Wheat germ and its ingredients

Wheat germ is the oil-rich component of mature wheat kernels and makes up approximately 3% of their total weight. The valuable wheatgrass develops from the wheat germ, from which wheat kernels later form. Wheat germ is usually a byproduct of wheat flour production. It has a high nutrient density and is rich in micronutrients and dietary fiber (1.5-4%). ​​The oil content is around 10%, containing many unsaturated fatty acids. The protein content is approximately 27%, although between 13% and 35% is possible depending on the origin.

The ingredients include:

• Vitamins (B1, B2, B3, B5, B6, B9 as well as 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.aAlpha-linolenic acid, linoleic acid, oleic acid and palmitoleic acid)
• Amino acids (arginine, tryptophan, lysine, methionine, phenylalanine, leucine and isoleucine)
• Secondary plant compounds (carotenoids, polyphenols and flavonoids)

The effects of wheat germ

The aforementioned ingredients indicate significant health potential. However, the effects of wheat germ have so far only been partially investigated experimentally; human studies are scarce. Nevertheless, the extensive knowledge about the individual ingredients and their significance for metabolism and general health allows for conclusions to be drawn about the overall effects of wheat germ. Research also identifies potential medical applications:

• Wheat germ extract has anti-inflammatory, antioxidant, antibacterial and immunomodulating 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, when used as an adjunct to corticosteroid 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 gut, increases the levels of butyric and propionic acid, and regulates the composition of the gut 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 Bifidobacteria. [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 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 is composed of many biologically active substances (including benzoquinones). Several experimental studies, small human trials, and animal studies have demonstrated cancer-preventive effects for alcoholic and fermented wheat germ extracts. z.B...in the case of colorectal cancer. Furthermore, its effectiveness as a complementary treatment for various types of cancer (melanoma, lung cancer, leukemia, breast cancer, colorectal cancer) has been confirmed. Therapy-related side effects such as decreased neutrophil count and fatigue/exhaustion improved. Survival time was also extended and quality of life improved. The extract exhibits anti-timetastatic, anti-proliferative, and tumor cell apoptosis-promoting effects 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, due to its micronutrient content, supports basic nutritional needs and enriches the overall diet. It is suitable for optimizing metabolism and preventing metabolic disorders, as well as 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 component of human and animal metabolism.

Polyamines are crucial for the development of many cells and also ensure their survival. Spermidine, due to its unique polycationic properties, is the most effective polyamine. [Mendez JD; The Other Legacy of Antonie Van Leeuwenhoek: The Polyamines. J Clin Mol Endocrinol 2017].

Availability, demand and metabolism of polyamines

The three polyamines spermine, spermidine, and putrescine can be obtained through food or produced by the body itself. Foods contain these 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) in the intestine. For the body to synthesize polyamines, it requires the amino acids arginine or ornithine, as well as various cofactors such as vitamin B12, folic acid, and S-adenosylmethionine (SAM).

Furthermore, several enzymes are involved in polyamine metabolism. These include, for example, 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. In this process, putrescine is initially produced, which is metabolized to spermidine, which can then be converted to spermine.

Approximately two-thirds of the polyamine requirement must be met through diet.Because the body can only produce about 1/3 of polyamines itself. So far, there is hardly any usable data that would allow conclusions to be drawn about polyamine requirements and possible additional dosage. According to a Japanese source, a daily intake of 70 mg (including in-house 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 need for polyamines, especially spermidine, is increased due to the heightened cell growth in the pregnancy and increased in infants during the first 28 days after birth. Also Pollution or the Participating in competitive sports can increase the need for competitive sports.Furthermore, they can Environmental influences and the Hormone status affect polyamine synthesis and the total polyamine pool. Furthermore, the body's own production decreases with age., which reduces the overall 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 traits and Bowel dysfunction This can lead to the body not being supplied with polyamines, or not being supplied sufficiently. If the body has too few polyamines available on a long-term basis, 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 effects of spermidine

Spermidine is the best-researched and most prominent polyamine. It plays a vital role in maintaining overall metabolism, cell function, and human health. For this reason, it can be expected to have diverse benefits in the treatment and prevention of diseases.

Spermidine exhibits the effects of polyamines already mentioned. Spermidine also possesses several independent effects, well described in the scientific literature, that go beyond those of polyamines.These effects contribute to spermidine reducing tumor development (carcinogenesis) and potentially 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”)
• It acts like a calorie restriction mimetic (mimicking the life-extending effect of reduced energy intake from food)
• Protects nerve cells (neuroprotection) and reduces age-related memory impairment.
• It suppresses pro-inflammatory cytokines and thus modulates the immune and inflammatory system.
• Slows down stem cell aging
• Improves diastolic function
• Reduces arterial stiffness and heart failure
• Reduces age-related and high blood pressure-related kidney damage
• Improves muscle strength and reduces myopathies ("muscle disorders")
• Reduces carcinogenesis and pathological tissue proliferation (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 helps the organism and its cells digest waste products and "junk," as well as break down misdirected, superfluous, or incorrectly formed cell components and recycle them. It plays a crucial role in maintaining cellular homeostasis and enables cells to adapt to molecular stress. Furthermore, it provides energy and materials for the formation of new cellular structures.

