The effect of spermidine

Spermidine is the most researched and most conspicuous polyamine.It is essential for maintaining the entire metabolism, cell functions and human health. For this reason, a wide range of benefits in the therapy and prevention of diseases can be expected.

The effects of polyamines already mentioned apply to spermidine. Spermidine also has some independent effects that are well described in the specialist literature and go beyond those of polyamines. These effects contribute to spermidine reducing tumor development (carcinogenesis) and may protect against cancer, neurodegeneration, metabolic diseases and heart disease [Madeo F et al. Spermidine in health and disease. Science. 2018,359]:

• Promotes autophagy ("cell recycling")
• Acts as a calorie restriction mimetic (imitates the life-prolonging effect of reduced energy intake from food)
• Protects nerve cells (neuroprotection) and reduces age-related memory disorders
• Suppresses pro-inflammatory cytokines, thereby modulating the immune and inflammatory systems
• Slows stem cell aging
• Improves diastolic functions
• Reduces arterial stiffness and heart failure
• Reduces kidney damage associated with aging and hypertension
• Improves muscle strength and reduces myopathies ("muscle disorders")
• Reduces carcinogenesis and abnormal tissue proliferation (fibrosis) in the liver
• Achieve blood pressure lowering effects by improving the bioavailability of arginine

Spermidine activates autophagy

Autophagy is an important cleaning and recycling program in the body. It is essential for homeostasis and survival. Autophagy supports the organism and the cells in digesting slag and "scrap" and in breaking down misdirected, superfluous or incorrectly formed cell components and recycling them. It plays a key role in maintaining cell homeostasis and enables cells to adapt to molecular stress conditions. Furthermore, it provides energy and material for the formation of new cellular structures.

Well-functioning autophagy also takes on important tasks in relation to pathological processes. These include, for example, improving metabolic disorders and preventing neurodegenerative diseases such as multiple sclerosis, Parkinson's disease or Alzheimer's disease by eliminating misfolded proteins.

In old age and with metabolic disorders, the body's ability to operate autophagy decreases. According to current knowledge, there are two ways to activate and enhance autophagy:

1. By limiting calorie intake. This can be achieved through fasting or a sustained low-calorie diet
2. By using so-called calorie restriction mimetics, which imitate the effects of a reduced calorie intake (= calorie restriction). Spermidine is an important member of the group of calorie restriction mimetics and acts in a similar way to the phytochemicals resveratrol from grapes and epigallocatechin gallate from green tea.

Spermidine: does it extend lifespan?

Nowadays, spermidine is considered a universal anti-aging drug because it is one of the few endogenous substances that act as calorie restriction mimics and thus actively promote autophagy [Morselli E et al.; Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J Cell Biol 2011;192(4):615-29].Spermidine also works via other mechanisms: it regulates growth, cell regeneration (proliferation), cell death (apoptosis) and modulates protein translation and gene expression. It also inhibits inflammation and the formation of fat cells (adipogenesis) and histone acetylation. Spermidine improves lipid metabolism.

The polyamine activates the "eukaryotic translation initiation factor sA" (eIFs A), which is essential for cell growth and protein synthesis, which is considered a translation stretching factor and is involved in the formation of peptide bonds during the translation (translation of genetic information) of mRNA. As currently the only known protein, eIFs A contains a special amino acid, which is formed by deoxyhypusine synthase and deoxyhypusine hydroxylase and requires spermidine as a substrate. Deoxyhypusine synthase is an enzyme with the systematic name lysine.

Spermidine reduced, among other things, the levels of malondialdehyde in mice (a breakdown product of polyunsaturated fatty acids; an important biomarker for oxidative stress) in the brain and increased SOD activity (superoxide dismutase; correlates with increased life expectancy). Spermidine also improves mitochondrial function [Minois N; Molecular basis of the "anti-aging" effect of spermidine and other natural polyamines - a mini review. Gerontology 2014;60(4):319-26 and Pegg AE; Functions of polyamines in mammals. J Biol Chem 2016;291(29):14904-12 and Soda K, Spermine and gene methylation: a mechanism of lifespan extension induced by polyamine-rich diet. Amino Acids 2020;52(2):213-224 and Xu TT et al.; Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice. Aging (Albany NY).2020;12(7):6401-6414].

