#302 Activate Autophagy with Spermidine Found in Natto! A Scientific Explanation of the Secret to Longevity
The key to longevity lies in "cellular cleaning"
In recent years, researchers around the world have been focusing on "natto," a traditional food that has supported the health and longevity of the Japanese people. The reason is that it has been scientifically proven that "spermidine," a natural component abundantly contained in natto, activates "autophagy," the cell's internal cleaning function, potentially leading to an extended lifespan.
In this article, we will explain in detail, based on the latest research findings, the molecular mechanisms by which spermidine induces autophagy and how the consumption of natto contributes to our health.
What is spermidine?
A natural polyamine present in the body
Spermidine is one of a group of molecules called polyamines and is a substance that exists naturally in our bodies. It plays many essential roles in life activities, such as cell growth, division, and protein synthesis. However, it is known that the concentration of spermidine in the body decreases with age, and this decline is thought to be associated with aging and an increased risk of various diseases.
A health component that can be obtained from food
Spermidine is not only synthesized in the body but can also be obtained from food. It is particularly abundant in natto, soy products, mushrooms, whole grains, and aged cheeses. Among these, natto is attracting attention as an excellent source of spermidine because its content increases through fermentation. According to research, natto contains as much as 75–124 mg/kg of spermidine, which is about 4 to 5 times that of tempeh, another fermented soy product.
What is autophagy: The cell rejuvenation system
Intracellular cleaning mechanism
Autophagy is a word derived from Greek that means "to eat oneself." It refers to a mechanism by which cells decompose and reuse unnecessary proteins and damaged mitochondria within themselves. The importance of autophagy was recognized globally through the research of Dr. Yoshinori Ohsumi, who was awarded the Nobel Prize in Physiology or Medicine in 2016.
Autophagy is a system that performs "cleaning" and "recycling" within the cell simultaneously. It keeps cells in a healthy state by decomposing old or damaged cellular components and reusing the materials for the synthesis of new proteins.
Aging and the decline of autophagy
Unfortunately, the activity of autophagy also declines with age. As a result, waste products and abnormal proteins accumulate within cells, leading to a decline in cellular function and causing various diseases. It has become clear that neurodegenerative diseases such as Alzheimer's and Parkinson's, cardiovascular diseases, and cancer are associated with a decline in autophagy function.
Therefore, activating autophagy can be said to be an important strategy for achieving healthy longevity. And spermidine is one of the few natural substances that can naturally activate this autophagy.
Three molecular mechanisms by which spermidine induces autophagy
Regarding how spermidine activates autophagy, three major pathways have been elucidated regarding its molecular mechanism.
Mechanism 1: Deacetylation of cytoplasmic proteins via EP300 inhibition
A study by Pietrocola et al. (2015) discovered that spermidine inhibits an acetyltransferase enzyme called EP300 (E1A-binding protein p300). In this study, screening of 43 types of acetyltransferases revealed that only two, EP300 and NAA20, simultaneously achieve autophagy induction and mTORC1 (mammalian target of rapamycin complex 1) inhibition.
EP300 is an enzyme that adds acetyl groups to lysine residues of proteins, regulating the function of many proteins within the cell. When spermidine inhibits EP300, proteins in the cytoplasm are deacetylated, which in turn suppresses the activity of mTORC1. mTORC1 is a central regulator of signaling pathways that promote cell growth, but if its activity is too high, autophagy is suppressed. EP300 inhibition by spermidine leads to the activation of autophagy by moderately suppressing mTORC1.
Interestingly, this study also conducted experiments using cells from which the nucleus had been removed (cytoplasts), confirming that spermidine can induce autophagy outside the nucleus, i.e., in the cytoplasm.
Mechanism 2: Increased expression of autophagy genes through epigenetic regulation
A groundbreaking study in Nature Cell Biology by Eisenberg et al. (2009) revealed that spermidine inhibits histone acetyltransferase (HAT), causing deacetylation of histone H3. This study was conducted using multiple model organisms, including yeast, nematodes, and fruit flies, and demonstrated that spermidine administration significantly extends lifespan.
Histones are proteins around which DNA is wrapped, and their acetylation state regulates gene expression. When histone H3 is deacetylated by spermidine, the chromatin structure changes, activating the transcription of autophagy-related genes. In fact, this study confirmed that spermidine treatment increases the expression of multiple autophagy-related genes.
