Spermidine was first discovered in semen by Antonie van Leeuwenhoek, the "father of microscopy," over 300 years ago. In 2016, the Nobel Prize in Physiology or Medicine was awarded for research on autophagy—propelling spermidine (which activates autophagy) to fame. Just two years later, a Science article reviewed over 130 studies and confirmed spermidine’s health benefits for organisms[1].
Subsequently, spermidine caught the attention of Professor Brian Kennedy (a renowned Singaporean scholar who previously identified the anti-aging molecule AKG, or α-ketoglutarate, a mitochondrial intermediate) and joined the ranks of promising anti-aging candidates. Professor Frank Madeo, who has studied autophagy and its regulation for over 20 years, also recognizes spermidine’s potential, calling it "a true geroprotector."
Recently, Madeo’s team published a review in Nature Aging (December 22, 2022) that comprehensively summarizes spermidine’s role in inducing autophagy and protecting against aging. It also analyzes hot topics such as its clinical applications in humans and whether it promotes tumor growth[2].
1. What Makes Spermidine So Special for Anti-Aging?
In recent years, spermidine has been found to prevent or even treat issues related to metabolism, inflammation, and loss of immune homeostasis. For aging—the biggest risk factor for age-related diseases—it regulates multiple aging hallmarks and extends organismal lifespan.
1.1 Targets the "Nine Classic Aging Hallmarks"
The nine aging hallmarks (including cellular senescence and telomere attrition) are the most well-established biomarkers in aging research. Spermidine exerts positive regulatory effects on nearly all of these key hallmarks. Below are four key examples:
Cellular Senescence
Cellular senescence alters cell cycle and molecular characteristics, produces a senescence-associated secretory phenotype (SASP), and accelerates systemic aging. In vitro cell models and mouse studies, spermidine significantly reduces the number of senescent cells[3, 4]. For instance, it lowers the level of the senescence marker p16 in female germline stem cells[5].
Telomere Attrition
Telomeres protect chromosome ends but shorten with age (as adult humans barely produce telomerase). However, when aged mice were supplemented with spermidine for 6 months, telomere shortening slowed significantly, reaching levels similar to young mice[6]—likely due to spermidine’s ability to promote autophagy and regulate reactive oxygen species (ROS)[7].
Mitochondrial Dysfunction
Mitochondrial structural and functional impairment is common in aging, reducing cellular energy supply and triggering chronic inflammation to accelerate aging. Spermidine stands out for improving mitochondrial function in senescent cells and model organisms (fruit flies, mice)[8-10], and restoring normal mitochondrial protein biosynthesis[11].
Stem Cell Exhaustion
Aging impairs cell differentiation potential, leaving older organisms unable to repair tissue damage or resolve inflammation. Spermidine reverses this by inducing autophagy: it restores the regenerative capacity of muscle stem cells, promotes muscle formation, and is a promising candidate for reversing sarcopenia[12, 13].
1.2 Extends Lifespan by Regulating Metabolic Pathways
Spermidine extends lifespan by activating autophagy and regulating transcription factors and energy-sensing pathways (AMPK and mTORC1) in cellular signaling, thereby restoring metabolic health.
This effect has been confirmed across organisms—from cells and invertebrates to mammals. In mouse models (a mammalian species), short-term or lifelong spermidine intake significantly extends lifespan, with the best results showing a 50% increase[14].
| Organism | Strain/Line | Sex | Intervention Duration | Dose | Lifespan Extension | Max Lifespan Extended | Median Lifespan Extended |
|---|---|---|---|---|---|---|---|
| Saccharomyces cerevisiae (Yeast) | BY4741, DBY746 | MATa | 24h after inoculation (stationary phase) | — (via medium) | ~4x | Yes | Yes |
| BY4741 | MATa | 24h after inoculation (stationary phase) | 4mM (via medium) | Up to 12x | Yes | Yes | |
| Caenorhabditis elegans (Worm) | N2 (Bristol) | NA | Lifelong | 0.2mM (via food) | ~15% | Yes | Yes |
| N2 (Bristol, B12-deficient) | NA | Lifelong | 10 pM (via food) | 13% (B12-deficient); ~4% (control) | Yes | Yes (B12-deficient); No (control) | |
| Drosophila melanogaster (Fruit Fly) | w1118 | Female | Lifelong (hatched on spermidine-containing food) | 5mM (via food) | ~7-10% | No | Yes |
| w1118 | Female | Lifelong | 0.01-1mM (dose-dependent, via food) | ~15-30% (at 1mM) | Yes | Yes | |
| Mus musculus (Mouse) | C57BL/6 | Female/Male | Lifelong (starting at 4 or 18 months) | 0.3mM, 3mM (via drinking water) | ~10% | No | Yes |
| C57BL/6 | Male | Lifelong | 3mM (via drinking water) | ~24% | Yes | Yes |
Note: Selected data on spermidine-induced lifespan extension in model organisms.
