Spermidine

updated

Spermidine is a natural polyamine sold to induce autophagy, support longevity and protect memory, and no FDA-approved spermidine drug or label turned up in searches on 11 October 2026. The longevity case rests on animal data and a food-questionnaire cohort. In SmartAge, the core randomized memory trial (100 adults aged 60 to 90, 12 months), the primary memory outcome did not change, and a PubMed search on 11 October 2026 found no trial reporting mortality, lifespan or disease-incidence outcomes.

Natural polyamine, promoted as an autophagy inducer

  • Spermidine extended the lifespan of yeast, flies, worms and mice in animal work, and several authors of the 2016 mouse paper declare equity in The Longevity Labs.
  • In the Bruneck cohort of 829 adults, the hazard ratio for all-cause mortality was 0.74 (95% CI 0.66 to 0.83) per 1-SD higher intake of spermidine from food, estimated from questionnaires.
  • In SmartAge (100 adults aged 60 to 90, 12 months, 0.9 mg spermidine per day), the primary outcome did not change: between-group difference -0.03, 95% CI -0.11 to 0.05, P = .47.
  • In 12 healthy volunteers, 15 mg/day of spermidine for 5 days raised plasma spermine, not plasma spermidine.
  • Human autophagy data come from pilots of 40 and 12 people; the 12-person pilot compared with baseline, not a control.
  • A cohort of 1164 people with a prior colorectal adenoma linked dietary polyamine intake above the median to a 39% higher adenoma risk (adjusted OR 1.39, 95% CI 1.06 to 1.83).

What is spermidine, and what is its regulatory status?

Spermidine is a natural polyamine sold as a supplement, and the products in trials are not one thing: wheat germ and rice germ extracts giving 0.9 to 3.3 mg per day and a purified trihydrochloride at 40 mg per day. On 11 October 2026, Drugs@FDA and DailyMed searches found no spermidine drug or label.

Spermidine is a natural polyamine. The free base is PubChem CID 1102 (C7H19N3, 145.25 g/mol, CAS 124-20-9). Spermidine trihydrochloride, the salt used in a 40 mg/day safety trial, is CID 9539 (C7H22Cl3N3, 254.6 g/mol, CAS 334-50-9).

The products in the trials are not one thing: a wheat germ extract giving 0.9 mg spermidine per day (SmartAge) or 1.2 mg per day (the 2018 safety study), a rice germ extract giving 1.5 or 3.3 mg per day, and a purified trihydrochloride at 40 mg per day. Doses and results do not transfer between these. The SmartAge dose is a plant extract, and retail products may differ; no study found here tested them.

On 11 October 2026, an openFDA Drugs@FDA query for spermidine returned no match and a DailyMed drug-name search returned no labels, so no FDA-approved spermidine drug was found in those two sources. Dietary-supplement, GRAS and EU novel food status are not established here.

PubChem: spermidine and its trihydrochloride; no FDA drug or label found, 11 October 2026

Chemical identity record

National Library of Medicine. PubChem compound records CID 1102 (spermidine) and CID 9539 (spermidine trihydrochloride). openFDA Drugs@FDA and DailyMed drug-name searches for spermidine run on 11 October 2026.

Spermidine free base: PubChem CID 1102, C7H19N3, 145.25 g/mol, CAS 124-20-9. Spermidine trihydrochloride, the salt used in the 40 mg/day safety trial: CID 9539, C7H22Cl3N3, 254.6 g/mol, CAS 334-50-9. It is a natural polyamine, and the products in the trials are not one thing: a wheat germ extract giving 0.9 mg spermidine per day (SmartAge) or 1.2 mg per day (the 2018 safety study), a rice germ extract giving 1.5 or 3.3 mg per day, and a purified trihydrochloride at 40 mg per day. On 11 October 2026 an openFDA Drugs@FDA query for spermidine returned no match and a DailyMed drug-name search returned no labels.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule and salt; several extract products
Follow-up
Searches run on 11 October 2026
Study design
NLM chemical record plus dated US approval-record search
Funding
not stated in the source

Doses and results do not transfer between these products. Dietary-supplement, GRAS and EU novel food status are not established here.

Read the original source

Where do the longevity and autophagy claims come from?

From animal and cell studies and a food-questionnaire cohort. Spermidine extended lifespan in yeast, flies, worms, cultured human immune cells and mice, and in the Bruneck cohort of 829 adults higher food spermidine intake went with lower all-cause mortality. The cohort measures food, not supplements.

A 2009 paper reported that spermidine extended the lifespan of yeast, flies, worms and human immune cells in culture, inhibited oxidative stress in ageing mice and raised autophagy-related transcripts, and the authors report that enhanced autophagy was crucial for the longevity effect. In 2016 the same group reported that oral spermidine extended the lifespan of mice, preserved diastolic function and reduced cardiac hypertrophy in old mice, and lowered blood pressure in Dahl salt-sensitive rats. Several authors of the 2016 paper declare equity in The Longevity Labs, a company that develops natural food extracts.

The cardioprotection failed in mice lacking the autophagy protein Atg5 in cardiomyocytes. In the same paper, higher dietary spermidine from food questionnaires in humans correlated with lower blood pressure and a lower incidence of cardiovascular disease.

In the Bruneck population-based cohort of 829 participants aged 45 to 84, with diet assessed by repeated food-frequency questionnaires from 1995 to 2010 and follow-up to 2015 (341 deaths), all-cause mortality per 1000 person-years was 40.5, 23.7 and 15.1 across rising thirds of spermidine intake. The age-, sex- and caloric-adjusted hazard ratio per 1-SD higher intake was 0.74 (95% CI 0.66 to 0.83), and after further adjustment for lifestyle factors, mortality predictors and other dietary features it was 0.76 (95% CI 0.67 to 0.86). A second cohort, SAPHIR, gave 0.71 (95% CI 0.53 to 0.95). The authors say the difference between the top and bottom thirds was like a 5.7-year younger age.

This is a link between spermidine from food and death, estimated from questionnaires. It is not an effect of taking a supplement, and whether questionnaire intake maps to supplement doses was not assessed here.

Origin of the claim: yeast, flies, worms, mice and rats; authors with company equity

Animal study

Eisenberg T et al. Nat Med. 2016;22(12):1428-1438. PMID 27841876.

In 2009 the same group reported that spermidine extended the lifespan of yeast, flies, worms and human immune cells in culture, inhibited oxidative stress in ageing mice and raised autophagy-related transcripts, and the authors report that enhanced autophagy was crucial for the longevity effect (PMID 19801973). In the 2016 paper, oral spermidine extended the lifespan of mice, preserved diastolic function and reduced cardiac hypertrophy in old mice, and lowered blood pressure in Dahl salt-sensitive rats; the cardioprotection failed in mice lacking the autophagy protein Atg5 in cardiomyocytes. In that paper, higher dietary spermidine from food questionnaires in humans correlated with lower blood pressure and a lower incidence of cardiovascular disease.

Participants / model
Yeast, flies, worms, cultured human immune cells, mice and rats; food-questionnaire data in humans
Treatment
Spermidine in the diet or water of animals; cell culture; doses not stated in the source
Follow-up
not stated in the source
Study design
Animal and cell studies, with a human food-questionnaire correlation
Funding
not stated in the source; several authors of the 2016 paper declare equity in The Longevity Labs, a company that develops natural food extracts

Animal and cell findings. The human link is a correlation from food questionnaires.

Read the original source
Bruneck cohort: 829 adults, hazard ratio 0.74 per SD of food spermidine

Human study

Kiechl S et al. Am J Clin Nutr. 2018;108(2):371-380. PMID 29955838.

