Age-related changes in liver structure and function: Implications for disease ?

The geriatric populations of many countries are growing rapidly and they present major problems to healthcare infrastructures from both medical and economic perspectives. The elderly are predisposed to a variety of diseases, which contribute to a marked increase in morbidity in this subpopulation. The incidence of liver disease increases in the elderly, but the cellular and subcellular perturbations that underlie this suspected predisposition to pathology remain unresolved. Several age-related changes have been documented, including (a) a decline in liver volume, (b) an increase in the hepatic dense body compartment (lipofuscin), (c) moderate declines in the Phase I metabolism of certain drugs, (d) shifts in the expression of a variety of proteins and (e) diminished hepatobiliary functions. Other more subtle changes (e.g., muted responses to oxidative stress, reduced expression of growth regulatory genes, diminished rates of DNA repair, telomere shortening) may contribute to reduced hepatic regenerative capacity, shorter post-liver transplant survival and increased susceptibility to certain liver diseases in the elderly.

Intestinal mucosal immunosenescence in rats.

The elderly are characterized by systemic immunosenescence and high rates of morbidity and mortality associated with infectious diseases of the intestinal tract. Despite the consensus that the mucosal immune compartment is largely unaffected by aging, there are marked deficits in the intestinal mucosal immune responses of old animals and elderly humans. However, little is known about the mechanism(s) whereby aging disrupts intestinal immunity. Events in the generation of an intestinal immune response may be susceptible to the insults of aging. The first step involves the uptake of antigens by specialized follicular epithelial cells (M cells). There have been no studies on the efficacy of antigen uptake by M cells as a function of age. Little is known about the next step, i.e. antigen presentation by dendritic cells and subsequent isotype switching. The third event is the differentiation of putative immunolobulin A (IgA) plasma cells and their homing from the Peyer's patches (inductive site) to the lamina propria of the small intestine (effector site). Quantitative immunohistochemical and flow cytometry analyses suggest that the homing of IgA immunoblasts may be compromised in old rats and monkeys. Local antibody production/secretion by mature IgA plasma cells in the intestinal wall constitutes the fourth step. In vitro anti-cholera toxin IgA antibody secretion by intestinal lamina propria lymphocytes is equivalent in cells isolated from young adult and senescent rats. The final event in the mucosal immune response is the transport of IgA antibodies across the mucosal epithelial cells and their secretion onto the mucosal surface, i.e. receptor-mediated vesicular translocation of IgA by the intestinal epithelial cells. Binding assays did not detect age-associated declines in either the number or binding affinity of the polymeric immunoglobulin receptor expressed on rodent and monkey intestinal epithelial cells.

Expression of lymphocyte homing receptors alpha4beta7 and MAdCAM-l in young and old rats.

The elderly constitute the most rapidly growing subpopulation in the United States. This age group represents a significant burden on the healthcare system due, in part, to increases in morbidity and mortality associated with an increase in the incidence of intestinal infectious diseases. Our previous studies suggest that impaired homing of IgA immunoblasts from the Peyer's patches to the intestinal lamina propria contributes to the diminished intestinal immune response in the elderly. The present study employs flow cytometry and quantitative immunohistochemistry to assess age-related changes in the numbers of peripheral blood mononuclear cells expressing the homing integrin alpha4beta7 and vascular endothelial cells in the intestine expressing its specific receptor, the address in MAdCAM-1, in inbred Fischer 344 rats. The proportion of alpha4beta7-positive mononuclear cells in young rats is significantly greater than that measured in the blood of senescent animals. Although the density of intestinal lamina propria blood vessels with MAdCAM-1-positive endothelium was greater in young adult rats in comparison to old animals, this difference achieved only borderline statistical significance. This is the first study to examine the expression of these two critical lymphocyte homing molecules as a function of age.

Quantifying dense bodies and lipofuscin during aging: a morphologist's perspective.

Secondary lysosomes, residual or dense bodies containing lipofuscin or age pigment accumulate in post-mitotic and inter-mitotic cells during aging. The consensus is that the accumulation of this auto-fluorescent material is an index of cellular senescence. Biochemical and morphological studies have independently demonstrated marked age-related increases in the cell and tissue contents of lipofuscin. Most morphological studies on aging have been qualitative, have included only two or three age groups and have not yielded data that are easily correlated with biochemical analyses. One of the best documented age-related changes in hepatocytes and cardiac myocytes is the accumulation of dense bodies and lipofuscin inclusions. Independent stereologic studies reported two- to eightfold age-related increases in the dense body volume fraction of rat hepatocytes. Furthermore, we reported a fourfold increase in the dense body volume fraction of cardiac myocytes in rats between 6 and 30 months of age. These and other studies confirm the use of quantitative morphology to estimate the increases in dense body and lipofuscin inclusions as indices of age. Whether or not the accumulated lipofuscin compromises cell functions in senescent animals has not been adequately addressed. On the one hand, there is little evidence that several-fold increases in this subcellular compartment impair the functional capacities of either hepatocytes or cardiac myocytes. On the other hand, the age-related accumulation of immunoprecipitable, but catalytically inactive, lysosomal enzymes in both liver and heart muscle may be a reflection of increased lipofuscin deposits in the dense bodies.

Liver regeneration and aging: a current perspective.

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.

Basis for the age-related decline in intestinal mucosal immunity.

The elderly are characterized by mucosal immunosenescence and high rates of morbidity and mortality associated with infectious diseases of the intestinal tract. Little is known about how the differentiation of immunoglobulin A (IgA) plasma cells in Peyer's patches (PPs) and their subsequent homing to the small intestinal lamina propria (LP) is affected by aging. Quantitative immunohistochemical analyses demonstrated a 2-fold increase in the number of IgA+ cells in the PPs, coupled with significant declines in the numbers of IgA+ and antibody-positive cells in the intestinal LP of senescent rats compared to young adult animals. These data suggest that aging diminishes the emigration of IgA immunoblasts from these lymphoid aggregates, as well as their migration to the intestinal LP. Flow cytometry and lymphocyte adoptive transfer studies showed 3- to 4-fold age-related declines in the homing of antibody-containing cells and mesenteric lymph node lymphocytes to the small intestines of rhesus macaques and rats, respectively. The number of peripheral blood IgA immunoblasts expressing the homing molecule alpha4beta7 declined 30% in senescent rats. This was accompanied by a > 17% decrease in the areal density of LP blood vessels staining positive for the cell adhesion molecule MAdCAM-1. Cumulatively, declines in expression of these homing molecules constitute a substantial age-related diminution of IgA immunoblast homing potential. In vitro antibody secretion by LP plasma cells, i.e. antibody secreted per antibody-positive cell, remains unchanged as a function of donor age. Intestinal mucosal immunosenescence is a consequence of reduced homing of IgA plasma cells to the intestinal LP as a result of declines in homing molecule expression.