outcomes |
| Pekar et al., Wien Klin Wochenschr 2021 | 85 nursing-home residents aged 60–96 (analyzed) | Wheat germ roll (3.3 mg spermidine) vs wheat bran roll (1.9 mg), 3 months; no placebo | CERAD total score rose in both groups (+6.25 and +4.00 points) |
SmartAge is the largest and longest trial. It was randomized, double-masked and placebo-controlled, and 89 of 100 participants completed it. Spermidine did not change mnemonic discrimination, the primary memory measure, or any secondary outcome in the main analysis. Possible benefits on verbal memory and on sICAM-1 (a blood marker of vascular inflammation) appeared only in exploratory per-protocol analyses and would not be significant after correction for multiple testing (Schwarz et al., JAMA Netw Open 2022).
The authors suggest the dose may have been too low: 0.9 mg/day added only about 10% to average dietary spermidine intake. They chose a low dose because of concerns about polyamines and tumor growth. A 2026 exploratory MRI analysis of 75 SmartAge participants found small regional differences in brain blood flow and white matter, but no change in brain volume or cortical thickness. These changes were not linked to memory, and the authors call them preliminary (Schwarz et al., Aging Dis 2026).
The Pekar trial had no placebo group. Both groups ate rolls containing spermidine and both improved, and the authors note a placebo effect cannot be excluded. The often-quoted MMSE gain of 2.23 points comes from a subgroup with mild dementia in the higher-spermidine group.
Other small trials
- Immune function. In a pilot RCT of 40 adults over 65, 6 mg/day for 13 weeks after a third SARS-CoV-2 vaccine dose was well tolerated. It improved antibody and memory B-cell responses specifically in vaccine non-responders (Alsaleh et al., Aging Cell 2026). This is a small pilot and needs confirmation.
- High-dose safety. 40 mg/day of high-purity spermidine trihydrochloride for up to 28 days caused no significant changes in clinical, lipid, chemistry or blood count measures compared with placebo in 37 men. Two authors were employees of Chrysea Labs and the other four received funding from the company (Keohane et al., Nutr Res 2024).
No trial has tested spermidine for lifespan, cardiovascular events, cancer or muscle and body composition in people.
Side effects and risks
Tolerability in trials
The trials so far report few side effects, but they are small and short:
- Phase 2a safety trial (n = 30, 3 months, 1.2 mg/day). No differences from placebo in vital signs, weight, blood chemistry, blood counts or self-reported health. Compliance was above 85% (Schwarz et al., Aging 2018).
- SmartAge (n = 100, 12 months). 58 adverse events on spermidine vs 71 on placebo. Serious adverse events occurred in 7 vs 12 participants, all rated unrelated to the supplement. Musculoskeletal complaints (such as arthritis, gout attacks and joint pain) were the one category more common on spermidine: 11 vs 4 participants (Schwarz et al., JAMA Netw Open 2022).
- 40 mg/day for 28 days (n = 37). No product-related adverse events (Keohane et al., Nutr Res 2024).
Theoretical concerns
- Cancer. Polyamines support cell growth and are found at higher levels in some tumors. This is why SmartAge used a low dose and excluded people with a history of cancer, so it could not assess effects on tumor growth (Schwarz et al., JAMA Netw Open 2022). Long-term safety in people with cancer or a high cancer risk is unknown.
- Kidneys. In the preclinical mouse study, high-dose spermidine increased relative kidney weight. Kidney measures were unremarkable in SmartAge (Schwarz et al., JAMA Netw Open 2022).
- Vitamin B12. In the Pekar trial, median vitamin B12 fell from 485.65 to 407.00 pg/mL in the higher-spermidine group (p = 0.016). This is a single uncontrolled finding (Pekar et al., Wien Klin Wochenschr 2021).
Who was not covered by the evidence
The EU and GB authorization for the wheat germ extract excludes pregnant and lactating women and is limited to adults (Food Standards Agency register). The trials enrolled adults only, and we found no published drug interaction studies.
Key takeaways
- A natural polyamine in everyday food. Wheat germ and soybeans are the richest sources. The 0.9 mg/day dose in SmartAge added only about 10% to average dietary intake.
- Strong animal data. Spermidine induces autophagy and extends lifespan in yeast, worms, flies and mice (≈10% median lifespan when started late in life in mice). These are animal results only.