Meanwhile it is considered certain that an external supply of spermidine at least extends the lifespan of model organisms such as fruit flies, yeasts and worms due to the autophagy activation and the other typical polyamine effects. It also stops age-related memory loss in fruit flies and reduces age-related protein damage in mice. It also reduces age-related diseases and loss of motor skills[Ilgarashi K, Kashiwagi K; modulation of cellular function by polyamines; The International Journal of Biochemistry & Cell Biology 2010;42;39-51 and Madeo F, Eisenberg T et al.; Spermidine: a novel autophagy inducer and longevity elixir and Miller-Fleming L et al. Remaining mysteries of molecular biology: the role of polyamines in the cell. Journal of Molecular Biology. 2015;427(21):3389-406].

In a study conducted by Gupta, spermidine extended the lifespan of flies, yeast, worms and human immune cells. It inhibits oxidative stress and tissue death (necrosis) in aging mice. It stimulates the deacylation of histone H3 in older yeast by inhibiting histone acyltransferases. When polyamines are removed from the body, it leads to excessive acetylation, early cell death, free radical formation, and a shortened lifespan. Spermidine strongly boosts autophagy, is important for suppressing necrosis and thereby prolongs lifespan [Eisenberg T et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11(11):1305-14].

In preclinical models, supplementation with spermidine increased health and lifespan in humans. A prospective cohort study by Kiechl confirms that spermidine increases human lifespan. All-cause mortality decreased in the study from 40.5 (95% CI) to 23.7 (95% CI) and 15.1% (95% CI) per third of increasing spermidine intake, which corresponds to a cumulative mortality incidence of 0.48 , 0.41 and0.38 corresponds The cumulative (mortality) incidence (CI) indicates how likely it is that a person will develop a specific disease or die (mortality incidence) within a specified period of time. The risk of mortality between the upper and lower third of spermidine intake was similar to that at age 5.7 years younger [Eisenberg et al.; Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 2016;22(12):1428-1438 and Kiechl S et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study. Am J Clin Nutr. 2018;108(2):371-380 and Madeo F, Eisenberg T et al.; Spermidine: a novel autophagy inducer and longevity elixir und Madeo F, Eisenberg et al.; Nutritional Aspects of Spermidine. Annu Rev Nutr 2020. doi:10.1146/].

Spermidine protects the heart

Disrupted autophagy can have a detrimental effect on the cardiovascular system. As a result, substances that activate autophagy can counteract the development of cardiovascular diseases such as arteriosclerosis, heart failure, CHD (coronary heart disease), cardiac arrhythmias and diabetic cardiomyopathy. Spermidine also stimulates mitochondrial respiration and improves the mechano-elastic function of heart muscle cells (cardiomyocytes) [Nilsson BO, Persson L; Beneficial effects of spermidine on cardiovascular health and longevity suggest a cell type-specific import of polyamines by cardiomyocytes. Biochem Soc Trans.2019;47(1):265-272 and Abdellatif M et al.; Autophagy in cardiovascular health and disease. Prog Mol Biol Transl Sci 2020;172:87-106].

In heart failure, there is an excess of the enzyme PP5 (serine/threonine protein phosphatase 5). This enzyme attaches itself to the ventricles, reducing their elasticity and reducing the elasticity of the heart. Spermidine can effectively inhibit PPs. Mice that were fed spermidine still had healthy hearts in old age. Cardiovascular diseases also occur less frequently in people who eat a diet rich in spermidine. Since the spermidine level decreases with age, supplementation could be useful [Eisenberg T et al.; Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 2016;22(12):1428-1438] and Soda K et al. Food polyamine and cardiovascular disease - an epidemiological study. Glob J Health Sci. 2012;4(6):170-178].

