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1.  Strategies for improving cognition with aging: insights from a longitudinal study of antioxidant and behavioral enrichment in canines 
Age  2008;31(3):211-220.
Studies in humans suggest that lifestyle factors can have a beneficial impact on the risk for developing cognitive decline and dementia with age. There is growing evidence that maintaining a physically and intellectually active lifestyle can positively impact cognitive ability in older individuals. Dietary factors, such as the intake of antioxidants, may also prevent age-related cognitive decline. However, studies in humans are challenging; many variables cannot be controlled, making it difficult for researchers to determine the exact types and quantities of enrichment and dietary factors necessary for positive effects on cognition. Studies in animal models of human aging allow researchers to precisely control such variables, and can be used to assess the mechanisms and molecular pathways underlying any positive effects. Here we review the results of an intervention study using a canine model of human aging. The study was unique in that it compared the effects of dietary antioxidant supplementation alone and in combination with behavioral enrichment. We found that both interventions lead to improvements in cognitive ability in aged dogs; however, combining the treatments preserved cognition to a greater extent than either treatment alone. Overall, the results suggest that antioxidant supplementation and behavioral enrichment target separate yet complementary molecular pathways to improve cognition, and support the idea that combinations of treatments to improve cognition and slow brain aging will produce greater benefits than single interventions.
doi:10.1007/s11357-008-9063-2
PMCID: PMC2734239  PMID: 19714491
Beta-amyloid; Dog; Mitochondrial cofactors; Neurogenesis; Oxidative stress; Proteomics
2.  Estradiol enhances sociosexual behavior and can have proliferative effects in ovariectomized rats 
Age  2008;31(3):221-229.
Although estradiol (E2) may have some beneficial effects as a treatment for menopause symptoms, E2 also has trophic effects that can increase vulnerability to some cancers, such as breast cancer. In the present study, a model to investigate the concomitant behavioral and proliferative effects of E2 was developed. First, the effects of different duration of chronic E2 exposure (2 vs 6 months), or no such exposure, on proliferation (tumor incidence and weight, uterine weight) in adult, ovariectomized (OVX) rats was determined. Second, the effects of different dosages of E2 (0.03 or 0.09 mg/kg) compared to vehicle only on sexual behavior, and measures of proliferation of adult OVX rats treated with a chemical carcinogen (DMBA; 1.25, 12.50, or 25.00 mg), or inert vehicle, were investigated. Vehicle or E2 was administered subcutaneously (SC) to OVX rats once per week for 14 weeks. Six months of continuous E2 exposure increased tumor incidence, tumor weight, and uterine weight, compared to 2 months of E2 or no E2 exposure. Rats administered DMBA had increased incidence, number, and size of tumors compared to vehicle treatment, and this effect appeared to be augmented by E2. Compared to vehicle, E2 increased lordosis and uterine weight. Thus, E2 may have the unfavorable effect of increasing proliferation when administered in chronic situations. Studies investigating the action of E2 for these effects are ongoing.
doi:10.1007/s11357-008-9079-7
PMCID: PMC2734240  PMID: 19714492
DMBA; Estrogen receptor; Estrous; Lordosis; Tumor
3.  Influence of age on inducibility and cholinergic modulation of arrhythmia in isolated rat right atria 
Age  2008;31(1):51-58.
The effects of carbachol and atropine on the number of trains (NT) and on the train stimulus strength (SS) necessary to induce arrhythmia were studied in isolated right atria of infant, young, adult and mature rats submitted to electric field stimulation (66.7 Hz, 5 ms pulse-duration, 250 pulses). Carbachol (1 μM) decreased NT from four (control) to two in all ages tested. Atropine (1 μM) prevented tachyarrhythmia induction in tissue of all ages, even with NT equal to 12, except for mature rats (typically four trains). The SS decreases from infant to adult age [5- to 2-fold atrial threshold (AT)] and increases in mature animals (5-fold AT). Carbachol changes this result only for mature rats (5- to 2-fold AT). The SS was decreased by carbachol (1 μM) from 5- to 3-fold AT in mature rats, but atropine did not modify SS in this age. These results indicate that inducibility and cholinergic modulation of atrial tachyarrhythmia is influenced by age.
doi:10.1007/s11357-008-9080-1
PMCID: PMC2645994  PMID: 19234768
Acetylcholine receptor; Age; Arrhythmia; Cardiac muscle; Cholinergic
4.  Age-related atrial fibrosis 
Age  2008;31(1):27-38.
