Hypoxia in Aging and Aging-Related Diseases: Mechanism and Therapeutic Strategies

Abstract

As the global aging process continues to lengthen, aging-related diseases (e.g., chronic obstructive pulmonary disease (COPD), heart failure) continue to plague the elderly population. Aging is a complex biological process involving multiple tissues and organs and is involved in the development and progression of multiple aging-related diseases. At the same time, some of these aging-related diseases are often accompanied by hypoxia, chronic inflammation, oxidative stress, and the increased secretion of the senescence-associated secretory phenotype (SASP). Hypoxia seems to play an important role in the process of inflammation and aging, but is often neglected in advanced clinical research studies. Therefore, we have attempted to elucidate the role played by different degrees and types of hypoxia in aging and aging-related diseases and their possible pathways, and propose rational treatment options based on such mechanisms for reference.

Keywords: aging; aging-related diseases; hypoxia; oxidative stress; therapeutic strategies.

Figure 1

Regulation of HIF-1α under hypoxic conditions. Under normoxia, HIF-1α is inhibited by PHD and FIH and cannot bind to HIF-1β. Hypoxia binds to HIF-1β and recruits p300 or CBP to respond adaptively to hypoxia, inducing the expression of many genes such as GLUT1 and HK2, thus promoting glycolysis to produce energy and also stimulating angiogenesis and DNA damage. Intracellular cAMP levels increase after sustained hypoxia, and cAMP and senescence act through signaling pathways such as AMPK-mTOR, ultimately producing SASP to play a physiological role. PHD—prolyl hydroxylase domain; FIH—factor inhibiting HIF-1; pVHL—VHL (Von Hippel–Lindau) tumor suppressor protein; SASP—senescence-associated secretory phenotype; ROS—reactive oxide species; TNF-α—tumor necrosis factor-α; VEGF—vascular endothelial growth factor; CCL—chemokine; HRE—hypoxia response element; GLUT1—glucose transporter type 1; HK-2—hexokinase 2; iNOS—inducible nitric oxide synthase.

Figure 2

Oxidative stress and hypoxia lead to inflammation and coagulation dysfunction in COPD. Tobacco and bacteria stimulate inflammatory factors such as elevated respiratory NF- κB and IL-1, leading to oxidative stress in airway epithelial cells, which promotes upregulation of HIF-1α gene expression through the PI3K/AKT/mTOR signaling pathway, and HIF-1α entry promotes the expression of factors such as VEGF, FGF-2, and TAT, inducing inflammatory responses and coagulation dysfunction. ROS—reactive oxygen species; VEGF—vascular endothelial growth factor; FGF-2—fibroblast growth factor; PAFR—platelet-activating factor receptor; TAT—thrombin-antithrombin complex.