Oral Spermidine Targets Brown Fat and Skeletal Muscle to Mitigate Diet-Induced Obesity and Metabolic Disorders.

INTRODUCTION: Obesity causes many life-threatening diseases. It is important to develop effective approaches for obesity treatment. Oral supplementation with spermidine retards age-related processes, but its influences on obesity and various metabolic tissues remain largely unknow. This study aims to investigate the effects of oral spermidine on brown adipose tissue (BAT) and skeletal muscle as well as its roles in counteracting obesity and metabolic disorders. METHODS AND RESULTS: Spermidine is orally administrated into high-fat diet (HFD)-fed mice. The weight gain, insulin resistance, and hepatic steatosis are attenuated by oral spermidine in HFD-fed mice, accompanied by an alleviation of white adipose tissue inflammation. Oral spermidine promotes BAT activation and metabolic adaptation of skeletal muscle in HFD-fed mice, evidenced by UCP-1 induction and CREB activation in both tissues. Notably, oral spermidine upregulates tyrosine hydroxylase in hypothalamus of HFD-fed mice; spermidine treatment increases tyrosine hydroxylase expression and norepinephrine production in neurocytes, which leads to CREB activation and UCP-1 induction in brown adipocytes and myotubes. Spermidine also directly promotes UCP-1 and PGC-1α expression in brown adipocytes and myotubes. CONCLUSION: Spermidine serves as an oral supplement to attenuate obesity and metabolic disorders through hypothalamus-dependent or -independent BAT activation and skeletal muscle adaptation.

Nutraceutical Approaches of Autophagy and Neuroinflammation in Alzheimer's Disease: A Systematic Review.

Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer's disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called "nutraceuticals" epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD.

Spermine and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo.

The global increase in neurodegenerative disorders is one of the most crucial public health issues. Oral polyamine intake was shown to improve memory performance which is thought to be mediated at least in part via increased autophagy induced in brain cells. In Alzheimer's Disease, T-cells were identified as important mediators of disease pathology. Since autophagy is a central regulator of cell activation and cytokine production, we investigated the influence of polyamines on T-cell activation, autophagy, and the release of Th1/Th2 cytokines from blood samples of patients (n=22) with cognitive impairment or dementia in comparison to healthy controls (n=12) ex vivo. We found that spermine downregulated all investigated cytokines in a dose-dependent manner. Spermidine led to an upregulation of some cytokines for lower dosages, while high dosages downregulated all cytokines apart from upregulated IL-17A. Autophagy and T-cell activation increased in a dose-dependent manner by incubation with either polyamine. Although effects in patients were seen in lower concentrations, alterations were similar to controls.We provide novel evidence that supplementation of polyamines alters the function of T-cells. Given their important role in dementia, these data indicate a possible mechanism by which polyamines would help to prevent structural and cognitive decline in aging.

Spermidine supplementation and voluntary activity differentially affect obesity-related structural changes in the mouse lung.

Obesity is associated with lung function impairment and respiratory diseases; however, the underlying pathophysiological mechanisms are still elusive, and therapeutic options are limited. This study examined the effects of prolonged excess fat intake on lung mechanics and microstructure and tested spermidine supplementation and physical activity as intervention strategies. C57BL/6N mice fed control diet (10% fat) or high-fat diet (HFD; 60% fat) were left untreated or were supplemented with 3 mM spermidine, had access to running wheels for voluntary activity, or a combination of both. After 30 wk, lung mechanics was assessed, and left lungs were analyzed by design-based stereology. HFD exerted minor effects on lung mechanics and resulted in higher body weight and elevated lung, air, and septal volumes. The number of alveoli was higher in HFD-fed animals. This was accompanied by an increase in epithelial, but not endothelial, surface area. Moreover, air-blood barrier and endothelium were significantly thicker. Neither treatment affected HFD-related body weights. Spermidine lowered lung volumes as well as endothelial and air-blood barrier thicknesses toward control levels and substantially increased the endothelial surface area under HFD. Activity resulted in decreased volumes of lung, septa, and septal compartments but did not affect vascular changes in HFD-fed mice. The combination treatment showed no additive effect. In conclusion, excess fat consumption induced alveolar capillary remodeling indicative of impaired perfusion and gas diffusion. Spermidine alleviated obesity-related endothelial alterations, indicating a beneficial effect, whereas physical activity reduced lung volumes apparently by other, possibly systemic effects.

Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial.

BACKGROUND: Given the global increase in the aging population and age-related diseases, the promotion of healthy aging is one of the most crucial public health issues. This trial aims to contribute to the establishment of effective approaches to promote cognitive and brain health in older individuals with subjective cognitive decline (SCD). Presence of SCD is known to increase the risk of objective cognitive decline and progression to dementia due to Alzheimer's disease. Therefore, it is our primary goal to determine whether spermidine supplementation has a positive impact on memory performance in this at-risk group, as compared with placebo. The secondary goal is to examine the effects of spermidine intake on other neuropsychological, behavioral, and physiological parameters. METHODS: The SmartAge trial is a monocentric, randomized, double-blind, placebo-controlled phase IIb trial. The study will investigate 12 months of intervention with spermidine-based nutritional supplementation (target intervention) compared with 12 months of placebo intake (control intervention). We plan to recruit 100 cognitively normal older individuals with SCD from memory clinics, neurologists and general practitioners in private practice, and the general population. Participants will be allocated to one of the two study arms using blockwise randomization stratified by age and sex with a 1:1 allocation ratio. The primary outcome is the change in memory performance between baseline and post-intervention visits (12 months after baseline). Secondary outcomes include the change in memory performance from baseline to follow-up assessment (18 months after baseline), as well as changes in neurocognitive, behavioral, and physiological parameters (including blood and neuroimaging biomarkers), assessed at baseline and post-intervention. DISCUSSION: The SmartAge trial aims to provide evidence of the impact of spermidine supplementation on memory performance in older individuals with SCD. In addition, we will identify possible neurophysiological mechanisms of action underlying the anticipated cognitive benefits. Overall, this trial will contribute to the establishment of nutrition intervention in the prevention of Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03094546 . Registered 29 March 2017-retrospectively registered. PROTOCOL VERSION: Based on EA1/250/16 version 1.5.

Beneficial effects of spermidine on cardiovascular health and longevity suggest a cell type-specific import of polyamines by cardiomyocytes.

Recent and exciting in vivo studies show that supplementation with the polyamine spermidine (Spd) is cardioprotective and prolongs lifespan in both mice and humans. The mechanisms behind Spd-induced cardioprotection are supposed to involve Spd-evoked stimulation of autophagy, mitophagy and mitochondrial respiration and improved the mechano-elastical function of cardiomyocytes. Although cellular uptake of Spd was not characterized, these results suggest that Spd is imported by the cardiomyocytes and acts intracellularly. In the light of these new and thrilling data, we discuss in the present review cellular polyamine import with a special focus on mechanisms that may be relevant for Spd uptake by electrically excitable cells such as cardiomyocytes.

Spermidine in health and disease.

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.

Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

Supplementation of spermidine, an autophagy-inducing agent, has been shown to protect against neurodegeneration and cognitive decline in aged animal models. The present translational study aimed to determine safety and tolerability of a wheat germ extract containing enhanced spermidine concentrations. In a preclinical toxicity study, supplementation of spermidine using this extract did not result in morbidities or changes in behavior in BALBc/Rj mice during the 28-days repeated-dose tolerance study. Post mortem examination of the mice organs showed no increase in tumorigenic and fibrotic events. In the human cohort (participants with subjective cognitive decline, n=30, 60 to 80 years of age), a 3-month randomized, placebo-controlled, double-blind Phase II trial was conducted with supplementation of the spermidine-rich plant extract (dosage: 1.2 mg/day). No differences were observed between spermidine and placebo-treated groups in vital signs, weight, clinical chemistry and hematological parameters of safety, as well as in self-reported health status at the end of intervention. Compliance rates above 85% indicated excellent tolerability. The data demonstrate that spermidine supplementation using a spermidine-rich plant extract is safe and well-tolerated in mice and older adults. These findings allow for longer-term intervention studies in humans to investigate the impact of spermidine treatment on cognition and brain integrity.