A well-functioning autophagy also plays important roles in relation to pathological processes. These include, for example, the improvement of metabolic disorders and the prevention of neurodegenerative diseases such as multiple sclerosis, Parkinson's disease, or Alzheimer's disease through the elimination of misfolded proteins.

With age and in cases of 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 permanently low-calorie diet.
2. This is achieved 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 compounds resveratrol from grapes and epigallocatechin gallate from green tea.

Spermidine: Does it extend lifespan?

Nowadays, spermidine is considered a universal anti-aging drug, as 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 via other mechanisms: It regulates cell growth, cell proliferation, cell death (apoptosis), and modulates protein translation and gene expression. Furthermore, it inhibits inflammation, 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. eIFs A acts as a translational stretch 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 containing a specific amino acid, which is produced by deoxyhypusin synthase and deoxyhypusin hydroxylase and requires spermidine as a substrate. Deoxyhypusin synthase is an enzyme with the systematic name lysine.

Spermidine reduced malondialdehyde levels (a breakdown product of polyunsaturated fatty acids; an important biomarker for oxidative stress) in the brains of mice and increased SOD (superoxide dismutase; correlated with increased lifespan) activity. 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, 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 inhibits oxidative stress and tissue death (necrosis) in aging mice.In older yeast cells, it stimulates the deacylation of histone H3 by inhibiting histone acyltransferases. The removal of polyamines from the body leads to excessive acetylation, premature cell death, free 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, spermidine supplementation extended the health and lifespan of individuals. A prospective cohort study by Kiechl confirms that spermidine prolongs human lifespan. In this study, overall mortality decreased for each third of increasing spermidine intake from 40.5% (95% CI) to 23.7% (95% CI) and 15.1% (95% CI), respectively, corresponding to cumulative mortality incidences of 0.48, 0.41, and 0.38. The cumulative mortality incidence (CI) indicates the likelihood that a person will develop a specific disease or die within a given timeframe. The mortality risk between the upper and lower thirds of spermidine intake was similar to that of individuals 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. 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 a detrimental effect on the cardiovascular system. Therefore, substances that activate autophagy can counteract the development of cardiovascular diseases such as arteriosclerosis, 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].

In heart failure, there is an excess of the enzyme PP5 (serine/threonine protein phosphatase 5). This enzyme accumulates in the heart chambers, reducing their elasticity and impairing the heart's elasticity. Spermidine can effectively inhibit PP5. Mice fed spermidine retained healthy hearts into old age. Cardiovascular diseases also occur less frequently in people who consume a spermidine-rich diet. Since spermidine levels decline with age, supplementation could 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 demonstrated in numerous experiments with rats and mice and have also 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 (a protein). Furthermore, spermidine inhibits mitochondrial dysfunction and preserves the ultrastructure of cardiac 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 downregulated. Conversely, SPD/spermin N1 acetyltransferase was upregulated. In the experiments, spermidine increased PGC-1a, SIRT1, NRF1, NRF2, TFAM (mitochondrial transcription factor a), and OXPHOS activity (oxidative phosphorylation) in cardiac 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 arterial aneurysms and improves the integrity of the aortic structure. Spermidine increases autophagy-dependent proteins and reduces the infiltration of inflammatory substances and inflammatory phagocytes (monocytes). Therefore, 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 enhances cardiac function and reduces infarct size as well as the increase in heart muscle mass (myocardial hypertrophy). Furthermore, it reduces inflammation, oxidative damage, and apoptosis (programmed cell death) both in vitro (in a test tube) and in vivo (observed/performed in 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].
• Spermidine supplementation slows arterial aging, which is triggered by reduced nitric oxide, elevated 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 dilatation (EDD = end-diastolic diameter; the diameter of the heart chambers at the end of diastole), and reduces oxidative stress, AGEs, and superoxide. This study suggests that spermidine could enhance treatments for arterial aging as well as preventive measures for 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 (fatty buildup) and necrotic nucleus formation in atherosclerotic plaques. Lipid accumulation decreases because spermidine stimulates cholesterol efflux by activating autophagy. The size and composition of the plaques are not altered by spermidine. Stimulation of autophagy may 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 fetus experiences dangerous oxygen deprivation in the womb (intrauterine hypoxia), this leads to a decrease in cardiac ornithine decarboxylase and an increased production of spermidine/spermine N1 acetyltransferase. This results in a reduction in body weight, heart weight, cardiac muscle cell proliferation, antioxidant capacity, mitochondrial structure, and mitochondrial biogenesis. Simultaneously, more cardiac muscle cells die, and abnormal tissue proliferation (fibrosis) occurs. These damages can be prevented by spermidine supplementation into 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 disease. In rats and mice, dietary spermidine exerted cardioprotective effects by increasing cardiac autophagy and mitophagy (mitochondrial breakdown). Furthermore, spermidine inhibits the development of hypertension by improving arginine bioavailability and protecting the kidneys. In humans, a correlation was found between spermidine supplementation and reduced blood pressure, as well as a decreased risk of developing cardiovascular disease. The risk of dying from these diseases was also reduced. Spermidine is a cardioprotective 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 cardiomyopathy, lowers systolic blood pressure, and maintains diastolic function in older animals. This dietary supplement enhances cardiac autophagy, mitophagy, and mitochondrial respiration. It improves the mechanoelasticity of heart muscle cells, increases titin phosphorylation, and suppresses mild inflammation. In humans, a correlation has been observed between a high dietary spermidine content and reduced blood pressure, as well as 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 using human data:

