دورية أكاديمية
In vitro and in vivo effects of zoledronic acid on senescence and senescence-associated secretory phenotype markers.
| العنوان: | In vitro and in vivo effects of zoledronic acid on senescence and senescence-associated secretory phenotype markers. |
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| المؤلفون: | Samakkarnthai P; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.; Division of Endocrinology, Phramongkutklao Hospital and College of Medicine, Bangkok 10400, Thailand., Saul D; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.; Department of Trauma and Reconstructive Surgery, Eberhard Karls University Tübingen, BG Trauma Center Tübingen, Tübingen 72076, Germany., Zhang L; Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA., Aversa Z; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA., Doolittle ML; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA., Sfeir JG; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA., Kaur J; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA., Atkinson EJ; Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, USA., Edwards JR; Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY, UK., Russell GG; Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7FY, UK.; Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, S10 2RX, UK., Pignolo RJ; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.; Division of Hospital Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA., Kirkland JL; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Division of General Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA., Tchkonia T; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.; Division of General Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA., Niedernhofer LJ; Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA., Monroe DG; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA., Lebrasseur NK; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA.; Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA., Farr JN; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA., Robbins PD; Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA., Khosla S; Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.; Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA. |
| المصدر: | Aging [Aging (Albany NY)] 2023 May 07; Vol. 15 (9), pp. 3331-3355. Date of Electronic Publication: 2023 May 07. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Impact Journals, LLC Country of Publication: United States NLM ID: 101508617 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1945-4589 (Electronic) Linking ISSN: 19454589 NLM ISO Abbreviation: Aging (Albany NY) Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Albany, NY : Impact Journals, LLC |
| مواضيع طبية MeSH: | Cellular Senescence*/physiology , Senescence-Associated Secretory Phenotype*, Humans ; Animals ; Mice ; Zoledronic Acid/pharmacology ; Zoledronic Acid/metabolism ; Senotherapeutics ; Proteomics ; Fibroblasts/metabolism |
| مستخلص: | In addition to reducing fracture risk, zoledronic acid has been found in some studies to decrease mortality in humans and extend lifespan and healthspan in animals. Because senescent cells accumulate with aging and contribute to multiple co-morbidities, the non-skeletal actions of zoledronic acid could be due to senolytic (killing of senescent cells) or senomorphic (inhibition of the secretion of the senescence-associated secretory phenotype [SASP]) actions. To test this, we first performed in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts, which demonstrated that zoledronic acid killed senescent cells with minimal effects on non-senescent cells. Next, in aged mice treated with zoledronic acid or vehicle for 8 weeks, zoledronic acid significantly reduced circulating SASP factors, including CCL7, IL-1β, TNFRSF1A, and TGFβ1 and improved grip strength. Analysis of publicly available RNAseq data from CD115+ (CSF1R/c-fms+) pre-osteoclastic cells isolated from mice treated with zoledronic acid demonstrated a significant downregulation of senescence/SASP genes (SenMayo). To establish that these cells are potential senolytic/senomorphic targets of zoledronic acid, we used single cell proteomic analysis (cytometry by time of flight [CyTOF]) and demonstrated that zoledronic acid significantly reduced the number of pre-osteoclastic (CD115+/CD3e-/Ly6G-/CD45R-) cells and decreased protein levels of p16, p21, and SASP markers in these cells without affecting other immune cell populations. Collectively, our findings demonstrate that zoledronic acid has senolytic effects in vitro and modulates senescence/SASP biomarkers in vivo . These data point to the need for additional studies testing zoledronic acid and/or other bisphosphonate derivatives for senotherapeutic efficacy. |
| التعليقات: | Update of: bioRxiv. 2023 Feb 24:2023.02.23.529777. doi: 10.1101/2023.02.23.529777. (PMID: 36865244) |
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| معلومات مُعتمدة: | R01 DK128552 United States DK NIDDK NIH HHS; R37 AG013925 United States AG NIA NIH HHS; R01 AG076515 United States AG NIA NIH HHS; P01 AG062413 United States AG NIA NIH HHS; R01 AG055529 United States AG NIA NIH HHS; U19 AG056278 United States AG NIA NIH HHS; R21 AG065868 United States AG NIA NIH HHS; R01 AG013925 United States AG NIA NIH HHS; R01 AG063707 United States AG NIA NIH HHS |
| فهرسة مساهمة: | Keywords: aging; bisphosphonates; bone; senescence; senolytics |
| المشرفين على المادة: | 6XC1PAD3KF (Zoledronic Acid) 0 (Senotherapeutics) |
| تواريخ الأحداث: | Date Created: 20230508 Date Completed: 20230523 Latest Revision: 20240701 |
| رمز التحديث: | 20240701 |
| مُعرف محوري في PubMed: | PMC10449299 |
| DOI: | 10.18632/aging.204701 |
| PMID: | 37154858 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1945-4589 |
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| DOI: | 10.18632/aging.204701 |