Many age-related diseases are associated with, and may be promoted by, cardiac fibrosis. Transforming growth factor (TGF)-β, hypoxia-induced factor (HIF), and the matrix metalloproteinase (MMP) system have been implicated in fibrogenesis. Thus, we investigated whether age is related to these systems and to atrial fibrosis. Right atrial appendages (RAA) obtained during heart surgery (n = 115) were grouped according to patients’ age (<50 years, 51–60 years, 61–70 years, or >70 years). Echocardiographic ejection fractions (EF) and fibrosis using Sirius-red-stained histological sections were determined. TGF-β was determined by quantitative RT-PCR and hypoxia-related factors [HIF1α, the vascular endothelial growth factor (VEGF)-receptor, CD34 (a surrogate marker for microvessel density), the factor inhibiting HIF (FIH), and prolyl hydroxylase 3 (PHD 3)] were detected by immunostaining. MMP-2 and -9 activity were determined zymographically, and mRNA levels of their common tissue inhibitor TIMP-1 were determined by RT-PCR. Younger patients (<50 years) had significantly less fibrosis (10.1% ± 4.4% vs 16.6% ± 8.3%) than older individuals (>70 years). While HIF1α, FIH, the VEGF-receptor, and CD34 were significantly elevated in the young, TGF-β and PHD3 were suppressed in these patients. MMP-2 and -9 activity was found to be higher while TIMP-1 levels were lower in older patients. Statistical analysis proved age to be the only factor influencing fibrogenesis. With increasing age, RAAs develop significantly more fibrosis. An increase of fibrotic and decrease of hypoxic signalling and microvessel density, coupled with differential expression of MMPs and TIMP-1 favouring fibrosis may have helped promote atrial fibrogenesis.
doi:10.1007/s11357-008-9077-9
PMCID: PMC2645993  PMID: 19234766
Atrial; Fibrosis; Age; Transforming growth factor-β; Hypoxia induced factor 1; Matrix metalloproteinase
5.  Curcumin ameliorates impaired insulin/IGF signalling and memory deficit in a streptozotocin-treated rat model 
Age  2008;31(1):39-49.
Increased serum insulin levels and reduced peripheral insulin activities seen in insulin resistance syndrome are associated with age-dependent cognitive impairment and Sporadic Alzheimer’s Disease (SAD), suggesting a disturbance in the insulin signalling system in the brain and possibly being one of the causes of dementia. Therefore, the streptozotocin (STZ)-induced animal may be an appropriate model for the investigation of SAD and related dementia. This study was designed to investigate the beneficial effect of Curcumin (CUR), a neuroprotective agent, on intracerebroventricular (ICV) STZ-induced cognitive impairment in rats. For this purpose, adult male Wistar rats were bilaterally ICV injected with STZ (3 mg/kg). An artificial cerebrospinal fluid (aCSF) was given to the control group (SHAM) instead of STZ on days 1 and 3. Learning and memory performance were assessed using the “passive avoidance task” and the “Morris water maze test”. After confirmation of acquisition impairment with these tests, the STZ group was divided into two subgroups: STZ + vehicle (Vh) and STZ + CUR. The rats in the SHAM and STZ + Vh groups were administered intraperitoneally with 0.5 ml Vh and the rats in the STZ + CUR group were treated intraperitoneally with CUR (300 mg kg−1 day−1 in Vh) for 10 days starting from the 25th day after STZ injection. The Morris water maze test was reapplied on the 35th day after STZ injection and all of the rats were sacrificed on day 36 for quantitation of IGF-1 and for histopathological evaluation. Rats in the STZ + CUR group were found to have a higher performance in cognitive tests than rats in the STZ + Vh group (P < 0.01). In parallel with the cognitive tests, IGF-1 levels were decreased in all of the STZ-injected groups (1.78 ± 0.34) compared to the SHAM group (3.46 ± 0.41). In contrast, CUR treatment significantly increased IGF-1 levels (P < 0.001). The degree of neuronal loss decreased after CUR treatment compared to the SHAM group (P < 0.02). These results clearly indicate that CUR treatment is effective in reducing the cognitive impairment caused by STZ in rats, and may be a potential therapeutic agent for altering neurodegeneration in SAD.
doi:10.1007/s11357-008-9078-8
PMCID: PMC2645992  PMID: 19234767
Alzheimer’s disease; Curcumin; Experimental; IGF-1; Streptozotocin
6.  Reduced neuronal co-localisation of nardilysin and the putative α-secretases ADAM10 and ADAM17 in Alzheimer’s disease and Down syndrome brains 
Age  2008;31(1):11-25.
