Older adults with osteoarthritis (OA) are more likely to experience increased fatigue following bouts of physical activity than those without OA. The highly “fatigable” nature of this population is problematic as it has been linked to OA severity and decreased function. This study examined the effects of engaging in standardized lab-based physical tasks on subsequent fatigue, pain, and activity in older adults with OA.
Thirty-five older adults with OA performed lab-based tasks (sweeping, grocery shopping, and walking) in 15-minute circuits until they felt too fatigued to continue. Fatigue and pain were self-reported (0–10 scale) following each circuit and at set intervals during a 4-day baseline (pretask) and a 5-day posttask home period. Activity was tracked via wrist-worn accelerometer. Multilevel modeling was used to examine levels and patterns of fatigue, pain, and activity across the study period.
The lab-based tasks altered subsequent levels and patterns of fatigue and activity but had no effects on pain. Compared with baseline, on the day of the lab-based tasks, fatigue was higher and more stable, and activity was significantly lower and dropped steadily toward evening. Activity returned to baseline levels and patterns by the day following the lab-based tasks while fatigue was lower for 3 days following task performance.
Among older adults with OA, a bout of standardized physical activity resulted in increased fatigue and reduced activity, but effects were short-lived. Future studies will need to identify factors that differentiate people who are particularly fatigable in order to target interventions.
Fatigue; Osteoarthritis; Activity; Fatigability; Older adults
Results of prospective studies examining the association between 25 hydroxyvitamin D
(25[OH]D) levels and cognitive decline have been inconsistent. We tested the hypothesis
that lower 25(OH)D levels are associated with a greater likelihood of cognitive
impairment and risk of cognitive decline.
The study is a cross-sectional and longitudinal analysis of a prospective cohort of
6,257 community-dwelling elderly women followed for 4 years. Global cognitive function
was measured by the Modified Mini-Mental State Examination and executive function was
measured by Trail Making Test Part B (Trails B). Cognitive impairment at baseline was
defined as a score >1.5 SD below the sample mean; cognitive decline
was defined as decline from baseline to follow-up >1 SD from mean
change in score.
Women with very low vitamin D levels had an increased odds of global cognitive
impairment at baseline: odds ratio (95% confidence interval), 1.60 (1.05–2.42) for
women with 25(OH)D <10 ng/mL (25 nmol/L) compared with those with 25(OH)D levels
≥30 ng/mL (75 nmol/L). Compared with women with baseline 25(OH)D level ≥30 ng/mL
(75 nmol/L), women with lower levels had an increased risk of global cognitive decline:
odds ratio (95% confidence interval), 1.58(1.12–2.22) for women with levels <10
ng/mL (25 nmol/L), and 1.31 (1.04–1.64) for those with levels 10–19.9 ng/mL
(25–49 nmol/L). Levels of 25(OH)D were not associated with executive cognitive
Low 25(OH)D levels among older women were associated with a higher odds of global
cognitive impairment and a higher risk of global cognitive decline.
Vitamin D; Cognitive decline; Executive function; Cohort studies; Risk factors in epidemiology
Heat shock protein (HSP)70 decreases with age. Often aging is associated with coincident
insulin resistance and higher blood glucose levels, which also associate with lower HSP70.
We aimed to understand how these factors interrelate through a series of experiments using
vervet monkeys (Chlorocebus aethiops sabaeous). Monkeys
(n = 284, 4–25 years) fed low-fat diets showed no
association of muscle HSP70 with age (r = .04, p
= .53), but levels were highly heritable. Insulin resistance was induced in vervet
monkeys with high-fat diets, and muscle biopsies were taken after 0.3 or 6 years. HSP70
levels were significantly greater after 0.3 years (+72%, p < .05)
but were significantly lower following 6 years of high-fat diet (−77%,
p < .05). Associations with glucose also switched from being
positive (r = .44, p = .03) to strikingly
negative (r = −.84, p < .001) with
increasing insulin resistance. In conclusion, a low-fat diet may preserve tissue HSP70 and
health with aging, whereas high-fat diets, insulin resistance, and genetic factors may be
more important than age for determining HSP70 levels.
