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Summary: External supply of the natural polyamine
spermidine can extend life span in model organisms
including yeast, nematodes, flies and mice. Recent
epidemiological evidence suggests that increased uptake
of spermidine with food also reduces overall, cardio-
vascular and cancer-related mortality in humans. Here,
we discuss the possible mechanisms of this intriguing
spermidine effect.
Polyamines including spermidine play an essential role
in intermediate metabolism. Since they are synthesized
by higher eukaryotic cells, they are not vitamins. How-
ever, the levels of polyamines are profoundly influenced
by their external supply, either by oral ingestion with
different food items or by the intestinal microbiota that
can synthesize polyamines as well [1].
Our groups have shown over the past decade that
supplementing spermidine by adding it to culture media
(as we did for the yeast Saccharomyces cerevisiae, the
nematode Caenorhabditis elegans and the fruit fly
Drosophila melanogaster) or to the drinking water (as
we did for the rodent Mus musculus) is sufficient to
extend longevity and to improve health span at multiple
levels [2, 3]. Thus, in mice, the supplementation was
able to suppress the age-related decline in cardio-
vascular function (as measured at 24 months of age) and
increased overall longevity by approximately 10%, [3].
Of note nutritional uptake of spermidine and spermine
but not putrescence could be linked to improved
cardiovascular health and autopsies performed at death
did not reveal any significant effect of spermidine on
the incidence of cancer, suggesting that the reduction of
cardiovascular morbidity was not compensated by an
increase in malignancies [3]. Rather, in mice, spermi-
dine postpones the manifestation cancer upon oncogenic
stimuli [4, 5].
Moreover, fragmentary evidence suggests that sper-
midine can also delay neurodegeneration, both in non-
mammalian model organisms [6] and in mouse models
[7, 8].
The molecular and cellular mechanisms through which
spermidine delays age-related disease and death have
been elucidated to some extent. Indeed, spermidine can
act as an inhibitor of the acetyl transferase activity of
E1A-associated protein p300 (where E1A = adenovirus
early region 1A), best known as EP300 [9]. EP300 act
as an endogenous inhibitor of autophagy by acetylating
lysine residues within multiple proteins that are involved
Letter to the Editor
in autophagy-regulatory or autophagy-executing cir-
cuitries [1, 10]. As a result, the inhibition of EP300 by
spermidine (which competes with the acetyl group
donor acetyl coenzyme A) stimulates auto-phagy [9]
Autophagy is required for the anti-aging effect of
spermidine as indicated by the fact that genetic
inhibition of autophagy (by knockout or knockdown of
essential autophagy-relevant genes) abolishes the lon-
gevity-extending effects of spermidine on yeast, worms
and flies [11]. Moreover, in mice, deletion/depletion of
essential autophagy genes in myocardial or cancer cells
reduces the beneficial effects of spermidine on cardio-
vascular disease and cancer, respectively [3, 4]. Auto-
phagy is a major mechanism of cellular adaptation to
stress, as well as the most important pathway for the
turnover of cytoplasmic structures including whole
organelles, thus facilitating the rejuvenation of impor-
tant portions of the cell. For this reason, autophagy has
a vast anti-aging potential to the point that most if not
all behavioural, nutritional, pharmacological or genetic
manipulations that extend longevity require autophagy
to be efficient [12-14].
Until now the literature on the longevity-enhancing
effects of spermidine has been limited to model orga-
nisms. Now, two prospective population-based studies
(summarized in the same paper) report for the first time
that nutritional spermidine uptake is also linked to
reduced overall, cardiovascular and cancer-related
mortality in humans [15]. Both studies were based on
the use of food questionnaires that allowed to calculate
for each individual the nutritional uptake of polyamines
including spermidine. Importantly, high spermidine
uptake constituted an independent favourable prog-
nostic parameter for reduced mortality, meaning that
this variable predicted a reduced incidence of death
even after correction for possible confounding factors
such as age, body mass index, consumption of alcohol
or aspirin, diabetes, metabolic syndrome, physical
activity, sex, socioeconomic status and even dietary
quality, supporting the idea that spermidine might
indeed be causally involved in a reduction of overall
morbidity and mortality [15].
