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jtitle_s:("Age (dodr)")
1.  Framingham cardiovascular disease risk scores and incident frailty: The English Longitudinal Study of Ageing 
Age (Dordrecht, Netherlands)  2014;36(4):9692.
Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95% confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74) respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.
doi:10.1007/s11357-014-9692-6
PMCID: PMC4129936  PMID: 25085033
frailty; cardiovascular risk; cohort; longitudinal study
2.  Framingham cardiovascular disease risk scores and incident frailty: the English longitudinal study of ageing 
Age  2014;36(4):9692.
Cross-sectional studies show that frailty is common in older people with cardiovascular disease. Whether older people at higher risk of developing cardiovascular disease are more likely to become frail is unclear. We used multinomial logistic regression to examine the prospective relation between Framingham cardiovascular disease risk scores and incidence of physical frailty or pre-frailty, defined according to the Fried criteria, in 1,726 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing who had no history of cardiovascular disease at baseline. Men and women with higher Framingham cardiovascular risk scores were more likely to become frail over the 4-year follow-up period. For a standard deviation higher score at baseline, the relative risk ratio (95 % confidence interval) for incident frailty, adjusted for sex and baseline frailty status, was 2.76 (2.18, 3.49). There was a significant association between Framingham cardiovascular risk score and risk of pre-frailty: 1.69 (1.46, 1.95). After further adjustment for other potential confounding factors, the relative risk ratios for frailty and pre-frailty were 2.15 (1.68, 2.75) and 1.50 (1.29, 1.74), respectively. The associations were unchanged after excluding incident cases of cardiovascular disease. Separate adjustment for each component of the risk score suggested that no single component was driving the associations between cardiovascular risk score and incident pre-frailty or frailty. Framingham cardiovascular risk scores may be useful for predicting the development of physical frailty in older people. We now need to understand the biological mechanisms whereby cardiovascular risk increases the risk of frailty.
doi:10.1007/s11357-014-9692-6
PMCID: PMC4129936  PMID: 25085033
Frailty; Cardiovascular risk; Cohort; Longitudinal study
3.  Physical capability and subsequent positive mental wellbeing in older people: findings from five HALCyon cohorts 
Age (Dordrecht, Netherlands)  2013;36(1):10.1007/s11357-013-9553-8.
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) five to ten years later. Data were drawn from five British cohorts participating in the HALCyon 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 (3 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.
doi:10.1007/s11357-013-9553-8
PMCID: PMC3818137  PMID: 23818103
physical capability; positive mental wellbeing; grip strength; walking speed; chair rise time
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
12.  Longitudinal impact of aging on muscle quality in middle-aged men 
Age  2014;36(4):9689.
The present follow-up study aims at assessing the longitudinal changes in muscle quality after an interval of 9.45 years in middle-aged men. In addition, the relative contribution of muscle mass, muscle strength, and muscle power at middle age to these changes was investigated. The results showed a small, though unexpected, increase in total body and leg muscle mass (respectively 0.22 ± 0.04 and 0.29 ± 0.06 % yearly, p < 0.0001), whereas basic strength (−0.71 to −0.87 % yearly, p < 0.0001) and velocity-dependent strength and power (−1.19 to −1.86 % yearly, p < 0.0001) declined. Consequently, muscle quality, defined as the ratio of basic strength or velocity-dependent strength and power to muscle mass decreased (−1.46 to −2.43 % yearly, p < 0.0001) from baseline to follow-up. We found that baseline basic strength is a strong determinant of the decline in muscle quality basic strength with advancing age, whereas only a small part of the age-associated decline in muscle quality based on velocity-dependent strength and power could be explained. To conclude, our results indicate that muscle becomes less efficient at middle age and that baseline muscle strength is a strong predictor of this change. These findings imply that unmeasured neural factors, influencing both contraction speed and the capacity of muscle to produce strength, are possibly other involved determinants. Therefore, timely interventions including strength training and higher-velocity strength training at middle age are recommended.
doi:10.1007/s11357-014-9689-1
PMCID: PMC4150881  PMID: 25104137
Sarcopenia; Dynapenia; Muscle function; Follow-up studies
13.  The skeletal muscle satellite cell response to a single bout of resistance-type exercise is delayed with aging in men 
Age  2014;36(4):9699.
