Effects of aging on liver microcirculatory function and sinusoidal phenotype

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.

4 in 1: Antibody‐free protocol for isolating the main hepatic cells from healthy and cirrhotic single rat livers

“…That is why we validated the phenotype of the four cell types obtained after this procedure, both with molecular markers and functional assays to determine their ability to respond to stimuli. Indeed, hepatocytes produced albumin and urea, LSEC displayed characteristic fenestrae and sinusoidal Ac‐LDL endocytosis, HMΦ responded to LPS stimulation, especially those isolated from Ch animals, which is in accordance with recent in vivo data on acute on chronic liver failure, and HSC expressed their characteristic activation marker α‐SMA. In addition, cells isolated from cirrhotic livers exhibited a phenotype that matched their pathologic situation (hepatocytes: reduced albumin synthesis, LSEC: lack of fenestrae, HMΦ: inflammatory hyperesponse, HSC: increased α‐SMA expression) suggesting that, unlike other protocols where selection is based on surface markers that may change during cirrhosis (CD31, CD32b) our protocol is phenotype‐unbiased and thus suitable for the study of different models of CLD.…”

“…P-value ≤0.05 vs Ct; @ P-value ≤0.05 vs 250.000; *P-value ≤0.05 vs Veh determine their ability to respond to stimuli. Indeed, hepatocytes produced albumin and urea,38 LSEC displayed characteristic fenestrae and sinusoidal Ac-LDL endocytosis,[39][40][41] HMΦ responded to LPS stimulation, especially those isolated from Ch animals, which is in accordance with recent in vivo data on acute on chronic liver failure,34 and HSC expressed their characteristic activation marker α-SMA. In addition, cells isolated from cirrhotic livers exhibited a phenotype that matched their pathologic situation (hepatocytes: reduced albumin synthesis, 42 LSEC: lack of fenestrae, 43 HMΦ: inflammatory hyperesponse,44 HSC: increased α-SMA expression45 ) …”

Older Donor Age Is a Risk Factor for Negative Outcomes After Adult Living Donor Liver Transplantation Using Small‐for‐Size Grafts

“…They found out that grafts from old donors had a very limited expression of SMP‐30, and they could not re‐express it even after years of transplantation in pediatric recipients . Moreover, healthy aging may be associated with hepatic and sinusoidal dysfunction causing enhanced sinusoidal vulnerability to acute or chronic injuries as well as with elevated hepatic vascular resistance that leads to decreased graft compliance and causes exacerbation of portal hypertension after liver transplantation using grafts from older donors . Similarly, grafts from ABO‐incompatible donors are associated with a higher risk of acute rejection mixing cellular as well as antibody‐mediated rejection .…”

“…(32) Moreover, healthy aging may be associated with hepatic and sinusoidal dysfunction causing enhanced sinusoidal vulnerability to acute or chronic injuries as well as with elevated hepatic vascular resistance that leads to decreased graft compliance and causes exacerbation of portal hypertension after liver transplantation using grafts from older donors. (33) Similarly, grafts from ABO-incompatible donors are associated with a higher risk of acute rejection mixing cellular as well as antibody-mediated rejection. (34) According to the Banff criteria, histological features of acute rejection include lymphocytic infiltration in the portal space and the venous endothelium, and severe inflammation can elevate vascular resistance.…”

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

“…According to the UNESA population division, approximately 900 million people are 60 years or older worldwide, and this will increase to 21.5% of the global population by 2050 [3] (see Figure 1). As aging progresses, it increases one's susceptibility to diseases associated with this process, such as vascular aging disorders [4][5][6], diabetes [7], muscle dysfunction [8,9], macular degeneration [10], Alzheimer's disease (AD) [11,12], skin diseases [13], and a series of other diseases [14][15][16][17][18] (see Figure 2). Aging-related diseases pose a serious threat to human health and reduce the quality of life among elderly people.…”