The role of spermidine on cell health
Soy spermidine is an important growth factor and is of fundamental importance in
cell growth (cell proliferation and cell differentiation), especially in the regulation
of gene expression, in protein synthesis (transcription and translation) and further
in the induction of autophagy and in resistance against oxidative stress
(nitrosative stress and toxic stress as a result of a dysregulated HPA axis).
Spermidine: Bioactivity that supports a healthy and long life
Soy Spermidine and DNA methylation
Soy spermidine is an epigenetically active key molecule which together with ademetionine (S-adenosyl-L-methionine) protects cellular health.
Gene methylation status is closely linked to age related changes and spermidine metabolism intimately connected with regulation of gene methylation.
Age related changes to the DNA methylation status – increased demethylation in some sections and hypermethylation in other sections – are seen as key factor in developing age-related pathologies (ageing).
Soy spermidine protects from negative consequences of ageing and increases the life span
Altered DNA methylation related to ageing and the resulting pathologic changes can be prevented with a timely and adequate dietary provision of soy spermidine (for example soy powder containing a high concentration of spermidine) thereby prolonging life expectancy.
Spermidine, being a caloric restriction mimetic, prolongs life expectancy
Spermidine is an inducer of autophagy and provides energy when fasting or repairs stress related cellular damage.
Our body and our cells are continuously provided with food and thereby with energy leading to cellular growth which in turn is enhanced through insulin and insulin-like growth factors IGF-1 and mTOR. This means, our cells are continuously ageing. However, if we choose to fast for a period of time, levels of insulin, IGF-1 and also of mTOR stabilise again. This induces an intrinsic cellular self-cleansing process called “autophagy”.
Molecular key events during caloric restriction (cr) and fasting on a molecular and metabolic level
Caloric restriction and fasting have effects at multiple levels and increase cellular and organismic multi-stress resistance which result in systemic health benefits.
The effect of spermidine on the lifespan of humans is being evaluated as part of a strategic project of the VASCage (Research Centre on Vascular Ageing and Stroke) group which was incorporated into the K1 Centre VASCage at the School of Medicine in Innsbruck.
The Bruneck Study recorded dietary habits of participants over a period of 20 years both qualitatively and quantitatively. Primary dietary sources of spermidine included whole grain foods, apples and pears, lettuce, vegetable sprouts and potatoes.
Actually, the level of dietary spermidine intake was inversely related to mortality rates: those who had a high intake spermidine as part of their diet showed a reduced risk of death over a 20-year follow-up period. A reduced level of autophagy is associated with nearly all age-related diseases and therefore it is not surprising to find positive effects of spermidine when deaths caused by vascular disease, tumours and other diseases are evaluated.
A diet rich in spermidine and spermidine supplementation correlate with increased survival rates in humans. Those with a high daily intake, at least 80mmol spermidine, show a significantly reduced risk of dying at a younger age.
According to this study, the risk of death in those who had a spermidine intake in the upper third and those who had an intake in the lower third (less than 60mmol a day) is equal to 5.7 years.
Stefan Kiechl, et al. Higher spermidine intake is linked to lower mortality: a prospective population-based study, The American Journal of Clinical Nutrition, Volume 108, Issue 2, August 2018, Pages 371–380
Soda, K., Spermine and gene methylation: a mechanism of lifespan extension induced by polyamine-rich diet. Amino Acids 52, 213–224 (2020)
Soy spermidine has the ability to stimulate autophagy
One of the most important effects of soy spermidine on cellular health is its ability to increase the rate of autophagy. Autophagy is a cellular process in which damaged or aged cell components are degraded, recycled or removed and which is also a source of energy during starvation or used to repair stress-related damages in order to maintain cellular health.
An adequate level of autophagy is critical to protect cells from ageing, inflammation and various diseases.
In 2019, Frank Madeo and his co-workers at the Institute of Molecular Biosciences at the University of Graz have emphasized the importance of spermidine as a natural autophagy inducer on an increased lifespan.
Cytoplasmic components are surrounded by a membrane (the phagophore) which can extend to a double membrane autophagosome. Membrane fusion between autophagosomes and lysosomes generates autolysosomes; these contain acid hydrolases and permeases which can degrade the content of the cytoplasm and the lysosomal membrane. Degraded macromolecules will be recycled in the cytoplasm.