The health effects of spermidine on the cardiovascular system have been proven in numerous experiments with rats and mice and transferred to the human organism:

• Spermidine supplementation activates the formation of new mitochondria in the cell (mitochondrial biogenesis) through SIRT1-mediated deacetylation of PGC-1alpha (protein). In addition, spermidine inhibits mitochondrial dysfunction and preserves the ultrastructure of the heart muscle. Ornithine decarboxylase (ODC) and SIRT1/PGC-1a (the sirtuin-1/peroxisome proliferator-activated receptor gamma-coactivator-alpha pathway), which regulates mitochondrial biogenesis, were also downregulated in the animals. In contrast, SPD/spermine N1 acetyltransferase was upregulated. In the experiments, spermidine increased PGC-1a, SIRT1, NRF1, NRF2, TFAM (mitochondrial transcription factor a) and the OXPHOS performance (oxidative phosphorylation) of heart muscle cells [Wang J et al. Spermidine alleviates cardiac aging by improving mitochondrial biogenesis and function. Aging (Albany NY). 2020;12(1):650-71].
• Spermidine supplementation reduces the risk of bulging of the walls of the arteries in the abdomen (abdominal artery aneurysms) and improves the integrity (intactness) of the aortic structure.Spermidine increases autophagy-dependent proteins and reduces the penetration of inflammatory substances (inflammatory infiltration) and inflammatory scavenger cells (monocytes). As a result, spermidine could be a promising therapy for abdominal aortic aneurysms [Liu S et al. Spermidine Suppresses Development of Experimental Abdominal Aortic Aneurysms. J Am Heart Assoc. 2020;9(8):e014757].
• Spermidine supplementation improves the function of heart muscle cells (cardiomyocytes) and reduces cell necrosis (cell death). After an infarction, spermidine increases heart function and reduces the size of the infarction and the increase in heart muscle mass (myocardial hypertrophy). Furthermore, it reduces inflammation, oxidative damage and apoptosis (programmed cell death) both in vitro (“performed in test tubes”) and in vivo (“observed/performed in living objects”) [Yan J et al. Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signaling pathway. British journal of pharmacology. 2019;176(17):3126-42].
• Spermidine supplementation slows arterial aging induced by reduced nitric oxide, increased AGEs (Advanced Glycation Endproducts), superoxide and oxidative stress. Spermidine normalizes arterial pulse wave velocity (aPWV; a direct measure of arterial stiffness), repairs endothelium-dependent arterial dilatation (EDD = end-diastolic diameter; diameter of the heart cavities at the end of diastole), and reduces oxidative stress, AGEs, and superoxide. This study suggests that spermidine may improve arterial aging treatments and measures to prevent age-related heart disease [La Rocca TJ et al.; The autophagy enhancer spermidine reverses arterial aging. Mch Aging Dev 2013;134(7-8):314-20].
• Spermidine significantly inhibits lipid accumulation ("fat accumulation") and necrotic nucleation in arteriosclerotic plaques. Lipid accumulation decreases because spermidine stimulates cholesterol efflux by activating autophagy. The size and composition of the deposits (plaques) do not change as a result of spermidine. The stimulation of autophagy could prevent the development of vascular diseases [Michiels CF et al.; Spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy. atherosclerosis. 2016;251:319-27].
• If a child suffers from a dangerous lack of oxygen in the womb (intrauterine hypoxia), this leads to a decrease in cardiac ornithine decarboxylase and to an increased formation of spermidine/spermine-N1-acetyltransferase. There is a reduction in body weight, heart weight, cardiomyocyte proliferation, antioxidant capacity, mitochondrial structure, and mitochondrial biogenesis. At the same time, more heart muscle cells die and the tissue proliferates abnormally (fibrosis). This damage can be avoided by spermidine supplementation in the placenta [Chai N et al.; Spermidine prevents heart injury in neonatal rats exposed to intrauterine hypoxia by inhibiting oxidative stress and mitochondrial fragmentation. Oxid Med Cell Longev. 2019;2019:5406468].
• Increased autophagy protects against cardiovascular disease. In rats and mice, dietary spermidine exerted cardioprotective effects by increasing cardiac autophagy and mitophagy (the breakdown of mitochondria). In addition, spermidine slows down the development of high blood pressure (hypertension) by improving arginine bioavailability and protecting the kidneys.In humans, there was a connection between spermidine supplementation and reduced blood pressure and a reduced risk of developing cardiovascular diseases. The risk of dying as a result of these diseases was also reduced. Spermidine is a cardiac and vascular protective autophagy activator [Eisenberg T et al.; Dietary spermidine for lowering high blood pressure. autophagy. 2017;13(4):767-769].
• Spermidine increases lifespan in mice and shows cardioprotective effects. It reduces abnormal myocardial enlargement, lowers systolic blood pressure and maintains diastolic function in older animals. The dietary supplement increases cardiac autophagy, mitophagy and mitochondrial respiration. It improves the mechanoelastic abilities of heart muscle cells, increases titin phosphorylation and suppresses mild inflammation. In humans, an association has been observed between high levels of spermidine in the diet and reduced blood pressure and a reduced incidence of cardiovascular disease [Eisenberg et al.; Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 2016;22(12):1428-1438].