Resembling breast milk: influence of polyamine-supplemented formula on neonatal BALB/cOlaHsd mouse microbiota.

Infant microbiota is influenced by numerous factors, such as delivery mode, environment, prematurity and diet (breast milk or formula). In addition to its nutritional value, breast milk contains bioactive substances that drive microbial colonisation and support immune system development, which are usually not present in infant formulas. Among these substances, polyamines have been described to be essential for intestinal and immune functions in newborns. However, their effect on the establishment of microbiota remains unclear. Therefore, the aim of the present study was to ascertain whether an infant formula supplemented with polyamines has an impact on microbial colonisation by modifying it to resemble that in breast-fed neonatal BALB/c mice. In a 4 d intervention, a total of sixty pups (14 d old) were randomly assigned to the following groups: (1) breast-fed group; (2) non-enriched infant formula-fed group; (3) three different groups fed an infant formula enriched with increasing concentrations of polyamines (mixture of putrescine, spermidine and spermine), following the proportions found in human milk. Microbial composition in the contents of the oral cavity, stomach and small and large intestines was analysed by quantitative PCR targeted at fourteen bacterial genera and species. Significantly different (P< 0·05) microbial colonisation patterns were observed in the entire gastrointestinal tract of the breast-fed and formula-fed mice. In addition, our findings demonstrate that supplementation of polyamines regulates the amounts of total bacteria, Akkermansia muciniphila, Lactobacillus, Bifidobacterium, Bacteroides-Prevotella and Clostridium groups to levels found in the breast-fed group. Such an effect requires further investigation in human infants, as supplementation of an infant formula with polyamines might contribute to healthy gastrointestinal tract development.

Antioxidant effect of polyamines on erythrocyte cell membrane lipoperoxidation after free-radical damage.

This in vitro study determined the effect of three doses each (100, 500 and 1000 microm) of putrescine, spermidine and spermine on malondialdehyde (MDA) release in red blood cells (RBCs) from healthy individuals after hydrogen peroxide stimulation (10 mM). Twenty-two volunteers, 9 males and 13 females, aged 41.5 +/- 16.4 years, were studied. MDA was measured by thiobarbituric reaction (TBARs) and the results were calculated using epsilon = 1.56 x 10(5). The analysis of variance (ANOVA) demonstrated a statistically significant overall decrease in MDA release in the polyamine-exposed cells (p < 0.0001) when compared with unexposed cells. Individual analysis of each polyamine separately showed a 52% decrease in MDA release with added spermine and a 39.5% decrease with added spermidine (p < 0.001). No evaluable effect was found for putrescine. There was no correlation between the effect produced and the three doses of spermidine or spermine added, indicating a non dose-dependent action.

Polyamine oxidase and tissue transglutaminase activation in rat small intestine by polyamines.

Polyamine degradation was studied in the small intestine from rats fed on a polyamine-supplemented diet. Lactalbumin diet was given to Hooded-Lister rats, with or without 5 mg rat(-1) day(-1) of putrescine or spermidine for 5 days. Polyamine oxidase activity increased with putrescine and spermidine in the diet, whereas spermidine/spermine N(1)-acetyltransferase and diamine oxidase activities were unchanged. We also studied the calcium-dependent and -independent tissue transglutaminase activities, since they can modulate intestinal polyamine levels. Both types of enzymes increased in the cytosolic fraction after putrescine (about 65%) or spermidine (80-100%). Our results indicate that exogenous polyamines stimulate intestinal polyamine oxidase and tissue transglutaminase activities, probably to prevent polyamine accumulation, when other pathways of polyamine catabolism (acetylation and terminal catabolism) are not activated.