Abstract
The socioeconomic and medical improvements of the last decades have led to a relevant increase in the median age of worldwide population. Although numerous studies described the impact of aging in different organs and the systemic vasculature, relatively little is known about liver function and hepatic microcirculatory status in the elderly. In this study, we aimed at characterizing the phenotype of the aged liver in a rat model of healthy aging, particularly focusing on the microcirculatory function and the molecular status of each hepatic cell type in the sinusoid. Moreover, major findings of the study were validated in young and aged human livers. Our results demonstrate that healthy aging is associated with hepatic and sinusoidal dysfunction, with elevated hepatic vascular resistance and increased portal pressure. Underlying mechanisms of such hemodynamic disturbances included typical molecular changes in the cells of the hepatic sinusoid and deterioration in hepatocyte function. In a specific manner, liver sinusoidal endothelial cells presented a dysfunctional phenotype with diminished vasodilators synthesis, hepatic macrophages exhibited a proinflammatory state, while hepatic stellate cells spontaneously displayed an activated profile. In an important way, major changes in sinusoidal markers were confirmed in livers from aged humans. In conclusion, our study demonstrates for the first time that aging is accompanied by significant liver sinusoidal deregulation suggesting enhanced sinusoidal vulnerability to chronic or acute injuries.
Highlights
Societies in developed countries are getting older due to the increase in life expectancy
Previous studies described the impact of aging on the vasculature of different territories, in the specific field of Hepatology, very little is known about the liver microcirculatory function and the molecular status of hepatic sinusoidal cells in aging (Le Couteur & McLean, 1998; Le Couteur et al, 2001)
We demonstrate for the first time that healthy aged rats exhibit a significant increase in the hepatic vascular resistance, which leads to reduced liver perfusion and to a mo‐derate increment in portal pressure
Summary
Societies in developed countries are getting older due to the increase in life expectancy. The liver plays essential roles in metabolism, toxicants clearance, regulation of inflammation, and molecule biosynthesis. To fulfill these complex tasks, it requires an adequate microcirculation and a correct coordinated function of all hepatic cell types (Arias et al, 2009). Previous studies characterized single variables in the liver during aging and showed reduction in liver mass and hepatic blood flow, partial loss of endothelial fenestration, and possibly activation of HSC (Le Couteur et al, 2001; Vollmar, Pradarutti, Richter, & Menger, 2002). This study aimed at comprehensively characterizing the phenotype of the sinusoid in aged liver using a preclinical rat model of healthy aging, focusing on the microcirculatory function and the molecular profile of each major liver cell type. Our study further compared these findings to the key cellular modifications related to aging in livers from young and aged humans
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