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1.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age  2013;36(1):445-456.
Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS) 5 to 10 years later. Data were drawn from five British cohorts participating in the Healthy Ageing across the Life Course research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10 % of a standard deviation (three studies, N = 3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-013-9553-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
Physical capability; Positive mental wellbeing; Grip strength; Walking speed; Chair rise time
2.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality; whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in 1 s, height FEV1), walking speed (2.44 m), cognitive function (memory and reasoning) and self-reported physical and mental functioning (SF-36) were available on 4,443 individuals, aged 50–74 years. In models adjusted for age, 1 standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta = 0.16, 95% CI: 0.13, 0.19), memory (beta = 0.09, 95% CI: 0.06, 0.12), reasoning (beta = 0.16, 95% CI: 0.13, 0.19) and self-reported physical functioning (beta = 0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), body mass index (BMI) and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good ‘summary’ measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Ageing; Lung function; Cognitive function; Physical function
3.  Association of lung function with physical, mental and cognitive function in early old age 
Age  2010;33(3):385-392.
Lung function predicts mortality, whether it is associated with functional status in the general population remains unclear. This study examined the association of lung function with multiple measures of functioning in early old age. Data are drawn from the Whitehall II study; data on lung function (forced expiratory volume in one second, height FEV1), walking speed (over 2.44 m), cognitive function (memory and reasoning), and self-reported physical and mental functioning (SF-36) were available on 4443 individuals, aged 50–74 years. In models adjusted for age, one standard deviation (SD) higher height-adjusted FEV1 was associated with greater walking speed (beta=0.16, 95% CI: 0.13, 0.19), memory (beta=0.09, 95% CI: 0.06, 0.12), reasoning (beta=0.16, 95% CI: 0.13, 0.19), and self-reported physical functioning (beta=0.13, 95% CI: 0.10, 0.16). Socio-demographic measures, health behaviours (smoking, alcohol, physical activity, fruit/vegetable consumption), BMI and chronic conditions explained two-thirds of the association with walking speed and self-assessed physical functioning and over 80% of the association with cognitive function. Our results suggest that lung function is a good “summary” measure of overall functioning in early old age.
doi:10.1007/s11357-010-9189-x
PMCID: PMC3168608  PMID: 20878489
Aged; Aging; physiology; psychology; Cognition; physiology; Female; Health Status; Humans; Lung; physiology; Male; Middle Aged; Spirometry; Walking; physiology; ageing; lung function; cognitive function; physical function
4.  The importance of cognitive ageing for understanding dementia 
Age  2010;32(4):509-512.
A third of those over 80 years of age are likely to have dementia, the lack of a cure requires efforts directed at prevention and delaying the age of onset. We argue here for the importance of understanding the cognitive ageing process, seen as the decline in various cognitive functions from adulthood to old age. The impact of age on cognitive function is heterogeneous and the identification of risk factors associated with adverse cognitive ageing profiles would allow well-targeted interventions, behavioural or pharmacological, to delay and reduce the population burden of dementia. A shift away from binary outcomes such as dementia assessed at one point in time in elderly populations to research on cognitive ageing using repeated measures of cognitive function and starting earlier in the life course would allow the sources of variability in ageing to be better understood.
doi:10.1007/s11357-010-9147-7
PMCID: PMC2980594  PMID: 20454932
Alzheimer’s disease; Dementia; Cognitive ageing
5.  The importance of cognitive aging for understanding dementia 
Age  2010;32(4):509-512.
