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3.  NK cell immunesenescence is increased by psychological but not physical stress in older adults associated with raised cortisol and reduced perforin expression 
Age  2015;37(1):11.
NK cell cytotoxicity (NKCC) reduces with age and this has been associated previously with increased mortality. The immune response is also modulated by stress, and here, we assessed the effect of the physical stress of hip fracture and the psychological stress of depression on NKCC in an aged immune system. NKCC was assessed in 101 hip fracture patients (81 female) 6 weeks and 6 months after injury and in 50 healthy age-matched controls (28 female). Thirty-eight patients were depressed at 6 weeks post-injury, and NKCC was reduced in patients who developed depression compared with non-depressed hip fracture patients (p = 0.004) or controls (p < 0.02). NKCC remained lower in the depressed patients compared to those without depression 6 months post-fracture (p = 0.017). We found reduced expression of perforin in NK cells of depressed hip fracture patients compared with controls at 6 weeks (p = 0.001) post-fracture. Serum cortisol levels were also elevated in patients with depression compared to non-depressed patients at 6 weeks (p = 0.01) and 6 months (p = 0.05). NK cells treated with dexamethasone showed a concentration-dependent reduction in NKCC and perforin expression. We propose that depression is the major factor affecting NK cell immunity after hip fracture.
doi:10.1007/s11357-015-9748-2
PMCID: PMC4320126  PMID: 25663421
NK cell; Stress; Immunesenescence; Cortisol
4.  Curcumin induces senescence of primary human cells building the vasculature in a DNA damage and ATM-independent manner 
Age  2015;37(1):7.
Curcumin is considered not only as a supplement of the diet but also as a drug in many types of diseases and even as a potential anti-aging compound. It can reduce inflammation that increases with age and accompanies almost all age-related diseases. It has been suggested that curcumin can play a beneficial role in the cardiovascular system. However, there are also data showing that curcumin can induce senescence in cancer cells, which is a beneficial effect in cancer therapy but an undesirable one in the case of normal cells. It is believed that cellular senescence accompanies age-related changes in the cardiovascular system. The aim of this study was to check if curcumin, in a certain range of concentrations, can induce senescence in cells building the vasculature. We have found that human vascular smooth muscle and endothelial cells derived from aorta are very sensitive to curcumin treatment and can senesce upon treatment with cytostatic doses. We observed characteristic senescence markers but the number of DNA damage foci decreased. Surprisingly, in vascular smooth muscle cell (VSMC) activation of DNA damage response pathway downstream of ataxia-telangiectasia mutated (ATM) was observed. ATM silencing and the supplementation of antioxidants, N-acetyl-L-cysteine (NAC) or trolox, did not reduce the number of senescent cells. Thus, we have shown that curcumin can induce senescence of cells building the vasculature, which is DNA damage and ATM independent and is not induced by increased reactive oxygen species (ROS) level. We postulate that an increase in the bioavailability of curcumin should be introduced very carefully considering senescence induction as a side effect.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-014-9744-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-014-9744-y
PMCID: PMC4315775  PMID: 25649709
Curcumin; Sirtuins; VSMCs; ECs; Aging; Atherosclerosis
5.  Mildly elevated blood pressure is a marker for better health status in Polish centenarians 
Age  2014;37(1):4.
The number of centenarians is projected to rise rapidly. However, knowledge of evidence-based health care in this group is still poor. Hypertension is the most common condition that leads to multiple organ complications, disability, and premature death. No guidelines for the management of high blood pressure (BP) in centenarians are available. We have performed a cross-sectional study to characterize clinical and functional state of Polish centenarians, with a special focus on BP. The study comprised 86 consecutive 100.9 ± 1.2 years old (mean ± SD) subjects (70 women and 16 men). The assessment included structured interview, physical examination, geriatric functional assessment, resting electrocardiography, and blood and urine sampling. The subjects were followed-up on the phone. Subjects who survived 180 days (83 %) as compared to non-survivors had higher systolic BP (SBP), diastolic BP (DPB), mean arterial pressure (MAP), pulse pressure (PP), higher mini-mental state examination, Barthel Index of Activities of Daily Living and Lawton Instrumental Activities of Daily Living Scale scores, higher serum albumin and calcium levels, and total iron-binding capacity, while lower serum creatinine, cystatin C, folate, and C-reactive protein levels. SBP ≥140 mm Hg, DBP ≥90 mm Hg, MAP ≥100 mm Hg, and PP ≥40 mm Hg were associated with higher 180-day survival probability. Results suggest that mildly elevated blood pressure is a marker for better health status in Polish centenarians.
doi:10.1007/s11357-014-9738-9
PMCID: PMC4312308  PMID: 25637333
Centenarians; Blood pressure; Cognitive performance; Physical performance
6.  Low resting metabolic rate is associated with greater lifespan because of a confounding effect of body fatness 
Age  2014;36(6):9731.
