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Senotherapeutics and Their Molecular Mechanism for Improving Aging.

ABSTRACT: Aging is defined as physiological dysfunction of the body and a key risk factor for human diseases. During the aging process, cellular senescence occurs in response to various extrinsic and intrinsic factors such as radiation-induced DNA damage, the activation of oncogenes, and oxidative stress. These senescent cells accumulate in many tissues and exhibit diverse phenotypes, such as resistance to apoptosis, production of senescence-associated secretory phenotype, cellular flattening, and cellular hypertrophy. They also induce abnormal dysfunction of the microenvironment and damage neighboring cells, eventually causing harmful effects in the development of various chronic diseases such as diabetes, cancer, and neurodegenerative diseases. Thus, pharmacological interventions targeting senescent cells, called senotherapeutics, have been extensively studied. These senotherapeutics provide a novel strategy for extending the health span and improving age-related diseases. In this review, we discuss the current progress in understanding the molecular mechanisms of senotherapeutics and provide insights for developing senotherapeutics.

SUBMITTER: Park J

PROVIDER: S-EPMC9622307 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Senotherapeutics and Their Molecular Mechanism for Improving Aging.

Park Jooho J Shin Dong Wook DW

Biomolecules & therapeutics 20221013 6

Aging is defined as physiological dysfunction of the body and a key risk factor for human diseases. During the aging process, cellular senescence occurs in response to various extrinsic and intrinsic factors such as radiation-induced DNA damage, the activation of oncogenes, and oxidative stress. These senescent cells accumulate in many tissues and exhibit diverse phenotypes, such as resistance to apoptosis, production of senescence-associated secretory phenotype, cellular flattening, and cellula ...[more]

PMID: 36226551

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Project description:Recent advances in aging research have provided novel insights for the development of senotherapy, which utilizes cellular senescence as a therapeutic target. Cellular senescence is involved in the pathogenesis of various chronic diseases, including metabolic and respiratory diseases. Senotherapy is a potential therapeutic strategy for aging-related pathologies. Senotherapy can be classified into senolytics (induce cell death in senescent cells) and senomorphics (ameliorate the adverse effects of senescent cells represented by the senescence-associated secretory phenotype). Although the precise mechanism has not been elucidated, various drugs against metabolic diseases may function as senotherapeutics, which has piqued the interest of the scientific community. Cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are aging-related respiratory diseases. Large-scale observational studies have reported that several drugs, such as metformin and statins, may ameliorate the progression of COPD and IPF. Recent studies have reported that drugs against metabolic diseases may exert a pharmacological effect on aging-related respiratory diseases that can be different from their original effect on metabolic diseases. However, high non-physiological concentrations are needed to determine the efficacy of these drugs under experimental conditions. Inhalation therapy may increase the local concentration of drugs in the lungs without exerting systemic adverse effects. Thus, the clinical application of drugs against metabolic diseases, especially through an inhalation treatment modality, can be a novel therapeutic approach for aging-related respiratory diseases. This review summarizes and discusses accumulating evidence on the mechanisms of aging, as well as on cellular senescence and senotherapeutics, including drugs against metabolic diseases. We propose a developmental strategy for a senotherapeutic approach for aging-related respiratory diseases with a special focus on COPD and IPF.

Project description:ObjectiveTo analyze the effects and mechanisms of berberine in the treatment of aging-related cognitive dysfunction based on network pharmacology methods, molecular docking techniques, and animal experiments.MethodsA mouse model of cognitive dysfunction was constructed by subcutaneous injection of D-galactose (D-gal) for 10 weeks, and the neuroprotective effects of berberine on aging-related cognitive dysfunction mice were evaluated by the Morris water maze (MWM) and immunofluorescence staining. The targets of berberine were obtained by SwissTargetPrediction, GeneCards, and PharmMapper. Putative targets of cognitive dysfunction were obtained by GeneCards, TTD, and DrugBank database. The STRING database and Cytoscape software were applied for protein-protein interaction (PPI) analysis and further screening of core targets. The DAVID database was used for Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) enrichment analysis to clarify the biological processes and pathways involved in the intersection targets, and AutoDockTools was adopted for molecular docking verification of core targets. Finally, the core genes were validated using real-time quantitative PCR.ResultsThe MWM results showed that treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-gal. Immunofluorescence staining indicated that berberine modified the levels of aging-related markers in the brain. A total of 386 berberine putative targets associated with cognitive dysfunction were identified based on the public database. The core targets of berberine for improving cognitive function, include Mapk1, Src, Ctnnb1, Akt1, Pik3ca, Tp53, Jun, and Hsp90aa1. GO enrichment and KEGG pathway enrichment analyses indicated that the mechanism of berberine in the treatment of aging-related cognitive dysfunction is attributed to pathways such as PI3K-AKT and MAPK pathways. In vivo experiments further confirmed that Akt1, Ctnnb1, Tp53, and Jun were involved in the neuroprotective actions of berberine.ConclusionThis study reveals the multi-target and multi-pathway effects of berberine on regulating aging-related cognitive dysfunction, which provides preclinical evidence and may promote new drug development in mitigating cognitive dysfunction.

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Senotherapeutics and Their Molecular Mechanism for Improving Aging.

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Senotherapeutics and Their Molecular Mechanism for Improving Aging.

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