A third of those over 80 years of age are likely to have dementia, the lack of a cure requires efforts directed at prevention and delaying the age of onset. We argue here for the importance of understanding the cognitive ageing process, seen as the decline in various cognitive functions from adulthood to old age. The impact of age on cognitive function is heterogeneous and the identification of risk factors associated with adverse cognitive ageing profiles would allow well targeted interventions, behavioural or pharmacological, to delay and reduce the population burden of dementia. A shift away from binary outcomes such as dementia assessed at one point in time in elderly populations to research on cognitive ageing using repeated measures of cognitive function and staring earlier in the lifecourse would allow the sources of variability in ageing to be better understood.
doi:10.1007/s11357-010-9147-7
PMCID: PMC2980594  PMID: 20454932
Aging; Alzheimer Disease; epidemiology; physiopathology; Cognition; Dementia; diagnosis; epidemiology; physiopathology; prevention & control; therapy; France; epidemiology; Humans; Prevalence; Risk Factors; World Health Organization
6.  Dehydroepiandrosterone and age-related cognitive decline 
Age  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
7.  Dehydroepiandrosterone and age-related cognitive decline 
Age (Dordrecht, Netherlands)  2009;32(1):61-67.
In humans the circulating concentrations of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) decrease markedly during aging, and have been implicated in age-associated cognitive decline. This has led to the hypothesis that DHEA supplementation during aging may improve memory. In rodents, a cognitive anti-aging effect of DHEA and DHEAS has been observed but it is unclear whether this effect is mediated indirectly through conversion of these steroids to estradiol. Moreover, despite the demonstration of correlations between endogenous DHEA concentrations and cognitive ability in certain human patient populations, such correlations have yet to be convincingly demonstrated during normal human aging. This review highlights important differences between rodents and primates in terms of their circulating DHEA and DHEAS concentrations, and suggests that age-related changes within the human DHEA metabolic pathway may contribute to the relative inefficacy of DHEA replacement therapies in humans. The review also highlights the value of using nonhuman primates as a pragmatic animal model for testing the therapeutic potential of DHEA for age-associate cognitive decline in humans.
doi:10.1007/s11357-009-9113-4
PMCID: PMC2829637  PMID: 19711196
Dehydroepiandrosterone; Cognitive decline; Intracrinology; Neurosteroidogenesis
10.  Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes 
Age  2011;35(2):419-429.
Factor structure analyses have revealed the presence of specific biological system markers in healthy humans and diseases. However, this type of approach in very old persons and in type 2 diabetes (T2DM) is lacking. A total sample of 2,137 Italians consisted of two groups: 1,604 healthy and 533 with T2DM. Age (years) was categorized as adults (≤65), old (66–85), oldest old (>85–98) and centenarians (≥99). Specific biomarkers of routine haematological and biochemical testing were tested across each age group. Exploratory factorial analysis (EFA) by principal component method with Varimax rotation was used to identify factors including related variables. Structural equation modelling (SEM) was applied to confirm factor solutions for each age group. EFA and SEM identified specific factor structures according to age in both groups. An age-associated reduction of factor structure was observed from adults to oldest old in the healthy group (explained variance 60.4% vs 50.3%) and from adults to old in the T2DM group (explained variance 57.4% vs 44.2%). Centenarians showed three-factor structure similar to those of adults (explained variance 58.4%). The inflammatory component became the major factor in old group and was the first one in T2DM. SEM analysis in healthy subjects suggested that the glucose levels had an important role in the oldest old. Factorial structure change during healthy ageing was associated with a decrease in complexity but showed an increase in variability and inflammation. Structural relationship changes observed in healthy subjects appeared earlier in diabetic patients and later in centenarians.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9348-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9348-8
PMCID: PMC3592946  PMID: 22174010
Ageing; Exploratory factor analysis; Structural equation modelling; Centenarians; Diabetic patients
11.  JAG1 and COL1A1 polymorphisms and haplotypes in relation to bone mineral density variations in postmenopausal Mexican-Mestizo Women 
Age  2011;35(2):471-478.
