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Science (New York, N.Y.) Jan 2018Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction... (Review)
Review
Interventions that delay aging and protect from age-associated disease are slowly approaching clinical implementation. Such interventions include caloric restriction mimetics, which are defined as agents that mimic the beneficial effects of dietary restriction while limiting its detrimental effects. One such agent, the natural polyamine spermidine, has prominent cardioprotective and neuroprotective effects and stimulates anticancer immunosurveillance in rodent models. Moreover, dietary polyamine uptake correlates with reduced cardiovascular and cancer-related mortality in human epidemiological studies. Spermidine preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence. Mechanistically, it shares the molecular pathways engaged by other caloric restriction mimetics: It induces protein deacetylation and depends on functional autophagy. Because spermidine is already present in daily human nutrition, clinical trials aiming at increasing the uptake of this polyamine appear feasible.
Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; Biological Transport; Caloric Restriction; Carcinogenesis; Cardiovascular Diseases; Dietary Supplements; Humans; Metabolic Syndrome; Neuroprotective Agents; Spermidine
PubMed: 29371440
DOI: 10.1126/science.aan2788 -
Nature Aging Dec 2022Aging involves the systemic deterioration of all known cell types in most eukaryotes. Several recently discovered compounds that extend the healthspan and lifespan of... (Review)
Review
Aging involves the systemic deterioration of all known cell types in most eukaryotes. Several recently discovered compounds that extend the healthspan and lifespan of model organisms decelerate pathways that govern the aging process. Among these geroprotectors, spermidine, a natural polyamine ubiquitously found in organisms from all kingdoms, prolongs the lifespan of fungi, nematodes, insects and rodents. In mice, it also postpones the manifestation of various age-associated disorders such as cardiovascular disease and neurodegeneration. The specific features of spermidine, including its presence in common food items, make it an interesting candidate for translational aging research. Here, we review novel insights into the geroprotective mode of action of spermidine at the molecular level, as we discuss strategies for elucidating its clinical potential.
Topics: Animals; Mice; Spermidine; Aging; Longevity; Autophagy; Polyamines
PubMed: 37118547
DOI: 10.1038/s43587-022-00322-9 -
Comprehensive Reviews in Food Science... May 2022Spermidine, a natural autophagy inducer, has a variety of health effects, such as antitumor, antiaging, anti-inflammation, cardiovascular protection, and... (Review)
Review
Spermidine, a natural autophagy inducer, has a variety of health effects, such as antitumor, antiaging, anti-inflammation, cardiovascular protection, and neuromodulation. It has been a hot topic in the field of food processing, and current research findings suggest that spermidine-rich foods may be used in intervention and prevention of age-related diseases. In this article, recent findings on the safety, health effects, absorption and metabolism of spermidine were reviewed, and advances in food processing, including the raw materials evaluation, physical and chemical processing, and biological processing of spermidine, were highlighted. In particular, the core metabolic pathways, key gene targets, and efficient metabolic engineering strategies involved in the biosynthesis of spermidine and its precursors were discussed. Moreover, limitations and future perspectives of spermidine research were proposed. The purpose of this review is to provide new insights on spermidine from its safety to its food processing, which will advance the commercial production and applications of spermidine-rich foods and nutraceuticals.
Topics: Autophagy; Dietary Supplements; Food Handling; Spermidine
PubMed: 35478379
DOI: 10.1111/1541-4337.12963 -
Pharmacological Research Sep 2020Spermidine, as a natural component from polyamine members, is originally isolated from semen and also existed in many natural plants, and can be responsible for cell... (Review)
Review
Spermidine, as a natural component from polyamine members, is originally isolated from semen and also existed in many natural plants, and can be responsible for cell growth and development in eukaryotes. The supplementation of spermidine can extend health and lifespan across species. Although the elevated levels of polyamines and the regulation of rate-limiting enzymes for polyamine metabolism have been identified as the biomarkers in many cancers, recent epidemiological data support that an increased uptake of spermidine as a caloric restriction mimic can reduce overall mortality associated with cancers. The possible mechanisms between spermidine and cancer development may be related to the precise regulation of polyamine metabolism, anti-cancer immunosurveillance, autophagy, and apoptosis. Increased intake of polyamine seems to suppress tumorigenesis, but appears to accelerate the growth of established tumors. Based on these observations and the absolute requirement for polyamines in tumor growth, spermidine could be a rational target for chemoprevention and clinical therapeutics of cancers.
Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Biomarkers, Tumor; Cell Proliferation; Humans; Neoplasms; Predictive Value of Tests; Signal Transduction; Spermidine
PubMed: 32461185
DOI: 10.1016/j.phrs.2020.104943 -
Aging Apr 2020The natural polyamine spermidine and spermine have been reported to ameliorate aging and aging-induced dementia. However, the mechanism is still confused. An aging...
