Polyamines, including spermidine, spermine and putrescine, are synthesized in every living cell and are contained in many foods. They have many physiological activities, such as antioxidant and anti-inflammatory properties, cell and gene protection, and autophagy activation. They also have multiple demonstrated applications for health and wellness, including healthy aging,1-4 cognitive health,5-7 hair health8,9 and hormonal health.10 In this article, we’re going to explore these benefits associated with the supplementation of polyamines (especially spermidine). Let’s start with aging.
Spermidine in Healthy Aging
To understand spermidine’s potential for healthy aging, we first need to understand it role in autophagy. Autophagy (pronounced “ah-TAH-fah-gee”) is the body’s process of breaking down old and damaged cell parts. This allows cells to disassemble junk parts and repurpose the salvageable components into new, usable cell parts, while discarding the unusable or unneeded parts. Autophagy helps eliminate cellular clutter, optimizing cellular performance. Furthermore, as a person ages, autophagy decreases, which can lead to a build-up of cellular junk parts and, in turn, cells that aren’t functioning at their best.11
Spermidine has been shown to increase autophagy.12-15 In a follow-up study of a cohort of 829 participants over 20 years, spermidine showed the strongest inverse relation with mortality among 146 nutrients investigated. This effect was dose-dependent, and the authors explain that spermidine effectively induced autophagy and can reduce the acetylation of histones, which are critical processes for cell homeostasis in aging. In this sense, a diet rich in spermidine, mainly from foods of vegetable origin, was associated with a decrease in the risk of all-cause mortality in the general community.16
Furthermore, spermidine can help with telomeres. In case you don’t already know telomeres are “sacrificial” DNA, some of which get removed from the end of each chromosome every time cell division takes place. When these telomeres have decreased to a critical length, cell division ceases, although cell senescence (aging) may continue for a time.17 In research18 on aged mice, six months of supplementation with spermidine in the drinking water protected against a decrease in telomere length. Furthermore, research19 has demonstrated that spermidine (from Miricell rice germ extract, Nutraland USA) lowered the rate at which telomeres were shortened in human cells. These results suggest that, in addition to autophagy, a reduction of telomere shortening is another mechanism of action whereby spermidine may positively impact the aging process.
Of course, maintaining healthy cellular function by impacting autophagy and telomere shortening has other benefits for human health and wellness.
Spermidine and Cognitive Health
Consider that memory function becomes less efficient with increasing age. In part, this is due to changes in the connections between nerve cells (neurons)—known as synaptic plasticity. Spermidine operates directly at synapses, allowing for an autophagy-dependent regulation of presynaptic specializations.20 The impact of this was demonstrated in human studies.
A three-month, multicentric, double-blind preliminary study21 focused on the effect of oral spermidine supplementation (1.9 mg or 3.3 mg, six days per week) on 85 older adults’ cognitive performance using memory tests. The results demonstrated a clear correlation between the intake of spermidine and the improvement in cognitive performance in the group treated with the higher spermidine dosage. The most substantial improvement in test performance was found in the group of subjects with mild dementia with an increase of 2.23 points (p= 0.026) in the mini mental state examination (MMSE) and 1.99 (p= 0.47) in phonematic fluidity.
Another three-month, randomized, placebo-controlled, double-blind Phase II a pilot trial22 evaluated the impact of spermidine supplementation (1.2 mg/day from a plant extract) on memory performance in 30 older adults at risk for the development of Alzheimer’s disease, but who were cognitively intact with subjective cognitive decline. Results were that memory performance was moderately enhanced in the spermidine group compared with placebo at the end of intervention. Mnemonic discrimination (i.e., the ability to differentiate between new and previously encountered stimuli, even when they are highly similar) improved in the spermidine-treated group with a medium effect size, with no effect in the placebo-treated group. In conclusion, this pilot trial demonstrated that supplementation with natural spermidine was associated with a positive impact on memory performance in older adults with subjective cognitive decline.