In addition to the aforementioned epidemiological
results, there are further, though admittedly indirect
arguments in favour of a health-improving role for sper-
midine in human health. Thus, spermidine has been
classified as a “caloric restriction mimetic” that has   AGING2018,Vol.10,No. 8
FrankMadeo,DidacCarmona-Gutierrez, OliverKepp, GuidoKroemer    2209AGING
broad health-promoting effects due to its capacity to
induce similar biochemical changes as does caloric
restriction [16]. Second, the proximal pharmacological
target of spermidine is the same as that of salicylic acid,
the active metabolite or aspirin (both inhibit EP300 by
competing for the binding of acetyl coenzyme 1) [17],
knowing that aspirin is probable the one single drug that
has the broadest positive impact on human mortality
from cardiovascular and malignant disease [18].
The fine mechanism through which spermidine (and
aspirin) have such a broad effect on human health have
not yet been fully elucidated. Based on current know-
ledge, these agents may slow down the general clock of
the aging process, for instance by a global effect on
cellular fitness, thereby mediating a pleiotropic effect
on all aging-related diseases. The health-improving
effects of aspirin have been initially attributed to its
capacity to inhibit thrombocyte aggregation (via
inhibition of cyclooxygenase) and hence to act as an
anti-coagulant. Since spermidine has not been reported
to have similar anti-coagulant activity, we prefer the
hypothesis that aspirin may mediate its broad pro-health
effects via the inhibition of EP300. As an alternative,
yet non-exclusive mechanism, the natural EP300
inhibitor spermidine and its pharmacological equivalent
aspirin may both act on different yet distinct cell types
including stem cell compartments and differentiated
cells engaged in cardiovascular function (cardiac
muscle cells, endothelial cells, pericytes, small vessel
myocytes…), anticancer immune surveillance (cancer
and immune cells) or neuro-degeneration (neuronal and
glial cells) to reduce the incidence of the major age-
related diseases (Figure 1). Future research must
elucidate the molecular pathways on which spermidine
acts to identify actionable targets that may be used for
the treatment and prevention of age-related diseases.
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Conflictsofinterest: Allauthorsarethescientificfounders
Published:August6,2018    2211AGING
... Spermidine is a natural biomolecule which has been reported to possess a broad spectrum of health improving effects, that includes remarkable anti-inflammatory effects (Madeo et al., 2018b;Liu et al., 2020). It is also a potent antioxidant, and reportedly improves the respiratory function (Madeo et al., 2018a;Kim et al., 2021). Spermidine possesses a positive charge at the physiological pH that enables its interaction with oppositely charged DNA and RNA (Madeo et al., 2018a). ...
... It is also a potent antioxidant, and reportedly improves the respiratory function (Madeo et al., 2018a;Kim et al., 2021). Spermidine possesses a positive charge at the physiological pH that enables its interaction with oppositely charged DNA and RNA (Madeo et al., 2018a). Dietary intake of spermidine reduces the risk of neurodegeneration, metabolic diseases, heart ailments, and cancer. ...
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Spermidine is a naturally occurring polyamine compound found in semen. It is also found in several plant sources and boasts a remarkable biological profile, particularly with regards to its anticancer properties. Spermidine specifically interferes with the tumour cell cycle, resulting in the inhibition of tumor cell proliferation and suppression of tumor growth. Moreover, it also triggers autophagy by regulating key oncologic pathways. The increased intake of polyamines, such as spermidine, can suppress oncogenesis and slow the growth of tumors due to its role in anticancer immunosurveillance and regulation of polyamine metabolism. Spermidine/spermine N-1-acetyltransferase (SSAT) plays a critical role in polyamine homeostasis and serves as a diagnostic marker in human cancers. Chemically modified derivatives of spermidine hold great potential for prognostic, diagnostic, and therapeutic applications against various malignancies. This review discusses in detail the recent findings that support the anticancer mechanisms of spermidine and its molecular physiology.
... The causative compound within Streptococcus supernatants is accepted to be spermidine, a polyamine capable of inducing cytoprotective autophagy associated with an increased turnover of cells, proteins and organelles. Spermidine is further associated with chemotherapy potentiation and tumorigenesis suppression in murine models [238,239]. Moreover, spermidine levels are shown to decrease with biological ageing, further supporting its role in ageing, and this polyamine displays low toxicity in mice and humans [240]. ...