The natural polyamine spermidine and spermine have been reported to ameliorate aging and aging-induced dementia. However, the mechanism is still confused. An aging model, the senescence accelerated mouse-8 (SAMP8), was used in this study. Novel object recognition and the open field test results showed that oral administration of spermidine, spermine and rapamycin increased discrimination index, modified number, inner squares distance and times. Spermidine and spermine increased the activity of SOD, and decreased the level of MDA in the aging brain. Spermidine and spermine phosphorylate AMPK and regulate autophagy proteins (LC3, Beclin 1 and p62). Spermidine and spermine balanced mitochondrial and maintain energy for neuron, with the regulation of MFN1, MFN2, DRP1, COX IV and ATP. In addition, western blot results (Bcl-2, Bax and Caspase-3, NLRP3, IL-18, IL-1β) showed that spermidine and spermine prevented apoptosis and inflammation, and elevate the expression of neurotrophic factors, including NGF, PSD95and PSD93 and BDNF in neurons of SAMP8 mice. These results indicated that the effect of spermidine and spermine on anti-aging is related with improving autophagy and mitochondrial function.
Topics: Animals; Autophagy; Brain; Cellular Senescence; Dementia; Disease Models, Animal; Mice; Mitochondria; Oxidative Stress; Spermidine; Spermine
PubMed: 32268299
DOI: 10.18632/aging.103035 -
Aging Cell Jun 2021Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular...
Vascular calcification is a common pathologic condition in patients with chronic kidney disease (CKD) and aging individuals. It has been established that vascular calcification is a gene-regulated biological process resembling osteogenesis involving osteogenic differentiation. However, there is no efficient treatment available for vascular calcification so far. The natural polyamine spermidine has been demonstrated to increase life span and protect against cardiovascular disease. It is unclear whether spermidine supplementation inhibits vascular calcification in CKD. Alizarin red staining and quantification of calcium content showed that spermidine treatment markedly reduced mineral deposition in both rat and human vascular smooth muscle cells (VSMCs) under osteogenic conditions. Additionally, western blot analysis revealed that spermidine treatment inhibited osteogenic differentiation of rat and human VSMCs. Moreover, spermidine treatment remarkably attenuated calcification of rat and human arterial rings ex vivo and aortic calcification in rats with CKD. Furthermore, treatment with spermidine induced the upregulation of Sirtuin 1 (SIRT1) in VSMCs and resulted in the downregulation of endoplasmic reticulum (ER) stress signaling components, such as activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein homologous protein (CHOP). Both pharmacological inhibition of SIRT1 by SIRT1 inhibitor EX527 and knockdown of SIRT1 by siRNA markedly blocked the inhibitory effect of spermidine on VSMC calcification. Consistently, EX527 abrogated the inhibitory effect of spermidine on aortic calcification in CKD rats. We for the first time demonstrate that spermidine alleviates vascular calcification in CKD by upregulating SIRT1 and inhibiting ER stress, and this may develop a promising therapeutic treatment to ameliorate vascular calcification in CKD.
Topics: Animals; Humans; Male; Rats; Renal Insufficiency, Chronic; Signal Transduction; Sirtuin 1; Spermidine; Vascular Calcification
PubMed: 33969611
DOI: 10.1111/acel.13377 -
Trends in Cell Biology May 2024Polyamines - putrescine, spermidine, and spermine - are widely distributed aliphatic compounds known to regulate important biological processes in prokaryotic and... (Review)
Review
Polyamines - putrescine, spermidine, and spermine - are widely distributed aliphatic compounds known to regulate important biological processes in prokaryotic and eukaryotic cells. Therefore, spermidine insufficiency is associated with various physio-pathological processes, such as aging and cancers. Recent advances in immuno-metabolism and immunotherapy shed new light on the role of spermidine in immune cell regulation and anticancer responses. Here, we review novel works demonstrating that spermidine is produced by collective metabolic pathways of gut bacteria, bacteria-host co-metabolism, and by the host cells, including activated immune cells. We highlight the effectiveness of spermidine in enhancing antitumor responses in aged animals otherwise nonresponsive to immune checkpoint therapy and propose that spermidine supplementation could be used to enhance the efficacy of anti-PD-1 treatment.
