Role of Senescence in the Impaired Wound Healing of Aging

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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.