Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease

Abstract

Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for 15 days. Hepatic and systemic hemodynamic, liver cells phenotype and hepatic fibrosis were evaluated. Additionally, the gene expression signature of cirrhosis was evaluated in a cohort of young and aged cirrhotic patients. Aged animals developed a more severe form of aCLD. Portal hypertension and liver fibrosis were exacerbated as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell-death and poorer function, LSEC were further capillarized, HSC over-activated and macrophage infiltration was significantly increased. The gene expression signature of cirrhosis significantly differed comparing young and aged patients, indicating alterations in sinusoidal-protective pathways and confirming the pre-clinical observations. Simvastatin administration for 15-day to aged cirrhotic rats improved the hepatic sinusoidal milieu, leading to significant amelioration in portal hypertension. This study provides evidence that aCLD pathobiology is different in aged individuals. As the median age of patients with aCLD is increasing, we propose a real-life pre-clinical model to develop more reliable therapeutic strategies. Simvastatin effects in this model further demonstrate its translational potential.

The Absence of NLRP3-inflammasome Modulates Hepatic Fibrosis Progression, Lipid Metabolism, and Inflammation in KO NLRP3 Mice during Aging

“…In fact, a recent study, in which elderly rats treated with simvastatin or PBS in those controls, resulted in a severe form of advanced chronic liver disease, exacerbating portal hypertension and hepatic fibrosis with increased hepatocyte cell death and poorer function, in the aged control animals. In addition, hepatic stellate cells were activated and there was a macrophage infiltration that aggravated the disease [ 20 ]. These data explain that in our elderly control mice, the protein levels of the COL1α1 fibrotic marker increased compared to those in which the NLRP3 complex was suppressed.…”

Aging and Chronic Liver Disease

“…Moreover, the initial manifestation of CHC in patients over 65 years is more often a complication of the disease (14%) than in younger (4%). 68 In the preclinical scenario, aged animals develop a more severe form of cirrhosis with aggravated portal hypertension and exacerbated liver fibrosis, 76 thus confirming the clinical observations also at the bench-side.…”

“…In the context of CLD, different works have described that aging increases the susceptibility to chronic injury and found some of the underlying molecular mechanisms, which are summarized in the following lines. 70,76,[79][80][81] As mentioned before, aged hepatocytes possess a deficient replicative capacity after partial hepatectomy. 43 However, different groups have observed that aged hepatocytes retain their proliferative capacity in response to a mitogen or after repeated CCl 4 injections and, actually, they initiate a much stronger proliferative response.…”

“…In a recent study, we analyzed for the first time the impact of aging in the liver sinusoid of decompensated cirrhotic animals. 76 We showed how aged animals developed a more severe form of cirrhosis with exacerbated portal hypertension and liver fibrosis, as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell death and poorer function, LSECs further capillarized, HSCs overactivated, and macrophage infiltration and activation was significantly increased. Additionally, we observed how the effects of acute liver damage in the hepatic endothelium are significantly worse in old animals, with exaggerated sinusoidal capillarization and reduced vasodilation, associated with liver damage and cellular stress, in comparison to young.…”

Aging-Related Molecular Pathways in Chronic Cholestatic Conditions

“…Old rats exhibited significantly higher hepatic vascular resistance in vivo, with reduced liver perfusion and increased portal pressure in comparison with young ones. From a molecular point of view, sinusoidal pseudocapillarization is associated with reduced expression of VEGFR2, KLF2, and CD32b, altered expression of the von Willebrands factor, CD31 and collagen (58), and so, in a reduction in the number and size of fenestrations, thickening of the endothelium, deposition of basal lamina and collagen (56,57) (Figure 1). Due to these alterations, the lipoproteins and insulin absorption is compromised causing hyperlipidemia and hepatic insulin resistance (59).…”