All Things Spermidine Pt 1: The Beneficial Health Effects of Spermidine 

Spermidine is a compound found in living cells and in foods including soybeans, wheat germ, nuts, fruits such as grapefruit and also in vegetables like broccoli. It is a polyamine, meaning that it is an organic compound with two or more amino groups. Human concentrations of spermidine decline with age and can change depending on nutrition, synthesis of polyamines within the gut microbiome, and disease state. Spermidine plays a crucial role in the survival and function of cells, including supporting cellular growth, DNA health, and apoptosis(33). Increased levels of spermidine have shown to have protective characteristics for the following: lifespan, cancer, metabolic conditions, cardiovascular conditions and cognitive conditions (24). 


Spermidine is also considered a calorie-restriction mimetic, meaning that it is thought to mimic the health benefits of calorie restriction(CR)(enhanced longevity) by impacting similar mechanisms as CR. One of the main health-promoting mechanisms of CR is autophagy, which clears cells of damage, and is critical for cellular homeostasis as well as preventing cells from going awol. Across the research, spermidine has been shown to induce autophagy(6). 


There are 9 hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, of which spermidine supplementation has been shown to counteract 5-6 hallmarks. These include epigenetic alterations, impaired proteostasis, mitochondrial dysfunction, stem cell dysfunction, and impaired and intercellular communication(22, 38). Early in 2021, spermidine was also suspected to prevent telomere attrition(55). This is impressive as there are not many well-researched sources that can counteract on average more than 2-3 hallmarks at a time. 


As briefly mentioned above, higher levels of spermidine have been associated with many health benefits. Across animal models, spermidine has been shown to extend lifespan. Across animal species, supplementation with spermidine has also shown to ameliorate age-related pathologies – thereby, supporting longevity. 


In animal and organism models, spermidine supplementation extends lifespan(6, 9, 34, 58). When blood levels of spermidine are increased in aged mice via supplementation of polyamine-producing probiotic bifidobacteria, decreased mortality is observed(17, 28). One study showed that in several Asian countries, the amount of polyamine uptake via food is correlated with life expectancy, however confounding factors in this study were not adequately adjusted for(1). In nonagenarians(90-99 y.o) and centenarians, an increase in levels of whole-level spermidine is linked to longevity(41).


As previously mentioned, polyamines are required for cellular life and growth. In relation to this, many growing cancers and tumors, such as skin, breast, lung and prostate have elevated polyamine concentrations(37). While polyamine levels might have procarcinogenic properties if cancer has already developed, they also might have anti-cancer properties. For instance, in mice, spermidine supplementation has been shown to reduce tumorigenesis. In aging female mice, the supplementation of a bacteria which produces polyamines, reduces the occurrence of visible skin tumors(28). In mice, supplementation of spermidine has also been shown to protect against liver cancer and colorectal tumor growth(29, 58). A study in humans showed that overweight women (BMI ≤ 25), with higher polyamine intake had a reduced risk of colorectal cancer(53). Spermidine also enhances the anticancer immune response in mice receiving chemotherapy, due to improved immunosurveillance(40). Due to the conflicting nature of polyamines in relation to cancer, future studies are needed to elucidate when polyamines are cancer-promoting and when they are cancer-preventing or chemopreventive.


Spermidine levels related to dietary uptake have been shown to protect from cardiac aging. In aged mice, dietary spermidine has been shown to improve diastolic function, left ventricle health, as well as mitochondrial function(8). Spermidine has also shown to reduce age-related arterial stiffness, mediate atherosclerosis plaques and reduce oxidative damage to endothelial cells in either aged mice or in ApoE deficient mice on a high-fat diet(18, 31). In mice modeled to have hypertensive heart failure, spermidine supplementation resulted in reduced blood pressure and prevented immediate transition into heart failure(8). In a human cohort, a higher combined dietary intake of spermidine and spermine correlated with a lower rate of cardiovascular disease. After spermidine supplementation, individuals in the higher tertile of spermidine intake also had lower blood pressure(8). Similarly another study, a meta-analysis, showed that lower spermidine and spermine levels were associated with higher CVD-related mortality rate(50).


