Department of Physical Therapy and Athletic Training, Boston University, Boston, Massachusetts, USA.
Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, USA.
Compr Physiol. 2022 Apr 26;12(3):3575-3620. doi: 10.1002/cphy.c210034.
Frailty is a complex syndrome affecting a growing sector of the global population as medical developments have advanced human mortality rates across the world. Our current understanding of frailty is derived from studies conducted in the laboratory as well as the clinic, which have generated largely phenotypic information. Far fewer studies have uncovered biological underpinnings driving the onset and progression of frailty, but the stage is set to advance the field with preclinical and clinical assessment tools, multiomics approaches together with physiological and biochemical methodologies. In this article, we provide comprehensive coverage of topics regarding frailty assessment, preclinical models, interventions, and challenges as well as clinical frameworks and prevalence. We also identify central biological mechanisms that may be at play including mitochondrial dysfunction, epigenetic alterations, and oxidative stress that in turn, affect metabolism, stress responses, and endocrine and neuromuscular systems. We review the role of metabolic syndrome, insulin resistance and visceral obesity, focusing on glucose homeostasis, adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), and nicotinamide adenine dinucleotide (NAD ) as critical players influencing the age-related loss of health. We further focus on how immunometabolic dysfunction associates with oxidative stress in promoting sarcopenia, a key contributor to slowness, weakness, and fatigue. We explore the biological mechanisms involved in stem cell exhaustion that affect regeneration and may contribute to the frailty-associated decline in resilience and adaptation to stress. Together, an overview of the interplay of aging biology with genetic, lifestyle, and environmental factors that contribute to frailty, as well as potential therapeutic targets to lower risk and slow the progression of ongoing disease is covered. © 2022 American Physiological Society. Compr Physiol 12:1-46, 2022.
衰弱是一种复杂的综合征，随着医学的发展降低了全球各地的人类死亡率，影响着全球不断增长的人口。我们目前对衰弱的理解来自实验室和临床研究，这些研究主要提供了表型信息。只有少数研究揭示了导致衰弱发生和发展的生物学基础，但随着临床前和临床评估工具、多组学方法以及生理和生化方法的出现，该领域已经做好了推进的准备。在本文中，我们全面介绍了衰弱评估、临床前模型、干预措施和挑战以及临床框架和流行率等方面的主题。我们还确定了可能发挥作用的核心生物学机制，包括线粒体功能障碍、表观遗传改变和氧化应激，这些机制反过来又影响代谢、应激反应以及内分泌和神经肌肉系统。我们回顾了代谢综合征、胰岛素抵抗和内脏肥胖的作用，重点关注葡萄糖稳态、一磷酸腺苷激活蛋白激酶 (AMPK)、雷帕霉素靶蛋白 (mTOR) 和烟酰胺腺嘌呤二核苷酸 (NAD) 作为影响与年龄相关的健康损失的关键因素。我们进一步关注免疫代谢功能障碍如何与氧化应激相关联，以促进肌肉减少症，这是导致行动缓慢、虚弱和疲劳的关键因素。我们探讨了涉及干细胞耗竭的生物学机制，这些机制影响再生，并可能导致与衰弱相关的恢复力和对压力的适应能力下降。总之，本文概述了衰老生物学与遗传、生活方式和环境因素的相互作用，这些因素导致了衰弱，以及降低风险和减缓现有疾病进展的潜在治疗靶点。2022 年美国生理学会。综合生理学 12:1-46, 2022.
