The Role of Hypoxia-Inducible Factor in the Mechanisms of Aging

Джалилова, Д. Ш.; Makarova, Olga

doi:10.1134/s0006297922090115

Cited by 7 publications

(6 citation statements)

References 155 publications

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“…This age-associated association may be linked to the impact of chronic hypoxia on the long-term development of laryngeal cancer. However, while the changes in HIFα expression between age groups are often contradictory across different studies, the present findings indicate the need for a more comprehensive understanding of the relationship between age and HIFα expression (24,25).…”

Section: Discussionmentioning

confidence: 63%

Exploration of the association between HIF3α mRNA and lncRNA MALAT1 in laryngeal squamous cell carcinoma by correlation analysis

Kyurkchiyan,

Stancheva,

Petkova

et al. 2024

Oncol Lett

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Laryngeal squamous cell carcinoma (LSCC) is a significant global health burden, for which there has been limited evidence of improved survival rates. Although the roles of hypoxia-inducible factor (HIF)1α and HIF2α have been well documented in hypoxia, the involvement of HIF3α, particularly in LSCC, has been inadequately explored. The present study aimed to investigate the correlation between HIFα subunits and the hypoxia-related long noncoding RNAs (lncRNAs) MALAT1 and HOTAIR in 63 patients diagnosed with LSCC. Total RNA was extracted from fresh-frozen laryngeal tumor and adjacent normal tissues, and was subjected to reverse transcription-quantitative PCR for target detection. Statistical analyses were conducted using SPSS software, with significance set at P<0.05. The present study is the first, to the best of our knowledge, to report a positive moderate monotonic correlation (rs= 0.347) and moderately strong positive linear correlation (r= 0.630) between HIF3α mRNA and lncRNA MALAT1 in LSCC. Regression analysis revealed a direct association between 39.6% of both variables. Additionally, a positive correlation was observed between lncRNAs MALAT1 and HOTAIR (rs= 0.353); HIF2α mRNA and lncRNA MALAT1 (rs= 0.431); HIF3α mRNA and lncRNA HOTAIR (rs= 0.279); and HIF3α mRNA and HIF2α mRNA (rs= 0.285). Notably, a significant negative correlation (rs=-0.341) was detected between HIF3α mRNA and HIF1α mRNA, potentially indicative of the HIF switch or negative regulation. In addition, the present study investigated the association between HIFα subunits and the clinicopathological characteristics of patients. The results revealed a notable association between HIF1α transcript levels and the location of LSCC; specifically, subglottic tumors exhibited elevated HIF1α levels compared with glottic and supraglottic LSCC. Furthermore, a significant association was identified between HIF3α transcript levels and patient age (P= 0.032) and positive family history (P= 0.047). In conclusion, the present findings suggested a pivotal role for HIF3α in LSCC development, potentially involving direct regulation of lncRNA MALAT1. However, further research is warranted to elucidate its precise mechanisms.

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Section: Discussionmentioning

confidence: 63%

Exploration of the association between HIF3α mRNA and lncRNA MALAT1 in laryngeal squamous cell carcinoma by correlation analysis

Kyurkchiyan,

Stancheva,

Petkova

et al. 2024

Oncol Lett

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“…Protection and repair of iron‐sulfur clusters have received some study [ 152 ] and factors governing the transcription, translation, and protein stability of HIF‐1 have been identified. [ 153–155 ]…”

Section: Discussionmentioning

confidence: 99%

“…Protection and repair of iron-sulfur clusters have received some study [152] and factors governing the transcription, translation, and protein stability of HIF-1 have been identified. [153][154][155] The decline in PEPCK expression with age presumably reflects, as does its suppression in embryo, methylation of its gene promoter region. [156] However, cAMP increases PEPCK Figure 4.…”

Section: Consideration Of the Tca Cycle Integrates Disparate Mechanis...mentioning

confidence: 99%

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Borkum

2023

Advanced Biology

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Certain metabolic interventions such as caloric restriction, fasting, exercise, and a ketogenic diet extend lifespan and/or health span. However, their benefits are limited and their connections to the underlying mechanisms of aging are not fully clear. Here, these connections are explored in terms of the tricarboxylic acid (TCA) cycle (Krebs cycle, citric acid cycle) to suggest reasons for the loss of effectiveness and ways of overcoming it. Specifically, the metabolic interventions deplete acetate and likely reduce the conversion of oxaloacetate to aspartate, thereby inhibiting the mammalian target of rapamycin (mTOR) and upregulating autophagy. Synthesis of glutathione may provide a high‐capacity sink for amine groups, facilitating autophagy, and prevent buildup of alpha‐ketoglutarate, supporting stem cell maintenance. Metabolic interventions also prevent the accumulation of succinate, thereby slowing DNA hypermethylation, facilitating the repair of DNA double‐strand breaks, reducing inflammatory and hypoxic signaling, and lowering reliance on glycolysis. In part through these mechanisms, metabolic interventions may decelerate aging, extending lifespan. Conversely, with overnutrition or oxidative stress, these processes function in reverse, accelerating aging and impairing longevity. Progressive damage to aconitase, inhibition of succinate dehydrogenase, and downregulation of hypoxia‐inducible factor‐1α, and phosphoenolpyruvate carboxykinase (PEPCK) emerge as potentially modifiable reasons for the loss of effectiveness of metabolic interventions.

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“…Oxygen homeostasis and its master regulator, the HIFs, are organizing principles for understanding metazoan evolution, ontology, physiology, and pathology ( Semenza, 2010 ). Aging is accompanied by the development of systemic, gradually increasing hypoxia-related dysfunctions, which are a characteristic of many human diseases ( Bowler and Ladomery, 2019 ; Dzhalilova and Makarova, 2022 ; Luo et al, 2022 ). Chronic (continuous, non-interrupted, and sustained) and cyclic (intermittent and transient) hypoxia, which are characterized by fluctuations in oxygen levels ( Bader et al, 2020 ), have been linked to the development of human diseases and cancer ( Saxena and Jolly, 2019 ; Chen et al, 2020 ; Liu et al, 2022 ).…”

Section: Middle-aging Hypovascularity Hypoxia Hypothesis Patternsmentioning

confidence: 99%

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

Phua

2023

Front. Aging

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Aging-related hypoxia, oxidative stress, and inflammation pathophysiology are closely associated with human age-related carcinogenesis and chronic diseases. However, the connection between hypoxia and hormonal cell signaling pathways is unclear, but such human age-related comorbid diseases do coincide with the middle-aging period of declining sex hormonal signaling. 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.

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The Role of Hypoxia-Inducible Factor in the Mechanisms of Aging

Cited by 7 publications

References 155 publications

Exploration of the association between HIF3α mRNA and lncRNA MALAT1 in laryngeal squamous cell carcinoma by correlation analysis

Exploration of the association between HIF3α mRNA and lncRNA MALAT1 in laryngeal squamous cell carcinoma by correlation analysis

The Tricarboxylic Acid Cycle as a Central Regulator of the Rate of Aging: Implications for Metabolic Interventions

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

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