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This article was written with Amy Lamotte, MS (biography below).
Why Are We Talking About Spermidine?
As the name implies, spermidine was first characterized in sperm, and while there is a high concentration present in semen (and it appears important for fertility), it’s everywhere- in all eukaryotic cells. In fact, wind the evolutionary clock back to the earliest endosymbiotic happenings, you’ll find spermidine and the broader family of polyamines on center stage, playing a central role in the development of… life. Indeed, bacteria, archaea and plants (and even viruses) all rely on polyamines. These facts alone illustrate the obvious: polyamines are important. Attribution for the discovery of spermine (the polyamine metabolite of spermidine) is given to Anton Leeuwenhoek, the father of microscopy, in 1678.
Spermidine is a darling in the longevity space, and while human evidence is preliminary, it probably deserves this status. When we look at the “hallmarks of aging,” or the drivers of aging at a cellular level, spermidine has been shown (in animal and cell models) to have pleiotropic effects, favorably modulating all of the nine original hallmarks plus the three new hallmarks, including dysregulation of macroautophagy, dysbiosis, and inflammation.
For those of you not wanting to plow through the full length of this article, let me tell you this: even with the somewhat limited amount of human data available, given the outsized role of polyamines, and the fact that they all drop with age, we probably want to be getting food sources, or consuming food-based substrates and cofactors for endogenous synthesis (ie, amino acids and methyl donors), tending to our gut microbiome to support microbial synthesis, or considering supplementation in some cases (ie fertility, cognitive impairment). The caveat? Higher levels and toxic endproducts have been identified in cancer and other proinflammatory conditions. The classic, uncomfortable U curve.
A Polyamine with Notable Beneficial Activity
Spermidine’s remarkable pleiotropic ability (ie, its ability to affect most if not all of the hallmarks of aging) is shared by its chemical cousins, collectively the polyamines. The additional polyamines also include putrescine, its precursor, and spermine, its derivative. Polyamines are organic, aliphatic compounds consisting of two or more amino groups which are positively charged at physiological pH. This positive charge is one of the fundamental features that allows polyamines to have an outsized role in many organisms- including us–through the stabilization of negatively charged molecules, such as DNA (genomic stability), RNA, nucleotide triphosphates (ATP), protein (proteostasis), and phospholipids (interacting with the negatively charged phosphate group).
(And yes, if you were wondering, the polyamine putrescine does smells like- and is present in- rotting flesh. All of the polyamines have a pretty distinct odor because of the presence of two or more amino groups.)
Of the polyamines, spermidine is best known for its ability to induce autophagy, or the body’s cellular cleaning mechanism. However, as a group the polyamines are central to cell growth, proliferation, differentiation and molecular stabilization, making them indispensable for healthy aging.
With the onset of human clinical trials to assess spermidine supplementation for a wide variety of conditions, a need for a clinical approach emerges, and begins with a comprehensive understanding of the primary sources of polyamines: endogenous metabolism; microbial production; and food. Let’s look more closely at each of these.
Endogenous Metabolism: Are Polyamines Conditionally Essential Nutrients?
It has been estimated that endogenous production is the primary source of polyamines, however there is a significant reduction in the body’s ability to produce polyamines with age. Research in animals has found that the thymus, spleen, ovary, liver, stomach, lung, kidney, heart, and muscle are the organs with the most age-induced polyamine decline. Interestingly, one small study found that super-agers (aged 90-106) had whole blood levels of spermidine and spermine that were more in line with a much younger (aged 31-56) cohort. That said, younger populations in this study had higher relative levels of putrescine when compared with the other polyamines, and we don’t yet fully understand the clinical significance of the balance between polyamines during different stages of life.
The Polyamine Stress Response
Endogenous production (from the amino acids arginine and ornithine) is tightly controlled and regulated through biosynthesis (including antizyme inhibition), interconversion, degradation, and transport. Importantly, there are several related concepts with clinical implications. First, while the body can interconvert polyamines as needed, their breakdown creates toxic byproducts, including hydrogen peroxide and acrolein. Second, dysregulated endogenous metabolism is known to occur in several disease states, including the autoimmune diseases rheumatoid arthritis and lupus, some neurodegenerative disorders, and events like stroke, with elevated levels of spermidine and/or its catabolic byproducts.
The trigger of dysregulated polyamine metabolism in these conditions is yet to be fully understood, but may include infection, inflammation, and mitochondrial dysfunction. Some researchers have called this the “Polyamine Stress Response,” suggesting that the upregulation of endogenous production is a beneficial, adaptive response that may become maladaptive with persistent stress (similar to acute vs. chronic inflammation). As endogenous polyamine metabolism also requires the use of decarboxylated SAMe as a cofactor, it is not surprising that dysregulated production may have negative downstream effects on methylation over time.
While some have argued that spermidine has anti-cancer properties, active cancer may be a contraindication for polyamine supplementation as cancer cells require polyamines (similar to glucose) for growth. Human associational data has been mixed, with some studies suggesting that high dietary polyamine intake may be chemopreventive. As a result, cancer is an area where more polyamine research is needed to clarify clinical implications.
Research into endogenous metabolism of polyamines is an area to follow regarding future clinical developments, as it may lead to new, early markers of disease and related treatment approaches.