The effects of spermidine on the cardiovascular system have now been verified with human data:

• According to current statements by the World Health Organization (WHO) and IMF, there is a negative association between dietary spermidine intake and the mortality rate from cardiovascular diseases [Soda K et al.; Food polyamine and cardiovascular disease - an epidemiological study. Glob J Health Sci. 2012;4(6):170-178].
• Researchers Tong and Madeo describe that in epidemiological studies, spermidine has a protective effect on cardiovascular health. They further wrote that a spermidine-rich diet reduces all-cause mortality associated with cardiovascular disease (and cancer) [Madeo F et al.; Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? autophagy. 2019;15(1):165-168 and Tong D et al.; Spermidine promotes cardioprotective autophagy. circulation research. 2017;120(8):1229-3].
• According to Nilsson, spermidine has a cardioprotective effect in both mice and humans [Pucciarelli S et al.; Spermidine and spermine are enriched in whole blood of nona/centenarians. Rejuvenation Res 2012, 15(6):590-5].
• In a randomized study by Matsjumoto, increased spermidine levels improved endothelial functions in healthy subjects and reduced the risk of atherosclerosis [Matsumoto M et al.; Endothelial function is improved by inducing microbial polyamine production in the gut: a randomized placebo-controlled trial. Nutrients.2019;11(5)].
• Eisenberg reports in a published study [Eisenberg T et al.; Cardioprotection and liefespan extension by the natural polyamine spermidine. Nat Med 2016;22(12):1428-1438]. reported that spermidine reverses age-related cardiac dysfunction in mice by activating autophagy. Spermidine "rejuvenates" striated muscle and improves mitochondrial function and key functions associated with cardiac aging (including hypertension, left ventricular hypertrophy, diastolic dysfunction, and increased left ventricular stiffness). In addition, it has an anti-inflammatory effect. The effects are dependent on autophagy.

Spermidine and its effects on the brain

Spermidine plays an important role in brain development.The functionality of the brain, memory acquisition and memory consolidation (consolidation of memories or learning content in long-term memory) are dependent on spermidine. Current studies indicate that the autophagy effects and the polyamine binding sites on the NMDA receptor (NMDAr) for the effects of spermidine on memory.

The effects on the brain were first demonstrated in animal models in rats and fruit flies. There are now first human studies that confirm the effects.