Induction of autophagy is linked to AMP-dependent kinase/mTOR independent signalling pathways and also to deacetylation reactions from autophagy associated proteins in the cytoplasm. In particular, spermidine induces autophagy by inhibiting acetyltransferase EP300.
Source: Eisenberg T, Knauer H, Madeo F et al. Induction of autophagy by spermidine promotes longevity. Nat Cell Biol. 2009 Nov;11(11):1305-14
Bio-spermidine plays a role in cell reprogramming and regulation of autophagy
Latest results have indicated that spermidine plays a role in cell reprogramming and the regulation of autophagy.
Reprogramming enables us to transform the cell nucleus of any cell in our body to an earlier embryonic developmental stage.
Soy spermidine can help to minimise oxidative damage in cells and increase protection against oxidative damage
Oxidative stress (ROS) is the result of an imbalance between pro-oxidative and anti-oxidative processes in our body and may lead to cell damage and inflammation.
Soy spermidine has anti-oxidative effects
Soy spermidine suppresses oxidative stress in cells (ROS stress), protects mitochondria and, as a result, all cells and organs.
A spermidine transporter controls spermidine levels during phases of oxidative stress and mediates the induction of anti-oxidative proteins (human anti-oxidation protein A1M)
Soy spermidine can boost the anti-oxidative effects of anti-oxidants if the anti-oxidant is given bevor, after or together with spermidine (Frank Madeo).
Soy spermidine is an anti-inflammatory
A chronically low level of proinflammatory cytokines and chemokines and the resulting increase of inflammatory biomarkers is linked to an age-related loss of function and to an increased risk of morbidity and mortality.
Soy spermidine has anti-inflammatory effects during acute and chronic inflammation due to its anti-oxidative and lysosome stabilising properties.
Soy spermidine improves the function of the immune system
Regulatory T-cells, abbreviated Treg cells, are a specialised subgroup of T-lymphocytes, mostly CD4+ T-cells, which regulate self-tolerance in our immune system.
Self-tolerance is the ability of the human immune system to differentiate between the body’s own and foreign matter.
Spermidine taken up from food helps to differentiate naïve CD4-positive immune cells leading to an increased production of Treg cells. Another effect is the reduction of the number of TH17 cells, a cell type which plays a major role in inflammatory reactions.
Soy spermidine promotes mitochondrial health
Normal and healthy functioning of mitochondria, also known as the power plants of cells, is promoted and maintained by spermidine. Spermidine can help to regulate the energy levels (ATP production) of the mitochondria to an ideal level and its antioxidative effects reduce ROS stress to which the proteins of the respiratory chain, the DNA, RNA and phospholipids are exposed. This protects mitochondria from oxidative ROS stress, ensuring good cell health and, as a result, good organ health.
Soy spermidine protects brain cells
Maintaining mitochondrial and autophagic pathways for improved cognition with spermidine supplementation is crucial.
Soy spermidine has positive effects in older people suffering from dementia.
Soy spermidine protects brain cells and the brain as a whole from oxidative cell stress, nitrosative stress and toxic stress by increasing HPA activity.
Soy spermidine plays a role in synaptic transmission and synaptic plasticity, both of which are fundamental to learning and memory.
The age-related loss of memory can be stopped by supplementation with natural spermidine.
Miranka Wirth. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)—study protocol for a randomized controlled trial.
Pekar, T., Bruckner, K., Pauschenwein-Frantsich, S. et al. The positive effect of spermidine in older adults suffering from dementia. Wien Klin Wochenschr 133, 484–491 (2021).
The results of a study by Thomas Pekar show a clear correlation between the intake of spermidine and improvement of cognitive abilities in people with mild or moderate dementia in those who were given a higher dosage of spermidine. The best effects were seen for those affected by mild dementia. In contrast, those with a lower supplementation of spermidine showed no change or declined cognitive abilities.
Further studies indicated that spermidine potentially helps to induce the degradation of proteins linked to dementia and Alzheimer’s disease. For example, a study published in “Neurobiology of Aging” showed that the accumulation of beta-amyloid, a protein linked to Alzheimer’s disease, is reduced in the brains of mice.
