Enhancing Sleep with Spermidine: A Scientific Perspective

Q: What is spermidine?

Spermidine is a powerful polyamine that promotes autophagy , the body’s cellular “clean-up” process, and inhibits 9 of the 12 scientifically identified root causes of aging, known as the “Hallmarks of Aging.” While two-thirds of the body’s spermidine is produced by the gut and body tissues, the remaining third comes from food. As we age, natural spermidine production declines, so maintaining youthful levels requires external sources, either from spermidine-rich foods or supplements like Primeadine.

Oct 17, 2024

By Georgia Pilling

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Sleep and brain health | Oxford Healthspan

In our rapidly evolving world, securing quality sleep and maintaining a balanced daily routine have become increasingly challenging yet remain essential for overall well-being. Recent scientific research has illuminated the potential of spermidine, a naturally-occurring polyamine, in promoting better sleep and regulating our internal clock. Here we present the scientific insights behind spermidine's benefits for sleep and circadian rhythm (your internal body clock) regulation, offering a comprehensive look at its mechanisms and potential applications.

Understanding Spermidine

Spermidine is a polyamine found in living things, playing crucial roles in various cellular processes including growth, proliferation, and autophagy - the body's vital cellular "clean up" and recycling process. This compound is also naturally present in foods such as wheat germ, soybeans, aged cheese, and mushrooms. As we age, our ability to produce and maintain adequate levels of spermidine diminishes, which has garnered significant attention for its potential benefits for health and longevity. Research suggests that spermidine supplementation may have a positive impact on various aspects of aging, including sleep quality and circadian rhythm.

The Critical Role of Sleep as we Age

The importance of adequate, high-quality sleep for physical and mental health, as well as overall longevity, cannot be overstated. As individuals progress through the aging process, they often experience shifts in both the quantity and quality of their sleep patterns. These changes are largely attributed to the gradual decline in the efficiency of our circadian rhythms. For many older adults, these alterations in sleep patterns can manifest in several ways, including:

Earlier onset of fatigue and correspondingly earlier wake times
Increased frequency of middle-of-the-night awakenings
Reduced ability to adapt to changes in sleep routines
Heightened feelings of fatigue during daytime hours

Research indicates that a significant proportion of the elderly population battle with persistent sleep-related issues, with around 50% of older adults struggling to fall and stay asleep, substantially impacting overall quality of life [1]. While it's natural for your sleep pattern to evolve over time, it's important to understand that feeling the need to sleep less or frequent sleep disturbances are not inevitable consequences of aging. In fact, many of these sleep-related challenges can be addressed and potentially prevented with appropriate interventions and lifestyle adjustments.

Evidence of Spermidine's Impact on Sleep

Bidirectional Relationship: Spermidine and the Circadian Rhythm

Substantial evidence suggests that spermidine plays a positive role in maintaining the circadian rhythm as we age. Research published in Cell Metabolism has revealed a bidirectional relationship between circadian clocks and polyamine biosynthesis, showing that spermidine supplementation in aged mice helped maintain a more regular circadian rhythm, similar to that of younger mice [3]. This impactful study suggests that the age-related decline in polyamine levels, including spermidine, may contribute to circadian rhythm disruptions commonly observed in older individuals. These findings not only indicate that spermidine could potentially mitigate age-related changes in sleep patterns and circadian function but also open up new possibilities for nutritional interventions to address sleep disorders.

Moreover, anecdotal evidence from individuals taking spermidine supplements, such as Primeadine, has been very encouraging. For instance, a circadian experiment conducted by gerontologist Zora Benhamou using Primeadine yielded positive results, substantiated by a number of customer testimonials commenting on improved sleep.

Pro tip: If you take Primeadine and haven't noticed an impact on your sleep yet, try taking it with your last meal of the day, or just before bedtime if you can tolerate it on an empty stomach. If you track your sleep with a wearable tracking device, you may notice taking Primeadine before bed improves your Deep Sleep and HRV scores.

As research in this field progresses, spermidine supplementation may emerge as a valuable tool in supporting healthy sleep patterns and circadian rhythms, particularly in aging populations.

Why Does Spermidine Help with Sleep?

The Role of Autophagy in Circadian Function

Autophagy, the body's cellular 'housekeeping' process, plays a crucial role in maintaining circadian rhythms and sleep-wake cycles. Research has shown that there is a bidirectional relationship between autophagy and circadian rhythms, with each process influencing the other [4,5]. Autophagy exhibits a circadian rhythm itself, peaking during the sleep phase, which suggests its importance in cellular repair and maintenance during rest. This process is therefore thought to contribute to the regulation of our molecular clock. In the cardiovascular system, for example, the temporal orchestration of circadian autophagy is critical for maintaining normal cardiac function [4]. Moreover, studies have demonstrated that disruption of autophagy can lead to negative alterations in circadian behaviours and sleep patterns [6].

Spermidine, a potent inducer of autophagy, may contribute to stable sleep cycles through this mechanism. By promoting autophagy, spermidine could potentially help maintain the optimal functioning of circadian clocks and sleep-regulating neurons (brain cells), thereby supporting more consistent and restorative sleep patterns.

Inflammation and Sleep Quality

Chronic inflammation has been identified as a significant factor in sleep disturbances, contributing to various sleep disorders and poor sleep quality [7]. Research has shown that elevated levels of pro-inflammatory cytokines can lead to fragmented sleep, low sleep quality, and alterations in sleeping patterns. Conversely, sleep deprivation itself can exacerbate inflammation, creating a vicious cycle [8]. This bidirectional relationship between inflammation and sleep disruption highlights the importance of anti-inflammatory interventions in improving sleep quality [4].

