Adverse outcomes of aged mice are associated with adipose tissue failure after burn

项目总结/文摘

Project Summary/Abstract Burn care in older adult patients has been extremely challenging. Not only do elderly burn patients have an increased susceptibility to burns, but more importantly, they have a substantially increased morbidity and mortality compared to adults. The cause and underlying mechanisms for these adverse outcomes are essentially unknown. We recently conducted several studies in older adult burn patients and aged mice to understand the pathophysiology after a burn. We found that older adult burn patients are hypo-inflammatory and hypometabolic. It, therefore, appears that elderly burn patients cannot initiate ubiquitous life-saving responses to burn. As we have recently shown that the adipose tissue is a central mediator for post-burn immune-metabolic responses, we investigated the response of the adipose tissue after a burn in older adult burn patients and aged mice. We found that older adult burn patients have an absence of the adipose tissue adaptive response, namely the browning of the adipose tissue and its ensuing immune-metabolic responses. Looking at a more molecular level, we found that older adult burn patients have profound mitochondrial dysfunction and depleted NAD levels. These findings indicate that the structure and the immune-metabolic function of the adipose tissue are substantially different in older adults compared to adults after a burn leading us to hypothesize that the adipose tissue is a central mediator in the post-burn response of older adults. To enable mechanistic studies, we conducted several experiments to determine if the previously mentioned phenomena can be recapitulated in aged mice. We found that aged mice underwent the same functional and structural changes of the adipose tissue and very similar immune-metabolic responses compared to older adult burn patients. Therefore, we concluded that aged mice could be used for our proposed studies, allowing translation from aged mice to older adult patients. Our overarching hypothesis is that the adipose tissue and its ensuing immune-metabolic responses are central to survival in burn patients. The dysfunctional adipose tissue found in older adult burn patients is one of the key mechanisms resulting in poor outcomes in this patient population.