With diet assessed by repeated food-frequency questionnaires from 1995 to 2010 and follow-up to 2015 (341 deaths), all-cause mortality per 1000 person-years was 40.5, 23.7 and 15.1 across rising thirds of spermidine intake. The age-, sex- and caloric-adjusted hazard ratio per 1-SD higher intake was 0.74 (95% CI 0.66 to 0.83), and after further adjustment for lifestyle factors, mortality predictors and other dietary features it was 0.76 (95% CI 0.67 to 0.86). A second cohort, SAPHIR, gave 0.71 (95% CI 0.53 to 0.95). The authors say the top versus bottom third difference was like a 5.7-year younger age.

Participants / model
829 adults aged 45 to 84 in an Austrian community cohort; a second validation cohort (SAPHIR)
Treatment
Dietary spermidine intake from food, not supplements
Follow-up
Diet assessed 1995 to 2010; follow-up to 2015 (341 deaths)
Study design
Prospective observational cohort (NCT03378843)
Funding
not stated in the source

This is a link between food spermidine and death, estimated from questionnaires, not an effect of taking a supplement.

Read the original source

What did the randomized memory trials find?

The core memory trial, SmartAge (100 adults aged 60 to 90 with subjective cognitive decline, 12 months, 0.9 mg spermidine per day), missed its primary memory outcome (between-group difference -0.03; 95% CI -0.11 to 0.05; P = .47). Two earlier small studies hinted at benefit, which SmartAge did not confirm on its primary outcome.

SmartAge was a 12-month randomized double-masked placebo-controlled phase 2b trial in 100 adults aged 60 to 90 with subjective cognitive decline (51 spermidine, 49 placebo; mean age 69; 89 completed). Participants took a wheat germ extract giving 0.9 mg spermidine per day or placebo. The primary outcome, mnemonic discrimination, did not change (between-group difference -0.03; 95% CI -0.11 to 0.05; P = .47), and secondary outcomes did not either (NCT03094546).

Exploratory analyses hinted at benefit for inflammation and verbal memory, and adverse events were balanced. The authors say a higher dosage is needed to validate these. Several authors had equity in or advised The Longevity Labs, and one led it as chief executive during the trial.

A 2026 exploratory MRI analysis of 75 participants reports higher precuneus blood flow (between-group difference 4.9 ml/100 g/min, 95% CI 1.0 to 8.9, P = .015) and fractional anisotropy in a cingulate white matter bundle that stayed stable on spermidine and fell on placebo. It is hypothesis-generating and online ahead of print, so it may change.

Two small studies preceded SmartAge. In a 3-month phase IIa pilot of 30 cognitively intact adults aged 60 to 80 with subjective cognitive decline, memory performance was moderately enhanced on spermidine versus placebo (contrast mean 0.17, 95% CI -0.01 to 0.35, Cohen's d 0.77, 95% CI 0 to 1.53), and mnemonic discrimination improved within the spermidine group (mean difference -0.11, 95% CI -0.19 to -0.03) but not within the placebo group. The between-group interval includes zero. In a double-blind preliminary study of 85 nursing-home residents aged 60 to 96, residents with mild dementia in the higher-dose group improved by 2.23 points on the MMSE (p = 0.026) while the lower-dose group was stable or declining. The abstract gives no placebo arm, and the study was investigator-funded.

SmartAge: 100 adults, 12 months, primary memory outcome not met

Randomized controlled trial

Schwarz C et al. JAMA Netw Open. 2022;5(5):e2213875. PMID 35616942.

In a 12-month randomized double-masked placebo-controlled phase 2b trial, 100 adults aged 60 to 90 with subjective cognitive decline (51 spermidine, 49 placebo; mean age 69; 89 completed) took a wheat germ extract giving 0.9 mg spermidine per day or placebo. The primary outcome, mnemonic discrimination, did not change (between-group difference -0.03; 95% CI -0.11 to 0.05; P = .47), and secondary outcomes did not either. Exploratory analyses hinted at benefit for inflammation and verbal memory, and adverse events were balanced. The authors say higher dosage is needed to validate these. A 2026 exploratory MRI analysis of 75 participants reports higher precuneus blood flow (between-group difference 4.9 ml/100 g/min, 95% CI 1.0 to 8.9, P = .015) and fractional anisotropy in a cingulate white matter bundle that stayed stable on spermidine and fell on placebo, and is hypothesis-generating.

Participants / model
100 adults aged 60 to 90 with subjective cognitive decline
Treatment
Oral spermidine-rich wheat germ extract giving 0.9 mg spermidine/day, or placebo
Follow-up
12 months
Study design
Randomized double-masked placebo-controlled phase 2b trial
Funding
not stated in the source; several authors had equity in or advised The Longevity Labs, and one led it as chief executive during the trial

The primary outcome was negative. The MRI analysis is online ahead of print and may change.

Read the original source
Earlier memory studies: a 30-person pilot and an 85-resident nursing-home study

Randomized controlled trial

Wirth M et al. Cortex. 2018;109:181-188. PMID 30388439.

In a 3-month phase IIa pilot of 30 cognitively intact adults aged 60 to 80 with subjective cognitive decline, memory performance was moderately enhanced on spermidine versus placebo (contrast mean 0.17, 95% CI -0.01 to 0.35, Cohen's d 0.77, 95% CI 0 to 1.53), and mnemonic discrimination improved within the spermidine group (mean difference -0.11, 95% CI -0.19 to -0.03) but not within the placebo group; the between-group interval includes zero. In a double-blind preliminary study of 85 nursing-home residents aged 60 to 96, subjects with mild dementia in the higher-dose group improved by 2.23 points on the MMSE (p = 0.026) while the lower-dose group was stable or declining; the abstract gives no placebo arm.

Participants / model
30 adults with subjective cognitive decline; 85 nursing-home residents with mild to moderate dementia
Treatment
Oral spermidine-rich extract for 3 months
Follow-up
3 months
Study design
Randomized pilot; double-blind dose-group study without a placebo arm in the abstract
Funding
not stated in the source for the 30-person pilot; the 85-resident study was investigator-funded

These are pilots whose signals SmartAge did not confirm on its primary outcome.

Read the original source

Is there human data on autophagy?

Only small pilots. In 40 adults over 65, 6 mg spermidine daily for 13 weeks raised expression of autophagy-related genes in B cells, and in 12 healthy adults only the 3.3 mg per day rice germ extract dose raised Beclin-1 by 7.3% and ULK-1 by 13.4% against baseline.

In a double-blind randomized placebo-controlled pilot of 40 adults over 65 after a third SARS-CoV-2 vaccine dose, 6 mg spermidine daily for 13 weeks was well tolerated, enhanced spike-specific IgG and neutralizing antibody activity in vaccine non-responders, and raised expression of TFEB targets and autophagy-related genes in B cells, which the authors read as elevated autophagic flux. Two authors consult for The Longevity Labs, which the paper says had no input into design, results, analysis or manuscript (NCT05421546).

In a single-blind pilot of 12 healthy adults randomized to 1.5 or 3.3 mg per day from a rice germ extract for 56 days, only the 3.3 mg dose raised Beclin-1 by 7.3% and ULK-1 by 13.4% against baseline. The authors note that human research showing a dose of spermidine that raises autophagy biomarkers was lacking before it. An author's affiliation line gives the chief scientific officer of Nutraland, which makes the extract.

Both pilots are small, and the second compares with baseline rather than a control. Their outcomes were vaccine antibody response and autophagy-related gene or protein markers.

Human autophagy data: a 40-person vaccine pilot and a 12-person rice germ extract pilot

Randomized controlled trial

Alsaleh G et al. Aging Cell. 2026;25(6):e70545. PMID 42169618.

