2.1 Hypoxia-inducible factors and aging

HIFs, particularly HIF-1α and HIF-2α, are transcription factors that serve as master regulators of the cellular response to low-oxygen levels. HIF-1α is stabilized under hypoxic conditions, translocates to the nucleus, and activates the transcription of genes involved in angiogenesis, glucose metabolism, and erythropoiesis.^{16, 47} During aging, there is a marked decline in the adaptive capacity of HIF signaling, which has been linked to reduced cellular stress resilience, mitochondrial dysfunction, and impaired angiogenesis.⁴⁸ Studies in animal models show that decreased HIF-1α activity with age contributes to a decline in vascular and metabolic homeostasis, promoting age-related diseases.^{33, 34}

The crosstalk between HIFs and other key signaling pathways also plays a critical role in aging. For example, HIFs modulate mTOR and AMPK pathways, which are essential for cellular metabolism, autophagy, and stress response.^{49, 50} Dysregulation of these pathways by altered HIF activity in aging cells leads to metabolic imbalances, reduced autophagy, and increased susceptibility to oxidative stress.⁵¹ The reduced function of HIFs with age may also affect stem cell maintenance and regenerative capacity, contributing to tissue aging and dysfunction.⁵² Furthermore, HIFs play a crucial role in modulating mitochondrial function, a key aspect of cellular metabolism and aging.⁵³ HIF-1α regulates mitochondrial respiration by altering the expression of genes involved in the electron transport chain and glycolysis, shifting energy production from oxidative phosphorylation to glycolysis under hypoxic conditions.⁵⁴ This metabolic reprogramming helps cells adapt to low-oxygen levels but can also lead to increased ROS production and mitochondrial damage, especially in aging cells with compromised antioxidant defenses.⁵⁵ The decline in HIF-1α function with age exacerbates mitochondrial dysfunction, contributing to the accumulation of cellular damage and promoting aging.

Recent studies suggest that enhancing HIF-1α activity may promote healthy aging by improving metabolic homeostasis, reducing oxidative stress, and enhancing angiogenesis.^56-58 However, the therapeutic potential of targeting HIFs in aging remains controversial, as chronic HIF activation has also been linked to tumorigenesis and other pathological condition.⁵⁹ Thus, a better understanding of the context-dependent effects of HIF modulation is necessary for developing effective antiaging therapies.

2.2 Oxidative stress and mitochondrial dysfunction

Oxidative stress, defined as the imbalance between ROS production and antioxidant defense, is a fundamental mechanism driving aging and age-related diseases. Hypoxia exacerbates oxidative stress by impairing mitochondrial respiration, leading to increased electron leakage and ROS generation.¹¹ ROS can cause extensive damage to cellular macromolecules, including DNA, proteins, and lipids, resulting in cellular dysfunction, senescence, and death.^{60, 61} Under hypoxic conditions, mitochondrial dysfunction is further aggravated, contributing to the progressive decline in cellular and tissue function observed with aging.^{27, 28}

Hypoxia also impacts mitochondrial dynamics, including fission, fusion, and mitophagy, processes essential for maintaining mitochondrial integrity and function.⁶² Hypoxia-induced oxidative stress disrupts these dynamics, leading to the accumulation of damaged mitochondria, decreased ATP production, and increased apoptosis. This mitochondrial dysfunction is particularly pronounced in aging cells, where the capacity for mitophagy and mitochondrial biogenesis is already compromised, resulting in a vicious cycle of increased oxidative damage and cellular decline.⁶³ Moreover, mitochondrial dysfunction under hypoxic conditions contributes to the activation of proinflammatory pathways, creating a feedback loop that promotes chronic inflammation and accelerates aging.⁶⁴ The release of mitochondrial DNA and other damage-associated molecular patterns (DAMPs) can activate the inflammasome and other innate immune responses, contributing to “inflammaging.”^{65, 66} Inhibition of mitochondrial ROS production or enhancement of mitochondrial quality control mechanisms has shown promise in delaying aging and extending lifespan in animal models.^{67, 68} Evidence from animal studies and clinical trials suggests that mitochondrial dysfunction and oxidative damage caused by excessive ROS production are major contributors to aging and age-related diseases. Mitochondrial abnormalities have been observed in the epithelial and airway smooth muscle cells of patients with chronic obstructive pulmonary disease (COPD), indicating the role of mitochondrial impairment in the pathology of this condition.⁶⁹ Recently, a study demonstrated that patients with COPD have significantly higher systemic inflammatory markers, such as high-sensitivity C-reactive protein (hs-CRP) and leukocytes, and reduced levels of the antioxidant glutathione (GSH), compared to individuals without COPD.⁷⁰

Moreover, excess ROS production can trigger ferroptosis, a type of cell death characterized by decreased cellular antioxidant capacity and ROS accumulation. Researchers have noted that this process is accompanied by substantial iron accumulation, lipid peroxidation, altered mitochondrial structure, somatic membrane wrinkling, and fragmentation of the outer membrane. Studies suggest that mitochondrial ROS are involved in regulating immune responses and autophagy-related signaling pathways, such as the AMPK–ULK1 axis, which promotes iron autophagy.⁷¹ Additionally, elevated free iron levels have been shown to induce ROS, resulting in cellular damage and potential cell death.⁷² These findings underscore the critical role of mitochondrial ROS in age-related conditions, influencing both cellular function and systemic health.