A human population study23 was conducted in which researchers evaluated possible correlations of dietary spermidine intake assessed from food frequency questionnaires with cognitive decline in 815 participants. Results were that spermidine intake correlated with memory scores and a reduction in cognitive impairment. When the participants were ranked into groups based on spermidine intake level (low, medium and high intake), the risk for cognitive impairment decreased across groups with greater improvements associated with higher spermidine intake. These findings meet the rules of evidence of causation, including a considerable strength and dose-response type of association, consistency in subgroups and sensitivity analysis.
Spermidine and Hair Health
In hair follicles, polyamines are important for normal hair growth. This was shown in a laboratory study24 using spermidine on human hair follicle epithelial stem cells. The study found that spermidine promoted hair shaft elongation and prolonged hair growth, and upregulated expression of the epithelial stem cell associated keratins. While this research was certainly interesting, two randomized, controlled human clinical studies were even more interesting.
A randomized, double blind, placebo-controlled clinical study25 with 60 men and women (aged 18-60 years) with telogen effluvium (stress-related hair loss) demonstrated that spermidine alone (0.5 mg) or spermidine in association with other nutrients (methionine 300 mg, vitamin C 90 mg, vitamin E 15 mg, pantothenic acid 9 mg, zinc 7.5 mg, polyphenols from red grape peels 5 mg, vitamin B6 2 mg, copper 1.25 mg, folic acid 300 mcg, biotin 50 mcg) helped to reduce significantly the clinical symptoms and the instrumental values related to the presence of telogen effluvium. This included a reduction in hair loss, an increase in hair stem diameter, and an increase in the anagen phase (hair growth phase when the hair follicle forms a new hair shaft).
The researchers concluded that “The statistical difference resulting from the comparison of the ‘active’ and the ‘placebo’ product is highly significant, since the placebo has not produced any changes in either the clinical, or the instrumental symptoms.”
Another randomized, double-blind, placebo-controlled trial26 in 100 healthy men and women found that the same combination of spermidine and other nutrients increased the number of anagen hair follicles after 90 days of treatment, accompanied by increased cellular proliferation and a decrease in apoptosis (cellular death of hair)—all significantly better when compared to the placebo group (P<0.0001). The hair pull test showed no loss of hair after six months in all patients receiving the spermidine supplement, while 68 percent of the subjects in the placebo group had hair loss with the pull test. An impressive outcome of this study is that, although the spermidine supplement was given for only 90 days, the effect was still evident at least three months later, as demonstrated by the negative pull test in the treatment group. The researchers concluded, “These preliminary results can serve as a proof of principle to the fact that oral spermidine can exert functional effects on human HFs (hair follicles) and further strengthen previous results that showed its effectiveness for the treatment of telogen effluvium.”
It should be noted that Nutraland USA won Nutrition Industry Executive’s New Ingredient Award (2023) in the personal care category for hair health.
Polyamines for Hormonal Health
This open-label pilot trial27 was designed to determine the impact of spermine and spermidine supplementation for 30 days on hormone levels of 15 otherwise healthy human subjects with no history of infertility or sexual dysfunction over a 60-day period. Results were meaningful changes in hormone levels in most subjects tested:
It should be noted that the decrease in estradiol at 30 days and subsequent increase in men at 60 days occurred after polyamine supplementation was discontinued, while the reverse was true for women after discontinuing supplementation. In conclusion, spermine and spermidine appear to support a trend toward hormone balance. Although the published study did not reveal the dosages of spermine/spermidine used, a close examination of researcher affiliation suggest that a product tested may have provided between 2.5-5 mg collectively of these polyamines.
Natural vs. Synthetic Spermidine
When used in dietary supplements, spermidine is available in naturally occurring forms and as synthetic spermidine trihydrochloride—but as with most nutraceuticals, the natural source is generally preferred over synthetic. One good reason is that synthetic spermidine does not come with the other polyamines that normally accompany spermidine in nature. This is significant since the presence of the other naturally occurring polyamines provides a recycling loop whereby the body can produce more spermidine, not just the amount given in the daily dose itself.28 The basis for this is that within mammalian cells, spermidine is generated from its precursor polyamine putrescine (which itself is generated from ornithine) or by oxidative degradation of spermine.29
Conclusions
Spermidine and other polyamines have many physiological activities. This includes applications for healthy aging, cognitive health, hair health and hormonal health. Furthermore, natural spermidine (e.g., from Miricell rice germ extract, Nutraland USA) is generally preferred over synthetic.VR
References
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4 Study Report for Nutraland: In vitro proliferative and telomere length analysis (TAT). LifeLength. January 17, 2023: 23 pgs.
