Hypoxia, Inflammation, and Cellular Senescence
Researchers here review what is know of links between hypoxia and the onset of inflammation in age-related disease. Hypoxia in tissues can arise for a range of reasons in aging, and the processes of regulation that respond to localized hypoxia, primarily in order to induce regrowth of blood vessels to the affected region, may be meaningfully detrimental when consistently triggered. Inflammation is involved in this response, while chronic inflammation is a well-known feature of aging, driving numerous forms of tissue dysfunction.
When tissues are subjected to acute injury resulting in ischemia/hypoxia, cells adapt to the hypoxic environment by inducing the expression of a number of adaptive genes and regulating post-translational modifications. These adaptive changes in tissue cells in hypoxic environments are controlled by the HIF family. The dysregulation or overexpression of HIF-1α induced by hypoxia is associated with many pathological processes, such as cardiovascular diseases, metabolic diseases, and tumors. For example, in lung diseases, HIF-1α induces the expression of the vascular endothelial growth factor, ROS, and inducible nitric oxide synthase (iNOS) through multiple signaling pathways and a broad target gene profile, promoting an increased inflammatory response. This leads to endothelial cell dysfunction and leukocyte adhesion, promoting the proliferation of pulmonary artery smooth muscle cells (PASMCs) and oxygen delivery to hypoxic regions.
At the same time, senescence may also be involved in promoting the expression of HIF-1α. During hypoxia and aging, the hypoxic signaling pathway interacts with the sirtuin, AMPK, and NF-κB signaling pathways. For example, hypoxia induces an inflammatory response in cells, and the activation of the NF-κB pathway in endothelial cells facilitates the release of cellular inflammatory factors and acts as positive feedback for HIF-1. There is an interconnection between HIF and the sirtuin family. SIRT1 and HIF-1α jointly regulate mitochondrial senescence, and SIRT1 has a regulatory effect on HIF-1α activity; however, the specific regulatory mechanism has been controversial. The evidence has shown that SIRT1 deletion or inactivation under hypoxic conditions leads to reduced hypoxic HIF-1α accumulation, accompanied by increased HIF-1α acetylation, that SIRT1 assists in stabilizing the HIF-1α protein through direct binding and deacetylation, and that the upregulation of SIRT1 may prevent premature cellular senescence and the development of many chronic diseases associated with aging.
Further, AMPK is an important regulator of energy metabolism, resilience, and cellular proteostasis, and hypoxia can activate AMPK directly or indirectly. However, the activation capacity of AMPK signaling decreases with age, which impairs the maintenance of cellular homeostasis and accelerates the aging process, thus triggering a variety of aging-related diseases.