Hypoxia and aging: molecular mechanisms, diseases, and therapeutic targets

Abstract

Aging is a complex biological process characterized by the gradual decline of cellular functions, increased susceptibility to diseases, and impaired stress responses. Hypoxia, defined as reduced oxygen availability, is a critical factor that influences aging through molecular pathways involving hypoxia-inducible factors (HIFs), oxidative stress, inflammation, and epigenetic modifications. This review explores the interconnected roles of hypoxia in aging, highlighting how hypoxic conditions exacerbate cellular damage, promote senescence, and contribute to age-related pathologies, including cardiovascular diseases, neurodegenerative disorders, cancer, metabolic dysfunctions, and pulmonary conditions. By examining the molecular mechanisms linking hypoxia to aging, we identify key pathways that serve as potential therapeutic targets. Emerging interventions such as HIF modulators, antioxidants, senolytics, and lifestyle modifications hold promise in mitigating the adverse effects of hypoxia on aging tissues. However, challenges such as the heterogeneity of aging, lack of reliable biomarkers, and safety concerns regarding hypoxia-targeted therapies remain. This review emphasizes the need for personalized approaches and advanced technologies to develop effective antiaging interventions. By integrating current knowledge, this review provides a comprehensive framework that underscores the importance of targeting hypoxia-induced pathways to enhance healthy aging and reduce the burden of age-related diseases.

Keywords: age‐related disease; aging; hypoxia; mechanism; therapeutic target.

FIGURE 1

Overview of hypoxia‐inducible factors (HIFs) regulation. The activation of HIF‐1α under hypoxic condition is depicted. Under normal oxygen levels, the interaction between HIF‐1α and the von Hippel–Lindau (VHL) protein is oxygen‐dependent and involves the hydroxylation of specific proline residues on HIF‐1α by prolyl hydroxylases (PHDs). This hydroxylation targets HIF‐1α for ubiquitination by VHL, leading to its subsequent degradation via the proteasome. In low‐oxygen (hypoxic) conditions, hydroxylation of HIF‐1α is inhibited, preventing its degradation. This allows HIF‐1α to accumulate, dimerize with HIF‐1β, and bind to hypoxia response elements (HREs) on DNA, activating the transcription of genes that mediate adaptive cellular responses to hypoxia. ERK1/2, extracellular signal‐regulated kinase 1/2; FIH‐1, factor inhibiting hypoxia‐inducible factor 1; GLUT1, glucose transporter 1; HIF‐1α, hypoxia‐inducible factor 1‐alpha; HIF‐2α, hypoxia‐inducible factor 2‐alpha; IκB, inhibitor of nuclear factor kappa B; IKKβ, IκB kinase beta; NF‐κB, nuclear factor kappa B; PHDs, prolyl hydroxylases; P50, the 50‐kDa subunit of the NF‐κB transcription factor (also known as NF‐κB1); P65, the 65‐kDa subunit of the NF‐κB transcription factor (also known as RelA); VEGFA, vascular endothelial growth factor A.

FIGURE 2

Molecular mechanisms underlying hypoxia‐induced aging. Hypoxia triggers a complex network of interconnected molecular pathways that contribute to aging and cellular dysfunction. Key mechanisms include oxidative stress, where an imbalance between reactive oxygen species (ROS) and antioxidant defenses leads to cellular damage; inflammation, characterized by the activation of proinflammatory signaling pathways that promote chronic inflammation; and cellular senescence, a state of permanent cell cycle arrest associated with the secretion of proinflammatory cytokines, growth factors, and matrix remodeling enzymes known as senescence‐associated secretory phenotype (SASP). Additionally, hypoxia induces epigenetic changes, such as DNA methylation, histone modification, and alterations in noncoding RNA expression, which impact gene expression and accelerate aging processes. Together, these mechanisms create a feedback loop that exacerbates cellular damage, impairs tissue function, and accelerates aging, contributing to age‐related diseases. CD18, integrin subunit beta‐2; EPO, erythropoietin; FGF‐2, fibroblast growth factor‐2; GBL, G protein beta subunit; GSH, glutathione; HDACs, histone deacetylases; HIF, hypoxia‐inducible factor; HIF‐1α, hypoxia‐inducible factor 1‐alpha; HIF‐1β, hypoxia‐inducible factor 1‐beta; IL‐1β, interleukin‐1 beta; iNOS, inducible nitric oxide synthase; KDMs, lysine demethylases; MAO, monoamine oxidase; MDA, malondialdehyde; NF‐κB, nuclear factor kappa B; NLRP3, NOD‐like receptor family pyrin domain containing‐3; PAR‐1, proteinase‐activated receptor‐1; ROS, reactive oxygen species; SOD, superoxide dismutase; TIMP1, metalloproteinase inhibitor‐1; TNFα, tumor necrosis factor‐alpha; TPH1, tryptophan hydroxylase‐1; VEGF, vascular endothelial growth factor.

FIGURE 3

Overview of the therapeutic targets and lifestyle interventions for mitigating hypoxia‐induced aging. Various interventions and therapeutic strategies are outlined, which are aimed at alleviating the effects of hypoxia‐induced aging. Key interventions include lifestyle modifications such as caloric restriction, intermittent hypoxia, and exercise, which enhance mitochondrial function, reduce oxidative stress, and decrease inflammation. Therapeutic targets include cellular senescence modifiers (e.g., senolytics like dasatinib and quercetin), antioxidants (e.g., vitamins, flavonoids, N‐acetyl cysteine), and anti‐inflammatory agents (e.g., nonsteroidal anti‐inflammatory drugs [NSAIDs], corticosteroids). Additional approaches include epigenetic modulators (e.g., 5‐azacytidine, mechanistic target of rapamycin [mTOR] inhibitors), mitochondrial‐targeted therapies (e.g., mitoquinone [MitoQ], SKQ1), and advanced treatments like cell replacement therapy, gene therapy, and immunotherapy. These approaches aim to improve mitochondrial function, reduce inflammation, and promote healthy aging and longevity.

FIGURE 4

Infographic of challenges and future directions in hypoxia and aging research. The challenges and future directions in the field of hypoxia and aging research are highlighted. Challenges in hypoxia and aging research include lack of biomarkers, variability in hypoxia response, heterogeneity of aging, and translational hurdles. Emphasized areas for future research include the development of advanced technologies, regenerative therapies, and personalized medicine to better understand the molecular mechanisms driving aging under hypoxic conditions. This could lead to potential breakthroughs such as new treatments for hypoxia‐induced aging and better understanding of aging mechanisms.