Heat shock protein 70; Aging; Nonhuman primate; Western diet; Insulin resistance;
Obesity-related increases in multiple inflammatory markers may contribute to the
persistent subclinical inflammation common with advancing age. However, it is unclear if
a specific combination of markers reflects the underlying inflammatory state. We used
factor analysis to identify inflammatory factor(s) and examine their associations with
adiposity in older adults at risk for disability.
Adiponectin, CRP, IL-1ra, IL-1sRII, IL-2sRα, IL-6, IL-6sR, IL-8, IL-15, sTNFRI,
sTNFRII, and TNF-α were measured in 179 participants from the Lifestyle
Interventions and Independence for Elders Pilot (Mean ± SD age
77 ± 4 years, 76% white, 70% women). Body mass index, waist circumference, and
total fat mass were assessed by anthropometry and dual-energy x-ray absorptiometry.
IL-2sRα, sTNFRI, and sTNFRII loaded highest on the first factor (factor 1). CRP,
IL-1ra, and IL-6 loaded highest on the second factor (factor 2). Factor 2, but not
factor 1, was positively associated with 1-SD increments in waist
circumference (β = 0.160 ± 0.057, p = .005),
body mass index (β = 0.132 ± 0.053, p = .01),
and total fat mass (β = 0.126 ± 0.053, p =
.02) after adjusting for age, gender, race/ethnicity, site, smoking, anti-inflammatory
medications, comorbidity index, health-related quality of life, and physical function.
These associations remained significant after further adjustment for grip strength, but
only waist circumference remained associated with inflammation after adjusting for total
lean mass. There were no significant interactions between adiposity and muscle mass or
strength for either factor.
Greater total and abdominal adiposity are associated with higher levels of an
inflammatory factor related to CRP, IL-1ra, and IL-6 in older adults, which may provide
a clinically useful measure of inflammation in this population.
Aging; Adiposity; Inflammation; Muscle impairment; Factor analysis
Obesity is increasingly prevalent among older adults, yet little is known about the
impact of health behaviors on the trajectories of body weight in this age group.
We examined the effect of time-varying smoking, physical activity (PA), alcohol use,
and changes thereof, on the 14-year (1992–2006) trajectory of body- mass index
(BMI) in a cohort of 10,314 older adults from the Health and Retirements Study, aged
51–61 years at baseline. Hierarchical linear modeling (HLM) quantifies the effect
of smoking, PA, and alcohol use (user status, initiation and cessation) on intercept and
rate-of-change in BMI trajectory, and tests for variations in the strength of
association between each behavior and BMI.
Over 14 years (82,512 observations), BMI increased approximated by a quadratic
function. Smoking and PA (user status and initiation) were associated with significantly
lower BMI trajectories over time. Cessation of smoking and PA resulted in higher BMI
trajectories over time. The weight-gaining effect of smoking cessation increased, while
the strength of association between BMI trajectories and PA or alcohol use were constant
over time. Socio-economic and health status differences explained the effects of alcohol
use on BMI trajectory.
In older adults, smoking and PA, and changes thereof, vary in their long-term effect on
trajectories of BMI. Barring increases in PA levels, older smokers who quit today are
expected to gain significantly more weight than two decades ago. This knowledge is
essential for the design of smoking cessation, physical activityPA, and weight-control
interventions in older adults.
Trajectory of BMI; Health behaviors; Multilevel models; Longitudinal analysis
It is widely accepted that food consumption in humans declines with advanced age;
however, data from mice remain controversial. Based on our previous observation that mice
spill a considerable amount of food while eating, we hypothesized that increased food
spillage in old mice masks actual food intake. To investigate whether mice exhibit
age-associated declines in food consumption, we evaluated the actual food consumption of
C57BL/6 mice at various ages by measuring both the amount of food in the food receptacle
and the amount dropped to the cage bottom during feeding. We found that old mice dropped
significantly more food (36% ± 8%) than young mice (18% ± 5%), which led to
overestimations of food consumption, particularly in old mice. Although actual food
consumption decreased in very old mice, food intake per body weight did not significantly
change. These findings suggest that caution should be taken to accurately quantify food
consumption by aged animals.