2.3 Inflammatory pathways activation

Chronic inflammation, also known as “inflammaging” is a hallmark of aging that is exacerbated by hypoxia. Hypoxia triggers the activation of various inflammatory pathways, including NF-κB and HIF-1, leading to the production of proinflammatory cytokines (Table 2) such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β).^{29, 30} These cytokines contribute to chronic low-grade inflammation, which is implicated in the pathogenesis of numerous age-related diseases, including cardiovascular disease (CVD), neurodegeneration, and cancer.⁷³ The relationship between hypoxia and inflammation is complex and involves multiple feedback loops. For instance, hypoxia-induced ROS can activate the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome, promoting the release of IL-1β and further exacerbating inflammation.^74-76 Additionally, hypoxia can induce the expression of adhesion molecules, such as ICAM-1 and VCAM-1, promoting leukocyte recruitment and perpetuating the inflammatory response.⁷⁷ The chronic activation of these inflammatory pathways under hypoxic conditions is implicated in the induction of tissue damage, promotion of cellular senescence, and acceleration of the aging process.

Hypoxia-induced activation of NF-κB involves multiple pathways, including the roles of oxygen sensors, hydroxylases, JmjC enzymes, and kinases like IκB kinase (IKK) and transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1). Among the oxygen sensors, 2OG-dependent dioxygenases, such as prolyl hydroxylases (PHDs) and factor inhibiting HIF (FIH), are crucial in stabilizing HIF and influencing pathways related to oxygen availability, including NF-κB. Proteomics studies have identified components of the NF-κB pathway, such as p105, IκBα, and OTU domain-containing ubiquitin aldehyde-binding proteins 1 (OTUB1), as hydroxylation targets of FIH, linking oxygen sensing to NF-κB regulation.^{78, 79} Although OTUB1 hydroxylation affects cellular metabolism, its direct involvement in hypoxia-induced NF-κB activation is yet to be fully understood. PHDs also modulate NF-κB activity by hydroxylating key regulators, including IKKβ, which is vital for NF-κB activation under hypoxic conditions.^80-84 JmjC enzymes, typically recognized for their role in demethylating lysine residues, also influence NF-κB signaling by targeting nonhistone proteins such as p65. For instance, lysine demethylase 2A (KDM2A) demethylates p65, thereby regulating NF-κB target gene expression. Notably, KDM2A is induced by both NF-κB and hypoxia, establishing a feedback loop that connects NF-κB signaling with hypoxic responses.^85-87 Other JmjC enzymes, including lysine demethylase 6B (KDM6B) and jumonji domain containing 8 (JMJD8), further modulate NF-κB signaling, illustrating the intricate crosstalk between hypoxia and inflammation pathways. Hypoxia also activates NF-κB through IKK-dependent pathways involving phosphorylation of IκBα, facilitated by TAK1 and ubiquitin-conjugating enzyme Ubc13, and conserved across different species, emphasizing their fundamental role in hypoxic responses.^{88, 89} The involvement of ubiquitin ligases, such as X-linked inhibitor of apoptosis (XIAP), in interacting with IKK further underscores the complexity of NF-κB regulation under hypoxic conditions. Under hypoxic conditions, IκBα undergoes unique post-translational modifications, such as SUMOylation instead of degradation, which distinctly influences NF-κB activity compared to normoxic conditions.⁹⁰ SUMOylation of IκBα can either promote or inhibit NF-κB activation depending on the SUMO isoform involved, reflecting a nuanced, context-dependent mechanism of NF-κB modulation in hypoxia.

Cellular senescence itself is both a consequence and a driver of inflammation. Senescent cells secrete a range of SASP factors which can be enhanced by hypoxia, contributing to a proinflammatory environment that accelerates tissue aging and dysfunction.^{91, 92} Hypoxia-induced inflammation has been confirmed in both clinical and experimental settings. A study from the University of Edinburgh reported hypoxemia and monocytopenia in patients with acute respiratory distress syndrome (ARDS) within 48 h of ventilation, which was also observed in mouse models of hypoxic acute lung injury, leading to reduced monocyte-derived macrophages and increased neutrophil-driven inflammation.⁹³ In respiratory viral infections, such as influenza and COVID-19, hypoxemia frequently occurs due to the interplay between lung inflammation and a hypoxic microenvironment that disrupts pulmonary function.⁹⁴ Hypoxia is also implicated in promoting tissue inflammation and fibrosis by enhancing profibrotic cytokine responses, reducing antigen presentation, and suppressing T-cell activity, particularly in nodular diseases.⁹⁵ HIF-1α and HIF-2α play distinct roles in inflammation; HIF-1α supports cardiomyocyte protection via macrophage glycolysis reprogramming, while HIF-2α inhibits mitochondrial metabolism in anti-inflammatory macrophages.⁹⁶ Hypoxia activates NLRP3 inflammasomes, triggering IL-1β release and inflammation in macrophages.⁷⁴ In the nervous system, hypoxia-induced S100A8 protein promotes neuroinflammation and apoptosis via JNK and ERK pathways.⁹⁷ Additionally, intermittent hypoxia in tumors enhances a proinflammatory macrophage phenotype through the JNK/p65 pathway, highlighting the link between hypoxia and immune dysregulation.⁹⁸ These findings underscore the complex relationship between hypoxia and inflammation, emphasizing the need to further explore hypoxia-driven inflammatory signaling for therapeutic advancements.