In multiple studies, spermidine has been shown to improve hair growth, hair follicle number and hair follicle health in ‘hair follicle epithelial stem cells in serum-free organ culture’(45, 46). An in vitro study found that spermidine supported the ability of somatic cells to reprogram into iPSC’s(induced pluripotent stem cells) specific to embryonic fibroblasts, which further supports spermidine’s ability to support stem cell function(3, 25). 


In aged mice, spermidine administration was able to prevent the senescence of muscle stem cells, improve muscle regeneration, and inhibit muscle atrophy(9, 12). In collagen-deficient mice, spermidine aided with improving muscle defects(4). Overall, spermidine has been shown to improve mitochondria health and structure in both cardiac and skeletal muscles in mice(4, 8, 9, 12).


Spermidine has also shown to be promising for metabolic issues. For instance, in mice fed a high-fat diet, spermidine administration(daily) prevented adiposity and mediated glucose intolerance(47). In another study, spermidine was shown to reduce weight gain and certain risk factors of obesity(10). Studies are needed to further support spermidine’s ability to attenuate metabolic issues.


In several animal and organism models, supplementation with spermidine has been shown to protect against neurodegeneration(11, 21). For instance, in flies fed spermidine, age-related memory issues were prevented, including locomotor activity (32).This protection was observed in an autophagy-dependent manner. In mice with an equivalent to multiple sclerosis, spermidine supplementation reduced normal disease-related damage to the optic nerve and spinal cord, as well as decreased loss of ganglia cells in the retina (13, 57). In mice, spermidine was also shown to reduce dementia (in a mouse model of frontotemporal lobar dementia)(54). In invertebrate models, spermidine was able to prevent neurotoxicity due to α-synuclein(2). In aged mice, arginine and probiotic supplementation(bifidobacteria LKM512), which increase polyamine levels, improved facets of memory and spatial learning(17). 


Spermidine may also mediate bone loss as a consequence of menopause – in a post-menopausal osteoporosis mouse model, spermidine supplementation prevented bone loss (56). In mice, Spermidine supplementation also prevented circadian rhythm dysregulation, as related to age(59). Spermidine has also shown promise in ameliorating certain facets of eye health, including the optic nerve and retinal ganglion survival, and by blunting retinal damage in mice with age-related glaucoma (35, 36).


As the aging population grows, rising rates of chronic illness need to be addressed. There are several ways to mediate these rising rates, including lifestyle factors, like diet and exercise, and pharmacological interventions. Currently in the spotlight is the CRM, spermidine, which as an intervention is able to target 5-6 hallmarks of aging, nearly doubling the amount of hallmarks targeted by most other pharmacologic interventions(ie.17alpha-estradiol or senolytic compounds)(38). Spermidine is found naturally in foods and is also created by the bacteria in our guts. As we age, spermidine concentrations decline. In animal and organism models, supplementation of spermidine has been shown to exert longevity benefits from extending lifespan, to preventing age-related diseases such as neurodegeneration and heart disease. In nonagenarians(90-99 y.o) and centenarians, an increase in levels of whole-level spermidine is linked to longevity(41). Epidemiological studies have also suggested that higher polyamine intakes prevent death from certain age-related diseases(8). Spermidine is currently one of the most promising geroprotective agents in the longevity field. 

Click here to read all about calorie-restriction mimetics

Click here to read all things spermidine: pt 2 the health-promoting mechanisms of spermidine

Author: Jacqueline Seymour
Jacki is a Master’s student at USC, home of Dr. Valter Longo’s Longevity Institute, where she’s studying her passion for life: Gerontology(the science of aging) and Nutrition. 


1. Binh P. N. T., K. Soda, C. Maruyama, M. Kawakami (2010), Relationship between food polyamines and gross domestic product in association with longevity in Asian countries. Health (N. Y.) 02, 1390 (2010).

