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

References

[1] Taylor CT. Mitochondria and cellular oxygen sensing in the HIF pathway. Biochem J. 2008; 409(1): 19-26.

[2] Semenza GL. Regulation of mammalian O₂ homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol. 1999; 15: 551-578.

[3] Jordan AS, McSharry DG, Malhotra A. Adult obstructive sleep apnoea. Lancet. 2014; 383(9918): 736-747.

[4] Raberin A, Burtscher J, Burtscher M, et al. Hypoxia and the aging cardiovascular system. Aging Dis. 2023; 14(6): 2051-2070.

[5] Liu H, Qiu H, Yang J, et al. Chronic hypoxia facilitates Alzheimer’s disease through demethylation of γ-secretase by downregulating DNA methyltransferase 3b. Alzheimers Dement. 2016; 12(2): 130-143.

[6] Liu H, Qiu H, Xiao Q, et al. Chronic hypoxia-induced autophagy aggravates the neuropathology of Alzheimer’s disease through AMPK-mTOR signaling in the APPSwe/PS1dE9 mouse model. J Alzheimers Dis. 2015; 48(4): 1019-1032.

[7] West JB. Physiological effects of chronic hypoxia. N Engl J Med. 2017; 376(20): 1965-1971.

[8] Fuhrmann DC, Wittig I, Dröse S, et al. Degradation of the mitochondrial complex I assembly factor TMEM126B under chronic hypoxia. Cell Mol Life Sci. 2018; 75(16): 3051-3067.

[9] Sen P, Shah PP, Nativio R, et al. Epigenetic mechanisms of longevity and aging. Cell. 2016; 166(4): 822-839.

[10] Wei Y, Giunta S, Xia S. Hypoxia in aging and aging-related diseases: mechanism and therapeutic strategies. Int J Mol Sci. 2022; 23(15): 8165.

[11] Finkel T. The metabolic regulation of aging. Nat Med. 2015; 21(12): 1416-1423.

[12] Yeo EJ. Hypoxia and aging. Exp Mol Med. 2019; 51(6): 1-15.

[13] Antikainen H, Driscoll M, Haspel G, et al. TOR-mediated regulation of metabolism in aging. Aging Cell. 2017; 16(6): 1219-1233.

[14] Hong S, Zhao B, Lombard DB, et al. Cross-talk between sirtuin and mammalian target of rapamycin complex 1 (mTORC1) signaling in the regulation of S6 kinase 1 (S6K1) phosphorylation. J Biol Chem. 2014; 289(19): 13132-13141.

[15] Pan H, Finkel T. Key proteins and pathways that regulate lifespan. J Biol Chem. 2017; 292(16): 6452-6460.

[16] Wenger RH, Stiehl DP, Camenisch G. Integration of oxygen signaling at the consensus HRE. Sci STKE. 2005; 2005(306): re12.

[17] Semenza GL. HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol (1985). 2000; 88(4): 1474-1480.

[18] Semenza GL. Oxygen sensing, homeostasis, and disease. N Engl J Med. 2011; 365(6): 537-547.

[19] Adebayo M, Singh S, Singh AP, et al. Mitochondrial fusion and fission: the fine-tune balance for cellular homeostasis. FASEB J. 2021; 35(6): e21620.

[20] Meyer JN, Leuthner TC, Luz AL. Mitochondrial fusion, fission, and mitochondrial toxicity. Toxicology. 2017; 391: 42-53.

[21] Freund A, Orjalo AV, Desprez PY, et al. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010; 16(5): 238-246.

[22] Oliveira PH, Boura JS, Abecasis MM, et al. Impact of hypoxia and long-term cultivation on the genomic stability and mitochondrial performance of ex vivo expanded human stem/stromal cells. Stem Cell Res. 2012; 9(3): 225-236.

[23] Bigot N, Mouche A, Preti M, et al. Hypoxia differentially modulates the genomic stability of clinical-grade ADSCs and BM-MSCs in long-term culture. Stem Cells. 2015; 33(12): 3608-3620.

[24] Huang W, Hickson LJ, Eirin A, et al. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol. 2022; 18(10): 611-627.

[25] Coppé JP, Desprez PY, Krtolica A, et al. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5: 99-118.

[26] Bacalini MG, Boattini A, Gentilini D, et al. A meta-analysis on age-associated changes in blood DNA methylation: results from an original analysis pipeline for infinium 450k data. Aging (Albany NY). 2015; 7(2): 97-109.

[27] Vakifahmetoglu-Norberg H, Ouchida AT, Norberg E. The role of mitochondria in metabolism and cell death. Biochem Biophys Res Commun. 2017; 482(3): 426-431.

[28] Bouhamida E, Morciano G, Perrone M, et al. The interplay of hypoxia signaling on mitochondrial dysfunction and inflammation in cardiovascular diseases and cancer: from molecular mechanisms to therapeutic approaches. Biology (Basel). 2022; 11(2): 300.

[29] Malkov MI, Lee CT, Taylor CT. Regulation of the hypoxia-inducible factor (HIF) by pro-inflammatory cytokines. Cells. 2021; 10(9): 2340.

[30] Eltzschig HK, Carmeliet P. Hypoxia and inflammation. N Engl J Med. 2011; 364(7): 656-665.

[31] Jiao B, Liu S, Zhao H, et al. Hypoxia-responsive circRNAs: a novel but important participant in non-coding RNAs ushered toward tumor hypoxia. Cell Death Dis. 2022; 13(8): 666.

[32] Huang Q, Yang J, Goh RMW, et al. Hypoxia-induced circRNAs in human diseases: from mechanisms to potential applications. Cells. 2022; 11(9): 1381.

[33] Abe H, Semba H, Takeda N. The roles of hypoxia signaling in the pathogenesis of cardiovascular diseases. J Atheroscler Thromb. 2017; 24(9): 884-894.

[34] Lim CS, Kiriakidis S, Sandison A, et al. Hypoxia-inducible factor pathway and diseases of the vascular wall. J Vasc Surg. 2013; 58(1): 219-230.

[35] Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013; 75: 685-705.

[36] Calcinotto A, Kohli J, Zagato E, et al. Cellular senescence: aging, cancer, and injury. Physiol Rev. 2019; 99(2): 1047-1078.

[37] He S, Sharpless NE. Senescence in health and disease. Cell. 2017; 169(6): 1000-1011.

[38] Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of ULK1. Nat Cell Biol. 2011; 13(2): 132-141.

[39] Cheng SC, Quintin J, Cramer RA, et al. mTOR-and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science. 2014; 345(6204): 1250684.

[40] Jiang S, Guo Y. Epigenetic clock: DNA methylation in aging. Stem Cells Int. 2020; 2020: 1047896.

[41] Ariumi Y, Turelli P, Masutani M, et al. DNA damage sensors ATM, ATR, DNA-PKcs, and PARP-1 are dispensable for human immunodeficiency virus type 1 integration. J Virol. 2005; 79(5): 2973-2978.