Osteoporosis is characterized by low bone mineral density (BMD). One of the most important factors that influence BMD is the genetic contribution. The collagen type 1 alpha 1 (COL1A1) and the JAGGED (JAG1) have been investigated in relation to BMD. The aim of this study was to investigate the possible association between two single-nucleotide polymorphisms (SNPs) of COL1A1, their haplotypes, and one SNP of JAG1 with BMD in postmenopausal Mexican-Mestizo women. Seven hundred and fifty unrelated postmenopausal women were included. Risk factors were recorded and BMD was measured in lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry. DNA was obtained from blood leukocytes. Two SNPs in COL1A1 (rs1800012 and rs1107946) and one in JAG1 (rs2273061) were studied. Real-time PCR allelic discrimination was used for genotyping. The differences between the means of the BMDs according to genotype were analyzed with covariance. Deviations from Hardy–Weinberg equilibrium were tested. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis of COL1A1 was conducted. Under a dominant model, the rs1800012 polymorphism of the COL1A1 showed an association with BMD of the lumbar spine (P = 0.021). In addition, analysis of the haplotype of COL1A1 showed that the G–G haplotype presented a higher BMD in lumbar spine. We did not find an association between the s1107946 and rs2273061 polymorphisms of the COL1A1 and JAG1, respectively. Our results suggest that the rs1800012 polymorphism of the COL1A1, in addition to one haplotype, were significantly associated with BMD variation in Mexican-Mestizo postmenopausal women.
doi:10.1007/s11357-011-9363-9
PMCID: PMC3592947  PMID: 22174012
Bone mineral density; Polymorphisms; COL1A1; JAG1; Haplotypes; Postmenopausal Mexican-Mestizo women
12.  Genomics of human health and aging 
Age  2011;35(2):455-469.
Despite notable progress of the candidate-gene and genome-wide association studies (GWAS), understanding the role of genes contributing to human health and lifespan is still very limited. We use the Framingham Heart Study to elucidate if recognizing the role of evolution and systemic processes in an aging organism could advance such studies. We combine throughput methods of GWAS with more detail methods typical for candidate-gene analyses and show that both lifespan and ages at onset of CVD and cancer can be controlled by the same allelic variants. The risk allele carriers are at highly significant risk of premature death (e.g., RR = 2.9, p = 5.0 × 10−66), onset of CVD (e.g., RR = 1.6, p = 4.6 × 10−17), and onset of cancer (e.g., RR = 1.6, p = 1.5 × 10−6). The mechanism mediating the revealed genetic associations is likely associated with biological aging. These aging-related phenotypes are associated with a complex network which includes, in this study, 62 correlated SNPs even so these SNPs can be on non-homologous chromosomes. A striking result is three-fold, highly significant (p = 3.6 × 10−10) enrichment of non-synonymous SNPs (N = 27) in this network compared to the entire qualified set of the studied SNPs. Functional significance of this network is strengthened by involvement of genes for these SNPs in fundamental biological processes related to aging (e.g., response to stimuli, protein degradation, apoptosis) and by connections of these genes with neurological (20 genes) and cardio-vascular (nine genes) processes and tumorigenesis (10 genes). These results document challenging role of gene networks in regulating human health and aging and call for broadening focus on genomics of such phenotypes.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9362-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9362-x
PMCID: PMC3592948  PMID: 22174011
Aging; Lifespan; Survival; Healthy aging; Gene networks
13.  Cognitive deficit is associated with phase advance of sleep–wake rhythm, daily napping, and prolonged sleep duration—a cross-sectional study in 2,947 community-dwelling older adults 
Age  2012;35(2):479-486.
This study aims to examine the phase advance of sleep–wake rhythm, napping habit, nocturnal sleep duration, prolonged sleep latency and insomnia and their relationship with cognitive function. This is a cross-sectional study. Participants in this study are 2,947 community-dwelling adults older than 65 years old. Measurements of mini-mental examination (MMSE) score, go-to-bed time, wake-up time, nocturnal sleep duration, prolonged sleep latency, napping, and insomnia were done. The mean (standard deviation) nocturnal sleep hours was 7.96 (1.39) h. Twenty-one percent and 16.2% of the participants complained of prolonged sleep latency longer than 1 h and insomnia, respectively. Fifty-six percent of the participants napped once or more than once weekly. With advancing age, the participants reported longer sleep duration (p < 0.001), went to bed earlier, and woke up earlier, which were significant both before and after adjustment. The participants who had lower MMSE score went to bed earlier and woke up earlier, which were statistically significant both before and after adjustment. An inverted U-shaped relationship was observed between MMSE score and napping frequency, p for tend 0.026.The MMSE score decreased when the sleep duration prolonged from 7 h to ≧10 h (p for trend 0.006). No trend was observed from the sleep duration <4 up to 7.9 h (p for trend 0.500). Modest age-independent phase advance of the sleep–wake rhythm is associated with lower cognitive function. Whether this is a manifestation of early pre-clinical dementia and whether its recognition with early stabilization can slow cognitive decline remain elusive.
