Caloric Restriction Mimetics in Nutrition and Clinical Trials

Frontiers in Nutrition, Год журнала: 2021, Номер 8

Опубликована: Сен. 6, 2021

The human diet and dietary patterns are closely linked to the health status. High-calorie Western-style diets have increasingly come under scrutiny as their caloric load composition contribute development of non-communicable diseases, such diabetes, cancer, obesity, cardiovascular disorders. On other hand, calorie-reduced health-promoting shown promising results in maintaining reducing disease burden throughout aging. More recently, pharmacological Caloric Restriction Mimetics (CRMs) gained interest public scientific community candidates that mimic some myriad effects induced by restriction. Importantly, many CRM activate autophagy, prolong life- healthspan model organisms ameliorate diverse symptoms without need cut calories. Among others, glycolytic inhibitors (e.g., D-allulose, D-glucosamine), hydroxycitric acid, NAD + precursors, polyamines spermidine), polyphenols resveratrol, dimethoxychalcones, curcumin, EGCG, quercetin) salicylic acid qualify candidates, which naturally available via foods beverages. However, it is yet unclear how these bioactive substances benefits healthy diets. In this review, we thus discuss sources, availability intake levels CRMs. Finally, since translational research on CRMs has entered clinical stage, provide a summary trials.

Язык: Английский

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NAD ⁺ Metabolism in Cardiac Health, Aging, and Disease

Circulation, Год журнала: 2021, Номер 144(22), С. 1795 - 1817

Опубликована: Ноя. 29, 2021

Nicotinamide adenine dinucleotide (NAD + ) is a central metabolite involved in energy and redox homeostasis as well DNA repair protein deacetylation reactions. Pharmacological or genetic inhibition of NAD -degrading enzymes, external supplementation precursors, transgenic overexpression -generating enzymes have wide positive effects on metabolic health age-associated diseases. pools tend to decline with normal aging, obesity, hypertension, which are all major risk factors for cardiovascular disease, replenishment extends healthspan, avoids syndrome, reduces blood pressure preclinical models. In addition, experimental elevation improves atherosclerosis, ischemic, diabetic, arrhythmogenic, hypertrophic, dilated cardiomyopathies, different modalities heart failure. Here, we critically discuss cardiomyocyte-specific circuitries metabolism, comparatively evaluate distinct precursors their efficacy, raise outstanding questions the optimal design clinical trials supraphysiological elevations assessed prevention treatment cardiac We surmise that patients hitherto intractable diseases such failure preserved ejection fraction may profit from administration precursors. The development -centered treatments will rely technological conceptual progress fine regulation metabolism.

Язык: Английский

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Sex differences in heart mitochondria regulate diastolic dysfunction

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Июль 4, 2022

Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial differences might underlie this bias. As part of genetic studies heart mice, observe DNA levels function tend to be reduced females as compared males. We also expression genes encoding proteins are higher males human cohorts. test our hypothesis panel genetically diverse inbred strains termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, find gene is highly correlated diastolic function, key trait HFpEF. Consistent this, "two-hit" mouse model HFpEF confirm differs between sexes strongly associated number traits. By integrating data from HMDP cohort, identify Acsl6 determinant function. validate its role using adenoviral over-expression heart. conclude underlie, part, bias

Язык: Английский

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Immunometabolic mechanisms of heart failure with preserved ejection fraction

Nature Cardiovascular Research, Год журнала: 2022, Номер 1(3), С. 211 - 222

Опубликована: Март 14, 2022

Язык: Английский

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Cardiac metabolism in HFpEF: from fuel to signalling

Cardiovascular Research, Год журнала: 2022, Номер 118(18), С. 3556 - 3575

Опубликована: Дек. 7, 2022

Heart failure (HF) is marked by distinctive changes in myocardial uptake and utilization of energy substrates. Among the different types HF, HF with preserved ejection fraction (HFpEF) a highly prevalent, complex, heterogeneous condition for which metabolic derangements seem to dictate disease progression. Changes intermediate metabolism cardiometabolic HFpEF-among most prevalent forms HFpEF-have large impact both on provision number signalling pathways heart. This dual, vs. signalling, role played particular long-chain fatty acids (LCFAs) short-chain carbon sources [namely, (SCFAs) ketone bodies (KBs)]. LCFAs are key fuels heart, but their excess can be harmful, as case toxic accumulation lipid by-products (i.e. lipotoxicity). SCFAs KBs have been proposed potential major, alternative source HFpEF. At same time, substrate protein post-translational modifications other direct indirect pivotal importance HFpEF pathogenesis. An in-depth molecular understanding biological functions substrates will instrumental development novel therapeutic approaches Here, we summarize current evidence HFpEF, discuss metabolites through, at least part, fate modifications, highlight clinical translational challenges around therapy

Язык: Английский

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The CD38 glycohydrolase and the NAD sink: implications for pathological conditions

