Victoria C. Cogger

The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice

The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.

Age-related pseudocapillarization of the human liver.

Age‐related changes in liver function are important because they may promote susceptibility to adverse drug reactions, neurotoxicity, atherosclerosis, and other important diseases in older people. Age‐related changes in the rat hepatic sinusoidal endothelium, termed pseudocapillarization, have been described recently and these may contribute to hepatic impairment. The present study has examined surgical and post‐mortem specimens with immunohistochemistry and transmission electron microscopy to determine whether pseudocapillarization also occurs in older humans. The age of the subject, independent of systemic disease or hepatic pathology in surgical and post‐mortem samples of human liver, was associated with increased peri‐sinusoidal expression of von Willebrands factor, collagen I, collagen IV, and staining with Massons trichrome. Electron microscopy revealed significant age‐related thickening of the sinusoidal endothelium (young 165 ± 17 nm, middle age 222 ± 11 nm, older 289 ± 9 nm, p < 0.001) with loss of fenestrations (young 7.7 ± 0.7 per 10 µm, middle age 3.6 ± 0.5 per 10 µm, older 1.5 ± 0.4 per 10 µm, p < 0.001), and age‐related deposition of basal lamina and collagen. In conclusion, ageing in humans is associated with morphological changes in the sinusoidal endothelium and space of Disse which are presumptively related to the ageing process and potentially represent an important link between the ageing process and disease susceptibility. Copyright

Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism

Long-term glucocorticoid treatment is associated with numerous adverse outcomes, including weight gain, insulin resistance, and diabetes; however, the pathogenesis of these side effects remains obscure. Glucocorticoids also suppress osteoblast function, including osteocalcin synthesis. Osteocalcin is an osteoblast-specific peptide that is reported to be involved in normal murine fuel metabolism. We now demonstrate that osteoblasts play a pivotal role in the pathogenesis of glucocorticoid-induced dysmetabolism. Osteoblast-targeted disruption of glucocorticoid signaling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of insulin resistance, glucose intolerance, and abnormal weight gain in corticosterone-treated mice. Nearly identical effects were observed in glucocorticoid-treated animals following heterotopic (hepatic) expression of both carboxylated and uncarboxylated osteocalcin through gene therapy, which additionally led to a reduction in hepatic lipid deposition and improved phosphorylation of the insulin receptor. These data suggest that the effects of exogenous high-dose glucocorticoids on insulin target tissues and systemic energy metabolism are mediated, at least in part, through the skeleton.

Hepatic pseudocapillarisation and atherosclerosis in ageing.

Cardiovascular disease secondary to atherosclerosis is the main cause of death and disability in industrialised countries, and ageing is the foremost risk factor for atherosclerosis. We present a hypothesis linking age-specific structural change in the liver with accepted pathogenic mechanisms leading to atherosclerosis. Ageing in the liver is associated with pseudocapillarisation of the sinusoidal endothelium, which is characterised by thickening of endothelium, basement membrane formation, and defenestration (loss of pores). Fenestrations (pores) normally form a liver sieve that allows passage of chylomicron remnants for subsequent uptake and metabolism by hepatocytes. Ageing is associated with impaired clearance of chylomicron remnants, postprandial hypertriglyceridaemia, and hence, atherosclerosis, which we propose is linked directly to loss of permeability of the liver sieve because of defenestration associated with pseudocapillarisation. Development of methods to maintain fenestrations of sinusoidal endothelium or to facilitate refenestration might be a new therapeutic strategy for management of cardiovascular disease in old people.

A High-Fat Diet and NAD+ Activate Sirt1 to Rescue Premature Aging in Cockayne Syndrome

Cockayne syndrome (CS) is an accelerated aging disorder characterized by progressive neurodegeneration caused by mutations in genes encoding the DNA repair proteins CS group A or B (CSA or CSB). Since dietary interventions can alter neurodegenerative processes, Csb(m/m) mice were given a high-fat, caloric-restricted, or resveratrol-supplemented diet. High-fat feeding rescued the metabolic, transcriptomic, and behavioral phenotypes of Csb(m/m) mice. Furthermore, premature aging in CS mice, nematodes, and human cells results from aberrant PARP activation due to deficient DNA repair leading to decreased SIRT1 activity and mitochondrial dysfunction. Notably, β-hydroxybutyrate levels are increased by the high-fat diet, and β-hydroxybutyrate, PARP inhibition, or NAD(+) supplementation can activate SIRT1 and rescue CS-associated phenotypes. Mechanistically, CSB can displace activated PARP1 from damaged DNA to limit its activity. This study connects two emerging longevity metabolites, β-hydroxybutyrate and NAD(+), through the deacetylase SIRT1 and suggests possible interventions for CS.

