Pseudocapillarization and associated energy limitation in the aged rat liver

Abstract

Age-related impairment of drug metabolism by the liver is consistent with hepatocyte hypoxia, suggestive of the development of a diffusional barrier to oxygen supply. Because the effects of aging on the diffusional pathway (sinusoidal endothelium and space of Disse) have not been described, we performed comparative studies on the livers of Fischer F344 rats aged 4 to 7, 12 to 15, and 24 to 27 months. Lightmicroscopic examination revealed no evidence of fibrosis, cirrhosis, or other specific pathology. In contrast, scanning and transmission electron-microscopic examination revealed that aging is associated with pseudocapillarization of the sinusoidal endothelium, indicated by defenestration with reduced porosity, thickening of the endothelium, infrequent development of basal lamina, and only minor collagen deposits in the space of Disse. Furthermore, immunohistochemistry studies showed strong expression of collagen IV, moderate expression of factor VIII-related antigen, and weak expression of collagen I along the sinusoids of livers from old rats (P < .0001). In vitro 31 P magnetic resonance spectroscopy analysis showed that aging is associated with changes in high-energy phosphate and other metabolites, consistent with hepatocyte hypoxia. Aging in the liver is associated with changes in the sinusoidal endothelium and space of Disse that may restrict the availability of oxygen and other substrates. (HEPATOLOGY 2001;33:537-543.)The effect of aging in the liver is often considered to be of a lesser degree than in other organs. [1][2][3][4] The major recognized changes in the aging liver include reduction in liver mass and hepatic blood flow 1,4,5 ; however, it has been concluded that there are few other significant structural or biochemical changes in the liver. 1,2 On the other hand, even subtle agerelated changes may have profound consequences for the rest of the body. For example, any age-related impairment in hepatic drug and xenobiotic detoxification could partly explain the susceptibility of elderly persons to adverse drug reactions or illnesses with toxic etiology. 5 In vivo, the hepatic clearance of many drugs is reduced in elderly persons. Traditional theories have attempted to attribute this to age-related reduction of liver mass and blood flow. 6 However, in a recent review, 5 we noted that there appears to be selective reduction of the clearance of drugs that undergo phase I metabolism, associated with preservation of the clearance of drugs that undergo phase II metabolism. Even more puzzling, the in vitro activities of phase I enzymes are maintained into old age. 7 Because these paradoxes cannot be attributed to changes in blood flow and liver mass alone, we suggested an explanation based on oxygen supply, as the activities of phase I enzymes are highly oxygen-dependent because they require oxygen as a substrate. 8 We hypothesized the development of a barrier to oxygen diffusion, leading to functional intracellular hypoxia in the hepatocytes of the aging liver. This provides a plausible mechanism for i...

Effects of aging on liver microcirculatory function and sinusoidal phenotype

“…Characterization of liver microcirculatory dysfunction in aged animals confirmed LSEC “pseudo‐capillarization,” which was defined by the decrease in the number and size of fenestrae (Le Couteur et al, 2001). Further analysis revealed a global deregulation in the hepatic endothelial phenotype in aging as demonstrated by significant decrease in key vasodilatory pathways, including nitric oxide and heme oxygenase, increment in intracellular inflammation and oxidative stress, and reduction in the expression of functional and angiocrine markers such as stabilin‐2, CD32b (Xie et al, 2013), and VEGFR2 (Carpenter et al, 2005).…”

“…Therefore, it is critical to understand the molecular basis of aging and to identify possible approaches for therapeutic intervention in case major abnormalities are detected (Longo et al, 2015; Mitchell, Morten, Longo, & Cabo, 2015). Although 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). …”

“…Liver sinusoidal ultrastructure was characterized using electron microscopy as previously described (Le Couteur et al, 2001). …”

“…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). Nevertheless, studies analyzing in depth the hepatic sinusoid, its cellular components, and the hepatic microcirculatory function in aging are limited.…”

Alterations in liver sinusoidal endothelium in a baboon model of type 1 diabetes

“…Of interest in diabetes mellitus is the observation that fenestrations in the LSECs appear to act as conduits for the transfer of some lipoproteins, especially chylomicron remnants, between the blood and hepatocytes [2,4]. In old age, a substantial loss of fenestrations in the LSECs occurs [5][6][7][8], which impairs lipoprotein transfer to the hepatocyte [9]. This provides a mechanism for age-related impairment in chylomicron remnant clearance and post-prandial hypertriacylglycerolaemia, thus possibly contributing to enhanced vascular risk among older people [4].…”