A negative association between resting metabolic rate (RMR) and lifespan is the cornerstone of the rate of living and free-radical damage theories of aging. Empirical studies supporting a negative association of RMR to lifespan may arise from the correlation between RMR and both daily energy expenditure (DEE) and thermoregulatory activity energy expenditure (TAEE). We screened 540 female mice for higher and lower DEE and measured RMR in the resulting 324 (60 %). We then selected 92 mice in which there was no link between residual from the regression of RMR against body mass (BM) and residual of DEE against BM to separate the effects of these traits. Lifespan was not significantly related to body mass, DEE and TAEE, but significantly negatively related to RMR. Fat-free mass (FFM) and fat mass (FM) were both significantly positively related to RMR. After removing the effect of FFM on RMR, the association between RMR and lifespan remained significantly negative; however, after statistically removing the effect of FM on RMR, the significant association between RMR and lifespan disappeared. We conclude that the negative association between RMR and lifespan is primarily due to the effect of FM, with FM positively related to both RMR and mortality and hence RMR negatively to lifespan. In 40 additional screened mice, greater FM was also associated with greater oxidative damage to DNA.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-014-9731-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-014-9731-3
PMCID: PMC4262579  PMID: 25502004
Metabolic rate; Lifespan; Body composition; Fat mass; Oxidative damage; Mice
7.  Spatial reversal learning is impaired by age in pet dogs 
Age  2013;35(6):2273-2282.
Aged dogs spontaneously develop progressive decline in both cognitive and behavioral function, in addition to neuropathological changes, that collectively parallel several aspects of human aging and Alzheimer’s disease progression and likely contribute to the development of canine cognitive dysfunction syndrome. In the current study, ethologically relevant spatial learning, retention, and reversal learning tasks were conducted, with the goal of expanding canine neuropsychological testing to pet dogs. Initially, dogs (N = 44, aged 7.8 ± 2.8 years, mean ± SD) had to learn which of two alternative routes successfully led out of a T-maze. Two weeks later, long-term memory retention was assessed, immediately followed by a reversal learning task in which the previously correct route out of the maze was reversed compared with the initial learning and memory retention tasks. No effects of age were evident on the learning or retention tasks. However, older (≥8 years) dogs were significantly impaired on the reversal learning task compared with younger ones (<8 years). Moreover, trial response latency was significantly increased in aged dogs across both the initial and reversal learning tasks but not on the retention task, which suggests that processing speed was impaired by increasing age during the acquisition of novel spatial information but not during performance of previously learned responses. Overall, the current study provides a framework for assessing cognitive function in pet dogs, which should improve understanding of the effects of aging on cognition in the dog population.
doi:10.1007/s11357-013-9524-0
PMCID: PMC3824977  PMID: 23529504
Aging; Cognitive impairment; Pet dog; Navigation task; Spatial cognition
8.  Neural stem cell- and neurogenesis-related gene expression profiles in the young and aged dentate gyrus 
Age  2013;35(6):2165-2176.
Hippocampal neurogenesis, important for memory and mood function, wanes greatly in old age. Studies in rat models have implied that this decrease is not due to loss of neural stem cells (NSCs) in the subgranular zone of the dentate gyrus (DG) but rather due to an increased quiescence of NSCs. Additional studies have suggested that changes in the microenvironment, particularly declines in the concentrations of neurotrophic factors, underlie this change. In this study, we compared the expression of 84 genes that are important for NSC proliferation and neurogenesis between the DG of young (4 months old) and aged (24 months old) Fischer 344 rats, using a quantitative real-time polymerase chain reaction array. Interestingly, the expression of a vast majority of genes that have been reported previously to positively or negatively regulate NSC proliferation was unaltered with aging. Furthermore, most genes important for cell cycle arrest, regulation of cell differentiation, growth factors and cytokine levels, synaptic functions, apoptosis, cell adhesion and cell signaling, and regulation of transcription displayed stable expression in the DG with aging. The exceptions included increased expression of genes important for NSC proliferation and neurogenesis (Stat3 and Shh), DNA damage response and NF-kappaB signaling (Cdk5rap3), neuromodulation (Adora1), and decreased expression of a gene important for neuronal differentiation (HeyL). Thus, age-related decrease in hippocampal neurogenesis is not associated with a decline in the expression of selected genes important for NSC proliferation and neurogenesis in the DG.