2. Büttner S., et al (2014), Spermidine protects against α-synuclein neurotoxicity. Cell Cycle 13, 3903–3908 . 10.4161/15384101.2014.973309

3. Chen T., L. Shen, J. Yu, H. Wan, A. Guo, J. Chen, Y. Long, J. Zhao, G. Pei (2011), Rapamycin and other longevity-promoting compounds enhance the generation of mouse induced pluripotent stem cells. Aging Cell 10, 908–911. 10.1111/j.1474-9726.2011.00722.x82

4. Chrisam M., M. Pirozzi, S. Castagnaro, B. Blaauw, R. Polishchuck, F. Cecconi, P. Grumati, P. Bonaldo (2015), Reactivation of autophagy by spermidine ameliorates the myopathic defects of collagen VI-null mice. Autophagy 11, 2142–2152 (2015). 10.1080/15548627.2015.1108508

5. Diler A. S., Y. Z. Ziylan, G. Uzum, J. M. Lefauconnier, J. Seylaz, E. Pinard (2002), Passage of spermidine across the blood-brain barrier in short recirculation periods following global cerebral ischemia: Effects of mild hyperthermia. Neurosci. Res. 43, 335–342. 10.1016/S0168-0102(02)00059-7

6. Eisenberg T. et al (2009), Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314. 10.1038/ncb1975

7. Eisenberg T. et al (2014), Nucleocytosolic depletion of the energy metabolite acetyl-coenzyme a stimulates autophagy and prolongs lifespan. Cell Metab. 19, 431–444 (2014). 10.1016/j.cmet.2014.02.010

8. Eisenberg, M. et al (2016). Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016). 10.1038/nm.4222

9. Fan J, X. Yang, J. Li, Z. Shu, J. Dai, X. Liu, B. Li, S. Jia, X. Kou, Y. Yang, N. Chen (2017), Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway. Oncotarget 8, 17475–17490 (2017). 28407698

10. Fernández Á. F. et al (2017), Autophagy counteracts weight gain, lipotoxicity and pancreatic β-cell death upon hypercaloric pro-diabetic regimens. Cell Death Dis. 8, e2970 (2017). 10.1038/cddis.2017.373

11. Frake R. A., T. Ricketts, F. M. Menzies, D. C. Rubinsztein, Autophagy and neurodegeneration (2015). J. Clin. Invest. 125, 65–74 (2015). 10.1172/JCI73944

12. García-Prat L. et al (2016), Autophagy maintains stemness by preventing senescence. Nature 529, 37–42 (2016). 10.1038/nature16187

13. Guo X., C. Harada, K. Namekata, A. Kimura, Y. Mitamura, H. Yoshida, Y. Matsumoto, T. Harada (2011), Spermidine alleviates severity of murine experimental autoimmune encephalomyelitis. Invest. Opthalmol. Vis. Sci. 52, 2696–2703. 10.1167/iovs.10-6015

14. Gupta V. K et al (2016), U. Pech, A. Bhukel, A. Fulterer, A. Ender, S. F. Mauermann, T. F. M. Andlauer, E. Antwi-Adjei, C. Beuschel, K. Thriene, M. Maglione, C. Quentin, R. Bushow, M. Schwärzel, T. Mielke, F. Madeo, J. Dengjel, A. Fiala, S. J. Sigrist, Spermidine suppresses age-associated memory impairment by preventing adverse increase of presynaptic active zone size and release. PLOS Biol. 14, e1002563. 10.1371/journal.pbio.1002563

15. Gupta V. K, et al (2013), Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat. Neurosci. 16, 1453–1460. 10.1038/nn.3512

16. Kano Y., K. Soda, F. Konishi (2013), Suppression of LFA-1 expression by spermine is associated with enhanced methylation of ITGAL, the LFA-1 promoter area. PLOS ONE 8, e56056. 10.1371/journal.pone.0056056

17. Kibe R., et al (2014), Upregulation of colonic luminal polyamines produced by intestinal microbiota delays senescence in mice. Sci. Rep. 4, 4548 (2014). 10.1038/srep04548

18. LaRocca T. J., R. A. Gioscia-Ryan, C. M. Hearon Jr., D. R. Seals (2013), The autophagy enhancer spermidine reverses arterial aging. Mech. Ageing Dev. 134, 314–320 (2013). 10.1016/j.mad.2013.04.004

19. Lee C., et al (2012), Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci. Transl. Med. 4, 124ra27. 10.1126/scitranslmed.3003293

20. Lee I. H., Finkel T. (2009), Regulation of autophagy by the p300 acetyltransferase. J. Biol. Chem. 284, 6322–6328 . 10.1074/jbc.M807135200

21. Lin M. T., M. F. Beal (2006), Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795. 10.1038/nature05292 

22. López-Otín, C. et al. (2013). The hallmarks of aging. Cell 153, 1194–1217 (2013). 10.1016/j.cell.2013.05.039

23. Ma Y., et al (2013), Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity 38, 729–741 (2013). 10.1016/j.immuni.2013.03.003

24. Madeo F, Eisenberg T, Büttner S, Ruckenstuhl C, Kroemer G. Spermidine: a novel autophagy inducer and longevity elixir. Autophagy (2010) Jan;6(1):160-2. doi: 10.4161/auto.6.1.10600. PMID: 20110777.