The peptidase nardilysin is involved in degradation of neuropeptides and limited intracellular proteolysis. Recent reports point to an involvement of nardilysin in the pathophysiology of Alzheimer’s disease. Nardilysin enhances the α-secretase activity of the disintegrin and metalloproteases (ADAMs) 10 and 17, thereby possibly contributing to reduced generation of amyloidogenic fragments from the amyloid precursor protein. A prerequisite for the α-secretase-stimulating effect of nardilysin on the activity of ADAMs in vivo is cellular co-expression of nardilysin with ADAM10 and/or ADAM17. We immunolocalised nardilysin, ADAM10, and ADAM17 in cortical regions of normal aged brain, in Alzheimer’s disease, and in Down syndrome brains and counted the number of protease-expressing neurons. A considerable portion of neurons co-express nardilysin together with either ADAM10 or ADAM17. Compared to controls, in Alzheimer’s disease and in Down syndrome brains there is a decreased cellular expression of all three antigens, and a reduction in the number of those neurons that co-express nardilysin with ADAM10 or with ADAM17. Our data are consistent with the notion that the proposed α-secretase-enhancing activity of nardilysin might play a role in human brain pathology.
doi:10.1007/s11357-008-9076-x
PMCID: PMC2645990  PMID: 19234765
Alzheimer’s disease; Down syndrome; Human cerebral cortex; Immunohistochemistry; Metalloprotease
7.  Probiotics modulate the Bifidobacterium microbiota of elderly nursing home residents 
Age  2008;31(1):59-66.
Gut Bifidobacterium microbiota of the elderly has been suggested to differ from that of adults, possibly promoting the risk of infections and gut barrier dysfunction. Specific probiotics may improve the gut barrier. In this randomized, placebo-controlled intervention study, 66 elders consumed a fermented oat drink containing probiotic Bifidobacterium longum 46 and B. longum 2C or a non-fermented placebo oat drink for 6 months. Faecal samples were collected before, during and after the intervention. Levels of faecal bifidobacteria were determined using species-specific quantitative PCR and plate counting. The Bifidobacterium levels in the elderly were high and the species composition diverse. Probiotic intervention increased the levels bifidobacteria significantly. Specifically, the levels of B. catenulatum, B. bifidum and B. breve were enhanced. Consumption of the fermented oat drink itself was also associated with certain changes in microbiota. In conclusion, Bifidobacterium microbiota of elderly subjects may be modulated by probiotic administration. In some healthy elderly populations, Bifidobacterium microbiota may be more abundant and diverse than previously suggested.
doi:10.1007/s11357-008-9081-0
PMCID: PMC2645989  PMID: 19234769
Bifidobacterium; Probiotics; Elderly; Microbiota; Oat
8.  Cellular senescence, ageing and disease 
Age  2008;31(1):1-9.
Cellular senescence is the irreversible growth arrest of individual mitotic cells, which as a consequence display a radically altered phenotype that is thought to impair tissue function and predispose tissues to disease development and/or progression as they gradually accumulate. However, in the past, research into mechanisms of ageing has commonly been researched and treated separately from disease development. This may partly be due to the lack of understanding concerning mechanisms of ageing and the difficulty in implementing what was known into models of disease development. Only in the last 10 years, with increasing knowledge of the senescent phenotype and the ability to detect senescent cells in human tissues, have biologists been able to investigate the relationship between cellular senescence and disease. This review therefore brings together and discusses recent findings which suggest that cellular senescence does contribute to ageing and the development/progression of disease.
doi:10.1007/s11357-008-9075-y
PMCID: PMC2645988  PMID: 19234764
Ageing; Disease; Cellular senescence; Senescent phenotype
9.  Lack of Socs2 expression reduces lifespan in high-growth mice 
Age  2008;30(4):245-249.
The high-growth (HG) phenotype in mice is characterized by a 30–50% postweaning overgrowth with a substantial increase in plasma insulin-like growth factor I (IGF1) levels, which is directly related to a deletion (hg) on chromosome 10 that includes the suppressor of cytokine signaling 2 (Socs2) gene. Reduced plasma IGF1 levels have been associated with extended lifespan in mice, although the aging-related effects of abnormally high IGF1 levels without elevated growth hormone levels have never been assessed in mammals. Within this context, the hg deletion was introgressed into C57BL/6J (B6) and FVB backgrounds, and a survival analysis was performed on the longevity records of 200 B6 (91 wild-type and 109 homozygous hg mutants) and 69 FVB (32 wild-type and 37 hg mutants) mice. Longevity was examined using a piecewise Weibull proportional hazards model solved through a Bayesian perspective and Markov chain Monte Carlo sampling. Lifespan was significantly reduced in both strains in homozygous hg mice, with a death risk between 3.689 (B6) and 4.347 (FVB) times higher than in wild-type mice (non-overlapped highest posterior density regions at 95%). These results highlight the effects of the Socs2 gene on aging regulation, likely related with variations described in plasma IGF1 levels. This result is consistent with previous research in dwarf mutant mice and other species, and characterizes the HG mutant mice as a unique and interesting animal model for accelerated aging research.
doi:10.1007/s11357-008-9064-1
PMCID: PMC2585654  PMID: 19424848
Cytokine signaling 2; Growth hormone; Insulin-like growth factor I; Lifespan; Mice; Survival analysis
10.  Age-dependent Wnt gene expression in bone and during the course of osteoblast differentiation 
Age  2008;30(4):273-282.
Wnt signaling is vital for osteoblast differentiation and recently has been associated with aging. Because impaired osteoblastogenesis is a cellular characteristic of age-induced bone loss, we investigated whether this process is associated with an altered expression of Wnt signaling-related proteins in bone and osteoblasts. Bone marrow cells were isolated from male C57BL/6 mice, aged 6 weeks, 6 months, and 18 months, respectively. Osteogenic differentiation was induced for 3 weeks and assessed using alizarin red staining. Gene expression of Wnt1, 3a, 4, 5a, 5b, 7b, 9b, 10b, lipoprotein receptor-related protein (LRP)-5/6, as well as dickkopf-1 (Dkk-1), sclerostin, and secreted frizzled related protein-1 (sFRP-1) was determined in bone tissue and osteoblasts on days 7, 14, and 21 by real-time RT-PCR. Osteoblast differentiation was significantly reduced in aged mice compared with young and adult mice. In bone tissue, expression levels of all genes assessed were decreased in adult and old mice, respectively, compared with young mice. Mature osteoblasts of aged compared with those of young mice showed enhanced expression of Wnt9b, LRP-6, and Dkk-1, and decreased expression of Wnt5a and 7b. In early osteoblasts, mRNA levels of Wnt1, 5a, 5b, and 7b were increased significantly in aged mice. The expression of Wnt3a, 4, LRP-5, and sclerostin was not altered in aged osteoblasts. In conclusion, osteoblastic expression of each Wnt-related protein is regulated individually by aging. The overall decreased expression of Wnt-related proteins in bone tissue of aged mice underlines the newly discovered association of Wnt signaling with aging.
doi:10.1007/s11357-008-9069-9
PMCID: PMC2585653  PMID: 19424851
Aging; Wnt proteins; Bone; Osteoblast
11.  Tissue-specific expression of receptor-interacting protein in aging mouse 
Age  2008;30(4):237-243.
Receptor-interacting protein (RIP) is a well-characterized coregulator for nuclear receptors. Here, we report the expression of RIP as two isoforms with molecular weights of 140 kDa and 137 kDa in liver and kidney, but only as one isoform of 140 kDa in lung, adipose tissue, prostate and testis of mice. The levels of both the isoforms decreased in liver and kidney of old mice compared with adult mice. The expression of RIP140 in kidney was relatively lower in old males than females. In contrast, adipose tissue showed remarkably higher levels of RIP140 in old than adult mice of both sexes. Thus, the expression of RIP varied with the type of tissue, sex and age of mice, suggesting differences in its function as a coregulator.
doi:10.1007/s11357-008-9062-3
PMCID: PMC2585652  PMID: 19424847
Receptor-interacting protein; Coregulator; Expression; Aging; Sex; Mouse
12.  Aging of the striatum: mechanisms and interventions 
Age  2008;30(4):251-261.
Motor function declines with increasing adult age. Proper regulation of the balance between dopamine (DA) and acetylcholine (ACh) in the striatum has been shown to be fundamentally important for motor control. Although other factors can also contribute to this age-associated decline, a decrease in the concentration and binding potential of the DA D2 receptor subtype in the striatum, especially in the cholinergic interneurons, are involved in the mechanism. Our studies have shown that gene transfer of the DA D2 receptor subtype with adenoiviral vectors is effective in ameliorating age-associated functional decline of the striatal cholinergic interneurons. These achievements confirm that an age-associated decrease of D2R contributes functional alteration of the interaction of DA and ACh in the striatum and demonstrate that these age-associated changes indeed are modifiable.
doi:10.1007/s11357-008-9066-z
PMCID: PMC2585651  PMID: 19424849
Dopamine receptor D2; Viral vector; Acetylcholine; Interneuron
13.  Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes 
Age  2008;30(4):209-215.
