HMGB1, an evolving pleiotropic protein critical for cellular and tissue homeostasis: Role in aging and age-related diseases

IF 12.5 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews Pub Date : 2024-10-18 DOI:10.1016/j.arr.2024.102550

Elena Ruggieri , Erika Di Domenico , Andrea Giacomo Locatelli , Flavio Isopo , Sarah Damanti , Rebecca De Lorenzo , Enrico Milan , Giovanna Musco , Patrizia Rovere-Querini , Simone Cenci , Emilie Vénéreau

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Abstract

Aging is a universal biological process characterized by a progressive, cumulative decline in homeostatic capabilities and physiological functions, which inevitably increases vulnerability to diseases. A number of molecular pathomechanisms and hallmarks of aging have been recognized, yet we miss a thorough understanding of their complex interconnectedness. This review explores the molecular and cellular mechanisms underlying human aging, with a focus on the multiple roles of high mobility group Box 1 protein (HMGB1), the archetypal damage-associated molecular pattern (DAMP) molecule. In the nucleus, this non-histone chromatin-associated protein functions as a DNA chaperone and regulator of gene transcription, influencing DNA structure and gene expression. Moreover, this versatile protein can translocate to the cytoplasm to orchestrate other processes, such as autophagy, or be unconventionally secreted into the extracellular environment, where it acts as a DAMP, combining inflammatory and regenerative properties. Notably, lower expression of HMGB1 within the cell and its heightened extracellular release have been associated with diverse age-associated traits, making it a suitable candidate as a universal biomarker of aging. In this review, we outline the evidence implicating HMGB1 in aging, also in light of an evolutionary perspective on its functional pleiotropy, and propose critical issues that need to be addressed to gauge the value of HMGB1 as a potential biomarker across age-related diseases and therapeutic target to promote healthy longevity.

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HMGB1，一种对细胞和组织稳态至关重要的不断演变的多效蛋白：在衰老和老年相关疾病中的作用。

衰老是一个普遍的生物学过程，其特点是体内平衡能力和生理功能的逐步累积衰退，这不可避免地增加了对疾病的脆弱性。人们已经认识到衰老的一些分子病理机制和特征，但我们对它们之间复杂的相互联系还缺乏透彻的了解。这篇综述探讨了人类衰老的分子和细胞机制，重点是高迁移率基团框 1 蛋白（HMGB1）的多重作用，它是典型的损伤相关分子模式（DAMP）分子。在细胞核中，这种非组蛋白染色质相关蛋白发挥着DNA伴侣和基因转录调节器的作用，影响着DNA结构和基因表达。此外，这种多用途蛋白质还能转运到细胞质中，协调自噬等其他过程，或以非传统方式分泌到细胞外环境中，在那里充当 DAMP，兼具炎症和再生特性。值得注意的是，HMGB1 在细胞内的低表达及其在细胞外的高释放与多种与年龄相关的特征有关，这使其成为衰老的通用生物标志物的合适候选者。在这篇综述中，我们概述了 HMGB1 与衰老有关的证据，还从进化的角度探讨了其功能的多义性，并提出了需要解决的关键问题，以衡量 HMGB1 作为跨年龄相关疾病的潜在生物标志物和促进健康长寿的治疗靶点的价值。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Ageing Research Reviews 医学-老年医学

CiteScore

19.80

自引率

2.30%

发文量

216

审稿时长

55 days

期刊介绍： With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.