Wheat germ and its ingredients

Wheat germ is the oil-containing component of mature wheat grains and accounts for approximately 3% of their total weight. Wheat germ initially develops into the valuable wheatgrass, which later forms wheat grains. Wheat germ is usually a byproduct of wheat flour production. It is highly nutrient-dense and rich in micronutrients and fiber (1.5-4%). ​​The oil content is approximately 10%, with many unsaturated fatty acids. The protein content is approximately 27%, but depending on the origin, it can also be between 13 and 35%.

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 (v.a. 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, and human studies are scarce. However, the extensive knowledge about the individual ingredients and their significance for metabolism and general health allows conclusions to be drawn about the overall effects of wheat germ. Research also identifies 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 associated with premenstrual syndrome (PMS). According to Balint, fermented wheat germ extract, as a complement to corticoid therapy, has a positive effect on rheumatoid arthritis, improving 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 pro-inflammatory cytokines in the intestine, increases the levels of butyric and propionic acid, and regulates the composition of the intestinal flora. Furthermore, it increases the levels of Lactobacilli and—as demonstrated in a small double-blind study by Moreira-Rosario—also the levels 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 environment 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 obesity in overweight mice u.a. visceral fat, cardiac mitochondrial dysfunction, serum insulin and insulin resistance [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 contains many biologically active substances (including benzoquinones). Cancer-preventive effects have been demonstrated for alcoholic and fermented wheat germ extracts in numerous experimental studies, small human studies, and animal studies. z.B. in colon cancer. Furthermore, its effects as a complementary measure in the treatment of various types of cancer (melanoma, lung cancer, leukemia, breast cancer, colorectal cancer) have been demonstrated. Treatment-related side effects such as a reduction in neutrophil granulocytes in the blood and fatigue/exhaustion improved. Survival time and quality of life were also prolonged. The extract exhibits 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 due to its micronutrient content and enriches the general diet. It is suitable for optimizing metabolism and preventing metabolic disorders and acute and chronic diseases.

Polyamine

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

The three polyamines spermine, spermidine, and putrescine can be obtained through food or produced naturally by the body. Foods contain the individual polyamines in varying amounts. Spermidine is particularly abundant in wheat and wheat germ. Dried soybeans, aged 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 are readily absorbed transepithelially ("through the intestinal mucosa") in the intestine. Putrescine, on the other hand, is less readily absorbed because it is broken down by diamine oxidase (DAO) present in the intestine. For the body to produce polyamines, it requires the amino acids arginine or ornithine, as well as various cofactors such as vitamin B12, folic acid, and S-adenosylmethionine (SAM).

In addition, numerous 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 through diet, because the body can only produce about 1/3 itself. So far, there is hardly any usable data available 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 The practice of competitive sports can increase the need. In addition, Environmental influences and the Hormone status affect 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 lacks polyamines 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 most well-researched and striking polyamine. It plays a key role in maintaining overall metabolism, cellular function, and human health. Therefore, it can be expected to have a wide range of benefits in the treatment and prevention of diseases.

The effects of polyamines already mentioned apply to spermidine. Spermidine also has some independent effects well described in the literature that go beyond those of polyaminesThese effects contribute to spermidine's ability to reduce tumor development (carcinogenesis) and 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 (mimicking the life-prolonging effect of 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 hypertension-related kidney damage
• Improves muscle strength and reduces myopathies (“muscle disorders”)
• 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 cleansing and recycling program in the body. It is essential for homeostasis and survival. Autophagy supports the organism and cells in digesting waste and "junk," as well as breaking down misdirected, superfluous, or incorrectly formed cellular components and recycling them. It plays a key role in maintaining cellular 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 plays important roles in 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.

With age and metabolic disorders, the body's ability to perform 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 permanent low-calorie diet.
2. Through the use of so-called calorie restriction mimetics, which mimic the effects of reduced calorie intake (= calorie restriction). Spermidine is an important representative of the group of calorie restriction mimetics and acts similarly to the secondary plant substances resveratrol from grapes and epigallocatechin gallate from green tea.