2.4 Cellular senescence and DNA damage

Cellular senescence is a state of irreversible growth arrest that occurs in response to various stressors, including hypoxia and DNA damage. Senescent cells accumulate with age and contribute to tissue dysfunction and aging by secreting inflammatory factors and degrading the extracellular matrix.^{35, 36} Hypoxia has been shown to induce cellular senescence by promoting DNA damage through increased ROS production and impairing DNA repair mechanisms. This DNA damage response (DDR) triggers the activation of p53 and p21, key regulators of cell cycle arrest and senescence.^{125, 126}

Hypoxia-induced DNA damage occurs via direct and indirect mechanisms. Directly, hypoxia increases the production of ROS, leading to oxidative damage to DNA, proteins, and lipids.¹²⁷ Indirectly, hypoxia downregulates key DNA repair pathways, such as homologous recombination and nonhomologous end joining, resulting in genomic instability and the accumulation of mutations.^{128, 129} This genomic instability contributes to cellular senescence and the development of age-related diseases, including cancer. Furthermore, hypoxia-induced senescence is associated with telomere attrition, where repeated exposure to low-oxygen levels accelerates telomere shortening, a key marker of cellular aging.¹³⁰ Telomere dysfunction activates the p53/p21 and p16^INK4a pathways, driving cells into a senescent state and contributing to aging and age-related diseases.¹³¹ Inhibiting telomere shortening or enhancing telomerase activity has been proposed as a potential strategy for mitigating the effects of hypoxia on aging.^{132, 133}

2.5 Epigenetic modifications in hypoxic aging

Epigenetic changes, including DNA methylation, histone modifications, and noncoding RNA regulation, play a crucial role in aging and are profoundly affected by hypoxia. Hypoxic conditions can lead to widespread epigenetic reprogramming (Table 3), impacting gene expression patterns associated with aging.¹³⁴ For instance, hypoxia-induced HIF-1α stabilization can modulate the expression of various genes involved in metabolism, angiogenesis, and cellular survival.^{135, 136} Hypoxia has been shown to cause DNA hypermethylation and histone modifications that alter chromatin structure and function, promoting the expression of proaging genes while silencing genes involved in DNA repair and cell cycle control.^137-139 Additionally, hypoxia can influence noncoding RNAs, such as microRNAs and long noncoding RNAs, which regulate gene expression at the post-transcriptional level and contribute to aging.^{31, 32} Recent studies suggest that reversing epigenetic changes associated with hypoxia may offer therapeutic potential in delaying aging and treating age-related diseases.¹⁴⁰ However, the exact mechanisms by which hypoxia modulates epigenetic landscapes remain to be fully elucidated, requiring further research.

Prenatal hypoxia influences gene expression through epigenetic modifications, including histone acetylation and DNA methylation, which alter fetal development and predispose individuals to aging-related pathologies. In a lamb model of high-altitude prenatal hypoxia, reduced histone acetylation and DNA methylation in fetal pulmonary arteries were linked to pulmonary arterial remodeling and hypertension in newborns.¹⁴¹ Similarly, maternal hypoxia decreased hepatic G6Pase expression in male offspring, associated with increased histone methylation around the G6Pase promoter.¹⁴² Hypoxia also modulates neurodevelopmental pathways, as seen in mid-gestational neural precursor cells where HIF1α-notch signaling promotes astrocyte differentiation through DNA demethylation of astrocytic genes, which may alter neuron–astrocyte ratios in the brain.¹⁴³ Hypoxia-induced hypermethylation of glucocorticoid receptor genes in the developing rat brain disrupts transcription factor binding and gene expression, impacting stress responses.¹⁴⁴ Also, demethylation of the corticotropin-releasing hormone gene (Crhr1) in the hypothalamus of male offspring exposed to intermittent hypoxia contributes to anxiety-like behaviors in adulthood.¹⁴⁵ These modifications can result in cognitive deficits and increased susceptibility to neurodegeneration, highlighting the significant role of hypoxia-induced chromatin changes in brain development.

Hypoxia alters microRNA (miRNA) expression in neuronal cells, as seen in studies on rat cortical pericytes and hippocampus, linking altered miRNA profiles to cognitive dysfunction and neurodegenerative phenotypes.^{146, 147} miRNAs, such as miR-210 and miR-23b-27b, are specifically regulated by hypoxia via HIF-1α and other transcription factors, contributing to neuronal apoptosis and altered brain development.^{148, 149} Changes in miRNA expression are also associated with neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), suggesting that hypoxia-induced miRNA dysregulation in developing brains can predispose individuals to neurodegeneration later in life.^150-152 Quantifying hypoxia-regulated miRNAs in maternal blood may offer a noninvasive method to assess fetal hypoxia risk and related neurodevelopmental issues.¹⁵³ In Alzheimer's models, hypoxia-induced demethylation and reduced DNA methyltransferase 3b expression elevated levels of amyloid precursor protein (APP), β- and γ-secretases, which are linked to learning and memory deficits in offspring, underscoring the long-term impact of hypoxic epigenetic changes on neurodegeneration.⁵