[42] Mir SM, Samavarchi Tehrani S, Goodarzi G, et al. Shelterin complex at telomeres: implications in ageing. Clin Interv Aging. 2020; 15: 827-839.

[43] Rossiello F, Jurk D, Passos JF, et al. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol. 2022; 24(2): 135-147.

[44] Pelullo M, Zema S, Nardozza F, et al. Wnt, notch, and TGF-β pathways impinge on hedgehog signaling complexity: an open window on cancer. Front Genet. 2019; 10: 711.

[45] Ovadya Y, Landsberger T, Leins H, et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun. 2018; 9(1): 5435.

[46] Wang Y, Jiao L, Qiang C, et al. The role of matrix metalloproteinase 9 in fibrosis diseases and its molecular mechanisms. Biomed Pharmacother. 2024; 171: 116116.

[47] Prabhakar NR, Semenza GL. Oxygen sensing and homeostasis. Physiology (Bethesda). 2015; 30(5): 340-348.

[48] Alique M, Sánchez-López E, Bodega G, et al. Hypoxia-inducible factor-1α: the master regulator of endothelial cell senescence in vascular aging. Cells. 2020; 9(1): 195.

[49] Chun Y, Kim J. AMPK-mTOR signaling and cellular adaptations in hypoxia. Int J Mol Sci. 2021; 22(18): 9765.

[50] Hindupur SK, González A, Hall MN. The opposing actions of target of rapamycin and AMP-activated protein kinase in cell growth control. Cold Spring Harb Perspect Biol. 2015; 7(8): a019141.

[51] Yu M, Zhang H, Wang B, et al. Key signaling pathways in aging and potential interventions for healthy aging. Cells. 2021; 10(3): 660.

[52] Lee HJ, Jung YH, Choi GE, et al. Role of HIF1α regulatory factors in stem cells. Int J Stem Cells. 2019; 12(1): 8-20.

[53] Bao X, Zhang J, Huang G, et al. The crosstalk between HIFs and mitochondrial dysfunctions in cancer development. Cell Death Dis. 2021; 12(2): 215.

[54] Heher P, Ganassi M, Weidinger A, et al. Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: metabolic stress as potential therapeutic target. Redox Biol. 2022; 51: 102251.

[55] Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol. 2020; 21(5): 268-283.

[56] Leiser SF, Begun A, Kaeberlein M. HIF-1 modulates longevity and healthspan in a temperature-dependent manner. Aging Cell. 2011; 10(2): 318-326.

[57] Leiser SF, Kaeberlein M. The hypoxia-inducible factor HIF-1 functions as both a positive and negative modulator of aging. Biol Chem. 2010; 391(10): 1131-1137.

[58] Hwang AB, Lee SJ. Regulation of life span by mitochondrial respiration: the HIF-1 and ROS connection. Aging (Albany NY). 2011; 3(3): 304-310.

[59] Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012; 148(3): 399-408.

[60] Juan CA, Pérez de la Lastra JM, Plou FJ, et al. The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int J Mol Sci. 2021; 22(9): 4642.

[61] Shields HJ, Traa A, Van Raamsdonk JM. Beneficial and detrimental effects of reactive oxygen species on lifespan: a comprehensive review of comparative and experimental studies. Front Cell Dev Biol. 2021; 9: 628157.

[62] Fuhrmann DC, Brüne B. Mitochondrial composition and function under the control of hypoxia. Redox Biol. 2017; 12: 208-215.

[63] Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol. 2018; 20(9): 1013-1022.

[64] Zong Y, Li H, Liao P, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther. 2024; 9(1): 124.

[65] Fulop T, Witkowski JM, Olivieri F, et al. The integration of inflammaging in age-related diseases. Semin Immunol. 2018; 40: 17-35.

[66] Franceschi C, Garagnani P, Parini P, et al. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018; 14(10): 576-590.

[67] Zhou L, Pinho R, Gu Y, et al. The role of SIRT3 in exercise and aging. Cells. 2022; 11(16): 2596.

[68] Palma FR, Gantner BN, Sakiyama MJ, et al. ROS production by mitochondria: function or dysfunction?. Oncogene. 2024; 43(5): 295-303.

[69] Agrawal A, Mabalirajan U. Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria. Am J Physiol Lung Cell Mol Physiol. 2016; 310(2): L103-L113.

[70] Fratta Pasini AM, Stranieri C, Ferrari M, et al. Oxidative stress and Nrf2 expression in peripheral blood mononuclear cells derived from COPD patients: an observational longitudinal study. Respir Res. 2020; 21(1): 37.

[71] Qin X, Zhang J, Wang B, et al. Ferritinophagy is involved in the zinc oxide nanoparticles-induced ferroptosis of vascular endothelial cells. Autophagy. 2021; 17(12): 4266-4285.

[72] Dixon SJ, Stockwell BR. The role of iron and reactive oxygen species in cell death. Nat Chem Biol. 2014; 10(1): 9-17.

[73] Taylor CT, Doherty G, Fallon PG, et al. Hypoxia-dependent regulation of inflammatory pathways in immune cells. J Clin Invest. 2016; 126(10): 3716-3724.

[74] Watanabe S, Usui-Kawanishi F, Karasawa T, et al. Glucose regulates hypoxia-induced NLRP3 inflammasome activation in macrophages. J Cell Physiol. 2020; 235(10): 7554-7566.

[75] Paik S, Kim JK, Silwal P, et al. An update on the regulatory mechanisms of NLRP3 inflammasome activation. Cell Mol Immunol. 2021; 18(5): 1141-1160.

[76] Chen C, Ma X, Yang C, et al. Hypoxia potentiates LPS-induced inflammatory response and increases cell death by promoting NLRP3 inflammasome activation in pancreatic β cells. Biochem Biophys Res Commun. 2018; 495(4): 2512-2518.

[77] Liang X, Arullampalam P, Yang Z, et al. Hypoxia enhances endothelial intercellular adhesion molecule 1 protein level through upregulation of arginase type II and mitochondrial oxidative stress. Front Physiol. 2019; 10: 1003.

[78] Cockman ME, Lancaster DE, Stolze IP, et al. Posttranslational hydroxylation of ankyrin repeats in IkappaB proteins by the hypoxia-inducible factor (HIF) asparaginyl hydroxylase, factor inhibiting HIF (FIH). Proc Natl Acad Sci U S A. 2006; 103(40): 14767-14772.

[79] Scholz CC, Rodriguez J, Pickel C, et al. FIH regulates cellular metabolism through hydroxylation of the deubiquitinase OTUB1. PLoS Biol. 2016; 14(1): e1002347.

[80] Zheng X, Zhai B, Koivunen P, et al. Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase. Genes Dev. 2014; 28(13): 1429-1444.

[81] Cummins EP, Berra E, Comerford KM, et al. Prolyl hydroxylase-1 negatively regulates IkappaB kinase-beta, giving insight into hypoxia-induced NFkappaB activity. Proc Natl Acad Sci U S A. 2006; 103(48): 18154-18159.

[82] Fu J, Taubman MB. EGLN3 inhibition of NF-κB is mediated by prolyl hydroxylase-independent inhibition of IκB kinase γ ubiquitination. Mol Cell Biol. 2013; 33(15): 3050-3061.

