Academic Journal
Targeting Cellular Senescence Enhances Post-Burn Wound Healing in Aged Mice.
| Τίτλος: | Targeting Cellular Senescence Enhances Post-Burn Wound Healing in Aged Mice. |
|---|---|
| Συγγραφείς: | Faour S; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.; Sunnybrook Research Institute, Toronto, Ontario, Canada.; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada., Khalaf F; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.; Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada., Chen Y; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada.; Department of Surgery, McMaster University, Hamilton, Ontario, Canada., Bieerkehazhi S; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada.; Department of Surgery, McMaster University, Hamilton, Ontario, Canada., de Brito Monteiro L; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada.; Department of Surgery, McMaster University, Hamilton, Ontario, Canada., Aijaz A; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada.; Department of Surgery, McMaster University, Hamilton, Ontario, Canada., Abdulkareem N; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada., Matveev A; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada.; Department of Surgery, McMaster University, Hamilton, Ontario, Canada., Hinz B; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.; Laboratory of Tissue Repair and Regeneration, Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Toronto, Ontario, Canada., Jeschke MG; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.; Sunnybrook Research Institute, Toronto, Ontario, Canada.; Department of Immunology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.; Centre for Burn Research, Hamilton Health Sciences, Hamilton, Ontario, Canada.; David Braley Research Institute, Hamilton, Ontario, Canada.; Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada.; Centre for Metabolism, Obesity, and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.; Department of Surgery, McMaster University, Hamilton, Ontario, Canada. |
| Πηγή: | Shock (Augusta, Ga.) [Shock] 2026 Oct 01; Vol. 66 (4), pp. 918-929. Date of Electronic Publication: 2026 Jun 22. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 9421564 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1540-0514 (Electronic) Linking ISSN: 10732322 NLM ISO Abbreviation: Shock Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2002- : Philadelphia : Lippincott Williams & Wilkins Original Publication: Augusta, GA : BioMedical Press, [1994- |
| Ιατρικοί όροι (MeSH): | Wound Healing*/drug effects , Wound Healing*/physiology , Burns*/pathology , Burns*/drug therapy , Burns*/metabolism , Cellular Senescence*/drug effects , Cellular Senescence*/physiology , Aging*, Quercetin/pharmacology ; Quercetin/therapeutic use ; Dasatinib/therapeutic use ; Dasatinib/pharmacology ; Senotherapeutics/pharmacology ; beta-Galactosidase/metabolism ; Animals ; Mice ; Male ; Mice, Inbred C57BL |
| Περίληψη: | -Despite advancements in burn care, older burn patients continue to experience disproportionately high mortality rates. Impaired wound healing is a major prognostic indicator of burn patient survival, yet the mechanisms underlying delayed repair in older adults remain poorly understood. Cellular senescence, a hallmark of aging, contributes to tissue dysfunction and impaired regeneration, making it a potential mediator of age-associated deficits in burn wound healing. Here, we investigated the role of cellular senescence in postburn wound repair using a validated adult and aged murine full-thickness scald burn model and evaluated whether senolytic treatment with Dasatinib and Quercetin improves healing outcomes in aged mice. Thermal injury increased senescence-associated features in burn wounds, including senescence-associated beta-galactosidase-positive skin cells, and was associated with