M. Schade1, J. A. Sanabria1, R. Aguilar1, M. Andryka1, A. Mallick1, J. Fannin1, J. Sanabria1,2 1Marshall University Schoool Of Medicine,Department Of Surgery,Huntington, WV, USA 2Case Western Reserve University School Of Medicine,Surgery, Nutrition And Preventive Medicine,Cleveland, OH, USA
Introduction:
Human life expectancy has increased to over 80years in the last decade and more than half of the Western population will be over the age of 50 in 2020. Surgical procedures are expected to increase in number and complexity in the older. The understanding of the aging process and its metabolic implications on cell energy requirements is of paramount importance. Nevertheless, biological markers of cell stress and/or healing reservoir on the aging liver remains unclear.
Methods:
C57Bl 6J mice (female: n=7/male: n=7 per each time point) and db/db (diabetic, female=7) were exposed to normal chow. Livers and plasma were collected at different stages of animal growth and aging (weeks 7, 12, 16, 20, 24 and 48). Body weight, total body water, lean mass and fat compartment were determined by MRI spectroscopy. Cardiac function was followed by echocardiography. The proportion of cells on mitosis or in senescence was determined against liver apoptotic index and collagen deposition by standard stains using morphometric techniques. Quantitative protein expression of genes involved in cell metabolism or cell senescence (p53, p21, p16, mTOR1, STAT33, SIRT7, FOX01, Grb2) were determined by Western Blots. In addition, Na/K-exchange pump regulation was determined by SRC expression. While liver oxidative stress was determined by glutathione sp, hepatic mitochondrial ß -lipid oxidation function was determined by octanoate/butyrate ratio. Metabolites (n=852) were measured in treated plasma by LC/MS-MS. Principal component analyses (PCA) and partial least square discriminant analysis (PLS-DA) were conducted to detect metabolite differences among groups.
Results:
The total body weight increases with aging manly due to an increase in the fat compartment with decreased lean mass and total body water (W7vsW24vsW48, p<005 by ANOVA). LVEF decreased and increased LV wall with age. An increased proportion of cells in senescence was observed with decreased mitotic index and increased apoptotic activity (W7vsW16vsW24vsW48, p<0.05 by ANOVA). Morphological changes correlated with expected gene expression and significant decreased in both mitochondrial ß-lipid oxidation function and Na/K-exchange pump activity (p<0.05, by ANOVA). Glutathione ratio reduced/oxidized was reduced with aging (p<0.05, ANOVA). These findings were more accentuated in the diabetic mice. Metabolic prints on cell aging showed disturbances of not only lipid but carbohydrate metabolism.
Conclusion:
Body aging under normal diet is characterized by an increase fat compartment with decreased lean mass and total body water. Changes that correlate with a decreased in liver mitochondrial function, Na/K-exchange pump activity and cell redox status, conferring metabolic signatures of liver aging. These changes must be taking into account on judging liver response to injury, liver disease development and progress and early detection of liver malignancy.