Phosphorylation of the histone family is not only a response to cell signaling stimuli, but also an important indicator of DNA damage preceding apoptotic changes. While astrocytic degeneration, including DNA damage, has been reported in Alzheimer disease (AD), its pathogenetic significance is somewhat unclear. In an effort to clarify this, we investigated the expression of γH2AX as evidence of DNA damage in astrocytes to elucidate the role of these cells in the pathogenesis of AD. In response to the formation of double-stranded breaks in chromosomal DNA, serine 139 on H2AX, a 14-kDa protein that is a member of the H2A histone family and part of the nucleosome structure, becomes rapidly phosphorylated to generate γH2AX. Using immunocytochemical techniques, we found significantly increased levels of γH2AX in astrocytes in regions know to be vulnerable in AD, i.e., the hippocampal regions and cerebral cortex. These results suggest that astrocytes contain DNA damage, possibly resulting in functional disability, which in turn reduces their support for neurons. These findings further define the role of astrocyte dysfunction in the progression of AD.
doi:10.1007/s11357-008-9050-7
PMCID: PMC2585649  PMID: 19424844
Alzheimer disease; Astrocytes; DNA damage; Neurodegeneration
14.  Does regular consumption of green tea influence expression of vascular endothelial growth factor and its receptor in aged rat erectile tissue? Possible implications for vasculogenic erectile dysfunction progression 
Age  2008;30(4):217-228.
Erectile dysfunction (ED) is a highly prevalent disease affecting millions of men worldwide with a tendency for widespread increase. ED is now considered an early manifestation of atherosclerosis and, consequently, a precursor of systemic vascular disease. Atherosclerosis and ED share potentially modifiable risk factors, as smoking or high-fat food intake, but it is unclear how regular consumption of anti-oxidant rich drinks, which exhibit recognised anti-atherosclerotic features, affects ED progression. The objective of this study was to evaluate the modulating effects of chronic consumption of catechin-rich beverages on the vascular structure of the rat corpus cavernosum, and how this could contribute to delay or prevention of the onset of ED. Male Wistar rats aged 12 months were treated with green tea (GT) or a green tea extract solution (GTE) as the only liquid source for 6 months. Consumption of GT and GTE led to decreased plasma androgen levels without any significant change in plasma lipid levels. A reduction in corpus cavernosum intracellular storage of lipids, associated with decreased expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR2 in endothelial cells, was observed. Taken together, these results suggest diminished atherosclerotic progression in cavernous tissue. However, functional studies will be necessary to elucidate if catechin-rich beverages are useful compounds in the prevention of deleterious vascular events associated with ED. It was also demonstrated that regular consumption of catechins reduces atherosclerotic progression and mortality due to cardiovascular disease. The results reported here suggest diminished atherosclerotic progression in cavernous tissue in aged rats following chronic ingestion of catechin-rich beverages.
doi:10.1007/s11357-008-9051-6
PMCID: PMC2585648  PMID: 19424845
Aging; Catechins; Erectile dysfunction; Testosterone; VEGF; VEGF receptors
15.  Design of aging intervention studies: the NIA interventions testing program 
Age  2008;30(4):187-199.
The field of biogerontology has made great strides towards understanding the biological processes underlying aging, and the time is ripe to look towards applying this knowledge to the pursuit of aging interventions. Identification of safe, inexpensive, and non-invasive interventions that slow the aging process and promote healthy aging could have a significant impact on quality of life and health care expenditures for the aged. While there is a plethora of supplements and interventions on the market that purport to slow aging, the evidence to validate such claims is generally lacking. Here we describe the development of an aging interventions testing program funded by the National Institute on Aging (NIA) to test candidate interventions in a model system. The development of this program highlights the challenges of long-term intervention studies and provides approaches to cope with the stringent requirements of a multi-site testing program.
doi:10.1007/s11357-008-9048-1
PMCID: PMC2585647  PMID: 19424842
Anti-aging; Lifespan; Longevity; Mice
16.  Pilot study for an age- and gender-based nutrient signaling system for weight control 
Age  2008;30(4):201-208.
Nutrient signaling has recently shown how nutraceuticals regulate specific functions of the brain and adipose tissue. In this pilot study to find an effective nutrient signaling system to cause weight loss, a double-blind placebo-controlled trial using leucine, olive oil, and fish oil was conducted on volunteers to signal metabolic and appetite effects to regulate body weight, while controls took only fiber. Men and women aged 18–26 and 39–62 years were given different dosages that they took orally twice daily for 14 days while recording body weight, followed by 2 weeks to check rebound. Most young men and women lost weight on low dose leucine and olive oil. Mature men required higher doses. Mature women’s weight was affected least, though results are consistent with a hypothesis that sufficient leucine and docosahexaenoic acid would be effective. Determining how age affects signaling pathways by nutrients will be important to reduce risk of chronic disease associated with age and obesity. This pilot study has led to hypotheses of practical strategies.
doi:10.1007/s11357-008-9049-0
PMCID: PMC2585646  PMID: 19424843
Leucine; Fish oil; Oleic acid; Branched chain amino acids; Docosahexaenoic acid; DHA; Olive oil; mTOR; Obesity; Weight loss
17.  Level of CD14+-endothelial progenitor cells is not associated with coronary artery disease or cardiovascular risk factors 
Age  2008;30(4):319-326.
