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1.  The Effects of Old Age on Hepatic Stellate Cells 
Aging is associated with marked changes in the hepatic sinusoid, yet the effect of old age on hepatic stellate cells (HSC) has not been well described. Transmission electron microscopy and immunohistochemistry were used to study the effects of aging on HSC in livers from rats (3-4 mths versus 24–27 mths) and mice (2-3 mths versus 20–22 mths). Desmin-positive HSC doubled in old age in both mice and rats. Alpha-smooth muscle actin- (αSMA-) positive cells did not increase significantly and remained only a small percentage of desmin-positive cells. Electron microscopy revealed that old age is associated with HSC that have a substantial increase in the number of lipid droplets which are larger in diameter. There was also a marked increase of HSC that protruded into the sinusoidal lumen in old mice. In conclusion, old age is associated with hyperplasia of HSC that are not activated and are engorged with lipid droplets.
PMCID: PMC3114409  PMID: 21687587
2.  Liver Sinusoidal Endothelial Fenestrations in Caveolin-1 Knockout Mice 
Fenestrations are pores in the liver sinusoidal endothelium that facilitate the transfer of particulate substrates between the sinusoidal lumen and hepatocytes. Fenestrations express caveolin-1 and have structural similarities to caveolae, therefore might be a form of caveolae and caveolin-1 may be integral to fenestration structure and function. Therefore, fenestrations were studied in the livers of caveolin-1 knockout mice.
Scanning, transmission and immunogold electron microscopic techniques were used to study the liver sinusoidal endothelium and other tissues in caveolin-1 knockout and wild-type mice.
Comparison of fenestrations in wild-type and knockout mice did not reveal any differences on either scanning or transmission electron microscopy. The diameter of the fenestrations was not significantly different (74 ± 13 nm knockout mice vs 78 ± 12 nm wild-type mice) nor was the fenestration porosity (6.5 ± 2.1 knockout vs 7.3 ± 2.4% wild-type mice). In contrast, adipocytes and blood vessels in other tissues lacked caveolae in the knockout mice. Caveolin-1 immunogold of livers of wild-type mice indicated sparse expression in sinusoidal endothelial cells.
The normal structure of fenestrations in the liver sinusoidal endothelium is not dependent upon caveolin-1 and fenestrations are not a form of caveolae.
PMCID: PMC4309280  PMID: 20141598
fenestrations; fenestrae; sinusoidal endothelial cell; liver; hepatic; caveolin-1; knockout mouse; electron microscopy; immunogold
3.  Diet mediates the relationship between longevity and reproduction in mammals 
Age  2012;35(3):921-927.
The disposable soma hypothesis posits a negative correlation between longevity and reproduction, presumably because these aspects of fitness compete for a limited pool of nutrients. However, diet, which varies widely among animals, could affect the availability of key nutrients required for both reproduction and longevity, especially protein. We used a comparative database of mammal life history data to test the hypothesis that carnivores experience less of a negative relationship between reproduction and longevity than herbivores. Annual reproduction and adult mass were significant predictors of longevity among all mammals; although, the relative importance of reproduction and mass for explaining longevity varied among trophic levels. In herbivores, reproduction was a stronger predictor of longevity than mass. Carnivores showed the opposite pattern with reproduction explaining much less of the variation in longevity. Omnivores showed an intermediate pattern with mass and reproduction explaining similar amounts of variation in longevity. In addition, longevity and reproduction were significantly higher in omnivores than herbivores and carnivores, which were not different from each other. Higher dietary protein at higher trophic levels may allow mammals to avoid potential conflicts between reproduction and longevity. However, there may be potential costs of carnivorous diets that limit the overall performance of carnivores and explain the peak in reproduction and longevity for omnivores.
PMCID: PMC3636383  PMID: 22237559
Mammal; Disposable soma theory; Trophic level; Diet
5.  Vitamin C restores healthy aging in a mouse model for Werner syndrome 
Werner syndrome (WS) 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 phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-κB, as well as protein kinase Cδ and Hif-1α transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARα. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.
PMCID: PMC3712979  PMID: 19741171 CAMSID: cams3020
ascorbate; metabolism; microarrays; liver; adipocyte; inflammation
6.  Statin use and clinical outcomes in older men: a prospective population-based study 
BMJ Open  2013;3(3):e002333.
The aim of this analysis was to investigate the relationship of statins with institutionalisation and death in older men living in the community, accounting for frailty.