doi:10.1007/s11357-011-9366-6
PMCID: PMC3592949  PMID: 22215376
Phase advance; Sleep/wake rhythm; Sleep duration; Dementia; Cognitive decline; Napping; Insomnia; Prolonged sleep latency
14.  Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats 
Age  2012;35(2):271-288.
The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequently responsible for chronic hyponatremia in the elderly due to age-related disruption of the inhibitory component of brain osmoregulatory mechanisms. Recent research has indicated that chronic hyponatremia is associated with gait disturbances, increased falls, and bone fragility in humans, and we have found that chronic hyponatremia causes increased bone resorption and reduced bone mineral density in young rats. In this study, we used a model of SIADH to study multi-organ consequences of chronic hyponatremia in aged rats. Sustained hyponatremia for 18 weeks caused progressive reduction of bone mineral density by DXA and decreased bone ash calcium, phosphate and sodium contents at the tibia and lumbar vertebrae. Administration of 10-fold higher vitamin D during the last 8 weeks of the study compensated for the reduction in bone formation and halted bone loss. Hyponatremic rats developed hypogonadism, as indicated by slightly lower serum testosterone and higher serum FSH and LH concentrations, markedly decreased testicular weight, and abnormal testicular histology. Aged hyponatremic rats also manifested decreased body fat, skeletal muscle sarcopenia by densitometry, and cardiomyopathy manifested as increased heart weight and perivascular and interstitial fibrosis by histology. These findings are consistent with recent results in cultured osteoclastic cells, indicating that low extracellular sodium concentrations increased oxidative stress, thereby potentially exacerbating multiple manifestations of senescence. Future prospective studies in patients with SIADH may indicate whether these multi-organ age-related comorbidities may potentially contribute to the observed increased incidence of fractures and mortality in this population.
doi:10.1007/s11357-011-9347-9
PMCID: PMC3592950  PMID: 22218780
Aged rats; Cardiomyopathy; Hypogonadism; Hyponatremia; Osteoporosis; Sarcopenia; Syndrome of inappropriate antidiuretic hormone secretion
15.  Effects of aging, antiaging calorie restriction and in vivo stimulation of autophagy on the urinary excretion of 8OHdG in male Sprague–Dawley rats 
Age  2012;35(2):261-270.
8-Hydroxy-2-deoxyguanosine (8OHdG) excreted into the urine is considered a marker of oxidative stress effect on DNA, and it is reported to be mainly produced by the DNA repair system. In previous works, we showed that autophagy was also involved in 8OHdG disposal through the degradation of oxidatively altered mitochondria. Here, we show that aging in Sprague–Dawley male rats is associated with a decline in the in vitro function of liver autophagy and a slight and not significant decrease in the urinary excretion of 8OHdG. In addition, we demonstrate that anti-aging caloric restriction maintains levels of both liver autophagy and urinary excretion of 8OHdG at very high levels throughout life. Finally, we show the in vivo stimulation of autophagy by the administration of an antilipolytic agent or everolimus, which rescues rats from the accumulation of 8OHdG in the liver mtDNA, also causes a dramatic increase in the urinary excretion of 8OHdG. The intensification of autophagy by the administration of the antilipolytic drugs to fasting rats faded progressively with increasing age, together with a reduced increase in 8OHdG output into the urine. It is concluded that the process of autophagy may play a major role in the disposal of 8OHdG with urine, and that the assay of 8OHdG levels in the urine before and after the stimulation of autophagy may provide a novel, non-invasive and safe procedure to monitor the in vivo functioning of the process.
doi:10.1007/s11357-011-9346-x
PMCID: PMC3592951  PMID: 22351421
Caloric restriction; Autophagy; Antilipolytic drugs; 8OHdG; Urine
16.  Age-related changes in nitric oxide activity, cyclic GMP, and TBARS levels in platelets and erythrocytes reflect the oxidative status in central nervous system 
Age  2012;35(2):331-342.