There is evidence for two subpopulations among circulating endothelial progenitor cells (EPCs), i.e., CD34+-EPCs and CD14+-EPCs. Prior studies on the relationship between the level of EPCs and coronary artery disease (CAD), either did not distinguish between the two types of EPCs or studied only CD34+-EPCs. We therefore investigated whether the number of circulating CD14+-EPCs correlates with either CAD and/or cardiovascular risk factors. Circulating CD14+-EPCs—as defined by the surface markers CD14+KDR+—were analyzed by flow cytometry in 100 individuals [34 control subjects, 41 patients with stable CAD and 25 patients with acute coronary syndromes (ACS)]. The level of circulating CD14+-EPCs was not significantly different in patients with normal coronary arteries compared to those with stable CAD or ACS. Neither was there any association between the severity of CAD or risk factors and the number of circulating CD14+-EPCs. Thus, the number of circulating CD14+-EPCs was not significantly correlated either with the severity of coronary disease or with cardiovascular risk factors.
doi:10.1007/s11357-008-9074-z
PMCID: PMC2585645  PMID: 19424856
Endothelial progenitor cells; Coronary disease; Risk factors; CD14+KDR+ cells; Monocytes
18.  For prediction of elder survival by a Gompertz model, number dead is preferable to number alive 
Age  2008;30(4):311-317.
The standard Gompertz equation for human survival fits very poorly the survival data of the very old (age 85 and above), who appear to survive better than predicted. An alternative Gompertz model based on the number of individuals who have died, rather than the number that are alive, at each age, tracks the data more accurately. The alternative model is based on the same differential equation as in the usual Gompertz model. The standard model describes the accelerated exponential decay of the number alive, whereas the alternative, heretofore unutilized model describes the decelerated exponential growth of the number dead. The alternative model is complementary to the standard and, together, the two Gompertz formulations allow accurate prediction of survival of the older as well as the younger mature members of the population.
doi:10.1007/s11357-008-9073-0
PMCID: PMC2585644  PMID: 19424855
Centenarians; Death rate; Gerontology; Gompertz survival; Mortality rate; Supercentenarians
19.  Advanced glycation end-products in senile diabetic and non-diabetic patients with cardiovascular complications 
Age  2008;30(4):303-309.
Advanced glycation end products (AGEs) have been reported to contribute to aging and cardiovascular complications. In the present study, the immunoreactivity of AGEs in human serum samples of healthy older subjects (n = 31), senile diabetic patients without cardiovascular complications (n = 33), senile diabetic patients with cardiovascular complications (n = 32), senile non-diabetic patients with cardiovascular complications (n = 30) ,and healthy young subjects (n = 31) were investigated. The patients were selected on clinical grounds from the National Institute of Cardiovascular Disease, Karachi and the Jinnah Postgraduate Medical Centre, Karachi, Pakistan. Fasting blood glucose, HbA1C and serum fructosamine levels were significantly (P < 0.001) increased in senile diabetic patients with and without cardiovascular complications as compared to non-diabetic senile patients with cardiovascular complications and healthy older subjects. Additionally, serum AGEs were found to be significantly (P < 0.001) increased in senile diabetic patients with cardiovascular complications and senile non-diabetic patients with cardiovascular complications, followed by diabetic patients without cardiovascular complications as compared to healthy older subjects and young control subjects. However, no significant difference was found in the senile diabetic patients without cardiovascular complications and senile non-diabetic patients with cardiovascular complications. In contrast to all four senile groups, serum AGEs were significantly (P < 0.001) lower in young control subjects. The AGEs distribution in the senile groups corroborates the hypothesis that the advanced glycation process might play a role in the development of cardiovascular complications, which are more severe in diabetic patients compared with non-diabetic patients with cardiovascular complications.
doi:10.1007/s11357-008-9072-1
PMCID: PMC2585643  PMID: 19424854
Advanced glycation end products; Cardiovascular complications; Senile; Diabetes; Aging
20.  Calorie restriction initiated at a young age activates the Akt/PKCζ/λ-Glut4 pathway in rat white adipose tissue in an insulin-independent manner 
Age  2008;30(4):293-302.