Spermidine: Does it extend lifespan?

Today, 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 acts through other mechanisms: It regulates growth, cell proliferation, and cell death (apoptosis), and modulates protein translation and gene expression. Furthermore, it inhibits inflammation and the formation of fat cells (adipogenesis), as well as histone acetylation. Spermidine improves lipid metabolism.

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

Among other things, spermidine reduced malondialdehyde levels (a breakdown product of polyunsaturated fatty acids; an important biomarker for oxidative stress) in the brain of mice and increased SOD (superoxide dismutase) activity (correlated 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 supplementation, due to autophagy activation and other typical polyamine effects, at least extends the lifespan of model organisms such as fruit flies, yeast, and worms. Furthermore, it halts 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 inhibited oxidative stress and tissue death (necrosis) in aging mice.It stimulates the deacylation of histone H3 in mature 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 thus 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 supplemental administration of spermidine extended human health and lifespan. A prospective cohort study by Kiechl confirmed that spermidine extends human lifespan. In the study, overall mortality decreased for each third of increased spermidine intake from 40.5% (95% CI) to 23.7% (95% CI) or 15.1% (95% CI), corresponding to a cumulative mortality incidence of 0.48, 0.41, and 0.38, respectively. The cumulative (mortality) incidence (CI) indicates the probability that a person will develop a particular disease or die (mortality incidence) within 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

Impaired autophagy can have detrimental effects on the cardiovascular system. Substances that activate autophagy can therefore counteract the development of cardiovascular diseases such as atherosclerosis, heart failure, coronary artery disease, cardiac arrhythmias, and diabetic cardiomyopathy. Spermidine also stimulates mitochondrial respiration and improves the mechanoelastic 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].

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 extensibility and limiting the heart's elasticity. Spermidine can effectively inhibit PP5. Mice fed spermidine continued to have healthy hearts as they aged. People who consume a spermidine-rich diet also have a lower incidence of cardiovascular disease. Since spermidine levels decline with age, supplementation may be beneficial. [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:

• Spermidine supplementation activates the formation of new mitochondria in the cell (mitochondrial biogenesis) through SIRT1-mediated deacetylation of PGC-1alpha (protein). Furthermore, 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, however, was upregulated. In these experiments, spermidine increased PGC-1a, SIRT1, NRF1, NRF2, TFAM (mitochondrial transcription factor alpha), and OXPHOS (oxidative phosphorylation) activity in 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). Therefore, spermidine could be a promising treatment 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 cardiac function and reduces infarct size and the increase in heart muscle mass (myocardial hypertrophy). Furthermore, it reduces inflammation, oxidative damage, and apoptosis (programmed cell death) both in vitro (“conducted in a test tube”) and in vivo (“observed/conducted on living subjects”). [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, which is triggered by reduced nitric oxide, increased AGEs (advanced glycation end products), 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 cardiac 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 preventive measures related to 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 nucleus formation in atherosclerotic plaques. Lipid accumulation decreases because spermidine stimulates cholesterol efflux through the activation of autophagy. The size and composition of the plaques are not altered by spermidine. Stimulation of autophagy could prevent the development of vascular disease. [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 production 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 pathological tissue proliferation (fibrosis) occurs. This damage can be prevented by placental spermidine supplementation. [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 disease. In rats and mice, dietary spermidine exerted cardioprotective effects by increasing cardiac autophagy and mitophagy (the breakdown of mitochondria). Furthermore, spermidine slows the development of high blood pressure (hypertension) by improving arginine bioavailability and protecting the kidneys. In humans, spermidine supplementation has been shown to be associated with reduced blood pressure and a reduced risk of developing cardiovascular disease. The risk of death from these diseases was also reduced. Spermidine is a cardio- 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 exhibits cardioprotective effects. It reduces pathological 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 capabilities of cardiac muscle cells, increases titin phosphorylation, and suppresses mild inflammation. In humans, a link has been observed between high dietary spermidine 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 spermidine has a protective effect on cardiovascular health in epidemiological studies. 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 function in healthy volunteers 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 aging-related cardiac dysfunction in mice by activating autophagy. Spermidine rejuvenates striated muscle and improves mitochondrial function and key features associated with cardiac aging (including hypertension, left ventricular hypertrophy, diastolic dysfunction, and increased left ventricular stiffness). It also exerts anti-inflammatory effects. These 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 (the consolidation of memories or learned content in long-term memory) also depend on spermidine. Current studies suggest that the effects of autophagy and polyamine binding sites on the NMDA receptor (NMDAr) are primarily responsible for spermidine's effects on memory.