More importantly, the fact that the lifespan-extending effect of spermidine was completely lost in organisms with genetically deficient autophagy function clearly indicates that the longevity effect of spermidine is dependent on autophagy.
Mechanism 3: Translational regulation via hypusination of eIF5A
A recent study by Hofer et al. (2024) elucidated another important mechanism of action for spermidine: the hypusination of a translation factor called eIF5A (eukaryotic translation initiation factor 5A).
Hypusination is a post-translational modification in which a unique amino acid called hypusine is added to a specific lysine residue of eIF5A, and spermidine is required as the sole substrate for this modification. Hypusinated eIF5A promotes the translation of proteins, particularly those containing polyproline sequences or those with mitochondrial transport sequences.
In this study, it was confirmed in yeast, fruit flies, mice, and human volunteers that spermidine levels increase during fasting or calorie restriction. It was also revealed that genetically or pharmacologically inhibiting spermidine synthesis completely abolishes the autophagy induction and lifespan-extending effects of fasting.
Hypusination of eIF5A promotes the synthesis of mitochondrial proteins and maintains mitochondrial function, thereby keeping cellular energy metabolism healthy. This function is also considered to play an important role in the longevity effects of spermidine.
Spermidine and Longevity: Evidence from Research
Lifespan extension effects in model organisms
The longevity effects of spermidine were first demonstrated in multiple model organisms. In the study by Eisenberg et al. (2009), significant lifespan extension was observed in yeast, nematodes, and fruit flies administered spermidine. Furthermore, spermidine administration to aged mice powerfully suppressed age-related oxidative stress and significantly reduced oxidative damage to proteins.
These effects were observed only when autophagy function was working normally. In organisms lacking essential autophagy genes, the lifespan-extending effect of spermidine completely disappeared.
Epidemiological evidence in humans
Following the results of animal experiments, the association between spermidine intake and health in humans was investigated. Kiechl et al. (2018) conducted a prospective cohort study over 20 years, from 1995 to 2015, involving 829 people aged 45 to 84.
In this study, participants' spermidine intake was estimated using food frequency questionnaires, and its association with mortality was analyzed. The results showed a clear association: higher spermidine intake was linked to lower all-cause mortality.
Specifically, when spermidine intake was compared across three groups, the number of deaths per 1,000 person-years was 40.5 in the lowest intake group, 23.7 in the moderate group, and 15.1 in the highest group. In other words, the group with the highest spermidine intake had less than half the mortality risk compared to the group with the lowest intake.
Furthermore, even after statistical adjustments, for every 1 standard deviation increase in spermidine intake, the hazard ratio for death was 0.76 (95% confidence interval: 0.67–0.86). The magnitude of this effect is estimated to be equivalent to the mortality risk of someone 5.7 years younger in chronological age.
This association remained consistent even after adjusting for age, sex, caloric intake, lifestyle habits, and other dietary factors, and was verified in another independent cohort study.
Spermidine Content in Natto and Effective Intake Methods
Natto is an Excellent Source of Spermidine
Natto is an excellent food source of spermidine. According to a study by Toro-Funes et al. (2015), commercially available natto contains 75–124 mg/kg of spermidine, which is approximately 4–5 times the concentration found in tempeh, another fermented soybean product.
The reason natto has such a high concentration of spermidine is due to the action of the fermentation bacterium, Bacillus subtilis natto. A study by Kobayashi et al. (2017) examined 16 soybean varieties and found that the spermidine content of the raw soybeans varied significantly, ranging from 1,055 to 2,306 nmol/g. It also revealed a high correlation (r=0.95) between the spermidine content of the raw soybeans and the fermented natto. In other words, using soybean varieties rich in spermidine could potentially lead to the production of natto with even higher concentrations of spermidine.
Effects of Natto Consumption in Humans
Soda et al. (2021) conducted an intervention study in which 30 healthy Japanese men aged 40–69 consumed polyamine-rich natto daily for 12 months. As a result, the participants' spermidine intake increased by 96.63±47.70 µmol per day.
Interestingly, blood levels of spermine (a polyamine synthesized from spermidine) significantly increased to 1.12±0.29 times the pre-intervention levels (p=0.019). Furthermore, the expression of Lymphocyte Function-Associated Antigen-1 (LFA-1), an indicator of age-related inflammation, gradually decreased in the natto consumption group. This suggests that the spermidine contained in natto may indeed exert anti-inflammatory and anti-aging effects within the human body.
