Sirtuin 6 Activation Rescues Age-Related DNA Repair Decline in Chondrocytes | Aging-US



December 18, 2023

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  • Aging-US published this research paper on December 9, 2023 in Volume 15, Issue 23, entitled, “Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes" by researchers from the Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC; Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, NC; School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; Department of Pediatrics, Rush University Medical Center, Chicago, IL; Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA; Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC. DOI - Corresponding author - Brian O. Diekman - Abstract While advanced age is widely recognized as the greatest risk factor for osteoarthritis (OA), the biological mechanisms behind this connection remain unclear. Previous work has demonstrated that chondrocytes from older cadaveric donors have elevated levels of DNA damage as compared to chondrocytes from younger donors. The purpose of this study was to determine whether a decline in DNA repair efficiency is one explanation for the accumulation of DNA damage with age, and to quantify the improvement in repair with activation of Sirtuin 6 (SIRT6). After acute damage with irradiation, DNA repair was shown to be more efficient in chondrocytes from young (≤45 years old) as compared to middle-aged (50–65 years old) or older (>70 years old) cadaveric donors. Activation of SIRT6 with MDL-800 improved the repair efficiency, while inhibition with EX-527 reduced the rate of repair and increased the percentage of cells that retain high levels of damage. In addition to affecting repair after acute damage, treating chondrocytes from older donors with MDL-800 for 48 hours significantly reduced the amount of baseline DNA damage. Chondrocytes isolated from the knees of mice between 4 months and 22 months of age revealed both an increase in DNA damage with aging, and a decrease in DNA damage following MDL-800 treatment. Lastly, treating murine cartilage explants with MDL-800 lowered the percentage of chondrocytes with high p16 promoter activity, which supports the concept that using SIRT6 activation to maintain low levels of DNA damage may prevent the initiation of senescence. Sign up for free Altmetric alerts about this article - Subscribe for free publication alerts from Aging - Keywords - aging, SIRT6, MDL-800, cartilage, comet assay About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at​​ and connect with us: SoundCloud - Facebook - X - Instagram - YouTube - LinkedIn - Pinterest - Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

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