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.

Hyperbaric oxygen therapy exerts anti‐osteoporotic effects in obese and lean D‐galactose‐induced aged rats

“…In the long‐term hypoxia, the two major members of hypoxia‐inducible factors (HIFs) family including HIF‐1α and HIF‐2α are transcription factors that were shown to serve as the master indicator of hypoxia and play crucial role in the cellular response to low‐oxygen levels 66 . Both HIF‐1α and HIF‐2α are involved in managing prolonged oxidative damage in aging‐ and obesity‐related diseases 67–70 . Particularly, HIF‐1α plays a key role in the stimulation of osteoclast formation in aging‐ and obesity‐induced osteoporosis 70–72 .…”

Aging and putative frailty biomarkers are altered by spaceflight

“…FGF23, KRT18, AKT1, B2M, NOS1, AOC1, SOD2 and SOD3) did not return to the pre-ight baseline expression levels, even after 120 days. The data suggest that space conditions activate the HIF1 pathway which stimulates the expression of various hypoxiaresponsive genes such as HIF1A, HIF1AN, ARNT, ARNT2, NOS1, NOS2, NOTCH1 and RBX1, that are known to regulate a wide variety of cellular physiology including metabolic reprogramming, anti-apoptosis, migration, proliferation, amyloid β production and prion stabilization 30,31 . An interesting observation emerging from the data is the elevation of HIF1A and HIF3A post-ight.…”

Immune system modulation in aging: Molecular mechanisms and therapeutic targets

“…When a chronic infection is established, a large amount of reactive oxygen species (ROS), chemokines and cytokines, such as IL-1b, are produced, which in turn increases inflammation and parallelly activates NF-kB-mediated HIF-1a synthesis (39,40). HIF-1a is a key transcription factor for modulating the inflammation response, because it promotes the expression of proinflammatory cytokines and chemokines (39,40). Consistent with this role is that HIF-1a-deficient mice were found to be resistant to develop inflammatory diseases; however, when they were subjected to chronic infection developed inflammatory responses and died early, compared with control animals (41)(42)(43).…”

“…It regulates immune cell proliferation and the response to pathogens through epigenetic regulation, which is largely controlled by transcription factor hypoxia-inducible factor 1 (HIF-1α) ( 38 ). When a chronic infection is established, a large amount of reactive oxygen species (ROS), chemokines and cytokines, such as IL-1β, are produced, which in turn increases inflammation and parallelly activates NF-κB-mediated HIF-1α synthesis ( 39 , 40 ). HIF-1α is a key transcription factor for modulating the inflammation response, because it promotes the expression of proinflammatory cytokines and chemokines ( 39 , 40 ).…”

“…Consistent with this role is that HIF-1α-deficient mice were found to be resistant to develop inflammatory diseases; however, when they were subjected to chronic infection developed inflammatory responses and died early, compared with control animals ( 41 – 43 ). Overall, these studies state that hypoxia-mediated HIF-1α activation promotes a chronic low-grade inflammatory state (inflammaging), which in turn can lead to immunosenescence ( 40 ). The crucial function of HIF-1α in these phenomena makes it an ideal therapeutic target to modulate immune responses during aging.…”