Role of Senescence in the Impaired Wound Healing of Aging

老年人伤口愈合受损和慢性伤口是日益严重的临床和经济问题。 每年用于伤口护理的费用约为250亿美元，预计随着年龄的增长，这一数字将会增加 世界各地的人口。最近的联邦医疗保险受益人数据估计，近五分之一的75年 老年人患有创伤，慢性创伤率几乎是65岁以上老年人的两倍。 很多年了。老年人由于固有的皮肤脆弱而患慢性伤口的风险增加， 伤口的内在愈合和合并症的累积。伤口愈合延迟增加感染风险 和组织坏死导致相当大的发病率，甚至在老年人中死亡。一位少校 未愈合伤口的诱因是与年龄相关的皮肤细胞和分子完整性丧失和伤口改变 康复生理学。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。 获得异常的促炎、蛋白降解衰老相关的分泌表型(SASP)。 并在组织内产生负面的局部旁观者效应。因为最近的数据表明，慢性衰老 对衰老中的组织修复产生负面影响，干扰细胞有害影响的治疗策略 衰老，如选择性消除衰老细胞或SASP，在预防衰老方面显示出希望 以及治疗与年龄相关的病理。这个R03 GEMSSTAR项目将测试慢性 衰老皮肤和创面中衰老细胞的积聚有助于老化和创面愈合的损害 减少衰老细胞负担是促进老年人创面愈合的有价值的临床工具 个人。该项目将确定和测量人体慢性创面的衰老细胞负荷(目标1)， 确定老年皮肤的慢性衰老是否改变了急性期内衰老细胞的分布和进展 伤口愈合。(目标2)，并确定操纵衰老细胞负荷对延迟的 老化的伤口愈合(目标3)。这个项目的结果将进一步加深我们对 伤口愈合中的衰老和探索局部衰老药物在伤口护理和组织修复中的潜力 衰老。完成本项目后，应聘者将继续朝着利用目标前进 老龄化人口中慢性创面的抗衰老疗法。此外，两种技术的结合 这一研究项目和专业发展计划将通过GEMSSTAR计划建立 作为一名内科医生，候选人将成为老年伤口护理和重建领域的临床领导者 科学家整形外科医生。

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.