Senescence in aging, within the brain and other diseases: Mechanisms and interventions

The relentless progression of aging remains a pivotal challenge in medical science, prompting a surge in research aimed at understanding and mitigating the impact of senescence on human health. The review delves into the multifaceted role of senescence in aging and associated diseases, providing a comprehensive overview of current therapeutic strategies and future directions in this burgeoning field.

Cellular senescence, a state of irreversible cell cycle arrest, is a fundamental biological process contributing to aging and age-related diseases. Senescent cells, characterized by the secretion of pro-inflammatory cytokines, chemokines, and proteases, collectively known as the senescence-associated secretory phenotype (SASP), can disrupt tissue structure and function. This phenomenon is implicated in various pathologies, including cancer, cardiovascular diseases, and neurodegenerative disorders. Chakrabarti et al. highlight the dual nature of senescence, noting its role in tumor suppression and wound healing, juxtaposed against its contribution to chronic inflammation and tissue degeneration.

The review explores several therapeutic strategies targeting senescent cells to alleviate aging-related pathologies. Senolytics, agents that selectively induce death of senescent cells, have shown promise in preclinical models. Compounds like dasatinib and quercetin have demonstrated efficacy in reducing senescent cell burden and improving healthspan. Additionally, the role of senomorphics, which modulate the SASP without killing the cells, is discussed as a complementary approach.

A significant focus of the research is on the epigenetic regulation of senescence. Chakrabarti et al. emphasize the potential of targeting epigenetic modifiers such as EZH2, which influences histone methylation, to reverse or mitigate senescence. Tetramethylpyrazine is highlighted as a compound that can decrease the senescent phenotype by modulating EZH2 activity. Furthermore, strategies to enhance mitochondrial function and delay replicative senescence through overexpression of nicotinamide nucleotide transhydrogenase and nicotinamide mononucleotide adenylyltransferase 3 are explored.

The implementation of senolytic therapies presents several challenges. The essential role of senescent cells in processes like wound healing and tissue remodeling necessitates careful consideration of the timing and specificity of these interventions. The potential off-target effects and the risk of disrupting normal physiological processes underscore the need for refined therapeutic approaches. The development of immune-based strategies, such as chimeric antigen receptor (CAR) T cells and vaccinations targeting senescent cell markers, offers a promising avenue, albeit with its own set of challenges.

Chakrabarti et al. underscore the importance of further research to unravel the complexities of SASP heterogeneity and the mechanisms underlying senescence resistance. The exploration of donor-derived mesenchymal stem cells (MSCs) for their immunomodulatory properties and potential to enhance immune clearance of senescent cells is proposed as a novel therapeutic strategy. Moreover, the need for advanced animal models and human translational research is emphasized to bridge the gap between preclinical findings and clinical applications.

The review by Chakrabarti et al. provides a comprehensive overview of the current understanding of senescence in aging and disease. It highlights the potential of targeting senescent cells and their associated pathways to mitigate aging-related pathologies and improve healthspan. However, the complexity of senescence biology and the challenges associated with therapeutic interventions necessitate continued research to develop safe and effective treatments. As the field advances, a deeper understanding of the molecular underpinnings of senescence will be crucial in devising strategies to promote healthy aging and combat age-related diseases.

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https://www.xiahepublishing.com/2472-0712/ERHM-2023-00018

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

Exploratory Research and Hypothesis in Medicine (ERHM) publishes original exploratory research articles and state-of-the-art reviews that focus on novel findings and the most recent scientific advances that support new hypotheses in medicine. The journal accepts a wide range of topics, including innovative diagnostic and therapeutic modalities as well as insightful theories related to the practice of medicine. The exploratory research published in ERHM does not necessarily need to be comprehensive and conclusive, but the study design must be solid, the methodologies must be reliable, the results must be true, and the hypothesis must be rational and justifiable with evidence.

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