• Spermidine administration enhanced fear memory consolidation in rats, with both the TrkB (tyrosine receptor kinase B; protein) antagonist ANA-12 and the Pl3K (phosphoinositide-3-kinase; enzyme) inhibitor LY294OOz potentiating the effects of spermidine on memory prevented. This suggests that spermidine-enhanced memory consolidation involves activation of the TrkB receptor and the PI3K/Akt pathway [Beck Fabbrin SB et al.; Spermidine-induced improvement of memory consolidation involves PI3K/Akt signaling pathway. Brain Res Bull 2020; S0361-9230(20)30607-9].
• Spermidine administration protects fruit flies (more precisely: Drosophila) from age-related memory disorders. The dietary supplement works directly at the synapses, allowing autophagy-dependent homeostatic regulation of the excitatory part of the synapse [Bhukel A, Madeo F, Sigrist SJ; Spermidine boosts autophagy to protect from synapse aging. Autophagy.2017;13(2):4444-445.doi:10.1080/15548627.2016.1265193].
• As we age, the polyamines in the brain decrease. In fruit flies, it was observed that the decrease in polyamines is also associated with a decline in memory. Supplementing with spermidine improves autophagy, restores youthful spermidine levels, and blocks memory loss. However, memory impairment does not improve if genetic deficits prevent or limit autophagy [Gupta VK et al.; Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci.2013;16(10):1453-60].
• In a recent 2020 paper, Rosh confirms that spermidine promotes longevity and stimulates autophagy. It maintains cellular and neuronal homeostasis. Spermidine and spermine interact with the opioid system and affect neuroinflammation (inflammation of nerve tissue). They also inhibit the influx of calcium into the cells, harmful free radicals and glutamate excitotoxicity. The development and function of the brain depends on the polyamine and, in particular, on the spermidine concentration. Furthermore, age-related fluctuations in spermidine levels lead to imbalances in the neural network and endanger neurogenesis (formation of nerve cells). An additional supply of spermidine therefore supports the treatment of brain diseases, although the exact mechanisms are not yet fully known [Gosh I et al.; Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders. Neuropeptides 2020].
• Huang found that the administration of spermidine after traumatic brain injury (abbreviated: TBI (traumatic brain injury)) significantly accelerated the neurological NNS score and the latency in the Morris Water Maze test (also: Morris water labyrinth) shortened. Studies have shown that spermidine improves the blood-brain barrier function. In addition, there were positive changes in terms of cell death and cerebral edema. Pro-inflammatory cytokines and TBI markers were significantly reduced.According to Huang, since the spermidine levels were significantly reduced in TBI patients with severe disorders, the dietary supplement could be used as a new form of therapy for craniocerebral trauma [Huang J et al; Spermidine exhibits protective effects against traumatic brain injury. Cell Mol Neurobiol.2020].
• In the randomized preSmartAge study led by Dr. Miranda Wirth at the Charité, spermidine significantly improved memory performance. The study shows that the effect is based on the stimulation of neuro-modulatory actions in the memory system [Wirth M et al.; Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge) - study protocol for a randomized controlled trial. Alzheimer Res Ther. 2019;11:36].

Spermidine: protection against neurodegenerative disorders?

In addition to the previously described effects of spermidine on the brain, the effects on neurodegenerative disorders are presented below and substantiated with new findings from human studies:

• In a small study, the researcher M. Fischer succeeded in proving that increased autophagy in the brain cells improves memory. Furthermore, he found that T cells and cytokines act as important mediators in the pathology of Alzheimer's disease. In high doses, spermidine downregulates all cytokines except IL-17A, promotes autophagy, and increases T cell activation [Fischer M et al.; Spermin and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo. Aging (Albany NY). 2020 Jul 15;12(13):13716-13739].
• In his study, Pekar found that spermidine triggers the elimination of amyloid beta plaques due to its influence on autophagy. It has a positive effect on dementia and leads to a significant improvement in cognitive performance in nursing home residents after just three months of use [Pekar T et al.; Spermidine in dementia: relation to age and memory performance. Wien Klein Wochenschr. 2020;132(1-2):42-46].
• In 2020, Schwarz described that higher spermidine intake in older people is linked to larger hippocampal volume. He also found greater mean cortical density and increased cortical thickness in brain areas prone to Alzheimer's, as well as in the parietal and temporal brain areas [Schwarz C et al.; Spermidine intake is associated with cortical thickness and hippocampal volume in older adults. Neuroimage 2020;221:117132].
• In an earlier randomized study from 2018, Schwarz found that spermidine can protect against cognitive deficits and neurodegeneration [Schwarz C et al.; Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging (Albany NY). 2018;10(1):19-33].

