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All Things Spermidine Pt 1: The Beneficial Health Effects of Spermidine 

Spermidine is a compound found in living cells and in foods including soybeans, wheat germ, nuts, fruits such as grapefruit and also in vegetables like broccoli. It is a polyamine, meaning that it is an organic compound with two or more amino groups. Human concentrations of spermidine decline with age and can change depending on nutrition, synthesis of polyamines within the gut microbiome, and disease state. Spermidine plays a crucial role in the survival and function of cells, including supporting cellular growth, DNA health, and apoptosis(33). Increased levels of spermidine have shown to have protective characteristics for the following: lifespan, cancer, metabolic conditions, cardiovascular conditions and cognitive conditions (24). 

SPERMIDINES ROLE AS A CALORIE RESTRICTION MIMETIC (CRM)

Spermidine is also considered a calorie-restriction mimetic, meaning that it is thought to mimic the health benefits of calorie restriction(CR)(enhanced longevity) by impacting similar mechanisms as CR. One of the main health-promoting mechanisms of CR is autophagy, which clears cells of damage, and is critical for cellular homeostasis as well as preventing cells from going awol. Across the research, spermidine has been shown to induce autophagy(6). 

EFFECTS OF SPERMIDINE ON THE HALLMARKS OF AGING

There are 9 hallmarks of aging: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, of which spermidine supplementation has been shown to counteract 5-6 hallmarks. These include epigenetic alterations, impaired proteostasis, mitochondrial dysfunction, stem cell dysfunction, and impaired and intercellular communication(22, 38). Early in 2021, spermidine was also suspected to prevent telomere attrition(55). This is impressive as there are not many well-researched sources that can counteract on average more than 2-3 hallmarks at a time. 

HEALTH BENEFITS OF SPERMIDINE

As briefly mentioned above, higher levels of spermidine have been associated with many health benefits. Across animal models, spermidine has been shown to extend lifespan. Across animal species, supplementation with spermidine has also shown to ameliorate age-related pathologies – thereby, supporting longevity. 

EFFECTS OF SPERMIDINE ON LIFESPAN

In animal and organism models, spermidine supplementation extends lifespan(6, 9, 34, 58). When blood levels of spermidine are increased in aged mice via supplementation of polyamine-producing probiotic bifidobacteria, decreased mortality is observed(17, 28). One study showed that in several Asian countries, the amount of polyamine uptake via food is correlated with life expectancy, however confounding factors in this study were not adequately adjusted for(1). In nonagenarians(90-99 y.o) and centenarians, an increase in levels of whole-level spermidine is linked to longevity(41).

EFFECTS OF SPERMIDINE ON CANCER

As previously mentioned, polyamines are required for cellular life and growth. In relation to this, many growing cancers and tumors, such as skin, breast, lung and prostate have elevated polyamine concentrations(37). While polyamine levels might have procarcinogenic properties if cancer has already developed, they also might have anti-cancer properties. For instance, in mice, spermidine supplementation has been shown to reduce tumorigenesis. In aging female mice, the supplementation of a bacteria which produces polyamines, reduces the occurrence of visible skin tumors(28). In mice, supplementation of spermidine has also been shown to protect against liver cancer and colorectal tumor growth(29, 58). A study in humans showed that overweight women (BMI ≤ 25), with higher polyamine intake had a reduced risk of colorectal cancer(53). Spermidine also enhances the anticancer immune response in mice receiving chemotherapy, due to improved immunosurveillance(40). Due to the conflicting nature of polyamines in relation to cancer, future studies are needed to elucidate when polyamines are cancer-promoting and when they are cancer-preventing or chemopreventive.

EFFECTS OF SPERMIDINE ON CARDIOVASCULAR DISEASE

Spermidine levels related to dietary uptake have been shown to protect from cardiac aging. In aged mice, dietary spermidine has been shown to improve diastolic function, left ventricle health, as well as mitochondrial function(8). Spermidine has also shown to reduce age-related arterial stiffness, mediate atherosclerosis plaques and reduce oxidative damage to endothelial cells in either aged mice or in ApoE deficient mice on a high-fat diet(18, 31). In mice modeled to have hypertensive heart failure, spermidine supplementation resulted in reduced blood pressure and prevented immediate transition into heart failure(8). In a human cohort, a higher combined dietary intake of spermidine and spermine correlated with a lower rate of cardiovascular disease. After spermidine supplementation, individuals in the higher tertile of spermidine intake also had lower blood pressure(8). Similarly another study, a meta-analysis, showed that lower spermidine and spermine levels were associated with higher CVD-related mortality rate(50).