Aging; C57BL/6 mice; Food consumption; Food spillage
A paucity of cancer in individuals with Alzheimer's disease (AD) and low rates of AD
in cancer survivors has been reported in epidemiological studies. Deregulation in opposite
directions of biological mechanisms, such as susceptibility to cell death, might be shared
in the two disorders. We analyzed lymphocytes from AD and skin cancer patients as well as
healthy controls and found significantly increased vulnerability of AD lymphocytes to
H2O2-induced apoptotic death and higher resistance to death of
skin cancer lymphocytes, due to reduced necrosis, as compared with healthy controls by
pairwise comparisons adjusted for age and sex. H2O2-induced death in
lymphocytes was caspase independent and significantly reduced by PARP-1 inhibition in all
three groups. These differences in the susceptibility to cell death observed for
lymphocytes from AD and skin cancer patients may be one of the mechanisms that help
explain the inverse correlation detected between these diseases in epidemiological
Alzheimer; Cancer; Cell death; Apoptosis; Necrosis
We evaluated the impact of long-term exercise on telomere dynamics in wild-derived short
telomere mice (CAST/Ei) over 1 year. We observed significant telomere shortening in liver
and cardiac tissues in sedentary 1-year-old mice compared with young (8 weeks) baseline
mice that were attenuated in exercised 1-year-old animals. In contrast, skeletal muscle
exhibited significant telomere shortening in exercise mice compared with sedentary and
young mice. Telomerase enzyme activity was increased in skeletal muscle of exercise
compared with sedentary animals but was similar in cardiac and liver tissues. We observed
significant age-related decreases in expression of telomere-related genes that were
attenuated by exercise in cardiac and skeletal muscle but not liver. Protein content of
TRF1 was significantly increased in plantaris muscle with age. In summary, long-term
exercise altered telomere dynamics, slowing age-related decreases in telomere length in
cardiac and liver tissue but contributing to shortening in exercised skeletal muscle.
Telomere length; Telomerase; Cast/Ei mice; Shelterin; Aging
Anemia has been associated with elevated cerebral blood flow (CBF) in animal models and
certain clinical conditions (eg, renal disease), but whether hemoglobin level variations
across a relatively normal range are associated with local or diffuse CBF changes is
unclear. We investigated whether lower hemoglobin is associated with regional increases
in relative CBF in older individuals, and if these increases occur in watershed
Seventy-four older nondemented adults underwent serial 15O water positron
emission tomography scans. Voxel-based analysis was used to investigate regional
relative CBF patterns in association with hemoglobin level and in individuals with and
without anemia. Analyses of cross-sectional relations between regional CBF and anemia
were performed separately at two time points, 2 years apart, to identify replicable
patterns of associations.
Restricting results to associations replicated across two cross-sectional analyses,
lower hemoglobin was associated with higher relative CBF within the middle/inferior
frontal, occipital, precuneus, and cerebellar regions. In addition, individuals with
anemia (n = 15) showed higher relative CBF in superior frontal,
middle temporal, hippocampal, and gyrus rectus regions than those without anemia. In
some regions (right superior temporal gyrus, left inferior frontal gyrus, midline
cuneus, and right precuneus); however, lower hemoglobin was associated with lower
In nondemented individuals, lower hemoglobin is associated with elevated relative CBF
in specific cortical areas but reduced CBF in other areas. Whether this association
between anemia and CBF in the absence of chronic diseases and in a normal physiologic
range is related to clinical endpoints warrants further study.
Cerebral blood flow; Anemia; PET; Aging
Age-associated influences on natural killer (NK) cell functions following cytokine
stimulation were examined in splenocytes from C57BL/6 mice. NK cells of both young and
aged mice exhibited significantly increased: interferon-γ production after
interleukin (IL)-12 or IL-15 alone or any combination of IL-12, IL-18, and IL-2;
cytotoxicity after IL-2 or IL-15; and granzyme B expression after IL-15. The only
significant age-associated differences were observed in interferon-γ production
after IL-15 or IL-12 + 18 + 2 and in granzyme B expression following IL-2 or
IL-15. Perforin expression did not increase following stimulation; however, NK cells from
aged mice expressed significantly higher levels than young mice. These results underscore
the complexity of the cytokine-induced functional activities of NK cells and illustrate
the differential response of NK cells from young and aged mice to cytokine
NK cells; Aging; Cytokines
In some older adults, higher blood pressure (BP) is associated with a lower risk of mortality. We hypothesized that higher BP would be associated with greater mortality in high-functioning elders and lower mortality in elders with lower functional status.
