I thank Dr. Vinciguerra for his kind comments about the significance of our study. It is important to note that the old age group studied was fed a high-fat diet from the ages of 18 to 22 months and that this group was analyzed at 22 months. At the time of analysis the mice in the aged group therefore corresponded to a human age of 69 years. This is an appropriate experimental group for an examination of the effects of aging as the current human life expectancy in the United States is 78.7 years. While I cannot rule out a different effect in even older mice, there is no reason to think that this would occur. I disagree with the statement that there is no association between nonalcoholic fatty liver disease (NAFLD) and aging, as evidence exists for an increased prevalence of this disease in aged individuals, particularly for steatohepatitis, as discussed in our article.
Our work was not designed to examine the effects of aging on the development of hepatocellular carcinoma (HCC), as the high-fat diet mouse model employed in our studies does not develop HCC. HCC is certainly prevalent in the elderly and the relationship of the incidence of this cancer to age is difficult to assess, as it varies with the patient population and underlying etiology of the HCC. In low-risk populations the highest incidence of HCC has been noted to be in individuals aged 75 or older. With more cases of HCC arising in patients with chronic hepatitis C virus (HCV) infection, the association of HCC with aging will likely increase. As the HCV-infected patient population has now aged, HCV-associated HCC from this etiology has been found to be 15-fold greater in those over 65 as compared to young individuals. As the burgeoning population with long-standing nonalcoholic steatohepatitis (NASH) ages, it is possible that a greater incidence of HCC will be detected in aged individuals with this disease as well. Certainly there are potential mechanisms for the preferential development of HCC in the elderly with NASH, such as the decrease in the tumor-suppressive pathway of autophagy that occurs from both steatosis and aging. The risk of complications of NAFLD such as HCC in the aged therefore remains an open question.
Mark J. Czaja M.D.
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY