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

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Abstract

Aging is accompanied by a reduction in the oxygen delivery to all organs and tissues and decrease in the oxygen partial pressure in them, resulting in the development of hypoxia. The lack of oxygen activates cell signaling pathway mediated by the hypoxia-inducible transcription factor (HIF), which exists in three isoforms – HIF-1, HIF-2, and HIF-3. HIF regulates expression of several thousand genes and is a potential target for the development of new drugs for the treatment of many diseases, including those associated with age. Human organism and organisms of laboratory animals differ in their tolerance to hypoxia and expression of HIF and HIF-dependent genes, which may contribute to the development of inflammatory, tumor, and cardiovascular diseases. Currently, the data on changes in the HIF expression with age are contradictory, which is mostly due to the fact that such studies are conducted in different age groups, cell types, and model organisms, as well as under different hypoxic conditions and mainly in vitro. Furthermore, the observed discrepancies can be due to the individual tolerance of the studied organisms to hypoxia, which is typically not taken into account. Therefore, the purpose of this review was to analyze the published data on the connection between the mechanisms of aging, basal tolerance to hypoxia, and changes in the level of HIF expression with age. Here, we summarized the data on the age-related changes in the hypoxia tolerance, HIF expression and the role of HIF in aging, which is associated with its involvement in the molecular pathways mediated by insulin and IGF-1 (IIS), sirtuins (SIRTs), and mTOR. HIF-1 interacts with many components of the IIS pathway, in particular with FOXO, the activation of which reduces production of reactive oxygen species (ROS) and increases hypoxia tolerance. Under hypoxic conditions, FOXO is activated via both HIF-dependent and HIF-independent pathways, which contributes to a decrease in the ROS levels. The activity of HIF-1 is regulated by all members of the sirtuin family, except SIRT5, while the mechanisms of SIRT interaction with HIF-2 and HIF-3 are poorly understood. The connection between HIF and mTOR and its inhibitor, AMPK, has been identified, but its exact mechanism has yet to be studied. Understanding the role of HIF and hypoxia in aging and pathogenesis of age-associated diseases is essential for the development of new approaches to the personalized therapy of these diseases, and requires further research.

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Abbreviations

AMPK:

AMP-activated protein kinase

EPO:

erythropoietin

FIH:

factor inhibiting HIF

GLUT:

glucose transporter

HIF:

hypoxia-inducible factor

HRE:

hypoxia response element

IGF-1:

insulin-like growth factor 1

IIS:

insulin and IGF-1 signaling

LPS:

lipopolysaccharide

MAPK:

mitogen-activated protein kinase

mTOR:

mammalian target of rapamycin

NF-κB:

nuclear factor-κB

PI3K:

phosphoinositide 3-kinase

SIRS:

systemic inflammatory response syndrome

ROS:

reactive oxygen species

SIRT:

sirtuin

VEGF:

vascular endothelial growth factor

VHL:

Von Hippel–Lindau E3 ubiquitin ligase complex

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Funding

This work was supported by the grant from the President of the Russian Federation for the state support of young Russian scientists – candidates of sciences MK-2573.2022.1.4 “Prediction of the course of a systemic inflammatory response in old rats based on initial resistance to hypoxia” and State Budget Project no. 122030200530-6 “Cellular and molecular-biological mechanisms of inflammation in the development of socially significant human diseases”.

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Authors and Affiliations

  1. Avtsyn Research Institute of Human Morphology, Petrovsky National Research Centre of Surgery, 117418, Moscow, Russia

    Dzhuliia Sh. Dzhalilova & Olga V. Makarova

  2. Faculty of Biology, Lomonosov Moscow State University, 119234, Moscow, Russia

    Olga V. Makarova

Authors
  1. Dzhuliia Sh. Dzhalilova
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  2. Olga V. Makarova
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D.S.D. analyzed the literature data and prepared the manuscript and the figures; O.V.M. discussed the published data and reviewed the manuscript.

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Correspondence to Dzhuliia Sh. Dzhalilova.

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The authors declare no conflicts of interest. This article does not contain the studies with human participants or animals performed by any of the authors.

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Dzhalilova, D.S., Makarova, O.V. The Role of Hypoxia-Inducible Factor in the Mechanisms of Aging. Biochemistry Moscow 87, 995–1014 (2022). https://doi.org/10.1134/S0006297922090115

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  • DOI: https://doi.org/10.1134/S0006297922090115

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