25. Madeo, Frank & Eisenberg, Tobias & Pietrocola, Federico & Kroemer, Guido. (2018). Spermidine in health and disease. Science. 359. eaan2788. 10.1126/science.aan2788. 

26. Mammucari C. et al (2007), FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 6, 458–471. 10.1016/j.cmet.2007.11.001

27. Mariño G. et al (2014), Regulation of autophagy by cytosolic acetyl-coenzyme A. Mol. Cell 53, 710–725. 10.1016/j.molcel.2014.01.016

28. Matsumoto M., S. Kurihara, R. 17, H. Ashida, Y. Benno (2011), Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLOS ONE 6, e23652 (2011). 10.1371/journal.pone.0023652

29. Miao H. et al (2016), Macrophage ABHD5 promotes colorectal cancer growth by suppressing spermidine production by SRM. Nat. Commun. 7, 11716 (2016). 10.1038/ncomms11716

30. Michaud M., et al (2011), Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577. 10.1126/science.1208347

31. Michiels C. F., A. Kurdi, J.-P. Timmermans, G. R. Y. De Meyer, W. Martinet (2016), Spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy. Atherosclerosis 251, 319–327 (2016). 10.1016/j.atherosclerosis.2016.07.899

32. Minois N., P. Rockenfeller, T. K. Smith, D. Carmona-Gutierrez (2014), Spermidine feeding decreases age-related locomotor activity loss and induces changes in lipid composition. PLOS ONE 9, e102435. 10.1371/journal.pone.0102435

33. Minois, N., Carmona-Gutierrez, D., & Madeo, F. (2011). Polyamines in aging and disease. Aging (Albany NY), 3(8), 716-732.)

34. Morselli E et al (2011), Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 192, 615–629 (2011). 10.1083/jcb.201008167

35. Noro T., K. Namekata, A. Kimura, X. Guo, Y. Azuchi, C. Harada, T. Nakano, H. Tsuneoka, T. Harada (2015), Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury. Cell Death Dis. 6, e1720. 10.1038/cddis.2015.93

36. Noro T., K. Namekata, Y. Azuchi, A. Kimura, X. Guo, C. Harada, T. Nakano, H. Tsuneoka, T. Harada (2015), Spermidine ameliorates neurodegeneration in a mouse model of normal tension glaucoma. Invest. Ophthalmol. Vis. Sci. 56, 5012–5019. 10.1167/iovs.15-17142

37. Nowotarski S. L., P. M. Woster, R. A. Casero (2013) Jr., Polyamines and cancer: Implications for chemotherapy and chemoprevention. Expert Rev. Mol. Med. 15, e3 (2013). 10.1017/erm.2013.3

38. Partridge, L., Fuentealba, M. & Kennedy, B.K (2020). The quest to slow ageing through drug discovery. Nat Rev Drug Discov 19, 513–532 (2020).

39. Pietrocola F. et al (2015), Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516. 10.1038/cdd.2014.215

40. Pietrocola F. et al (2016), Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147–160 (2016). 10.1016/j.ccell.2016.05.016

41. Pucciarelli, S. et al. “Spermidine and spermine are enriched in whole blood of nona/centenarians.” Rejuvenation research 15 6 (2012): 590-5 .

42. Puleston D. J., et al (2014), Autophagy is a critical regulator of memory CD8+ T cell formation. eLife 3, e03706. 10.7554/eLife.03706

43. Puleston D. J., Simon A. K. (2015), New roles for autophagy and spermidine in T cells. Microb. Cell 2, 91–93. 10.15698/mic2015.03.195

44. Qi Y., Q. Qiu, X. Gu, Y. Tian, Y. Zhang (2016), ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci. Rep. 6, 24700. 10.1038/srep24700

45. Ramot Y., et al (2011), Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions. PLOS ONE 6, e22564 (2011). 10.1371/journal.pone.0022564

46. Rinaldi, F., Marzani, B., Pinto, D., & Ramot, Y. (2017). A spermidine-based nutritional supplement prolongs the anagen phase of hair follicles in humans: a randomized, placebo-controlled, double-blind study. Dermatology practical & conceptual, 7(4), 17–21.