3.1 Cardiovascular diseases

CVDs are among the leading causes of morbidity and mortality worldwide, and their incidence significantly increases with age. Hypoxia is a crucial factor in the pathogenesis of many cardiovascular conditions, including atherosclerosis, hypertension, and heart failure. Hypoxia-induced oxidative stress and inflammation contribute to endothelial dysfunction, a key event in the development of atherosclerosis.¹⁶⁶ Under hypoxic conditions, endothelial cells produce increased levels of ROS and proinflammatory cytokines, leading to vascular damage, plaque formation, and progression of atherosclerosis.¹⁶⁷ Aging further exacerbates these effects by reducing endothelial cell function and enhancing oxidative stress, creating a vicious cycle that promotes cardiovascular pathology.

Hypertension, another common age-related cardiovascular condition, is closely linked to hypoxia. Chronic hypoxia activates the renin–angiotensin–aldosterone system (RAAS), leading to increased blood pressure and vascular remodeling.¹⁶⁸ Hypoxia-induced activation of HIFs also promotes the expression of genes involved in vascular tone regulation, such as endothelin-1 and nitric oxide synthase, contributing to hypertension.¹⁶⁹ With aging, the capacity of the vascular system to respond to these hypoxic stimuli diminishes, resulting in sustained hypertension and increased risk of cardiovascular events.

Heart failure, a cardiovascular condition, is also exacerbated by hypoxia and aging. In heart failure, reduced cardiac output leads to tissue hypoxia, which triggers compensatory mechanisms, including HIF activation, to restore oxygen delivery.¹⁷⁰ However, chronic hypoxia can lead to maladaptive cardiac remodeling, characterized by fibrosis, hypertrophy, and impaired contractility.¹⁷¹ Aging further impairs the heart's ability to adapt to hypoxic stress, contributing to the progression of heart failure and poor clinical outcomes.¹⁷² Targeting hypoxia-related pathways may offer therapeutic benefits in managing age-related CVDs.

Hypoxia has been linked to increased thrombosis, particularly in conditions like polycythemia vera and hypoxic cancer tissues.¹⁷³ Studies demonstrated that HIF-1α downregulates the antithrombotic factor protein S in liver cells, leading to increased thrombin and a prothrombotic state. This suggests that hypoxia-driven HIF-1α activity contributes to thrombotic risk by altering key antithrombotic pathways.

Acute mountain sickness (AMS) arises from complex physiological responses to hypoxia, including inflammation, vasogenic edema, and acidosis. Recent studies indicate that proinflammatory cytokines such as IL-1β, IL-6, and TNF-α are elevated in individuals exposed to high altitudes, suggesting inflammation's role in AMS development.^99-103 AMS-susceptible individuals show lower anti-inflammatory markers like IL-10 and higher proinflammatory markers, highlighting a potential imbalance in inflammatory responses.^{101, 174} The disruption of the blood–brain barrier and vasogenic edema due to hypoxia-driven inflammatory mediators may contribute to AMS symptoms, although the exact mechanisms remain to be fully elucidated.

High-altitude cerebral edema (HACE) is a severe condition that often develops after AMS and involves hypoxia-mediated cerebral vasodilation, loss of blood–brain barrier integrity, and increased intracranial pressure.^{175, 176} Proinflammatory cytokines and increased AQP4 activity in astrocytes, triggered by TLR4 and MAPK signaling, exacerbate astrocyte permeability and contribute to vasogenic edema.^{99, 110} Although inflammation likely plays a role in HACE development, further research is needed to clarify its exact contribution and how it interacts with hypoxic pathways.

High-altitude pulmonary hypertension (HAPH) results from generalized hypoxic pulmonary vasoconstriction (HPV), leading to increased pulmonary artery pressures. Chronic hypoxia induces a proinflammatory microenvironment that drives vascular remodeling, marked by increased vessel muscularization and inflammatory cell recruitment.^{177, 178} High-altitude pulmonary edema (HAPE) is primarily caused by exaggerated HPV, acute pulmonary hypertension, and increased capillary permeability, leading to alveolar fluid accumulation.^179-182 Inflammation appears to contribute to HAPE susceptibility, with HAPE-prone individuals showing elevated baseline inflammation and reduced lung function compared to resistant individuals.^{111, 112} Pre-existing pulmonary vascular remodeling and chronic inflammation may further exacerbate susceptibility, though direct mechanisms remain under investigation.¹⁸³