Prospective cohort study.
Community-dwelling men participating in the Concord Health and Ageing in Men Project, Sydney, Australia.
Men aged ≥70 years (n=1665).
Data collected during baseline assessments and follow-up (maximum of 6.79 years) were obtained. Information regarding statin use was captured at baseline, between 2005 and 2007. Proportional hazards regression analysis was conducted to estimate the risk of institutionalisation and death according to statin use (exposure, duration and dose) and frailty status, with adjustment for sociodemographics, medical diagnosis and other clinically relevant factors. A secondary analysis used propensity score matching to replicate covariate adjustment in regression models.
At baseline, 43% of participants reported taking statins. Over 6.79 years of follow-up, 132 (7.9%) participants were institutionalised and 358 (21.5%) participants had died. In the adjusted models, baseline statin use was not statistically associated with increased risk of institutionalisation (HR=1.60; 95% CI 0.98 to 2.63) or death (HR=0.88; 95% CI 0.66 to 1.18). There was no significant association between duration and dose of statins used with either outcome. Propensity scoring yielded similar findings. Compared with non-frail participants not prescribed statins, the adjusted HR for institutionalisation for non-frail participants prescribed statins was 1.43 (95% CI 0.81 to 2.51); for frail participants not prescribed statins, it was 2.07 (95% CI 1.11 to 3.86) and for frail participants prescribed statins, it was 4.34 (95% CI 2.02 to 9.33).
These data suggest a lack of significant association between statin use and institutionalisation or death in older men. These findings call for real-world trials specifically designed for frail older people to examine the impact of statins on clinical outcomes.
PMCID: PMC3612783  PMID: 23474793
Clinical Pharmacology; Geriatric Medicine
7.  High risk prescribing in older adults: prevalence, clinical and economic implications and potential for intervention at the population level 
BMC Public Health  2013;13:115.
High risk prescribing can compromise independent wellbeing and quality of life in older adults. The aims of this project are to determine the prevalence, risk factors, clinical consequences, and costs of high risk prescribing, and to assess the impact of interventions on high risk prescribing in older people.
The proposed project will utilise data from the 45 and Up Study, a large scale cohort of 267,153 men and women aged 45 and over recruited during 2006–2009 from the state of New South Wales, Australia linked to a range of administrative health datasets. High risk prescribing will be assessed using three indicators: polypharmacy (use of five or more medicines); Beers Criteria (an explicit measure of potentially inappropriate medication use); and Drug Burden Index (a pharmacologic dose-dependent measure of cumulative exposure to anticholinergic and sedative medicines). Individual risk factors from the 45 and Up Study questionnaire, and health system characteristics from health datasets that are associated with the likelihood of high risk prescribing will be identified. The main outcome measures will include hospitalisation (first admission to hospital, total days in hospital, cause-specific hospitalisation); admission to institutionalised care; all-cause mortality, and, where possible, cause-specific mortality. Economic costs to the health care system and implications of high risk prescribing will be also investigated. In addition, changes in high risk prescribing will be evaluated in relation to certain routine medicines-related interventions. The statistical analysis will be conducted using standard pharmaco-epidemiological methods including descriptive analysis, univariate and multivariate regression analysis, controlling for relevant confounding factors, using a number of different approaches.
The availability of large-scale data is useful to identify opportunities for improving prescribing, and health in older adults. The size of the 45 and Up Study, along with linkage to health databases provides an important opportunity to investigate the relationship between high risk prescribing and adverse outcomes in a real-world population of older adults.
PMCID: PMC3570486  PMID: 23388494
High-risk prescribing; Prevalence; Clinical outcomes; Costs; Older adults
8.  Aging Biology and Novel Targets for Drug Discovery 
Despite remarkable technological advances in genetics and drug screening, the discovery of new pharmacotherapies has slowed and new approaches to drug development are needed. Research into the biology of aging is generating many novel targets for drug development that may delay all age-related diseases and be used long term by the entire population. Drugs that successfully delay the aging process will clearly become “blockbusters.” To date, the most promising leads have come from studies of the cellular pathways mediating the longevity effects of caloric restriction (CR), particularly target of rapamycin and the sirtuins. Similar research into pathways governing other hormetic responses that influence aging is likely to yield even more targets. As aging becomes a more attractive target for drug development, there will be increasing demand to develop biomarkers of aging as surrogate outcomes for the testing of the effects of new agents on the aging process.
