Dysregulated Hypoxia-Inducible Factor Signaling in the Aging Lung
This review paper looks at what is known of hypoxia-inducible factor (HIF) signaling in the aging of lung tissue, with a particular focus on the burden of cellular senescence as a measure of age-related dysfunction. In the view of these researchers, chronic expression of HIF with age promotes cellular senescence. Why HIF expression becomes dysregulated with age is one of many questions that are hard to answer; it takes a great deal of effort to trace the chain of cause and consequence that leads to any given alteration in gene expression, and in near all cases the long and winding connection to some fundamental causative mechanism of aging has not been definitively established.
Hypoxia-inducible factor (HIF) is a key transcriptional mediator of cellular responses to low oxygen, which regulates lung physiology and pathogenesis. It is a central regulator of hypoxic adaptation in lung tissues and plays a dual role in maintaining homeostasis and driving pathological processes. At low levels, hypoxia induced activation of HIF is hormetic, triggering adaptive cellular responses that enhance stress resistance and longevity. However, excessive or prolonged HIF activation skews this adaptive response, fostering fibrosis, inflammation, and disease progression.
During normal aging, HIF maintains oxygen homeostasis, regulates mitochondrial activity, and supports adaptive stress responses in lung tissues. With advancing age, HIF signaling efficiency declines, leading to reduced stress tolerance and impaired repair mechanisms in lung cells. Chronic HIF dysregulation in aging lungs has been linked to increased oxidative stress, senescence induction, and pro-inflammatory signalling. In the lungs, HIF is also essential for oxygen homeostasis and adaptation to hypoxic environments. Beyond its role in oxygen sensing, HIF modulates cellular metabolism, inflammation, and senescence pathways, directly influencing lung aging.
Recent studies indicate that HIF and cellular senescence interact at multiple levels, where HIF can both induce and suppress senescence, depending on cellular conditions. While transient HIF activation supports tissue repair and stress resistance, chronic dysregulation exacerbates pulmonary pathologies. Emerging evidence suggests that targeting HIF and senescence pathways could offer new therapeutic strategies to mitigate age-related lung diseases. This review explores the intricate crosstalk between these mechanisms, shedding light on how their interplay influences pulmonary aging and disease progression.