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Bioprospecting is the discovery and exploration of biological diversity found within organisms, genetic elements or produced compounds with prospective commercial or therapeutic applications. The human skin is an ecological niche which harbours a rich and compositional diversity microbiome stemming from the multifactorial interactions between the host and microbiota facilitated by exploitable effector compounds. Advances in the understanding of microbial colonisation mechanisms alongside species and strain interactions have revealed a novel chemical and biological understanding which displays applicative potential. Studies elucidating the organismal interfaces and concomitant understanding of the central processes of skin biology have begun to unravel a potential wealth of molecules which can exploited for their proposed functions. A variety of skin-microbiome-derived compounds display prospective therapeutic applications, ranging from antioncogenic agents relevant in skin cancer therapy to treatment strategies for antimicrobial-resistant bacterial and fungal infections. Considerable opportunities have emerged for the translation to personal care products, such as topical agents to mitigate various skin conditions such as acne and eczema. Adjacent compound developments have focused on cosmetic applications such as reducing skin ageing and its associated changes to skin properties and the microbiome. The skin microbiome contains a wealth of prospective compounds with therapeutic and commercial applications; however, considerable work is required for the translation of in vitro findings to relevant in vivo models to ensure translatability.
... 7 Several studies have focused on the impact of SPD on the aging process, demonstrating its ability to enhance mitochondrial biogenesis and function. 4,8,9 Newer studies indicate that SPD can alleviate cardiac injury by reducing stress damage; 5 however, no research has been conducted to date to investigate the effects of SPD on diabetic myocardial fibrosis. ...
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Background: The main pathological feature of diabetic cardiomyopathy (DCM) caused by diabetes mellitus is myocardial fibrosis. According to recent studies in cardiology, it has been suggested that spermidine (SPD) has cardioprotective properties. Aims: To explore the role and mechanism of SPD in alleviating myocardial fibrosis of DCM. Study design: In vivo and in vitro study. Methods: Type 2 diabetic mice and primary neonatal mouse cardiac fibroblasts (CFs) were selected. Measurements of serum-related markers, echocardiographic analysis, and immunohistochemistry were used to evaluate myocardial fibrosis injury and the effects of SPD. The proliferation and migration of CFs undergoing different treatments were studied. Immunoblotting and real-time quantitative reverse transcription polymerase chain reaction were used to demonstrate molecular mechanisms. Results: In vivo immunoblotting analysis indicated a downregulation of ornithine decarboxylase and an upregulation of SPD/spermine N1-acetyltransferase. We observed cardiac dysfunction in diabetic mice after 12 weeks. However, the administration of exogenous SPD improved cardiac function, decreased collagen deposition, and reduced myocardial tissue damage. mRNA expression levels of NLRP3, Caspase-1, GSDMD-N, interleukin (IL)-1β, IL-17A, and IL-18 were increased and suppressed in the myocardium of db/db mice upon treatment with SPD. SPD inhibited the proliferation, migration, and collagen secretion of high-glucose-treated fibroblasts in vitro. SPD inhibits the activation of the TGF-β1/Smad signaling pathway and decreases collagen deposition by reducing pyroptosis and Smad-7 ubiquitination levels. Conclusion: Based on our findings, SPD may have potential applications in protecting against the deterioration of cardiac function in patients with DCM due to a significant new mechanism for diabetic myocardial fibrosis that we discovered.
... Furthermore, as a geroprotector, spermidine decreases markers of age-related oxidative damage in mice [156], preserves mitochondrial function, holds anti-inflammatory properties, and prevents stem cell senescence [161]. In particular, the anti-inflammatory properties are exerted by several mechanisms that directly result on the reduction in the expression of pro-inflammatory cytokines, as recently well-reviewed by Ni et al. [162]: (I) Inhibition of accumulation of ROS, (II) decrease in the expression levels of tumor necrosis factor-α (TNF-α), (III) suppression of the translocation in the nucleus of nuclear factor-kB (NF-kB) p65 subunit [163], (IV) inhibition of the expression of IL-18 and IL-1β [162,164], and (V) attenuation of receptor interacting protein (RIP1) deubiquitination in macrophages, chondrocytes, and synovial tissue of osteoarthritic mice model [165,166]. ...