PMCID: PMC4007976  PMID: 21693687
9.  DNA damage, NF-κB and accelerated aging 
Asian Journal of Andrology  2012;14(6):811-812.
PMCID: PMC3720098  PMID: 22922322
10.  Mild Cognitive Impairment Predicts Institutionalization among Older Men: A Population-Based Cohort Study 
PLoS ONE  2012;7(9):e46061.
There is a lack of evidence on the contribution of mild cognitive impairment (MCI) to institutionalization in older adults. This study aimed to evaluate a range of risk factors including MCI of institutionalization in older men.
Men aged ≥70 years (n = 1705), participating in the Concord Health and Ageing in Men Project, Sydney, Australia were studied. Participants completed self-reported questionnaires and underwent comprehensive clinical assessments during 2005–2007. Institutionalization was defined as entry into a nursing home facility or hostel at any time over an average of 5 years of follow-up. Cox regression analysis was conducted to generate hazard ratios (HR) with 95% confidence intervals (CI).
A total of 125 (7.3%) participants were institutionalized. Piecewise Cox proportional models were generated and divided at 3.4 years (1250 days) of follow-up due to violation of the proportional hazards assumption for the association between MCI and institutionalization (χ2 = 6.44, p = 0.01). Dementia, disability in Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL), poor grip strength, few social interactions, being a Non-English speaking immigrant and age were predictive of institutionalization during both time periods, whereas MCI (HR = 4.39, 95%CI 2.17–8.87) only predicted institutionalization in the period beyond 3.4 years of follow-up. Being married (HR = 0.42, 95%CI: 0.24–0.72) was protective only during the period after 3.4 years of follow-up.
In this study, the strongest predictors of institutionalization were dementia, MCI, ADL and IADL disability. MCI was not a predictor of early institutionalization but became a significant predictor beyond 3.4 years of follow-up.
PMCID: PMC3454331  PMID: 23029389
11.  The Relationship between Fenestrations, Sieve Plates and Rafts in Liver Sinusoidal Endothelial Cells 
PLoS ONE  2012;7(9):e46134.
Fenestrations are transcellular pores in endothelial cells that facilitate transfer of substrates between blood and the extravascular compartment. In order to understand the regulation and formation of fenestrations, the relationship between membrane rafts and fenestrations was investigated in liver sinusoidal endothelial cells where fenestrations are grouped into sieve plates. Three dimensional structured illumination microscopy, scanning electron microscopy, internal reflectance fluorescence microscopy and two-photon fluorescence microscopy were used to study liver sinusoidal endothelial cells isolated from mice. There was an inverse distribution between sieve plates and membrane rafts visualized by structured illumination microscopy and the fluorescent raft stain, Bodipy FL C5 ganglioside GM1. 7-ketocholesterol and/or cytochalasin D increased both fenestrations and lipid-disordered membrane, while Triton X-100 decreased both fenestrations and lipid-disordered membrane. The effects of cytochalasin D on fenestrations were abrogated by co-administration of Triton X-100, suggesting that actin disruption increases fenestrations by its effects on membrane rafts. Vascular endothelial growth factor (VEGF) depleted lipid-ordered membrane and increased fenestrations. The results are consistent with a sieve-raft interaction, where fenestrations form in non-raft lipid-disordered regions of endothelial cells once the membrane-stabilizing effects of actin cytoskeleton and membrane rafts are diminished.
PMCID: PMC3454341  PMID: 23029409
12.  Age-Related Pseudocapillarization of the Liver Sinusoidal Endothelium Impairs the Hepatic Clearance of Acetaminophen in Rats 
We investigated the effect of age-related pseudocapillarization of the liver sinusoidal endothelium on the hepatic disposition of acetaminophen. The multiple indicator dilution technique assessed the hepatic disposition of tracer 14C-acetaminophen and reference markers in isolated perfused livers of young (n = 11) and old (n = 12) rats. Electron microscopy confirmed defenestration of the sinusoidal endothelium in old rats compared with young rats. Acetaminophen recovery following a single pass through the liver was significantly increased in old rats (0.64 ± 0.04, old; 0.59 ± 0.05, young; p < .05). In old age, there was significant reduction of the intercompartmental rate constant k1 (0.34 ± 0.10s-1, old; 0.61 ± 0.38s-1, young; p < .05) and the permeability-surface area product for the transfer of acetaminophen across the sinusoidal endothelium (0.034 ± 0.006 mL/s/g, old; 0.048 ± 0.014 mL/s/g, young; p < .005). There was no difference in k3, the measure of sequestration of acetaminophen that reflects enzyme activity. Age-related pseudocapillarization of the liver sinusoid resulted in increased acetaminophen recovery and decreased transfer of acetaminophen into the liver.