The effects on the brain were initially demonstrated in animal models using rats and fruit flies. Initial human studies have now confirmed these effects.

• Spermidine administration improved fear memory consolidation in rats, with both the TrkB (tyrosine receptor kinase B; protein) antagonist ANA-12 and the PI3K (phosphoinositide 3-kinase; enzyme) inhibitor LY29400z 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 impairment. The dietary supplement acts directly on the synapses, enabling 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].
• With age, brain polyamines decrease. In fruit flies, it has been observed that the decrease in polyamines is also associated with a decline in memory performance. Supplemental spermidine administration improves autophagy, restores youthful spermidine levels, and blocks memory loss. However, improvement in memory impairment 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 2020 study, 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, damaging radicals, and glutamate excitotoxicity. Brain development and function depend on polyamine and, in particular, spermidine concentrations. Furthermore, age-related fluctuations in spermidine levels lead to imbalances in the neural network and compromise neurogenesis (the formation of nerve cells). Supplemental spermidine supplementation therefore supports the treatment of brain diseases, although the exact mechanisms are not yet fully understood. [Gosh I et al.; Spermidine, an autophagy inducer, as a therapeutic strategy in neurological disorders. Neuropeptides 2020].
• Huang discovered that the administration of spermidine after traumatic brain injury (TBI) significantly accelerated the neurological NNS score and shortened the latency in the Morris water maze test. Studies have shown that spermidine improved blood-brain barrier function. Furthermore, positive changes were observed in cell death and brain edema. Pro-inflammatory cytokines and TBI markers were significantly reduced. Because spermidine levels were significantly reduced in TBI patients with severe disorders, Huang believes the dietary supplement could be used as a new form of therapy for traumatic brain injury. [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 neuromodulatory 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 demonstrated that increased autophagy in brain cells improves memory. He also discovered 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, due to its influence on autophagy, triggers the elimination of amyloid beta plaques. 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 brain areas susceptible to Alzheimer's disease, as well as in the parietal and temporal regions. [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 has also now recognized the great potential of spermidine in its protective effect on dementia, stating that previous data suggest that spermidine has a positive effect on brain function and cognitive abilities. These effects are currently the focus of the SmartAge study, which is being conducted under the direction of Professor Flöel. Wheat germ supplements enriched with spermidine are being used. [Diener HC; Brain-Healthy Nutrition: How Food Can Protect Against Dementia; IWD Science Information Service 2017].

Spermidine in oncology

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

• Levesque used spermidine as an anticancer drug in one of his studies. A combination of calorie restriction mimetics (CRMs; z.BSpermidine) 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, through activated autophagy, can reduce cancer cell defects that trigger oxidative, stress-induced cell death and promote liver carcinoma and liver fibrosis. 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 lesions. [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 (s.o.), which shows that spermidine reduces cancer mortality, and wrote that cancer can only develop if the immune system fails to recognize the threat and 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 87In a study involving 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 noting, however, that both cancer cells with increased metabolic activity and healthy cells utilize polyamines. For this reason, there is currently discussion about whether dysregulation of polyamine metabolism could promote cancer. The total polyamine concentration is elevated, and enzymes involved in 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. Udo Böhm