Sarcopenic obesity: emerging mechanisms and therapeutic potential

Metabolism, Год журнала: 2023, Номер 146, С. 155639 - 155639

Опубликована: Июнь 27, 2023

Sarcopenic obesity, or the loss of muscle mass and function associated with excess adiposity, is a largely untreatable medical condition diminished quality life increased risk mortality. To date, it remains somewhat paradoxical mechanistically undefined as to why subset adults obesity develop muscular decline, an anabolic stimulus generally retention lean mass. Here, we review evidence surrounding definition, etiology, treatment sarcopenic emphasis on emerging regulatory nodes therapeutic potential. We available clinical focused diet, lifestyle, behavioral interventions improve in patients obesity. Based upon evidence, relieving consequences energy burden, such oxidative stress, myosteatosis, and/or mitochondrial dysfunction, promising area for development management

Язык: Английский

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Metformin normalizes mitochondrial function to delay astrocyte senescence in a mouse model of Parkinson’s disease through Mfn2-cGAS signaling

Journal of Neuroinflammation, Год журнала: 2024, Номер 21(1)

Опубликована: Апрель 2, 2024

Abstract Background Senescent astrocytes play crucial roles in age-associated neurodegenerative diseases, including Parkinson’s disease (PD). Metformin, a drug widely used for treating diabetes, exerts longevity effects and neuroprotective activities. However, its effect on astrocyte senescence PD remains to be defined. Methods Long culture-induced replicative model 1-methyl-4-phenylpyridinium/α-synuclein aggregate-induced premature model, mouse of were investigate the metformin vivo vitro. Immunofluorescence staining flow cytometric analyses performed evaluate mitochondrial function. We stereotactically injected AAV carrying GFAP-promoter-cGAS-shRNA substantia nigra pars compacta regions specifically reduce astrocytic cGAS expression clarify potential molecular mechanism by which inhibited PD. Results showed that vitro mice. Mechanistically, normalized function DNA release through mitofusin 2 (Mfn2), leading inactivation cGAS-STING, delayed prevented neurodegeneration. Mfn2 overexpression reversed inhibitory role cGAS-STING activation senescence. More importantly, ameliorated dopamine neuron injury behavioral deficits mice reducing accumulation senescent via inhibition activation. Deletion abolished suppressive Conclusions This work reveals delays inhibiting Mfn2-cGAS suggest is promising therapeutic agent diseases.

Язык: Английский

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Mitochondria and the Repurposing of Diabetes Drugs for Off-Label Health Benefits

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(1), С. 364 - 364

Опубликована: Янв. 3, 2025

This review describes our current understanding of the role mitochondria in repurposing anti-diabetes drugs metformin, gliclazide, GLP-1 receptor agonists, and SGLT2 inhibitors for additional clinical benefits regarding unhealthy aging, long COVID, mental neurogenerative disorders, obesity. Metformin, most prominent these diabetes drugs, has been called “Drug Miracles Wonders,” as trials have found it to be beneficial human patients suffering from maladies. To promote viral replication all infected cells, SARS-CoV-2 stimulates liver cells produce glucose export into blood stream, which can cause COVID patients, reduces levels blood, was shown cut incidence rate half recovering SARS-CoV-2. Metformin leads phosphorylation AMP-activated protein kinase AMPK, accelerates import via transporter GLUT4 switches starvation mode, counteracting virus. Diabetes also stimulate unfolded response thus mitophagy, is healthy aging health. were mimic exercise help reduce body weight.

Язык: Английский

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Pentadecanoic Acid (C15:0), an Essential Fatty Acid, Shares Clinically Relevant Cell-Based Activities with Leading Longevity-Enhancing Compounds

Nutrients, Год журнала: 2023, Номер 15(21), С. 4607 - 4607

Опубликована: Окт. 30, 2023

Pentadecanoic acid (C15:0) is an essential odd-chain saturated fatty with broad activities relevant to protecting cardiometabolic, immune, and liver health. C15:0 activates AMPK inhibits mTOR, both of which are core components the human longevity pathway. To assess potential for enhance processes associated healthspan, we used cell-based molecular phenotyping assays compare three longevity-enhancing candidates: acarbose, metformin, rapamycin. (n = 36 in 10 12 cell systems) rapamycin 32 had most clinically relevant, dose-dependent activities. At their optimal doses, (17 µM) (9 shared 24 across systems, including anti-inflammatory (e.g., lowered MCP-1, TNFα, IL-10, IL-17A/F), antifibrotic, anticancer activities, further supported by previously published vitro vivo studies. Paired prior demonstrated abilities target pathways, hallmarks aging, aging rate biomarkers, type 2 diabetes, heart disease, cancer, nonalcoholic our results support as nutrient equivalent to, or surpassing, leading candidate compounds.

Язык: Английский

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The Anti-Aging Mechanism of Metformin: From Molecular Insights to Clinical Applications

Molecules, Год журнала: 2025, Номер 30(4), С. 816 - 816

Опубликована: Фев. 10, 2025

Aging represents a complex biological phenomenon marked by the progressive deterioration of physiological functions over time, reduced resilience, and increased vulnerability to age-related diseases, ultimately culminating in mortality. Recent research has uncovered diverse molecular mechanisms through which metformin extends its benefits beyond glycemic control, presenting it as promising intervention against aging. This review delves into anti-aging properties metformin, highlighting role mitochondrial energy modulation, activation AMPK-mTOR signaling pathway, stimulation autophagy, mitigation inflammation linked cellular Furthermore, we discuss influence on epigenetic modifications that underpin genomic stability homeostasis. Metformin's potential addressing age-associated disorders including metabolic, cardiovascular, neurodegenerative diseases is also explored. The Targeting with Metformin (TAME) trial aims provide key evidence efficacy delaying aging humans. Despite these insights, significant challenges persist gaining more comprehensive understanding underlying mechanisms, determining optimal dosing strategies, evaluating long-term safety non-diabetic populations. Addressing crucial fully realizing metformin's an therapeutic.