Skeletal muscle satellite cells (SCs) have been shown to be instrumental in the muscle adaptive response to exercise. The present study determines age-related differences in SC content and activation status following a single bout of exercise. Ten young (22 ± 1 years) and 10 elderly (73 ± 1 years) men performed a single bout of resistance-type exercise. Muscle biopsies were collected before and 12, 24, 48, and 72 h after exercise. SC content and activation status were assessed in type I and type II muscle fibers by immunohistochemistry. Myostatin and MyoD protein and messenger RNA (mRNA) expression were determined by Western blotting and rtPCR, respectively. In response to exercise, it took 48 h (young) and 72 h (elderly) for type II muscle fiber SC content to exceed baseline values (P < 0.01). The number of myostatin + SC in type I and II muscle fibers was significantly reduced after 12, 24, and 48 h of post-exercise recovery in both groups (P < 0.01), with a greater reduction observed at 24 and 48 h in the young compared with that in the elderly men (P < 0.01). In conclusion, the increase in type II muscle fiber SC content during post-exercise recovery is delayed with aging and is accompanied by a blunted SC activation response.
doi:10.1007/s11357-014-9699-z
PMCID: PMC4150882  PMID: 25108351
Muscle stem cells; Myostatin; MyoD; Myogenin
14.  Diphenyl diselenide-supplemented diet and swimming exercise enhance novel object recognition memory in old rats 
Age  2014;36(4):9666.
The benefits of exercise and the element selenium on mental health and cognitive performance are well documented. The purpose of the present study was to investigate whether the intake of a diet supplemented with diphenyl diselenide [(PhSe)2] and the swimming exercise could enhance memory in old Wistar rats. Male Wistar rats (24 months) were fed daily with standard diet chow or standard chow supplemented with 1 ppm of (PhSe)2 during 4 weeks. Animals were submitted to swimming training with a workload (3 % of body weight, 20 min/day for 4 weeks). After 4 weeks, the object recognition test (ORT) and the object location test (OLT) were performed. The results of this study demonstrated that intake of a supplemented diet with (PhSe)2 and swimming exercise was effective in improving short-term and long-term memory as well as spatial learning, increasing the hippocampal levels of phosphorylated cAMP-response element-binding protein (CREB) in old rats. This study also provided evidence that (PhSe)2-supplemented diet facilitated memory of old rats by modulating cAMP levels and stimulating CREB phosphorylation, without altering the levels of Akt.
doi:10.1007/s11357-014-9666-8
PMCID: PMC4150883  PMID: 24994534
Selenium; Organoselenium; Exercise; Memory; Age
15.  Associations between muscle strength, spirometric pulmonary function and mobility in healthy older adults 
Age  2014;36(4):9667.
Pathological obstruction in lungs leads to severe decreases in muscle strength and mobility in patients suffering from chronic obstructive pulmonary disease. The purpose of this study was to investigate the interdependency between muscle strength, spirometric pulmonary functions and mobility outcomes in healthy older men and women, where skeletal muscle and pulmonary function decline without interference of overt disease. A total of 135 69- to 81-year-old participants were recruited into the cross-sectional study, which was performed as a part of European study MyoAge. Full, partial and no mediation models were constructed to assess the interdependency between muscle strength (handgrip strength, knee extension torque, lower extremity muscle power), spirometric pulmonary function (FVC, FEV1 and FEF50) and mobility (6-min walk and Timed Up and Go tests). The models were adjusted for age, sex, total fat mass, body height and site of enrolment. Partial mediation models, indicating both direct and pulmonary function mediated associations between muscle strength and mobility, fitted best to the data. Greater handgrip strength was significantly associated with higher FVC, FEV1 and FEF50 (p < 0.05). Greater muscle power was significantly associated with better performance in mobility tests. Results suggest that decline in mobility with aging may be caused by decreases in both muscle strength and power but also mediated through decreases in spirometric pulmonary function. Future longitudinal studies are warranted to better understand how loss of function and mass of the respiratory muscles will affect pulmonary function among older people and how these changes are linked to mobility decline.
doi:10.1007/s11357-014-9667-7
PMCID: PMC4150884  PMID: 25073451
Spirometric pulmonary function; Spirometry; Handgrip strength; Knee extension torque; Lower extremity muscle power; Six-minute walk test; Timed Up and Go test
16.  Life-long caloric restriction does not alter the severity of age-related osteoarthritis 
Age  2014;36(4):9669.