Microbial Production: Does Dysbiosis Impact Polyamine Availability?
The second primary source of polyamines is from microbial production, making spermidine a post-biotic, or one of many important compounds produced by intestinal microbes. Bacterial production and secretion of polyamines exceeds that of our own cells. Further, according to a recent review, humans can more efficiently utilize post-biotic spermidine when compared with dietary spermidine. That said, we are far from fully understanding the delicate balance between microbial polyamine producers, polyamine degraders, and any related clinical implications.
Gut bacteria that have been found to produce spermidine include primarily lactobacillus, bifidobacterium, bacteroides, and other gram negative bacteria. Bifidobacterium animalis sp. Lactis LKM512 and Bifidobacterium animalis subsp, lactis BB-12 have both been validated as polyamine-producing probiotics in human clinical trials. Further, animal research has shown that prebiotic fermentable fibers (including pectin) increase the production of polyamines by some bacteria. By contrast, bacteria can also secrete spermidine degrading enzymes. More research is needed to understand the potential clinical implications, with further refinement in functional testing to allow for the measurement of these enzymes.
Prebiotics may not be the only trigger to increase microbial polyamine production. One interesting study in a menopause mouse model found that heat-exposure of 34 degrees Celsius (93.2 degrees Fahrenheit), upregulated microbial polyamine production, which had a beneficial impact on bone health. These bone benefits were further preserved in a fecal microbiota transplant into mice which had not been exposed to heat.
Microbial spermidine production has also been implicated in skin health, with one study finding increased levels of microbial spermidine in younger participants with improved skin elasticity and hydration.
While it’s a bit early to draw clinical conclusions from this research, it further highlights the importance of the microbiome for improved healthspan.
Dietary Polyamines: Who Benefits?
The benefits of a polyamine-rich diet have been elucidated in numerous epidemiological studies, with mostly positive findings in predominantly European and U.S. cohorts (where baseline consumption is lower). Increased dietary intake has been associated with improved cardiovascular health, increased cortical thickness and hippocampal volume, reduced risk for cognitive decline, and lower all cause-mortality in several studies. Recently, however, a large, longitudinal study in Japan did not find any associations between increased dietary polyamine intake and positive health outcomes. As the authors noted, these results may be related to the fact that polyamine-rich foods like natto and shiitake mushrooms are widely consumed in Japan when compared to European and American diets, making their baseline polyamine consumption higher and perhaps limiting the benefit of additional polyamines.
Every whole food has a unique balance of polyamines. The dietary sources with the highest concentrations of spermidine include wheat germ, soy, mushrooms, rice bran, green pepper, and broccoli. While spermidine is not found in high concentrations in muscle meat, organ meats contain relatively higher concentrations. Fermented foods, such as natto, teas (e.g., pu-erh and oolong), and some aged cheeses also contain significant amounts due to microbial polyamine production. More recently, a study on bee products as functional foods, found that bee pollen, a vital food source for bee larvae and young bees, is also rich in spermidine.
Importantly, polyamine concentrations in colostrum and breast milk are the first exogenous source an infant is exposed to, and involved in both seeding the microbiome and development of the infant immune system. Studies have found that a mother’s diet influences the polyamine content of her milk, and that obese mothers had lower levels of polyamines in breast milk compared with normal weight mothers. The clinical implications of this research are significant, and can help guide postnatal nutrition recommendations. While human studies are lacking, preclinical research suggests that spermidine may play a role in fertility and inhibition of ovarian aging- and is therefore an important area to follow with respect to preconception nutrition.
What We Know from Human Clinical Trials
Important to know is that, despite a significant amount of preclinical and epidemiological research, clinical studies using spermidine supplementation are only in the early stages. To date, four human clinical trials (two early stage studies and their follow-on cohorts) have found mixed results in older adult populations with pre-existing cognitive deficits. Further discussion of these results can be found here, however some have argued that the lower dosage of 0.9 mg/day may have been inadequate in a population of older adults whose cognition was already in a state of decline. By contrast, a higher dosage of 3.3mg/day for 12-months was confirmed to increase measures of cognitive performance in institutionalized older adults with mild dementia. Together, these results suggest that spermidine supplementation may be beneficial for older adults with cognitive decline. Stay tuned for more clinical trials investigating a range of indications.
Summary – What To Know
Polyamines are important players in health and longevity-in the right amounts they can favorably alter all of the hallmarks of aging. We can get them from a healthy, whole foods diet; we synthesize them endogenously and our microbiome can produce them. Polyamines decline with age, although super agers have polyamines akin to younger people. Supplementation with spermidine has its place, particularly with cognitive decline. A host of additional trials are coming, including in cardiovascular disease, which we will follow.
Excess polyamines and/or disordered metabolism have been identified as potential drivers of certain diseases, including cancer and autoimmunity. How do we approach this? As a functional medicine clinician, I would look to correcting underlying imbalances that may be contributing to the rogue behavior of the polyamines (diet, gut health, lifestyle, etc). I would not avoid a whole food diet in the hopes of avoiding polyamines; however, I may consider doing underlying functional work before I would introduce supplementation, if at all (dietary sources are a safer choice for now). And right now, I would likely avoid supplementation in those with cancer.
Contributing co-author: Amy Lamotte MS