Spermidine

Spermidine is an aliphatic polyamine that is synthesized from its precursor putrescine through the enzyme spermidine synthase¹. Spermidine is present in all living cells and plays a critical role in maintaining cellular homeostasis. Its primary function is to engage cytoprotective autophagy, and it affects several processes, including cell growth, tissue regeneration, and DNA/RNA stabilization. Spermidine also possesses anti-inflammatory and antioxidant properties.

Spermidine is endogenously produced in mammalian cells throughout the body and can also be synthesized by the gut microbiome². Exogenously, spermidine is found in food items, particularly unprocessed plant-derived foods (e.g., cereals, legumes, vegetables, fruits) and fermented items (e.g., mature cheese or soybean products)³. Dietary spermidine is rapidly reabsorbed from the intestines and distributed throughout the body. Systemic spermidine levels can be modulated directly through diet or indirectly through dietary effects on spermidine-producing bacteria⁴.

Due to spermidine’s cytoprotective effects, its impact has been observed across several age-related diseases and physiological processes. Interestingly, spermidine supplementation is strongly implicated in promoting longevity by mitigating the harmful consequences of cancer, metabolic syndrome, and cardiovascular diseases⁵.

(Figure from Choksomngam et al., 2021⁶)

Spermidine and Metabolic Health

In general, spermidine has protective effects on cardiovascular and metabolic health. However, there are some inconsistencies in epidemiological studies. For example, one report indicated that consumption of polyamine-rich food was associated with a lower incidence of cardiovascular disease⁷, while others have reported increased polyamine levels in metabolic syndrome patients with Type 2 diabetes⁸. Scientists hypothesize that this discrepancy is associated with the disease stage, where spermidine levels are elevated in more severe cases⁶.

Regardless, mechanistic examinations of spermidine are in support of its cytoprotective effects. Studies in aging mice demonstrated that spermidine supplementation improves diastolic function, ventricular elasticity, and mitochondrial function⁹. In another report that examined mice fed a high-fat diet, administration of spermidine resulted in weight loss, improved glucose utilization, and prevented adiposity¹⁰. In support of these data, others have demonstrated that the autophagy induced by spermidine is critical for its protective effects against weight gain, lipotoxicity, and pancreatic β-cell death¹¹.

Spermidine and Gastrointestinal Health

A major source of endogenous spermidine is intestinal bacteria. With a wealth of literature implicating the gut microbiome and gastrointestinal health, polyamines like spermidine have been shown to have protective effects for gastrointestinal health, including maintenance of gut barrier function and reducing inflammation.

In a study involving diet-induced obese mice, spermidine supplementation improved metabolic parameters, an effect associated with the enhancement of gut barrier function and the increase of beneficial short-chain fatty acid producing bacteria¹². Another report examining a mouse model of inflammatory bowel disease (IBD) demonstrated that spermidine supplementation promoted anti-inflammatory macrophages and prevented the shift toward a dysbiotic microbiome¹³.

Spermidine and Neuroscience

Polyamines like spermidine are also critical for maintaining central nervous system (CNS) function. Spermidine in the CNS helps mediate nerve growth and regeneration, responds to neuronal injury, and helps regulate neuronal ion channels¹⁴. Early studies demonstrated that individuals with Alzheimer’s disease exhibit abnormally elevated levels of spermidine, while more recent studies have shown that cognitive decline associated with Alzheimer’s disease is linked to a decrease in spermidine levels¹⁵. Interestingly, studies have shown that age-related cognitive decline in Drosophila can be ameliorated with spermidine supplementation, which prevents adverse changes in synaptic signaling¹⁶.

Spermidine’s neuroprotective effects can also be observed across other neurodegenerative disorders. For example, spermidine supplementation in mouse models of multiple sclerosis slows disease progression and mitigates the loss of retinal ganglion cells¹⁷.

Spermidine and Drug Development

Due to its cytoprotective and anti-aging effects, spermidine has generated considerable attention in therapeutics and drug development. Indeed, spermidine is currently being investigated as a treatment for cognitive decline and Alzheimer’s disease in a phase IIIb clinical trial¹⁸. Moreover, since systemic spermidine levels are altered across many diseases, it is also useful as a biomarker and target for therapeutics.

In developing countries with a high prevalence of tropical diseases caused by parasitic protozoa (e.g., Sleeping sickness), spermidine and other polyamine analogs are effective treatments for many parasite-borne diseases, with new polyamine-based treatments in development¹⁹. With an eye towards maximizing life span, polyamine therapeutics and spermidine intake are emerging as promising candidates for drugs designed to treat cancer, metabolic disease, cardiovascular disease, and neurodegeneration.

Spermidine in research

As of July 2023, there are over 14,000 citations for “spermidine” in research publications (excluding books and documents) on Pubmed. The vast number of publications linking this metabolite to metabolic and gastrointestinal health (including the microbiome component) suggests that any research program seeking to better understand gut and metabolic disorders may benefit from quantitative analysis of spermidine. Similarly, researchers may consider adding spermidine quantification to academic and preclinical research efforts focused on gut, metabolic, and neurological health.

References

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