Spermidine Abstracts 1

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Spermidine protects against α-synuclein neurotoxicity.
            (Büttner et al., 2014) Download
As our society ages, neurodegenerative disorders like Parkinson`s disease (PD) are increasing in pandemic proportions. While mechanistic understanding of PD is advancing, a treatment with well tolerable drugs is still elusive. Here, we show that administration of the naturally occurring polyamine spermidine, which declines continuously during aging in various species, alleviates a series of PD-related degenerative processes in the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, two established model systems for PD pathology. In the fruit fly, simple feeding with spermidine inhibited loss of climbing activity and early organismal death upon heterologous expression of human α-synuclein, which is thought to be the principal toxic trigger of PD. In this line, administration of spermidine rescued α-synuclein-induced loss of dopaminergic neurons, a hallmark of PD, in nematodes. Alleviation of PD-related neurodegeneration by spermidine was accompanied by induction of autophagy, suggesting that this cytoprotective process may be responsible for the beneficial effects of spermidine administration.

Induction of autophagy by spermidine promotes longevity.
            (Eisenberg et al., 2009) Download
Ageing results from complex genetically and epigenetically programmed processes that are elicited in part by noxious or stressful events that cause programmed cell death. Here, we report that administration of spermidine, a natural polyamine whose intracellular concentration declines during human ageing, markedly extended the lifespan of yeast, flies and worms, and human immune cells. In addition, spermidine administration potently inhibited oxidative stress in ageing mice. In ageing yeast, spermidine treatment triggered epigenetic deacetylation of histone H3 through inhibition of histone acetyltransferases (HAT), suppressing oxidative stress and necrosis. Conversely, depletion of endogenous polyamines led to hyperacetylation, generation of reactive oxygen species, early necrotic death and decreased lifespan. The altered acetylation status of the chromatin led to significant upregulation of various autophagy-related transcripts, triggering autophagy in yeast, flies, worms and human cells. Finally, we found that enhanced autophagy is crucial for polyamine-induced suppression of necrosis and enhanced longevity.


Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).
            (Klionsky et al., 2016) Download

The autophagy enhancer spermidine reverses arterial aging.
            (LaRocca et al., 2013) Download
Arterial aging, characterized by stiffening of large elastic arteries and the development of arterial endothelial dysfunction, increases cardiovascular disease (CVD) risk. We tested the hypothesis that spermidine, a nutrient associated with the anti-aging process autophagy, would improve arterial aging. Aortic pulse wave velocity (aPWV), a measure of arterial stiffness, was ~20% greater in old (O, 28 months) compared with young C57BL6 mice (Y, 4 months, P<0.05). Arterial endothelium-dependent dilation (EDD), a measure of endothelial function, was ~25% lower in O (P<0.05 vs. Y) due to reduced nitric oxide (NO) bioavailability. These impairments were associated with greater arterial oxidative stress (nitrotyrosine), superoxide production, and protein cross-linking (advanced glycation end-products, AGEs) in O (all P<0.05). Spermidine supplementation normalized aPWV, restored NO-mediated EDD and reduced nitrotyrosine, superoxide, AGEs and collagen in O. These effects of spermidine were associated with enhanced arterial expression of autophagy markers, and in vitro experiments demonstrated that vascular protection by spermidine was autophagy-dependent. Our results indicate that spermidine exerts a potent anti-aging influence on arteries by increasing NO bioavailability, reducing oxidative stress, modifying structural factors and enhancing autophagy. Spermidine may be a promising nutraceutical treatment for arterial aging and prevention of age-associated CVD.

Molecular basis of the 'anti-aging' effect of spermidine and other natural polyamines - a mini-review.
            (Minois, 2014) Download
BACKGROUND:  Spermidine, a naturally occurring polyamine, has recently emerged as exhibiting anti-aging properties. Its supplementation increases lifespan and resistance to stress, and decreases the occurrence of age-related pathology and loss of locomotor ability. Its mechanisms of action are just beginning to be understood. OBJECTIVES:  An up-to-date overview of the so far identified mechanisms of action of spermidine and other polyamines on aging is presented. METHODS:  Studies of aging and of the molecular effects of polyamines in general and spermidine in particular are used to synthesize our knowledge on what molecular mechanisms spermidine and other polyamines trigger to positively affect aging. RESULTS:  Autophagy is the main mechanism of action of spermidine at the molecular level. However, recent research shows that spermidine can act via other mechanisms, namely inflammation reduction, lipid metabolism and regulation of cell growth, proliferation and death. It is suggested that the main pathway used by spermidine to trigger its effects is the MAPK pathway. CONCLUSIONS:  Given that polyamines can interact with many molecules, it is not surprising that they affect aging via several mechanisms. Many of these mechanisms discovered so far have already been linked with aging and by acting on all of these mechanisms, polyamines may be strong regulators of aging.