Aging is associated with an increased susceptibility to neurodegenerative disorders which has been linked to chronic inflammation. This process generates oxygen-reactive species, ultimately responsible for a process known as oxidative stress, leading to changes in nitric oxide (NO), and cyclic guanosine monophosphate (cyclic GMP) signaling pathway. In previous studies, we showed that human aging was associated with an increase in NO Synthase (NOS) activity, a decrease in basal cyclic GMP levels in human platelets, and an increase in thiobarbituric acid-reactant substances (TBARS) in erythrocytes. The aim of the present work was to evaluate NOS activity, TBARS and cyclic GMP levels in hippocampus and frontal cortex and its correlation to platelets and erythrocytes of 4-, 12-, and 24-month-old rats. The result showed an age-related decrease in cyclic GMP levels which was linked to an increase in NOS activity and TBARS in both central areas as well as in platelets and erythrocytes of rats. The present data confirmed our previous studies performed in human platelets and erythrocytes and validate NOS activity and cyclic GMP in human platelet as well as TBARS in erythrocytes as biomarkers to study age-related disorders and new anti-aging therapies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9365-7) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9365-7
PMCID: PMC3592952  PMID: 22278206
Nitric oxide; Aging; Cyclic GMP; TBARS; Peripheral markers
17.  Accelerated protein evolution analysis reveals genes and pathways associated with the evolution of mammalian longevity 
Age  2011;35(2):301-314.
The genetic basis of the large species differences in longevity and aging remains a mystery. Thanks to recent large-scale genome sequencing efforts, the genomes of multiple species have been sequenced and can be used for cross-species comparisons to study species divergence in longevity. By analyzing proteins under accelerated evolution in several mammalian lineages where maximum lifespan increased, we identified genes and processes that are candidate targets of selection when longevity evolves. We identified several proteins with longevity-specific selection patterns, including COL3A1 that has previously been related to aging and proteins related to DNA damage repair and response such as DDB1 and CAPNS1. Moreover, we found that processes such as lipid metabolism and cholesterol catabolism show such patterns of selection and suggest a link between the evolution of lipid metabolism, cholesterol catabolism, and the evolution of longevity. Lastly, we found evidence that the proteasome–ubiquitin system is under selection specific to lineages where longevity increased and suggest that its selection had a role in the evolution of longevity. These results provide evidence that natural selection acts on species when longevity evolves, give insights into adaptive genetic changes associated with the evolution of longevity in mammals, and provide evidence that at least some repair systems are selected for when longevity increases.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9361-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9361-y
PMCID: PMC3592953  PMID: 22205409
Aging; Evolutionary genomics; Protein evolution; Mammals; Proteasome
18.  Troponin T nuclear localization and its role in aging skeletal muscle 
Age  2011;35(2):353-370.
Troponin T (TnT) is known to mediate the interaction between Tn complex and tropomyosin (Tm), which is essential for calcium-activated striated muscle contraction. This regulatory function takes place in the myoplasm, where TnT binds Tm. However, recent findings of troponin I and Tm nuclear translocation in Drosophila and mammalian cells imply other roles for the Tn–Tm complex. We hypothesized that TnT plays a nonclassical role through nuclear translocation. Immunoblotting with different antibodies targeting the NH2- or COOH-terminal region uncovered a pool of fast skeletal muscle TnT3 localized in the nuclear fraction of mouse skeletal muscle as either an intact or fragmented protein. Construction of TnT3–DsRed fusion proteins led to the further observation that TnT3 fragments are closely related to nucleolus and RNA polymerase activity, suggesting a role for TnT3 in regulating transcription. Functionally, overexpression of TnT3 fragments produced significant defects in nuclear shape and caused high levels of apoptosis. Interestingly, nuclear TnT3 and its fragments were highly regulated by aging, thus creating a possible link between the deleterious effects of TnT3 and sarcopenia. We propose that changes in nuclear TnT3 and its fragments cause the number of myonuclei to decrease with age, contributing to muscle damage and wasting.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9368-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9368-4
PMCID: PMC3592954  PMID: 22189912
Troponin T; Nuclear localization; Skeletal muscle; Aging; Apoptosis; Nucleolus; RNA polymerase
19.  Angiotensin-converting enzyme inhibitors and incidence of mild cognitive impairment. The Italian Longitudinal Study on Aging 
Age  2011;35(2):441-453.
