NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(709)

Published: Aug. 16, 2023

Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues ameliorates diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated vitro, regardless of stimuli induced cellular various mice nonhuman primates vivo. Accordingly, developed demonstrated chimeric antigen receptor (CAR) T targeting human NKG2DLs selectively effectively diminish undergoing senescence oncogenic stress, replicative DNA damage, or P16 INK4a overexpression vitro. Targeting with mouse NKG2D-CAR alleviated multiple aging-associated pathologies improved physical performance both irradiated mice. Autologous armed the NKG2D CAR delete naturally occurring without any observed adverse effects. Our findings establish could serve as potent selective senolytic agents for diseases driven senescence.

Language: Английский

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Targeting aging and age-related diseases with vaccines

Nature Aging, Journal Year: 2024, Volume and Issue: 4(4), P. 464 - 482

Published: April 15, 2024

Language: Английский

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Energy metabolism as therapeutic target for aged wound repair by engineered extracellular vesicle

Science Advances, Journal Year: 2024, Volume and Issue: 10(15)

Published: April 12, 2024

Aging skin, vulnerable to age-related defects, is poor in wound repair. Metabolic regulation accumulated senescent cells (SnCs) with aging essential for tissue homeostasis, and adequate ATP important cell activation aged Strategies metabolism intervention hold prospects therapeutic advances. Here, we found energy metabolic changes skin from patients mice. Our data show that metformin engineered EV (Met-EV) can enhance mouse repair, as well ameliorate cellular senescence restore dysfunctions. Notably, was remodeled reduced glycolysis enhanced OXPHOS after Met-EV treatment. We rescue senescence-induced mitochondria dysfunctions mitophagy suppressions, indicating the role of remodeling mitochondrial functions via production results reveal mechanism SnCs rejuvenation by suggest disturbed metabolism, be a potential target facilitating

Language: Английский

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Targeting senescent cells with NKG2D-CAR T cells

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: May 4, 2024

Abstract This study investigates the efficacy of NKG2D chimeric antigen receptor (CAR) engineered T cells in targeting and eliminating stress-induced senescent vitro. Cellular senescence contributes to age-related tissue decline is characterized by permanent cell cycle arrest senescence-associated secretory phenotype (SASP). Immunotherapy, particularly CAR-T therapy, emerges as a promising approach selectively eliminate cells. Our focus on receptor, which binds ligands (NKG2DLs) upregulated cells, offering target for Using mouse embryonic fibroblasts (MEFs) astrocytes (AST) models, we demonstrate elevated expression NKG2DLs response genotoxic oxidative stress. NKG2D-CAR displayed potent cytotoxicity against these with minimal effects non-senescent suggesting their potential targeted senolytics. In conclusion, our research presents first evidence cells’ ability brain novel manage diseases. The findings pave way future investigations into therapeutic applicability NKG2D-targeting naturally aged organisms models aging-associated diseases vivo.

Language: Английский

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Topical drug delivery strategies for enhancing drug effectiveness by skin barriers, drug delivery systems and individualized dosing

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 16, 2024

Topical drug delivery is widely used in various diseases because of the advantages not passing through gastrointestinal tract, avoiding irritation and hepatic first-pass effect, reaching lesion directly to reduce unnecessary adverse reactions. The skin helps organism defend itself against a huge majority external aggressions one most important lines defense body. However, skin’s strong barrier ability also obstacle effectiveness topical medications. Allowing bioactive, composition pass stratum corneum as needed reach target site essential need for exert its therapeutic effect. state barrier, choice system composition, individualized disease detection dosing planning influence Nowadays, enhancing transdermal absorption topically applied drugs hottest research area. first improve all drugs. Excessive enhances accumulation at non-target sites occurrence This paper introduces strategies from three perspectives: delivery, describes current status shortcomings research, provides new directions ideas research.

Language: Английский

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Redox regulation: mechanisms, biology and therapeutic targets in diseases

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: March 7, 2025

Redox signaling acts as a critical mediator in the dynamic interactions between organisms and their external environment, profoundly influencing both onset progression of various diseases. Under physiological conditions, oxidative free radicals generated by mitochondrial respiratory chain, endoplasmic reticulum, NADPH oxidases can be effectively neutralized NRF2-mediated antioxidant responses. These responses elevate synthesis superoxide dismutase (SOD), catalase, well key molecules like nicotinamide adenine dinucleotide phosphate (NADPH) glutathione (GSH), thereby maintaining cellular redox homeostasis. Disruption this finely tuned equilibrium is closely linked to pathogenesis wide range Recent advances have broadened our understanding molecular mechanisms underpinning dysregulation, highlighting pivotal roles genomic instability, epigenetic modifications, protein degradation, metabolic reprogramming. findings provide foundation for exploring regulation mechanistic basis improving therapeutic strategies. While antioxidant-based therapies shown early promise conditions where stress plays primary pathological role, efficacy diseases characterized complex, multifactorial etiologies remains controversial. A deeper, context-specific signaling, particularly redox-sensitive proteins, designing targeted aimed at re-establishing balance. Emerging small molecule inhibitors that target specific cysteine residues proteins demonstrated promising preclinical outcomes, setting stage forthcoming clinical trials. In review, we summarize current intricate relationship disease also discuss how these insights leveraged optimize strategies practice.

