Role of Senescence in the Impaired Wound Healing of Aging

老年人伤口愈合不良和慢性伤口是日益严重的临床和经济问题。 每年约有250亿美元用于伤口护理，预计随着年龄的增长， 世界各地的人口。最近的医疗保险受益人数据估计，在那些>75岁的人中， 老年人患有伤口，与<65岁的人相比，慢性伤口的发生率几乎是两倍 岁老年人由于固有的皮肤脆弱性、受损的 内在伤口愈合和合并症的累积。伤口愈合延迟增加感染风险 以及组织坏死，导致老年人中相当大的发病率甚至死亡率。一个主要 不愈合伤口的促成因素是与年龄相关的细胞和分子皮肤完整性的丧失以及改变的伤口 愈合生理学这种与年龄相关的修复能力下降可能涉及衰老细胞的积累 其获得异常促炎、蛋白水解衰老相关分泌表型（SASP）， 并且在组织内具有负的局部旁观者效应。最近的数据表明， 负面影响组织修复老化，治疗策略，干扰细胞的有害影响， 衰老，如选择性消除衰老细胞或SASP，显示出预防衰老的希望。 和治疗与年龄相关的病理学。该RO3 GEMSSTAR项目将测试慢性 老化皮肤和伤口中的衰老细胞积累导致老化的受损伤口愈合， 衰老细胞负荷减少可以是改善老年人伤口愈合的有价值的临床工具， 个体该项目将确定和测量人类慢性伤口中的衰老细胞负荷（目标1）， 确定老年皮肤的慢性衰老是否会改变衰老细胞的分布和在急性衰老过程中的进展。 伤口愈合(Aim 2），并确定衰老细胞负荷的操纵对延迟的 衰老的伤口愈合（目标3）。该项目的结果将进一步加深我们对 在伤口愈合中的衰老，并探索局部衰老剂在伤口护理和组织修复中的潜力， 衰老在完成这个项目后，候选人将继续朝着利用的目标前进 老年人群慢性伤口的衰老修饰疗法。此外， 该研究项目和专业发展计划通过GEMSSTAR计划将建立 为候选人成为老年伤口护理和重建医生的临床领导者奠定了基础 整形外科医生

Impaired wound healing and chronic wounds in older adults are growing clinical and economic problems. Approximately $25 billion is spent on wound care annually, which is projected to increase with aging of populations worldwide. Recent Medicare beneficiary data estimates that almost one in five of those >75 years old are suffering from a wound and have almost double the rates of chronic wounds compared to those <65 years old. Older adults are at increased risk of developing chronic wounds due to inherent skin fragility, impaired intrinsic wound healing, and accumulation of comorbidities. Delayed wound healing increases risk of infections and tissue necrosis resulting in considerable morbidity and even mortality among older adults. A major contributor of non-healing wounds is age-related loss of cellular and molecular skin integrity and altered wound healing physiology. This age-related decline in reparative capacity may involve accumulation of senescent cells which obtain an abnormal pro-inflammatory, proteolytic senescence-associated secretory phenotype (SASP) and have negative local bystander effects within tissues. As recent data demonstrate that chronic senescence negatively impacts tissue repair in aging, therapeutic strategies that interfere with detrimental effects of cellular senescence, such as the selective elimination of senescent cells or SASP, are showing promise in preventing and treating age-related pathology. This RO3 GEMSSTAR project will test the overall hypothesis that chronic senescent cell accumulation in aged skin and wounds contributes to the impaired wound healing of aging and that reduction of senescent cell burden can be a valuable clinical tool to improve wound healing in aged individuals. The project will determine and measure senescent cell burden in human chronic wounds (Aim 1), determine if chronic senescence of aged skin alters senescent cell distribution and progression during acute wound healing. (Aim 2), and determine the effects of manipulation of senescent cell burden on the delayed wound healing of aging (Aim 3). The results of this project will further our understanding of the role of senescence in wound healing and explore the potential of topical senolytics in wound care and tissue repair in aging. After completion of this project, the candidate will continue to progress towards goals of utilizing senescence-modifying therapies for chronic wounds in the aging population. Furthermore, the combination of this research project and professional development plan through the GEMSSTAR program will establish the foundation for the candidate to become a clinical leader in geriatric wound care and reconstruction as a physician scientist plastic surgeon.