Spermidine and the Gut-Brain Connection

Sep 28, 2023

By Georgia Pilling

Spermidine and the gut-brain connection | Oxford Healthspan

Spermidine and the Gut-Brain Axis: What's the Link?

Spermidine's Role in the Gut Microbiome

The human gut microbiome (the community of bacteria living in our gut) is unique to every individual and has many roles in regulating our immune system, metabolism, growth and general health. Spermidine, a natural polyamine, is believed to play an important role in gut microbiome regulation [1]. An intracellular spermidine pool is formed from synthesis in our gut microbiome and tissues, excretion, either from its precursor, another polyamine called putrescine, from the degradation of spermine, or absorbed directly from our diet.

Spermidine and the Brain

Spermidine has been shown to be important for not only gut health but also cognitive function. The recent link found between gut and brain health, termed 'the gut-brain axis' [2], confirms a bidirectional cross-over between the enteric and central nervous systems - with each intrinsically reliant on the other. This means the brain may influence intestinal activities, for instance immune cells, and the gut may influence cognition and general mood. It is therefore now known that to maximize mental health and wellbeing we must maintain a healthy gut microbiome. And spermidine's importance to this gut-brain connection is becoming increasingly apparent, with low levels negatively affecting health, wellbeing and longevity. As we age our intracellular spermidine pool significantly reduces as we become less able to synthesize it ourselves, having negative implications on the gut and in turn on brain health.

Spermidine and Gut Dysbiosis

Aging is defined as the progressive loss of physiological integrity outlined by the 12 proposed 'Hallmarks of aging' [3], where physiological function and vulnerability to death progressively increase as a result. With regards to the gut-brain axis, preventative measures against the hallmark, 'gut microbial dysbiosis' [4], are important for not only gut health but also to prevent cognitive decline.

In normal, healthy conditions, our gut microbiome consists of a diverse collection of microbes that exist in equilibrium. This complex ecosystem within us is essential for immune regulation, efficient digestion, metabolic processes, hormonal regulation and overall health. Optimal gut health relies on gut bacterial diversity in the microbiome, a balance between commensals, potentially harmful bacteria, and functional capacity. When an imbalance or disruption to the gut microbiome occurs, this is known as gut dysbiosis. Novel research suggests gut dysbiosis can negatively impact mood through the gut-brain axis. As we age we become more vulnerable to this, therefore being conscious of gut health through diet and beneficial pre- and probiotics appears essential to prevent dysbiosis and in turn ensure a happy and healthy emotional state.

Spermidine and Mood

Gut microbiota in the small intestine are important for determining polyamine levels [5]. Spermidine, spermine, and putrescine, the most abundant polyamines found in living organisms, are essential in a variety of cellular processes important for maintaining good health and longevity. If a dysregulation in gut microbiota occurs, then polyamine levels may decrease, and this is a characterizing feature of a short healthspan. Accumulating research points to the importance of the polyamine system in preventing the onset of mental disorders [6], with many polyamines and their precursors exhibiting antidepressant and anxiety reducing effects.

Spermidine and SAM-E

There is a growing interest in SAM-E (S-adenosylmethionine), a metabolite present in all living cells, and its positive effect on mental wellbeing [7]. SAM-E initially gained recognition as an alternative to anti-depressant drugs, proving effective for relieving depression devoid of the negative side effects associated with the drugs currently in circulation. This metabolite not only boosts synthesis of positive brain chemicals but has been further proven to promote synthesis of vital functional compounds. Thus, it is thought to be important for preventing or reversing aging disorders. Interestingly, it plays a key role in synthesizing polyamines in the gut, such as spermidine. Given the positive impact mentioned above of maintaining spermidine levels as we age, ]. Although further research is required to consolidate this, SAM-E is a promising novel therapeutic for anti-aging, anti-disease and strengthening cognition.

Spermidine and 'Leaky Gut'

Spermidine also plays a key part in maintaining gut epithelial barrier integrity. In a healthy gut, the lining of the gut wall is composed of tight junctions between adjacent cells which act as a barrier to harmful substances while selectively allowing absorption of key nutrients into our bloodstream. In older adults with poor health, a condition known as 'leaky gut' [8] can occur, where this barrier becomes more porous than it should be. This increase in permeability compromises the selectivity of substances passing into the bloodstream, inappropriately activating the immune system and leading to a variety of health issues from digestive problems to neurological disorders. From research, spermidine can be beneficial in preventing this problem. Primarily, spermidine has been shown to promote autophagy, the cellular process of reusing and disposing of dysfunctional or old cell components, preserving the health of gut cells and maintaining tight junction integrity.

Research has further displayed spermidine's anti-inflammatory and anti-oxidative effects and, as chronic inflammation and harmful reactive oxygen species (ROS) can contribute to damage of gut epithelium, these properties may act as a protective mechanism for gut barrier function.

