Research Paper Volume 15, Issue 23 pp 13628—13645
Sirtuin 6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes
- 1 Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- 2 Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, Raleigh, NC 27606, USA
- 3 School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- 4 Department of Pediatrics, Rush University Medical Center, Chicago, IL 60612, USA
- 5 Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA 19144, USA
- 6 Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Received: May 15, 2023 Accepted: November 15, 2023 Published: December 9, 2023
https://doi.org/10.18632/aging.205394How to Cite
Copyright: © 2023 Copp et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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.