In a double-blind randomized placebo-controlled pilot of 40 adults over 65 after a third SARS-CoV-2 vaccine dose, 6 mg spermidine daily for 13 weeks was well tolerated, enhanced spike-specific IgG and neutralizing antibody activity in vaccine non-responders, and raised expression of TFEB targets and autophagy-related genes in B cells, which the authors read as elevated autophagic flux. In a single-blind pilot of 12 healthy adults randomized to 1.5 or 3.3 mg per day from a rice germ extract for 56 days, only the 3.3 mg dose raised Beclin-1 by 7.3% and ULK-1 by 13.4% against baseline, and the authors themselves note that human research showing a dose of spermidine that raises autophagy biomarkers was lacking before it.

Participants / model
40 adults over 65; 12 healthy adults aged about 55
Treatment
Oral spermidine 6 mg/day for 13 weeks; rice germ extract 1.5 or 3.3 mg/day for 56 days
Follow-up
13 weeks; 56 days
Study design
Double-blind randomized placebo-controlled pilot; single-blind randomized dose pilot compared with baseline
Funding
not stated in the source; two authors of the 40-person pilot consult for The Longevity Labs, which the paper says had no input into design, results, analysis or manuscript, and an author affiliation line for the 12-person pilot gives the chief scientific officer of Nutraland, which makes the extract

Both are small, and the second compares with baseline rather than a control.

Read the original source

Does spermidine induce autophagy, extend life or protect memory?

The evidence differs by claim. Longevity rests on animal data and food-intake observation, autophagy on pilots of 12 and 40 people, and memory was tested at 0.9 mg per day for 12 months and missed its primary endpoint. A PubMed search on 11 October 2026 found no trial reporting mortality, lifespan or disease-incidence outcomes.

Sellers say spermidine induces autophagy, supports longevity and protects memory in older adults. The evidence differs by claim. Longevity rests on animal data and food-intake observation, autophagy has small human biomarker pilots, and memory was tested at 0.9 mg per day for 12 months and did not meet its primary endpoint.

A PubMed search on 11 October 2026 for spermidine in the title or abstract with randomized controlled trial as publication type returned 42 records, and the first 30 by relevance were reviewed by title. The spermidine supplementation trials among them were SmartAge and its earlier pilot and safety papers, two exposure trials, a multi-ingredient fasting mimetic, a 2026 vaccine pilot and a 2025 rice germ extract pilot. The rest were unrelated, local uses (a peri-implant mucositis gel), polyamine biomarker studies, or trials of the ODC inhibitor DFMO. None reported mortality, lifespan or disease-incidence outcomes.

A ClinicalTrials.gov search with spermidine as an intervention returned 24 studies, 11 completed (1 with posted results), 6 unknown and 4 recruiting. Named trials without results include NCT06186102 (Aarhus, 187 participants aged 65 to 90 with coronary artery disease, 8 mg three times daily, completed 29 June 2026 per the registry), NCT04405388 (Graz, phase 3 crossover, 4 mg/day, blood pressure, status unknown) and NCT05128331 (Greifswald, exercise capacity, status unknown). Registered studies without results show that a study was registered, not that it works.

The SmartAge dose is a plant extract at 0.9 mg per day, and retail products may differ; no study found here tested them.

PubMed search, 11 October 2026: 42 records, none with mortality, lifespan or disease-incidence outcomes

PubMed search record

PubMed search run on 11 October 2026: spermidine[tiab] AND randomized controlled trial[pt]. 42 records returned; the first 30 by relevance were reviewed by title. ClinicalTrials.gov search with spermidine as an intervention run the same day.

The search returned 42 records, and the first 30 by relevance were reviewed by title. The spermidine supplementation trials among them were SmartAge and its earlier pilot and safety papers, the 2024 and 2023 exposure trials, a multi-ingredient fasting mimetic (PMID 39549554), the 2026 vaccine pilot and the 2025 rice germ extract pilot. The rest were unrelated, local uses (a peri-implant mucositis gel), polyamine biomarker studies, or trials of the ODC inhibitor DFMO. None reported mortality, lifespan or disease-incidence outcomes. A ClinicalTrials.gov search with spermidine as an intervention returned 24 studies, 11 completed (1 with posted results), 6 unknown and 4 recruiting. Named trials without results include NCT06186102 (Aarhus, 187 participants aged 65 to 90 with coronary artery disease, 8 mg three times daily, completed 29 June 2026 per the registry), NCT04405388 (Graz, phase 3 crossover, 4 mg/day, blood pressure, status unknown) and NCT05128331 (Greifswald, exercise capacity, status unknown).

Participants / model
Records reviewed and registered trials, not a population
Treatment
Not applicable
Follow-up
Search run on 11 October 2026
Study design
Literature search and trial registry
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists. Registered studies without results show that a study was registered, not that it works.

Read the original source
SmartAge: 100 adults, 12 months, primary memory outcome not met

Randomized controlled trial

Schwarz C et al. JAMA Netw Open. 2022;5(5):e2213875. PMID 35616942.

In a 12-month randomized double-masked placebo-controlled phase 2b trial, 100 adults aged 60 to 90 with subjective cognitive decline (51 spermidine, 49 placebo; mean age 69; 89 completed) took a wheat germ extract giving 0.9 mg spermidine per day or placebo. The primary outcome, mnemonic discrimination, did not change (between-group difference -0.03; 95% CI -0.11 to 0.05; P = .47), and secondary outcomes did not either. Exploratory analyses hinted at benefit for inflammation and verbal memory, and adverse events were balanced. The authors say higher dosage is needed to validate these. A 2026 exploratory MRI analysis of 75 participants reports higher precuneus blood flow (between-group difference 4.9 ml/100 g/min, 95% CI 1.0 to 8.9, P = .015) and fractional anisotropy in a cingulate white matter bundle that stayed stable on spermidine and fell on placebo, and is hypothesis-generating.

Participants / model
100 adults aged 60 to 90 with subjective cognitive decline
Treatment
Oral spermidine-rich wheat germ extract giving 0.9 mg spermidine/day, or placebo
Follow-up
12 months
Study design
Randomized double-masked placebo-controlled phase 2b trial
Funding
not stated in the source; several authors had equity in or advised The Longevity Labs, and one led it as chief executive during the trial

The primary outcome was negative. The MRI analysis is online ahead of print and may change.

Read the original source
Origin of the claim: yeast, flies, worms, mice and rats; authors with company equity

Animal study

Eisenberg T et al. Nat Med. 2016;22(12):1428-1438. PMID 27841876.

In 2009 the same group reported that spermidine extended the lifespan of yeast, flies, worms and human immune cells in culture, inhibited oxidative stress in ageing mice and raised autophagy-related transcripts, and the authors report that enhanced autophagy was crucial for the longevity effect (PMID 19801973). In the 2016 paper, oral spermidine extended the lifespan of mice, preserved diastolic function and reduced cardiac hypertrophy in old mice, and lowered blood pressure in Dahl salt-sensitive rats; the cardioprotection failed in mice lacking the autophagy protein Atg5 in cardiomyocytes. In that paper, higher dietary spermidine from food questionnaires in humans correlated with lower blood pressure and a lower incidence of cardiovascular disease.

Participants / model
Yeast, flies, worms, cultured human immune cells, mice and rats; food-questionnaire data in humans
Treatment
Spermidine in the diet or water of animals; cell culture; doses not stated in the source
Follow-up
not stated in the source
Study design
Animal and cell studies, with a human food-questionnaire correlation
Funding
not stated in the source; several authors of the 2016 paper declare equity in The Longevity Labs, a company that develops natural food extracts

Animal and cell findings. The human link is a correlation from food questionnaires.