doi:10.1007/s11357-012-9507-6
PMCID: PMC3824978  PMID: 23322452
Aging; Hippocampus; Dentate gyrus; Dentate neurogenesis; Genes; Gene expression; Hippocampal neurogenesis; Neural stem cells; Stem cells and aging; qRT-PCR
9.  Association between polymorphisms in the TRHR gene, fat-free mass, and muscle strength in older women 
Age  2013;35(6):2477-2483.
A previous genome-wide association study suggested that polymorphisms in the thyrotrophin-releasing hormone receptor (TRHR) gene contribute to fat-free mass (FFM) variation. The aim of the present study was to examine the association between polymorphisms in the TRHR gene with FFM and muscle strength in older women. Volunteers (n = 241; age = 66.65 ± 5.5 years) underwent quadriceps strength assessment using isokinetics and fat-free mass by dual-energy X-ray absorptiometry. TRHR polymorphisms and ancestry-informative markers were genotyped through standard procedures. No significant difference was observed for rs7832552. Regarding the rs16892496, ANCOVA revealed that appendicular fat-free mass (AFFM) and relative AFFM were significantly different between groups (p = 0.04 and p = 0.05, respectively). Individuals carrying A/A and A/C genotypes respectively showed, on average, an extra 1 kg and 900 g of AFFM when compared to C/C genotype carriers. Also, the C/C genotype group presented a significantly higher chance to have reduced muscle strength. The observations presented here provide further evidence that the rs16892496 polymorphism in the TRHR gene may play a role in FFM variation. Moreover, the results bring the novel insight that this genetic variant can present a modest contribution to muscle strength in older women.
doi:10.1007/s11357-013-9526-y
PMCID: PMC3824979  PMID: 23543262
Aging; Sarcopenia; Genetic variation
10.  Dietary fat modifies mitochondrial and plasma membrane apoptotic signaling in skeletal muscle of calorie-restricted mice 
Age  2012;35(6):2027-2044.
Calorie restriction decreases skeletal muscle apoptosis, and this phenomenon has been mechanistically linked to its protective action against sarcopenia of aging. Alterations in lipid composition of membranes have been related with the beneficial effects of calorie restriction. However, no study has been designed to date to elucidate if different dietary fat sources with calorie restriction modify apoptotic signaling in skeletal muscle. We show that a 6-month calorie restriction decreased the activity of the plasma membrane neutral sphingomyelinase, although caspase-8/10 activity was not altered, in young adult mice. Lipid hydroperoxides, Bax levels, and cytochrome c and AIF release/accumulation into the cytosol were also decreased, although caspase-9 activity was unchanged. No alterations in caspase-3 and apoptotic index (DNA fragmentation) were observed, but calorie restriction improved structural features of gastrocnemius fibers by increasing cross-sectional area and decreasing circularity of fibers in cross sections. Changing dietary fat with calorie restriction produced substantial alterations of apoptotic signaling. Fish oil augmented the protective effect of calorie restriction decreasing plasma membrane neutral sphingomyelinase, Bax levels, caspase-8/10, and −9 activities, while increasing levels of the antioxidant coenzyme Q at the plasma membrane, and potentiating the increase of cross-sectional area and the decrease of fiber circularity in cross sections. Many of these changes were not found when we used lard. Our data support that dietary fish oil with calorie restriction produces a cellular anti-apoptotic environment in skeletal muscle with a downregulation of components involved in the initial stages of apoptosis engagement, both at the plasma membrane and the mitochondria.
doi:10.1007/s11357-012-9492-9
PMCID: PMC3824980  PMID: 23179253
Apoptotic signaling; Calorie restriction; Dietary fat; Sarcopenia; Skeletal muscle
11.  Role of p38MAPK and oxidative stress in copper-induced senescence 
Age  2013;35(6):2255-2271.
