Wheat germ and its ingredients

Wheat germ is an oil-containing component of ripe wheat grains and makes up about 3% of their total weight. The valuable wheat grass develops from the wheat germ, which later forms wheat grains. Wheat germ is usually a by-product of the production of wheat flour. It has a high nutrient density and is rich in micronutrients and fiber (1.5-4%). ​​The oil content is about 10%, and contains many unsaturated fatty acids. The protein content is about 27%, but depending on the origin, between 13 and 35% is also possible.

The ingredients include:

• Vitamins (B1, B2, B3, B5, B6, B9 and vitamins A, K and E)
• Minerals and trace elements (calcium, magnesium, iron, potassium, iodine, phosphorus, chromium, manganese, zinc, molybdenum and sulfur)
• polyamines (spermine, spermidine and putrescine)
• fatty acids (especially alpha-linolenic acid, linoleic acid, oleic acid and palmitoleic acid)
• Amino acids (arginine, tryptophan, lysine, methionine, phenylalanine, leucine and isoleucine)
• Secondary plant substances (carotenoids, polyphenols and flavonoids)

The Effects of Wheat Germ

The ingredients mentioned indicate great health potential. However, the effects of wheat germ have only been partially researched experimentally so far, and there are hardly any human studies. However, the extensive knowledge about the individual ingredients and their significance for metabolism and general health allows statements to be made about the overall effect of wheat germ. Research also names possible medical applications:

• Wheat germ extract has anti-inflammatory, antioxidant, antibacterial and immunomodulatory effects due to its high micronutrient content [Mahmoud AA et al.; Wheat germ: An overview on nutritional value, antioxidant potential and antibacterial characteristics. Food and Nutrition Sciences, 2015, 6, 265-277].
• According to a human study by Ataollahi, wheat germ significantly reduces the various symptoms that occur with premenstrual syndrome (PMS). According to Balint, fermented wheat germ extract as a supplement to corticoid therapy has a positive effect on rheumatoid arthritis and improves symptoms and quality of life. [Ataollahi M et al.; The effect of wheat germ extract on premenstrual syndrome symptoms. Iran J Pharm Res Winter 2015;14(1):159-66 and Balint G et al.; Effect of Avemar – a fermented wheat germ extract – on rheumatoid arthritis. Preliminary data, Clin Exp Rheumatol. 2006;24(3):325-8]
• Wheat germ improves the function of the gastrointestinal tract. It reduces inflammatory cytokines in the intestine, increases the proportion of butyric and propionic acid and regulates the composition of the intestinal flora. Furthermore, it increases the proportion of lactobacilli and – as a small double-blind study by Moreira-Rosario showed – also the amount of Bacteroides and Bifidobacterium. [Moreira-Rosario A et al.; Daily intake of wheat germ-enriched bread may promote a healthy gut bacterial microbiota: a randomized controlled trial. Eur J Nutr 2020 Aug;59(5):1951-1961 and Ojo BA et al.; Wheat germ supplementation increases lactobacillaceae and promotes an anti-inflammatory gut milieu in C57BL/6 mice fed a high-fat, high-sucrose diet. J Nutr 2019;149(7):1107-1115].
• In a double-blind study by Mohammadi, wheat germ significantly reduced cholesterol levels and increased antioxidant capacity in type 2 diabetics.Ostlund also writes that wheat germ inhibits cholesterol absorption in the intestine. According to Ojo, wheat germ minimizes visceral fat, cardiac mitochondrial dysfunction, serum insulin and insulin resistance in obese mice, among other things. [Mohammadi H et al.; The effects of wheat germ supplementation on metabolic profile in patients with type 2 diabetes mellitus: A randomized, double-blind, placebo-controlled trial. Phytother Res 2020 Apr;34(4):879-885 and Ojo BA et al.; Wheat germ supplementation alleviates insulin resistance and cardiac mitochondrial dysfunction in an animal model of diet-induced obesity. Br J Nutr 2017;118(4):241-249 and Ostlund R et al.; Inhabitation of cholesterol absorption by phytosterol replete wheat germ. The American Journal of Clinical Nutrition 2003;77,1385-1389].
• Oncology is also showing interest in wheat germ extract, as it is composed of many biologically active substances (including benzoquinones). In numerous experimental studies, small human studies and animal studies, alcoholic and fermented wheat germ extracts have been shown to have cancer-preventive effects, e.g. in colon cancer. Furthermore, effects as a complementary measure in the treatment of various types of carcinoma (melanoma, lung cancer, leukemia, breast cancer, colorectal carcinoma) have been attested. Therapy-related side effects such as a reduction in neutrophil granulocytes in the blood and tiredness/exhaustion improved. Survival time was also extended and quality of life improved. The extract shows anti-metastatic, anti-proliferative effects, promotes tumor cell apoptosis and supports the cytotoxicity of natural killer cells. [Boros LG et al.; Fermented wheat germ extract (Avemar) in the treatment of cancer and autoimmune diseases. Ann NY Acad Sci 2005;1051:529-42 and Comin-Anduix B et al.; Fermented wheat germ extract inhibits glycolysis/pentose cycle enzymes and induces apoptosis through poly(ADP-ribose) polymerase activation in Jurkat T-cell leukemia tumor cells. J Biol Chem,2002;277(48):46408-14 and Demidov LV et al.; Adjuvant fermented wheat germ extract (Avemar) nutraceutical improves survival of high-risk skin melanoma patients; a randomized, pilot, phase II clinical study with a 7-year follow-up. Cancer Biother Radiopharm 2008;23(4):477-82 and Farkas E; Fermented wheat germ extract in the supportive therapy of colorectal cancer. Orv Hetil 2005;146(37):1925-31 and Garami M et al.; Fermented wheat germ extract reduces chemotherapy-induced febrile neutropenia in pediatric cancer patients, J Pediatr Hematol Oncol. 2004;26(10):631-5 and Koh EM et al.; Anticancer activity and mechanism of action of fermented wheat germ extract against ovarian cancer. Food biochemistry 2018;42.6 and Marcsek Z et al.; The efficacy of tamoxifen in estrogen receptor-positive breast cancer cells is enhanced by a medical nutriment. Cancer Biother Radiopharm. 2004;19(6):746-53 and Mueller T, Voigt W; Fermented wheat germ extract – nutritional supplement or anticancer drug? Nutr J 2011;10:89 and Telekes A et al.; Avemar (wheat germ extract) in cancer prevention and treatment. Nutr Cancer 2009;61(6):891-9].