reduced myofibroblast-associated marker expression, increased extracellular matrix-degrading components, and delayed wound healing in aged mice. In contrast, senolytic treatment in aged burn mice reduced cellular senescence, demonstrated by a 4.4-fold decrease in senescence-associated beta-galactosidase-positive skin cells to baseline levels, increased alpha smooth muscle actin and type I collagen expression, and improved macroscopic burn wound healing. Together, these findings suggest that cellular senescence is associated with impaired skin repair after burn injury and that senescence-targeting therapies may represent a potential strategy to improve wound healing outcomes in older burn patients. (Copyright © 2026 by the Shock Society.) |
| References: | Jeschke MG, Patsouris D, Stanojcic M, et al. Pathophysiologic response to burns in the elderly. EBioMedicine. 2015;2(10):1536–1548. Nitzschke SL, Aden JK, Serio-Melvin ML, et al. Wound healing trajectories in burn patients and their impact on mortality. J Burn Care Res. 2014;35(6):474–479. Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell. 2014;31(6):722–733. Jun JI, Lau LF. The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol. 2010;12(7):676–685. Paramos-de-Carvalho D, Jacinto A, Saúde L. The right time for senescence. eLife. 2021;10:e72449. Jiang D, de Vries JC, Muschhammer J, et al. Local and transient inhibition of p21 expression ameliorates age-related delayed wound healing. Wound Repair Regen. 2020;28(1):49–60. Samdavid Thanapaul RJR, Shvedova M, Shin GH, Crouch J, Roh DS. Elevated skin senescence in young mice causes delayed wound healing. Geroscience. 2022;44(3):1871–1878. Shi B, Tsou PS, Ma F, et al. Senescent cells accumulate in systemic sclerosis skin. J Invest Dermatol. 2023;143(4):661–664.e5. Shi L, Jiang Z, Li J, et al. Metformin improves burn wound healing by modulating microenvironmental fibroblasts and macrophages. Cells. 2022;11(24):4094. Stanley A, Osler T. Senescence and the healing rates of venous ulcers. J Vasc Surg. 2001;33(6):1206–1211. Cuollo L, Antonangeli F, Santoni A, Soriani A. The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology (Basel). 2020;9(12):485. Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine. 2019;40:554–563. Martyanov V, Whitfield ML, Varga J. Senescence signature in skin biopsies from systemic sclerosis patients treated with senolytic therapy: potential predictor of clinical response? Arthritis Rheumatol. 2019;71(10):1766–1767. Darmawan CC, Hur K, Kusumaningrum N, Chung JH, Lee SH, Mun JH. Dasatinib attenuates fibrosis in keloids by decreasing senescent cell burden. Acta Derm Venereol. 2023;103:adv4475. Wang H, Wang Z, Huang Y, et al. Senolytics (DQ) mitigates radiation ulcers by removing senescent cells. Front Oncol. 2019;9:1576. Bieerkehazhi S, Barayan D, Khalaf F, et al. Burns induce alterations in the acyl proteome of mice and humans. Shock. 2024;61(6):877–884. Bieerkehazhi S, Abdullahi A, Khalaf F, et al. β-Adrenergic blockade attenuates adverse adipose tissue responses after burn. J Mol Med (Berl). 2024;102(10):1245–1254. Vinaik R, Aijaz A, Jeschke MG. Small animal models of thermal injury. Methods Cell Biol. 2022;168:161–189. Novais EJ, Tran VA, Johnston SN, et al. Long-term treatment with senolytic drugs Dasatinib and Quercetin ameliorates age-dependent intervertebral disc degeneration in mice. Nat Commun. 2021;12(1):5213. Abdullahi A, Amini-Nik S, Jeschke MG. Animal models in burn research. Cell Mol Life Sci. 2014;71(17):3241–3255. Mirza R, DiPietro LA, Koh TJ. Selective and specific macrophage ablation is detrimental to wound healing in mice. Am J Pathol. 2009;175(6):2454–2462. López-Antona I, Contreras-Jurado C, Luque-Martín L, Carpintero-Leyva A, González-Méndez P, Palmero I. Dynamic regulation of myofibroblast phenotype in cellular senescence. Aging Cell. 2022;21(4):e13580. Tchkonia T, Pirtskhalava T, Thomou T, et al. Increased TNFalpha and CCAAT/enhancer-binding protein homologous protein with aging predispose preadipocytes to resist adipogenesis. Am J Physiol Endocrinol Metab. 