3.2 Neurodegenerative disorders

Neurodegenerative disorders, including AD, PD, and HD, are characterized by the progressive loss of neurons and cognitive decline. Hypoxia is a known contributor to the pathogenesis of these disorders through mechanisms involving oxidative stress, inflammation, and mitochondrial dysfunction.^184-186 In AD, hypoxia exacerbates amyloid beta (Aβ) aggregation and tau hyperphosphorylation, two hallmark features of the disease, by increasing ROS production and activating inflammatory pathways.^107-109 Studies show that chronic hypoxia induces blood–brain barrier disruption, further promoting neuroinflammation and neuronal damage in aging brains. Hypoxia upregulates β- and γ-secretases, key enzymes in Aβ production, and reduces neprilysin (NEP), an enzyme involved in Aβ degradation.^{187, 188} Animal studies have shown that hypoxic conditions enhance tau phosphorylation, disrupt APP processing, and impair memory, indicating that hypoxia accelerates AD progression through multiple molecular pathways.^{108, 109, 189} Antenatal hypoxia has been linked to early onset AD-related pathology, particularly in genetically susceptible models such as 5 × Familial Alzheimer's Disease (FAD) mice. Hypoxia during fetal development exacerbates cognitive decline and neuroinflammation, increasing the vulnerability of the brain to AD-related damage later in life.¹⁹⁰ This highlights a potential developmental origin of aging-related neurodegenerative disorders influenced by hypoxic conditions. Hypoxia and ischemia are known to worsen cerebrovascular dysfunctions seen in AD, such as reduced cerebral blood flow and capillary amyloid angiopathy. These hypoxic conditions elevate β- and γ-secretase activities, increasing Aβ deposition and contributing to AD pathology.¹⁹¹ HIF-1α plays a critical role in this process by upregulating secretase activities and interacting with key components of the Aβ pathway, reinforcing the link between hypoxia, vascular dysfunction, and AD progression.

In PD, hypoxia contributes to dopaminergic neuron loss in the substantia nigra, a key pathological feature of the disease. Hypoxic conditions have been shown to impair mitochondrial function and increase oxidative stress in dopaminergic neurons, leading to their degeneration.¹⁹² Furthermore, hypoxia activates HIF-1α, which modulates the expression of genes involved in apoptosis and autophagy, processes implicated in PD progression. As the brain's capacity to cope with hypoxic stress declines with age, the risk of developing PD increases, highlighting the importance of understanding hypoxia's role in neurodegeneration.¹⁹³ Hypoxia also plays a role in the progression of HD, a genetic neurodegenerative disorder characterized by the accumulation of mutant huntingtin protein. Research indicates that hypoxia can exacerbate mitochondrial dysfunction and enhance the aggregation of mutant huntingtin, leading to neuronal death. Moreover, hypoxia-induced oxidative stress and inflammation contribute to the loss of striatal neurons, a hallmark of HD pathology.^194-196 These findings suggest that hypoxia is a common pathogenic factor in various neurodegenerative diseases, particularly in the context of aging.

3.3 Cancer

Cancer is a complex and multifaceted disease that becomes increasingly prevalent with age, partly due to the accumulation of cellular damage and the diminished ability to respond to stressors like hypoxia. Hypoxia is a critical driver of tumorigenesis, especially in aging populations, as it promotes genetic instability, metabolic reprogramming, and resistance to cell death.¹⁹⁷ Hypoxic tumor microenvironments, characterized by low-oxygen levels, stabilize HIFs, which induce the expression of genes involved in angiogenesis, cell survival, and invasion, contributing to cancer progression.¹⁹⁸

One of the key ways that hypoxia contributes to tumor progression is by promoting angiogenesis—the formation of new blood vessels essential for tumor growth and metastasis. HIF-1α upregulates vascular endothelial growth factor (VEGF), a crucial mediator of angiogenesis, thereby facilitating tumor expansion.^{113, 199} Aging tissues are more susceptible to hypoxia-induced DNA damage and cellular transformation, increasing the risk of cancer development. Additionally, the ability to respond to hypoxic stress diminishes with age, leading to more aggressive tumor phenotypes and poorer clinical outcomes.^{10, 200}

Hypoxia also induces significant metabolic reprogramming in cancer cells. Under hypoxic conditions, cancer cells shift their energy production from oxidative phosphorylation to glycolysis—a phenomenon known as the “Warburg effect”. This metabolic shift provides a growth advantage to tumor cells, allowing them to thrive even in low-oxygen environments.^{201, 202} Moreover, hypoxic conditions enhance the resistance of tumor cells to therapies such as chemotherapy and radiation. These cells exhibit altered metabolism, increased expression of drug efflux pumps, and enhanced DNA repair capacity, making them less responsive to conventional treatments. Hypoxia also supports the maintenance of cancer stem cells, which are implicated in tumor recurrence and metastasis, posing a significant challenge in cancer treatment, particularly in older patients with reduced physiological reserve.²⁰³

The interplay between hypoxia and inflammation further complicates cancer progression, particularly through the activation of NF-κB signaling. In colorectal cancer (CRC), hypoxia-induced NF-κB activation drives tumor growth, angiogenesis, and metastasis.¹⁰⁶ HIF-1α and HIF-2α have different roles in CRC, with HIF-1α driving cancer development and HIF-2α acting as a tumor suppressor.²⁰⁴ However, in colon cancer, HIF-2α plays a crucial role in promoting cancer progression by activating inflammatory pathways. Specifically, it increases the production of proinflammatory mediators like TNF-α, which is a key contributor to cancer development.²⁰⁵ Studies have demonstrated that anti-inflammatory drugs such as nimesulide, which inhibit HIF-2α, can significantly reduce tumor growth.²⁰⁵ The crosstalk between NF-κB and Wnt/β-catenin underscores the complex regulatory networks at play and highlights the need for targeted therapeutic strategies.