Read the original source
Bruneck cohort: 829 adults, hazard ratio 0.74 per SD of food spermidine

Human study

Kiechl S et al. Am J Clin Nutr. 2018;108(2):371-380. PMID 29955838.

With diet assessed by repeated food-frequency questionnaires from 1995 to 2010 and follow-up to 2015 (341 deaths), all-cause mortality per 1000 person-years was 40.5, 23.7 and 15.1 across rising thirds of spermidine intake. The age-, sex- and caloric-adjusted hazard ratio per 1-SD higher intake was 0.74 (95% CI 0.66 to 0.83), and after further adjustment for lifestyle factors, mortality predictors and other dietary features it was 0.76 (95% CI 0.67 to 0.86). A second cohort, SAPHIR, gave 0.71 (95% CI 0.53 to 0.95). The authors say the top versus bottom third difference was like a 5.7-year younger age.

Participants / model
829 adults aged 45 to 84 in an Austrian community cohort; a second validation cohort (SAPHIR)
Treatment
Dietary spermidine intake from food, not supplements
Follow-up
Diet assessed 1995 to 2010; follow-up to 2015 (341 deaths)
Study design
Prospective observational cohort (NCT03378843)
Funding
not stated in the source

This is a link between food spermidine and death, estimated from questionnaires, not an effect of taking a supplement.

Read the original source
Human autophagy data: a 40-person vaccine pilot and a 12-person rice germ extract pilot

Randomized controlled trial

Alsaleh G et al. Aging Cell. 2026;25(6):e70545. PMID 42169618.

In a double-blind randomized placebo-controlled pilot of 40 adults over 65 after a third SARS-CoV-2 vaccine dose, 6 mg spermidine daily for 13 weeks was well tolerated, enhanced spike-specific IgG and neutralizing antibody activity in vaccine non-responders, and raised expression of TFEB targets and autophagy-related genes in B cells, which the authors read as elevated autophagic flux. In a single-blind pilot of 12 healthy adults randomized to 1.5 or 3.3 mg per day from a rice germ extract for 56 days, only the 3.3 mg dose raised Beclin-1 by 7.3% and ULK-1 by 13.4% against baseline, and the authors themselves note that human research showing a dose of spermidine that raises autophagy biomarkers was lacking before it.

Participants / model
40 adults over 65; 12 healthy adults aged about 55
Treatment
Oral spermidine 6 mg/day for 13 weeks; rice germ extract 1.5 or 3.3 mg/day for 56 days
Follow-up
13 weeks; 56 days
Study design
Double-blind randomized placebo-controlled pilot; single-blind randomized dose pilot compared with baseline
Funding
not stated in the source; two authors of the 40-person pilot consult for The Longevity Labs, which the paper says had no input into design, results, analysis or manuscript, and an author affiliation line for the 12-person pilot gives the chief scientific officer of Nutraland, which makes the extract

Both are small, and the second compares with baseline rather than a control.

Read the original source

How does spermidine work, and does an oral dose reach the blood?

Spermidine is proposed to induce autophagy, and in mice the cardioprotection failed when the autophagy protein Atg5 was missing from heart cells. In 12 healthy volunteers, 15 mg/day for 5 days raised plasma spermine, not spermidine, and in 37 men 40 mg/day did not substantially change serum or urine polyamines.

Spermidine is a natural polyamine proposed to induce autophagy. In mice, the cardioprotection from oral spermidine failed in animals lacking the autophagy protein Atg5 in cardiomyocytes, and the 2009 authors report that enhanced autophagy was crucial for the longevity effect in their models. In people, the autophagy evidence is two small pilots: raised expression of TFEB targets and autophagy-related genes in B cells in 40 adults over 65 on 6 mg daily, and raised Beclin-1 and ULK-1 against baseline in 12 adults on 3.3 mg per day.

Exposure is a problem for supplements. In 12 healthy volunteers given 15 mg/day of spermidine for 5 days in a randomized placebo-controlled crossover study, plasma spermine rose but plasma spermidine and putrescine did not. The authors conclude dietary spermidine is converted before it reaches the circulation and that spermidine supplements below 15 mg/day are unlikely to have short-term effects.

In 37 healthy men aged 50 to 70 given purified spermidine trihydrochloride (40 mg/day) for 7 and 28 days, serum and urine polyamine concentrations did not change substantially, and the authors read this as tight homeostatic control. The trial was funded by Chrysea Labs, and two authors are its employees. The SmartAge dose (0.9 mg/day) is well below the 15 mg/day level. No half-life appears in the sources reviewed.

Origin of the claim: yeast, flies, worms, mice and rats; authors with company equity

Animal study

Eisenberg T et al. Nat Med. 2016;22(12):1428-1438. PMID 27841876.

In 2009 the same group reported that spermidine extended the lifespan of yeast, flies, worms and human immune cells in culture, inhibited oxidative stress in ageing mice and raised autophagy-related transcripts, and the authors report that enhanced autophagy was crucial for the longevity effect (PMID 19801973). In the 2016 paper, oral spermidine extended the lifespan of mice, preserved diastolic function and reduced cardiac hypertrophy in old mice, and lowered blood pressure in Dahl salt-sensitive rats; the cardioprotection failed in mice lacking the autophagy protein Atg5 in cardiomyocytes. In that paper, higher dietary spermidine from food questionnaires in humans correlated with lower blood pressure and a lower incidence of cardiovascular disease.

Participants / model
Yeast, flies, worms, cultured human immune cells, mice and rats; food-questionnaire data in humans
Treatment
Spermidine in the diet or water of animals; cell culture; doses not stated in the source
Follow-up
not stated in the source
Study design
Animal and cell studies, with a human food-questionnaire correlation
Funding
not stated in the source; several authors of the 2016 paper declare equity in The Longevity Labs, a company that develops natural food extracts

Animal and cell findings. The human link is a correlation from food questionnaires.

Read the original source
Human autophagy data: a 40-person vaccine pilot and a 12-person rice germ extract pilot

Randomized controlled trial

Alsaleh G et al. Aging Cell. 2026;25(6):e70545. PMID 42169618.

In a double-blind randomized placebo-controlled pilot of 40 adults over 65 after a third SARS-CoV-2 vaccine dose, 6 mg spermidine daily for 13 weeks was well tolerated, enhanced spike-specific IgG and neutralizing antibody activity in vaccine non-responders, and raised expression of TFEB targets and autophagy-related genes in B cells, which the authors read as elevated autophagic flux. In a single-blind pilot of 12 healthy adults randomized to 1.5 or 3.3 mg per day from a rice germ extract for 56 days, only the 3.3 mg dose raised Beclin-1 by 7.3% and ULK-1 by 13.4% against baseline, and the authors themselves note that human research showing a dose of spermidine that raises autophagy biomarkers was lacking before it.

Participants / model
40 adults over 65; 12 healthy adults aged about 55
Treatment
Oral spermidine 6 mg/day for 13 weeks; rice germ extract 1.5 or 3.3 mg/day for 56 days
Follow-up
13 weeks; 56 days
Study design
Double-blind randomized placebo-controlled pilot; single-blind randomized dose pilot compared with baseline
Funding
not stated in the source; two authors of the 40-person pilot consult for The Longevity Labs, which the paper says had no input into design, results, analysis or manuscript, and an author affiliation line for the 12-person pilot gives the chief scientific officer of Nutraland, which makes the extract

Both are small, and the second compares with baseline rather than a control.

Read the original source
Exposure: 12 volunteers at 15 mg/day raised spermine, not spermidine; 37 men at 40 mg/day, no change

Randomized controlled trial

Senekowitsch S et al. Nutrients. 2023;15(8). PMID 37111071.