Язык: Английский

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Drugs Targeting Mechanisms of Aging to Delay Age-Related Disease and Promote Healthspan: Proceedings of a National Institute on Aging Workshop

The Journals of Gerontology Series A, Год журнала: 2023, Номер 78(Supplement_1), С. 53 - 60

Опубликована: Июнь 1, 2023

Abstract The geroscience hypothesis posits that by targeting key hallmarks of aging we may simultaneously prevent or delay several age-related diseases and thereby increase healthspan, life span spent free significant disease disability. Studies are underway to examine possible pharmacological interventions for this purpose. As part a National Institute on Aging workshop the development function-promoting therapies, scientific content experts provided literature reviews state-of-the-field assessments studies senolytics, nicotinamide adenine dinucleotide (NAD+) boosters, metformin. Cellular senescence increases with age, preclinical demonstrate use senolytic drugs improves healthspan in rodents. Human using senolytics progress. NAD+ its phosphorylated form, NADP+, play vital roles metabolism cellular signaling. Increasing supplementation precursors including riboside mononucleotide appears extend model organisms, but human limited results mixed. Metformin is biguanide widely used glucose lowering, which believed have pleiotropic effects aging. Preclinical suggest it observational benefits prevention diseases. Clinical trials metformin frailty prevention. emerging clinical there potential improve through pharmacologic agents reviewed. However, much further research needed general safety wider use, appropriate target populations, longer-term outcomes.

Язык: Английский

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Kidney Aging and Chronic Kidney Disease

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6585 - 6585

Опубликована: Июнь 14, 2024

The process of aging inevitably leads to an increase in age-related comorbidities, including chronic kidney disease (CKD). In many aspects, CKD can be considered a state accelerated and premature aging. Aging have numerous common characteristic features, ranging from pathological presentation clinical manifestation underlying mechanisms. shared mechanisms the development include cellular senescence, decrease autophagy, mitochondrial dysfunction, alterations epigenetic regulation, suggesting existence potential therapeutic targets that are applicable both conditions. this review, we provide comprehensive overview characteristics between CKD, encompassing morphological changes, functional alterations, recent advancements understanding Moreover, discuss strategies for targeting senescent cells CKD.

Язык: Английский

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Metformin: The Winding Path from Understanding Its Molecular Mechanisms to Proving Therapeutic Benefits in Neurodegenerative Disorders

Pharmaceuticals, Год журнала: 2023, Номер 16(12), С. 1714 - 1714

Опубликована: Дек. 11, 2023

Metformin, a widely prescribed medication for type 2 diabetes, has garnered increasing attention its potential neuroprotective properties due to the growing demand treatments Alzheimer's, Parkinson's, and motor neuron diseases. This review synthesizes experimental clinical studies on metformin's mechanisms of action therapeutic benefits neurodegenerative disorders. A comprehensive search electronic databases, including PubMed, MEDLINE, Embase, Cochrane library, focused key phrases such as "metformin", "neuroprotection", "neurodegenerative diseases", with data up September 2023. Recent research glucoregulatory reveals new molecular targets, activation LKB1-AMPK signaling pathway, which is crucial chronic administration metformin. The pleiotropic impact may involve other stress kinases that are acutely activated. precise role respiratory chain complexes (I IV), mitochondrial or lysosomes in metformin effects remains be established by further research. Research extrahepatic targets like gut microbiota, well antioxidant immunomodulatory properties, understanding Experimental animal models shows promising results, but inconclusive. Understanding could help design trials explore and, hopefully, prove conditions.

Язык: Английский

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Pharmacologic Modulation of Aging: Metformin–Mitochondrial Interplay

American Journal of Therapeutics, Год журнала: 2025, Номер 32(2), С. 159 - 161

Опубликована: Фев. 27, 2025

Язык: Английский

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The Science of Aging: Therapeutic Approaches to Extend Lifespan and Healthspan

SBV Journal of Basic Clinical and Applied Health Science, Год журнала: 2025, Номер 8(1), С. 13 - 17

Опубликована: Янв. 1, 2025

The growing field of antiaging pharmacology represents a significant shift in our understanding aging, characterized by progressive physiological decline and increased susceptibility to diseases. World Health Organization estimates that 2050, the number individuals aged 60 years older will reach 2 billion, emphasizing need for interventions not only extend lifespan but also enhance healthspan – duration life spent free from chronic disease. Key mechanisms aging include cellular senescence, inflammation, mitochondrial dysfunction, telomere shortening, which collectively contribute age-related diseases such as cardiovascular disorders neurodegeneration. Promising candidates therapies rapamycin, metformin, senolytics. Rapamycin, mechanistic target rapamycin inhibitor, has demonstrated lifespan-extending properties preclinical studies inducing autophagy maintaining integrity. Metformin been recognized its potential insulin sensitivity metabolic health, leading ongoing Targeting Aging with trial, investigates effects on conditions. Senolytics are designed eliminate senescent cells linked tissue dysfunction may improve phenotypes. Current clinical trials vital assessing safety efficacy these therapies, focusing distinction between healthspan. Investigating nicotinamide adenine dinucleotide (NAD+) precursors riboside mononucleotide presents new avenues reversing mechanisms. Incorporating biomarker assessments help monitor biological age support personalized treatment approaches. Despite advancements, ethical considerations surrounding accessibility, resource allocation, implications treating modifiable condition must be addressed. future therapeutics lies interdisciplinary collaboration, precision medicine, continual exploration biology signaling promising path toward improving health outcomes an population.

Язык: Английский

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