Language: Английский

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The role of cellular senescence in skin aging and age-related skin pathologies

Frontiers in Physiology, Journal Year: 2023, Volume and Issue: 14

Published: Nov. 22, 2023

Aging is the result of a gradual functional decline at cellular, and ultimately, organismal level, resulting in an increased risk developing variety chronic illnesses, such as cardiovascular disease, stroke, cancer diabetes. The skin largest organ human body, site where signs aging are most visible. These include thin dry skin, sagging, loss elasticity, wrinkles, well aberrant pigmentation. appearance these features accelerated by exposure to extrinsic factors ultraviolet (UV) radiation or pollution, intrinsic including time, genetics, hormonal changes. At cellular associated with impaired proteostasis accumulation macromolecular damage, genomic instability, chromatin reorganization, telomere shortening, remodelling nuclear lamina, proliferation defects premature senescence. Cellular senescence state permanent growth arrest key hallmark many tissues. Due their inability proliferate, senescent cells no longer contribute tissue repair regeneration. Moreover, impair homeostasis, promote inflammation extracellular matrix (ECM) degradation secreting molecules collectively known “senescence-associated secretory phenotype” (SASP). Senescence can be triggered number different stimuli oncogene expression, persistent activation DNA damage checkpoints. As result, accumulate tissues, skin. In this review, we focus on role during development age-related pathologies, discuss potential strategies rejuvenate aged

Language: Английский

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Escape from senescence: molecular basis and therapeutic ramifications

The Journal of Pathology, Journal Year: 2023, Volume and Issue: 260(5), P. 649 - 665

Published: Aug. 1, 2023

Abstract Cellular senescence constitutes a stress response mechanism in reaction to plethora of stimuli. Senescent cells exhibit cell‐cycle arrest and altered function. While withdrawal has been perceived as permanent, recent evidence cancer research introduced the so‐called escape‐from‐senescence concept. In particular, under certain conditions, senescent may resume proliferation, acquiring highly aggressive features. As such, they have associated with tumour relapse, rendering less effective inhibiting progression. Thus, conventional treatments, incapable eliminating senescence, benefit if revisited include senolytic agents. To this end, it is anticipated that assessment burden everyday clinical material by pathologists will play crucial role near future, laying foundation for more personalised approaches. Here, we provide an overview investigations phenomenon, identified mechanisms, well major implications pathology therapy. © 2023 The Authors. Journal Pathology published John Wiley & Sons Ltd on behalf Pathological Society Great Britain Ireland.

Language: Английский

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Cellular senescence and wound healing in aged and diabetic skin

Frontiers in Physiology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 19, 2024

Cellular senescence is a biological mechanism that prevents abnormal cell proliferation during tissue repair, and it often accompanied by the secretion of various factors, such as cytokines chemokines, known senescence-associated secretory phenotype (SASP). SASP-mediated cell-to-cell communication promotes regeneration, development. However, senescent cells can accumulate abnormally at injury sites, leading to excessive inflammation, dysfunction, intractable wounds. The effects cellular on skin wound healing be both beneficial detrimental, depending condition. Here, we reviewed functional differences in emerge healing, chronic aging. We also review latest mechanisms epidermis, dermis, subcutaneous fat, with focus senescence, regeneration. Finally, discuss potential clinical applications promoting inhibiting maximize benefits minimize detrimental effects.

Language: Английский

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Research Progress in Skin Aging and Immunity

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 4101 - 4101

Published: April 7, 2024

Skin aging is a complex process involving structural and functional changes characterized by decrease in collagen content, reduced skin thickness, dryness, the formation of wrinkles. This underpinned multiple mechanisms including free radical theory, inflammation photoaging metabolic theory. The immune system, an indispensable part body’s defense mechanism, comprises macrophages, lymphocytes, dendritic cells, mast cells. These cells play pivotal role maintaining homeostasis responding to injury or infection. As age advances, along with various internal external environmental stimuli, may undergo senescence accelerated aging, cell division capability, increased mortality, gene expression patterns signaling pathways, altered functions. collectively impact overall function system. review summarizes relationship between immunity explores characteristics composition effects these on aging. Immune dysfunction plays significant suggesting that immunoregulation become one important strategies for prevention treatment

Language: Английский

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