Verabreichung der natürlichen Substanz Spermidin stoppt Demenz (Supplementation with the natural substance spermidine stops dementia). Freie Universität Berlin, September 1st 2013, accessed September 4th 2013.
Gupta VK, ScheunemannL, EisenbergT, MertelS, BhukelA, Koemans TS, et al. Restoring polyamines protects from age-induced memory impairment in an autophagy-dependent manner. Nat Neurosci. 2013;16(10):1453–60.
Hofer SJ, LiangY, ZimmermannA, et al. Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging. Autophagy. 2021;17(8):2037-2039.
LiangY, Piao C, BeuschelCB, et al. eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. Cell Rep. 2021;35(2):108941.
Schroeder S, Hofer SJ, ZimmermannA, et al. Dietary spermidine improves cognitive function. Cell Rep. 2021;35(2):108985.
Wirth M, Benson G, Schwarz C, Köbe T, Grittner U, Schmitz D, et al. The effect of spermidine on memory performance in older adults at risk for dementia: a randomized controlled trial. Cortex. 2018;109: 181–8.
The important role of soy spermidine in cell health as a “growth factor”
“A cell is the simplest unit we know, that definitely exhibits the characteristics of life. Therefore, a cell can be seen as “life’s atom” (Paul Nurse). Proteins are of utter importance within the cell. From proteins, all cell matter is built and proteins in deed the molecules of life.
Spermidine is present in all living organisms and in all types of cells and is closely linked to cellular growth, production of nucleic acids and proteins or membrane stabilisation.
Polyamines influence chromatin structure and are involved in gene regulation, because polyamines – as positively charged cations- will bind to DNA and stimulate deacetylation of histone proteins. Transcription is controlled through histone proteins.
An increase in the rate of metabolism also sees an increase in the amount of spermidine in an organism. Likewise, when metabolism slows down, the amount of spermidine also decreases. In addition, the concentration of spermidine is age-related and gets lower with increasing age.
There are natural situations in which the spermidine concentration increases: growth, pregnancy, repair of muscle cells after vigorous physical exercise and the regeneration of red blood cells after blood loss or anaemia.
Kazuei Igarashi, Keiko Kashiwagi: Modulation of cellular function by polyamines. In: The International Journal of Biochemistry & Cell Biology. Band 42, 2010, S. 39.
Mandal, A. Mandal, H. E. Johansson, A. V. Orjalo, M. H. Park: Depletion of cellular polyamines, spermidine and spermine, causes a total arrest in translation and growth in mammalian cells.In: Proceedings of the National Academy of Sciences.Band 110, 2013, S. 2169.
Spermidine increases the overall level of protein synthesis 1.5 to 2.0-fold
Soy spermidine plays an important part in the stimulation of protein synthesis.
Spermidine enhances the ability to synthesise RNA, is involved in the regulation at the level of genome transcription and stabilises proteins at translational level.
Proteins are produced in ribosomes, which are macromolecular protein factories.
The role of ribosomes in biosynthesis within the cell is to chemically link amino acids – there are 20 different naturally occurring amino acid building blocks- using peptide bonds to form a linear polypeptide chain which typically consists of several hundred amino acids. Protein synthesis is a step-by-step process in which ribosomes start production at one end of the polypeptide chain and finish at the other end.
For a protein to become active, the polypeptide chain first has to be “folded” into a particular three-dimensional pattern. This maturation process is complex and fascinating at the same time and has been the focus of generations of scientists. It is all down to interactions between the amino acids within the polypeptide chain, some of which happen within seconds whereas others may take minutes.
After amino acids are linked, the newly formed polypeptide chain has to pass through a narrow tunnel inside the ribosome before reaching the surface of this molecular machine. It is here, that the protein folding process takes place. Folding is a very complex process prone to errors leading to “misfolded” proteins which are either non-functional or, in the worst case, toxic to the cell.
Dr Madl (born in 1980), of Graz, is a structural biologist and particularly interested in signal transduction (cell signalling) (biomolecular NMR spectroscopy). Signal transduction is an essential process in all organisms and most proteins involved in this process are not folded. Malfunctioning proteins are the cause of many diseases and are also linked to ageing.
