Abstract
Many organ systems exhibit significant age-related deficits, but, based on studies in old rodents and elderly humans, the liver appears to be relatively protected from such changes. A remarkable feature of the liver is its capacity to regenerate its mass following partial hepatectomy. Reports suggests that aging compromises the liver's regenerative capacity, both in the rate and to the extent the organ's original volume is restored. There has been modest definitive information as to which cellular and molecular mechanisms regulating hepatic regeneration are affected by aging. Changes in hepatic sensitivity to growth factors, for example, epidermal growth factor (EGF), appear to influence regeneration in old animals. Studies have demonstrated (a) a 60% decline in EGF binding to hepatocyte plasma membranes, (b) reduced expression of the hepatic high affinity EGF receptor and (c) a block between G1 and S-phases of the cell cycle in old rats following EGF stimulation. Recent studies suggest that reduced phosphorylation and dimerization of the EGF receptor, critical steps in the activation of the extracellular signal-regulated kinase pathway and subsequent cell proliferation are responsible. Other studies have demonstrated that aging affects the upregulation of a Forkhead Box transcription factor, FoxM1B, which is essential for growth hormone-stimulated liver regeneration in hepatectomized mice. Aging appears to compromise liver regeneration by influencing several pathways, the result of which is a reduction in the rate of regeneration, but not in the capacity to restore the organ to its original volume.
Highlights
On the one hand, the liver, unlike most other organs, does not exhibit well-documented or marked changes in either structure or function during the aging process
Studies using human liver tissue have suffered from dependence on postmortem samples or on samples from subjects diagnosed with liver disease
There is quantitative evidence that hepatocytes in males of one inbred rat strain (Fischer 344) increase in volume through maturity and, subsequently, become smaller such that the size of cells in immature and senescent animals is equivalent [5]
Summary
The liver, unlike most other organs, does not exhibit well-documented or marked changes in either structure or function during the aging process (see [1,2,3,4] for reviews). Other changes in hepatocellular structure include (a) a loss of smooth surfaced endoplasmic reticulum, (b) an increase in the volume of the dense body compartment, for example, secondary lysosomes, residual bodies, or lipofuscin, and (c) an increase in hepatocyte polyploidy (see [6] for a review) None of these age-related changes is manifested in significant declines in hepatic function(s). Perhaps a more clinically significant age-related change is a marked decline in the rate of hepatic regeneration following partial resection (hepatectomy) or chemically induced injury This is manifested as a delay in hepatocyte proliferation following hepatectomy and is documented by a number of studies, including that of Popper [16] (Figure 1). The purpose of this brief review is to present a perspective of the current understanding of the cellular and molecular factors and mechanisms that contribute to the diminished hepatic regeneration rate in old-animal models and in elderly humans
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