In 12 healthy volunteers given 15 mg/day of spermidine for 5 days in a randomized placebo-controlled crossover study, plasma spermine rose but plasma spermidine and putrescine did not. The authors conclude dietary spermidine is converted before it reaches the circulation and that spermidine supplements below 15 mg/day are unlikely to have short-term effects. In 37 healthy men aged 50 to 70 given purified spermidine trihydrochloride (40 mg/day) for 7 and 28 days, serum and urine polyamine concentrations did not change substantially, and the authors read this as tight homeostatic control. The SmartAge dose (0.9 mg/day) is well below the 15 mg/day level.

Participants / model
12 healthy volunteers; 37 healthy men aged 50 to 70
Treatment
Oral spermidine 15 mg/day for 5 days; spermidine trihydrochloride 40 mg/day for up to 28 days
Follow-up
5 days; 7 and 28 days
Study design
Randomized placebo-controlled crossover pharmacokinetic study; randomized exploratory trial
Funding
The 12-volunteer study declared no conflict of interest and its funding is not stated in the source; the 37-man trial was funded by Chrysea Labs, and two authors are its employees

These measure plasma, serum and urine polyamine levels, not memory or longevity.

Read the original source

What risks and cautions do the studies show?

Short-term safety was reassuring: no difference from placebo in vital signs, weight, chemistry or hematology in 30 adults over 3 months, and no product-related adverse events at 40 mg/day over 28 days. Two observational cautions exist, a 39% higher adenoma risk with higher dietary polyamines and higher plasma spermidine with poststroke cognitive impairment, and the longest trial ran 12 months.

In 30 adults aged 60 to 80 with subjective cognitive decline, 3 months of a spermidine-rich plant extract at 1.2 mg/day showed no difference from placebo in vital signs, weight, clinical chemistry or hematology, with compliance above 85%. A 28-day mouse study found no increase in tumorigenic or fibrotic events, and four authors disclose a financial interest in The Longevity Labs. The 40 mg/day trial reported no study-product-related adverse events over 28 days, and adverse events were balanced in SmartAge.

Two cautions come from other designs. In 1164 people with a prior colorectal adenoma, dietary polyamine intake above the median was associated with a 39% higher risk of adenoma at follow-up (adjusted OR 1.39, 95% CI 1.06 to 1.83). In 619 patients with ischemic stroke, higher plasma spermidine was associated with higher odds of poststroke cognitive impairment (highest versus lowest quartile adjusted OR 1.81, 95% CI 1.09 to 3.01). Both are associations in disease populations, not trials of supplements.

A review states that polyamine intake seems to suppress tumorigenesis but appears to accelerate the growth of established tumors. No search here covered spermidine and cancer progression beyond that cohort and one review. The longest trial found ran 12 months (SmartAge), so long-term supplement safety is not established.

Short-term safety: 30 older adults for 3 months, plus two cautions from cohorts

Randomized controlled trial

Schwarz C et al. Aging (Albany NY). 2018;10(1):19-33. PMID 29315079.

In 30 adults aged 60 to 80 with subjective cognitive decline, 3 months of a spermidine-rich plant extract at 1.2 mg/day showed no difference from placebo in vital signs, weight, clinical chemistry or hematology, with compliance above 85%, and a 28-day mouse study found no increase in tumorigenic or fibrotic events. The 40 mg/day trial reported no study-product-related adverse events over 28 days. Two cautions come from other designs. In 1164 people with a prior colorectal adenoma, dietary polyamine intake above the median was associated with a 39% higher risk of adenoma at follow-up (adjusted OR 1.39, 95% CI 1.06 to 1.83; Vargas 2012). In 619 patients with ischemic stroke, higher plasma spermidine was associated with higher odds of poststroke cognitive impairment (highest versus lowest quartile adjusted OR 1.81, 95% CI 1.09 to 3.01; He 2025). A review states that polyamine intake seems to suppress tumorigenesis but appears to accelerate the growth of established tumors.

Participants / model
30 older adults; 1164 people with prior colorectal adenoma; 619 patients with ischemic stroke
Treatment
Oral spermidine-rich plant extract 1.2 mg/day; dietary and plasma polyamines
Follow-up
3 months; the longest spermidine trial found ran 12 months (SmartAge)
Study design
Randomized safety trial plus observational cohorts
Funding
not stated in the source; four authors disclose a financial interest in The Longevity Labs

The adenoma and stroke findings are associations in disease populations, not trials of supplements.

Read the original source
SmartAge: 100 adults, 12 months, primary memory outcome not met

Randomized controlled trial

Schwarz C et al. JAMA Netw Open. 2022;5(5):e2213875. PMID 35616942.

In a 12-month randomized double-masked placebo-controlled phase 2b trial, 100 adults aged 60 to 90 with subjective cognitive decline (51 spermidine, 49 placebo; mean age 69; 89 completed) took a wheat germ extract giving 0.9 mg spermidine per day or placebo. The primary outcome, mnemonic discrimination, did not change (between-group difference -0.03; 95% CI -0.11 to 0.05; P = .47), and secondary outcomes did not either. Exploratory analyses hinted at benefit for inflammation and verbal memory, and adverse events were balanced. The authors say higher dosage is needed to validate these. A 2026 exploratory MRI analysis of 75 participants reports higher precuneus blood flow (between-group difference 4.9 ml/100 g/min, 95% CI 1.0 to 8.9, P = .015) and fractional anisotropy in a cingulate white matter bundle that stayed stable on spermidine and fell on placebo, and is hypothesis-generating.

Participants / model
100 adults aged 60 to 90 with subjective cognitive decline
Treatment
Oral spermidine-rich wheat germ extract giving 0.9 mg spermidine/day, or placebo
Follow-up
12 months
Study design
Randomized double-masked placebo-controlled phase 2b trial
Funding
not stated in the source; several authors had equity in or advised The Longevity Labs, and one led it as chief executive during the trial

The primary outcome was negative. The MRI analysis is online ahead of print and may change.

Read the original source
Exposure: 12 volunteers at 15 mg/day raised spermine, not spermidine; 37 men at 40 mg/day, no change

Randomized controlled trial

Senekowitsch S et al. Nutrients. 2023;15(8). PMID 37111071.

In 12 healthy volunteers given 15 mg/day of spermidine for 5 days in a randomized placebo-controlled crossover study, plasma spermine rose but plasma spermidine and putrescine did not. The authors conclude dietary spermidine is converted before it reaches the circulation and that spermidine supplements below 15 mg/day are unlikely to have short-term effects. In 37 healthy men aged 50 to 70 given purified spermidine trihydrochloride (40 mg/day) for 7 and 28 days, serum and urine polyamine concentrations did not change substantially, and the authors read this as tight homeostatic control. The SmartAge dose (0.9 mg/day) is well below the 15 mg/day level.

Participants / model
12 healthy volunteers; 37 healthy men aged 50 to 70
Treatment
Oral spermidine 15 mg/day for 5 days; spermidine trihydrochloride 40 mg/day for up to 28 days
Follow-up
5 days; 7 and 28 days
Study design
Randomized placebo-controlled crossover pharmacokinetic study; randomized exploratory trial
Funding
The 12-volunteer study declared no conflict of interest and its funding is not stated in the source; the 37-man trial was funded by Chrysea Labs, and two authors are its employees

These measure plasma, serum and urine polyamine levels, not memory or longevity.

Read the original source

Why does spermidine sit in C tier?

C fits real animal lifespan and autophagy data and a cohort link to lower mortality, set against a negative primary result in the one adequately sized randomized trial, a dosing and exposure problem, and no randomized outcome data on longevity.