Similarly, in breast and lung cancers, NF-κB and HIF signaling are pivotal in driving disease progression. In breast cancer, NF-κB activation, often triggered by hypoxic and inflammatory stimuli, promotes epithelial–mesenchymal transition (EMT) and metastasis.¹⁵⁵ In non–small-cell lung carcinoma (NSCLC), NF-κB activation contributes to resistance against tyrosine kinase inhibitors, underscoring its critical role in cancer survival and positioning it as a potential therapeutic target.²⁰⁶ The involvement of JmjC enzymes, such as KDM4 family members, further demonstrates the intricate relationship between inflammation, hypoxia, and cancer progression in these tumors.

Intra tumoral hypoxia significantly influences the immune landscape of tumors. In NSCLC, loss of HIF-2α increases tumor burden and immune cell infiltration, particularly of granulocytic cells, indicating that HIF-2α can exert antitumor effects by modulating immune responses.²⁰⁷ In contrast, the loss of HIF-1α does not impact NSCLC progression, highlighting the distinct functional roles of HIF isoforms in cancer biology. In pancreatic ductal adenocarcinoma (PDAC), HIF-1α and HIF-2α also exhibit opposing effects on tumor progression: HIF-1α deletion enhances tumor proliferation and immune infiltration, whereas loss of HIF-2α reduces the progression of precursor lesions, further underscoring the nuanced roles of these factors in cancer.^{208, 209}

3.4 Metabolic disorders

Metabolic disorders, including type 2 diabetes, obesity, and metabolic syndrome, are closely associated with aging and are exacerbated by hypoxia. Hypoxia affects metabolic homeostasis by altering glucose metabolism, lipid metabolism, and insulin signaling.²¹⁰ Under hypoxic conditions, HIF-1α activation promotes glycolysis and suppresses oxidative phosphorylation, leading to hyperglycemia and insulin resistance, key features of diabetes.^{119, 211-213} Additionally, hypoxia-induced inflammation and oxidative stress contribute to pancreatic beta-cell dysfunction, further impairing glucose homeostasis.^{114, 115}

Obesity, a major risk factor for metabolic disorders, is also linked to hypoxia. Adipose tissue hypoxia in obese individuals leads to increased inflammation, adipocyte dysfunction, and insulin resistance.^{124, 214, 215} Hypoxia in adipose tissue promotes macrophage infiltration and the production of proinflammatory cytokines, which exacerbate metabolic dysregulation.^{123, 213} Aging further compounds these effects by reducing adipose tissue oxygenation and enhancing systemic inflammation, increasing the risk of metabolic diseases. Hypoxia affects lipid metabolism by regulating key enzymes involved in lipogenesis and lipolysis. HIF-1α activation under hypoxic conditions promotes lipogenesis while inhibiting lipolysis, leading to lipid accumulation and dyslipidemia, which are common in aging individuals. Hypoxia-induced dyslipidemia contributes to the development of CVDs and other metabolic complications, further linking hypoxia to age-related metabolic disorders.^{216, 217}

3.5 Pulmonary diseases

Pulmonary diseases, including COPD and pulmonary fibrosis, are common in aging populations and are significantly influenced by hypoxia. Hypoxia plays a central role in the pathogenesis of these conditions by promoting inflammation, fibrosis, and tissue remodeling.^{218, 219} In COPD, hypoxia-induced oxidative stress and inflammation contribute to airway remodeling, alveolar destruction, and impaired gas exchange.^219-222 Aging further exacerbates these effects by reducing lung function and increasing susceptibility to hypoxia-induced damage.²²³ In COPD, acute hypoxic exposure triggers both inflammatory and coagulation responses, marked by increased levels of thrombin–antithrombin complexes (TAT), D-dimers, and von Willebrand factor (VWF) antigen, along with elevated inflammatory mediators.²²⁴

Hypoxia promotes fibroblast activation, extracellular matrix deposition, and tissue remodeling, leading to the development and progression of pulmonary fibrosis. Aging is a significant risk factor for pulmonary fibrosis, as the capacity for tissue repair and regeneration declines with age. Hypoxia-induced activation of HIF-1α and other profibrotic pathways further accelerates disease progression in aging individuals.

3.6 Prenatal hypoxia and aging

Prenatal hypoxia, resulting from complications during pregnancy, is a critical factor influencing fetal brain development, leading to long-term consequences in postnatal life. Hypoxic conditions during gestation have been linked to an increased risk of various central nervous system (CNS) disorders, including autism, schizophrenia, and neurodegenerative diseases such as PD and AD.²²⁵ Prenatal hypoxia alters gene expression and protein metabolism, notably affecting key proteins like acetylcholinesterase and APP, which are crucial for brain function.²²⁶ The disruption of these pathways can lead to early cognitive dysfunctions and predispose individuals to neurodegenerative processes. Additionally, hypoxia impairs the activity of Aβ-degrading enzymes, resulting in toxic Aβ accumulation and neuronal damage.²²⁷

Prenatal hypoxia also affects the body's response to hypoxia later in life by altering catecholaminergic components of the chemoafferent pathway, impairing respiratory behavior, and increasing oxidative stress.²²⁸ These findings highlight the importance of addressing prenatal hypoxia as a modifiable risk factor for aging-related cognitive decline and neurodegeneration.

