As part of our continued exploration of how spermidine influences the 12 hallmarks of aging, this article focuses on the 9th: stem cell exhaustion. Aging is a complex biological process marked by different hallmarks, which are interconnected cellular and molecular changes that collectively drive the gradual decline of tissue function and organismal homeostasis. One of its most critical hallmarks is stem cell exhaustion, or the gradual decline in the number and functionality of stem cells. This phenomenon leads to impaired tissue regeneration and contributes to age-related diseases such as sarcopenia, osteoporosis, and infertility. Recent studies highlight spermidine as a natural compound that combats stem cell exhaustion. By inducing autophagy and maintaining cellular homeostasis, spermidine helps preserve stem cell function and delays the aging process. Below, we explore the mechanisms through which spermidine combats stem cell exhaustion, supported by findings from scientific studies.
What are stem cells? What is stem cell exhaustion?
Stem cells are unique cells distinguished by two remarkable abilities. First, they can self-renew, continuously dividing to replenish their own population. Second, they can differentiate, transforming into specialized cell types with distinct functions, such as muscle fibers, neurons, or blood cells, enabling the body to grow, repair, and maintain tissues throughout life. Stem cells are like master keys: they can unlock and become any cell type needed to repair or build the body.
Stem cells come from several sources. Embryonic stem cells are pluripotent cells from early embryos that can become almost any cell type. Adult stem cells, found in tissues like bone marrow and fat, are typically multipotent, with a more limited differentiation potential. Induced pluripotent stem cells (iPSCs) are reprogrammed adult cells that mimic embryonic stem cells, offering regenerative potential, especially when derived from the same individual. Perinatal stem cells, found in umbilical cord blood and amniotic fluid, can generate specialized cells and provide a less controversial source for therapy.
Stem cell exhaustion refers to the decline in the number and functionality of stem cells, leading to impaired tissue regeneration. This phenomenon is particularly evident in aging tissues, where stem cells either enter a state of irreversible senescence (a permanent cell-cycle arrest or “retirement” of the cells, e.g. they stop dividing) or lose their ability to self-renew and differentiate. The consequences of stem cell exhaustion are profound, contributing to age-related diseases such as sarcopenia, osteoporosis, and impaired wound healing.
How spermidine fights stem cell exhaustion
-
Restoration and maintenance of autophagy
Autophagy is essential for removing damaged organelles and proteins, preserving stem cell function and preventing senescence. Spermidine is a potent inducer of autophagy, restoring impaired flux in aged cells and ensuring proper turnover of autophagosomes and lysosomes.Muscle stem cells (satellite cells): Spermidine treatment improved autophagosome turnover and restored regenerative capacity in aged satellite cells (García-Prat et al., 2016; Balnis et al., 2022).
Female germline stem cells (FGSCs): Spermidine induces cytoprotective autophagy, upregulates p62, and prevents oxidative stress–induced senescence (Yuan et al., 2021).
-
Reduction of oxidative stress via mitophagy
Oxidative stress accelerates stem cell exhaustion by damaging mitochondria and cellular components. Spermidine reduces oxidative stress by enhancing mitophagy, the selective clearance of defective mitochondria. In FGSCs, spermidine lowered aging markers (p16, p53) and inhibited the PI3K/AKT/mTOR pathway, protecting against oxidative damage (Yuan et al., 2021).
-
Enhancement of stem cell proliferation and viability
Spermidine supports stem cell survival and replication by protecting against stress-induced damage. In FGSCs, it significantly increased proliferation and survival, even under oxidative stress conditions (Yuan et al., 2021).
-
Epigenetic regulation of stem cell function
Spermidine influences gene expression through epigenetic mechanisms, including histone acetylation, ensuring optimal expression of autophagy-related and regenerative genes. In epithelial stem cells, it enhanced keratins K15 and K19, markers of stem cell activity (Ramot et al., 2011). -
Promotion of cellular reprogramming
Spermidine improves the efficiency of reprogramming somatic cells into induced pluripotent stem cells (iPSCs) by inducing autophagy, suggesting a role in rejuvenating aged cells and restoring pluripotency (Chen et al., 2011).
Conclusion
Spermidine represents a promising natural strategy to counteract stem cell exhaustion, a key hallmark of aging, by promoting autophagy, reducing oxidative stress, and enhancing stem cell proliferation. These properties position it as a potential therapeutic agent for age-related conditions such as sarcopenia, infertility, and other degenerative diseases. To fully realize this potential, long-term clinical studies are needed to establish its safety and efficacy in humans, as well as to explore its synergistic effects with other interventions like caloric restriction and exercise. As research continues to uncover the molecular mechanisms behind its benefits, spermidine may become a cornerstone in advancing healthier aging.
(Adapted from López-Otín et al., 2022)
Curious about the other hallmarks of aging and how spermidine can help combat them? Read more here.