Midlife elevated blood pressure and hypertension contribute to the development of Alzheimer's disease (AD) and overall dementia. We sought to estimate whether angiotensin-converting enzyme inhibitors (ACE-Is) reduced the risk of developing mild cognitive impairment (MCI) in cognitively normal individuals. In the Italian Longitudinal Study on Aging, we evaluated 1,445 cognitively normal individuals treated for hypertension but without congestive heart failure from a population-based sample from eight Italian municipalities with a 3.5-year follow-up. MCI was diagnosed with current clinical criteria. Dementia, AD, and vascular dementia were diagnosed based on DSM-IIIR criteria, NINCDS–ADRDA criteria, and ICD-10 codes. Among 873 hypertension-treated cognitively normal subjects, there was no significant association between continuous exposure to all ACE-Is and risk of incident MCI compared with other antihypertensive drugs [hazard ratio (HR), 0.45, 95% confidence interval (CI), 0.16–1.28]. Captopril exposure alone did not significantly modify the risk of incident MCI (HR, 1.80, 95% CI, 0.39–8.37). However, the enalapril sub-group alone (HR, 0.17, 95% CI, 0.04 –0.84) or combined with the lisinopril sub-group (HR, 0.27, 95% CI, 0.08–0.96), another ACE-I structurally related to enalapril and with similar potency, were associated with a reduced risk of incident MCI. Study duration exposure to ACE-Is as a “class” was not associated with incident MCI in older hypertensive adults. However, within-class differences linked to different chemical structures and/or drug potencies may exist, with a possible effect of the enalapril and lisinopril sub-groups in reducing the risk of incident MCI.
doi:10.1007/s11357-011-9360-z
PMCID: PMC3592955  PMID: 22203459
Angiotensin-converting enzyme inhibitors; Mild cognitive impairment; Dementia; Antihypertensive drugs
20.  Inter-chromosomal level of genome organization and longevity-related phenotypes in humans 
Age  2012;35(2):501-518.
Studies focusing on unraveling the genetic origin of health span in humans assume that polygenic, aging-related phenotypes are inherited through Mendelian mechanisms of inheritance of individual genes. We use the Framingham Heart Study (FHS) data to examine whether non-Mendelian mechanisms of inheritance can drive linkage of loci on non-homologous chromosomes and whether such mechanisms can be relevant to longevity-related phenotypes. We report on genome-wide inter-chromosomal linkage disequilibrium (LD) and on chromosome-wide intra-chromosomal LD and show that these are real phenomena in the FHS data. Genetic analysis of inheritance in families based on Mendelian segregation reveals that the alleles of single nucleotide polymorphisms (SNPs) in LD at loci on non-homologous chromosomes are inherited as a complex resembling haplotypes of a genetic unit. This result implies that the inter-chromosomal LD is likely caused by non-random assortment of non-homologous chromosomes during meiosis. The risk allele haplotypes can be subject to dominant-negative selection primary through the mechanisms of non-Mendelian inheritance. They can go to extinction within two human generations. The set of SNPs in inter-chromosomal LD (N = 68) is nearly threefold enriched, with high significance (p = 1.6 × 10−9), on non-synonymous coding variants (N = 28) compared to the entire qualified set of the studied SNPs. Genes for the tightly linked SNPs are involved in fundamental biological processes in an organism. Survival analyses show that the revealed non-genetic linkage is associated with heritable complex phenotype of premature death. Our results suggest the presence of inter-chromosomal level of functional organization in the human genome and highlight a challenging problem of genomics of human health and aging.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9374-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9374-6
PMCID: PMC3592956  PMID: 22282054
Linkage disequilibrium; Non-Mendelian inheritance; Epistasis; Complex phenotypes; Longevity; Evolution; Quasi-linkage; Dominate-negative selection; Transmission ratio distortion
21.  DHEA, DHEA-S and cortisol responses to acute exercise in older adults in relation to exercise training status and sex 
Age  2011;35(2):395-405.