2. Spermidine’s Efficacy Confirmed in Human Clinical Trials
Many anti-aging candidates fail in human trials, but spermidine has passed this critical test. Key clinical findings include:
2.1 Improves Memory and Cognition
Elderly adults (average age >70 years) who took spermidine-rich wheat germ extract for 3 or 12 months showed improved age-related cognitive impairment, with no adverse reactions[15-18].
2.2 Anti-Inflammatory Effects
After 1 year of spermidine supplementation via natto (fermented soybeans), subjects showed reduced abnormal activation of immune lymphocytes and significantly lower chronic inflammation[19].
2.3 Regulates Cardiovascular Function
Combining arginine with yogurt containing Bifidobacterium animalis subsp. lactis increased gut spermidine levels, significantly improving subjects’ endothelial function and blood lipid profiles[20, 21].
2.4 Aids Hair Loss Treatment
A randomized, placebo-controlled, double-blind human trial confirmed that spermidine extends the anagen (growth) phase of hair follicles, supporting hair loss treatment[22].
Even before formal clinical trials, epidemiological studies in parts of Asia and Europe found that spermidine intake is closely associated with reduced risks of cardiovascular disease[23], cancer[24], and cognitive impairment[25]; lower mortality[24]; and longer life expectancy[26]. Additionally, healthy elderly or centenarians have higher spermidine levels than unhealthy peers of the same age[27].
3. How to Supplement Spermidine (Levels Decline With Age)
Spermidine levels in the human body decrease with age—making supplementation essential for maintaining health.
3.1 Spermidine Levels in Aging Humans
| Organism (Max Lifespan) | Strain/Origin | Normalization Method (Age Range) | Cell/Tissue Type | Spermidine Level Change |
|---|---|---|---|---|
| Human (~120 years) | Central Italian Caucasians (50% female) | Protein content (31–106 years) | Whole blood | Decreased in the elderly; normal in 90–106-year-olds |
| Japanese males | General | Whole blood | Slight increase in 60-year-olds | |
| Austrians (67.12% female) | General (up to 80 years) | Serum | Continuous decline | |
| Protein content (up to 80 years) | Peripheral blood mononuclear cells | Continuous decline | ||
| Cell count (up to 79 years) | Red blood cells | Decline in early adulthood | ||
| Canadians | Protein content | Cerebral cortex (post-mortem) | No change in adults | |
| Japanese (35.9% female) | Protein content | Liver (post-mortem) | No change in adults |
3.2 Recommended Supplementation and Sources
- Daily dose: 5–15 mg of spermidine, shown to delay or even reverse age-related organ dysfunction in human tests.
- Natural food sources:
| Food Category | Examples | Spermidine Content (nmol/g) |
|---|---|---|
| Fruits | Apples, avocados, bananas, cherries, kiwis, citrus, oranges, pears, peaches, pineapples, strawberries | 6.9–98 |
| Vegetables | Broccoli, cabbage, cauliflower, carrots, celeriac, zucchini, cucumbers, eggplants, green beans, bell peppers, lettuce, mushrooms, onions, potatoes, spinach, tomatoes | 6.9–398 |
| Legumes & soy products | Chickpeas, lentils, peas, white beans, red kidney beans, soybeans, bean sprouts, soy milk, tofu, soy sauce | 1.0–1425 |
| Nuts & seeds | Almonds, chestnuts, pistachios, seeds | 41–383 |
| Grains | Rice, wheat germ, white bread | 2.8–2437 |
| Fresh meat | Beef, veal, lamb, pork, chicken, rabbit, turkey, duck | 1–92 |
| Cooked meat products | Cooked ham, salami, Vienna sausages, Frankfurt sausages | 15–28 |
| Fermented/cured meats | Dry-cured ham, dry-fermented sausages | 8–62 |
| Fresh fish & seafood | White fish, cod, salmon, tuna, sardines, shrimp, crab, squid, oysters, scallops | ~167 |
| Canned fish | Canned tuna, canned anchovies | 6.2–28 |
| Eggs | Chicken eggs, duck eggs, quail eggs | 1–4 |
| Milk & dairy | Milk, yogurt | 0.41–5 |
| Cheese | Goat cheese, feta, gorgonzola, blue cheese, camembert, brie, comté, emmental, yellow cheese | ~262 |
- Supplements: Formal spermidine supplements are available, though specific brands are not recommended here.
3.3 Safety Note
Professor Frank Madeo advises: "Extra spermidine supplementation is not recommended for people with tumors, cancer, or those in recovery." However, it is premature to conclude that spermidine promotes cancer—some studies even show it inhibits tumor growth[28-30]. More research is needed on this widely occurring substance first discovered over 300 years ago.
References
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