Chronic adipose tissue inflammation and its associated adipokines have been linked to the development of osteoarthritis (OA). It has been shown that caloric restriction may decrease body mass index and adiposity. The objectives of this study were to investigate the effect of lifelong caloric restriction on bone morphology, joint inflammation, and spontaneously occurring OA development in aged mice. C57BL/NIA mice were fed either a calorie-restricted (CR) or ad libitum (AL) diet starting at 14 weeks of age. All mice were sacrificed at 24 months of age. Adipose tissue and knee joints were then harvested. Bone parameters of the joints were analyzed by micro-CT. OA and joint synovitis were determined using histology and semiquantitative analysis. Lifelong caloric restriction did not alter the severity of OA development in C57BL/NIA aged mice, and there was no difference in the total joint Mankin score between CR and AL groups (p = 0.99). Mice also exhibited similar levels of synovitis (p = 0.54). The bone mineral density of the femur and the tibia was comparable between the groups with a small increase in cancellous bone volume fraction in the lateral femoral condyle of the CR group compared with the AL group. Lifelong caloric restriction did not alter the incidence of OA or joint synovitis in C57BL/NIA mice, indicating that a reduction of caloric intake alone was not sufficient to prevent spontaneous age-related OA. Nonetheless, early initiation of CR continued throughout a life span did not negatively impact bone structural properties.
doi:10.1007/s11357-014-9669-5
PMCID: PMC4150885  PMID: 24981112
Osteoarthritis; Bone density; Synovitis; Inflammation; Osteoporosis
17.  Clustered granules present in the hippocampus of aged mice result from a degenerative process affecting astrocytes and their surrounding neuropil 
Age  2014;36(4):9690.
Clusters of pathological granular structures appear and progressively increase in number with age in the hippocampus of several mice strains, markedly in the senescence-accelerated mouse prone 8 mice. In the present work, we performed an ultrastructural study of these granules paying special attention to the first stages of their formation, which have not been previously explored. The analysis of the immature granules allowed concluding that granules are not simple accumulations of molecular waste but the result of a degenerative process involving principally astrocytic processes, although nearby neuronal structures can be also affected. The granule generation includes the instability of the plasmatic membranes and the appearance of abnormal membranous structures that form intracellular bubbles or blebs of variable sizes and irregular shapes. These structures and some organelles degenerate producing some membranous fragments, and an assembly process of the resulting fragments generates the dense-core nucleus of the mature granule. Moreover, we found out that the neo-epitope recently described in the mature granules and localised abundantly in the membranous fragments of their dense-core nucleus emerges in the first stages of the granule formation. On the other hand, with this study, we increase the evidences that each cluster of granules is formed by the granules comprised in one astrocyte. A better knowledge of the causes of the granule formation and the function of the neo-epitope will help in both the interpretation of the physiological significance of the granules and their contribution to the degenerating processes in aging brain.
doi:10.1007/s11357-014-9690-8
PMCID: PMC4150886  PMID: 25070375
Aging; Hippocampus; Astrocyte; Granules; Neo-epitope; Periodic acid–Schiff; SAMP8
18.  Association of exceptional parental longevity and physical function in aging 
Age  2014;36(4):9677.
Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited. The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance (p = 0.009) and gait speed (p = 0.002). Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.
doi:10.1007/s11357-014-9677-5
PMCID: PMC4150888  PMID: 24997018
Aging; Genetics; Longevity; Physical Function
19.  Acute effects of passive stretching of the plantarflexor muscles on neuromuscular function: the influence of age 
Age  2014;36(4):9672.