AJP Cell Physiology, Год журнала: 2022, Номер 322(3), С. C521 - C545

Опубликована: Фев. 9, 2022

Nicotinamide adenine dinucleotide (NAD) acts as a cofactor in several oxidation-reduction (redox) reactions and is substrate for number of nonredox enzymes. NAD fundamental to variety cellular processes including energy metabolism, cell signaling, epigenetics. homeostasis appears be paramount importance health span longevity, its dysregulation associated with multiple diseases. metabolism dynamic maintained by synthesis degradation. The enzyme CD38, one the main NAD-consuming enzymes, key component homeostasis. majority CD38 localized plasma membrane catalytic domain facing extracellular environment, likely purpose controlling systemic levels NAD. Several types express but expression predominates on endothelial cells immune capable infiltrating organs tissues. Here we review potential roles disease postulate ways which causes changes contributes pathophysiology conditions. Indeed, animal models development infectious diseases, autoimmune disorders, fibrosis, metabolic age-associated diseases cancer, heart disease, neurodegeneration are altered enzymatic activity. Many these conditions modified CD38-deficient mice or blocking NADase In play role, CD38-dependent decline often common denominator pathophysiology. Thus, understanding may open new avenues treatment human

Язык: Английский

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Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

Circulation Research, Год журнала: 2022, Номер 131(6), С. 476 - 491

Опубликована: Авг. 15, 2022

Background: Experimental evidence suggests a key role of SIRT1 (silent information regulator 1) in age- and metabolic-related vascular dysfunction. Whether these effects hold true the human microvasculature is unknown. We aimed to investigate very early stages obesity-related microvascular dysfunction humans. Methods: Ninety-five subjects undergoing elective laparoscopic surgery were recruited stratified based on their body mass index status (above or below 30 kg/m 2 ) age 40 years) 4 groups: Young Nonobese, Obese, Old Obese. measured small resistance arteries’ endothelial function by pressurized micromyography before after incubation with agonist (SRT1720) mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO). assessed levels mtROS nitric oxide availability confocal microscopy gene expression mitochondrial proteins qPCR. Chromatin immunoprecipitation assay was employed SIRT1-dependent epigenetic regulation proteins. Results: Compared obese older patients showed lower antioxidant (FOXO3 [forkhead box protein O3] SOD2) higher pro-oxidant aging p66 Shc Arginase II. Obese Nonobese groups rescued SRT1720. The restoration comparable one obtained mitoTEMPO. These explained chromatin changes leading reduced upregulation involved respiratory chain. Conclusions: novel central modulator earliest damage induced obesity. Through complex control mainly involving II, it influences levels, NO availability, Therapeutic modulation restores obesity- age-related Early targeting might represent crucial strategy prevent

Язык: Английский

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Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice

Journal of Molecular and Cellular Cardiology, Год журнала: 2022, Номер 165, С. 76 - 85

Опубликована: Янв. 5, 2022

Язык: Английский

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Colchicine alleviates inflammation and improves diastolic dysfunction in heart failure rats with preserved ejection fraction

European Journal of Pharmacology, Год журнала: 2022, Номер 929, С. 175126 - 175126

Опубликована: Июнь 30, 2022

Several studies have reported that colchicine attenuates cardiac inflammation and improves function in myocardial infarction atrial fibrillation. However, no study has investigated its effect on heart failure with preserved ejection fraction (HFpEF). Hence, this aimed to assess efficacy a high salt diet (HSD)-induced HFpEF rat model.A hypertension-induced model was created by treating Dahl/SS salt-sensitive rats an HSD for 6 weeks. Colchicine given via gavage daily as treatment. Cardiac were assessed using echocardiography, histology, ELISA. Furthermore, the expression levels of NLRP3 NF-κB signaling pathways examined.Treatment increased survival attenuated dysfunction, indicated decreased echocardiographic E/A ratio longer exercise endurance along reduced ventricular fibrosis remodeling HSD-induced Dahl rats. The treatment also oxidative stress inflammatory cell infiltration, inferred from lower mRNA expressions TNFα CCL2 well protein pathways.The findings signify plays crucial role alleviating systemic activation attenuating dysfunction model. Colchicine, therefore, holds therapeutic potential further clinical applications.

Язык: Английский

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Molecular properties and regulation of NAD+ kinase (NADK)

Redox Biology, Год журнала: 2022, Номер 59, С. 102561 - 102561

Опубликована: Дек. 5, 2022

Nicotinamide adenine dinucleotide (NAD+) kinase (NADK) phosphorylates NAD+, thereby producing nicotinamide phosphate (NADP). Both NADK genes and the NADP(H)-producing mechanism are evolutionarily conserved among archaea, bacteria, plants mammals. In mammals, is activated by phosphorylation protein-protein interaction. Recent studies conducted using genetically altered models validate essential role of in cellular redox homeostasis metabolism multicellular organisms. Here, we describe evolutionary conservation, molecular properties, signaling mechanisms discuss pathophysiological significance NADK.

Язык: Английский

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