Spermidine And Its Effects On Human Health And Wellbeing

In 1677, Antony Van Leeuwenhoek, a modestly educated Dutchman who was an unassuming textile business owner, peered through the carefully crafted high-power lens of his microscope and made a startling discovery. Endlessly curious, Leeuwenhoek had already made a number of ground-breaking discoveries using his self-crafted lenses, including the existence of single-celled animals and plants, as well as bacteria.

But on this day in 1678, at the urging of colleagues, he rather reluctantly decided to place a sample of his own semen under the lens and was astonished to see tiny, wiggling “animalcules” as he termed them, swimming about under his gaze. A year later, in 1679, Leeuwenhoek discovered the presence of microscopic crystals in semen.

But it was not until 1888 that the name “spermine” was given to these crystals and it took until 1926 for the correct chemical structure to be identified and for this compound and others like it, termed the polyamines, to be isolated from microorganisms, animal organs, and plants. Chemically, polyamines are a group of small molecules with two or more amino groups within their structure.

Spermidine, like all polyamines, is important in cell division and growth. These compounds are just beginning to reveal their multiple benefits, with spermidine emerging as a star on the forefront of new therapies and preventatives for aging, cognitive decline, diabetes, cancer and more.

Let’s get a closer look at the specific ways in which spermidine influences human health. Then we will look at what foods contain spermidine, how diet alone is not apt to give you enough of this important compound, especially as you age, and then what to look for when considering spermidine supplementation.

Because spermidine has a positive effect on so many different health conditions, we would expect to find some underlying biological pathways which might explain this. Current research points to three main ways in which spermidine seems to exert its powerful effects across so many domains: autophagy, anti-inflammatory actions, and as a caloric restriction mimicry molecule...

Spermidine And Autophagy

First of all, let’s get a look at autophagy. The term itself is derived from the Ancient Greek αὐτόφαγος autóphagos,. The first, "autó", means self, and “phagos” means to eat. So literally, the term means self-eating. As body cells go through their lifespans, they accumulate cellular debris, including old, damaged and misshapen, or otherwise abnormal proteins. Autophagy is a naturally occurring, orderly process that removes these damaged or dysfunctional components.

Although four different forms of autophagy have been identified, the most researched and well-understood type is macroautophagy, in which damaged cellular components are isolated and then walled-off by double membrane vesicles within the cell known as autophagosomes. After the autophagosomes have collected the damaged components, they fuse with an available lysosome, a membrane-bound organelle within the cell that contains hydrolytic enzymes and can break down many different kinds of biomolecules. A reduction in autophagy has been linked to many of the diseases related to aging. Autophagy is the most important mechanism for the rejuvenation of critical parts of the cell and for this reason has enormous anti-aging potential with its potential to delay age-related disease and death.

Spermidine is an autophagy activator and does so primarily by inhibiting a group of enzymes known as acetyltransferases. These enzymes, particularly a group identified as the histone acetyltransferases, are known as the “workhorses of the epigenome” and have a very large role in the epigenetic regulation of actual gene expression.

Spermidine As An Anti-Inflammatory

With aging comes a seemingly inevitable increase in chronic inflammation. Polyamine levels, including spermidine, increase during inflammation and work to stimulate the production of anti-inflammatory cytokines, while at the same time decreasing the production of pro-inflammatory ones. Cytokines are small proteins that are active in immune responses and signal the movement of cells to the sites of inflammation, infection, or trauma. Recent research suggests that spermidine also augments the anti-inflammatory properties of macrophages, specialized immune cells that work to detect and destroy bacteria and other harmful organisms. 

Spermidine As A Calorie Restriction Mimetic

Calorie restriction and various fasting regimens are among the very few proven lifestyle interventions that unequivocally extend life and improve health across many organisms, including rodent models as well as non-human primates. But as much as intermittent fasting has become popular in many health and wellness circles over the last few years, the vast majority of people are unwilling or unable to drastically change the way they eat, especially for an extended period of time.

Compounds that mimic the effects of calorie restriction, known as calorie restriction mimetics or CRMs, are attractive strategies. Spermidine definitely fits the definition of a CRM and is emerging as a leading contender for this role. Although many of the benefits of both fasting and calorie restriction can presumably be attributed to an increase in autophagy, there seem to be mechanisms outside of autophagy to explain spermidine’s positive effect on aging. These include the direct antioxidant effects of spermidine itself, as well as metabolic effects on both arginine bioavailability and nitric oxide production. Arginine is an amino acid used in the biosynthesis of proteins and nitric oxide induces vasodilation, the relaxation of the inner muscle lining of the blood vessels, causing them to widen and improve circulation.

Spermidine And Its Role In Health And Well-Being

Now that we have examined spermidine’s roles as an autophagy activator, an anti-inflammatory, and as a calorie restriction mimetic, let’s look a bit closer at spermidine’s effects on aging, cognitive decline, and cancer, arguably three of the most vexing and costly health problems that face us as human beings. Plus we will take a look at research which is showing promise that spermidine could be an effective antiviral, even against SARS-CoV-2 infection.

Spermidine And Aging
Research has shown that supplemented spermidine can extend the life span of many model organisms including yeast, nematodes, fruit flies, and rodents. There is also recent data that suggests an increased dietary supply of spermidine results in a reduction, not only in overall human mortality, but in cardiovascular and cancer-related deaths as well.

Spermidine And Cognition
SmartAge, the first human trial of spermidine’s effect on neurodegeneration, was a randomized, double-blind, placebo-controlled study carried out by the Charitè Universitätsmedizin in Berlin, initiated in 2018 when the European Union ruled the first spermidine-rich plant extract to be legally available.

