Stress response mechanisms have been shown to be important in the way in which metabolism determines longevity in any given species. Short-lived species exhibit great plasticity of life span in response to stresses such as heat, cold, nutrient deprivation, and hypoxia. A mild or transient stress can trigger lasting upregulation of cell and tissue maintenance activities, leading to improved function and a slowed aging process. Most such stress responses converge on the processes of autophagy responsible for recycling unwanted or damaged protein machinery and cell structures.
One of numerous lines of inquiry in this part of the field of aging research is focused on hypoxia-inducible factors (HIFs), proteins that manage the response to hypoxia, the stress resulting from insufficient oxygen to supply cellular operations. HIFs are involved in many age-related conditions, but their relationship with aging and disease is a complicated one. In some cases inappropriate overactivation of HIFs is harmful, such as in cancerous tissue. In the case of aging as a whole, HIFs may be involved in a range of processes that are both helpful and harmful. Thus a more careful exploration is required in order to pick out possible points of intervention.
Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging
Since the discovery of HIF-1α, several seminal works have identified the changes in HIF associated with age and the development of age-related disorders, including neurodegenerative diseases. Importantly, in 2009, researchers described HIF-1 as a longevity factor, demonstrating that HIF-1 stabilization is associated with a 30-50% increase in lifespan in nematodes. Several studies have shown that stabilization of HIF-1 increases longevity and healthspan through different pathways in Caenorhabditis elegans. These critical findings in worms yielded a new perspective on the study of HIF stabilization and lifespan among mammals. However, the stabilization of mammalian HIF-1α has been implicated in tumor growth and cancer development and may therefore be harmful. Consequently, a balance between the beneficial and detrimental effects of HIF is critical for homeostasis and depends on the involved components and their contribution to longevity.
Studies on skin, a tissue that is continuously exposed to intrinsic and extrinsic aging factors, have identified HIF-1α as a crucial determinant of skin homeostasis, especially in epidermal aging and wound healing. Results have reported that the loss of epidermal HIF-1α accelerates epidermal aging and affects re-epithelialization in humans and mice. Notably, significant elevations in both hypoxia-inducible transcription factors HIF-1α and HIF-1β gene expression have also been found in the gingival tissues of aged animals, even though these tissues were deemed clinically healthy. In a model of limb ischemia in mice, HIF-1 was found to mediate angiogenesis and, therefore, has been proposed to contribute to the pathological aging process.
HIF is not only a transcriptional factor that regulates tissue oxygenation (including angiogenesis and vascular remodeling) but also controls redox balance, inflammation, and glucose metabolism to eventually maintain cellular homeostasis. According to current knowledge, the age-dependent impairment of HIF-1α induction leads to diminished vascular responses to limb ischemia and less effective wound healing. Some evidence shows the functionally important expression of HIF-1α among ischemic limb mice. It has been demonstrated that the abundance of the HIF-1α protein is decreased in ischemic tissues from aged mice and has also been linked with the downregulation of genes encoding angiogenic growth factors. Another vital player of vascular aging, which is positively regulated by HIF-1, is vascular endothelial growth factor (VEGF), a central mediator of angiogenesis. During aging, there is a defect in HIF-1 activity, yielding VEGF expression reduction and leading to the impairment of angiogenesis in response to the ischemia model.
Recently, we found that HIF-1α is involved in p53, p16, cyclin D1, and lamin B1-mediated senescence in vascular endothelial cells (ECs). Moreover, senescent ECs failed to express HIF-1α, and the microvesicles released by these cells were unable to carry HIF-1α. In another study, HIF-1α was found to play a critical regulatory role in vascular inflammation among macrophages after intimal injury through limiting excessive vascular remodeling. The mechanism by which macrophage-derived HIF-1α mediated this effect is still unknown. Considering these findings, HIF-1α may represent a possible therapeutic target in vascular diseases, especially in vascular aging.
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