- Human mortality data are observational. The Bruneck cohort linked higher dietary spermidine to lower death rates (HR 0.76 per SD after adjustment), but this does not show that spermidine causes the difference.
- The largest trial was null. SmartAge found no effect of 12 months of wheat germ extract on its primary memory outcome. Positive signals come from small pilots, exploratory analyses or an uncontrolled study.
- Supplements barely change blood spermidine. Even 15–40 mg/day did not raise blood spermidine meaningfully, so how much reaches tissues is unclear.
- Regulated as a food, not a drug. The EU authorized a spermidine-rich wheat germ extract as a novel food (up to 6 mg/day in GB); the US GRAS notice was closed without an FDA decision.
Sources
- Muñoz-Esparza NC, Latorre-Moratalla ML, Comas-Basté O, et al. Polyamines in food. Front Nutr. 2019;6:108. PubMed.
- National Center for Biotechnology Information. PubChem Compound Summary for CID 1102, Spermidine. PubChem.
- Eisenberg T, Knauer H, Schauer A, et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11(11):1305–1314. PubMed.
- Eisenberg T, Abdellatif M, Schroeder S, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22(12):1428–1438. PubMed.
- Hofer SJ, Daskalaki I, Bergmann M, et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nat Cell Biol. 2024;26(9):1571–1584. PubMed.
- Madeo F, Eisenberg T, Pietrocola F, Kroemer G. Spermidine in health and disease. Science. 2018;359(6374):eaan2788. PubMed.
- Kiechl S, Pechlaner R, Willeit P, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018;108(2):371–380. PubMed.
- Wu H, Wang J, Jiang H, et al. The association of dietary spermidine with all-cause mortality and CVD mortality: the U.S. National Health and Nutrition Examination Survey, 2003 to 2014. Front Public Health. 2022;10:949170. PubMed.
- Schwarz C, Stekovic S, Wirth M, et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging (Albany NY). 2018;10(1):19–33. PubMed.
- Wirth M, Benson G, Schwarz C, et al. The effect of spermidine on memory performance in older adults at risk for dementia: a randomized controlled trial. Cortex. 2018;109:181–188. PubMed.
- Schwarz C, Benson GS, Horn N, et al. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline: a randomized clinical trial. JAMA Netw Open. 2022;5(5):e2213875. PubMed.
- Schwarz C, Wurdack K, Hetzer S, et al. Effects of spermidine supplementation on vascular brain health in older individuals with subjective cognitive decline: an exploratory MRI analysis. Aging Dis. Published online October 9, 2026. PubMed.
- Pekar T, Bruckner K, Pauschenwein-Frantsich S, et al. The positive effect of spermidine in older adults suffering from dementia: first results of a 3-month trial. Wien Klin Wochenschr. 2021;133(9-10):484–491. PubMed.
- Senekowitsch S, Wietkamp E, Grimm M, et al. High-dose spermidine supplementation does not increase spermidine levels in blood plasma and saliva of healthy adults: a randomized placebo-controlled pharmacokinetic and metabolomic study. Nutrients. 2023;15(8):1852. PubMed.
- Keohane P, Everett JR, Pereira R, et al. Supplementation of spermidine at 40 mg/day has minimal effects on circulating polyamines: an exploratory double-blind randomized controlled trial in older men. Nutr Res. 2024;132:1–14. PubMed.
- Alsaleh G, Ali M, Kayvanjoo AH, et al. Spermidine mitigates immune cell senescence and boosts vaccine responses in healthy older adults: a pilot study. Aging Cell. 2026;25(6):e70545. PubMed.
- European Commission. Commission Implementing Regulation (EU) 2020/443 of 25 March 2020 authorising the change of the specifications of the novel food spermidine-rich wheat germ extract (Triticum aestivum) and amending Implementing Regulation (EU) 2017/2470. Official Journal of the European Union. 2020;L 92:7–9. EUR-Lex.
- Food Standards Agency. Register of authorised novel foods: NOVEL-130, spermidine-rich wheat germ extract (Triticum aestivum). FSA.
- US Food and Drug Administration. GRAS Notice Inventory: GRN No. 889, spermidine rich wheat germ extract. FDA.
- World Anti-Doping Agency. The 2026 Prohibited List. WADA.