• According to recent statements from the World Health Organization (WHO) and the 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 how 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 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 function 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]Spermidine reverses age-related cardiac dysfunction in mice by activating autophagy. Spermidine "rejuvenates" striated muscle and improves mitochondrial function as well as key functions associated with cardiac aging (including hypertension, left ventricular hypertrophy, diastolic dysfunction, and increased left ventricular stiffness). It also exhibits 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 strengthening of memories or learned content in long-term memory) are also dependent on spermidine. Current research suggests that autophagy effects and the polyamine binding sites at the NMDA receptor (NMDAr) are primarily responsible for spermidine's impact on memory.

The effects on the brain were initially demonstrated in animal models using rats and fruit flies. Now, initial human studies confirming these effects exist.

• Administration of spermidine improved the consolidation of fear memories in rats, while both the TrkB antagonist (tyrosine receptor kinase B; protein) ANA-12 and the Pl3K inhibitor (phosphoinositide 3-kinase; enzyme) LY29400z prevented the effect of spermidine on memory. This suggests that the 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 supplementation 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 synaptic component from which 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].
• Polyamine levels in the brain decrease with age. In fruit flies, this decline in polyamines has been observed to be associated with a decline in memory performance. Supplementation with spermidine improves autophagy, restores youthful spermidine levels, and halts memory loss. However, no improvement in memory impairment occurs if genetic deficiencies prevent or restrict 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 study 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). Furthermore, they inhibit calcium influx into cells, harmful free radicals, and glutamate excitotoxicity. Brain development and function depend on polyamine and, in particular, spermidine concentrations. Age-related fluctuations in spermidine levels also lead to imbalances in the neural network and jeopardize neurogenesis (the formation of new nerve cells). Therefore, additional spermidine intake may support the treatment of brain disorders, although the precise 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 administering spermidine after traumatic brain injury (TBI) significantly accelerated the neurological NNS score and shortened the latency in the Morris water maze test. Studies showed that spermidine improved blood-brain barrier function. Furthermore, positive changes were observed regarding cell death and cerebral edema. Pro-inflammatory cytokines and TBI markers were significantly reduced. Since spermidine levels were significantly lowered in TBI patients with severe impairments, Huang suggested that 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 Charité Hospital, spermidine significantly improved memory performance. The study indicates that this 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 effects of spermidine on the brain described so far, the following section presents the effects on neurodegenerative disorders and supports them with new findings from human studies:

• In a small study, researcher M. Fischer succeeded in demonstrating that increased autophagy in brain cells improves memory. Furthermore, he discovered that T cells and cytokines act as important mediators in the pathology of Alzheimer's disease. At 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].
• Pekar's study found that spermidine, due to its influence on autophagy, triggers the removal 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 how higher spermidine intake in older adults is associated with a larger hippocampal volume. He also observed greater mean cortical density and increased cortical thickness in brain regions susceptible to Alzheimer's disease, as well as in the parietal and temporal lobes. [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 already 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 for Neurology now also recognizes the great potential of spermidine regarding its protective effect against dementia and states that current data suggest 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. This study uses wheat germ preparations enriched with spermidine. [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 field of cancer prevention. The polyamine may even be helpful in the case of small tumors in their early stages. Studies have yielded the following results:

• Levesque used spermidine as an anticancer agent in one of his studies. A combination of calorie restriction mimetics (CRMs; z.BSpermidine combined with immunogenic cell death activators (ICDs) and immune checkpoint inhibitors (ICIs) improved tumor growth control in mice. Without calorie restriction mimetics, ICDs and ICIs only result in 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-induced cell death and promote liver cancer and liver fibrosis by activating autophagy. As a dietary supplement, this polyamine can not only extend the lifespan of mice by up to 25%, but also minimize liver fibrosis and liver cancer 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 on Kiechl's prospective study in 2019 (s.o.), which shows that spermidine reduces cancer mortality, and wrote that cancer can only develop if the immune system fails to recognize the danger and eliminate malignant cells. According to this, autophagy activated by spermidine is 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, at the 87thIn a study of 602 women, a higher daily polyamine intake was associated with a reduced risk of colorectal cancer (HR average 0.81), particularly 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, it is currently being discussed whether a dysregulation of polyamine metabolism could promote cancer. In such cases, the total polyamine concentration is elevated, and the enzymes involved in polyamine metabolism (such as adenosylmethionine decarboxylase (SAMDC) and spermine oxidase (SMO)) are highly active. Should this prove 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