[83] Fu J, Taubman MB. Prolyl hydroxylase EGLN3 regulates skeletal myoblast differentiation through an NF-kappaB-dependent pathway. J Biol Chem. 2010; 285(12): 8927-8935.

[84] Xie X, Xiao H, Ding F, et al. Over-expression of prolyl hydroxylase-1 blocks NF-κB-mediated cyclin D1 expression and proliferation in lung carcinoma cells. Cancer Genet. 2014; 207(5): 188-194.

[85] Lu T, Jackson MW, Wang B, et al. Regulation of NF-kappaB by NSD1/FBXL11-dependent reversible lysine methylation of p65. Proc Natl Acad Sci U S A. 2010; 107(1): 46-51.

[86] Lu T, Yang M, Huang DB, et al. Role of lysine methylation of NF-κB in differential gene regulation. Proc Natl Acad Sci U S A. 2013; 110(33): 13510-13515.

[87] Batie M, Druker J, D’Ignazio L, et al. KDM2 family members are regulated by HIF-1 in hypoxia. Cells. 2017; 6(1): 8.

[88] Melvin A, Mudie S, Rocha S. Further insights into the mechanism of hypoxia-induced NFκB. Cell Cycle. 2011; 10(6): 879-882. [corrected].

[89] Bandarra D, Biddlestone J, Mudie S, et al. Hypoxia activates IKK-NF-κB and the immune response in Drosophila melanogaster. Biosci Rep. 2014; 34(4): e00127.

[90] Culver C, Sundqvist A, Mudie S, et al. Mechanism of hypoxia-induced NF-kappaB. Mol Cell Biol. 2010; 30(20): 4901-4921.

[91] Acosta JC, Banito A, Wuestefeld T, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013; 15(8): 978-990.

[92] Tasdemir N, Lowe SW. Senescent cells spread the word: non-cell autonomous propagation of cellular senescence. EMBO J. 2013; 32(14): 1975-1976.

[93] Mirchandani AS, Jenkins SJ, Bain CC, et al. Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation. Nat Immunol. 2022; 23(6): 927-939.

[94] Bhattacharya S, Agarwal S, Shrimali NM, et al. Interplay between hypoxia and inflammation contributes to the progression and severity of respiratory viral diseases. Mol Aspects Med. 2021; 81: 101000.

[95] Jeny F, Bernaudin JF, Valeyre D, et al. Hypoxia promotes a mixed inflammatory-fibrotic macrophages phenotype in active sarcoidosis. Front Immunol. 2021; 12: 719009.

[96] Zhang J, Zhang Q, Lou Y, et al. Hypoxia-inducible factor-1α/interleukin-1β signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology. 2018; 67(5): 1872-1889.

[97] Ha JS, Choi HR, Kim IS, et al. Hypoxia-induced S100A8 expression activates microglial inflammation and promotes neuronal apoptosis. Int J Mol Sci. 2021; 22(3): 1205.

[98] Delprat V, Tellier C, Demazy C, et al. Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway. Sci Rep. 2020; 10(1): 882.

[99] Song TT, Bi YH, Gao YQ, et al. Systemic pro-inflammatory response facilitates the development of cerebral edema during short hypoxia. J Neuroinflamm. 2016; 13(1): 63.

[100] Lundeberg J, Feiner JR, Schober A, et al. Increased cytokines at high altitude: lack of effect of ibuprofen on acute mountain sickness, physiological variables, or cytokine levels. High Alt Med Biol. 2018; 19(3): 249-258.

[101] Wang C, Jiang H, Duan J, et al. Exploration of acute phase proteins and inflammatory cytokines in early stage diagnosis of acute mountain sickness. High Alt Med Biol. 2018; 19(2): 170-177.

[102] Malacrida S, Giannella A, Ceolotto G, et al. Transcription factors regulation in human peripheral white blood cells during hypobaric hypoxia exposure: an in-vivo experimental study. Sci Rep. 2019; 9(1): 9901.

[103] Kammerer T, Faihs V, Hulde N, et al. Hypoxic-inflammatory responses under acute hypoxia: in vitro experiments and prospective observational expedition trial. Int J Mol Sci. 2020; 21(3): 1034.

[104] Farishta M, Sankari A. Pulmonary Hypertension Due to Lung Disease or Hypoxia. StatPearls. StatPearls Publishing Copyright © 2024, StatPearls Publishing LLC.; 2024.

[105] Nathan SD, Barbera JA, Gaine SP, et al. Pulmonary hypertension in chronic lung disease and hypoxia. Eur Respir J. 2019; 53(1): 1801914.

[106] Wang S, Liu Z, Wang L, et al. NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol. 2009; 6(5): 327-334.

[107] Šimić G, Babić Leko, M, Wray S, et al. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies. Biomolecules. 2016; 6(1): 6.

[108] Zhang CE, Yang X, Li L, et al. Hypoxia-induced tau phosphorylation and memory deficit in rats. Neurodegener Dis. 2014; 14(3): 107-116.

[109] Gao L, Tian S, Gao H, et al. Hypoxia increases Aβ-induced tau phosphorylation by calpain and promotes behavioral consequences in AD transgenic mice. J Mol Neurosci. 2013; 51(1): 138-147.

[110] Zhou Y, Huang X, Zhao T, et al. Hypoxia augments LPS-induced inflammation and triggers high altitude cerebral edema in mice. Brain Behav Immun. 2017; 64: 266-275.

[111] Mishra KP, Sharma N, Soree P, et al. Hypoxia-induced inflammatory chemokines in subjects with a history of high-altitude pulmonary edema. Indian J Clin Biochem. 2016; 31(1): 81-86.

[112] Gupta RK, Soree P, Desiraju K, et al. Subclinical pulmonary dysfunction contributes to high altitude pulmonary edema susceptibility in healthy non-mountaineers. Sci Rep. 2017; 7(1): 14892.

[113] Wang LM, Zhang LL, Wang LW, et al. Influence of miR-199a on rats with non-small cell lung cancer via regulating the HIF-1α/VEGF signaling pathway. Eur Rev Med Pharmacol Sci. 2019; 23(23): 10363-10369.

[114] Kaneto H, Kawamori D, Matsuoka TA, et al. Oxidative stress and pancreatic beta-cell dysfunction. Am J Ther. 2005; 12(6): 529-533.

[115] Argaev-Frenkel L, Rosenzweig T. Redox balance in type 2 diabetes: therapeutic potential and the challenge of antioxidant-based therapy. Antioxidants (Basel). 2023; 12(5): 994.

[116] Snodgrass RG, Boß M, Zezina E, et al. Hypoxia potentiates palmitate-induced pro-inflammatory activation of primary human macrophages. J Biol Chem. 2016; 291(1): 413-424.

[117] Hoyos CM, Melehan KL, Liu PY, et al. Does obstructive sleep apnea cause endothelial dysfunction? A critical review of the literature. Sleep Med Rev. 2015; 20: 15-26.