The German Society for Neurology now also recognizes the great potential of spermidine in terms of its protective effect in relation to dementia and writes that previous data suggest that spermidine has a positive effect on brain functions and mental abilities. These effects are currently the focus of the SmartAge study, which is being conducted under the direction of Professor Flöel. Here, spermidine-enriched wheat germ preparations are used [Diener HC; Brain-Healthy Eating: How Eating May Protect Against Dementia; IWD Science Information Service 2017].

Spermidine in oncology

Spermidine is now said to have positive effects in the area of ​​cancer prevention.The polyamine may even be able to help with small tumors that are in an early stage. Investigations yielded the following results:

• Levesque used spermidine as an anti-cancer drug in one of his studies. A combination of caloric restriction mimetics (CRM; e.g. spermidine) with activators of immunogenic cell death (ICD) and immune checkpoint inhibitors (ICI) improved tumor growth control in mice. Without calorie restriction mimetics, ICDs and ICIs induce only partial sensitization to treatment [Levesque S et al.; A synergistic triad of chemotherapy, immune checkpoint inhibitors, and caloric restriction mimetics eradicates tumors in mice. Oncoimmunology 2019;8(11):e1657375].
• As Yue and colleagues discovered, spermidine can reduce cancer cell defects through activated autophagy, which trigger oxidative stress-related cell death and promote liver carcinoma and liver fibrosis. As a dietary supplement, the polyamine can not only extend the life span of mice by up to 25%, but also minimize liver fibrosis and liver carcinoma foci [Yue F et al.; Spermidine prolongs lifespan and prevents liver fibrosis and hepatocellular carcinoma by activating MAP1S-mediated autophagy. Cancer Res. 2017;77(11):2938-2951].
• Pietrocola commented in 2019 on the prospective study by Kiechl (see above), which shows that spermidine reduces cancer mortality, and wrote that cancer can only develop if the immune system does not recognize the danger and does not eliminate malignant cells. Autophagy activated by spermidine is therefore able to suppress malignant changes, inhibit procarcinogenic inflammatory reactions and promote antitumor immunity [Pietrocola F et al.; Spermidine reduces cancer-related mortality in humans. Autophagy 2019;15(2):362-5].
• In a prospective study by Vargas involving 87,602 women, higher daily polyamine intake was associated with a reduced risk of colorectal cancer (HR average 0.81), particularly in obese women [Vargas AJ et al. Dietary polyamine intake and colorectal cancer risk in postmenopausal women. Am J Clin Nutr. 2015;102(2):411-9]. However, it is worth mentioning that both cancer cells with increased metabolic activity and healthy cells use polyamines. For this reason, it is currently being discussed whether dysregulation of the polyamine metabolism could promote cancer. The total polyamine concentration is increased and the enzymes from the polyamine metabolism (such as adenosylmethionine decarboxylase (SAMDC) and spermine oxidase (SMO)) are highly active. If this proves to be true, high polyamine levels should be avoided or reduced during cancer therapy [Nowotarski SL et al.; Polyamines and cancer: implications for chemotherapy and chemoprevention. Expert Rev Mol Med 2013;15:e3 and Murray-Stewart TR et al.; Targeting polyamine metabolism for cancer therapy and prevention. Biochem J. 2016;473(19):2937-53].

Source: Spermidine and wheat germ - an impressive duo with numerous functions; an overview by dr. medical Udo Boehm