PMCID: PMC3055277  PMID: 21300741
Acetaminophen; Pseudocapillarization; Aging; Isolated liver perfusion; Extraction
13.  Determinants of Serum-Induced SIRT1 Expression in Older Men: The CHAMP Study 
Circulating factors that have an effect on SIRT1 expression are influenced by caloric restriction. To determine the association between frailty and such circulating factors, we measured serum-induced SIRT1 expression from a nested cohort of frail (n = 77) and robust (n = 82) participants from Concord Health and Ageing in Men Project, a population-based study of community-dwelling men older than 70 years. Serum-induced SIRT1 expression was not different between frail and robust men (103.1 ± 17.0 versus 100.4 ± 19.3 μg/L). However, subsequent analyses showed that men with the lowest values (first quartile) were less likely to be frail (odds ratio = 0.5, 95% confidence interval = 0.2–1.0, p = .04) and had higher total body lean mass (p = .001) than the other participants. Serum-induced SIRT1 expression did not correlate with age, diseases, medications, albumin, fasting glucose, or lipids. Overall, there was no association between frailty and serum-induced SIRT1 expression; however, post hoc analysis suggested that there might be a paradoxical association between low serum-induced SIRT1 expression and robustness.
PMCID: PMC4007825  PMID: 20819794
SIRT1 expression; Frailty
14.  Age-Related Changes in Scavenger Receptor–Mediated Endocytosis in Rat Liver Sinusoidal Endothelial Cells 
Liver sinusoidal endothelial cells (LSECs) play an essential role in systemic waste clearance by effective endocytosis of blood-borne waste macromolecules. We aimed to study LSECs’ scavenger function during aging, and whether age-related morphological changes (eg, defenestration) affect this function, in F344/BN F1 rats. Endocytosis of the scavenger receptor ligand formaldehyde-treated serum albumin was significantly reduced in LSECs from old rats. Ligand degradation, LSEC protein expression of the major scavenger receptors for formaldehyde-treated serum albumin endocytosis, stabilin-1 and stabilin-2, and their staining patterns along liver sinusoids, was similar at young and old age, suggesting that other parts of the endocytic machinery are affected by aging. Formaldehyde-treated serum albumin uptake per cell, and cell porosity evaluated by electron microscopy, was not correlated, indicating that LSEC defenestration is not linked to impaired endocytosis. We report a significantly reduced LSEC endocytic capacity at old age, which may be especially important in situations with increased circulatory waste loads.
PMCID: PMC2920583  PMID: 20576648
Aging; Hepatic sinusoid; Porosity; Stabilin; Scavenger endothelial cells
15.  Three dimensional structured illumination microscopy of liver sinusoidal endothelial cell fenestrations 
Journal of structural biology  2010;171(3):382-388.
Fenestrations are pores in liver sinusoidal endothelial cells that filter substrates and debris between the blood and hepatocytes. Fenestrations have significant roles in aging and the regulation of lipoproteins. However their small size (<200 nm) has prohibited any functional analysis by light microscopy. We employed structured illumination light microscopy to observe fenestrations in isolated rat liver sinusoidal endothelial cells with great clarity and spatial resolution. With this method, the three dimensional structure of fenestrations (diameter 123±24 nm) and sieve plates was elucidated and it was shown that fenestrations occur in areas of abrupt cytoplasmic thinning (165±54 nm vs 292±103 nm in non-fenestrated regions, P<0.0001). Sieve plates were not preferentially co-localized with fluorescently labeled F-actin stress fibers and endothelial nitric oxide synthase but appeared to occur in primarily attenuated non-raft regions of the cell membrane. Labyrinthine structures were not seen and all fenestrations were short cylindrical pores. In conclusion, three dimensional structured illumination microscopy has enabled the unlimited power of fluorescent immunostaining and colocalization to reveal new structural and functional information about fenestrations and sieve plates.