In the present work, we indicate that copper is involved in the senescence of human diploid fibroblasts and we describe mechanisms to explain it. Using different techniques, we show for the first time an accumulation of copper in cells during replicative senescence. This accumulation seems to be co-localized with lipofuscin. Second, we observed that an incubation of cells with copper sulfate induced oxidative stress, antioxidant response and premature senescence. Antioxidant molecules reduced the appearance of premature senescence. Third, we found that Nrf2 transcription factor was activated and regulated the expression of genes involved in antioxidant response while p38MAPK regulated the appearance of premature senescence.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9521-3) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-013-9521-3
PMCID: PMC3824981  PMID: 23576095
Aging; Senescence; Copper; Metals; p38MAPK; Oxidative stress; Human fibroblasts
12.  Obestatin is associated to muscle strength, functional capacity and cognitive status in old women 
Age  2013;35(6):2515-2523.
Obestatin has been proposed to have anorexigenic and anti-ghrelin actions. The objective was to study obestatin concentrations in relation to handgrip strength, functional capacity and cognitive state in old women. The prospective study included 110 women (age, 76.93 ± 6.32) from the Mataró Ageing Study. Individuals were characterized by anthropometric variables, grip strength, Barthel and assessment of cognitive impairment [Mini Cognoscitive Examination (MCE) Spanish version], depressive status by the Geriatric Depression Scale (GDS) and frailty by the Fried criteria. Obestatin was measured by IRMA. Obestatin showed negative correlation to handgrip at basal time point (r = −0.220, p = 0.023) and at 2-year follow-up (r = −0.344, p = 0.002). Obestatin, divided into quartiles, showed a negative lineal association with handgrip: 11.03 ± 4.88 kg in first, 8.75 ± 4.08 kg in second, 8.11 ± 3.66 kg in third and 7.61 ± 4.08 kg in fourth quartile (p = 0.018). Higher obestatin levels were associated to increased weakness (categorized by handgrip of frailty criteria): 2.24 ± 0.42 ng/ml in weak vs. 1.87 ± 0.57 ng/ml in non-weak (p = 0.01). The decrease of either MCE or Barthel scores at 2-year follow-up was significantly higher in individuals in the fourth quartile of obestatin in comparison with individuals in the first quartile (p = 0.046 and p = 0.019, respectively). No association was found between obestatin and GDS score and neither with frailty as a condition. Obestatin is associated to low muscle strength, and impaired functional and cognitive capacity in old women participating in the Mataró Ageing Study.
doi:10.1007/s11357-013-9532-0
PMCID: PMC3824982  PMID: 23604919
Obestatin; Muscle strength; Functional capacity; Cognition
13.  The muscle protein synthetic response to the combined ingestion of protein and carbohydrate is not impaired in healthy older men 
Age  2013;35(6):2389-2398.
Aging is associated with a progressive decline in skeletal muscle mass. It has been hypothesized that an attenuated muscle protein synthetic response to the main anabolic stimuli may contribute to the age-related loss of muscle tissue. The aim of the present study was to compare the muscle protein synthetic response following ingestion of a meal-like amount of dietary protein plus carbohydrate between healthy young and older men. Twelve young (21 ± 1 years) and 12 older (75 ± 1 years) men consumed 20 g of intrinsically l-[1-13C]phenylalanine-labeled protein with 40 g of carbohydrate. Ingestion of specifically produced intrinsically l-[1-13C]phenylalanine-labeled protein allowed us to assess the subsequent incorporation of casein-derived amino acids into muscle protein. Blood samples were collected at regular intervals, with muscle biopsies obtained prior to and 2 and 6 h after protein plus carbohydrate ingestion. The acute post-prandial rise in plasma glucose and insulin concentrations was significantly greater in the older compared with the younger males. Plasma amino acid concentrations increased rapidly following drink ingestion in both groups. However, plasma leucine concentrations were significantly lower at t = 90 min in the older when compared with the young group (P < 0.05). Muscle protein-bound l-[1-13C]phenylalanine enrichments increased to 0.0071 ± 0.0016 and 0.0072 ± 0.0013 mole percent excess (MPE) at 2 h and 0.0229 ± 0.0016 and 0.0213 ± 0.0024 MPE at 6 h following ingestion of the intrinsically labeled protein in the young and older males, respectively, with no differences between groups (P > 0.05). We conclude that the use of dietary protein-derived amino acids for muscle protein synthesis is not impaired in healthy older men following intake of protein plus carbohydrate.
doi:10.1007/s11357-013-9522-2
PMCID: PMC3824983  PMID: 23529503
Skeletal muscle; Aging; Sarcopenia; Amino acids; Anabolic resistance
14.  Coffee, but not caffeine, has positive effects on cognition and psychomotor behavior in aging 
Age  2013;35(6):2183-2192.