[118] Akhtar S, Hartmann P, Karshovska E, et al. Endothelial hypoxia-inducible factor-1α promotes atherosclerosis and monocyte recruitment by upregulating microRNA-19a. Hypertension. 2015; 66(6): 1220-1226.

[119] Coughlan MT, Sharma K. Challenging the dogma of mitochondrial reactive oxygen species overproduction in diabetic kidney disease. Kidney Int. 2016; 90(2): 272-279.

[120] Muthamil S, Kim HY, Jang HJ, et al. Understanding the relationship between cancer associated cachexia and hypoxia-inducible factor-1. Biomed Pharmacother. 2023; 163: 114802.

[121] Dubois-Deruy E, Peugnet V, Turkieh A, et al. Oxidative stress in cardiovascular diseases. Antioxidants (Basel). 2020; 9(9): 864.

[122] Shaito A, Aramouni K, Assaf R, et al. Oxidative stress-induced endothelial dysfunction in cardiovascular diseases. Front Biosci. 2022; 27(3): 105.

[123] Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. 2013; 93(1): 1-21.

[124] Trayhurn P. Hypoxia and adipocyte physiology: implications for adipose tissue dysfunction in obesity. Annu Rev Nutr. 2014; 34: 207-236.

[125] Gao H, Nepovimova E, Heger Z, et al. Role of hypoxia in cellular senescence. Pharmacol Res. 2023; 194: 106841.

[126] You L, Nepovimova E, Valko M, et al. Mycotoxins and cellular senescence: the impact of oxidative stress, hypoxia, and immunosuppression. Arch Toxicol. 2023; 97(2): 393-404.

[127] McGarry T, Biniecka M, Veale DJ, et al. Hypoxia, oxidative stress and inflammation. Free Radic Biol Med. 2018; 125: 15-24.

[128] Cowman S, Pizer B, Sée V. Downregulation of both mismatch repair and non-homologous end-joining pathways in hypoxic brain tumour cell lines. PeerJ. 2021; 9: e11275.

[129] Begg K, Tavassoli M. Inside the hypoxic tumour: reprogramming of the DDR and radioresistance. Cell Death Discov. 2020; 6: 77.

[130] O’Callaghan NJ, Fenech M. A quantitative PCR method for measuring absolute telomere length. Biol Proc Online. 2011; 13: 3.

[131] Wang AS, Dreesen O. Biomarkers of cellular senescence and skin aging. Front Genet. 2018; 9: 247.

[132] Hayashi MT. Telomere biology in aging and cancer: early history and perspectives. Genes Genet Syst. 2018; 92(3): 107-118.

[133] Blackburn EH, Epel ES, Lin J. Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science. 2015; 350(6265): 1193-1198.

[134] Chen Y, Liu M, Niu Y, et al. Romance of the three kingdoms in hypoxia: HIFs, epigenetic regulators, and chromatin reprogramming. Cancer Lett. 2020; 495: 211-223.

[135] Lee JW, Bae SH, Jeong JW, et al. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med. 2004; 36(1): 1-12.

[136] Ke Q, Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 2006; 70(5): 1469-1480.

[137] Batie M, Frost J, Frost M, et al. Hypoxia induces rapid changes to histone methylation and reprograms chromatin. Science. 2019; 363(6432): 1222-1226.

[138] Kim I, Park JW. Hypoxia-driven epigenetic regulation in cancer progression: a focus on histone methylation and its modifying enzymes. Cancer Lett. 2020; 489: 41-49.

[139] Kim J, Lee H, Yi SJ, et al. Gene regulation by histone-modifying enzymes under hypoxic conditions: a focus on histone methylation and acetylation. Exp Mol Med. 2022; 54(7): 878-889.

[140] de Lima Camillo LP, Quinlan RBA. A ride through the epigenetic landscape: aging reversal by reprogramming. Geroscience. 2021; 43(2): 463-485.

[141] Yang Q, Lu Z, Ramchandran R, et al. Pulmonary artery smooth muscle cell proliferation and migration in fetal lambs acclimatized to high-altitude long-term hypoxia: role of histone acetylation. Am J Physiol Lung Cell Mol Physiol. 2012; 303(11): L1001-L1010.

[142] Osumek JE, Revesz A, Morton JS, et al. Enhanced trimethylation of histone h3 mediates impaired expression of hepatic glucose 6-phosphatase expression in offspring from rat dams exposed to hypoxia during pregnancy. Reprod Sci. 2014; 21(1): 112-121.

[143] Mutoh T, Sanosaka T, Ito K, et al. Oxygen levels epigenetically regulate fate switching of neural precursor cells via hypoxia-inducible factor 1α-notch signal interaction in the developing brain. Stem Cells. 2012; 30(3): 561-569.

[144] Gonzalez-Rodriguez PJ, Xiong F, Li Y, et al. Fetal hypoxia increases vulnerability of hypoxic-ischemic brain injury in neonatal rats: role of glucocorticoid receptors. Neurobiol Dis. 2014; 65: 172-179.

[145] Wang X, Meng FS, Liu ZY, et al. Gestational hypoxia induces sex-differential methylation of Crhr1 linked to anxiety-like behavior. Mol Neurobiol. 2013; 48(3): 544-555.

[146] Gao H, Han Z, Huang S, et al. Intermittent hypoxia caused cognitive dysfunction relate to miRNAs dysregulation in hippocampus. Behav Brain Res. 2017; 335: 80-87.

[147] Truettner JS, Katyshev V, Esen-Bilgin N, et al. Hypoxia alters microRNA expression in rat cortical pericytes. Microrna. 2013; 2(1): 32-44.

[148] Liu FJ, Kaur P, Karolina DS, et al. MiR-335 regulates Hif-1α to reduce cell death in both mouse cell line and rat ischemic models. PLoS One. 2015; 10(6): e0128432.

[149] Chen Q, Zhang F, Wang Y, et al. The transcription factor c-Myc suppresses MiR-23b and MiR-27b transcription during fetal distress and increases the sensitivity of neurons to hypoxia-induced apoptosis. PLoS One. 2015; 10(3): e0120217.

[150] Maciotta S, Meregalli M, Torrente Y. The involvement of microRNAs in neurodegenerative diseases. Front Cell Neurosci. 2013; 7: 265.

[151] da Silva FC, Iop RD, Vietta GG, et al. microRNAs involved in Parkinson’s disease: a systematic review. Mol Med Rep. 2016; 14(5): 4015-4022.

[152] Salta E, De Strooper B. microRNA-132: a key noncoding RNA operating in the cellular phase of Alzheimer’s disease. FASEB J. 2017; 31(2): 424-433.

[153] Whitehead CL, Teh WT, Walker SP, et al. Circulating microRNAs in maternal blood as potential biomarkers for fetal hypoxia in-utero. PLoS One. 2013; 8(11): e78487.

[154] Stratilov V, Potapova S, Safarova D, et al. Prenatal hypoxia triggers a glucocorticoid-associated depressive-like phenotype in adult rats, accompanied by reduced anxiety in response to stress. Int J Mol Sci. 2024; 25(11): 5902.