Calorie restriction (CR) may exert an anti-aging effect through a metabolic adaptation to limited energy intake. The present study investigated the effect of CR on insulin signaling in response to glucose load in the epididymal adipose tissue of male F344 rats at 7 and 22 months of age. Young and middle-aged rats were fed ad libitum (AL) or 30% CR diets for 4 months, underwent glucose tolerance tests and were sacrificed 15 min after an intraperitoneal glucose or saline injection to evaluate glucose-stimulated insulin response and subsequent activation of insulin signaling molecules in the adipose tissue. In the 7- and 22- month AL groups, glucose administration increased serum insulin levels and also increased phosphorylated (p) levels of the insulin receptor (IR), v-akt murine thymoma viral oncogene homolog (Akt), protein kinase C (PKC) ζ/λ and the membrane fraction of glucose transporter 4 (mGlut4). In contrast, in the 7-month CR group, p-Akt, p-PKCζ/λ and mGlut4 levels were upregulated without glucose stimulation; the glucose load augmented the p-IR level but there was no additional activation of the downstream molecules. In the 22-month CR group, these unexpected findings were not observed. In summary, basal levels of insulin signaling molecules such as p-Akt, p-PKCζ/λ, and mGlut4 were significantly increased with a low insulin response in the 7-month CR group. The present results suggest the presence of an age-specific insulin-independent mechanism that is induced by CR to regulate energy metabolism in white adipose tissue.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-008-9071-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-008-9071-2
PMCID: PMC2585642  PMID: 19424853
Calorie restriction; Aging; Glucose intolerance; Insulin signal; Adipose tissue
21.  High-dose statin use does not impair aerobic capacity or skeletal muscle function in older adults 
Age  2008;30(4):283-291.
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) are lipid-lowering agents widely employed for atherosclerosis prevention. HMG-CoA reductase blockade reduces skeletal muscle coenzyme Q10 (CoQ10) levels and mitochondrial respiratory chain activities and may produce mild to severe skeletal muscle myopathy. This study investigated whether high-dose statin treatment would result in measurably decreased exercise capacity in older men and women. Maximal oxygen consumption, aerobic endurance, oxygen uptake kinetics, maximal strength, muscular power, and muscular endurance were measured before and after 12 weeks of statin treatment (simvastatin, 80 mg/day) in nine men and one woman, ages 55–76 years, with LDL-cholesterol levels >3.3 mmol/l (mean = 4.2 ± 0.2 mmol/l). Myalgia symptoms were assessed every 4 weeks. As expected, statin treatment resulted in significant decreases in LDL- and total-cholesterol levels (P < 0.01) with no significant changes in HDL-cholesterol or triglyceride levels. No significant changes were observed in aerobic capacity, endurance, oxygen kinetics or any measures of muscle function. No subject reported symptoms of myalgia, cramps, or weakness during the study. In the absence of myalgia or myopathic symptoms, high-dose simvastatin treatment did not impair exercise capacity in hyperlipidemic older individuals. We conclude that decreases in intramuscular CoQ10, in most patients on high dose statin treatment may not be clinically relevant, due to inter-individual variability in the degree of CoQ10 depletion, sensitivity of muscle to decreases in CoQ10, or both.
doi:10.1007/s11357-008-9070-3
PMCID: PMC2585641  PMID: 19424852
Aging; Simvastatin; Vo2max; Strength; O2 uptake kinetics; Myalgia
22.  Relationship between oxidative and occupational stress and aging in nurses of an intensive care unit 
Age  2008;30(4):229-236.
Stressful conditions lead to formation of excessive reactive oxygen species (ROS) and cause oxidative stress and aging. The aim of this study was to determine superoxide dismutase (SOD) and catalase (CAT) activity, and malondialdehyde (MDA) levels in nurses of a hospital intensive care unit according to demographic and occupational parameters, and to analyse the relationship with aging. Thirty-two nurses working in an intensive care unit and 35 aged-matched healthy individuals of both sexes as a control group were surveyed. No significant variations with respect to sex were detected in SOD, CAT, MDA and burnout levels. MDA levels increased with age in both the control group and the nurses, and we observed significant differences in MDA levels between the control group and nurses for all age groups. Significant variations in MDA levels were detected between single (286.12 ± 8.41) and married (318.82 ± 6.02), people, between those who frequently practice some kind of sport (281.41 ± 7.32) and those who never participate in sport (298.24 ± 8.11) ,and between those who frequently eat fruit and greens (289.75 ± 8.41) and those who never eat them (315.12 ± 7.21). Significant differences were detected between smokers and nonsmokers in SOD, CAT and MDA, but not for alcohol, coffee, tea or cola consumption. Higher SOD activity and MDA levels were detected in nurses on evening and night shifts (P < 0.01); these nurses also scored significantly higher on burnout subscales. These results suggest that: (1) occupational stress increases oxidative stress levels as a response to elevated ROS generation; (2) occupational stress increases MDA levels as a response to an elevation in free radical generation and can lead to aging; (3) working evening and night shifts increases oxidative and burnout levels. It is evident that preventive changes in job conditions and lifestyle are necessary to improve the quality of life of nurses who work in intensive care units.