The complex mixture of phytochemicals in fruits and vegetables provides protective health benefits, mainly through additive and/or synergistic effects. The presence of several bioactive compounds, such as polyphenols and caffeine, implicates coffee as a potential nutritional therapeutic in aging. Moderate (three to five cups a day) coffee consumption in humans is associated with a significant decrease in the risk of developing certain chronic diseases. However, the ability of coffee supplementation to improve cognitive function in aged individuals and the effect of the individual components in coffee, such as caffeine, have not been fully evaluated. We fed aged rats (19 months) one of five coffee-supplemented diets (0, 0.165, 0.275, 0.55, and 0.825 % of the diet) for 8 weeks prior to motor and cognitive behavior assessment. Aged rats supplemented with a 0.55 % coffee diet, equivalent to ten cups of coffee, performed better in psychomotor testing (rotarod) and in a working memory task (Morris water maze) compared to aged rats fed a control diet. A diet with 0.55 % coffee appeared to be optimal. The 0.165 % coffee-supplemented group (three cups) showed some improvement in reference memory performance in the Morris water maze. In a subsequent study, the effects of caffeine alone did not account for the performance improvements, showing that the neuroprotective benefits of coffee are not due to caffeine alone, but rather to other bioactive compounds in coffee. Therefore, coffee, in achievable amounts, may reduce both motor and cognitive deficits in aging.
doi:10.1007/s11357-012-9509-4
PMCID: PMC3824984  PMID: 23344884
Antioxidant; Anti-inflammatory; Spatial learning and memory; Chlorogenic acid
15.  TNF-α, IL6, and IL10 polymorphisms and the effect of physical exercise on inflammatory parameters and physical performance in elderly women 
Age  2013;35(6):2455-2463.
High levels of inflammatory mediators are associated with reduced physical capabilities and muscle function in the elderly. Single nucleotide polymorphisms (SNPs) may affect the expression and synthesis of these molecules, thus influencing the intensity of the inflammatory response and susceptibility to certain diseases. Physical exercise may attenuate age-related chronic inflammation and improve physical performance. This study evaluated the interaction between the SNP rs1800629 in TNF-α, rs1800795 in IL6, and rs1800896 in IL10 and the effect of physical exercise on physical performance and inflammation in elderly women. There was a significant interaction between rs1800629 and the effect of exercise on physical performance and between the combined 3-SNP genotype and changes in physical performance in response to exercise. These SNPs did not influence the effect of exercise on inflammatory parameters. Elderly women with a combination of genotypes associated with an anti-inflammatory profile (low TNF-α and IL-6 production, high IL-10 production) showed better physical performance independent of exercise modality, evidence of an interactive influence of genetic and environmental factors on improving physical performance in elderly women.
doi:10.1007/s11357-013-9515-1
PMCID: PMC3824985  PMID: 23430759
Polymorphism; Cytokines; Physical exercise; Elderly
16.  BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat 
Age  2012;35(6):2057-2070.