Effective Intake Methods
To obtain the health benefits of spermidine, daily consumption of natto is effective. One pack (approximately 40–50g) of natto is estimated to contain about 3–6 mg of spermidine. Referring to the spermidine intake levels associated with longevity benefits in the study by Kiechl et al. (2018), habitually eating 1–2 packs of natto per day may contribute to healthy longevity.
In addition to natto, you can increase your overall dietary intake of spermidine by combining it with whole grains, mushrooms, aged cheeses, and other soy products. Incorporating these spermidine-rich foods into a balanced diet is a practical approach to supporting healthy aging.
Lifestyle Habits that Activate Autophagy
In addition to consuming spermidine through natto, incorporating lifestyle habits that activate autophagy can lead to synergistic effects.
Ensuring Adequate Fasting Periods
As shown in the study by Hofer et al. (2024), fasting or calorie restriction increases internal spermidine levels and activates autophagy. Even without strict fasting, mild time-restricted eating (intermittent fasting), such as ensuring a 12–16 hour fasting window from dinner to breakfast, can be expected to have certain effects.
Moderate Exercise
Exercise is also known to activate autophagy. In particular, aerobic exercise and light strength training alter the energy state within cells and induce autophagy. It is recommended to have an exercise habit of about 30 minutes several times a week.
Quality Sleep
During sleep, cellular repair and autophagy are actively performed. Ensuring sufficient, high-quality sleep is important for the proper functioning of autophagy.
Summary
Spermidine activates autophagy within cells through three molecular mechanisms: EP300 inhibition, histone deacetylation, and eIF5A hypusination. Multiple studies have demonstrated that this process removes cellular waste and maintains cell function, leading to healthy longevity. Natto is an excellent food rich in spermidine, and incorporating it into your daily diet can provide scientifically backed health benefits.
Supporting Autophagy in Skincare
Cellular autophagy is important not only for the body but also for skin health. As we age, autophagy function in skin cells declines, making it easier for signs of aging such as disrupted turnover, dryness, and loss of firmness to appear.
That is why we recommend the "Kingly Deep Green Nemu-Repair All-in-One Gel." This product contains "Nemu-Repair (Aspergillus/Pilea mongolica bulb ferment filtrate)," which is specialized for skin care during sleep, supporting your skin's condition throughout the night.
Furthermore, it is formulated with a high concentration of rare ingredients like "exosomes" and "human stem cell culture fluid," achieving high moisturizing power through five types of carefully selected hyaluronic acids and ceramides. It also contains vitamin C derivatives, offering an approach to various skin concerns, including aging skin.
This single product performs seven roles: toner, milky lotion, serum, cream, face mask, aftershave lotion, and anti-aging care, making it perfect for busy people who cannot spend much time on skincare, or for those who travel frequently. By combining an internal approach through natto consumption with external skincare, you can achieve total health and beauty care.
References
Eisenberg, T., Knauer, H., Schauer, A., Büttner, S., Ruckenstuhl, C., Carmona-Gutierrez, D., ... & Madeo, F. (2009). Induction of autophagy by spermidine promotes longevity. Nature Cell Biology, 11(11), 1305-1314. https://doi.org/10.1038/ncb1975
Pietrocola, F., Lachkar, S., Enot, D. P., Niso-Santano, M., Bravo-San Pedro, J. M., Sica, V., ... & Kroemer, G. (2015). Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death & Differentiation, 22(3), 509-516. https://doi.org/10.1038/cdd.2014.215
Hofer, S. J., Daskalaki, I., Bergmann, M., Friščić, J., Zimmermann, A., Mueller, M. I., ... & Madeo, F. (2024). Spermidine is essential for fasting-mediated autophagy and longevity. Nature Cell Biology, 26(9), 1571-1584. https://doi.org/10.1038/s41556-024-01468-x
Kiechl, S., Pechlaner, R., Willeit, P., Notdurfter, M., Paulweber, B., Willeit, K., ... & Madeo, F. (2018). Higher spermidine intake is linked to lower mortality: a prospective population-based study. The American Journal of Clinical Nutrition, 108(2), 371-380. https://doi.org/10.1093/ajcn/nqy102
Toro-Funes, N., Bosch-Fuste, J., Latorre-Moratalla, M. L., Veciana-Nogués, M. T., & Vidal-Carou, M. C. (2015). Biologically active amines in fermented and non-fermented commercial soybean products from the Spanish market. Food Chemistry, 173, 1119-1124. https://doi.org/10.1016/j.foodchem.2014.10.118
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