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Autophagy dysregulation is commonplace in the pathogenesis of several invalidating diseases, such as musculoskeletal diseases. Polyamines, as spermidine and spermine, are small aliphatic cations essential for cell growth and differentiation, with multiple antioxidant, anti-inflammatory, and anti-apoptotic effects. Remarkably, they are emerging as natural autophagy regulators with strong anti-aging effects. Polyamine levels were significantly altered in the skeletal muscles of aged animals. Therefore, supplementation of spermine and spermidine may be important to prevent or treat muscle atrophy. Recent in vitro and in vivo experimental studies indicate that spermidine reverses dysfunctional autophagy and stimulates mitophagy in muscles and heart, preventing senescence. Physical exercise, as polyamines, regulates skeletal muscle mass inducing proper autophagy and mitophagy. This narrative review focuses on the latest evidence regarding the efficacy of polyamines and exercise as autophagy inducers, alone or coupled, in alleviating sarcopenia and aging-dependent musculoskeletal diseases. A comprehensive description of overall autophagic steps in muscle, polyamine metabolic pathways, and effects of the role of autophagy inducers played by both polyamines and exercise has been presented. Although literature shows few data in regard to this controversial topic, interesting effects on muscle atrophy in murine models have emerged when the two “autophagy-inducers” were combined. We hope these findings, with caution, can encourage researchers to continue investigating in this direction. In particular, if these novel insights could be confirmed in further in vivo and clinical studies, and the two synergic treatments could be optimized in terms of dose and duration, then polyamine supplementation and physical exercise might have a clinical potential in sarcopenia, and more importantly, implications for a healthy lifestyle in the elderly population.
... In this latter category, we found a core circadian clock gene, CRY2 (Hazlerigg & Wagner, 2006;Vallone et al., 2007), an inhibitor of gluconeogenesis (Zhang et al., 2010) and promoter of lipogenesis (Machicao et al., 2016) that was upregulated in dispersers ( Fig. 3H) as well as FAM3A, an inhibitor of gluconeogenesis and of lipogenesis being downregulated in dispersers (Wang et al., 2014). Other enriched categories were related to pigmentation (GO: endosome to melanosome transport) and the synthesis of polyamines (spermidine metabolic process, polyamine biosynthetic process), the latter category including the gene SRM that produces spermidine (an aging related polyamine in animals (Madeo, Carmona-Gutierrez, Kepp, & Kroemer, 2018)). ...
Although animal dispersal is known to play key roles in ecological and evolutionary processes such as colonization, population extinction and local adaptation, little is known about its genetic basis, particularly in vertebrates. Untapping the genetic basis of dispersal should deepen our understanding of how dispersal behaviour evolves, the molecular mechanisms that regulate it and link it to other phenotypic aspects in order to form the so‐called dispersal syndromes. Here, we comprehensively combined quantitative genetics, genome‐wide sequencing and transcriptome sequencing to investigate the genetic basis of natal dispersal in a known ecological and evolutionary model of vertebrate dispersal: the common lizard, Zootoca vivipara. Our study supports the heritability of dispersal in semi‐natural populations, with less variation attributable to maternal and natal environment effects. In addition, we found an association between natal dispersal and both variation in the Carbonic Anhydrase (CA10) gene, and in the expression of several genes (TGFB2, SLC6A4, NOS1) involved in central nervous system functioning. These findings suggest that neurotransmitters (serotonin and nitric oxide) are involved in the regulation of dispersal and shaping dispersal syndromes. Several genes from the circadian clock (CRY2, KCTD21) were also differentially expressed between disperser and resident lizards, supporting that the circadian rhythm, known to be involved in long‐distance migration in other taxa, might affect dispersal as well. Since neuronal and circadian pathways are relatively well conserved across vertebrates, our results are likely to be generalisable, and we therefore encourage future studies to further investigate the role of these pathways in shaping dispersal in vertebrates.