[155] Biswas DK, Shi Q, Baily S, et al. NF-kappa B activation in human breast cancer specimens and its role in cell proliferation and apoptosis. Proc Natl Acad Sci U S A. 2004; 101(27): 10137-10142.

[156] Lindén M, Vannas C, Österlund T, et al. FET fusion oncoproteins interact with BRD4 and SWI/SNF chromatin remodelling complex subtypes in sarcoma. Mol Oncol. 2022; 16(13): 2470-2495.

[157] Bell CG, Lowe R, Adams PD, et al. DNA methylation aging clocks: challenges and recommendations. Genome Biol. 2019; 20(1): 249.

[158] Shih JW, Kung HJ. Long non-coding RNA and tumor hypoxia: new players ushered toward an old arena. J Biomed Sci. 2017; 24(1): 53.

[159] Belenichev IF, Aliyeva OG, Popazova OO, et al. Involvement of heat shock proteins HSP70 in the mechanisms of endogenous neuroprotection: the prospect of using HSP70 modulators. Front Cell Neurosci. 2023; 17: 1131683.

[160] Tang X, Chang C, Hao M, et al. Heat shock protein-90alpha (Hsp90α) stabilizes hypoxia-inducible factor-1α (HIF-1α) in support of spermatogenesis and tumorigenesis. Cancer Gene Ther. 2021; 28(9): 1058-1070.

[161] Batie M, Del Peso L, Rocha S. Hypoxia and chromatin: a focus on transcriptional repression mechanisms. Biomedicines. 2018; 6(2): 47.

[162] Verdikt R, Thienpont B. Epigenetic remodelling under hypoxia. Semin Cancer Biol. 2024; 98: 1-10.

[163] Chand Dakal T, Choudhary K, Tiwari I, et al. Unraveling the triad: hypoxia, oxidative stress and inflammation in neurodegenerative disorders. Neuroscience. 2024; 552: 126-141.

[164] Pezzuto A, Carico E. Role of HIF-1 in cancer progression: novel insights. A review. Curr Mol Med. 2018; 18(6): 343-351.

[165] Sullivan R, Graham CH. Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007; 26(2): 319-331.

[166] Yu B, Wang X, Song Y, et al. The role of hypoxia-inducible factors in cardiovascular diseases. Pharmacol Ther. 2022; 238: 108186.

[167] Gimbrone MA Jr, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016; 118(4): 620-636.

[168] Nangaku M, Fujita T. Activation of the renin-angiotensin system and chronic hypoxia of the kidney. Hypertens Res. 2008; 31(2): 175-184.

[169] Ball MK, Waypa GB, Mungai PT, et al. Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α. Am J Respir Crit Care Med. 2014; 189(3): 314-324.

[170] Jiang M, Fan X, Wang Y, et al. Effects of hypoxia in cardiac metabolic remodeling and heart failure. Exp Cell Res. 2023; 432(1): 113763.

[171] Wu J, Xia S, Kalionis B, et al. The role of oxidative stress and inflammation in cardiovascular aging. Biomed Res Int. 2014; 2014: 615312.

[172] Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011; 32(6): 670-679.

[173] Pilli VS, Datta A, Afreen S, et al. Hypoxia downregulates protein S expression. Blood. 2018; 132(4): 452-455.

[174] Liu B, Chen J, Zhang L, et al. IL-10 dysregulation in acute mountain sickness revealed by transcriptome analysis. Front Immunol. 2017; 8: 628.

[175] Hackett PH. The cerebral etiology of high-altitude cerebral edema and acute mountain sickness. Wilderness Environ Med. 1999; 10(2): 97-109.

[176] Li Y, Zhang Y, Zhang Y. Research advances in pathogenesis and prophylactic measures of acute high altitude illness. Respir Med. 2018; 145: 145-152.

[177] Burke DL, Frid MG, Kunrath CL, et al. Sustained hypoxia promotes the development of a pulmonary artery-specific chronic inflammatory microenvironment. Am J Physiol Lung Cell Mol Physiol. 2009; 297(2): L238-L250.

[178] Stenmark KR, Yeager ME, El Kasmi KC, et al. The adventitia: essential regulator of vascular wall structure and function. Annu Rev Physiol. 2013; 75: 23-47.

[179] Dunham-Snary KJ, Wu D, Sykes EA, et al. Hypoxic pulmonary vasoconstriction: from molecular mechanisms to medicine. Chest. 2017; 151(1): 181-192.

[180] Brito J, Siques P, Pena E. Long-term chronic intermittent hypoxia: a particular form of chronic high-altitude pulmonary hypertension. Pulm Circ. 2020; 10(suppl 1): 5-12.

[181] Swenson ER. Early hours in the development of high-altitude pulmonary edema: time course and mechanisms. J Appl Physiol (1985). 2020; 128(6): 1539-1546.

[182] Sydykov A, Mamazhakypov A, Maripov A, et al. Pulmonary hypertension in acute and chronic high altitude maladaptation disorders. Int J Environ Res Public Health. 2021; 18(4): 1692.

[183] Wilkins MR, Ghofrani HA, Weissmann N, et al. Pathophysiology and treatment of high-altitude pulmonary vascular disease. Circulation. 2015; 131(6): 582-590.

[184] Zhang F, Niu L, Li S, et al. Pathological impacts of chronic hypoxia on Alzheimer’s disease. ACS Chem Neurosci. 2019; 10(2): 902-909.

[185] Choi YK. Detrimental roles of hypoxia-inducible factor-1α in severe hypoxic brain diseases. Int J Mol Sci. 2024; 25(8): 4465.

[186] Mitroshina EV, Vedunova MV. The role of oxygen homeostasis and the HIF-1 factor in the development of neurodegeneration. Int J Mol Sci. 2024; 25(9): 4581.

[187] Gertsik N, Chiu D, Li YM. Complex regulation of γ-secretase: from obligatory to modulatory subunits. Front Aging Neurosci. 2014; 6: 342.

[188] Fisk L, Nalivaeva NN, Boyle JP, et al. Effects of hypoxia and oxidative stress on expression of neprilysin in human neuroblastoma cells and rat cortical neurones and astrocytes. Neurochem Res. 2007; 32(10): 1741-1748.

[189] Smith IF, Boyle JP, Green KN, et al. Hypoxic remodelling of Ca²⁺ mobilization in type I cortical astrocytes: involvement of ROS and pro-amyloidogenic APP processing. J Neurochem. 2004; 88(4): 869-877.

[190] Shen G, Hu S, Zhao Z, et al. Antenatal hypoxia accelerates the onset of Alzheimer’s disease pathology in 5xFAD mouse model. Front Aging Neurosci. 2020; 12: 251.

[191] Salminen A, Kauppinen A, Kaarniranta K. Hypoxia/ischemia activate processing of amyloid precursor protein: impact of vascular dysfunction in the pathogenesis of Alzheimer’s disease. J Neurochem. 2017; 140(4): 536-549.