doi:10.1007/s11357-008-9052-5
PMCID: PMC2585640  PMID: 19424846
Aging; Antioxidant enzymes; Burnout; Lipid peroxidation; Malondialdehyde; Oxidative stress; Occupational stress
23.  Energetics and longevity in birds 
Age  2008;30(2-3):75-87.
The links between energy expenditure and ageing are different at different levels of enquiry. When studies have examined the relationships between different species within a given class the association is generally negative—animals with greater metabolism per gram of tissue live shorter lives. Within species, or between classes (e.g. between birds and mammals) the association is the opposite—animals with higher metabolic rates live longer. We have previously shown in mammals that the negative association between lifespan and metabolic rate is in fact an artefact of using resting rather than daily energy expenditure, and of failing to adequately take into account the confounding effects of body size and the lack of phylogenetic independence of species data. When these factors are accounted for, across species of mammals, the ones with higher metabolism also have the largest lifetime expenditures of energy—consistent with the inter-class and intra-specific data. A previous analysis in birds did not yield the same pattern, but this may have been due to a lack of sufficient power in the analysis. Here we present an analysis of a much enlarged data set (>300 species) for metabolic and longevity traits in birds. These data show very similar patterns to those in mammals. Larger individuals have longer lives and lower per-gram resting and daily energy expenditures, hence there is a strong negative relationship between longevity and mass-specific metabolism. This relationship disappears when the confounding effects of body mass and phylogeny are accounted for. Across species of birds, lifetime expenditure of energy per gram of tissue based on both daily and resting energy expenditure is positively related to metabolic intensity, mirroring these statistical relationships in mammals and synergising with the positive associations of metabolism with lifespan within species and between vertebrate classes.
doi:10.1007/s11357-008-9054-3
PMCID: PMC2527636  PMID: 19424858
Birds; Daily energy expenditure; Lifespan; Phylogeny; Rate of living theory; Metabolic rate
24.  Rodents for comparative aging studies: from mice to beavers 
Age  2008;30(2-3):111-119.
After humans, mice are the best-studied mammalian species in terms of their biology and genetics. Gerontological research has used mice and rats extensively to generate short- and long-lived mutants, study caloric restriction and more. Mice and rats are valuable model organisms thanks to their small size, short lifespans and fast reproduction. However, when the goal is to further extend the already long human lifespan, studying fast aging species may not provide all the answers. Remarkably, in addition to the fast-aging species, the order Rodentia contains multiple long-lived species with lifespans exceeding 20 years (naked mole-rat, beavers, porcupines, and some squirrels). This diversity opens great opportunities for comparative aging studies. Here we discuss the evolution of lifespan in rodents, review the biology of slow-aging rodents, and show an example of how the use of a comparative approach revealed that telomerase activity coevolved with body mass in rodents.
doi:10.1007/s11357-008-9053-4
PMCID: PMC2527635  PMID: 19424861
Aging; Comparative studies; Rodents; Telomerase
25.  Explaining longevity of different animals: is membrane fatty acid composition the missing link? 
Age  2008;30(2-3):89-97.
Saturated and monounsaturated fatty acids are very resistant to peroxidative damage, while the more polyunsaturated a fatty acid, the more susceptible it is to peroxidation. Furthermore, the products of lipid peroxidation can oxidatively damage other important molecules. Membrane fatty acid composition is correlated with the maximum lifespans of mammals and birds. Exceptionally long-living mammal species and birds have a more peroxidation-resistant membrane composition compared to shorter-living similar-sized mammals. Within species, there are also situations in which extended longevity is associated with peroxidation-resistant membrane composition. For example, caloric restriction is associated more peroxidation-resistant membrane composition; long-living queens have more peroxidation-resistant membranes than shorter-living worker honeybees. In humans, the offspring of nonagenarians have peroxidation-resistant erythrocyte membrane composition compared to controls. Membrane fatty acid composition is a little appreciated but important correlate of the rate of aging of animals and the determination of their longevity.
doi:10.1007/s11357-008-9055-2
PMCID: PMC2527634  PMID: 19424859
Polyunsaturates; Monounsaturates; Lipid peroxidation; Maximum lifespan; Aging; Birds; Mammals; Honey bees; Human longevity

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