In summary, wheat germ supports basic nutrition and enriches the general diet due to the micronutrients it contains. It is suitable for optimizing metabolism and preventing metabolic disorders and acute and chronic diseases.

polyamines

The group of polyamines can be divided into spermidine and spermine as well as putrescine and cadaverine. These natural compounds are all a necessary component of human and animal metabolism.

Polyamines play a key role in the development of many cells and also ensure their survival. Spermidine is the most effective polyamine due to its special polycationic properties [Mendez JD; The Other Legacy of Antonie Van Leeuwenhoek: The Polyamines. J Clin Mol Endocrinol 2017].

Availability, Requirements and Metabolism of Polyamines

The three polyamines spermine, spermidine and putrescine can be obtained through food or produced by the body itself. Foods contain the individual polyamines in varying amounts. Spermidine is particularly abundant in wheat and wheat germ. But dried soybeans, mature cheddar cheese, green peas and mushrooms also contain spermidine and other polyamines. [Ali MA et al. Polyamines in foods: development of a food database. Food Nutr Res. 2011;55].

Spermine and spermidine can be absorbed well in the intestine transepithelially ("through the intestinal mucosa"). Putrescine, on the other hand, is less well absorbed because it is broken down by the diamine oxidase (DAO) found in the intestine. In order for the body to produce polyamines itself, it needs the amino acids arginine or ornithine as well as various cofactors such as vitamin B12, folic acid and S-adenosyl methionine (SAM).

In addition, a number of enzymes are involved in polyamine metabolism. These include spermidine and spermine synthase, arginine and ornithine decarboxylase, the enzymes of the 1-carbon pathway, polyamine oxidase and diamine oxidase (DAO), which is known from histamine metabolism. This process initially produces putrescine, which is metabolized to spermidine, which can then be converted to spermine.

About 2/3 of the polyamine requirement must be covered by diet, because the body can only produce about 1/3 itself. So far, there is hardly any usable data that allows conclusions to be drawn about the polyamine requirement and a possible additional dosage. According to a Japanese source, a daily intake of 70 mg (including self-synthesis) can be achieved [Oryza; Brochure on Polyamines, rev. 2”. Japan: Oryza Oil & Fat Chemocial Co., Ltd. 2011-12-26. Retrieved 2013-11-06].

The polyamine requirement, especially the spermidine requirement, is due to the increased cell growth in the pregnancy and in infants in the first 28 days after birth. pollution or the Participating in competitive sports can increase the need. In addition, environmental influences and the hormone status on polyamine synthesis and the total polyamine pool. With age, the body’s own production also decreases, which reduces the total polyamine concentration [Munoz-Esparza NC et al.; Polyamines in Food. Front Nutr. 2019;6: 108 and Nishimura K et al. Decrease in polyamines with aging and their ingestion from food and drink. J Biochem 2006; 139:81-90].