The acute effects of stretching on peak force (Fpeak), percent voluntary activation (%VA), electromyographic (EMG) amplitude, maximum range of motion (MROM), peak passive torque, the passive resistance to stretch, and the percentage of ROM at EMG onset (%EMGonset) were examined in 18 young and 19 old men. Participants performed a MROM assessment and a maximal voluntary contraction of the plantarflexors before and immediately after 20 min of passive stretching. Fpeak (−11 %), %VA (−6 %), and MG EMG amplitude (−9 %) decreased after stretching in the young, but not the old (P > 0.05). Changes in Fpeak were related to reductions in all muscle activation variables (r = 0.56–0.75), but unrelated to changes in the passive resistance to stretch (P ≥ 0.24). Both groups experienced increases in MROM and peak passive torque and decreases in the passive resistance to stretch. However, the old men experienced greater changes in MROM (P < 0.001) and passive resistance (P = 0.02–0.06). Changes in MROM were correlated to increases in peak passive torque (r = 0.717), and the old men also experienced a nonsignificant greater (P = 0.08) increase in peak passive torque. %EMGonset did not change from pre- to post-stretching for both groups (P = 0.213), but occurred earlier in the old (P = 0.06). The stretching-induced impairments in strength and activation in the young but not the old men may suggest that the neural impairments following stretching are gamma-loop-mediated. In addition, the augmented changes in MROM and passive torque and the lack of change in %EMGonset for the old men may be a result of age-related changes in muscle-tendon behavior.
doi:10.1007/s11357-014-9672-x
PMCID: PMC4150889  PMID: 24981113
Stretching-induced force deficit; Muscle activation; Range of motion; Stretch tolerance; Passive torque
20.  Peritoneal exudate cells from long-lived rats exhibit increased IL-10/IL-1β expression ratio and preserved NO/urea ratio following LPS-stimulation in vitro 
Age  2014;36(4):9696.
In humans, usual aging, differently from successful aging, is associated with deregulation of proinflammatory/anti-inflammatory cytokine balance. The corresponding data from rat studies are limited. Therefore, we examined (i) cytokine messenger RNA (mRNA) profile of fresh peritoneal cells from 6- (adult), 24- (old), and 31-month-old (long-lived) AO rats and (ii) proinflammatory (IL-1β and IL-6) and anti-inflammatory (IL-10) cytokine, NO, and urea production in their LPS-stimulated cultures. Comparing with adult rats, cells from old ones expressed lower amount of TNF-α and IL-6 mRNAs, but greater amount of IL-1β mRNA. On the other hand, cells from long-lived rats exhibited a dramatic increase in IL-10 mRNA expression followed by diminished TNF-α and IL-6 mRNA expression, and comparable expression of IL-1β mRNA relative to adult rats. Consequently, IL-10/IL-1β mRNA ratio was greater in cells from long-lived rats than in adult and old rats. In LPS-stimulated peritoneal cell cultures (contained ≥95 % macrophages) from old rats, concentration of common proinflammatory cytokines was higher than in those from adult rats. Comparing with adult and old rats, in LPS-stimulated macrophage cultures from long-lived rats, TNF-α and IL-6 concentrations were lower; IL-1β concentration was comparable or greater (in respect to adult rats), whereas that of IL-10 was strikingly higher. Consistently, in macrophage cultures from long-lived rats, NO (iNOS activity marker)/urea (arginase activity marker) ratio was less and not different from that in old and adult rats, respectively. The study suggests that macrophages from long-lived rats, differently from those of old ones, have substantial ability to limit proinflammatory mediator production, which may contribute to their longevity.
doi:10.1007/s11357-014-9696-2
PMCID: PMC4150890  PMID: 25081109
Aging; Macrophages; Proinflammatory cytokines; Anti-inflammatory cytokines; NO/urea balance; TLR4
21.  Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries 
Age  2014;36(4):9701.
The activation of the Pi3k-Akt1-FOXO pathway seems to be involved in the extended longevity observed in growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice and is related to the growth of primordial ovarian follicles. The aim of this work was to measure the expression of genes in the ovaries of GHRKO and normal (N) mice treated with phorbol 12-myristate 13-acetate (PMA), an inhibitor of GH and IRS1 signaling. For this study, a group of N (n = 10) and GHRKO (n = 10) mice, N mice treated (n = 10) or not (n = 10) with PMA, and GHRKO mice treated (n = 10) or not (n = 10) with PMA were used. All were 6-month-old female mice. After the last PMA injection, the ovaries were collected for gene expression analysis. Expression of Amh, Gdf9, and Bmp15 was higher in GHRKO than N mice (P < 0.05), but was not different between PMA-treated N mice (P > 0.10). Expression of Amh and Gdf9 was higher (P < 0.05) for GHRKO PMA-treated mice. In addition, we observed a higher expression of Socs3 (P < 0.001) in GHRKO than N mice and a tendency for increased expression of Foxo3a (P = 0.07). For GHRKO PMA-treated mice, Foxo3a mRNA expression was higher (P = 0.02) and a tendency for higher expression of Mtor (P = 0.06) and Socs3 (P = 0.10) in GHRKO PMA-treated mice was observed. To summarize, the present data further confirm the previous histological observations that GHRKO mice have an ovarian phenotype characteristic of younger mice indicated by higher expression of Amh, Gdf9, and Bmp15 mRNA. In addition, we have shown a higher expression of Socs3 in GHRKO mice and higher Foxo3a expression in PMA-treated GHRKO mice, suggesting a role for these mediators in the process of ovarian aging.