47. Sadasivan S. K., B. Vasamsetti, J. Singh, V. V. Marikunte, A. M. Oommen, M. R. Jagannath, R. Pralhada Rao (2014), Exogenous administration of spermine improves glucose utilization and decreases bodyweight in mice. Eur. J. Pharmacol. 729, 94–99 (2014). 10.1016/j.ejphar.2014.01.073

48. Sebti S. et al (2014), BAT3 modulates p300-dependent acetylation of p53 and autophagy-related protein 7 (ATG7) during autophagy. Proc. Natl. Acad. Sci. U.S.A. 111, 4115–4120. 10.1073/pnas.1313618111

49. Shin W. W., W. F. Fong, S. F. Pang, P. C. Wong (1985), Limited blood-brain barrier transport of polyamines. J. Neurochem. 44, 1056–1059. 10.1111/j.1471-4159.1985.tb08724.x

50. Soda K., Y. Kano, F. Chiba (2012), Food polyamine and cardiovascular disease—An epidemiological study. Glob. J. Health Sci. 4, 170–178. 10.5539/gjhs.v4n6p170

51. Soda K., Y. Kano, F. Chiba, K. Koizumi, Y. Miyaki (2013), Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazine-induced tumorigenesis. PLOS ONE 8, e64357. 10.1371/journal.pone.0064357

52. Soda K., Y. Kano, T. Nakamura, K. Kasono, M. Kawakami, F. Konishi (2005), Spermine, a natural polyamine, suppresses LFA-1 expression on human lymphocyte. J. Immunol. 175, 237–245. 10.4049/jimmunol.175.1.237

53. Vargas A. J., E. L. Ashbeck, B. C. Wertheim, R. B. Wallace, M. L. Neuhouser, C. A. Thomson, P. A. Thompson (2015), Dietary polyamine intake and colorectal cancer risk in postmenopausal women. Am. J. Clin. Nutr. 102, 411–419 (2015). 10.3945/ajcn.114.103895

54. Wang I.-F., B.-S. Guo, Y.-C. Liu, C.-C. Wu, C.-H. Yang, K.-J. Tsai, C.-K. J. Shen (2012), Autophagy activators rescue and alleviate pathogenesis of a mouse model with proteinopathies of the TAR DNA-binding protein 43. Proc. Natl. Acad. Sci. U.S.A. 109, 15024–15029. 10.1073/pnas.1206362109

55. Wirth, A., et al (2021). Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length. GeroScience, 43(2), 673–690.

56. Yamamoto T., E. Hinoi, H. Fujita, T. Iezaki, Y. Takahata, M. Takamori, Y. Yoneda (2012), The natural polyamines spermidine and spermine prevent bone loss through preferential disruption of osteoclastic activation in ovariectomized mice. Br. J. Pharmacol. 166, 1084–1096. 10.1111/j.1476-5381.2012.01856.x

57. Yang Q. et al (2016). Shi, Spermidine alleviates experimental autoimmune encephalomyelitis through inducing inhibitory macrophages. Cell Death Differ. 23, 1850–1861. 10.1038/cdd.2016.71

58. Yue F, Li W., Zou J., Jiang X.,Xu G.,Huang H.,Liu L. (2017) Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. 77, 2938–2951 (2017). 10.1158/0008-5472.CAN-16-3462 

59. Zwighaft Z. et al (2015), Circadian clock control by polyamine levels through a mechanism that declines with age. Cell Metab. 22, 874–885. 10.1016/j.cmet.2015.09.011

Boost your NAD+

Induce mitochondrial biogenesis and regulate mitochondrial maintenance by increasing NAD+ levels to optimize cellular homeostasis and health.
Ramp up energy production by increasing cellular NAD+ in the brain, immune cells and muscle tissue.
Facilitate metabolism and the repair of damaged DNA through SIRT1 activation.