A lack of basic substances, particular genetic characteristics and disorders of intestinal function can lead to the body not being supplied with polyamines or not being supplied with enough of them. If the organism permanently has too few polyamines available or if spermidine/spermine homeostasis is disrupted, this triggers numerous pathological processes [Moinard C et al.; Polyamines: metabolism and implications in human diseases. Clin Nutr 2005; 24(2):184-97 and Rocha RO, Wilson RA; Essential, deadly, enigmatic: Polyamine metabolism and roles in fungal cells. Fungal Biology Reviews 2019;33;47-57].

The Effect of Spermidine

Spermidine is the best researched and most striking polyamine. It is essential in maintaining the overall metabolism, cellular 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 literature and go beyond those of polyaminesThese effects contribute to spermidine reducing tumor development (carcinogenesis) and protecting 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 like a calorie restriction mimetic (imitating the life-prolonging effect of a reduced energy intake from food)
• Protects nerve cells (neuroprotection) and reduces age-related memory impairment
• Suppresses pro-inflammatory cytokines and thus modulates the immune and inflammatory system
• Slows down stem cell aging
• Improves diastolic functions
• Reduces arterial stiffness and heart failure
• Reduces age- and high blood pressure-related kidney damage
• Improves muscle strength and reduces myopathies (“muscle diseases”)
• Reduces carcinogenesis and the pathological proliferation of tissue (fibrosis) in the liver
• Achieves blood pressure lowering effects by improving the bioavailability of arginine

Spermidine activates autophagy

Autophagy is an important cleaning and recycling program of the body. It is essential for homeostasis and survival. Autophagy supports the organism and the cells in digesting waste and "junk" as well as 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. It also provides energy and material for the formation of new cellular structures.

A well-functioning autophagy also performs 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.

As we age and experience metabolic disorders, the body's ability to perform autophagy decreases. According to current knowledge, there are two ways to activate and improve autophagy:

1. By limiting calorie intake. This can be achieved through fasting or a permanent low-calorie diet.
2. Through the use of so-called calorie restriction mimetics, which mimic the effects of a reduced calorie intake (= calorie restriction). Spermidine is an important representative in the group of calorie restriction mimetics and works in a similar way to the secondary plant substances 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 mimetics 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 through other mechanisms: it regulates growth, the formation of new cells (proliferation), cell death (apoptosis) and modulates protein translation and gene expression. It also inhibits inflammation and the formation of fat cells (adipogenesis) as well as histone acetylation. Spermidine improves fat metabolism.

The polyamine activates the "eukaryotic translation initiation factor sA" (eIFs A), which is essential for cell growth and protein synthesis. This is considered a translation elongation factor and is involved in the formation of peptide bonds during the translation (translation of genetic information) of mRNA. eIFs A is currently the only known protein that 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, malondialdehyde levels (a breakdown product of polyunsaturated fatty acids; an important biomarker for oxidative stress) in the brain of mice 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].

It is now considered certain that external spermidine supply extends the lifespan of at least model organisms such as fruit flies, yeast and worms due to autophagy activation and 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 the 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, this leads to excessive acetylation, early cell death, radical formation and a shortened lifespan. Spermidine strongly stimulates autophagy, is important for suppressing necrosis and thereby extends lifespan [Eisenberg T et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009;11(11):1305-14].

In preclinical models, the additional administration of spermidine extended the health and lifespan of humans. A prospective cohort study by Kiechl confirmed that spermidine extends human lifespan. In the study, total mortality fell from 40.5 (95% CI) to 23.7 (95% CI) or 15.1% (95% CI) for each third of increasing spermidine intake, which corresponds to a cumulative mortality incidence of 0.48, 0.41 and 0.38, respectively. The cumulative (mortality) incidence (CI) indicates how likely it is that a person will develop a certain disease or die (mortality incidence) in a specified period of time. The mortality risk between the upper and lower third of spermidine intake was similar to that at a 5.7 year younger age. [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. At J Clin Nutr. 2018;108(2):371-380 and Madeo F, Eisenberg T et al.; Spermidine: a novel autophagy inducer and longevity elixir and Madeo F, Eisenberg et al.; Nutritional Aspects of Spermidine. Annu Rev Nutr 2020. doi:10.1146/].

