Hypoxia and senescence signaling pathways

Hypoxia and senescence signaling pathways are interconnected biological processes that dictate cellular adaptation to stress and aging. Hypoxia signaling is primarily mediated by Hypoxia-Inducible Factors (HIFs), which act as transcription factors to regulate oxygen homeostasis, erythropoiesis, and glycolysis [1]. Cellular senescence is a state of permanent cell cycle arrest characterized by the expression of p16INK4a and the secretion of pro-inflammatory factors known as the Senescence-Associated Secretory Phenotype (SASP) [2]. The crosstalk between these pathways is significant; chronic hypoxia can induce senescence through HIF-1α-dependent activation of p53 or p21, while senescence can alter the hypoxic response of neighboring cells via SASP [3]. In oncology, hypoxia-induced senescence can contribute to therapy resistance and tumor dormancy, whereas in aging, the accumulation of senescent cells under hypoxic conditions drives tissue degeneration [4]. Therapeutic targeting of these pathways involves the use of senolytics, such as Navitoclax or Dasatinib plus Quercetin, to selectively eliminate senescent cells [2]. Additionally, HIF inhibitors like Belzutifan are employed to treat cancers where hypoxia signaling is constitutively active [5]. Monitoring these pathways often involves biomarkers such as SA-β-galactosidase activity for senescence and HIF-1α protein stabilization for hypoxia [1, 2]. Understanding the synergy between hypoxia and senescence is crucial for developing treatments for chronic kidney disease, cardiovascular disorders, and various cancers [4]. References: [1] Semenza, G. L. (2012) Cell; [2] Kirkland, J. L., & Tchkonia, T. (2017) EBioMedicine; [3] Leontieva, O. V., et al. (2015) Aging (Albany NY); [4] Prattichizzo, F., et al. (2018) Front. Genet.; [5] Jonasch, E., et al. (2021) NEJM.

Other names

Hypoxia-senescence axisHIF-mediated senescenceHypoxia-induced cellular senescenceHIF-p53 axis

Therapeutic strategies targeting these pathways include the use of senolytics to induce apoptosis in senescent cells by inhibiting anti-apoptotic proteins like BCL-2, and the use of HIF inhibitors to block the transcriptional activity of Hypoxia-Inducible Factors in tumors [2, 5].