Empagliflozin protects against heart failure with preserved ejection fraction partly by inhibiting the senescence-associated STAT1–STING axis

Cardiovascular Diabetology, Journal Year: 2024, Volume and Issue: 23(1)

Published: July 23, 2024

Abstract Heart failure with preserved ejection fraction (HFpEF) is a mortal clinical syndrome without effective therapies. Empagliflozin (EMPA) improves cardiovascular outcomes in HFpEF patients, but the underlying mechanism remains elusive. Here, mice were fed high-fat diet (HFD) supplemented L-NAME for 12 weeks and subsequently intraperitoneally injected EMPA another 4 weeks. A 4D-DIA proteomic assay was performed to detect protein changes failing hearts. We identified 310 differentially expressed proteins (DEPs) (ctrl vs. group) 173 DEPs (HFpEF group). The regulation of immune system processes enriched all groups interferon response genes (STAT1, Ifit1, Ifi35 Ifi47) upregulated downregulated after administration. In addition, treatment suppressed increase levels aging markers (p16 p21) Further bioinformatics analysis verified STAT1 as hub transcription factor during pathological mice. next treated H9C2 cells IFN-γ, primary agonist phosphorylation, investigate whether plays beneficial role by blocking activation. Our results showed that IFN-γ caused cardiomyocyte senescence activation, which inhibited Notably, inhibition significantly reduced cellular possibly regulating STING expression. findings revealed mitigates cardiac inflammation inhibiting STAT1–STING axis may act pivotal pathogenesis HFpEF, especially under inflammatory conditions. Graphical abstract schematic figure depicts model (this drawn using FigDraw software).

Language: Английский

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Gut microbiota and immunosenescence in cancer

Seminars in Cancer Biology, Journal Year: 2024, Volume and Issue: 104-105, P. 32 - 45

Published: Aug. 8, 2024

Language: Английский

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Renin–angiotensin system inhibitors positively impact on multiple aging regulatory pathways: Could they be used to protect against human aging?

Physiological Reports, Journal Year: 2024, Volume and Issue: 12(12)

Published: June 1, 2024

The renin-angiotensin system (RAS)-a classical blood pressure regulator-largely contributes to healthy organ development and function. Besides, RAS activation promotes age-related changes age-associated diseases, which are attenuated/abolished by RAS-blockade in several mammalian species. RAS-blockers also increase rodent lifespan. In previous work, we discussed how downregulates mTOR growth hormone/IGF-1 signaling, stimulates AMPK activity (together with klotho, sirtuin, vitamin D-receptor upregulation), proposed that at least some of RAS-blockade's aging benefits mediated through regulation these intermediaries their signaling mitochondria. Here, included impact on other regulatory pathways, is, TGF-ß, NF-kB, PI3K, MAPK, PKC, Notch, Wnt, all affect No direct evidence is available RAS/RAS-blockade-aging pathway-mitochondria interactions. However, existing results allow conjecture neutralize mitochondrial dysfunction acting the pathways. reviewed led us propose foundation laid for conducting clinical trials aimed testing whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB)-even subclinical doses-offer possibility live longer better health. As ACEi ARB low cost well-tolerated anti-hypertension therapies use over 35 years, investigating administration attenuate/prevent effects seems simple implement.

Language: Английский

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Is it time to revise the fighting strategy toward type 2 diabetes? Sex and pollution as new risk factors

Ageing Research Reviews, Journal Year: 2024, Volume and Issue: 99, P. 102405 - 102405

Published: July 4, 2024

Diabetes mellitus, a metabolic condition affecting around 537 million individuals worldwide, poses significant challenges, particularly among the elderly population. The etiopathogenesis of type 2 diabetes (T2D) depends on combination effects driven by advancing age, genetic background, and lifestyle habits, e.g. overnutrition. These factors influence development T2D differently in men women, with an obvious sexual dimorphism possibly underlying diverse clinical features disease different sexes. More recently, environmental pollution, estimated to cause 9 deaths every year, is emerging as novel risk factor for T2D. Indeed, exposure atmospheric pollutants such PM2.5, O3, NO2, Persistent Organic Pollutants (POP)s, along their bioaccumulation, associated obesity, 15 % excess case very high levels PM2.5. Similar data are available plasticizer molecules, bisphenol A phthalates, endocrine-disrupting chemicals. Even though causality still debated at this stage, preclinical evidence sustains ability multiple affect pancreatic function, promote insulin resistance, alter lipid metabolism, contributing onset progression. In addition, findings suggest possible role also plastic itself pioneeristic studies evidenced that micro- or nanoplastics (MNP)s, particles nano- range, cellular damage, senescence, inflammation, disturbances, leading resistance impaired glucose metabolism animal and/or vitro models. Here we synthesize recent knowledge relative association between air-related plastic-derived incidence T2D, discussing mechanistic links suggested literature. We then anticipate need future field candidate therapeutic strategies limiting pollution-induced damage models, SGLT-2 inhibitors. finally postulate guidelines prevention should consider pollution sex additional limit pandemic.