Spermidine protects the heart

Disturbed autophagy can have a detrimental effect on the cardiovascular system. Substances that activate autophagy can therefore counteract the development of cardiovascular diseases such as arteriosclerosis, heart failure, coronary heart disease, cardiac arrhythmias and diabetic cardiomyopathy. Spermidine also stimulates mitochondrial respiration and improves the mechano-elastic function of the 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].

Heart failure is caused by an excess of the enzyme PP5 (serine/threonine protein phosphatase 5). This enzyme accumulates in the heart chamber, reducing its elasticity and limiting the heart's elasticity. Spermidine can effectively inhibit PPs. Mice fed spermidine still had a healthy heart in old age. People who eat a diet rich in spermidine also have a lower incidence of cardiovascular disease. Since spermidine levels decrease 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 have been transferred to the human organism:

• Supplementation with spermidine activates the formation of new mitochondria in the cell (mitochondrial biogenesis) through the SIRT1-mediated deacetylation of PGC-1alpha (protein). In addition, spermidine inhibits mitochondrial dysfunction and preserves the ultrastructure of the heart muscle. In the animals, ornithine decarboxylase (ODC) and SIRT1/PGC-1a (the sirtuin-1/peroxisome proliferator-activated receptor gamma coactivator alpha signaling pathway), which regulates mitochondrial biogenesis, were also downregulated. SPD/spermine N1-acetyltransferase, on the other hand, was upregulated. In the experiments, spermidine increased PGC-1a, SIRT1, NRF1, NRF2, TFAM (mitochondrial transcription factor a) and the OXPHOS performance (oxidative phosphorylation) of the 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 abdominal artery wall bulging (abdominal artery aneurysms) and improves the integrity of the aortic structure. Spermidine increases autophagy-dependent proteins and reduces the penetration of inflammatory substances (inflammatory infiltration) and inflammatory phagocytes (monocytes). Consequently, 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 a heart attack, spermidine increases heart function and reduces infarct size and the increase in heart muscle mass (myocardial hypertrophy). It also reduces inflammation, oxidative damage and apoptosis (programmed cell death) both in vitro (“performed in a test tube”) and in vivo (“observed/performed on a living object”) [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].
• Supplemental spermidine slows arterial aging caused by reduced nitric oxide, increased advanced glycation endproducts (AGEs), superoxide and oxidative stress. Spermidine normalizes arterial pulse wave velocity (aPWV; a direct measure of arterial stiffness), repairs endothelium-dependent arterial dilation (EDD = end-diastolic diameter; diameter of the heart chambers at the end of diastole) and reduces oxidative stress, AGEs and superoxide. This study suggests that spermidine could improve treatments for arterial aging 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 and necrotic nucleus formation in atherosclerotic plaques. Lipid accumulation decreases because spermidine stimulates cholesterol efflux by activating autophagy.The size and composition of the deposits (plaques) are not changed by 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. Artherosclerosis. 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 an increased formation of spermidine/spermine N1-acetyltransferase. This leads to a reduction in body weight, heart weight, cardiac muscle cell proliferation, antioxidant capacity, mitochondrial structure and mitochondrial biogenesis. At the same time, more cardiac muscle cells die and there is a pathological proliferation of tissue (fibrosis). This damage can be prevented 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. Oxide Med Cell Longev. 2019;2019:5406468].
• Increased autophagy protects against cardiovascular diseases. In rats and mice, dietary spermidine had a heart-protective effect by increasing cardiac autophagy and mitophagy (the breakdown of mitochondria). In addition, spermidine slows the development of high blood pressure (hypertension) by improving arginine bioavailability and protecting the kidneys. In humans, spermidine supplementation was found to be associated with reduced blood pressure and a reduced risk of developing cardiovascular diseases. The risk of dying from the consequences of these diseases was also reduced. Spermidine is an autophagy activator that protects the heart and blood vessels. [Eisenberg T et al.; Dietary spermidine for lowering high blood pressure. Autophagy. 2017;13(4):767-769].
• Spermidine increases lifespan in mice and has cardioprotective effects. It reduces pathological enlargement of the heart muscle, 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 capabilities of cardiac muscle cells, increases titin phosphorylation and suppresses mild inflammation. In humans, a connection has been observed between a high spermidine content in the diet and reduced blood pressure and a lower 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 recent statements by the World Health Organization (WHO) and IMF, there is a negative association between dietary spermidine intake and mortality 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 the overall mortality rate 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 heart-protective 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 health span extension by the natural polyamine spermidine. Nat Med 2016;22(12):1428-1438]. that spermidine reverses age-related cardiac dysfunction in mice by activating autophagy. Spermidine "rejuvenates" striated muscle and improves mitochondrial functions and key functions associated with cardiac aging (including hypertension, left ventricular hypertrophy, diastolic dysfunction, and increased left ventricular stiffness). It also has anti-inflammatory effects. The effects are dependent on autophagy.