Spermidine induces autophagy by inhibiting the acetyltransferase EP300.
            (Pietrocola et al., 2015) Download
Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors.

Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions.
            (Ramot et al., 2011) Download
BACKGROUND:  Rapidly regenerating tissues need sufficient polyamine synthesis. Since the hair follicle (HF) is a highly proliferative mini-organ, polyamines may also be important for normal hair growth. However, the role of polyamines in human HF biology and their effect on HF epithelial stem cells in situ remains largely unknown. METHODS AND FINDINGS:  We have studied the effects of the prototypic polyamine, spermidine (0.1-1 µM), on human scalp HFs and human HF epithelial stem cells in serum-free organ culture. Under these conditions, spermidine promoted hair shaft elongation and prolonged hair growth (anagen). Spermidine also upregulated expression of the epithelial stem cell-associated keratins K15 and K19, and dose-dependently modulated K15 promoter activity in situ and the colony forming efficiency, proliferation and K15 expression of isolated human K15-GFP+ cells in vitro. Inhibiting the rate-limiting enzyme of polyamine synthesis, ornithine decarboyxlase (ODC), downregulated intrafollicular K15 expression. In primary human epidermal keratinocytes, spermidine slightly promoted entry into the S/G2-M phases of the cell cycle. By microarray analysis of human HF mRNA extracts, spermidine upregulated several key target genes implicated e.g. in the control of cell adherence and migration (POP3), or endoplasmic reticulum and mitochondrial functions (SYVN1, NACA and SLC25A3). Excess spermidine may restrict further intrafollicular polyamine synthesis by inhibiting ODC gene and protein expression in the HF's companion layer in situ. CONCLUSIONS:  These physiologically and clinically relevant data provide the first direct evidence that spermidine is a potent stimulator of human hair growth and a previously unknown modulator of human epithelial stem cell biology.

Acetyl-coenzyme A: a metabolic master regulator of autophagy and longevity.
            (Schroeder et al., 2014) Download
As the major lysosomal degradation pathway, autophagy represents the guardian of cellular homeostasis, removing damaged and potentially harmful material and replenishing energy reserves in conditions of starvation. Given its vast physiological importance, autophagy is crucially involved in the process of aging and associated pathologies. Although the regulation of autophagy strongly depends on nutrient availability, specific metabolites that modulate autophagic responses are poorly described. Recently, we revealed nucleo-cytosolic acetyl-coenzyme A (AcCoA) as a phylogenetically conserved inhibitor of starvation-induced and age-associated autophagy. AcCoA is the sole acetyl-group donor for protein acetylation, explaining why pharmacological or genetic manipulations that modify the concentrations of nucleo-cytosolic AcCoA directly affect the levels of protein acetylation. The acetylation of histones and cytosolic proteins inversely correlates with the rate of autophagy in yeast and mammalian cells, respectively, despite the fact that the routes of de novo AcCoA synthesis differ across phyla. Thus, we propose nucleo-cytosolic AcCoA to act as a conserved metabolic rheostat, linking the cellular metabolic state to the regulation of autophagy via effects on protein acetylation.


 

Spermidine-triggered autophagy ameliorates memory during aging.
            (Sigrist et al., 2014) Download
The aging process drives the progressive deterioration of an organism and is thus subject to a complex interplay of regulatory and executing mechanisms. Our understanding of this process eventually aims at the delay and/or prevention of age-related pathologies, among them the age-dependent decrease in cognitive performance (e.g., learning and memory). Using the fruit fly Drosophila melanogaster, which combines a generally high mechanistic conservation with an efficient experimental access regarding aging and memory studies, we have recently unveiled a protective function of polyamines (including spermidine) against age-induced memory impairment (AMI). The flies' age-dependent decline of aversive olfactory memory, an established model for AMI, can be rescued by both pharmacological treatment with spermidine and genetic modulation that increases endogenous polyamine levels. Notably, we find that this effect strictly depends on autophagy, which is remarkable in light of the fact that autophagy is considered a key regulator of aging in other contexts. Given that polyamines in general and spermidine in particular are endogenous metabolites, our findings place them as candidate target substances for AMI treatment.

The role of glia in stress: polyamines and brain disorders.
            (Skatchkov et al., 2014) Download
This review focuses on the roles of glia and polyamines (PAs) in brain function and dysfunction, highlighting how PAs are one of the principal differences between glia and neurons. The novel role of PAs, such as putrescine, spermidine, and spermine and their precursors and derivatives, is discussed. However, PAs have not yet been a focus of much glial research. They affect many neuronal and glial receptors, channels, and transporters. They are therefore key elements in the development of many diseases and syndromes, thus forming the rationale for PA-focused and glia-focused therapy for these conditions.