Ageing is a complex biological process which has significant effects on host physiology. It is associated with an altered gut microbiome structure and function characterised by a lower diversity, stability, increase in pathogenic microorganisms (such as Clostridium, Escherichia, Staphylococcus, Streptococcus, Proteobacteria, etc.) and a decrease in beneficial microbes (such as Actinobacteria). Age-associated impairment of the gut mucosal barrier (also known as ‘leaky gut’) allows such pathogenic microbes and microbial components to enter the circulation, causing hyperinflammatory responses and inflammageing leading to several diseases. Gut microbes utilise different dietary components to produce a wide range of metabolites, such as short chain fatty acids (e.g. acetate, propionate, butyrate), aryl hydrocarbon receptor ligands (e.g. metabolites of tryptophan), polyamines (e.g. putrescine, spermidine, spermine), etc., thereby exerting local effects and mediating cross-talks between the gut and other organs such as the brain, liver, kidney, heart, eye, bone, muscle, adipose tissue, etc. Age-related gut dysbiosis is associated with the production of harmful metabolites which impair health outcomes. Specific gut microbial metabolites, such as trimethylamine (TMA), p-cresol, and indole, are related to clinical conditions such as cardiovascular diseases, renal diseases, liver diseases, respiratory diseases, diabetes, etc. Supplementation with probiotics, prebiotics, synbiotics, and dietary and lifestyle modifications may be helpful to improve and maintain gut eubiosis, although results are still inconclusive. In this chapter, we will highlight the age-associated changes in gut microbiome composition and associated metabolite profile, along with its involvement with commonly encountered age-associated conditions.KeywordsElderlyAgeingGut microbiomeInflammationSCFATMAO
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Diabetic cardiomyopathy (DCM) is a serious complication and death cause of diabetes mellitus (DM). Recent cardiology studies suggest that spermidine has cardioprotective effects. Here, we verified the hypothesis of spermidine's protective effects on DCM. Therefore, db/db mice and primary neonatal mouse cardiomyocytes were used to observe the effects of spermidine. Immunoblotting showed that ornithine decarboxylase (ODC) and SPD/spermine N1-acetyltransferase (SSAT) were downregulated and upregulated in the myocardium of db/db mice, respectively. We found that diabetic mice showed cardiac dysfunction in 12 weeks. Conversely, exogenous spermidine could improve cardiac functions and reduce the deposition of collagens, myocardial damage, reactive oxygen species (ROS) levels and endoplasmic reticulum stress (ERS) in diabetic mouse hearts. Our results also demonstrated that cardiomyocytes displayed ferroptosis and then activated Pannexin-1 expression, which resulted in the increase of the extracellular adenosine triphosphate (ATP). Subsequently, increased ATP as a paracrine molecule combined to purinergic receptor P2X7 (P2X7) to activate ERK1/2 signaling pathway in cardiomyocytes and activated NCOA4-mediated ferroptinophagy to promote lipid peroxidation and ferroptosis. Interestingly, spermidine could reverse these molecular processes. Our findings indicate an important new mechanism for DCM, and suggest spermidine have potential applicability to protect against deterioration of cardiac function with DCM.
Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.
Background & aims: Liver diseases present a wide range of fibrosis, from fatty liver with no inflammation to steatohepatitis with varying degrees of fibrosis, to established cirrhosis leading to HCC. In a multivariate analysis, serum levels of spermidine were chosen as the top metabolite from 237 metabolites and its levels were drastically reduced along with progression to advanced steatohepatitis. Our previous studies that showed spermidine supplementation helps mice prevent liver fibrosis through MAP1S have prompted us to explore the possibility that spermidine can alleviate or cure already-developed liver fibrosis. Methods: We collected tissue samples from patients with liver fibrosis to measure the levels of MAP1S. We treated wild-type and MAP1S knockout mice with CCl4 -induced liver fibrosis with spermidine and isolated HSCs in culture to test the effects of spermidine on HSC activation and liver fibrosis. Results: Patients with increasing degrees of liver fibrosis had reduced levels of MAP1S. Supplementing spermidine in mice that had already developed liver fibrosis after one month of CCl4 induction for an additional three months resulted in significant reductions in levels of ECM proteins and a remarkable improvement in liver fibrosis through MAP1S. Spermidine also suppressed HSC activation by reducing ECM proteins at both the mRNA and protein levels, and increasing the number of lipid droplets in stellate cells. Conclusions: Spermidine supplementation is a potentially clinically meaningful approach to treating and curing liver fibrosis, preventing cirrhosis and HCC in patients.