Spermidine and its effects on the brain

Spermidine plays an important role in brain development. Brain function, memory acquisition and memory consolidation (consolidation of memories or learning content in long-term memory) also depend on spermidine. Current studies suggest that the autophagy effects and the polyamine binding sites on the NMDA receptor (NMDAr) are primarily responsible for the effects of spermidine on memory.

The effects on the brain were first demonstrated in animal models using rats and fruit flies. The first human studies have now been carried out which confirm the effects.

• Spermidine administration improved 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 preventing the effect of spermidine on memory. This suggests that spermidine-enhanced memory consolidation involves activation of the TrkB receptor and the PI3K/Akt signaling 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 on the synapses and allows autophagy-dependent homeostatic regulation of the part of the synapse from which the excitation originates [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 has been observed that the decrease in polyamines is also associated with a decline in memory performance. The additional administration of spermidine improves autophagy, restores youthful spermidine levels and blocks memory loss.However, improvement in memory disorders does not occur if genetic deficiencies 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 paper from 2020, Rosh confirms that spermidine promotes longevity and stimulates autophagy. It maintains cellular and neuronal homeostasis. Spermidine and spermine interact with the opioid system and influence neuroinflammation (inflammation of nerve tissue). They also inhibit calcium influx into cells, harmful radicals and glutamate excitotoxicity. The development and function of the brain depends on the polyamine and especially spermidine concentration. Furthermore, age-related fluctuations in spermidine levels lead to imbalances in the neural network and endanger neurogenesis (formation of nerve cells). Additional spermidine intake 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 has discovered that the administration of spermidine after traumatic brain injury (TBI) significantly accelerates the neurological NNS score and shortens the latency in the Morris Water Maze test. Studies have shown that spermidine improves blood-brain barrier function. In addition, there were positive changes in cell death and brain edema. Inflammatory cytokines and TBI markers were significantly reduced. Since spermidine levels were significantly reduced in TBI patients with severe disorders, the dietary supplement could be used as a new form of therapy for traumatic brain injury, according to Huang. [Huang J et al.; Spermidine exhibits protective effects against traumatic brain injury. Cell Mol Neurobiol.2020].
• In the randomized preSmartAge study conducted 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 supported by new findings from human studies:

• In a small study, researcher M. Fischer was able to prove that increased autophagy in brain cells improves memory. He also 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.; Spermine 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 associated with larger hippocampal volume. He also found greater mean cortical density and increased cortical thickness in areas of the brain susceptible to Alzheimer's disease, as well as in the parts of the brain associated with the parietal bone and the temples. [Black 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 [Black 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 of Neurology also now recognizes the great potential of spermidine in terms of its protective effect on 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. Wheat germ preparations enriched with spermidine are used. [Diener HC; Brain-healthy nutrition: How food can protect against dementia; IWD-Informationsdienst Wissenschaften 2017].

Spermidine in Oncology

Spermidine is now also said to have positive effects in the area of ​​cancer prevention. The polyamine may even be helpful in treating small tumors that are in an early stage. Studies have produced the following results:

• Levesque used spermidine as an anticancer agent in one of his studies. A combination of calorie restriction mimetics (CRM; e.g. spermidine) with activators of immunogenic cell death (ICD) and immune checkpoint inhibitors (ICI) improved control of tumor growth in mice. Without calorie restriction mimetics, ICDs and ICIs only cause 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 that trigger oxidative, stress-related cell death and promote liver carcinoma and liver fibrosis by activating autophagy. As a dietary supplement, the polyamine can not only extend the lifespan 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].
• In 2019, Pietrocola commented on Kiechl’s prospective study (see), 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, a higher daily polyamine intake was associated with a reduced risk of colorectal cancer (HR average 0.81), especially in overweight women [Vargas AJ et al. Dietary polyamine intake and colorectal cancer risk in postmenopausal women. At J Clin Nutr. 2015;102(2):411-9]. It is worth mentioning, however, that both cancer cells with increased metabolic activity and healthy cells use polyamines. For this reason, there is currently discussion as to whether dysregulation of polyamine metabolism could promote cancer. The total polyamine concentration is increased and the enzymes from polyamine metabolism (such as adenosylmethionine decarboxylase (SAMDC) and spermine oxidase (SMO)) are highly active. If this turns out 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. med. Udo Böhm