The results of the three-month trial phase, in which a group of elderly participants with cognitive decline received the spermidine-rich plant extract or got a placebo, were impressive. The participants were assessed on memory at the beginning and end of the three-month trial. The results were positive, even for the short time span of the trial, with the participants taking the spermidine-rich extract showing memory improvement, while the placebo controls showed no change in their memory performance.

Spermidine And Cancer
Because of their role in cell proliferation and growth, polyamines were always promising candidates for cancer research. Polyamine metabolism disturbances have been observed in many types of cancer, including breast, lung, colon, prostate, and skin cancers.

As spermidine is a caloric restriction “mimicker” as well as an autophagy activator, spermidine has multiple pathways by which to affect tumor growth as well as prevention. Research shows that with an increase in spermidine intake, all-cause mortality (deaths from any cause, including cancer) is reduced.

Spermidine As An Anti-Viral Therapeutic
In a very promising pre-print study, investigators showed that SARS-CoV-2 infection limits autophagy by interfering with multiple metabolic pathways and that compounds, including spermidine, substantially reduce SARS-CoV-2 propagation in vitro. This is a very promising development and paves the way for more research in humans on spermidine’s effectiveness as an antiviral therapeutic.

Why Spermidine Supplementation Is Key

By now, you’ve probably got a fairly good picture of the positive effects spermidine has across a wide variety of the body’s biological systems. There is even research showing that spermidine is effective in promoting hair growth and resistance in human subjects. While hair loss and thinning is certainly not among the most worrisome human health problems, it does cause a great amount of emotional suffering for many people, so this is good news. Spermidine works by boosting keratin production, so it affects not only hair growth and health but is good for your nails as well.

You are capable of synthesizing spermidine via your microbiome in the large intestine, but the amounts produced are apt to decrease considerably as you age. Humans produce about 66 percent of the total spermidine present in the body, with the remainder coming from foods. Spermidine is present in foods such as soybeans, wheat germ, aged cheese and mushrooms, but the effect of ingesting these foods on actual blood levels of spermidine are quite variable among individuals.

Perhaps the most attractive feature of spermidine that makes it a wonderful candidate for supplementation is its extremely low toxicity profile combined with its strong efficacy. One of the things to look for in a supplement is the actual amount of spermidine present in the product. Most so-called spermidine supplements are actually synthetic spermidine. This synthetic product is usually added to wheat germ powder and contains a very low dose of spermidine, only 0.1% spermidine out of 800 mg total.

Here at Nutriop Longevity, our Nutriop® Pure-Spermidine is completely natural, as it’s derived from wheat germ. Each 1 gram serving (2 caps) contains 1%, i.e. 10 mg, of pure spermidine in contrast to most synthetic products containing less than 0.1% pure spermidine. To get the highest bioavailability, you should plan to take your spermidine with meals, typically your two largest meals of the day.

You can find more information on our high potency spermidine supplement here. Taken just twice daily with meals, spermidine supplementation will help you to begin taking advantage of this powerful compound’s anti-aging, anti-inflammatory, anti-viral, and neuroprotective effects.

Antony Van Leeuwenhoek would be pleased!

References:

1. Pietrocola, F., Lachkar, S., Enot, D. et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ 22, 509–516 (2015). https://doi.org/10.1038/cdd.2014.215

2. Minois N: Molecular Basis of the ‘Anti-Aging' Effect of Spermidine and Other Natural Polyamines - A Mini-Review. Gerontology 2014;60:319-326. https://doi.org/10.1159/000356748

3. Rui Liu, Xiaolei Li, Hui Ma, Qian Yang, Qianwen Shang, Lin Song et al. Spermidine endows macrophages anti-inflammatory properties by inducing mitochondrial superoxide-dependent AMPK activation, Hif-1α upregulation and autophagy. Free Radical Biology and Medicine, Volume 161, 2020, Pages 339-350, https://doi.org/10.1016/j.freeradbiomed.2020.10.029.

4. Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. 2018. Spermidine in health and disease. Science 359, Issue 6374. DOI: 10.1126/science.aan2788

5. Madeo, F., Carmona-Gutierrez, D., Kepp, O., & Kroemer, G. (2018). Spermidine delays aging in humans. Aging, 10(8), 2209–2211. https://doi.org/10.18632/aging.101517

6. Nowotarski, S., Woster, P., & Casero, R. (2013). Polyamines and cancer: Implications for chemotherapy and chemoprevention. Expert Reviews in Molecular Medicine, 15, E3. doi:10.1017/erm.2013.3

7. Wirth, M., Benson, G., Schwarz, C., Köbe, T.,  Grittner, U. et al. 2018. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial, Cortex, 109, pp 181-188, https://doi.org/10.1016/j.cortex.2018.09.014.

8. Kiechl, S., Pechlaner, R.,  Willeit, P., Notdurfter, M., Paulweber, B., Willeit, K. 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, https://doi.org/10.1093/ajcn/nqy102

9. Gassen, N.C., Papies, J., Bajaj, T., Dethloff, F., Emanuel, J. et al. Analysis of SARS-CoV-2 controlled autophagy reveals spermidine, MK-2206, and niclosamide as putative antiviral therapeutics. bioRxiv 2020.04.15.997254; doi: https://doi.org/10.1101/2020.04.15.997254

10. Rinaldi, F., Marzani, B., Pinto, D., & Ramot, Y. A spermidine-based nutritional supplement prolongs the anagen phase of hair follicles in humans: a randomized, placebo-controlled, double-blind study Dermatol Pract Concept 2017;7(4):17-21. DOI: https://doi.org/10.5826/dpc.0704a05