Neuropathic pain is one of the most critical types of chronic pain despite the increasing advances in medical science. Spermidine (SPD) is a natural polyamine that has wide roles in several cellular processes inducing autophagy and reducing oxidative stress. This study aimed to investigate the effects of SPD on oxidative stress markers and pain threshold in the neuropathic rat model of chronic constriction injury (CCI) model. Eighteen adult male rats were divided into 3 groups: sham, CCI and CCI+ SPD. After induction of neuropathy via CCI model in the CCI and CCI+SPD groups, SPD (1 mg/kg/day, orally) was administered to the CCI+SPD group for 3 weeks. The behavioral tests (von Frey, hot plate) were done 4 times during the experiment. At the end of the study, electrophysiological tests, the H & E staining, and oxidative stress assay of the prefrontal cortex (PFC), spinal cord, and sciatic nerve were performed. The threshold of pain in hot plate and von Frey tests was significantly lower in the CCI group than the sham group, which was reversed by SPD treatment in the CCI+ SPD group. In addition, nerve conduction was considerably lower in the CCI group than in the sham and CCI+SPD groups (P<0.01, P< 0.05, respectively). The CCI group showed neuronal degeneration and fibrosis in the different tissues in the H & E assay; elevated tissues level of nitrite, decreased levels of SOD, GPx, and catalase were also observed. However, SPD treatment modulated the pathological changes and oxidative stress biomarkers. In conclusion, SPD showed beneficial effects in decreasing neuropathic pains. SPD treatment reduced oxidative stress, improved histopathological changes and behavioral tests in the CCI-induced neuropathic pain in in vivo model.
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Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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To assess the therapeutic potential of spermidine in mice with excitatory amino acid carrier 1 (EAAC1) deletion (EAAC1 knockout [KO] mice), a mouse model of normal tension glaucoma. Spermidine, at 30 mM in drinking water, was administered to EAAC1 KO mice from 5 to 12 weeks old. Optical coherence tomography, multifocal electroretinograms, and the measurement of intraocular pressure (IOP) were performed at 5, 8, and 12 weeks old. Histopathology analyses were carried out at 8 and 12 weeks old, and immunoblot and immunohistochemical analyses of 4-hydroxy-2-nonenal (4-HNE) in the retina were performed at 8 weeks old. Spermidine ameliorated retinal degeneration and improved visual function in EAAC1 KO mice at both 8 and 12 weeks old, without affecting IOP. A significant increase of 4-HNE was observed in vehicle-treated EAAC1 KO mice, but spermidine treatment reduced this increase, suggesting that spermidine alleviated the severity of the glaucoma-like phenotype by acting as an antioxidant. The results from this study suggest that oral spermidine administration could be a useful treatment for retinal degenerative disorders including glaucoma.
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Spermidine acts as an endogenous free radical scavenger and inhibits the action of reactive oxygen species. In this study, we examined the effects of spermidine on retinal ganglion cell (RGC) death in a mouse model of optic nerve injury (ONI). Daily ingestion of spermidine reduced RGC death following ONI and sequential in vivo retinal imaging revealed that spermidine effectively prevented retinal degeneration. Apoptosis signal-regulating kinase-1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase kinase kinase and has an important role in ONI-induced RGC apoptosis. We demonstrated that spermidine suppresses ONI-induced activation of the ASK1-p38 mitogen-activated protein kinase pathway. Moreover, production of chemokines important for microglia recruitment was decreased with spermidine treatment and, consequently, accumulation of retinal microglia is reduced. In addition, the ONI-induced expression of inducible nitric oxide synthase in the retina was inhibited with spermidine treatment, particularly in microglia. Furthermore, daily spermidine intake enhanced optic nerve regeneration in vivo. Our findings indicate that spermidine stimulates neuroprotection as well as neuroregeneration, and may be useful for treatment of various neurodegenerative diseases including glaucoma.