doi:10.1007/s11357-014-9701-9
PMCID: PMC4150892  PMID: 25099774
GHRKO; FOXO3a; AMH; Aging; Ovary
22.  Relationship between vitamin D and inflammatory markers in older individuals 
Age  2014;36(4):9694.
In older persons, vitamin D insufficiency and a subclinical chronic inflammatory status frequently coexist. Vitamin D has immune-modulatory and in vitro anti-inflammatory properties. However, there is inconclusive evidence about the anti-inflammatory role of vitamin D in older subjects. Thus, we investigated the hypothesis of an inverse relationship between 25-hydroxyvitamin D (25(OH)D) and inflammatory markers in a population-based study of older individuals. After excluding participants with high-sensitivity C-reactive protein (hsCRP) ≥ 10 mg/dl and those who were on chronic anti-inflammatory treatment, we evaluated 867 older adults ≥65 years from the InCHIANTI Study. Participants had complete data on serum concentrations of 25(OH)D, hsCRP, tumor necrosis factor (TNF)-α, soluble TNF-α receptors 1 and 2, interleukin (IL)-1β, IL-1 receptor antagonist, IL-10, IL-18, IL-6, and soluble IL-6 receptors (sIL6r and sgp130). Two general linear models were fit (model 1—adjusted for age, sex, and parathyroid hormone (PTH); model 2—including covariates of model 1 plus dietary and smoking habits, physical activity, ADL disability, season, osteoporosis, depressive status, and comorbidities). The mean age was 75.1 ± 17.1 years ± SD. In model 1, log(25OH-D) was significantly and inversely associated with log(IL-6) (β ± SE = −0.11 ± 0.03, p = <0.0001) and log (hsCRP) (β ± SE = −0.04 ± 0.02, p = 0.04) and positively associated with log(sIL6r) (β ± SE = 0.11 ± 0.04, p = 0.003) but not with other inflammatory markers. In model 2, log (25OH-D) remained negatively associated with log (IL-6) (β ± SE = −0.10 ± 0.03, p = 0.0001) and positively associated with log(sIL6r) (β ± SE = 0.11 ± 0.03, p = 0.004) but not with log(hsCRP) (β ± SE = −0.01 ± 0.03, p = 0.07). 25(OH)D is independently and inversely associated with IL-6 and positively with sIL6r, suggesting a potential anti-inflammatory role for vitamin D in older individuals.
doi:10.1007/s11357-014-9694-4
PMCID: PMC4150893  PMID: 25086618
Vitamin D; Inflammation; Inflammatory markers; Elderly subjects
23.  Life-long endurance running is associated with reduced glycation and mechanical stress in connective tissue 
Age  2014;36(4):9665.
Life-long regular endurance exercise is known to counteract the deterioration of cardiovascular and metabolic function and overall mortality. Yet it remains unknown if life-long regular endurance exercise can influence the connective tissue accumulation of advanced glycation endproducts (AGEs) that is associated with aging and lifestyle-related diseases. We therefore examined two groups of healthy elderly men: 15 master athletes (64 ± 4 years) who had been engaged in life-long endurance running and 12 old untrained (66 ± 4 years) together with two groups of healthy young men; ten young athletes matched for running distance (26 ± 4 years), and 12 young untrained (24 ± 3 years). AGE cross-links (pentosidine) of the patellar tendon were measured biochemically, and in the skin, it was assessed by a fluorometric method. In addition, we determined mechanical properties and microstructure of the patellar tendon. Life-long regular endurance runners (master athletes) had a 21 % lower AGE cross-link density compared to old untrained. Furthermore, both master athletes and young athletes displayed a thicker patellar tendon. These cross-sectional data suggest that life-long regular endurance running can partly counteract the aging process in connective tissue by reducing age-related accumulation of AGEs. This may not only benefit skin and tendon but also other long-lived protein tissues in the body. Furthermore, it appears that endurance running yields tendon tissue hypertrophy that may serve to lower the stress on the tendon and thereby reduce the risk of injury.