EFFECTS OF SPERMIDINE ON HAIR GROWTH

In multiple studies, spermidine has been shown to improve hair growth, hair follicle number and hair follicle health in ‘hair follicle epithelial stem cells in serum-free organ culture’(45, 46). An in vitro study found that spermidine supported the ability of somatic cells to reprogram into iPSC’s(induced pluripotent stem cells) specific to embryonic fibroblasts, which further supports spermidine’s ability to support stem cell function(3, 25). 

EFFECTS OF SPERMIDINE ON MUSCLE-RELATED DISEASE

In aged mice, spermidine administration was able to prevent the senescence of muscle stem cells, improve muscle regeneration, and inhibit muscle atrophy(9, 12). In collagen-deficient mice, spermidine aided with improving muscle defects(4). Overall, spermidine has been shown to improve mitochondria health and structure in both cardiac and skeletal muscles in mice(4, 8, 9, 12).

EFFECTS OF SPERMIDINE ON METABOLIC CONDITIONS

Spermidine has also shown to be promising for metabolic issues. For instance, in mice fed a high-fat diet, spermidine administration(daily) prevented adiposity and mediated glucose intolerance(47). In another study, spermidine was shown to reduce weight gain and certain risk factors of obesity(10). Studies are needed to further support spermidine’s ability to attenuate metabolic issues.

EFFECTS OF SPERMIDINE ON THE BRAIN

In several animal and organism models, supplementation with spermidine has been shown to protect against neurodegeneration(11, 21). For instance, in flies fed spermidine, age-related memory issues were prevented, including locomotor activity (32).This protection was observed in an autophagy-dependent manner. In mice with an equivalent to multiple sclerosis, spermidine supplementation reduced normal disease-related damage to the optic nerve and spinal cord, as well as decreased loss of ganglia cells in the retina (13, 57). In mice, spermidine was also shown to reduce dementia (in a mouse model of frontotemporal lobar dementia)(54). In invertebrate models, spermidine was able to prevent neurotoxicity due to α-synuclein(2). In aged mice, arginine and probiotic supplementation(bifidobacteria LKM512), which increase polyamine levels, improved facets of memory and spatial learning(17). 

OTHER EFFECTS OF SPERMIDINE

Spermidine may also mediate bone loss as a consequence of menopause – in a post-menopausal osteoporosis mouse model, spermidine supplementation prevented bone loss (56). In mice, Spermidine supplementation also prevented circadian rhythm dysregulation, as related to age(59). Spermidine has also shown promise in ameliorating certain facets of eye health, including the optic nerve and retinal ganglion survival, and by blunting retinal damage in mice with age-related glaucoma (35, 36).

WHAT DOES THIS ALL MEAN? 

As the aging population grows, rising rates of chronic illness need to be addressed. There are several ways to mediate these rising rates, including lifestyle factors, like diet and exercise, and pharmacological interventions. Currently in the spotlight is the CRM, spermidine, which as an intervention is able to target 5-6 hallmarks of aging, nearly doubling the amount of hallmarks targeted by most other pharmacologic interventions(ie.17alpha-estradiol or senolytic compounds)(38). Spermidine is found naturally in foods and is also created by the bacteria in our guts. As we age, spermidine concentrations decline. In animal and organism models, supplementation of spermidine has been shown to exert longevity benefits from extending lifespan, to preventing age-related diseases such as neurodegeneration and heart disease. In nonagenarians(90-99 y.o) and centenarians, an increase in levels of whole-level spermidine is linked to longevity(41). Epidemiological studies have also suggested that higher polyamine intakes prevent death from certain age-related diseases(8). Spermidine is currently one of the most promising geroprotective agents in the longevity field. 

Click here to read all about calorie-restriction mimetics

Click here to read all things spermidine: pt 2 the health-promoting mechanisms of spermidine

Author: Jacqueline Seymour
Jacki is a Master’s student at USC, home of Dr. Valter Longo’s Longevity Institute, where she’s studying her passion for life: Gerontology(the science of aging) and Nutrition. 

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