3.7 Obstructive sleep apnea-induced intermittent hypoxia and aging

Obstructive sleep apnea (OSA) is characterized by repeated episodes of upper airway obstruction leading to intermittent hypoxia. OSA-induced cyclical hypoxemia–reoxygenation activates chemoreceptors, causing sympathetic overactivation, increased blood pressure, and chronic intermittent hypoxia (CIH).²²⁹ These hypoxic episodes contribute to molecular and cellular impairments that accelerate the progression of various diseases and aging.²³⁰ The OSA is associated with pulmonary hypertension, as demonstrated in highland populations, where sleep apnea and hypoxemia were linked to increased pulmonary artery pressure.^{231, 232} The recurrent hypoxic stress triggers inflammatory responses, sympathetic activation, and vascular damage, contributing to conditions like atherosclerosis and further aggravating pulmonary hypertension.^12-114 This suggests a complex interplay between OSA, intermittent hypoxia, and cardiovascular risk, underscoring the need for targeted therapeutic interventions to mitigate the adverse effects of hypoxia-induced aging.

The OSA is more common in aging and is associated with comorbidities such as male sexual dysfunction. Oxidative stress, which increases with both age and CIH, is a proposed mechanism linking sleep apnea to sexual dysfunction.²³³ Studies in animal models of CIH showed that middle-aged male rats experienced elevated oxidative stress, reduced testosterone, and increased sexual dysfunction. Notably, CIH had more profound effects on younger intact males, suggesting that hypoxia mimics aging-related dysfunction in sexual behavior and oxidative stress.

4.1 Targeting hypoxia-inducible factors

HIFs, particularly HIF-1α, are key regulators of the cellular response to hypoxia and represent promising therapeutic targets for aging and age-related diseases. Pharmacological modulation of HIF pathways has the potential to enhance adaptive responses to hypoxia, improve metabolic homeostasis, and reduce inflammation.²⁵⁶ While HIF inhibition has shown promise in preclinical models, its therapeutic potential in aging remains controversial. Chronic HIF activation has been associated with increased tumorigenesis and other pathological conditions, raising concerns about the long-term safety of HIF-targeted therapies.²⁵⁷ However, recent studies suggest that selective modulation of HIF pathways, such as transient HIF activation or targeting specific HIF isoforms, may offer a safer and more effective approach for promoting healthy aging.^234-236

In addition to HIF inhibitors, other strategies for targeting HIF pathways include the use of small molecules, peptides, and gene therapy approaches to modulate HIF activity.²⁵⁸ These approaches have shown promise in preclinical models of aging and age-related diseases, but further research is needed to determine their efficacy and safety in humans. Overall, targeting HIFs represents a promising avenue for therapeutic intervention in aging, but careful consideration of the risks and benefits is essential.

4.2 Antioxidants and mitochondrial therapies

Given the central role of oxidative stress in aging and age-related diseases, antioxidants have been extensively studied as potential therapeutic agents. Antioxidants, such as vitamins C and E, coenzyme Q10, and N-acetylcysteine, aim to neutralize ROS and reduce oxidative damage.^{237, 238} However, the efficacy of antioxidant therapy in promoting healthy aging and preventing age-related diseases remains uncertain, with some studies showing limited benefits or even potential harm. This has led to a shift in focus toward more targeted approaches, such as mitochondrial-targeted antioxidants and therapies that enhance endogenous antioxidant defenses.²⁵⁹ These antioxidants, such as MitoQ and SkQ1, are designed to accumulate selectively within mitochondria, where they can more effectively neutralize ROS and reduce mitochondrial damage.^{246, 247} Preclinical studies have shown that these compounds can improve mitochondrial function, reduce oxidative stress, and extend lifespan in animal models.^{246, 260, 261} Clinical trials are currently underway to evaluate the efficacy of mitochondrial-targeted antioxidants in human aging and age-related diseases.²⁶²

In addition to antioxidant therapies, other mitochondrial-targeted interventions, such as agents that enhance mitochondrial biogenesis, mitophagy, and metabolic flexibility like FOXO, are being explored for their potential to promote healthy aging.^{263, 264} These approaches aim to restore mitochondrial function and improve cellular energy metabolism, which may help mitigate the effects of hypoxia and oxidative stress on aging. However, further research is needed to identify the most effective strategies for targeting mitochondrial dysfunction in aging.

4.3 Anti-inflammatory and senolytic agents

Chronic inflammation, or “inflammaging” is a key driver of aging and age-related diseases, making anti-inflammatory agents a promising therapeutic target. Nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and other anti-inflammatory agents have been studied for their potential to reduce inflammation and improve health outcomes in aging populations.^{239, 240} However, these agents have significant side effects and may not be suitable for long-term use in the elderly.²⁶⁵

Senolytic agents, which selectively eliminate senescent cells, have emerged as a novel therapeutic strategy for promoting healthy aging. Senescent cells accumulate with age and secrete proinflammatory factors, contributing to chronic inflammation and tissue dysfunction.²⁶⁶ Senolytic drugs, such as dasatinib and quercetin, have shown promise in preclinical models of aging by reducing senescent cell burden, improving tissue function, and extending lifespan.^248-250 Clinical trials are currently underway to evaluate the safety and efficacy of senolytic agents in humans.^267-269 Several other senolytic drugs such as ABT-737, ABT-263, FOXO4-DRI (D-retro inverso), and the HSP90 inhibitor 17-DMAG primarily exert their senolytic effects by inducing apoptosis and mitochondrial dysfunction. However, their interactions with epigenetic mechanisms require further exploration.^270-273