Finally, spermidine has been found to positively influence cell signaling pathways [9] associated with the gut wall as well as the composition of the gut microbiome. Both are involved in tight junction regulation, thus spermidine is useful in optimizing epithelial gut barrier function.

Spermidine and Inflammation

Beyond the gut epithelial barrier, the anti-inflammatory properties of spermidine are believed to have a positive effect on mood and overall cognitive function. Inflammation in the gut can cause an inappropriate immune signaling response, gut dysbiosis and, as mentioned, compromise gut barrier integrity - all of which may impact the brain via the gut-brain axis. For example, there is emerging evidence linking inflammation and the development of depression in individuals. As inflammation is one of the 12 hallmarks of aging, it is important to be aware of how to reduce and prevent inflammation and the negative knock-on effects it can cause. Notably, multiple studies have shown spermidine supplementation reduces harmful inflammation [10] by playing an integral part in immune response modulation, for example by upregulating anti-inflammatory macrophages. Additionally, healthier lifestyle and dietary choices are a beneficial way of preventing the onset of inflammation, in particular, by opting for foods rich in polyamines.

Spermidine and Autophagy: Brain Health and Sleep

The benefits of targeting the gut-brain axis don’t stop there. Do you struggle with getting enough sleep?

Getting sufficient, good quality sleep is absolutely key to healthy physical and mental wellbeing and overall longevity. As we age, often the duration and quality of our sleep changes. This is due to a negative change in the function of our 'internal body clock' (which dictates our sleep-wake cycle through daily cycles know as 'circadian rhythms'). In older adults, this can manifest as: a shift forward in sleep schedule (becoming fatigued in the afternoon and waking up earlier), waking up through the night, difficulty adjusting to changes in sleep schedule, and daytime drowsiness. It is estimated that between 40%-70% of older adults have chronic sleep issues [11], affecting their quality of life significantly. Although changes to sleep architecture are normal throughout lifespan, a decreased need for sleep and sleep disruption are not and thus can be prevented. Given spermidine supplementation has been shown to promote autophagy and autophagy occurs mainly at night in the overnight fasted state, used by the glymphatic system to repair and recycle brain cells, this is a promising therapeutic strategy of preventing the deterioration of our internal body clock. Although the exact mechanism for this is not fully understood, there is strong evidence for positive involvement of spermidine in improving circadian rhythm [12] as we age as it modulates 2 of the 8 clock genes that regulate our body clock. Furthermore, there have been encouraging results from those taking Primeadine - check out gerontologist and host of the Hack My Age podcast, Zora Benhamou's, circadian experiment taking Primeadine spermidine here.

Plant-Derived Spermidine Supplements

So how do you boost your polyamine levels and unlock these anti-aging effects for the gut and the brain?

Primeadine is a pure, wholly plant-derived Spermidine supplement - Primeadine Original is made from concentrated Japanese wheat germ extract and Primeadine GF from a unique blend of Okinawan chlorella, turmeric and "Shikuwasa" or citrus lime peel.

As it is food-derived, the spermidine is highly bioavailable. Primeadine Original contains other essential, naturally occurring polyamines - spermine and putrescine, while Primeadine GF contains putrescine, not spermine. The presence of these polyamines further works to accentuate spermidine production, creating a favorable polyamine recycling loop. Additionally, linking back to the importance of a healthy gut microbiome, Primeadine Original contains prebiotic fiber frutooligosaccharides (FOS) derived from beetroot; Primeadine GF includes chlorella which is a prebiotic in its own right. This acts as a food source for spermidine-producing bacteria, promoting their growth while maintaining a balanced microbiome. Taking spermidine supplements therefore helps to retain healthy polyamine levels in the body, supporting gut and brain health.

Written by Georgia Pilling, BSc Physiological Sciences; MA Student, Neuroscience.

Reference list:

[1] Tofalo R, Cocchi S, Suzzi G. Polyamines and Gut Microbiota. Front Nutr. 2019 Feb 25;6:16. doi: 10.3389/fnut.2019.00016. PMID: 30859104; PMCID: PMC6397830.

[2] Appleton J. The Gut-Brain Axis: Influence of Microbiota on Mood and Mental Health. Integr Med (Encinitas). 2018 Aug;17(4):28-32. PMID: 31043907; PMCID: PMC6469458.

[3] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349.

[4] Ragonnaud, E., Biragyn, A. Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun Ageing 18, 2 (2021). https://doi.org/10.1186/s12979-020-00213-w

[5] Tofalo R, Cocchi S and Suzzi G (2019) Polyamines and Gut Microbiota. Front. Nutr. 6:16. doi: 10.3389/fnut.2019.00016

[6] Fiori LM, Turecki G. Implication of the polyamine system in mental disorders. J Psychiatry Neurosci. 2008 Mar;33(2):102-10. PMID: 18330456; PMCID: PMC2265312.