Neurotrophins are established molecular mediators of neuronal plasticity in the adult brain. We analyzed the impact of aging on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein isoforms, their receptors, and on the expression patterns of multiple 5′ exon-specific BDNF transcripts in the rat cortex and hippocampus throughout the life span of the rat (6, 12, 18, and 24 months of age). ProNGF was increased during aging in both structures. Mature NGF gradually decreased in the cortex, and, in 24-month-old animals, it was 30 % lower than that in adult 6-month-old rats. The BDNF expression did not change during aging, while proBDNF accumulated in the hippocampus of aged rats. Hippocampal total BDNF mRNA was lower in 12-month-old animals, mostly as a result of a decrease of BDNF transcripts 1 and 2. In contrast to the region-specific regulation of specific exon-containing BDNF mRNAs in adult animals, the same BDNF RNA isoforms (containing exons III, IV, or VI) were present in both brain structures of aged animals. Deficits in neurotrophin signaling were supported by the observed decrease in Trk receptor expression which was accompanied by lower levels of the two main downstream effector kinases, pAkt and protein kinase C. The proteolytic processing of p75NTR observed in 12-month-old rats points to an additional regulatory mechanism in early aging. The changes described herein could contribute to reduced brain plasticity underlying the age-dependent decline in cognitive function.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9495-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9495-6
PMCID: PMC3824987  PMID: 23255148
Aging; BDNF and proBDNF; NGF and proNGF; BDNF mRNA isoforms; Cortex and hippocampus
17.  Asymmetric dimethylarginine predicts survival in the elderly 
Age  2013;35(6):2465-2475.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase implicated in several age-related biological mechanisms such as telomere shortening and cell senescence. We tested the hypothesis that ADMA blood level is an independent predictor of mortality in elderly. This is a longitudinal population-based cohort study. Participants are a representative cohort of 1,025 men and women (age range 65–102 years) living in Chianti area, Tuscany, Italy. The plasma ADMA was measured by liquid chromatography–tandem mass spectrometry. During the follow-up (95 ± 32 months), 384 individuals died, of whom 141 (37 %) died of cardiovascular (CV) causes. In adjusted analyses, the plasma ADMA was the strongest predictor of all-cause mortality (HR (0.1 μMol/L) 1.26, 95 % CI 1.10–1.44, P < 0.001) with a non-significant trend for CV mortality (HR 1.22, P = 0.07). The predictive effect of the ADMA level on mortality was statistically significant among participants with low to low-normal l-arginine levels (≤60 μMol/L), but not in those with l-arginine >60 μMol/L. Notwithstanding the association of ADMA with all-cause mortality was robust, this biomarker failed to add predictive power to a simple model based on the risk factors in the elderly (area under the ROC curve 0.85 ± 0.01 vs. 0.84 ± 0.01). ADMA is a strong independent predictor of mortality in the older population, and l-arginine modifies the effect of ADMA on survival. The mechanisms for this association should be targeted by future studies.
doi:10.1007/s11357-013-9523-1
PMCID: PMC3824988  PMID: 23584888
ADMA; Elderly; Cardiovascular risk factor; Survival; Population study
18.  Polymorphisms of the WRN gene and DNA damage of peripheral lymphocytes in age-related cataract in a Han Chinese population 
Age  2013;35(6):2435-2444.
Werner syndrome is caused by mutations in the DNA repair Werner helicase (WRN) gene and characterized by accelerated aging including cataracts. Age-related cataract (ARC) cases (N = 504) and controls (N = 244) were recruited from a population-based study to evaluate the association of single-nucleotide polymorphisms (SNPs) of WRN and another DNA repair gene (human 8-oxoguanine DNA N-glycosylase 1) with ARC. Among the five SNPs tested, only WRN rs1346044 was found to be significantly associated between cases and controls before multiple-testing adjustment. The minor C allele of rs1346044 was associated with ARC with an odds ratio (OR) of 0.66, suggesting a protective role of the C allele for developing ARC. The stratification analysis on the subtypes of ARC showed that rs1346044 was significantly associated with cortical cataract, but not with nuclear, posterior subcapsular, and mixed types after multiple-testing adjustment (OR = 0.51, p < 0.01). The genetic model analysis showed that the results fit the dominant model (OR = 0.44, p < 0.001). The comet assay used to assess the extent of DNA damage in peripheral lymphocytes of ARC cases found that the DNA damage in lymphocytes from patients with CC genotype was significantly less than that in patients with TT genotype. We concluded that the C allele of rs1346044, a non-synonymous SNP resulting in the conversion of Cys to Arg at amino acid position 1367 of WRN, alters susceptibility to ARC, especially the cortical type of the disease, in the Han Chinese. The underlying mechanism of its protective role might be related to the improved DNA repair function.
doi:10.1007/s11357-013-9512-4
PMCID: PMC3824989  PMID: 23334603
Age-related cataract (ARC); WRN; Single-nucleotide polymorphism; Comet assay; DNA damage; Cortical cataract
19.  Attenuated mesangial cell proliferation related to store-operated Ca2+ entry in aged rat: the role of STIM 1 and Orai 1 
Age  2013;35(6):2193-2202.