In addition to senolytics, senomorphic agents such as rutin that modulate the SASP without eliminating senescent cells are being explored as a potential therapeutic approach.²⁷⁴ These agents aim to reduce the proinflammatory and profibrotic effects of senescent cells, potentially slowing the progression of age-related diseases and improving healthspan.²⁷⁵ Further research is needed to determine the optimal strategies for targeting inflammation and senescence in aging.

4.4 Epigenetic modulators

Epigenetic changes, including DNA methylation, histone modifications, and noncoding RNA regulation, play a crucial role in aging and age-related diseases. Epigenetic modulators, such as DNA methyltransferase inhibitors (e.g., 5-azacytidine) and histone deacetylase (HDAC) inhibitors (e.g., valproic acid), have been studied for their potential to reverse age-associated epigenetic changes and promote healthy aging.²⁷⁶ Targeting specific epigenetic marks associated with aging, such as hypermethylation of tumor suppressor genes or hypoacetylation of histones, may offer therapeutic benefits in age-related diseases. HDACs, which act as corepressors in conjunction with histone acetyltransferases (HATs), play a significant role in longevity. Among them, sirtuins, a class of HDACs, are particularly important for maintaining genome stability. SIRT6, a member of this class, functions as an NAD⁺-dependent H3K9 deacetylase, influencing telomeric chromatin.²⁷⁷ Overexpression of SIRT6 has been linked to increased longevity in both rat and human nucleus pulposus cells by inhibiting cellular senescence.²⁴³

Emerging research suggests that lifestyle interventions, such as diet, exercise, and environmental exposures, may also influence the epigenome and promote healthy aging. Understanding the role of epigenetics in aging may reveal novel targets for therapeutic intervention and help identify individuals who are most likely to benefit from specific treatments. Future research should focus on identifying safe and effective strategies for modulating the epigenome to promote healthy aging and prevent age-related diseases.

4.5 Lifestyle and environmental interventions

Lifestyle and environmental interventions, such as exercise, CR, and exposure to intermittent hypoxia, have been shown to promote healthy aging and reduce the risk of age-related diseases. Exercise is a well-established intervention that can significantly impact epigenetic modifications, influencing gene expression and contributing to various health benefits. Physical activity has been shown to remodel DNA methylation patterns on the promoters of key genes in skeletal muscle,²⁷⁸ and histone modifications may also be affected through the inhibition of HDACs, thus altering gene expression profiles.²⁴⁵ Additionally, exercise can regulate the expression of miRNAs, which play crucial roles in mediating these beneficial effects.²⁴¹ For example, after just 8 weeks of voluntary resistance training, aged mice demonstrate an epigenetic rejuvenation equivalent to about 8 weeks of younger muscle tissue, along with a modest extension in lifespan.²⁷⁹ Similarly, voluntary wheel running in aged mice enhances neurogenesis, improves learning abilities, and mitigates age-related synaptic abnormalities.²⁸⁰ These rejuvenating effects are not limited to animal models; they are also evident in humans. Physically active elderly individuals show a significantly different transcriptional profile compared to their sedentary counterparts, and endurance exercise has been found to improve muscle function in older adults.²⁸¹

CR, a dietary strategy that lowers calorie intake without causing malnutrition, has been associated with increased lifespan and enhanced health across various animal studies. By reducing calorie consumption by 10%–40%, CR has been shown to significantly extend the lifespan of rodents.²⁴² This intervention also offers several health benefits, including improved vascular endothelial function, enhanced aerobic capacity of skeletal muscles, and a reduction in muscle fiber loss and motor neuron turnover.^282-285

Intermittent hypoxia, a practice that involves short-term exposure to low-oxygen levels, has been studied for its potential to mimic the benefits of exercise and promote healthy aging.²⁸⁶ Intermittent hypoxia training has been shown to improve neuronal function, enhance mitochondrial biogenesis, and reduce oxidative stress in animal models.^287-289 Recently, a study conducted by researchers at Massachusetts General Hospital explored the effects of oxygen restriction on longevity in mice.²⁹⁰ The study revealed significant findings, demonstrating that oxygen restriction led to notable improvements in lifespan and delayed neurological decline in mice. Mice exposed to mild hypoxia exhibited an impressive 50% increase in lifespan compared to control animals maintained under normoxic conditions. Additionally, hypoxia-exposed mice showed delayed onset and progression of neurological decline, suggesting a protective effect against age-related neurodegenerative processes. However, the long-term safety and efficacy of this intervention in humans remain uncertain.

Overall, dietary modifications and physical exercise remain the most widely endorsed approaches for addressing aging and related diseases, largely due to their proven efficacy and safety. While recent developments in pharmacological treatments, such as geroprotectors, have demonstrated potential benefits for various age-related conditions, concerns about their safety and variable outcomes underscore the need for additional clinical research to establish their reliability.