[7] Cuomo A, Beccarini Crescenzi B, Bolognesi S, Goracci A, Koukouna D, Rossi R, Fagiolini A. S-Adenosylmethionine (SAMe) in major depressive disorder (MDD): a clinician-oriented systematic review. Ann Gen Psychiatry. 2020 Sep 5;19:50. doi: 10.1186/s12991-020-00298-z. PMID: 32939220; PMCID: PMC7487540.

[8] Ahmadi S, Wang S, Nagpal R, Wang B, Jain S, Razazan A, Mishra SP, Zhu X, Wang Z, Kavanagh K, Yadav H. A human-origin probiotic cocktail ameliorates aging-related leaky gut and inflammation via modulating the microbiota/taurine/tight junction axis. JCI Insight. 2020 May 7;5(9):e132055. doi: 10.1172/jci.insight.132055. PMID: 32302292; PMCID: PMC7253024.

[9] Ma L, Ni Y, Wang Z, Tu W, Ni L, Zhuge F, Zheng A, Hu L, Zhao Y, Zheng L, Fu Z. Spermidine improves gut barrier integrity and gut microbiota function in diet-induced obese mice. Gut Microbes. 2020 Nov 9;12(1):1-19. doi: 10.1080/19490976.2020.1832857. PMID: 33151120; PMCID: PMC7668533.

[10] Anna Niechcial, Marlene Schwarzfischer, Marcin Wawrzyniak, Kirstin Atrott, Andrea Laimbacher, Yasser Morsy, Egle Katkeviciute, Janine Häfliger, Patrick Westermann, Cezmi A Akdis, Michael Scharl, Marianne R Spalinger, Spermidine Ameliorates Colitis via Induction of Anti-Inflammatory Macrophages and Prevention of Intestinal Dysbiosis, Journal of Crohn's and Colitis, Volume 17, Issue 9, September 2023, Pages 1489–1503, https://doi.org/10.1093/ecco-jcc/jjad058

[11] Miner B, Kryger MH. Sleep in the Aging Population. Sleep Med Clin. 2017 Mar;12(1):31-38. doi: 10.1016/j.jsmc.2016.10.008. Epub 2016 Dec 20. PMID: 28159095; PMCID: PMC5300306.

[12] Zwighaft Z, Aviram R, Shalev M, Rousso-Noori L, Kraut-Cohen J, Golik M, Brandis A, Reinke H, Aharoni A, Kahana C, Asher G. Circadian Clock Control by Polyamine Levels through a Mechanism that Declines with Age. Cell Metab. 2015 Nov 3;22(5):874-85. doi: 10.1016/j.cmet.2015.09.011. Epub 2015 Oct 8. PMID: 26456331.

Georgia Pilling

Georgia Pilling has recently completed a degree in Physiological Science and is currently pursuing a Master of Research in Neuroscience at Newcastle University. Through her academic journey, she has formed a comprehensive understanding of underlying processes governing how our body functions, developing an interest in exploring methods to enhance these processes to improve longevity. Her specific area of intrigue is cognitive neuroscience, driven by a passion for uncovering ways individuals can optimize their brain function and overall mental well-being.

FAQs

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What is spermidine?

Spermidine is a vital, naturally-occurring molecule called a polyamine, which is a type of protein. It is known for inducing autophagy, the body's cellular "clean up" and recycling process, and targeting the root causes of aging.

We naturally produce spermidine when we are young, but this declines with age, making us much more reliant on food-derived sources of spermidine, like Primeadine.

What are the benefits of spermidine?

Human clinical trials using food-derived spermidine have shown it to support cognition and heart health, promote hormonal balance, improve hair growth and fullness (including eyelashes and brows), increase collagen synthesis, and strengthen nails.

Studies have correlated higher plant-derived spermidine levels with a longer life. They have also shown its potential in improving fertility and restoring sleep by regulating the body's internal clock (aka circadian rhythm).

Other benefits noticed by our clients include deeper, sounder sleep, gray hair reversal, enhanced energy levels, brighter, more supple skin, and improved gut health. Read our Reviews to find out more.

What makes Primeadine superior to other spermidine supplements?

While we can’t speak directly about the formulation of other spermidine products, here are some of the main differentiators of Primeadine®/Oxford Healthspan.