Spermidine has demonstrated significant anti-inflammatory properties. Studies have shown that spermidine effectively reduces inflammatory markers in the body. By mitigating inflammation across the body, spermidine may contribute to better sleep quality and more regular sleep patterns. While more research is needed to fully understand this as a mechanism, the anti-inflammatory effects of spermidine present a promising avenue for addressing sleep disturbances associated with inflammation. These findings suggest that incorporating spermidine into one's diet or through supplementation could potentially serve as a natural approach to improving sleep quality by modulating inflammatory processes.

How to Incorporate Spermidine into Your Routine

Incorporating spermidine into your daily routine can be achieved through dietary sources and supplements:

Diet: Consume foods rich in spermidine, such as wheat germ, soy products, aged cheese, and mushrooms.
Supplements: Spermidine supplements, like food derived spermidine supplement Primeadine®, offer a convenient way to ensure adequate intake, especially if dietary sources are insufficient.
Consistency: Regular intake of spermidine is essential to experience its full benefits for sleep and circadian regulation.

Conclusion

Spermidine emerges as a potent compound in the quest for better sleep and a well-regulated circadian rhythm, particularly as we age. By promoting autophagy, reducing inflammation, and directly influencing the body's internal clock, spermidine could offer a multifaceted approach to improving sleep quality and overall health. With its scientifically backed benefits, spermidine might be the key to unlocking restful nights and a balanced daily rhythm, potentially mitigating age-related sleep issues and enhancing overall quality of life.

References

[1] Tatineny P, Shafi F, Gohar A, Bhat A. Sleep in the Elderly. Mo Med. 2020 Sep-Oct;117(5):490-495. PMID: 33311760; PMCID: PMC7723148.

[2] Madeo, F., Eisenberg, T., Pietrocola, F., & Kroemer, G. (2018). Spermidine in health and disease. Science, 359(6374), eaan2788.

[3] 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

[4] Ma D, Li S, Molusky MM, Lin JD. Circadian autophagy rhythm: a link between clock and metabolism? Trends Endocrinol Metab. 2012 Jul;23(7):319-25. doi: 10.1016/j.tem.2012.03.004. Epub 2012 Apr 18. PMID: 22520961; PMCID: PMC3389582.

[5] Wang X, Xu Z, Cai Y, Zeng S, Peng B, Ren X, Yan Y, Gong Z. Rheostatic Balance of Circadian Rhythm and Autophagy in Metabolism and Disease. Front Cell Dev Biol. 2020 Nov 24;8:616434. doi: 10.3389/fcell.2020.616434. PMID: 33330516; PMCID: PMC7732583.

[6] Prakash P, Nambiar A, Sheeba V, Manjithaya R. Restoration of Sleep and Circadian Behavior by Autophagy Modulation in Huntington's Disease. J Neurosci. 2023 Jun 28;43(26):4907-4929. doi: 10.1523/JNEUROSCI.1765-22.2023.

[7] Irwin MR. Sleep disruption induces activation of inflammation and heightens risk for infectious disease: Role of impairments in thermoregulation and elevated ambient temperature. Temperature (Austin). 2022 Aug 21;10(2):198-234. doi: 10.1080/23328940.2022.2109932. PMID: 37332305; PMCID: PMC10274531.

[8] Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab. 2010 Oct;24(5):775-84. doi: 10.1016/j.beem.2010.08.014. PMID: 21112025; PMCID: PMC3548567.

Georgia Pilling, BSc, Physiological Sciences (Newcastle University); MRes, Neuroscience (Newcastle University)

Georgia Pilling is a researcher interested in enhancing human longevity by optimizing physiological health and cognitive function. She holds a Bachelor's degree in Physiological Sciences (BSc) and a Master of Research in Neuroscience (MRes) from Newcastle University. In her free time, Georgia enjoys practicing yoga, running, and experimenting with cooking.

FAQs

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What is spermidine?

Spermidine is a powerful polyamine that promotes autophagy, the body’s cellular “clean-up” process, and inhibits 9 of the 12 scientifically identified root causes of aging, known as the “Hallmarks of Aging.” While two-thirds of the body’s spermidine is produced by the gut and body tissues, the remaining third comes from food. As we age, natural spermidine production declines, so maintaining youthful levels requires external sources, either from spermidine-rich foods or supplements like Primeadine.

What are the benefits of spermidine?

Studies link higher levels of spermidine with longevity. Human trials show that food-derived spermidine supports cognition, heart health, hormonal balance, hair growth, collagen production, and nail strength, with potential benefits for fertility and circadian rhythm. These effects stem from spermidine's ability to trigger autophagy—the body's cell renewal process—and inhibit nine of the twelve "Hallmarks of Aging," including inflammation, stem cell and mitochondrial dysfunction, and gut imbalance. Clients also report deeper sleep, increased energy, gray hair reversal, improved skin, and better gut health. Read this blog post to learn 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.

What is the best spermidine dose to take?

The US FDA has not set a safe upper limit for food-derived spermidine, but the European Food Safety Authority considers up to 6 mg safe. Most studies use a daily dose of 1 mg of natural spermidine, along with spermine and putrescine, which are absent in synthetic versions. Synthetic spermidine has not been tested for human safety or efficacy.

Why is your spermidine supplement more expensive compared to other products I see on the internet?

We prioritize the highest quality, avoiding common additives like industrial seed oils, magnesium stearate, and talc often used in supplements. Unlike cheap synthetic spermidine often "cut" into products, we use food-derived spermidine sourced and manufactured in Japan under strict regulatory standards. Our products undergo rigorous third-party testing to ensure purity and effectiveness. This commitment to quality, like choosing the best ingredients for a child’s birthday cake, is our guiding philosophy.

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