2007;293(6):E1810–E1819. Khalaf F, Ricciuti Z, Barayan D, Wojtowicz-Piotrowski S, Jeschke MG. Post-burn endocrine-immune dynamics and ageing considerations. Nat Rev Endocrinol. 2024;20(10):567–568. Xia W, Li M, Jiang X, et al. Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing. J Nanobiotechnology. 2022;20(1):144. Li H, Wang Z, Zhou F, et al. Sustained activation of NLRP3 inflammasome contributes to delayed wound healing in aged mice. Int Immunopharmacol. 2023;116:109828. Jeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S. Burn injury. Nat Rev Dis Primers. 2020;6(1):11. Khalaf F, Barayan D, Saldanha S, Jeschke MG. Metabolaging: a new geroscience perspective linking aging pathologies and metabolic dysfunction. Metabolism. 2025;166:156158. Khalaf F, Yang S, Barayan D, et al. Burn injuries accelerate biological aging and increase the epigenetically inferred risk of mortality and frailty. Aging Dis. 2025;17(4):2198–2212. Amini-Nik S, Abdullahi A, Vinaik R, et al. Aging impairs the cellular interplay between myeloid cells and mesenchymal cells during skin healing in mice. Aging Dis. 2022;13(2):540–551. Egashira M, Hirota Y, Shimizu-Hirota R, et al. F4/80+ macrophages contribute to clearance of senescent cells in the mouse postpartum uterus. Endocrinology. 2017;158(7):2344–2353. Kale A, Sharma A, Stolzing A, Desprez PY, Campisi J. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing. 2020;17:16. van Beek AA, Van den Bossche J, Mastroberardino PG, de Winther MPJ, Leenen PJM. Metabolic alterations in aging macrophages: ingredients for inflammaging? Trends Immunol. 2019;40(2):113–127. Strid J, Tigelaar RE, Hayday AC. Skin immune surveillance by T cells--a new order? Semin Immunol. 2009;21(3):110–120. Davis PA, Corless DJ, Aspinall R, Wastell C. Effect of CD4+ and CD8+ cell depletion on wound healing. J Br Surg. 2001;88(2):298–304. Bordon Y. T cells target viral protein to remove senescent fibroblasts. Nat Rev Immunol. 2023;23(5):5. Ovadya Y, Landsberger T, Leins H, et al. Impaired immune surveillance accelerates accumulation of senescent cells and aging. Nat Commun. 2018;9(1):5435. Yosef R, Pilpel N, Tokarsky-Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL. Nat Commun. 2016;7(1):11190. Anerillas C, Herman AB, Rossi M, et al. Early SRC activation skews cell fate from apoptosis to senescence. Sci Adv. 2022;8(14):eabm0756. Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246–1256. Hickson LJ, Langhi Prata LGP, Bobart SA, et al. Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. eBioMedicine. 2019;47:446–456. Kim H, Jang J, Song MJ, et al. Attenuation of intrinsic ageing of the skin via elimination of senescent dermal fibroblasts with senolytic drugs. J Eur Acad Dermatol Venereol. 2022;36(7):1125–1135. Hinz B, Phan SH, Thannickal VJ, Galli A, Bochaton-Piallat ML, Gabbiani G. The myofibroblast: one function, multiple origins. Am J Pathol. 2007;170(6):1807–1816. Rose LF, Chan RK. The burn wound microenvironment. Adv Wound Care (New Rochelle). 2016;5(3):106–118. Klingberg F, Hinz B, White ES. The myofibroblast matrix: implications for tissue repair and fibrosis. J Pathol. 2013;229(2):298–309. |
| Contributed Indexing: | Keywords: Aging; burns; cellular senescence; senolytics; skin; wound healing |
| Substance Nomenclature: | 9IKM0I5T1E (Quercetin) RBZ1571X5H (Dasatinib) 0 (Senotherapeutics) EC 3.2.1.23 (beta-Galactosidase) |
| Entry Date(s): | Date Created: 20260619 Date Completed: 20260911 Latest Revision: 20260911 |
| Update Code: | 20260911 |
| DOI: | 10.1097/SHK.0000000000002898 |
| PMID: | 42320016 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1540-0514 |
|---|---|
| DOI: | 10.1097/SHK.0000000000002898 |