Topics: Spermidine; Humans; Animals; Aging; Gastrointestinal Microbiome; Neoplasms; Immunotherapy
PubMed: 37723019
DOI: 10.1016/j.tcb.2023.08.002 -
Neuropeptides Oct 2020Spermidine is a naturally occurring endogenous polyamine synthesized from diamine putrescine. It is a well-known autophagy inducer that maintains cellular and neuronal... (Review)
Review
Spermidine is a naturally occurring endogenous polyamine synthesized from diamine putrescine. It is a well-known autophagy inducer that maintains cellular and neuronal homeostasis. Healthy brain development and function are dependent on brain polyamine concentration. Polyamines interact with the opioid system, glutamatergic signaling and neuroinflammation in the neuronal and glial compartments. Among the polyamines, spermidine is found highest in the human brain. Age-linked fluctuations in the spermidine levels may possibly contribute to the impairments in neural network and neurogenesis. Exogenously administered spermidine helps in the treatment of brain diseases. Further, current studies highlight the ability of spermidine to promote longevity by inducing autophagy. Still, the causal neuroprotective mechanism of spermidine in neuronal dysfunction remains unidentified. This review aims to summarize various neuroprotective effects of spermidine related to anti-aging/ anti-inflammatory properties and the prevention of neurotoxicity that helps in achieving beneficial effects in age-related neurological disorder. We also expose the signaling cascades modulated by spermidine which might result in therapeutic action. The present review highlights clinical studies along with in-vivo and in-vitro preclinical studies to provide a new dimension for the therapeutic potential of spermidine in neurological disorders.
Topics: Animals; Autophagy; Brain; Humans; Nervous System Diseases; Neuroprotective Agents; Spermidine
PubMed: 32873420
DOI: 10.1016/j.npep.2020.102083 -
JAMA Network Open May 2022Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Developing interventions against age-related memory decline and for older adults experiencing neurodegenerative disease is one of the greatest challenges of our generation. Spermidine supplementation has shown beneficial effects on brain and cognitive health in animal models, and there has been preliminary evidence of memory improvement in individuals with subjective cognitive decline.
OBJECTIVE
To determine the effect of longer-term spermidine supplementation on memory performance and biomarkers in this at-risk group.
DESIGN, SETTING, AND PARTICIPANTS
This 12-month randomized, double-masked, placebo-controlled phase 2b trial (the SmartAge trial) was conducted between January 2017 and May 2020. The study was a monocenter trial carried out at an academic clinical research center in Germany. Eligible individuals were aged 60 to 90 years with subjective cognitive decline who were recruited from health care facilities as well as through advertisements in the general population. Data analysis was conducted between January and March 2021.
INTERVENTIONS
One hundred participants were randomly assigned (1:1 ratio) to 12 months of dietary supplementation with either a spermidine-rich dietary supplement extracted from wheat germ (0.9 mg spermidine/d) or placebo (microcrystalline cellulose). Eighty-nine participants (89%) successfully completed the trial intervention.
MAIN OUTCOMES AND MEASURES
Primary outcome was change in memory performance from baseline to 12-month postintervention assessment (intention-to-treat analysis), operationalized by mnemonic discrimination performance assessed by the Mnemonic Similarity Task. Secondary outcomes included additional neuropsychological, behavioral, and physiological parameters. Safety was assessed in all participants and exploratory per-protocol, as well as subgroup, analyses were performed.
RESULTS
A total of 100 participants (51 in the spermidine group and 49 in the placebo group) were included in the analysis (mean [SD] age, 69 [5] years; 49 female participants [49%]). Over 12 months, no significant changes were observed in mnemonic discrimination performance (between-group difference, -0.03; 95% CI, -0.11 to 0.05; P = .47) and secondary outcomes. Exploratory analyses indicated possible beneficial effects of the intervention on inflammation and verbal memory. Adverse events were balanced between groups.
CONCLUSIONS AND RELEVANCE
In this randomized clinical trial, longer-term spermidine supplementation in participants with subjective cognitive decline did not modify memory and biomarkers compared with placebo. Exploratory analyses indicated possible beneficial effects on verbal memory and inflammation that need to be validated in future studies at higher dosage.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03094546.
Topics: Aged; Animals; Biomarkers; Cognition; Cognitive Dysfunction; Dietary Supplements; Female; Humans; Inflammation; Neurodegenerative Diseases; Spermidine
PubMed: 35616942
DOI: 10.1001/jamanetworkopen.2022.13875 -
European Journal of Medicinal Chemistry Oct 2022Spermidine alkaloids are a kind of natural products possessing an aliphatic triamine structure with three or four methylene groups between two N-atoms. Spermidine... (Review)
Review
Spermidine alkaloids are a kind of natural products possessing an aliphatic triamine structure with three or four methylene groups between two N-atoms. Spermidine alkaloids exist in plants, microorganisms, and marine organisms, which usually form amide structures with cinnamic acid or fatty acid derivatives. Their unique structures showed a wide range of biological activities such as neuroprotective, anti-aging, anti-cancer, antioxidant, anti-inflammatory, and antimicrobial. In order to better understand the research status of spermidine alkaloids and promote their applications in human health, this paper systematically reviewed the biological sources, structures, pharmacological actions, and synthetic processes of spermidine alkaloids over the past two decades. This will help to open up new pharmacological investigation fields and better drug design based on these spermidine alkaloids.
Topics: Alkaloids; Anti-Infective Agents; Biological Products; Humans; Neoplasms; Spermidine
PubMed: 35863273
DOI: 10.1016/j.ejmech.2022.114600