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7 Schroeder S, Hofer SJ, Zimmermann A, et al. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr 13;35(2):108985.
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9 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 Oct 31;7(4):17-21.
10 Bendera R, Wilson LS. The Regulatory Effect of Biogenic Polyamines Spermine and Spermidine in Men and Women. Open Journal of Endocrine and Metabolic Diseases. 2019; 9(3): 35-48.
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16 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. Am J Clin Nutr. 2018; 108:371–80.
17 Bryan TM, Reddel RR. Telomerase, Immortality and Cancer. Today’s Life Science. 1996;8(1): 26-28.
18 Wirth A, Wolf B, Huang CK, Glage S, Hofer SJ, Bankstahl M, Bär C, Thum T, Kahl KG, Sigrist SJ, Madeo F, Bankstahl JP, Ponimaskin E. Novel aspects of age-protection by spermidine supplementation are associated with preserved telomere length. Geroscience. 2021 Apr;43(2):673-690.
19 Study Report for Nutraland: In vitro proliferative and telomere length analysis (TAT). LifeLength. January 17, 2023: 23 pgs.
20 Bhukel A, Madeo F, Sigrist SJ. Spermidine boosts autophagy to protect from synapse aging. Autophagy. 2017 Feb;13(2):444-445.
21 Pekar T, Bruckner K, Pauschenwein-Frantsich S, Gschaider A, Oppliger M, Willesberger J, Ungersbäck P, Wendzel A, Kremer A, Flak W, Wantke F, Jarisch R. The positive effect of spermidine in older adults suffering from dementia : First results of a 3-month trial. Wien Klin Wochenschr. 2021 May;133(9-10):484-491.
22 Wirth M, Benson G, Schwarz C, Köbe T, Grittner U, Schmitz D, Sigrist SJ, Bohlken J, Stekovic S, Madeo F, Flöel A. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex. 2018 Dec;109:181-188.
23 Schroeder S, Hofer SJ, Zimmermann A, et al. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr 13;35(2):108985.
24 Ramot Y, Tiede S, Bíró T, Abu Bakar MH, Sugawara K, Philpott MP, Harrison W, Pietilä M, Paus R. Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions. PLoS One. 2011;6(7):e22564.
25 Rinaldi F, Sorbellini E, Bezzola P, Marchioretto DI. Biogenina based food supplement: hair growth enhancer. NutraFood. 2003;2:1-7.
26 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 Oct 31;7(4):17-21.
27 Bendera R, Wilson LS. The Regulatory Effect of Biogenic Polyamines Spermine and Spermidine in Men and Women. Open Journal of Endocrine and Metabolic Diseases. 2019; 9(3): 35-48.
28 Kenny L. Food-derived vs. synthetic spermidine and dosage. January 17, 2003. Retrieved June 28, 2023 from https://oxfordhealthspan.com/blogs/aging-well/food-derived-vs-synthetic-spermidine-and-dosage#:~:text=While%20synthetic%20spermidine%20mimics%20the,such%20as%20spermine%20and%20putrescine.
29 Madeo F, Bauer MA, Carmona-Gutierrez D, Kroemer G. Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans? Autophagy. 2019 Jan;15(1):165-168.
Gene Bruno, MS, MHS, Professor Emeritus of Nutraceutical Science, is a writer, educator and a nutraceutical scientist with more than 45 years of experience educating natural product retailers and health care professionals and formulating natural products for dozens of dietary supplement companies. He has written articles on nutrition, herbal medicine, nutraceuticals and integrative health issues for trade, consumer magazines and peer-reviewed publications. Bruno also hosts “The Vitamin Professor Podcast” brought to you by VRM Media. He can be reached at eugenejbruno@gmail.com.