doi:10.1007/s11357-014-9665-9
PMCID: PMC4150896  PMID: 24997017
Master athletes; Life-long; Endurance training; AGE; Aging
24.  Age-associated alterations of cardiac structure and function in the female F344xBN rat heart 
Age  2014;36(4):9684.
The Fischer 344/NNiaHSD × Brown Norway/BiNia F1 (F344xBN) rat model exhibits an increased life span and fewer age-associated pathologies compared to commonly used Fischer 344 (F344). How aging may affect cardiac structure and function in these animals, has to our knowledge, not been investigated. Echocardiography was performed on female F344xBN rats at 6, 26, and 30 months of age using a Phillips 5500 Echocardiography system. Before sacrifice, electrocardiograms were measured in the female F344xBN in order to determine heart rhythm interval changes. Aging was associated with an increase in heart to body weight ratio, cardiomyocyte cross-sectional area, posterior wall thickening, and left ventricle chamber dilatation. Aging was associated with slight evidence of diastolic dysfunction. Alterations in heart rhythm intervals were associated with alterations in the spatial distribution of connexin 43. The incidence of arrhythmias was not different with age; however, valvular dysfunction was increased. These data suggest that aging in the female F344xBN rat heart is associated with changes in cardiac structure as well as function. Further investigation regarding other parameters of cardiac biochemistry and function is needed to better understand the normal compensated cardiovascular aging process in the female F344xBN.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-014-9684-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-014-9684-6
PMCID: PMC4150897  PMID: 25062714
Aging; Female; Echocardiography; Arrythmias; Connexin 43
25.  Effects of polyprenols from pine needles of Pinus massoniana on ameliorating cognitive impairment in a d-galactose-induced mouse model 
Age  2014;36(4):9676.
Cognitive deficiency and oxidative stress have been well documented in aging and in neurodegenerative disorders such as Alzheimer’s disease. In this study, we assessed the therapeutic effect of polyprenols on d-galactose-induced cognitive impairment in mice by testing on of behavioral and cognitive performance. In order to explore the possible role of polyprenols against d-galactose-induced oxidative damages, we assessed various biochemical indicators. Chronic administration of d-galactose (150 mg/kg·d, s.c.) for 7 weeks significantly impaired cognitive performance (both in step-through passive and active avoidance tests) and locomotor activity (in open-field test) and the ability of spatial learning and memory (in Morris water maze test) compared with the control group. The results revealed that polyprenols treatment for 2 weeks significantly ameliorated model mice’s cognitive performance and oxidative defense. All groups of polyprenols enhanced the learning and memory ability in step-through passive and active avoidance tests, locomotor activity in open-field test, and the ability of spatial learning and memory in Morris water maze test. Furthermore, high and middle level of polyprenols significantly increased total antioxidative capacity (T-AOC), glutathione peroxidase (GSH-Px), super oxide dismutase (SOD) activity, neprilysin (NEP), and β-site AβPP cleaving enzyme 1 (BACE1) expression, while nitric oxide (NO), nitric oxide synthase (NOS) activity, malondialdehyde (MDA) concentration, and the level of Aβ1-42 and presenilin 1 (PS1) were decreased. Polyprenols have a significant relieving effect on learning, memory, and spontaneous activities in a d-galactose-induced mouse model and ameliorates cognitive impairment and biochemical dysfunction in mice. In summary, we have demonstrated that polyprenols may ameliorate memory and cognitive impairment via enhancing oxidative defense and affecting generation and dissimilation of Aβ-related enzymes, suggesting that polyprenols represent a novel drug for treating Alzheimer’s disease.
doi:10.1007/s11357-014-9676-6
PMCID: PMC4150899  PMID: 24981114
Alzheimer’s disease; Polyprenols; d-galactose; Oxidative stress; Amyloid-beta (Aβ)

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