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The elderly are characterized by immunosenescence accompanied by high rates of morbidity and mortality associated with infectious diseases. Despite suggestions that the mucosal immune compartment is relatively unaffected by aging, there are marked deficits in the intestinal mucosal immune responses of old animals and elderly humans. Little is known about the mechanism(s) whereby aging disrupts intestinal immunity. However, several events in the genesis of the intestinal immune response may be perturbed during aging. The first step is the uptake of antigens by specialized epithelial cells (M cells) that overlie the domes of Peyer's patches. We are unaware of any studies on the efficacy of antigen uptake in the intestine as a function of age. The effects of aging on the next step, antigen presentation by dendritic cells and lymphocyte isotype switching, have not been resolved. The third event is the maturation of immunoglobulin A (IgA) immunoblasts and their migration from the Peyer's patches to the intestinal mucosa. Quantitative immunohistochemical analyses suggest that the migration of these putative plasma cells to the intestinal effector site is compromised in old animals. Local antibody production by mature IgA plasma cells in the intestinal mucosa constitutes the fourth step. We recently reported that in vitro IgA antibody secretion by intestinal lamina propria lymphocytes from young and senescent rats is equivalent. The last event is the transport of IgA antibodies across the epithelial cells via receptor-mediated vesicular translocation onto the mucosal surface of the intestine. Receptor-binding assays did not detect age-associated declines in receptor number or binding affinity in either rodent or primate enterocytes as a function of donor age. Efforts to identify the mechanism(s) responsible for the age-related decline in intestinal mucosal immune responsiveness may benefit by focusing on the homing of IgA immunoblasts to the effector site.

The hepatic drug-metabolizing capacities of rodents and man exhibit age-dependent declines. The extensive use of medication in geriatric patients demonstrates the need to characterize the mechanism(s) responsible for this reduced liver function. An analysis of microsomal NADPH-cytochrome c (P-450) reductase in young adult (3 months), mature (9 months) and senescent (27 months) male Fischer 344 rats revealed specific age-related qualitative and quantitative changes in this enzyme. The specific activity of the purified enzyme from young animals was two-fold higher than that recovered from the other age groups. In addition, there was: (1) no change in molecular weight, (2) alterations in heat inactivation profiles, (3) an apparent reduction in substrate affinity, and (4) a two-fold loss of enzyme activity per unit of immunoprecipitable material as a function of animal age. Our data suggest that this important liver drug-metabolizing enzyme undergoes post-translational modifications in its conformation which are reflected in the above parameters and which, ultimately, affect its efficacy.

Significant declines in the non-induced activities of liver microsomal drug-metabolizing enzymes and in the amount of cytochrome P-450 occur between maturity (16 months) and senescence (27 months) in male Fischer 344 rats, whereas there are essentially no differences between very young (1 month) and mature animals. Several hepatic responses to chronic phenobarbital administration also demonstrate marked age-dependent changes. The livers of young and mature animals exhibit: (1) greater hepatomegaly; (2) faster rates of induction and post-induction recovery of microsomal mixed function oxidase enzyme activities and hemoprotein concentration; and (3) higher maximally induced levels of these components in comparison to senescent rats. When considered with information from previous studies, the present data suggest that the age-related decline in liver drug metabolism may be due to qualitative and/or quantitative changes in the structural and/or functional components of the hepatic microsomal mixed function oxidase system.

Aging results in a significant decline in liver drug metabolism which is largely attributable to changes in the microsomal mixed function oxidase system. For example, the mixed function oxidase system in the livers of senescent rats is characterized by: (1) a reduced cytochrome P-450 content; (2) a decline in the specific activity of NADPH-cytochrome c (P-450) reductase; and (3) a slower rate of ethylmorphine N-demethylation in comparison to young adult animals. Since several factors intrinsic to the microsomes may influence the efficacy of the mixed function oxidase system, e.g. the phospholipid and cholesterol contents, the saturation index of the fatty acids and the fluidity of the membranes, we conducted a physicochemical analysis of liver microsomes isolated from young adult (3-4 months), mature (12-16 months) and senescent (25-27 months) male Fischer rats. Although the microsomal cholesterol content did not change appreciably between maturity and senescence, there was a marked decline in the total phospholipid content. This resulted in a significant increase in the cholesterol/phospholipid ratio, 0.49 to 0.65 between 16 and 27 months of age. The age-related changes in the total phospholipid content were largely reflected in each of the major fractions, i.e. phosphatidylcholine, phosphatidylinositol and phosphatidylethanolamine + phosphatidylserine. Small increases in the relative percentages of highly unsaturated fatty acid species were offset by similar decreases in the more frequent and more saturated species as a function of increased age. As a result, the net change in the fatty acid saturation index was probably minimal. However, the increase in the cholesterol/phospholipid ratio most likely contributes to the significant decline in the order parameter of microsomes isolated from old rats which, in turn, may impair the functional capacity of the hepatic mixed function oxidase system.

A quantitative electron microscopic examination of the ventricular myocardium of the male Fischer 344 rat was undertaken to determine the extent of age-dependent changes in ultrastructure. Rats of 6, 16 and 30 months of age were examined using a non-biased stereological test system. Volume fractions of mitochondria, myofibrillar mass and lipid remained unchanged during aging. Dense body volume fraction increased four-fold over the period studied, while the sarcoplasmic reticulum volume increased only from 6 months to 16 months and did not change thereafter. Biochemical analysis of the specific activities of the two lysosomal enzymes, acid phosphatase and beta-glucuronidase demonstrated a differential response to aging, with acid phosphatase remaining constant and beta-glucuronidase increasing slightly. Neither enzyme activity correlated with the pronounced change in dense body volume fraction. This study provides clear evidence that the previously observed changes in cardiac performance associated with aging are not readily explicable on the basis of a degradation of cardiac ultrastructure.