Poster abstracts

Poster number 79 submitted by Jack Wellmerling

Mice Lacking the Cystic Fibrosis Transmembrane Conductance Regulator Develop Emphysema upon Aging

Jack Wellmerling (Biophysics Graduate Program), Sheng-Wei Chang, Eunsoo Kim, Haley Steiner, Wissam Osman, Prosper Boyaka, Estelle Cormet-Boyaka (Department of Veterinary Biosciences)

Abstract:
Aging is characterized by cellular senescence, consistent low-grade inflammation, and progressive decline of organ function. Causes of aging are thought to include chronic exposure to free radicals and DNA damage. A breakthrough study in the 1990s identified a “Life-extension factor,” Klotho (KL) [1]. In addition to severely reduced lifespan, mice bearing a defunct klotho mutation displayed signs of accelerated aging in several tissues, including emphysema in the lung. Mice overexpressing KL live 20-30% longer than wild-type mice [2]. KL has pleiotropic effects on intracellular signaling, including elevation of intracellular cyclic adenosine monophosphate (cAMP). It has been shown in aortic smooth muscle cells that KL treatment protects against oxidative stress in a cAMP-dependent fashion [3]. This is of interest to our laboratory, because the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), an anion channel, is activated by intracellular cAMP. While often studied in the context of chloride transport, CFTR is also permeable to the antioxidants glutathione and thiocyanate. Knowing this, we consider the possibility that the effects of KL are mediated in-part by CFTR. To address this hypothesis, WT and CFTR-knockout (KO) mice were aged under standard housing conditions. Histological quantification of lung tissue revealed emphysema in KO mice only. Human cystic fibrosis (CF) patients, who lack functional CFTR, are vulnerable to airway infection and suffer from chronic inflammation. CF patients also develop age-associated emphysema [4]. Mice however do not develop CF lung disease, which may suggest a mechanism independent of the CF immunodeficiency. While our results do not directly implicate CFTR in the aging process, studies of KL may foreshadow challenges that CF patients will face as their life-expectancy improves - and encourage research on topics that currently receive little attention in the CF field, such as cardiovascular and neurological disorders.

References:
1. Kuro-o et al, Nature. 1997
2. Kurosu et al, Science. 2005
3. Wang et al, Aging Cell. 2012
4. Mets et al, PLoS One. 2015

Keywords: CFTR, Aging, Emphysema