Age-related changes in the hepatic microcirculation in mice

Abstract

Aging of the liver is associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins. Since reduced hepatic blood flow is suspected to contribute this impairment, we examined age-related alterations in hepatic microcirculation.. Livers of C57Bl/6 mice were examined at 0.8 (pre-pubertal), 3 (young adult), 14 (middle-aged) and 27 (senescent) months of age using in vivo and electron microscopic methods. The results demonstrated a 14% reduction in the numbers of perfused sinusoids between 0.8 and 27 month mice associated with 35% reduction in sinusoidal blood flow. This was accompanied by an inflammatory response evidenced by a 5-fold increase in leukocyte adhesion in 27 month mice, up-regulated expression of ICAM-1, and increases in intrahepatic macrophages. Sinusoidal diameter decreased 6-10%. Liver sinusoidal endothelial cell (LSEC) dysfunction was seen as early as 14 months when there was a 3-fold increase in the numbers of swollen LSEC. The endocytotic capacity of LSEC also was found to be reduced in older animals. The sinusoidal endothelium in 27 month old mice exhibited pseudocapillarization. In conclusion, the results suggest that leukocyte accumulation in the sinusoids and narrowing of sinusoidal lumens due to pseudocapillarization and dysfunction of LSEC reduce sinusoidal blood flow in aged livers.

Oxidative stress-associated rise of hepatic protein glycation increases inflammatory liver injury in uncoupling protein-2 deficient mice

“…40,41 Further, there is accumulating evidence that during aging mitochondrial dysfunction occurs 42,43 and that age-related oxidative stress and subsequently altered gene expression may cause a dysfunction of liver metabolism. 21 This in vivo study now adds that mitochondrial dysfunction, as given by the deficiency for UCP2, elicits increased oxidative stress. We assumed that this may support the generation of nonenzymatically formed AGE, which are able to form crosslinks leading to accumulation of high-modified AGE.…”

“…Interestingly, the endocytotic clearance of AGE 20,49 is reduced in the aging liver because of the pseudocapillarization process of sinusoids with loss of fenestrae and basal lamina formation. 21 In addition, the detoxification of AGE by the glyoxalase system is described to be age-dependent. 19 Extending this information, we now show that mitochondrial dysfunction in UCP2À/À mice is associated with a decrease of glyoxalase-I activity that in turn may be causative for the increased AGE formation.…”

“…20 The capacity of AGE endocytosis is found to be reduced in aging livers, resulting in spillover into the systemic circulation and extrahepatic deposition of these waste macromolecules. 21 The receptor for AGEs (RAGEs), a member of the immunoglobulin superfamily of cell-surface molecules, is a multiligand-binding receptor with an extracellular, transmembranal and cytosolic domain. [22][23][24] Interaction of RAGE with diverse ligands was demonstrated to be involved in distinct developmental and pathological processes.…”

Immune Functioning in Non lymphoid Organs: The Liver

“…In a study of hepatic blood flow in 0.8-, 3-, 14-, and 27-month-old C57Bl/6 mice there was a 14% reduction in perfused sinusoids between 0.8 and 27 months, with associated 35% reduction in sinusoidal blood flow (Ito et al 2007). This was accompanied by a fivefold increase in leukocyte adhesion, up-regulated ICAM-1 expression, and increases in intrahepatic macrophages in 27-monthold mice.…”

“…The endocytotic capacity of SEC is known to be decreased in older mice (Ito et al 2007). SEC dysfunction was seen as early as fourteen months, when there was a threefold increase in swollen SEC on transmission electron microscopy (TEM.…”