[192] Ebadpour N, Mahmoudi M, Kamal Kheder R, et al. From mitochondrial dysfunction to neuroinflammation in Parkinson’s disease: pathogenesis and mitochondrial therapeutic approaches. Int Immunopharmacol. 2024; 142(pt A):113015.

[193] Lestón Pinilla L, Ugun-Klusek A, Rutella S, et al. Hypoxia signaling in Parkinson’s disease: there is use in asking “what HIF”?. Biology (Basel). 2021; 10(8): 723.

[194] Burtscher J, Maglione V, Di Pardo A, et al. A rationale for hypoxic and chemical conditioning in Huntington’s disease. Int J Mol Sci. 2021; 22(2): 582.

[195] Dai Y, Wang H, Lian A, et al. A comprehensive perspective of Huntington’s disease and mitochondrial dysfunction. Mitochondrion. 2023; 70: 8-19.

[196] Sawant N, Morton H, Kshirsagar S, et al. Mitochondrial abnormalities and synaptic damage in Huntington’s disease: a focus on defective mitophagy and mitochondria-targeted therapeutics. Mol Neurobiol. 2021; 58(12): 6350-6377.

[197] Wicks EE, Semenza GL. Hypoxia-inducible factors: cancer progression and clinical translation. J Clin Invest. 2022; 132(11): e159839.

[198] Chen Z, Han F, Du Y, et al. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023; 8(1): 70.

[199] Zhu H, Zhang S. Hypoxia inducible factor-1α/vascular endothelial growth factor signaling activation correlates with response to radiotherapy and its inhibition reduces hypoxia-induced angiogenesis in lung cancer. J Cell Biochem. 2018; 119(9): 7707-7718.

[200] Li CH, Haider S, Boutros PC. Age influences on the molecular presentation of tumours. Nat Commun. 2022; 13(1): 208.

[201] Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells?. Trends Biochem Sci. 2016; 41(3): 211-218.

[202] Bose S, Zhang C, Le A. Glucose metabolism in cancer: the Warburg effect and beyond. Adv Exp Med Biol. 2021; 1311: 3-15.

[203] Li Z, Rich JN. Hypoxia and hypoxia inducible factors in cancer stem cell maintenance. Curr Top Microbiol Immunol. 2010; 345: 21-30.

[204] Imamura T, Kikuchi H, Herraiz MT, et al. HIF-1alpha and HIF-2alpha have divergent roles in colon cancer. Int J Cancer. 2009; 124(4): 763-771.

[205] Xue X, Ramakrishnan S, Anderson E, et al. Endothelial PAS domain protein 1 activates the inflammatory response in the intestinal epithelium to promote colitis in mice. Gastroenterology. 2013; 145(4): 831-841.

[206] Bivona TG, Hieronymus H, Parker J, et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature. 2011; 471(7339): 523-526.

[207] Mazumdar J, Hickey MM, Pant DK, et al. HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci U S A. 2010; 107(32): 14182-14187.

[208] Criscimanna A, Duan LJ, Rhodes JA, et al. PanIN-specific regulation of Wnt signaling by HIF2α during early pancreatic tumorigenesis. Cancer Res. 2013; 73(15): 4781-4790.

[209] Lee KE, Spata M, Bayne LJ, et al. Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov. 2016; 6(3): 256-269.

[210] Wheaton WW, Chandel NS. Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol. 2011; 300(3): C385-C393.

[211] Drager LF, Yao Q, Hernandez KL, et al. Chronic intermittent hypoxia induces atherosclerosis via activation of adipose angiopoietin-like 4. Am J Respir Crit Care Med. 2013; 188(2): 240-248.

[212] Beckman JA, Creager MA. Vascular complications of diabetes. Circ Res. 2016; 118(11): 1771-1785.

[213] Norouzirad R, González-Muniesa P, Ghasemi A. Hypoxia in obesity and diabetes: potential therapeutic effects of hyperoxia and nitrate. Oxid Med Cell Longev. 2017; 2017: 5350267.

[214] Todorčević M, Manuel AR, Austen L, et al. Markers of adipose tissue hypoxia are elevated in subcutaneous adipose tissue of severely obese patients with obesity hypoventilation syndrome but not in the moderately obese. Int J Obes (Lond). 2021; 45(7): 1618-1622.

[215] Kayser B, Verges S. Hypoxia, energy balance, and obesity: an update. Obes Rev. 2021; 22(suppl 2):e13192.

[216] Čolak E, Pap D. The role of oxidative stress in the development of obesity and obesity-related metabolic disorders. J Med Biochem. 2021; 40(1): 1-9.

[217] Mylonis I, Simos G, Paraskeva E. Hypoxia-inducible factors and the regulation of lipid metabolism. Cells. 2019; 8(3): 214.

[218] Kent BD, Mitchell PD, McNicholas WT. Hypoxemia in patients with COPD: cause, effects, and disease progression. Int J Chron Obstruct Pulmon Dis. 2011; 6: 199-208.

[219] Lodge KM, Vassallo A, Liu B, et al. Hypoxia increases the potential for neutrophil-mediated endothelial damage in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2022; 205(8): 903-916.

[220] Hogea SP, Tudorache E, Fildan AP, et al. Risk factors of chronic obstructive pulmonary disease exacerbations. Clin Respir J. 2020; 14(3): 183-197.

[221] Otoupalova E, Smith S, Cheng G, et al. Oxidative stress in pulmonary fibrosis. Compr Physiol. 2020; 10(2): 509-547.

[222] Veith C, Boots AW, Idris M, et al. Redox imbalance in idiopathic pulmonary fibrosis: a role for oxidant cross-talk between NADPH oxidase enzymes and mitochondria. Antioxid Redox Signal. 2019; 31(14): 1092-1115.

[223] Cho SJ, Stout-Delgado HW. Aging and lung disease. Annu Rev Physiol. 2020; 82: 433-459.

[224] Sabit R, Thomas P, Shale DJ, et al. The effects of hypoxia on markers of coagulation and systemic inflammation in patients with COPD. Chest. 2010; 138(1): 47-51.

[225] Faa G, Marcialis MA, Ravarino A, et al. Fetal programming of the human brain: is there a link with insurgence of neurodegenerative disorders in adulthood?. Curr Med Chem. 2014; 21(33): 3854-3876.

[226] Lahiri DK, Ghosh C, Ge YW. A proximal gene promoter region for the beta-amyloid precursor protein provides a link between development, apoptosis, and Alzheimer’s disease. Ann N Y Acad Sci. 2003; 1010: 643-647.

[227] Nalivaeva NN, Turner AJ, Zhuravin IA. Role of prenatal hypoxia in brain development, cognitive functions, and neurodegeneration. Front Neurosci. 2018; 12: 825.

[228] Nanduri J, Prabhakar NR. Epigenetic regulation of carotid body oxygen sensing: clinical implications. Adv Exp Med Biol. 2015; 860: 1-8.

[229] Chiang AA. Obstructive sleep apnea and chronic intermittent hypoxia: a review. Chin J Physiol. 2006; 49(5): 234-243.

[230] Drager LF, Lopes HF, Maki-Nunes C, et al. The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome. PLoS One. 2010; 5(8): e12065.

