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This scoping review evaluates the relevant interdisciplinary evidence to assess the systems biology of function, regulation, and homeostasis in order to discern and decipher the etiology of the connection between hypoxia and hormonal signaling in human age-related comorbid diseases. The hypothesis charts the accumulating evidence to support the development of a hypoxic milieu and oxidative stress-inflammation pathophysiology in middle-aged individuals, as well as the induction of amyloidosis, autophagy, and epithelial-to-mesenchymal transition in aging-related degeneration. Taken together, this new approach and strategy can provide the clarity of concepts and patterns to determine the causes of declining vascularity hemodynamics (blood flow) and physiological oxygenation perfusion (oxygen bioavailability) in relation to oxygen homeostasis and vascularity that cause hypoxia (hypovascularity hypoxia). The middle-aging hypovascularity hypoxia hypothesis could provide the mechanistic interface connecting the endocrine, nitric oxide, and oxygen homeostasis signaling that is closely linked to the progressive conditions of degenerative hypertrophy, atrophy, fibrosis, and neoplasm. An in-depth understanding of these intrinsic biological processes of the developing middle-aged hypoxia could provide potential new strategies for time-dependent therapies in maintaining healthspan for healthy lifestyle aging, medical cost savings, and health system sustainability.<\/jats:p>","DOI":"10.3389\/fragi.2023.1196648","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T04:25:40Z","timestamp":1686630340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis"],"prefix":"10.3389","volume":"4","author":[{"given":"Teow J.","family":"Phua","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,6,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"102624","DOI":"10.1016\/j.pdpdt.2021.102624","article-title":"Normative data assessment of age-related changes in macular and optic nerve head vessel density using optical coherence tomography angiography","volume":"37","author":"Abay","year":"2022","journal-title":"Photodiagnosis Photodyn. 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