Spermidine has real animal lifespan and autophagy data, a notable cohort link between food spermidine and lower mortality, and short human safety data at doses from 0.9 to 40 mg per day.

Against that, the one adequately sized randomized trial, SmartAge, missed its primary memory endpoint, a pharmacokinetic study found that 15 mg/day of oral spermidine raised plasma spermine, not spermidine, the human autophagy data come from pilots of 12 and 40 people, and no randomized outcome data on longevity exist. Much of the clinical work has company-linked authorship, and two cancer-adjacent observational cautions add reasons for care.

The grade covers spermidine as sold for autophagy, longevity and memory support.

Origin of the claim: yeast, flies, worms, mice and rats; authors with company equity

Animal study

Eisenberg T et al. Nat Med. 2016;22(12):1428-1438. PMID 27841876.

In 2009 the same group reported that spermidine extended the lifespan of yeast, flies, worms and human immune cells in culture, inhibited oxidative stress in ageing mice and raised autophagy-related transcripts, and the authors report that enhanced autophagy was crucial for the longevity effect (PMID 19801973). In the 2016 paper, oral spermidine extended the lifespan of mice, preserved diastolic function and reduced cardiac hypertrophy in old mice, and lowered blood pressure in Dahl salt-sensitive rats; the cardioprotection failed in mice lacking the autophagy protein Atg5 in cardiomyocytes. In that paper, higher dietary spermidine from food questionnaires in humans correlated with lower blood pressure and a lower incidence of cardiovascular disease.

Participants / model
Yeast, flies, worms, cultured human immune cells, mice and rats; food-questionnaire data in humans
Treatment
Spermidine in the diet or water of animals; cell culture; doses not stated in the source
Follow-up
not stated in the source
Study design
Animal and cell studies, with a human food-questionnaire correlation
Funding
not stated in the source; several authors of the 2016 paper declare equity in The Longevity Labs, a company that develops natural food extracts

Animal and cell findings. The human link is a correlation from food questionnaires.

Read the original source
Bruneck cohort: 829 adults, hazard ratio 0.74 per SD of food spermidine

Human study

Kiechl S et al. Am J Clin Nutr. 2018;108(2):371-380. PMID 29955838.

With diet assessed by repeated food-frequency questionnaires from 1995 to 2010 and follow-up to 2015 (341 deaths), all-cause mortality per 1000 person-years was 40.5, 23.7 and 15.1 across rising thirds of spermidine intake. The age-, sex- and caloric-adjusted hazard ratio per 1-SD higher intake was 0.74 (95% CI 0.66 to 0.83), and after further adjustment for lifestyle factors, mortality predictors and other dietary features it was 0.76 (95% CI 0.67 to 0.86). A second cohort, SAPHIR, gave 0.71 (95% CI 0.53 to 0.95). The authors say the top versus bottom third difference was like a 5.7-year younger age.

Participants / model
829 adults aged 45 to 84 in an Austrian community cohort; a second validation cohort (SAPHIR)
Treatment
Dietary spermidine intake from food, not supplements
Follow-up
Diet assessed 1995 to 2010; follow-up to 2015 (341 deaths)
Study design
Prospective observational cohort (NCT03378843)
Funding
not stated in the source

This is a link between food spermidine and death, estimated from questionnaires, not an effect of taking a supplement.

Read the original source
SmartAge: 100 adults, 12 months, primary memory outcome not met

Randomized controlled trial

Schwarz C et al. JAMA Netw Open. 2022;5(5):e2213875. PMID 35616942.

In a 12-month randomized double-masked placebo-controlled phase 2b trial, 100 adults aged 60 to 90 with subjective cognitive decline (51 spermidine, 49 placebo; mean age 69; 89 completed) took a wheat germ extract giving 0.9 mg spermidine per day or placebo. The primary outcome, mnemonic discrimination, did not change (between-group difference -0.03; 95% CI -0.11 to 0.05; P = .47), and secondary outcomes did not either. Exploratory analyses hinted at benefit for inflammation and verbal memory, and adverse events were balanced. The authors say higher dosage is needed to validate these. A 2026 exploratory MRI analysis of 75 participants reports higher precuneus blood flow (between-group difference 4.9 ml/100 g/min, 95% CI 1.0 to 8.9, P = .015) and fractional anisotropy in a cingulate white matter bundle that stayed stable on spermidine and fell on placebo, and is hypothesis-generating.

Participants / model
100 adults aged 60 to 90 with subjective cognitive decline
Treatment
Oral spermidine-rich wheat germ extract giving 0.9 mg spermidine/day, or placebo
Follow-up
12 months
Study design
Randomized double-masked placebo-controlled phase 2b trial
Funding
not stated in the source; several authors had equity in or advised The Longevity Labs, and one led it as chief executive during the trial

The primary outcome was negative. The MRI analysis is online ahead of print and may change.

Read the original source
Exposure: 12 volunteers at 15 mg/day raised spermine, not spermidine; 37 men at 40 mg/day, no change

Randomized controlled trial

Senekowitsch S et al. Nutrients. 2023;15(8). PMID 37111071.

In 12 healthy volunteers given 15 mg/day of spermidine for 5 days in a randomized placebo-controlled crossover study, plasma spermine rose but plasma spermidine and putrescine did not. The authors conclude dietary spermidine is converted before it reaches the circulation and that spermidine supplements below 15 mg/day are unlikely to have short-term effects. In 37 healthy men aged 50 to 70 given purified spermidine trihydrochloride (40 mg/day) for 7 and 28 days, serum and urine polyamine concentrations did not change substantially, and the authors read this as tight homeostatic control. The SmartAge dose (0.9 mg/day) is well below the 15 mg/day level.

Participants / model
12 healthy volunteers; 37 healthy men aged 50 to 70
Treatment
Oral spermidine 15 mg/day for 5 days; spermidine trihydrochloride 40 mg/day for up to 28 days
Follow-up
5 days; 7 and 28 days
Study design
Randomized placebo-controlled crossover pharmacokinetic study; randomized exploratory trial
Funding
The 12-volunteer study declared no conflict of interest and its funding is not stated in the source; the 37-man trial was funded by Chrysea Labs, and two authors are its employees

These measure plasma, serum and urine polyamine levels, not memory or longevity.

Read the original source
Human autophagy data: a 40-person vaccine pilot and a 12-person rice germ extract pilot

Randomized controlled trial

Alsaleh G et al. Aging Cell. 2026;25(6):e70545. PMID 42169618.

In a double-blind randomized placebo-controlled pilot of 40 adults over 65 after a third SARS-CoV-2 vaccine dose, 6 mg spermidine daily for 13 weeks was well tolerated, enhanced spike-specific IgG and neutralizing antibody activity in vaccine non-responders, and raised expression of TFEB targets and autophagy-related genes in B cells, which the authors read as elevated autophagic flux. In a single-blind pilot of 12 healthy adults randomized to 1.5 or 3.3 mg per day from a rice germ extract for 56 days, only the 3.3 mg dose raised Beclin-1 by 7.3% and ULK-1 by 13.4% against baseline, and the authors themselves note that human research showing a dose of spermidine that raises autophagy biomarkers was lacking before it.

Participants / model
40 adults over 65; 12 healthy adults aged about 55
Treatment
Oral spermidine 6 mg/day for 13 weeks; rice germ extract 1.5 or 3.3 mg/day for 56 days
Follow-up
13 weeks; 56 days
Study design
Double-blind randomized placebo-controlled pilot; single-blind randomized dose pilot compared with baseline
Funding
not stated in the source; two authors of the 40-person pilot consult for The Longevity Labs, which the paper says had no input into design, results, analysis or manuscript, and an author affiliation line for the 12-person pilot gives the chief scientific officer of Nutraland, which makes the extract

Both are small, and the second compares with baseline rather than a control.

Read the original source
Short-term safety: 30 older adults for 3 months, plus two cautions from cohorts

Randomized controlled trial

Schwarz C et al. Aging (Albany NY). 2018;10(1):19-33. PMID 29315079.

In 30 adults aged 60 to 80 with subjective cognitive decline, 3 months of a spermidine-rich plant extract at 1.2 mg/day showed no difference from placebo in vital signs, weight, clinical chemistry or hematology, with compliance above 85%, and a 28-day mouse study found no increase in tumorigenic or fibrotic events. The 40 mg/day trial reported no study-product-related adverse events over 28 days. Two cautions come from other designs. In 1164 people with a prior colorectal adenoma, dietary polyamine intake above the median was associated with a 39% higher risk of adenoma at follow-up (adjusted OR 1.39, 95% CI 1.06 to 1.83; Vargas 2012). In 619 patients with ischemic stroke, higher plasma spermidine was associated with higher odds of poststroke cognitive impairment (highest versus lowest quartile adjusted OR 1.81, 95% CI 1.09 to 3.01; He 2025). A review states that polyamine intake seems to suppress tumorigenesis but appears to accelerate the growth of established tumors.

Participants / model
30 older adults; 1164 people with prior colorectal adenoma; 619 patients with ischemic stroke
Treatment
Oral spermidine-rich plant extract 1.2 mg/day; dietary and plasma polyamines
Follow-up
3 months; the longest spermidine trial found ran 12 months (SmartAge)
Study design
Randomized safety trial plus observational cohorts
Funding
not stated in the source; four authors disclose a financial interest in The Longevity Labs

The adenoma and stroke findings are associations in disease populations, not trials of supplements.

Read the original source
PubMed search, 11 October 2026: 42 records, none with mortality, lifespan or disease-incidence outcomes

PubMed search record

PubMed search run on 11 October 2026: spermidine[tiab] AND randomized controlled trial[pt]. 42 records returned; the first 30 by relevance were reviewed by title. ClinicalTrials.gov search with spermidine as an intervention run the same day.

The search returned 42 records, and the first 30 by relevance were reviewed by title. The spermidine supplementation trials among them were SmartAge and its earlier pilot and safety papers, the 2024 and 2023 exposure trials, a multi-ingredient fasting mimetic (PMID 39549554), the 2026 vaccine pilot and the 2025 rice germ extract pilot. The rest were unrelated, local uses (a peri-implant mucositis gel), polyamine biomarker studies, or trials of the ODC inhibitor DFMO. None reported mortality, lifespan or disease-incidence outcomes. A ClinicalTrials.gov search with spermidine as an intervention returned 24 studies, 11 completed (1 with posted results), 6 unknown and 4 recruiting. Named trials without results include NCT06186102 (Aarhus, 187 participants aged 65 to 90 with coronary artery disease, 8 mg three times daily, completed 29 June 2026 per the registry), NCT04405388 (Graz, phase 3 crossover, 4 mg/day, blood pressure, status unknown) and NCT05128331 (Greifswald, exercise capacity, status unknown).

Participants / model
Records reviewed and registered trials, not a population
Treatment
Not applicable
Follow-up
Search run on 11 October 2026
Study design
Literature search and trial registry
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists. Registered studies without results show that a study was registered, not that it works.

Read the original source

Studies and sources

PubChem: spermidine and its trihydrochloride; no FDA drug or label found, 11 October 2026

Chemical identity record

National Library of Medicine. PubChem compound records CID 1102 (spermidine) and CID 9539 (spermidine trihydrochloride). openFDA Drugs@FDA and DailyMed drug-name searches for spermidine run on 11 October 2026.

Spermidine free base: PubChem CID 1102, C7H19N3, 145.25 g/mol, CAS 124-20-9. Spermidine trihydrochloride, the salt used in the 40 mg/day safety trial: CID 9539, C7H22Cl3N3, 254.6 g/mol, CAS 334-50-9. It is a natural polyamine, and the products in the trials are not one thing: a wheat germ extract giving 0.9 mg spermidine per day (SmartAge) or 1.2 mg per day (the 2018 safety study), a rice germ extract giving 1.5 or 3.3 mg per day, and a purified trihydrochloride at 40 mg per day. On 11 October 2026 an openFDA Drugs@FDA query for spermidine returned no match and a DailyMed drug-name search returned no labels.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule and salt; several extract products
Follow-up
Searches run on 11 October 2026
Study design
NLM chemical record plus dated US approval-record search
Funding
not stated in the source

Doses and results do not transfer between these products. Dietary-supplement, GRAS and EU novel food status are not established here.

Read the original source
Origin of the claim: yeast, flies, worms, mice and rats; authors with company equity

Animal study

Eisenberg T et al. Nat Med. 2016;22(12):1428-1438. PMID 27841876.

In 2009 the same group reported that spermidine extended the lifespan of yeast, flies, worms and human immune cells in culture, inhibited oxidative stress in ageing mice and raised autophagy-related transcripts, and the authors report that enhanced autophagy was crucial for the longevity effect (PMID 19801973). In the 2016 paper, oral spermidine extended the lifespan of mice, preserved diastolic function and reduced cardiac hypertrophy in old mice, and lowered blood pressure in Dahl salt-sensitive rats; the cardioprotection failed in mice lacking the autophagy protein Atg5 in cardiomyocytes. In that paper, higher dietary spermidine from food questionnaires in humans correlated with lower blood pressure and a lower incidence of cardiovascular disease.

Participants / model
Yeast, flies, worms, cultured human immune cells, mice and rats; food-questionnaire data in humans
Treatment
Spermidine in the diet or water of animals; cell culture; doses not stated in the source
Follow-up
not stated in the source
Study design
Animal and cell studies, with a human food-questionnaire correlation
Funding
not stated in the source; several authors of the 2016 paper declare equity in The Longevity Labs, a company that develops natural food extracts

Animal and cell findings. The human link is a correlation from food questionnaires.

Read the original source
Bruneck cohort: 829 adults, hazard ratio 0.74 per SD of food spermidine

Human study

Kiechl S et al. Am J Clin Nutr. 2018;108(2):371-380. PMID 29955838.

With diet assessed by repeated food-frequency questionnaires from 1995 to 2010 and follow-up to 2015 (341 deaths), all-cause mortality per 1000 person-years was 40.5, 23.7 and 15.1 across rising thirds of spermidine intake. The age-, sex- and caloric-adjusted hazard ratio per 1-SD higher intake was 0.74 (95% CI 0.66 to 0.83), and after further adjustment for lifestyle factors, mortality predictors and other dietary features it was 0.76 (95% CI 0.67 to 0.86). A second cohort, SAPHIR, gave 0.71 (95% CI 0.53 to 0.95). The authors say the top versus bottom third difference was like a 5.7-year younger age.

Participants / model
829 adults aged 45 to 84 in an Austrian community cohort; a second validation cohort (SAPHIR)
Treatment
Dietary spermidine intake from food, not supplements
Follow-up
Diet assessed 1995 to 2010; follow-up to 2015 (341 deaths)
Study design
Prospective observational cohort (NCT03378843)
Funding
not stated in the source

This is a link between food spermidine and death, estimated from questionnaires, not an effect of taking a supplement.

Read the original source
Exposure: 12 volunteers at 15 mg/day raised spermine, not spermidine; 37 men at 40 mg/day, no change

Randomized controlled trial

Senekowitsch S et al. Nutrients. 2023;15(8). PMID 37111071.