Store-operated Ca2+ entry (SOCE) is a common and ubiquitous mechanism regulating Ca2+ influx into cells and participates in numerous biological processes including cell proliferation. Glomerular mesangial cells (GMCs) play a role in the regulation of the glomerular filtration rate. From a clinical point of view, many physiological functions alter with age. In the present study, we used angiotensin II, glucagon, and the sarco/endoplasmic reticulum membrane Ca2+ pump inhibitor thapsigargin to deplete the internal Ca2+ stores for the activation of SOCE. We found that SOCE was significantly attenuated in GMCs from aged (22-month-old) rats. The expression of SOCE-related components, stromal interaction molecule 1 (STIM 1) and Orai 1, in freshly isolated glomeruli notably decreased, and STIM 1 and Orai 1 puncta formation significantly reduced in primary-cultured GMCs in aged rats. Moreover, specific knockdown of STIM 1 and Orai 1 by small interfering RNA markedly suppressed SOCE and cell proliferation of GMCs isolated from young (3-month-old) rats. We conclude that the attenuation of GMCs proliferation can be attributed to the decreased SOCE partially caused by reduced expression of STIM 1 and Orai 1.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9511-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-013-9511-5
PMCID: PMC3824990  PMID: 23334602
Aging; STIM 1; Orai 1; Glomerular mesangial cell; Proliferation
20.  Age-related mobility loss is joint-specific: an analysis from 6,000 Flexitest results 
Age  2013;35(6):2399-2407.
Although aging is commonly linked to a reduction in joint range of motion, it is unclear if all body joints behave similarly. To address this issue, the main purpose of this study was to compare age-related loss of mobility of seven body joints. A total of 6,000 participants (3,835 men and 2,165 women) aged 5 to 92 years took part in this study. The maximal passive range of motion of 20 movements was evaluated by Flexitest, and each movement was scored from 0 to 4. Composite scores were obtained for each of seven joints and for overall flexibility (Flexindex (FLX)) by adding individual movement scores. Confirming previous findings, FLX systematically decreased with aging (p < .001), with female participants being more flexible for all ages (p < 0.001) and having a more gradual, 0.6 % vs. 0.8 %/year, age reduction (p < .001). Starting at 30 and 40 years, respectively, for male and female participants, the relative contribution of each composite joint score to FLX dramatically changed. Shoulder contribution to FLX male’s score went from 13.9 % at 28 years of age to only 5.2 % at 85 years of age. In general, proportionally, shoulder and trunk became less flexible, while elbow and knee mobility was preserved to a greater extent. Our findings indicated that age-related loss of mobility is rather joint-specific, which could be related to distinct routine usage patterns of the major body joints along life.
doi:10.1007/s11357-013-9525-z
PMCID: PMC3824991  PMID: 23529505
Aging; Flexibility; Range of motion; Hypermobility; Musculoskeletal fitness; Exercise
21.  Senescence-dependent impact of anti-RAGE antibody on endotoxemic liver failure 
Age  2013;35(6):2153-2163.
Aging often restricts the capacity of the immune system. Endotoxemia is characterized by an immune response initiated by a group of pattern recognition receptors including the receptor for advanced glycation end products (RAGE). The aim of this study was to clarify to which extent RAGE and its signaling pathways such as the so called mitogen-activated protein kinase (MAPK) pathways can contribute to the perpetuation of inflammation in the aging organism. We used senescence-accelerated-prone (SAMP8) and senescence-accelerated-resistant (SAMR1) mice and studied them at the age of 2 and 6 months. Livers of SAMP8 mice had significantly higher malondialdehyde concentrations and a modest reduction of glyoxalase-I expression. Consequently, the abundance of highly modified advanced glycation end products was increased in the liver and plasma of these mice. After galactosamine/lipopolysaccharide-induced acute liver injury, significant activation of the MAPK cascade was observed in both mouse strains. Administration of an anti-RAGE antibody diminished p42/44-phosphorylation as well as tissue injury in SAMP8 mice, whereas the identical treatment in SAMR1 mice leads to a significant increase in p42/44-phosphorylation and intensified liver injury. This observation suggests that dependent on the senescence of the organism, anti-RAGE antibody can have differential effects on the progression of endotoxemic liver failure.
doi:10.1007/s11357-012-9506-7
PMCID: PMC3824992  PMID: 23319363
Senescence; Oxidative stress; Advanced glycation end products; RAGE blockade; Inflammation
22.  Association between ultrasound measurements of muscle thickness, pennation angle, echogenicity and skeletal muscle strength in the elderly 
Age  2013;35(6):2377-2388.
