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However, long\u2010term use can be associated with signs of premature aging. Highly active antiretroviral therapy generally comprises two nucleoside reverse transcriptase inhibitors (NRTIs), with one of three additional antiretroviral drug classes, including protease inhibitors (PIs). One commonality between mitochondrial dysfunction (induced by NRTIs) and defects in lamin A (induced by PIs) is they can cause or accelerate cellular senescence, a state of essentially irreversible growth arrest, and the secretion of many bioactive molecules collectively known as the senescence\u2010associated secretory phenotype (SASP). We hypothesized that senescent cells increase following treatment with certain HIV therapies. We compared the effects of two distinct HIV PIs: ritonavir\u2010boosted atazanavir (ATV\/r) and ritonavir\u2010boosted darunavir (DRN\/r), used in combination treatments for HIV infection. Upon ATV\/r, but not DRN\/r, treatment, cells arrested growth, displayed multiple features of senescence, and expressed significantly upregulated levels of many SASP factors. Furthermore, mice receiving sustained ATV\/r treatment showed an increase in senescent cells and age\u2010related decline in physiological function. However, removing treatment reversed the features of senescence observed in vivo and cell culture. Given how these features disappeared with drug removal, certain features of senescence may not be prognostic as defined by an irreversible growth arrest. Importantly, for patients that are treated or have been treated with ATV\/r, our data suggest that switching to another PI that does not promote premature aging conditions (DRN\/r) may improve the associated age\u2010related complications.<\/jats:p>","DOI":"10.1111\/acel.13750","type":"journal-article","created":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T05:05:27Z","timestamp":1671599127000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Antiretroviral protease inhibitors induce features of cellular senescence that are reversible upon drug removal"],"prefix":"10.1111","volume":"22","author":[{"given":"Chisaka","family":"Kuehnemann","sequence":"first","affiliation":[{"name":"Buck Institute for Research on Aging  Novato California USA"},{"name":"University of Southern California  Los Angeles California USA"},{"name":"Jean Mayer USDA Human Nutrition Research Center on Aging Tufts University  Boston 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