[231] Costa-Silva JH, Zoccal DB, Machado BH. Chronic intermittent hypoxia alters glutamatergic control of sympathetic and respiratory activities in the commissural NTS of rats. Am J Physiol Regul Integr Comp Physiol. 2012; 302(6): R785-R793.

[232] Latshang TD, Furian M, Aeschbacher SS, et al. Association between sleep apnoea and pulmonary hypertension in Kyrgyz highlanders. Eur Respir J. 2017; 49(2): 1601530.

[233] Wilson EN, Anderson M, Snyder B, et al. Chronic intermittent hypoxia induces hormonal and male sexual behavioral changes: hypoxia as an advancer of aging. Physiol Behav. 2018; 189: 64-73.

[234] Figarella K, Kim J, Ruan W, et al. Hypoxia-adenosine axis as therapeutic targets for acute respiratory distress syndrome. Front Immunol. 2024; 15: 1328565.

[235] Bui BP, Nguyen PL, Lee K, et al. Hypoxia-inducible factor-1: a novel therapeutic target for the management of cancer, drug resistance, and cancer-related pain. Cancers (Basel). 2022; 14(24): 6054.

[236] Wigerup C, Påhlman S, Bexell D. Therapeutic targeting of hypoxia and hypoxia-inducible factors in cancer. Pharmacol Ther. 2016; 164: 152-169.

[237] Janciauskiene S. The beneficial effects of antioxidants in health and diseases. Chronic Obstr Pulm Dis. 2020; 7(3): 182-202.

[238] Cirilli I, Damiani E, Dludla PV, et al. Role of coenzyme Q(10) in health and disease: an update on the last 10 years (2010-2020). Antioxidants (Basel). 2021; 10(8): 1325.

[239] Ghlichloo I, Gerriets V. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). StatPearls. StatPearls Publishing Copyright © 2024, StatPearls Publishing LLC.; 2024.

[240] Atkinson TJ, Fudin J. Nonsteroidal antiinflammatory drugs for acute and chronic pain. Phys Med Rehabil Clin N Am. 2020; 31(2): 219-231.

[241] Fyfe JJ, Bishop DJ, Zacharewicz E, et al. Concurrent exercise incorporating high-intensity interval or continuous training modulates mTORC1 signaling and microRNA expression in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2016; 310(11): R1297-R1311.

[242] Hahn O, Grönke S, Stubbs TM, et al. Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism. Genome Biol. 2017; 18(1): 56.

[243] Huang B, Zhong D, Zhu J, et al. Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines. Aging Cell. 2020; 19(4): e13129.

[244] Lanigan SM, O’Connor JJ. Prolyl hydroxylase domain inhibitors: can multiple mechanisms be an opportunity for ischemic stroke?. Neuropharmacology. 2019; 148: 117-130.

[245] Gomez-Pinilla F, Zhuang Y, Feng J, et al. Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation. Eur J Neurosci. 2011; 33(3): 383-390.

[246] Sacks B, Onal H, Martorana R, et al. Mitochondrial targeted antioxidants, mitoquinone and SKQ1, not vitamin C, mitigate doxorubicin-induced damage in H9c2 myoblast: pretreatment vs. co-treatment. BMC Pharmacol Toxicol. 2021; 22(1): 49.

[247] Jiang Q, Yin J, Chen J, et al. Mitochondria-targeted antioxidants: a step towards disease treatment. Oxid Med Cell Longev. 2020; 2020: 8837893.

[248] Kirkland JL, Tchkonia T. Senolytic drugs: from discovery to translation. J Intern Med. 2020; 288(5): 518-536.

[249] Islam MT, Tuday E, Allen S, et al. Senolytic drugs, dasatinib and quercetin, attenuate adipose tissue inflammation, and ameliorate metabolic function in old age. Aging Cell. 2023; 22(2): e13767.

[250] Novais EJ, Tran VA, Johnston SN, et al. Long-term treatment with senolytic drugs dasatinib and quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat Commun. 2021; 12(1): 5213.

[251] Min YJ, Ling EA, Li F. Immunomodulatory mechanism and potential therapies for perinatal hypoxic-ischemic brain damage. Front Pharmacol. 2020; 11: 580428.

[252] Han F, Hu B. Stem cell therapy for Parkinson’s disease. Adv Exp Med Biol. 2020; 1266: 21-38.

[253] Zhuo Y, Li WS, Lu W, et al. TGF-β1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson’s disease models and patients. Mil Med Res. 2024; 11(1): 48.

[254] Tsoukalas D, Fragkiadaki P, Docea AO, et al. Discovery of potent telomerase activators: unfolding new therapeutic and anti-aging perspectives. Mol Med Rep. 2019; 20(4): 3701-3708.

[255] Cabreiro F, Au C, Leung KY, et al. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013; 153(1): 228-239.

[256] Zhuang Y, Liu K, He Q, et al. Hypoxia signaling in cancer: implications for therapeutic interventions. MedComm. 2023; 4(1): e203.

[257] Rankin EB, Giaccia AJ. Hypoxic control of metastasis. Science. 2016; 352(6282): 175-180.

[258] Stampone E, Bencivenga D, Capellupo MC, et al. Genome editing and cancer therapy: handling the hypoxia-responsive pathway as a promising strategy. Cell Mol Life Sci. 2023; 80(8): 220.

[259] Fields M, Marcuzzi A, Gonelli A, et al. Mitochondria-targeted antioxidants, an innovative class of antioxidant compounds for neurodegenerative diseases: perspectives and limitations. Int J Mol Sci. 2023; 24(4): 3739.

[260] Shabalina IG, Vyssokikh MY, Gibanova N, et al. Improved health-span and lifespan in mtDNA mutator mice treated with the mitochondrially targeted antioxidant SkQ1. Aging (Albany NY). 2017; 9(2): 315-339.

[261] Smith RA, Murphy MP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci. 2010; 1201: 96-103.

[262] Zinovkin RA, Zamyatnin AA. Mitochondria-targeted drugs. Curr Mol Pharmacol. 2019; 12(3): 202-214.

[263] Rodriguez-Colman MJ, Dansen TB, Burgering BMT. FOXO transcription factors as mediators of stress adaptation. Nat Rev Mol Cell Biol. 2024; 25(1): 46-64.

[264] Martins R, Lithgow GJ, Link W. Long live FOXO: unraveling the role of FOXO proteins in aging and longevity. Aging Cell. 2016; 15(2): 196-207.

[265] Wongrakpanich S, Wongrakpanich A, Melhado K, et al. A comprehensive review of non-steroidal anti-inflammatory drug use in the elderly. Aging Dis. 2018; 9(1): 143-150.

[266] Regulski MJ. Cellular senescence: what, why, and how. Wounds. 2017; 29(6): 168-174.

[267] Gonzales MM, Garbarino VR, Kautz TF, et al. Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial. Nat Med. 2023; 29(10): 2481-2488.

[268] Nambiar A, Kellogg D 3rd, Justice J, et al. Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability. EBioMedicine. 2023; 90: 104481.

