Molecular and cellular mechanisms of Spermidine in age-related diseases

Connection between Spermidine trihydrochloride and Spermine

Spermidine trihydrochloride is a compound belonging to the polyamine family. It is a derivative of spermidine. It has received widespread attention for its ability to regulate autophagy, enhance cardiovascular health, prevent neurodegenerative diseases, and antioxidant activity, and for its high impact on human health. However, it is often used as a laboratory reagent in the field of physiological and biochemical research.

What is Spermidine?

Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice.

Roles of spermidine in aged-related diseases

Spermidine is a critical factor in aging and age-related diseases, including CVDs, neurodegenerative diseases, metabolic diseases, musculoskeletal diseases, and immune diseases. Details of the role of spermidine in age-related diseases are shown below.

Mechanisms of spermidine in age-related diseases

Spermidine is an inducer of autophagy, which is the main mechanism of anti-aging. First, spermidine triggers autophagy by modulating the expressions of Atg genes. Second, it regulates transcription factor elF5A to promote the synthesis of transcription factor TFEB. Third, spermidine inhibits EP300, which directly promotes the acetylation of Atg genes and indirectly stimulates deacetylation of tubulin due to inhibition of aTAT1. Besides, spermidine exerts potent anti-inflammatory roles by suppressing of multiple inflammatory cytokines, such as ROS, NF-κB, IL-1β and IL-18. Moreover, it isinvolved in regulation of cell proliferation, differentiation, senescence, apoptosis and necrosis, ultimately promoting cell growth and inhibiting cell death. As an anti-aging agent, spermidine suppresses histone acetylation.

Moreover, spermidine regulates lipid metabolism. On the one hand, it promotes the differentiation of preadipocytes into mature adipocytes. On the other hand, it alters lipid profile, modulates lipogenic gene expressions, and represses lipid accumulation. Furthermore, spermidine can delay aging through specific signaling pathways, such as SIRT1/PGC-1α, insulin/ IGF, AMPK-FOXO3a, and CK2/MAPK signaling pathways. Abbreviations: Atg: autophagy-related genes; aTAT1: a-tubulin acetyltransferase 1; EP300: E1A-associated protein p300; ROS: reactive oxygen species; NF-κB: nuclear factor kappa-B; IL: interleukin; SIRT1: Sirtuin-1; PGC-1α: peroxisome proliferator-activated receptor gamma coactivator alpha; IGF: insulin-like  growth factor; AMPK: AMP-activated protein kinase; MAPK: mitogen-activated protein kinase. As shown in the figure below:

References:

[1] YU-QING NI; You S L. New Insights into the Roles and Mechanisms of Spermidine in Aging and Age-Related Diseases.[J]. Aging and Disease, 2021: 1948-1963. DOI:10.14336/AD. 2021. 0603.

[2] SEBASTIAN J HOFER. Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging.[J]. Autophagy, 2021: 2037-2039. DOI:10.1080/15548627.2021.1933299.

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