Background: Spermidine administration is linked to increased survival in several animal models. Objective: The aim of this study was to test the potential association between spermidine content in diet and mortality in humans. Design: This prospective community-based cohort study included 829 participants aged 45-84 y, 49.9% of whom were male. Diet was assessed by repeated dietitian-administered validated food-frequency questionnaires (2540 assessments) in 1995, 2000, 2005, and 2010. During follow-up between 1995 and 2015, 341 deaths occurred. Results: All-cause mortality (deaths per 1000 person-years) decreased across thirds of increasing spermidine intake from 40.5 (95% CI: 36.1, 44.7) to 23.7 (95% CI: 20.0, 27.0) and 15.1 (95% CI: 12.6, 17.8), corresponding to an age-, sex- and caloric intake-adjusted 20-y cumulative mortality incidence of 0.48 (95% CI: 0.45, 0.51), 0.41 (95% CI: 0.38, 0.45), and 0.38 (95% CI: 0.34, 0.41), respectively. The age-, sex- and caloric ratio-adjusted HR for all-cause death per 1-SD higher spermidine intake was 0.74 (95% CI: 0.66, 0.83; P < 0.001). Further adjustment for lifestyle factors, established predictors of mortality, and other dietary features yielded an HR of 0.76 (95% CI: 0.67, 0.86; P < 0.001). The association was consistent in subgroups, robust against unmeasured confounding, and independently validated in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) Study (age-, sex-, and caloric ratio-adjusted HR per 1-SD higher spermidine intake: 0.71; 95% CI: 0.53, 0.95; P = 0.019). The difference in mortality risk between the top and bottom third of spermidine intakes was similar to that associated with a 5.7-y (95% CI: 3.6, 8.1 y) younger age. Conclusion: Our findings lend epidemiologic support to the concept that nutrition rich in spermidine is linked to increased survival in humans. This trial was registered at as NCT03378843.
The capacity of cells and organisms to sustain, and to eventually adapt to, environmental and genetic insults declines with age. Because macroautophagy/autophagy is regarded as one of the major determinants of cellular fitness in vitro and in vivo, maneuvers that aim at promoting autophagy may slow down aging and promote health span. Caloric restriction (CR), a reduction in caloric intake without malnutrition, efficiently counteracts aging-associated features, yet is difficult to be applied to humans. Caloric-restriction mimetics (CRMs) are pharmacological agents that recapitulate the main biochemical properties of CR, namely a global reduction of protein acetylation and the induction of autophagy. We found that the ancient drug aspirin and its active metabolite salicylate stimulate autophagic flux by virtue of their inhibitory action on acetyltransferase EP300. The inhibition of EP300 results from a direct competition between salicylate and acetyl coenzyme A for binding to the catalytic domain of the enzyme. This mode of action appears to be conserved across evolution as it accounts for the induction of autophagy by aspirin in various mouse models and in the nematode Caenorhabditis elegans. In sum, aspirin acts as a CRM.
The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.
Having your longevity and eating too Although caloric restriction has clear benefits for maximizing health span and life span, it is sufficiently unpleasant that few humans stick to it. Madeo et al. review evidence that increased intake of the polyamine spermidine appears to reproduce many of the healthful effects of caloric restriction, and they explain its cellular actions, which include enhancement of autophagy and protein deacetylation. Spermidine is found in foods such as wheat germ, soybeans, nuts, and some fruits and vegetables and produced by the microbiota. Increased uptake of spermidine has protective effects against cancer, metabolic disease, heart disease, and neurodegeneration. Science , this issue p. eaan2788
Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy which trigger oxidative stress-induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan.
Several metabolic alterations accumulate over time along with a reduction in biological fitness, suggesting the existence of a “metabolic clock” that controls aging. Multiple inborn defects in metabolic circuitries accelerate aging, whereas genetic loci linked to exceptional longevity influence metabolism. Each of the nine hallmarks of aging is connected to undesirable metabolic alterations. The main features of the “westernized” lifestyle, including hypercaloric nutrition and sedentariness, can accelerate aging as they have detrimental metabolic consequences. Conversely, lifespan-extending maneuvers including caloric restriction impose beneficial pleiotropic effects on metabolism. The introduction of strategies that promote metabolic fitness may extend healthspan in humans.
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.