The aim of the present study was to investigate resting measures of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEA-S) and cortisol, and the response and recovery of these hormones to acute exercise, in male and female older adults of different exercise training status. Participants were 49 community-dwelling older adults (23 females) aged between 60 and 77 years who were either sedentary (n = 14), moderately active (n = 14) or endurance trained (n = 21). Participants undertook an acute bout of exercise in the form of an incremental submaximal treadmill test. The exercise lasted on average 23 min 49 s (SD = 2 min 8 s) and participants reached 76.5% (SD = 5.44) of the predicted maximal heart rate. Blood samples were collected prior to exercise, immediately, and 1 h post-exercise. DHEA levels significantly increased immediately post-exercise; however, DHEA-S levels only significantly increased in females. Cortisol significantly decreased immediately post-exercise and 1 h post-exercise compared to pre-exercise. There were no significant differences in resting hormone levels or hormonal responses to exercise between training status groups. The findings suggest that exercise can stimulate DHEA production in older adults and that hormonal responses to exercise differ between male and female older adults.
doi:10.1007/s11357-011-9345-y
PMCID: PMC3592957  PMID: 22105939
DHEA; DHEA-S; Cortisol; Acute exercise; Training status; Sex; Older adults
22.  The impact of age on the physical and cellular properties of the human limbal stem cell niche 
Age  2012;35(2):289-300.
The limbal niche in the corneoscleral junction of the eye, habitat of the limbal epithelial stem cells (LESC), facilitates corneal epithelial regeneration by providing physical support and chemical signalling. Anatomical structures within the limbus, namely, limbal epithelial crypts and focal stromal projections, are believed to function as a putative niche for LESCs. In this study, the impact of age on the topography of this niche was investigated. Also, the relationship between niche topography and limbal epithelial cell phenotype was assessed. Ex vivo imaging of the limbus in cadaveric tissue of donors aged from infancy to 90 years was carried out using electron and confocal microscopy. The data suggested that the area occupied by the crypts was sharply reduced after the age of 60 years. The niche microstructures also became smoother with donor age. The phenotypic assessment of cultured limbal epithelial cells harvested from donors of different ages showed that the levels of putative stem cell markers as well as telomerase activity and telomere length remained unchanged, regardless of niche topography. However, the colony forming efficiency of the cultures was significantly reduced with age (p < 0.05). This is the first comprehensive study of the effect of age on the structural and phenotypic characteristics of the human limbal niche. The results have a significant biological value as they suggest a correlation of limbal architecture with decline of re-epithelialisation rate in older patients. Overall, the data also suggest that LESCs harvested from younger donors may be more suitable for cultured LESC therapy production.
doi:10.1007/s11357-011-9359-5
PMCID: PMC3592958  PMID: 22252434
Stem cells; Cornea; Stem cell markers; Telomerase activity; Telomere length; Imaging
23.  Effect of Bcl-2 rs956572 SNP on regional gray matter volumes and cognitive function in elderly males without dementia 
Age  2011;35(2):343-352.
The Bcl-2 gene is a major regulator of neural plasticity and cellular resilience. A single-nucleotide polymorphism (SNP) in the Bcl-2 gene, Bcl-2 rs956572, significantly modulates the expression of Bcl-2 protein and cellular vulnerability to apoptosis. This study investigated the association between the Bcl-2 rs956572 SNP and brain structural abnormalities in non-demented elders, and to test the relationship between neuropsychological performance and regional gray matter (GM) volumes. Our sample comprised 97 non-demented elderly men with a mean age of 80.6 ± 5.6 years (range, 65 to 92 years). Cognitive test results, magnetic resonance imaging, and genotyping of Bcl-2 rs956572 were examined for each subject. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. Subjects with G homozygotes exhibited significantly worse performance in the language domain of the Cognitive Abilities Screening Instrument (CASI; p = 0.009). They also showed significantly smaller GM volumes in the right middle temporal gyrus (MTG) (BA 21), but larger GM volumes in the left precuneus (BA 31), right lingual gyrus (BA 18), and left superior occipital gyrus (BA 19) relative to A-allele carriers (p < 0.001). A trend toward a positive correlation between right MTG GM volumes and the language domain of CASI was also evident (r = 0.181; p = 0.081). The findings suggest that Bcl-2 rs956572 SNP may modulate cognitive function and regional GM volume in non-demented elderly men, and that this polymorphism may affect language performance through its effect on the right MTG.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9367-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9367-5
PMCID: PMC3592959  PMID: 22198673
Bcl-2; MRI; Volumetry; Cognition; Aged; Polymorphism
24.  The negative effect of prolonged somatotrophic/insulin signaling on an adult bone marrow-residing population of pluripotent very small embryonic-like stem cells (VSELs) 
Age  2012;35(2):315-330.
It is well known that attenuated insulin/insulin-like growth factor signaling (IIS) has a positive effect on longevity in several animal species, including mice. Here, we demonstrate that a population of murine pluripotent very small embryonic-like stem cells (VSELs) that reside in bone marrow (BM) is protected from premature depletion during aging by intrinsic parental gene imprinting mechanisms and the level of circulating insulin-like growth factor-I (IGF-I). Accordingly, an increase in the circulating level of IGF-I, as seen in short-lived bovine growth hormone (bGH)-expressing transgenic mice, which age prematurely, as well as in wild-type animals injected for 2 months with bGH, leads to accelerated depletion of VSELs from bone marrow (BM). In contrast, long-living GHR-null or Ames dwarf mice, which have very low levels of circulating IGF-I, exhibit a significantly higher number of VSELs in BM than their littermates at the same age. However, the number of VSELs in these animals decreases after GH or IGF-I treatment. These changes in the level of plasma-circulating IGF-I corroborate with changes in the genomic imprinting status of crucial genes involved in IIS, such as Igf-2-H19, RasGRF1, and Ig2R. Thus, we propose that a chronic increase in IIS contributes to aging by premature depletion of pluripotent VSELs in adult tissues.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-011-9364-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-011-9364-8
PMCID: PMC3592960  PMID: 22218782
VSELs; IGF-1; GH; Aging
25.  Chronic training increases blood oxidative damage but promotes health in elderly men 
Age  2012;35(2):407-417.
The objective of the present study was to investigate a large panel of oxidative stress biomarkers in long-term trained elderly men to analyse the effects of chronic training on an aged population. We collected blood samples from two groups of male volunteers older than 65 years who maintain a measure of functional independence: one group of sedentary subjects without a history of regular physical activity and the other of subjects who have sustained training, starting during middle age (mean training time = 49 ± 8 years). We studied morbidity and polypharmacy, as well as haematological parameters including red cell count, haemoglobin concentration, haematocrit, mean corpuscular volume, red cell distribution width and several oxidative biomarkers including protein carbonyl content and lipid peroxidation in plasma and erythrocytes, red blood cell H2O2-induced haemolysis test, plasma total antioxidant activity and the main antioxidant enzymes of erythrocytes: superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase. After adjusting for confounding factors, we observed an increase in all oxidative damage biomarkers in the plasma and erythrocytes of the long-term exercise group. However, we reported a decrease in the number of diseases per subject with statistical differences nearly significant (p = 0.061), reduced intake of medications per subject and lower levels of red cell distribution width in the chronic exercise group. These results indicate that chronic exercise from middle age to old age increases oxidative damage; however, chronic exercise appears to be an effective strategy to attenuate the age-related decline in the elderly.
doi:10.1007/s11357-011-9358-6
PMCID: PMC3592962  PMID: 22215375
Aging; Long-term training; Oxidative stress; Oxidative damage; Red blood cell distribution width

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