PMCID: PMC3043550  PMID: 20570732
Structured illumination microscopy; liver sinusoidal endothelial cell; fenestrations; nitric oxide synthase; actin
16.  The Association of Alanine Transaminase With Aging, Frailty, and Mortality 
The relationships between blood tests of liver function and injury (alanine transaminase [ALT], gamma-glutamyl transferase, bilirubin, and albumin) with age, frailty, and survival were investigated in 1,673 community-dwelling men aged 70 years or older. ALT was lower in older participants. Those participants with ALT below the median at baseline had reduced survival (hazard ratio 2.10, 95% confidence interval [CI] 1.53–2.87) up to 4.9 years. Older age, frailty, low albumin, low body mass index, and alcohol abstinence also were associated with reduced survival, with age and frailty being the most powerful predictors. Low ALT was associated with frailty (odds ratio 3.54, 95% CI 2.45–5.11), and the relationship between ALT and survival disappeared once frailty and age were included in the survival analysis. Low ALT activity is a predictor of reduced survival; however, this seems to be mediated by its association with frailty and increasing age. ALT has potential value as a novel biomarker of aging.
PMCID: PMC4085878  PMID: 20498223
Alanine transaminase; Aging; Biomarker of aging; Frailty; Liver; Mortality
17.  Effects of old age on vascular complexity and dispersion of the hepatic sinusoidal network 
In old age, there are marked changes in both the structure of the liver sinusoidal endothelial cell and liver perfusion. The objective of this study was to determine whether there are also aging changes in the microvascular architecture and vascular dispersion of the liver that might influence liver function.
Vascular corrosion casts and light micrographs of young (4 mths) and old (24 mths) rat livers were compared. Fractal and Fourier analyses, and microcomputed tomography were used. Vascular dispersion was determined from the dispersion number for sucrose and 100 nm microspheres in impulse response experiments.
Age did not affect sinusoidal dimensions, sinusoidal density or dispersion number. There were changes in the geometry and complexity of the sinusoidal network as determined by Fractal dimension and degree of anisotropy.
There are small age-related changes in the architecture of the liver sinusoidal network, which may influence hepatic function and reflect broader aging changes in the microcirculation. However sinusoidal dimensions and hepatic vascular dispersion are not markedly influenced by old age.
PMCID: PMC3081854  PMID: 18386215
aging; liver; microcirculation; liver sinusoid; vascular casts; Fractal dimensions; Fourier analysis; vascular dispersion; multiple indicator dilution
18.  The effect of old age on apolipoprotein E and its receptors in rat liver 
Age  2009;32(1):69-77.
Apolipoprotein E (apoE) is associated with aging and some age-related diseases. The majority of apoE is produced by hepatocytes for the receptor-mediated uptake of lipoproteins. Here, the effects of age on the hepatic expression and distribution of apoE and its receptors were determined using immunofluorescence, Western blots, and quantitative PCR in rat liver tissue and isolated hepatocytes. The expression of apoE mRNA and protein was not influenced significantly by aging. Immunofluorescence studies in isolated hepatocytes showed that apoE was more likely to be co-localized with early endosomes, golgi, and microtubules in isolated old hepatocytes. The mRNA expression of the receptor involved in sequestration of apoE, heparan sulfate proteoglycan was reduced in old age, without any significant effect on the expression of either the low-density lipoprotein receptor or low density-lipoprotein receptor-related protein. Old age is associated with changes in hepatic apoE intracellular trafficking and heparan sulfate proteoglycan expression that might contribute to age-related disease.
PMCID: PMC2829642  PMID: 19809892
Apolipoprotein E; Liver; Hepatocyte; Ageing; Aging; Low-density lipoprotein receptor; Low density-lipoprotein receptor-related protein; Heparan sulfate proteoglycan
19.  Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending lifespan 
Cell metabolism  2008;8(2):157-168.
A small molecule that safely mimics the ability of dietary restriction (DR) to delay age-related diseases in laboratory animals is greatly sought after. We and others have shown that resveratrol mimics effects of DR in lower organisms. In mice, we find that resveratrol induces gene expression patterns in multiple tissues that parallel those induced by DR and every-other-day feeding. Moreover, resveratrol-fed elderly mice show a marked reduction in signs of aging including reduced albuminuria, decreased inflammation and apoptosis in the vascular endothelium, increased aortic elasticity, greater motor coordination, reduced cataract formation, and preserved bone mineral density. However, mice fed a standard diet did not live longer when treated with resveratrol beginning at 12 months of age. Our findings indicate that resveratrol treatment has a range of beneficial effects in mice but does not increase the longevity of ad libitum-fed animals when started mid-life.