[269] Gonzales MM, Garbarino VR, et al. Senolytic therapy to modulate the progression of Alzheimer’s disease (SToMP-AD): a pilot clinical trial. J Prev Alzheimers Dis. 2022; 9(1): 22-29.

[270] Kim H, Jang J, Song MJ, et al. Inhibition of matrix metalloproteinase expression by selective clearing of senescent dermal fibroblasts attenuates ultraviolet-induced photoaging. Biomed Pharmacother. 2022; 150: 113034.

[271] Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017; 169(1): 132-147.e16.

[272] Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016; 22(1): 78-83.

[273] Fuhrmann-Stroissnigg H, Ling YY, Zhao J, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun. 2017; 8(1): 422.

[274] Liu H, Xu Q, Wufuer H, et al. Rutin is a potent senomorphic agent to target senescent cells and can improve chemotherapeutic efficacy. Aging Cell. 2024; 23(1): e13921.

[275] Childs BG, Gluscevic M, Baker DJ, et al. Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov. 2017; 16(10): 718-735.

[276] Patnaik E, Madu C, Lu Y. Epigenetic modulators as therapeutic agents in cancer. Int J Mol Sci; 24(19):14964.

[277] Mostoslavsky R, Chua KF, Lombard DB, et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell. 2006; 124(2): 315-329.

[278] Barrès R, Yan J, Egan B, et al. Acute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012; 15(3): 405-411.

[279] Murach KA, Dimet-Wiley AL, Wen Y, et al. Late-life exercise mitigates skeletal muscle epigenetic aging. Aging Cell. 2022; 21(1): e13527.

[280] van Praag H, Shubert T, Zhao C, et al. Exercise enhances learning and hippocampal neurogenesis in aged mice. J Neurosci. 2005; 25(38): 8680-8685.

[281] Rubenstein AB, Hinkley JM, Nair VD, et al. Skeletal muscle transcriptome response to a bout of endurance exercise in physically active and sedentary older adults. Am J Physiol Endocrinol Metab. 2022; 322(3): e260-e277.

[282] Hepple RT, Baker DJ, Kaczor JJ, et al. Long-term caloric restriction abrogates the age-related decline in skeletal muscle aerobic function. FASEB J. 2005; 19(10): 1320-1322.

[283] Rippe C, Lesniewski L, Connell M, et al. Short-term calorie restriction reverses vascular endothelial dysfunction in old mice by increasing nitric oxide and reducing oxidative stress. Aging Cell. 2010; 9(3): 304-312.

[284] Valdez G, Tapia JC, Kang H, et al. Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proc Natl Acad Sci U S A. 2010; 107(33): 14863-14868.

[285] Cerletti M, Jang YC, Finley LW, et al. Short-term calorie restriction enhances skeletal muscle stem cell function. Cell Stem Cell. 2012; 10(5): 515-519.

[286] Rybnikova EA, Nalivaeva NN, Zenko MY, et al. Intermittent hypoxic training as an effective tool for increasing the adaptive potential, endurance and working capacity of the brain. Front Neurosci. 2022; 16: 941740.

[287] Li J, Li Y, Atakan MM, et al. The molecular adaptive responses of skeletal muscle to high-intensity exercise/training and hypoxia. Antioxidants (Basel). 2020; 9(8): 656.

[288] Su Y, Ke C, Li C, et al. Intermittent hypoxia promotes the recovery of motor function in rats with cerebral ischemia by regulating mitochondrial function. Exp Biol Med (Maywood). 2022; 247(15): 1364-1378.

[289] Zhao YC, Guo W, Gao BH. Hypoxic training upregulates mitochondrial turnover and angiogenesis of skeletal muscle in mice. Life Sci. 2022; 291: 119340.

[290] Rogers RS, Wang H, Durham TJ, et al. Hypoxia extends lifespan and neurological function in a mouse model of aging. PLoS Biol. 2023; 21(5): e3002117.

[291] Justice JN, Ferrucci L, Newman AB, et al. A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME biomarkers workgroup. Geroscience. 2018; 40(5–6): 419-436.

[292] Le Couteur DG, Solon-Biet S, Cogger VC, et al. The impact of low-protein high-carbohydrate diets on aging and lifespan. Cell Mol Life Sci. 2016; 73(6): 1237-1252.

[293] Ferrucci L, Kuchel GA. Heterogeneity of aging: individual risk factors, mechanisms, patient priorities, and outcomes. J Am Geriatr Soc. 2021; 69(3): 610-612.

[294] Tian YE, Cropley V, Maier AB, et al. Heterogeneous aging across multiple organ systems and prediction of chronic disease and mortality. Nat Med. 2023; 29(5): 1221-1231.

[295] van Gisbergen MW, Offermans K, Voets AM, et al. Mitochondrial dysfunction inhibits hypoxia-induced HIF-1α stabilization and expression of its downstream targets. Front Oncol. 2020; 10: 770.

[296] Zhang Z, Yang R, Zi Z, Liu B. A new clinical age of aging research. Trends Endocrinol Metab. 2024; 2: S1043-2760(24)00223-6. doi: 10.1016/j.tem.2024.08.004

[297] Campisi J, Kapahi P, Lithgow GJ, et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019; 571(7764): 183-192.

[298] Belsky DW, Caspi A, Houts R, et al. Quantification of biological aging in young adults. Proc Natl Acad Sci U S A. 2015; 112(30): E4104-E4110.

[299] Goetz LH, Schork NJ. Personalized medicine: motivation, challenges, and progress. Fertil Steril. 2018; 109(6): 952-963.

[300] Li G, Liu J, Guan Y, et al. The role of hypoxia in stem cell regulation of the central nervous system: from embryonic development to adult proliferation. CNS Neurosci Ther. 2021; 27(12): 1446-1457.

[301] Nowak-Stępniowska A, Osuchowska PN, Fiedorowicz H, et al. Insight in hypoxia-mimetic agents as potential tools for mesenchymal stem cell priming in regenerative medicine. Stem Cells Int. 2022; 2022: 8775591.

[302] Marino N, Putignano G, Cappilli S, et al. The role of hypoxia in stem cell regulation of the central nervous system: from embryonic development to adult proliferation towards AI-driven longevity research: an overview. Front Aging. 2023; 4: 1057204.

[303] Shirini D, Schwartz LH, Dercle L. Artificial intelligence for aging research in cancer drug development. Aging (Albany NY). 2023; 15(22): 12699-12701.

[304] Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018; 24(8): 1246-1256.

[305] Murphy MP, Hartley RC. Mitochondria as a therapeutic target for common pathologies. Nat Rev Drug Discov. 2018; 17(12): 865-886.

[306] Pulido-Escribano V, Torrecillas-Baena B, Camacho-Cardenosa M, et al. Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles. World J Stem Cells. 2022; 14(7): 453-472.

[307] Sohi GK, Farooqui N, Mohan A, et al. The impact of hypoxia preconditioning on mesenchymal stem cells performance in hypertensive kidney disease. Stem Cell Res Ther. 2024; 15(1): 162.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd