Spermidine
Spermidine is a polyamine compound found in living tissues and is known for its role in cellular function and development. It has been increasingly recognized for its potential health benefits, particularly concerning longevity and age-related diseases. Studies have indicated that spermidine has the ability to promote autophagy, the body's intracellular recycling mechanism, which is crucial for cellular maintenance, homeostasis, and overall health. Spermidine is a naturally occurring biogenic polyamine, synthesized from the amino acid ornithine through the action of the enzyme ornithine decarboxylase (ODC). It is involved in various fundamental biological processes, including DNA stability, RNA transcription, translation, enzyme function, and cell proliferation. As a cellular polyamine, spermidine is essential for both normal and neoplastic tissue growth and is found in all eukaryotic cells.
Dietary Sources
Good dietary sources of spermidine are aged cheese, mushrooms, soy products, legumes, corn, and whole grains.[1] Spermidine is plentiful in a Mediterranean diet.[2]
For comparison: The spermidine content in human seminal plasma varies between approx. 15 and 50 mg/L (mean 31 mg/L).[3]
| Food | Spermidine
mg/kg |
notes & refs |
|---|---|---|
| Wheat germ | 243 | [4] |
| Soybean, dried | 207 | Japanese [1] |
| Cheddar, 1yr old | 199 | [1] |
| Soybean, dried | 128 | German [1] |
| Mushroom | 89 | Japanese [1] |
| Rice bran | 50 | [1] |
| chicken liver | 48 | [1] |
| Green peas | 46 | [1] |
| Mango | 30 | [1] |
| Chickpea | 29 | [1] |
| Cauliflower (cooked) | 25 | [1] |
| Broccoli (cooked) | 25 | [1] |
Spermidine and Longevity
Research has identified a significant correlation between the exogenous supplementation of spermidine and increased lifespan in several model organisms such as yeast, worms, flies, and mice.[5] The longevity-promoting properties of spermidine are primarily attributed to its role in inducing autophagy.[6]
The Interventions Testing Program (ITP) gave mice spermidine for 6 month. However, no increase in spermidine or spermine levels was observed in the blood, liver, or other tissues. The lack of change in spermidine levels led to the decision not to proceed with further lifespan testing in mice.[7]
Autophagy
Autophagy is a cellular process involved in the degradation and recycling of obsolete or dysfunctional cellular components. This mechanism is vital for maintaining cellular homeostasis and plays a central role in cell and tissue health. Spermidine's ability to enhance autophagy is of particular interest in the context of aging, as the decline in autophagy has been associated with several age-related pathologies, including neurodegeneration, cardiovascular disease, and cancer.
Spermidine promotes autophagy through the inhibition of a specific enzyme called acetyltransferase EP300. This inhibition leads to a series of cellular events that eventually increase the autophagic processes within the cells. Essentially, spermidine helps in "cleaning up" the cell interiors, which is crucial for cellular maintenance and health, especially as the body ages[8].
Cardiovascular Health
Apart from its role in autophagy, spermidine has been observed to contribute to cardiovascular health. A study demonstrated that oral supplementation of spermidine (as well as spermine) extended the lifespan of mice and exerted cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Moreover, spermidine feeding enhanced cardiac autophagy, mitophagy, and mitochondrial respiration, also improving the mechano-elastical properties of cardiomyocytes in vivo. In a model of hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. High levels of dietary spermidine in humans, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease[6].
Bioavailability
In a randomized controlled trail [9] 15 mg/d of spermidine was administered orally in 12 healthy volunteers for 5 days and the blood levels of spermidine and two related compounds, spermine and putrescine, were measured. Only spermine blood levels increased significantly, but no effect on spermidine or putrescine could be detected. That suggests, when spermidine is taken orally as a supplement, it gets converted into spermine before it enters the bloodstream. This conversion happens presystemically, meaning it occurs before spermidine gets into the systemic circulation. This suggest that the bioavailability of spermidine, in its original form, might be low or perhaps altered, but the compound is still bioavailable in a different form (as spermine) which then has systemic effects.
The study also found that a daily dose of 15 mg of spermidine was needed to see a significant increase in spermine levels in the blood. Lower doses like 0.9-1.2 mg of spermidine per day didn't show changes in blood levels of spermidine, spermine or putrescine. This suggests that there's a certain amount of spermidine you need to take to see an effect.
Safety and Dosage
Safety
A 3-month randomized, placebo-controlled, double-blind Phase II trial conducted on older adults with subjective cognitive decline demonstrated that a daily dose of 1.2 mg spermidine was safe and well-tolerated, with no significant differences in vital signs, weight, and clinical chemistry observed between the spermidine and placebo-treated groups[10].
Dosage
The optimal dosage for human health and longevity outcomes remains unclear. In a separate study, 15 mg/day of spermidine was administered orally in 12 healthy volunteers for 5 days. Although spermidine was converted into spermine before entering the bloodstream, a significant increase in spermine levels was only observed at the 15 mg daily dose. Lower doses like 0.9-1.2 mg of spermidine per day didn't show changes in blood levels of spermidine, spermine or putrescine, suggesting that a certain amount of spermidine is necessary to see an effect[9].
On the supplemental market, in 2023 dosage between 1 and 6 mg/day were advertised.
See Also
- Wikipedia - Spermidine
ToDo
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 Atiya Ali M et al.: Polyamines in foods: development of a food database. Food Nutr Res 2011. (PMID 21249159) [PubMed] [DOI] [Full text] BACKGROUND: Knowing the levels of polyamines (putrescine, spermidine, and spermine) in different foods is of interest due to the association of these bioactive nutrients to health and diseases. There is a lack of relevant information on their contents in foods. OBJECTIVE: To develop a food polyamine database from published data by which polyamine intake and food contribution to this intake can be estimated, and to determine the levels of polyamines in Swedish dairy products. DESIGN: Extensive literature search and laboratory analysis of selected Swedish dairy products. Polyamine contents in foods were collected using an extensive literature search of databases. Polyamines in different types of Swedish dairy products (milk with different fat percentages, yogurt, cheeses, and sour milk) were determined using high performance liquid chromatography (HPLC) equipped with a UV detector. RESULTS: Fruits and cheese were the highest sources of putrescine, while vegetables and meat products were found to be rich in spermidine and spermine, respectively. The content of polyamines in cheese varied considerably between studies. In analyzed Swedish dairy products, matured cheese had the highest total polyamine contents with values of 52.3, 1.2, and 2.6 mg/kg for putrescine, spermidine, and spermine, respectively. Low fat milk had higher putrescine and spermidine, 1.2 and 1.0 mg/kg, respectively, than the other types of milk. CONCLUSIONS: The database aids other researchers in their quest for information regarding polyamine intake from foods. Connecting the polyamine contents in food with the Swedish Food Database allows for estimation of polyamine contents per portion.
- ↑ Madeo F et al.: Spermidine in health and disease. Science 2018. (PMID 29371440) [PubMed] [DOI] Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction mimetics, which are defined as agents that mimic the beneficial effects of dietary restriction while limiting its detrimental effects. One such agent, the natural polyamine spermidine, has prominent cardioprotective and neuroprotective effects and stimulates anticancer immunosurveillance in rodent models. Moreover, dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Spermidine preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence. Mechanistically, it shares the molecular pathways engaged by other caloric restriction mimetics: It induces protein deacetylation and depends on functional autophagy. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.
- ↑ Ciba-Geigy, ed. (1977), "Sperma", Wissenschaftliche Tabellen Geigy (in German) (8 ed.), Basel: CIBA-GEIGY Limited, vol. Teilband Körperflüssigkeiten, pp. 181-189
- ↑ Brochure on Polyamines, rev. 2, http://www.oryza.co.jp/html/english/pdf/polyamine_vol.2.pdf
- ↑ https://genomics.senescence.info/drugs/browse.php?search_term=spermidine
- ↑ 6.0 6.1 Eisenberg T et al.: Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 2016. (PMID 27841876) [PubMed] [DOI] [Full text] Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
- ↑ 2022-04-12 - Dr. Richard Miller - Longevity Supplements - Interventions Testing Program Results
- ↑ Pietrocola F et al.: Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ 2015. (PMID 25526088) [PubMed] [DOI] [Full text] Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.
- ↑ 9.0 9.1 Senekowitsch S 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. (PMID 37111071) [PubMed] [DOI] [Full text] (1) Background: Spermidine is a biogenic polyamine that plays a crucial role in mammalian metabolism. As spermidine levels decline with age, spermidine supplementation is suggested to prevent or delay age-related diseases. However, valid pharmacokinetic data regarding spermidine remains lacking. Therefore, for the first time, the present study investigated the pharmacokinetics of oral spermidine supplementation. (2) Methods: This study was designed as a randomized, placebo-controlled, triple-blinded, two-armed crossover trial with two 5-day intervention phases separated by a washout phase of 9 days. In 12 healthy volunteers, 15 mg/d of spermidine was administered orally, and blood and saliva samples were taken. Spermidine, spermine, and putrescine were quantified by liquid chromatography-mass spectrometry (LC-MS/MS). The plasma metabolome was investigated using nuclear magnetic resonance (NMR) metabolomics. (3) Results: Compared with a placebo, spermidine supplementation significantly increased spermine levels in the plasma, but it did not affect spermidine or putrescine levels. No effect on salivary polyamine concentrations was observed. (4) Conclusions: This study's results suggest that dietary spermidine is presystemically converted into spermine, which then enters systemic circulation. Presumably, the in vitro and clinical effects of spermidine are at least in part attributable to its metabolite, spermine. It is rather unlikely that spermidine supplements with doses <15 mg/d exert any short-term effects.
- ↑ Schwarz C et al.: Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging (Albany NY) 2018. (PMID 29315079) [PubMed] [DOI] [Full text] Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.