To counteract these problems, the cell possesses an arsenal of molecular chaperones, making up approximately 10 percent of all cellular proteins. Chaperones bind to and protect newly synthesised proteins until they have fully established their three-dimensional structure. They prevent unwanted protein aggregation and the synthesis of “mis-folded” proteins.
Spermidine has the ability to bind to DNA, RNA and various different protein molecules and is involved in a range of cellular processes such as transcription, RNA modification, protein synthesis and modulation of enzyme activity. According to some estimates, a very high percentage of polyamines are bound to nucleic acids, proteins and other negatively charged molecules through ionic interactions.
In summary, soy spermidine is involved in protein synthesis by boosting the binding of mRNA to ribosomes and autophagy, which makes amino acids available again after amino acid recycling and which are needed for protein synthesis.
A healthy heart
Soy spermidine has cardioprotective effects: it stabilises mitochondrial functioning, has anti-inflammatory properties, stopps ageing processes in stem cells and thereby reduces the incidence of cardiovascular mortality.
Supplementing with spermidine induces autophagy and prevents ageing of the heart.
Activation of autophagy through nutritional or pharmacological intervention slows down the process of cardiovascular ageing and promotes longevity.
A healthy sleep
Soy spermidine also influences our sleeping patterns. Those with an inadequate intake of spermidine have a delayed circadian rhythm.
Supplementing with spermidine can improve the sleep/wake cycle.
Regeneration of cartilage and intervertebral discs
Soy spermidine has protective and regenerative effects on joint cartilage and intervertebral discs. Spermidine normalises dysregulated autophagy and spermidine synthesis in aged and osteoarthritic cartilage cells.
Beautiful hair and skin
Soy spermidine improves complexion and functional properties of skin, hair and nails.
Soy spermidine promotes growth and regeneration of skin, hair and nails because it stimulates skin cells and skin appendages and counteracts skin ageing. Spermidine has been shown to be highly activating for healthy human skin fibroblasts and this was also accompanied by an anti-ageing effect.
Soy spermidine acts as an anti-inflammatory in acute and chronic inflammations; this is due to its antioxidative and lysosomal stabilising properties. Skin, hair and nails also benefit.
A diet rich in spermidine may protect from cancer
Epidemiological analysis and intervention studies have shown that not only life style choices but also dietary preferences and habits contribute to inhibit age-related diseases and senescence.
For example, eating more soybeans or soybean by-products is linked to a lower incidence of cardiovascular disease and malignant diseases such as breast or colon cancer.
Results indicate that substances in these foods play an important role in reducing the incidence of age-related pathologies.
Anti-oxidative polyphenols are substances which are thought to be candidates to be important for prolonged life expectancy. Genistein is an isoflavone found in soybeans and, being a natural estrogen receptor modulator, involved in prevention of osteoporosis. Genistein also significantly reduces the risk of breast and prostate cancer (https://mediatum.ub.tum.de/doc/603761/603761.pdf).
Soy spermidine lowers the level of insulin and reduces the risk of diabetes and obesity
Spermidine is involved in translation of insulin mRNA.
Spermidine is a known insulin sensitising agent and potentially delays the onset of or even prevent insulin-dependent diabetes.
There is some evidence that soy spermidine may lower the level of insulin. Insulin is a hormone which is produced by the pancreas and regulates the concentration of blood sugar. High concentrations of insulin are linked to a higher risk of diseases such as diabetes and obesity.
Several studies in animals and human cells have shown that spermidine positively influences the concentration of insulin. A study in mice has shown that supplementing with spermidine reduced insulin resistance and improved glucose metabolism. Another study showed that spermidine lowered the level of insulin in human cells by improving insulin secretion and insulin sensitivity.
Source: Oka T, Ohtani M, Suzuki J. [Identification of novel molecules regulating differentiation and hormone secretion and clarification of their functional mechanisms in pancreatic endocrine cells]. Yakugaku Zasshi. 2010 Mar;130(3):377-88. Japanese. doi: 10.1248/yakushi.130.377. PMID: 20190522.