Downregulation of Inflamm-aging for Protection Against Organ Damage in Sepsis

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Older adults make a large proportion of sepsis patients. Organ dysfunction is common in patients with severe sepsis, and old septic patients often have more severe organ injury and longer-lasting organ dysfunction. However, the mechanism underlying exacerbated organ injury/dysfunction in old septic patients remain unclear. This proposal tests the central hypothesis that aging enhances and prolongs inflammation to exacerbate organ injury and to impede the recovery of organ function following sepsis. The central hypothesis is based on our novel findings in preliminary studies using an animal model of sepsis. Specifically, we observed that old mice display enhanced and prolonged inflammation, as well as more severe cardiac and renal dysfunction, mimicking the clinical manifestations of old septic patients. Aging-related deficiency in anti-aging protein Klotho in the myocardium and kidney tissue is responsible for the augmented inflammation, and such altered inflammation occupies a major role in organ injury and dysfunction. Further, sepsis induces the over-production of pro-inflammatory mediator FGF23, and Klotho has a novel function in down-regulation of FGF23 production and its pro-inflammatory activity. More importantly, anti-inflammatory cytokine IL-37 up-regulates Klotho expression in old mice and protects against organ dysfunction and mortality in sepsis. We will pursue two interrelated Specific Aims to test the hypothesis that aging impedes the recovery of organ function following sepsis by prolonging inflammation and to explore therapeutic approaches for promotion of organ recovery from injury caused by sepsis. Proposed studies will address the role of aging-related Klotho deficiency in the mechanism underlying the augmented inflammation and exacerbated organ injury/dysfunction in old septic mice and will elucidate the mechanism by which FGF23 augments inflammation. Further, the proposed studies will explore the therapeutic potential of recombinant Klotho and IL-37 for protection of organs against injury/dysfunction. Overall, the proposed studies will provide insights into the mechanisms underlying exacerbated organ injury/dysfunction in old septic subjects and offer preclinical information for development of novel therapeutic approaches for down-regulation inflamm-aging to protect organs in old people affected by sepsis.