We source our raw materials from Japan, which is known for its Nobel Prize-winning scientific leadership on autophagy, or cell renewal. Japan has the most rigorous quality control and testing policies in the world, meaning our ingredients have the most advanced extraction process and meet the incredibly high standards of the Japan Health Food and Nutrition Food Association. They are tested for heavy metals, mold, fungi, and bacteria at the Japan Food Research Lab (JFRL), a third party independent testing lab.
Every single batch is tested for its amount of food-derived spermidine so we ensure it contains the minimum effective dose of 1mg stated on our labels.
Primeadine® is manufactured in Japan in an FDA-registered and -inspected facility with ISO22000 standards, the highest in food quality control. It is then encapsulated in an FDA cGMP facility in the USA and undergoes purity testing there as well at Eurofins or Delta.
Our capsules and tablets do not contain any synthetic ingredients, whereas other supplements typically contain magnesium stearate (of which circa 80% has hydrogenated fats in it; the supplement industry is not legally required to get rid of hydrogenated oils the way the processed food industry has been mandated by law to), shellac, talc and glycerin. Our products are all suitable for vegans. Learn more about our sourcing, quality, and testing standards.
The Primeadine® Original formulation includes a special type of prebiotic fiber, called FOS (fructooligosaccharide), that selectively feeds the friendly, spermidine-producing bacteria in the gut microbiome. The idea is to increase both supplemental, or 'exogenous' spermidine, as well as encourage your own body's natural ability to produce spermidine in your gut microbiome.
Primeadine® GF comes from a sub-strain of chlorella singled out from over 100 others because it alone contains a high level of spermidine and also contains putrescine, the precursor polyamine to both spermine and spermidine. Our chlorella is grown in the nutrient-abundant longevity islands of Okinawa, Japan, and exposed to sunlight to increase the chlorophyll and other nutrient content, such as vitamins D and K, which together help drive calcium to the bones. We combine the chlorella with two other anti-inflammatories and autophagy inducers, Okinawan turmeric and nobiletin (from Okinawan "Shikuwasa" citrus lime peel).
We do not use liposomes in Primeadine® because this is unnecessary for absorption and would prevent the benefits that happen when spermidine is exposed directly to the gut lining. There is no evidence that spermidine cannot be taken up by the cells on its own. Similar to amino acids, polyamines do not need a liposome to cross into the cell or to be taken up with epithelial cells. The process of creating a liposomal version also creates unnecessary expense.
We do not synthetically enrich our product with synthetic spermidine. Be wary of labels that say "wheat germ with spermidine" as this indicates that the wheat germ has been soaked in synthetic spermidine, thereby increasing the overall amount of spermidine but meaning it is no longer a natural source.
We do not use doses beyond what the European Food Safety Authority (EFSA) has mandated as safe for human consumption, which is 6mg daily. Please note that this is related to food-derived spermidine. Synthetic spermidine and synthetically enriched spermidine have never been tested in humans for safety or efficacy and are being sold without regulatory oversight.
We work closely with our scientific and clinical advisers at the University of Oxford and abroad, all of whom take our product and share it with their loved ones. Learn more about our scientific advisory board here.
We are also the only non-Japanese member of the Japan Autophagy Consortium, whose Senior Adviser is the 2016 Nobel Prize Winner in Medicine or Physiology, Prof Yoshimori Ohsumi, and whose Director is Prof Tamotsu Yoshimori, Osaka University. Prof Yoshimori conducted all of the mammalian research in autophagy that helped underpin Prof Ohsumi's work in yeast cells. Find out more about our story here.

Why is Primeadine more expensive than other spermidine supplements?

We take great care to use the highest quality ingredients available and to keep out the 'nasties' commonly found in the supplement manufacturing process. We take the same approach that we do when baking a birthday cake for our children: we use the highest quality ingredients - no industrial seed oils such as wheat germ oil that oxidizes rapidly and wreaks havoc in our cells, no magnesium stearate to make the powder flow faster through automated encapsulation equipment (approximately 80% of all magnesium stearate used as 'flow agents' contain hydrogenated industrial seed oils), and no talc to make the powder denser and fit more compactly into fewer capsules.
We also do not use synthetic spermidine, which is very cheap and often 'cut' into products stating they contain 'wheat germ with spermidine.'
We choose food-derived spermidine, sourced and manufactured in Japan, which has one of the strictest food and supplement regulatory regimens in the world. Our products undergo rigorous third party lab testing to ensure they are of the purest and most effective quality. Yes, it is more costly, just as the best cake ingredients for your child's birthday cake would be too. It's a choice and philosophy we wholeheartedly believe in and follow every step of the way.

What is the best spermidine dose to take?

To date, most studies have been conducted using a daily dose of 1mg of food-derived spermidine, which is the amount present in Primeadine.

The US FDA has not ruled on a safe upper limit for food-derived spermidine, but the European Union's European Food Safety Authority has deemed 6mg of supplemental food-derived spermidine to be the safe upper limit.

Synthetic spermidine has not been tested for safety in humans.

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