PMCID: PMC2538685  PMID: 18599363
20.  The influence of oxygen tension on the structure and function of isolated liver sinusoidal endothelial cells 
Liver sinusoidal endothelial cells (LSECs) are specialized scavenger cells, with crucial roles in maintaining hepatic and systemic homeostasis. Under normal physiological conditions, the oxygen tension encountered in the hepatic sinusoids is in general considerably lower than the oxygen tension in the air; therefore, cultivation of freshly isolated LSECs under more physiologic conditions with regard to oxygen would expect to improve cell survival, structure and function. In this study LSECs were isolated from rats and cultured under either 5% (normoxic) or 20% (hyperoxic) oxygen tensions, and several morpho-functional features were compared.
Cultivation of LSECs under normoxia, as opposed to hyperoxia improved the survival of LSECs and scavenger receptor-mediated endocytic activity, reduced the production of the pro-inflammatory mediator, interleukin-6 and increased the production of the anti-inflammatory cytokine, interleukin-10. On the other hand, fenestration, a characteristic feature of LSECs disappeared gradually at the same rate regardless of the oxygen tension. Expression of the cell-adhesion molecule, ICAM-1 at the cell surface was slightly more elevated in cells maintained at hyperoxia. Under normoxia, endogenous generation of hydrogen peroxide was drastically reduced whereas the production of nitric oxide was unaltered. Culture decline in high oxygen-treated cultures was abrogated by administration of catalase, indicating that the toxic effects observed in high oxygen environments is largely caused by endogenous production of hydrogen peroxide.
Viability, structure and many of the essential functional characteristics of isolated LSECs are clearly better preserved when the cultures are maintained under more physiologic oxygen levels. Endogenous production of hydrogen peroxide is to a large extent responsible for the toxic effects observed in high oxygen environments.
PMCID: PMC2408922  PMID: 18457588
21.  Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid 
Experimental gerontology  2007;42(4):374-378.
Age-related changes in the hepatic sinusoid, called pseudocapillarization, may contribute to the pathogenesis of dyslipidaemia. Caloric restriction (CR) is a powerful model for the study of aging because it extends lifespan. We assessed the effects of CR on the hepatic sinusoid to determine whether pseudocapillarization is preventable and hence a target for the prevention of age-related dyslipidemia. Livers from young (6 months) and old (24 months) CR and ad libitum fed (AL) F344 rats were examined using electron microscopy and immunohistochemistry. In old age, there was increased thickness of the liver sinusoidal endothelium and reduced endothelial fenestration porosity. In old CR rats, endothelial thickness was less and fenestration porosity was greater than in old AL rats. Immunohistochemistry showed that CR prevented age-related decrease in caveolin-1 expression and increase in peri-sinusoidal collagen IV staining, but did not alter the age-related increase of von Willebrand’s factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression.
PMCID: PMC1892153  PMID: 17204388
liver sinusoidal endothelial cell; pseudocapillarization; caloric restriction; aging; caveolin-1; liver; fenestrations
22.  Caloric restriction versus drug therapy to delay the onset of aging diseases and extend life 
Age  2005;27(1):39-48.
There are two firmly established methods of prolonging life. Calorie restriction (CR) using nutrient-rich diets to prolong life in lower animals, and life saving medications in humans to delay the development of the major diseases of middle and old age. These two approaches have different mechanisms of action. In rats, CR at 40% below ad libitum intake begun soon after weaning and continued until death, reduces body weight by about 40% and increases lifespan. There have been no lifelong CR studies performed on humans. However, in healthy adult human subjects about 20% CR over a period of 2–15 years, lowers body weight by about 20% and decreases body mass index (BMI) to about 19. This CR treatment in humans reduces blood pressure and blood cholesterol to a similar extent as the specific drugs used to delay the onset of vascular disease and so extend human life. These same drugs may act by mechanisms that overlap with some of the mechanisms of CR in retarding these pathologies and thus may have similar antiaging and life prolonging actions. Such drugs may be regarded as CR mimetics which inhibit the development of certain life shortening diseases, without the need to lower calorie intake. In developed countries, better medical care, drug therapy, vaccinations, and other public health measures have extended human life by about 30 years during the 20th century without recourse to CR, which is so effective in the rat. The percentage gain in human life expectancy during the 20th century is twice that achieved by CR in rat survival. However, rat longevity studies now use specific pathogen-free animals and start CR after weaning or later, thereby excluding deaths from infectious diseases and those associated with birth and early life. There is a need to develop CR mimetics which can delay the development of life-threatening diseases in humans. In the 21st century due to the human epidemic of overeating with a sedentary lifestyle, it may necessary to utilize CR to counter the aging effects of overweight. Since the greatest life-extending effects of CR in the rodent occur when started early in life, long-term antiaging therapy in humans should be initiated soon after maturity, when physiological systems have developed optimally.
