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INTRODUCTION
Aging is a condition in which a person gradually loses the ability to maintain homeostasis, due to structural alteration or dysfunction, and subsequently becomes vulnerable to external stress or damage. Aging is a major risk factor for most chronic diseases. Thanks to remarkable socioeconomic development and the advancement of medical care during the past century, the lifespan of humans has been increasing at a steady pace. This has led to a dramatic increase in the elderly population in the world, and the total number of the people aged 65 or more was recorded at 524 million people, equivalent to about 8% of the total global popuplation. It is expected that the elderly population will exceed the 1.5 billion mark or 16% of the world population. In the United States, the population who are 65 years or higher stood at 39.6 million people as of 2009, which is equal to about 13% of the country’s total population, and is expected to increase to 72 million people or about 19% of the total population in 2030. Among the elderly people, the premature mortality rate due to noninfectious diseases, including ischemic heart disease, cerebrovascular disease, chronic obstructive disability, cancer, and diabetes, is expected to increase, and they are more susceptible to clinical disorders such as visual disturbance, hearing loss, arthritis, and dementia.
Studies have been conducted on the changes in the normal liver and in liver diseases in relation to aging. Aging is associated with gradual alteration of hepatic structure and function as well as various changes in liver cells including hepatic sinusoidal endothelial cells. Aging can also increase the risks for various liver diseases and plays as an adverse prognostic factor, causing an increase in the mortality rate. In this review, we provide updated information on the aging-related changes of liver and liver diseases.
AGING AND LIVER VOLUME, BLOOD FLOW, AND FUNCTION
The volume and blood flow of the liver gradually decrease with aging. According to studies using ultrasound, the liver volume decreases by 20–40% as one gets older. Such changes are related to a decline in the blood flow in the liver, in that those aged 65 years or higher showed an approximately 35% decrease in the blood volume of the liver compared with those aged less than 40 years. Meanwhile, the studies that scanned the liver with radioisotopes observed a decrease not in the total liver volume but in the mass of the functional liver cells. Studies have reported mixed results about aging-induced changes in the liver. Humans show a slight decrease in the serum albumin concentration or maintain the normal level in the natural aging process. The neural fat and cholesterol volumes in the liver gradually expand as one gets older, and the blood cholesterol, high-density lipoprotein cholesterol, and neutral fat levels also increase over time. Meanwhile, the metabolism of the low-density lipoprotein cholesterol decreases by 35%. The serum γ-glutamyltransferase and alkaline phosphatase levels are elevated with aging. Although the serum aminotransferase maintains the normal level, the serum bilirubin is gradually reduced, as humans get older.
AGING AND LIVER CELLS
Aging-related changes in liver cells include volume changes, polyploidy (polyploidy nuclei), accumulation of dense bodies (lipofuscin) inside liver cells, a decreased area of smooth endoplasmic reticulum, and a declining number and dysfunction of mitochondria. The volume of the liver cells gradually increases as they approach maturity, but starts to decrease due to aging. Lipofuscins are highly cross-linked undegradable protein aggregates that are formed when proteins damaged and denatured by oxidative stress are not degraded inside the liver cells. Such lipofuscins cause increased generation of reactive oxygen species (ROS) in cells and reduced cell survivability. As a result of aging, hepatocyte polyploidy tends to occur more frequently over time, which is accompanied by a decreased number and dysfunction of mitochondria, and results in a decline in the ATP level. Also, the area of smooth endoplasmic reticulum is reduced, causing decreased generation of smooth endoplasmic reticulum and reducing the synthesis of microsomal proteins in the liver.
Compared with the studies on liver cells, relatively little is known about what kind of effect aging has on liver sinusoidal endothelial cells (LSECs), Kupffer cells, and hepatic stellate cells (HSCs). Some studies suggested that aging negatively influences the function of the liver by causing a substantial morphological change in the sinusoidal vascular system. With old age, the thickness of LSECs is enlarged by 50%, whereas the number and diameter of fenestrations (pores) are reduced. Also, aging can result in an increase in von Willebrand factor expression, a decrease in caveolin-1 expression, and increased intracellular adhesion molecule-1 expression in the LSECs. The defenestration of endothelial cells can cause the deposition of lipoprotein-like chylomicron in the liver, negatively influence the effective removal of the substance deposited in excess in the liver, and trigger an autoimmune disease by interfering with the interaction between T lymphocytes and hepatocytes. As the endocytosis in the LSECs becomes dysfunctional with old age, the deposition of circulating products in the form of giant molecules outside the liver is augmented, which may subsequently increase the risks for aging-related diseases including diabetes, arteriosclerosis, arthritis, and neurodegenerative disorders. The function of Kupffer cells is to remove antigen–antibody complexes or nanoparticles such as senescent cell fragments in the liver sinusoidal vascular system. With old age, the number and activation level of Kupffer cells are increased. Although the number of desmin-positive HSCs goes up with aging, the number of α-smooth muscle actin (SMA)-positive HSCs is observed to maintain the same level. Meanwhile, a recent study analyzing the lengths of telomeres in 73 donors has reported that aging-induced decrease in the length of telomeres was limited only to the ones in Kupffer cells and HSCs, and the length of telomeres in cholangiocytes and hepatocytes was not reduced.
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