The increase of elderly in our society requires simple tools for quantification of sarcopenia in inpatient and outpatient settings. The aim of this study was to compare parameters determined with musculoskeletal ultrasound (M-US) with muscle strength in young and elderly patients. In this prospective, randomised and observer blind study, 26 young (24.2 ± 3.7 years) and 26 old (age 67.8 ± 4.8 years) patients were included. Muscle thickness, pennation angle and echogenicity of all muscles of musculus quadriceps were measured by M-US and correlated with isometric maximum voluntary contraction force (MVC) of musculus quadriceps. Reproducibility of M-US measurements as well as simple and multiple regression models were calculated. Of all measured M-US variables the highest reproducibility was found for measurements of thickness (intraclass correlation coefficients, 85–97 %). Simple regression analysis showed a highly significant correlation of thickness measurements of all muscles of musculus quadriceps with MVC in the elderly and in the young. Multiple regression analysis revealed that thickness of musculus vastus medialis had the best correlation with MVC in the elderly. This study showed that measurement of muscle thickness, especially of musculus vastus medialis, by M-US is a reliable, bedside method for monitoring the extent of sarcopenia.
doi:10.1007/s11357-013-9517-z
PMCID: PMC3824993  PMID: 23456136
Musculoskeletal ultrasound; Muscle thickness; Pennation angle; Echogenicity; Skeletal muscle strength; Sarcopenia
23.  β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice 
Age  2013;35(6):2099-2109.
Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease all-cause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality. Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P < 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans.
doi:10.1007/s11357-012-9498-3
PMCID: PMC3824994  PMID: 23314750
Adrenoceptor; β-blocker; Longevity; Life span; Intracellular signaling; Epinephrine; Norepinephrine; Octopamine; Catecholamine
24.  Age-related neural correlates of cognitive task performance under increased postural load 
Age  2012;35(6):2111-2124.
Behavioral studies suggest that postural control requires increased cognitive control and visuospatial processing with aging. Consequently, performance can decline when concurrently performing a postural and a demanding cognitive task. We aimed to identify the neural substrate underlying this effect. A demanding cognitive task, requiring visuospatial transformations, was performed with varying postural loads. More specifically, old and young subjects performed mental rotations of abstract figures in a seated position and when standing on a force platform. Additionally, functional magnetic resonance imaging (fMRI) was used to identify brain regions associated with mental rotation performance. Old as compared to young subjects showed increased blood oxygenation level-dependent (BOLD) responses in a frontoparietal network as well as activations in additional areas. Despite this overall increased activation, they could still modulate BOLD responses with increasing task complexity. Importantly, activity in left lingual gyrus was highly predictive (r = −0.83, adjusted R2 = 0.65) of the older subjects' degree of success in mental rotation performance when shifting from a sitting to a standing position. More specifically, increased activation in this area was associated with better performance, once postural load increased.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-012-9499-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-012-9499-2
PMCID: PMC3824995  PMID: 23274853
Aging; Postural control; Mental rotation; Dual-tasking; fMRI
25.  Age- and gender-specific reference values of pulse wave velocity for African adults: preliminary results 
Age  2013;35(6):2345-2355.
Pulse wave velocity (PWV) is an independent predictor of cardiovascular (CV) risk. Higher PWV values have been observed in Africans; however, there are no established age- and gender-adjusted reference values for this population. Therefore, PWV was measured using a validated device (Complior SP) in 544 subjects recruited from an occupational cohort of employees of a public university in Angola. Since high blood pressure (BP) is an important factor influencing PWV, a subsample of 301 normotensive subjects (aged 22–72 years) was selected for this study. A subset of 131 individuals without CV risk factors was considered the healthy group (HG), while the entire group (n = 301) comprised the less healthy group (LHG). Predictors of PWV were evaluated using multiple regression analyses and age- and gender-specific percentile tables and curves were constructed. Age and PWV means were 36 ± 9.7 years and 6.6 ± 1.0 m/s in the HG, respectively, and 39.9 ± 10.2 years and 7.3 ± 1.3 m/s in the LHG. Age and plasma uric acid (UA) were the only significant PWV predictors in the HG, while age, mean BP (MBP), and gender showed significant prediction of PWV in the multiple regression analysis in the LHG. Age- and gender-adjusted reference values of PWV were provided for healthy and less healthy normotensive Africans. Considering the small sample size of our cohort, these preliminary results should be used cautiously until data on robust sample of the general population can be obtained.
doi:10.1007/s11357-012-9504-9
PMCID: PMC3824996  PMID: 23319362
Pulse wave velocity; Reference values; Africans

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