In 12 healthy volunteers given 15 mg/day of spermidine for 5 days in a randomized placebo-controlled crossover study, plasma spermine rose but plasma spermidine and putrescine did not. The authors conclude dietary spermidine is converted before it reaches the circulation and that spermidine supplements below 15 mg/day are unlikely to have short-term effects. In 37 healthy men aged 50 to 70 given purified spermidine trihydrochloride (40 mg/day) for 7 and 28 days, serum and urine polyamine concentrations did not change substantially, and the authors read this as tight homeostatic control. The SmartAge dose (0.9 mg/day) is well below the 15 mg/day level.

Participants / model
12 healthy volunteers; 37 healthy men aged 50 to 70
Treatment
Oral spermidine 15 mg/day for 5 days; spermidine trihydrochloride 40 mg/day for up to 28 days
Follow-up
5 days; 7 and 28 days
Study design
Randomized placebo-controlled crossover pharmacokinetic study; randomized exploratory trial
Funding
The 12-volunteer study declared no conflict of interest and its funding is not stated in the source; the 37-man trial was funded by Chrysea Labs, and two authors are its employees

These measure plasma, serum and urine polyamine levels, not memory or longevity.

Read the original source
Short-term safety: 30 older adults for 3 months, plus two cautions from cohorts

Randomized controlled trial

Schwarz C et al. Aging (Albany NY). 2018;10(1):19-33. PMID 29315079.

In 30 adults aged 60 to 80 with subjective cognitive decline, 3 months of a spermidine-rich plant extract at 1.2 mg/day showed no difference from placebo in vital signs, weight, clinical chemistry or hematology, with compliance above 85%, and a 28-day mouse study found no increase in tumorigenic or fibrotic events. The 40 mg/day trial reported no study-product-related adverse events over 28 days. Two cautions come from other designs. In 1164 people with a prior colorectal adenoma, dietary polyamine intake above the median was associated with a 39% higher risk of adenoma at follow-up (adjusted OR 1.39, 95% CI 1.06 to 1.83; Vargas 2012). In 619 patients with ischemic stroke, higher plasma spermidine was associated with higher odds of poststroke cognitive impairment (highest versus lowest quartile adjusted OR 1.81, 95% CI 1.09 to 3.01; He 2025). A review states that polyamine intake seems to suppress tumorigenesis but appears to accelerate the growth of established tumors.

Participants / model
30 older adults; 1164 people with prior colorectal adenoma; 619 patients with ischemic stroke
Treatment
Oral spermidine-rich plant extract 1.2 mg/day; dietary and plasma polyamines
Follow-up
3 months; the longest spermidine trial found ran 12 months (SmartAge)
Study design
Randomized safety trial plus observational cohorts
Funding
not stated in the source; four authors disclose a financial interest in The Longevity Labs

The adenoma and stroke findings are associations in disease populations, not trials of supplements.

Read the original source
SmartAge: 100 adults, 12 months, primary memory outcome not met

Randomized controlled trial

Schwarz C et al. JAMA Netw Open. 2022;5(5):e2213875. PMID 35616942.

In a 12-month randomized double-masked placebo-controlled phase 2b trial, 100 adults aged 60 to 90 with subjective cognitive decline (51 spermidine, 49 placebo; mean age 69; 89 completed) took a wheat germ extract giving 0.9 mg spermidine per day or placebo. The primary outcome, mnemonic discrimination, did not change (between-group difference -0.03; 95% CI -0.11 to 0.05; P = .47), and secondary outcomes did not either. Exploratory analyses hinted at benefit for inflammation and verbal memory, and adverse events were balanced. The authors say higher dosage is needed to validate these. A 2026 exploratory MRI analysis of 75 participants reports higher precuneus blood flow (between-group difference 4.9 ml/100 g/min, 95% CI 1.0 to 8.9, P = .015) and fractional anisotropy in a cingulate white matter bundle that stayed stable on spermidine and fell on placebo, and is hypothesis-generating.

Participants / model
100 adults aged 60 to 90 with subjective cognitive decline
Treatment
Oral spermidine-rich wheat germ extract giving 0.9 mg spermidine/day, or placebo
Follow-up
12 months
Study design
Randomized double-masked placebo-controlled phase 2b trial
Funding
not stated in the source; several authors had equity in or advised The Longevity Labs, and one led it as chief executive during the trial

The primary outcome was negative. The MRI analysis is online ahead of print and may change.

Read the original source
Earlier memory studies: a 30-person pilot and an 85-resident nursing-home study

Randomized controlled trial

Wirth M et al. Cortex. 2018;109:181-188. PMID 30388439.

In a 3-month phase IIa pilot of 30 cognitively intact adults aged 60 to 80 with subjective cognitive decline, memory performance was moderately enhanced on spermidine versus placebo (contrast mean 0.17, 95% CI -0.01 to 0.35, Cohen's d 0.77, 95% CI 0 to 1.53), and mnemonic discrimination improved within the spermidine group (mean difference -0.11, 95% CI -0.19 to -0.03) but not within the placebo group; the between-group interval includes zero. In a double-blind preliminary study of 85 nursing-home residents aged 60 to 96, subjects with mild dementia in the higher-dose group improved by 2.23 points on the MMSE (p = 0.026) while the lower-dose group was stable or declining; the abstract gives no placebo arm.

Participants / model
30 adults with subjective cognitive decline; 85 nursing-home residents with mild to moderate dementia
Treatment
Oral spermidine-rich extract for 3 months
Follow-up
3 months
Study design
Randomized pilot; double-blind dose-group study without a placebo arm in the abstract
Funding
not stated in the source for the 30-person pilot; the 85-resident study was investigator-funded

These are pilots whose signals SmartAge did not confirm on its primary outcome.

Read the original source
Human autophagy data: a 40-person vaccine pilot and a 12-person rice germ extract pilot

Randomized controlled trial

Alsaleh G et al. Aging Cell. 2026;25(6):e70545. PMID 42169618.

In a double-blind randomized placebo-controlled pilot of 40 adults over 65 after a third SARS-CoV-2 vaccine dose, 6 mg spermidine daily for 13 weeks was well tolerated, enhanced spike-specific IgG and neutralizing antibody activity in vaccine non-responders, and raised expression of TFEB targets and autophagy-related genes in B cells, which the authors read as elevated autophagic flux. In a single-blind pilot of 12 healthy adults randomized to 1.5 or 3.3 mg per day from a rice germ extract for 56 days, only the 3.3 mg dose raised Beclin-1 by 7.3% and ULK-1 by 13.4% against baseline, and the authors themselves note that human research showing a dose of spermidine that raises autophagy biomarkers was lacking before it.

Participants / model
40 adults over 65; 12 healthy adults aged about 55
Treatment
Oral spermidine 6 mg/day for 13 weeks; rice germ extract 1.5 or 3.3 mg/day for 56 days
Follow-up
13 weeks; 56 days
Study design
Double-blind randomized placebo-controlled pilot; single-blind randomized dose pilot compared with baseline
Funding
not stated in the source; two authors of the 40-person pilot consult for The Longevity Labs, which the paper says had no input into design, results, analysis or manuscript, and an author affiliation line for the 12-person pilot gives the chief scientific officer of Nutraland, which makes the extract

Both are small, and the second compares with baseline rather than a control.

Read the original source

Why is Spermidine in C tier?

C fits real animal lifespan and autophagy data and a notable cohort link between food spermidine and lower mortality, set against a negative primary result in the one adequately sized randomized trial, a pharmacokinetic study in which oral spermidine raised plasma spermine and not spermidine, human autophagy data from pilots of 12 and 40 people, and no randomized outcome data on longevity. The grade covers spermidine as sold for autophagy, longevity and memory support.