Senolytics reduce endothelial cell DNA damage and telomere dysfunction in old age

Autor: Samuel Bloom, Eric Tuday, Md Torikul Islam, Venkateswara Gogulamudi, Lisa Lesniewski, Anthony Donato
Rok vydání: 2023
Předmět:
Zdroj: Physiology. 38
ISSN: 1548-9221
1548-9213
Popis: Aging results in an accumulation of cellular damage that activates tumor suppressor pathways leading to permanent cell cycle arrest known as cellular senescence. Damage to DNA is a robust inducer of cellular senescence. Furthermore, repeat DNA sequences at the ends of chromosomes known as telomeres are particularly susceptible to damage that leads to senescence. Senescent cells adopt a pro-oxidative, pro-inflammatory phenotype that often adversely impacts the local tissue milieu. Senolytics are drugs that specifically induce cell death in senescent cells. Senolytic drugs have been shown to delay or reduce a multitude of age-related diseases in pre-clinical studies and are currently under investigation for use in clinical trials in humans. Many senolytic drugs were originally discovered based on their ability to induce cell death in senescent endothelial cells in cell culture. However, a key unanswered question is whether this phenomenon occurs in vivo. This is critical to understand because endothelial cell senescence contributes to both cardiovascular and metabolic diseases. In the present study, we tested the hypothesis that chronic administration of a senolytic cocktail will reduce the burden of endothelial cell senescence, as well as other molecular hallmarks of aging, including DNA damage and telomere dysfunction. To test this hypothesis, we treated 21-month-old mice (N = 10 / group) with the senolytic drug cocktail dasatinib (D, 5 mg/kg body mass) and quercetin (Q, 50mg/kg body mass) on three consecutive days every two weeks for three months via oral gavage. Control mice were treated with vehicle control (10% polyethylene glycol 4000 solution). At 24 months of age, carotid artery endothelial cell mRNA was isolated and expression of the cyclin-dependent kinase inhibitor that enforces senescence known as p21 was reduced in D+Q treated compared to vehicle-treated mice (p < 0.05). Additionally, lungs from 10 mice per group were collected and pooled, CD31+ lung endothelial cells were isolated and cultured briefly, and ~267 cells per group were examined. Immunofluorescence for the DNA damage marker 53BP1 demonstrated that treatment with D+Q reduced the percentage of endothelial cells with DNA damage (p < 0.05). We also performed immunofluorescence-fluorescent in situ hybridization to detect the abundance of 53BP1 foci colocalized to telomeres, a measure of telomere-specific damage known as telomere dysfunction-induced foci (TIF). Treatment with D+Q reduced the percentage of endothelial cells containing TIF (p < 0.05). Taken together, these data demonstrate that treating aged mice with D+Q reduces endothelial cell senescence likely in part by clearing cells that have accumulated DNA damage and dysfunctional telomeres. National Institutes of Health Awards R01 AG048366 (LAL), R01 AG060395 (AJD), 5K08AG070281 (ET), 1F31AG076312 (SIB). Veteran's Affairs Merit Review Award I01 BX004492 (LAL) from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory Research and Development Service. The contents do not represent the views of the U.S. Department of Veterans Affairs, the National Institutes of Health, or the United States Government. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Databáze: OpenAIRE
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