Old Age and the Hepatic Sinusoid

Morphological changes in the hepatic sinusoid with old age are increasingly recognized. These include thickening and defenestration of the liver sinusoidal endothelial cell, sporadic deposition of collagen and basal lamina in the extracellular space of Disse, and increased numbers of fat engorged, nonactivated stellate cells. In addition, there is endothelial up‐regulation of von Willebrand factor and ICAM‐1 with reduced expression of caveolin‐1. These changes have been termed age‐related pseudocapillarization. The effects of old age on Kupffer cells are inconsistent, but impaired responsiveness is likely. There are functional implications of these aging changes in the hepatic sinusoid. There is reduced sinusoidal perfusion, which will impair the hepatic clearance of highly extracted substrates. Blood clearance of a variety of waste macromolecules takes place in liver sinusoidal endothelial cells (LSECs). Previous studies indicated either that aging had no effect, or reduced the endocytic capacity of LSECs. However, a recent study in mice showed reduced endocytosis in pericentral regions of the liver lobules. Reduced endocytosis may increase systemic exposure to potential harmful waste macromolecules such as advanced glycation end products Loss of fenestrations leads to impaired transfer of lipoproteins from blood to hepatocytes. This provides a mechanism for impaired chylomicron remnant clearance and postprandial hyperlipidemia associated with old age. Given the extensive range of substrates metabolized by the liver, age‐related changes in the hepatic sinusoid and microcirculation have important systemic implications for aging and age‐related diseases. Anat Rec, 291:672–683, 2008.

Age‐related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat

The mechanisms for the association of old age with post‐prandial hyperlipidemia and atherosclerosis are not well understood. Post‐prandial hyperlipidemia has emerged as a significant risk for atherosclerosis. The liver is the central organ for lipoprotein metabolism. The initial step in the hepatic uptake of post‐prandial lipoproteins is their transfer from the hepatic sinusoidal capillary lumen across the hepatic sinusoidal endothelium into the space of Disse. Here, they access hepatocytes for receptor‐mediated uptake. We proposed that fenestrations (pores) within the hepatic sinusoidal endothelium filter lipoproteins on the basis of size. Recently we discovered age‐related changes in the sinusoidal endothelium (pseudocapillarization), including reduction in the porosity of the endothelium. Using the impulse response technique in perfused rat livers, we found that aging is associated with impaired hepatic transendothelial transfer of chylomicrons with diameters smaller than those of fenestrations. In conclusion, age‐related pseudocapillarization of the hepatic sinusoidal endothelium provides a novel mechanism for the association of old age with impaired hepatic lipoprotein metabolism and with atherosclerosis. (HEPATOLOGY 2005.)

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted.

Hepatic sinusoidal pseudocapillarization with aging in the non-human primate

BACKGROUND/AIMS Age-related changes in the hepatic sinusoid termed pseudocapillarization have been reported in the rat and human and have implications for disease susceptibility in old age. In this study, we investigated whether similar changes occur in the livers of old baboons and thus represent a widespread aging change. METHODS Liver tissue from five young baboons (5.4+/-0.5yrs) and five old baboons (21.8+/-0.7yrs) was compared by transmission electron microscopy, scanning electron microscopy and immunohistochemistry. RESULTS The thickness of the sinusoidal endothelium was increased in old baboons (130+/-8 nm versus 186+/-9 nm, P<0.001) and the frequency of endothelial fenestrae decreased, with the porosity declining from 4.2+/-0.5% to 2.4+/-0.4% (P=0.006). The expression of laminin and von Willebrands factor was more extensive in old baboons. Novel perisinusoidal ring-shaped cells, probably fat-engorged stellate cells, were prominent in the old baboons. CONCLUSIONS Pseudocapillarization is a significant age-related change in the baboon liver. Aging in baboons is associated with a novel aging change in the stellate cell not reported in other species. Hepatic pseudocapillarization is a widespread aging liver change found in several species including humans and other non-human primates.

Resveratrol Improves Insulin Resistance Hyperglycemia and Hepatosteatosis But Not Hypertriglyceridemia, Inflammation, and Life Span in a Mouse Model for Werner Syndrome

Werner syndrome is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many features of Werner syndrome, including a pro-oxidant status and a shorter mean life span. Here, we show that resveratrol supplementation improved the hyperglycemia and the insulin resistance phenotype in these Wrn mutant mice. In addition, resveratrol reversed liver steatosis, lipid peroxidaton, and the defenestration phenotypes observed in such mice. Resveratrol, however, did not improve the hypertriglyceridemia, inflammatory stress, nor extend the mean life span of these mutant mice. Microarray and biologic pathway enrichment analyses on liver tissues revealed that resveratrol mainly decreased lipidogenesis and increased genes involved in the insulin signaling pathway and the glutathione metabolism in Wrn mutant mice. Finally, resveratrol-treated mutant mice exhibited an increase in the frequency of lymphoma and of several solid tumors. These results indicate that resveratrol supplementation might exert at least metabolic benefits for Werner syndrome patients.