Language: Английский

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Addition of Polyphenols to Drugs: The Potential of Controlling “Inflammaging” and Fibrosis in Human Senescent Lung Fibroblasts In Vitro

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7163 - 7163

Published: June 28, 2024

The combination of a polyphenol, quercetin, with dasatinib initiated clinical trials to evaluate the safety and efficacy senolytics in idiopathic pulmonary fibrosis, lung disease associated presence senescent cells. Another approach senotherapeutics consists controlling inflammation related cellular senescence or “inflammaging”, which participates, among other processes, establishing fibrosis. We whether polyphenols such as caffeic acid, chlorogenic epicatechin, gallic resveratrol combined different metformin rapamycin, antifibrotic drugs nintedanib pirfenidone, could present beneficial actions an vitro model MRC-5 fibroblasts. A senescent-associated secretory phenotype (SASP) was evaluated by measurement interleukin (IL)-6, IL-8, IL-1β. β-galactosidase (SA-β-gal) activity proliferation were assessed. Fibrosis using Picrosirius red assay gene expression fibrosis-related genes. Epithelial-mesenchymal transition (EMT) assayed A549 cell line exposed Transforming Growth Factor (TGF)-β vitro. that demonstrated best results inhibiting IL-6 IL-8 Metformin acid also restore reduce SA-β-gal during induction. collagen production cells inhibited epicatechin alone drugs. Epicatechin able control EMT In conclusion, can potentially increase effectiveness senotherapeutic diseases whose pathophysiological component is

Language: Английский

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A new clinical age of aging research

Trends in Endocrinology and Metabolism, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 1, 2024

Aging is a major risk factor for variety of diseases, thus, translation aging research into practical applications driven by the unmet need existing clinical therapeutic options. Basic and translational efforts are converging at critical stage, yielding insights how fundamental mechanisms used to identify promising geroprotectors or therapeutics. This review highlights several areas from perspective, including senescent cell targeting, alleviation inflammaging, optimization metabolism with endogenous metabolites precursors. Refining our understanding these key areas, especially angle, may help us better understand attenuate processes improve overall health outcomes.

Language: Английский

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Alpha-Glucosidase Inhibitors in Aging and Aging-Related Diseases: Clinical Applications and Relevant Mechanisms

Aging and Disease, Journal Year: 2025, Volume and Issue: unknown, P. 0 - 0

Published: Jan. 1, 2025

Aging is a complex and universal process marked by gradual functional declines at the cellular tissue levels, often leading to range of aging-related diseases such as diabetes, cardiovascular diseases, cancer. Delaying aging can help prevent, slow down, alleviate severity these various conditions, enhancing overall health well-being. Alpha-glucosidase inhibitors (AGIs) are class widely used antidiabetic drugs that inhibit alpha-glucosidase in small intestinal mucosa, delaying carbohydrate absorption reducing postprandial hyperglycemia. Beyond their roles diabetes treatment, AGIs have shown potential extending lifespan effectively treating modulating oxidative stress, gut microbiota, inflammatory responses, nutrient-sensing pathways. This review summarizes recent advancements application for preventing with focus on mechanisms processes.

Language: Английский

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Impact of sodium-glucose cotransporter-2 inhibitors on aging biomarkers and plasma ceramide levels in type 2 diabetes: beyond glycemic control

Annals of Medicine, Journal Year: 2025, Volume and Issue: 57(1)

Published: April 28, 2025

Aging is a complex biological process marked by the decline of physiological functions and heightened susceptibility to chronic illnesses, notably cardiometabolic disorders. Ceramides (Cer) are lipid derivatives linked aging metabolic diseases. Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i), widely used in managing type 2 diabetes, have an unclear impact on biomarkers Cer profiles. This study explored association between SGLT2i use, plasma levels (CerC16:0, CerC18:0, CerC22:0, CerC24:0, CerC24:1), biomarkers-Human Insulin-Like Growth Factor 1 (IGF-1), mammalian target rapamycin (mTOR), 5-Methylcytosine (5MC), Human H2AFX (Histone H2AX) patients with diabetes mellitus (T2DM). In this retrospective study, 95 participants were divided into three groups: (n = 34), non-SGLT2i anti-diabetic treatments 36), healthy controls 25). Plasma quantified using Liquid Chromatography tandem mass spectrometry (LC-MS-MS) ELISA, respectively. Principal component analysis (PCA) assessed group-based clustering, while ANCOVA evaluated group differences confounder adjustment. SGLT2i-treated showed significantly lower CerC16:0, CerC24:1 (p < 0.01) decreased 5MC H2AX 0.05) compared patients. IGF-1 was elevated 0.01), suggesting possible protective effect health. PCA distinguished control from diabetic groups but revealed overlap groups. Beyond glucose control, may improve markers patients, supporting their broader therapeutic potential age-related Further large-scale studies warranted confirm these effects underlying mechanisms.

Language: Английский

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SGLT2 inhibitors as a novel senotherapeutic approach

npj Aging, Journal Year: 2025, Volume and Issue: 11(1)

Published: May 10, 2025

Language: Английский

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mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(16), P. 8676 - 8676

Published: Aug. 8, 2024

The aging process contributes significantly to the onset of chronic diseases, which are primary causes global mortality, morbidity, and healthcare costs. Numerous studies have shown that removal senescent cells from tissues extends lifespan reduces occurrence age-related diseases. Consequently, there is growing momentum in development drugs targeting these cells. Among them, mTOR SGLT-2 inhibitors garnered attention due their diverse effects: regulate cellular growth, metabolism, immune responses, while glucose reabsorption kidneys, resulting various beneficial metabolic effects. Importantly, may act synergistically by influencing senescence processes pathways. Although direct on combined effects inhibition limited, this review aims highlight potential synergistic benefits senescence.

Language: Английский

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