PMCID: PMC3456093  PMID: 23598602
blood pressure; calorie restriction mimetics; cardiovascular disease; cholesterol; lifespan; medications
23.  Dietary Approaches that Delay Age-Related Diseases 
Reducing food intake in lower animals such as the rat decreases body weight, retards many aging processes, delays the onset of most diseases of old age, and prolongs life. A number of clinical trials of food restriction in healthy adult human subjects running over 2–15 years show significant reductions in body weight, blood cholesterol, blood glucose, and blood pressure, which are risk factors for the development of cardiovascular disease and diabetes. Lifestyle interventions that lower energy balance by reducing body weight such as physical exercise can also delay the development of diabetes and cardiovascular disease. In general, clinical trials are suggesting that diets high in calories or fat along with overweight are associated with increased risk for cardiovascular disease, type 2 diabetes, some cancers, and dementia. There is a growing literature indicating that specific dietary constituents are able to influence the development of age-related diseases, including certain fats (trans fatty acids, saturated, and polyunsaturated fats) and cholesterol for cardiovascular disease, glycemic index and fiber for diabetes, fruits and vegetables for cardiovascular disease, and calcium and vitamin D for osteoporosis and bone fracture. In addition, there are dietary compounds from different functional foods, herbs, and neutraceuticals such as ginseng, nuts, grains, and polyphenols that may affect the development of age-related diseases. Long-term prospective clinical trials will be needed to confirm these diet—disease relationships. On the basis of current research, the best diet to delay age-related disease onset is one low in calories and saturated fat and high in wholegrain cereals, legumes, fruits and vegetables, and which maintains a lean body weight. Such a diet should become a key component of healthy aging, delaying age-related diseases and perhaps intervening in the aging process itself. Furthermore, there are studies suggesting that nutrition in childhood and even in the fetus may influence the later development of aging diseases and lifespan.
PMCID: PMC2682451  PMID: 18047254
food intake; obesity; cardiovascular disease; diabetes; cancer; osteoporosis; macular degeneration; dementia; preventive dietary therapy
24.  Clinical implications of changes in hepatic drug metabolism in older people 
Prescribing for older people is challenging because of the paucity of clinical trial evidence of therapeutic benefit in this population and the presence of evidence that older people are at increased risk of adverse drug reactions. The outcomes of pharmacotherapies in older people depend on age-related changes in both pharmacokinetics and pharmacodynamics. Of the pharmacokinetic changes, those in hepatic metabolism are the most significant. Recent advances in biogerontology have improved our understanding of changes that occur in hepatic pharmacokinetics in older people. Knowledge of age-related changes in hepatic metabolism can guide prescribing and help reduce the risk–benefit ratio of using medications in older people.
PMCID: PMC1661619  PMID: 18360554
aging; pharmacokinetics; liver; adverse drug reactions; prescribing
25.  The Vascular Implications of Post-prandial Lipoprotein Metabolism 
Impaired lipoprotein metabolism is one of the major aetiological factors for the pathogenesis of atherosclerosis and cardiovascular disease (CVD). Assessment is usually made in the fasting state, and particular attention is directed towards the measurement of the cholesterol content of both the low and high-density lipoprotein fractions. By comparison, a massive amount of lipid fluxes through the intra-vascular compartment during the post-prandial period. This has led to the hypothesis that atherosclerosis could be partially, or even predominantly, due to the pathological effects of this flux of post-prandial lipoproteins on the vessel wall. This justifies efforts to systematically study the relationship between the lipoprotein responses to food (particularly fat) ingestion and cardiovascular disease or its surrogate markers. This review will consider the mechanisms by which post-prandial metabolism might affect the risk of CVD. It will examine the evidence for and against such an association. It will also consider the practical and methodological issues that are likely to determine the future utility of post-prandial lipoprotein assessment.
PMCID: PMC1853364  PMID: 18516208

Results 1-25 (27)