Polyamines and Gut Mucosal Homeostasis.
            (Timmons et al., 2012) Download
The epithelium of gastrointestinal (GI) mucosa has the most rapid turnover rate of any tissue in the body and its integrity is preserved through the dynamic balance between cell migration, proliferation, growth arrest and apoptosis. To maintain tissue homeostasis of the GI mucosa, the rates of epithelial cell division and apoptosis must be highly regulated by various extracellular and intracellular factors including cellular polyamines. Natural polyamines spermidine, spermine and their precursor putrescine, are organic cations in eukaryotic cells and are implicated in the control of multiple signaling pathways and distinct cellular functions. Normal intestinal epithelial growth depends on the available supply of polyamines to the dividing cells in the crypts, and polyamines also regulate intestinal epithelial cell (IEC) apoptosis. Although the specific molecular processes controlled by polyamines remains to be fully defined, increasing evidence indicates that polyamines regulate intestinal epithelial integrity by modulating the expression of various growth-related genes. In this review, we will extrapolate the current state of scientific knowledge regarding the roles of polyamines in gut mucosal homeostasis and highlight progress in cellular and molecular mechanisms of polyamines and their potential clinical applications.

Spermidine may decrease ER stress in pancreatic beta cells and may reduce apoptosis via activating AMPK dependent autophagy pathway.
            (Tirupathi Pichiah et al., 2011) Download
The risk for diabetes increases with increasing BMI<25. Insulin resistance is the key factor for type 2 diabetes; studies revealed that endoplasmic reticulum stress is the main factor behind this disease. With increase in ER stress, pancreatic beta cells start to undergo apoptosis, leading to a decline in the pancreatic beta cell population. The ER stress arises due to unfolded protein response. Recently, spermidine get importance for increasing the longevity in most of the eukaryotes including yeast, Caenorhabditis elegans, Drosophila and human peripheral blood mononuclear cells via induction of autophagy pathway. Autophagy is also involved in regulation of scavenging of proteins. One of the major cellular pathways for scavenging the aggregated intracellular protein is autophagy. Hence spermidine can be a candidate for the treatment type 2 diabetes. Autophagy genes are regulated by mTOR (mammalian Target Of Rapamycin) dependent or independent pathway via AMPK. Hence either inhibition of mTOR or activation of AMPK by spermidine will play two crucial roles, first being the activation of autophagy and secondly the reduction of endoplasmic reticulum stress which will reduce beta cell death by apoptosis and thus can be a novel therapeutic candidate in the treatment of insulin resistance in type 2 diabetes and preserving pancreatic beta cell mass.


 

References

Büttner, S, et al. (2014), ‘Spermidine protects against α-synuclein neurotoxicity.’, Cell Cycle, 13 (24), 3903-8. PubMed: 25483063
Eisenberg, T, et al. (2009), ‘Induction of autophagy by spermidine promotes longevity.’, Nat Cell Biol, 11 1305-14. PubMed: 19801973
Klionsky, DJ, et al. (2016), ‘Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition).’, Autophagy, 12 (1), 1-222. PubMed: 26799652
LaRocca, TJ, et al. (2013), ‘The autophagy enhancer spermidine reverses arterial aging.’, Mech Ageing Dev, 134 (7-8), 314-20. PubMed: 23612189
Minois, N (2014), ‘Molecular basis of the ‘anti-aging’ effect of spermidine and other natural polyamines - a mini-review.’, Gerontology, 60 (4), 319-26. PubMed: 24481223
Pietrocola, F, et al. (2015), ‘Spermidine induces autophagy by inhibiting the acetyltransferase EP300.’, Cell Death Differ, 22 (3), 509-16. PubMed: 25526088
Ramot, Y, et al. (2011), ‘Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions.’, PLoS One, 6 (7), e22564. PubMed: 21818338
Schroeder, S, et al. (2014), ‘Acetyl-coenzyme A: a metabolic master regulator of autophagy and longevity.’, Autophagy, 10 (7), 1335-37. PubMed: 24904996
Sigrist, SJ, et al. (2014), ‘Spermidine-triggered autophagy ameliorates memory during aging.’, Autophagy, 10 (1), 178-79. PubMed: 24262970
Skatchkov, SN, MA Woodbury-Fariña, and M Eaton (2014), ‘The role of glia in stress: polyamines and brain disorders.’, Psychiatr Clin North Am, 37 (4), 653-78. PubMed: 25455070
Timmons, J, et al. (2012), ‘Polyamines and Gut Mucosal Homeostasis.’, J Gastrointest Dig Syst, 2 (Suppl 7), PubMed: 25237589
Tirupathi Pichiah, PB, et al. (2011), ‘Spermidine may decrease ER stress in pancreatic beta cells and may reduce apoptosis via activating AMPK dependent autophagy pathway.’, Med Hypotheses, 77 (4), 677-79. PubMed: 21831529