Participants were 1,562 Latino adults aged 60–101 years in the Sacramento Area Latino Study on Aging. Functional status was measured by self-reported walking speed, and BP was measured by automatic sphygmomanometer. Death information was determined from vital statistics records.
There were 442 deaths from 1998 to 2010; 53% were cardiovascular. Mean BP levels (mmHg) varied across fast, medium, and slow walkers: 136, 139, and 140 mmHg (systolic), p = .02 and 75, 76, and 77 mmHg (diastolic), p = .08, respectively. The relationship between systolic BP and mortality varied by self-reported walking speed: The adjusted hazard ratio for mortality in slow walkers was 0.96 per 10 mmHg higher systolic BP (95% confidence interval: 0.89, 1.02) and 1.29 (95% confidence interval: 1.08, 1.55) in fast walkers (p value for interaction <.001). We found a similar pattern for diastolic BP, although the interaction did not reach statistical significance; the adjusted hazard ratio per 10 mmHg higher diastolic BP was 0.89 (95% confidence interval: 0.78, 1.02) in slow walkers and 1.20 (95% confidence interval: 0.82, 1.76) in fast walkers (p value for interaction = .06).
In high-functioning older adults, elevated systolic BP is a risk factor for all-cause mortality. If confirmed in other studies, the assessment of functional status may help to identify persons who are most at-risk for adverse outcomes related to high BP.
Blood pressure; Functional status; Latinos
Maintaining spatial movement through the environment is an important feature of healthy aging. We examined whether being licensed to drive is associated with maintaining spatial movement in older persons initially reporting maximum spatial mobility.
From the Rush Memory and Aging Project, 571 nondemented, community-dwelling older persons were identified with (i) baseline data on driving status, (ii) baseline report of spatial mobility to the largest life space zone, and (iii) at least one annual follow-up evaluation. Incident constriction of life space was the primary outcome of interest.
Over an average follow-up of 4.3 years, 303 participants reported incident constriction of life space. In a proportional hazards model adjusted for age, sex, and education, having a valid driver's license at baseline was associated with a decreased hazard of reporting a life space constriction (hazard ratio = 0.39; 95% confidence interval = 0.29–0.54). Results were unchanged after controlling for number of vascular risk factors and vascular diseases, low visual acuity, social isolation, and gait speed. Of participants reporting incident life space constriction, 188 subsequently reported reexpansion of spatial mobility to the largest zone of life space. Having a valid driver's license was associated with a greater likelihood of life space recovery (hazard ratio = 2.00; 95% confidence interval = 1.27–3.17).
In older persons, having a valid driving license was associated with reduced hazard of reporting life space constriction and a greater likelihood of life space recovery if incident life space constriction occurred.
Driving; Life space; Spatial mobility; Elderly; Prospective cohort study
Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996–1997 and 2005–2006.
In 2005–2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996–1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005–2006 level, only level was associated with CVD events and mortality.
Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
Inflammation; Aging; Physical function; Cognitive function
Identify the neuroimaging correlates of parkinsonian signs in older adults living in the community.
Magnetic resonance imaging was obtained in 307 adults (82.9 years, 55% women, 39% blacks) concurrently with the Unified Parkinson Disease Rating scale—motor part. Magnetic resonance imaging measures included volume of whole-brain white matter hyperintensities and of gray matter for primary sensorimotor, supplementary motor, medial temporal areas, cerebellum, prefronto-parietal cortex, and basal ganglia.
About 25% of the participants had bradykinesia, 26% had gait disturbances, and 12% had tremor. Compared with those without, adults with any one of these signs were older, walked more slowly, had worse scores on tests of cognition, mood and processing speed, and higher white matter hyperintensities volume (all p ≤ .002). Gray matter volume of primary sensorimotor area was associated with bradykinesia (standardized odds ratio [95% confidence interval]: 0.46 [0.31, 0.68], p < .0001), and gray matter volume of medial temporal area was associated with gait disturbances (0.56 [0.42, 0.83], p < .0001), independent of white matter hyperintensities volume and age. Further adjustment for measures of muscle strength, cardiovascular health factors, cognition, processing speed, and mood or for gait speed did not substantially change these results.
Atrophy within primary sensorimotor and medial temporal areas might be important for development of bradykinesia and of gait disturbances in community-dwelling elderly adults. The pathways underlying these associations may not include changes in white matter hyperintensities volume, cognition, information processing speed, mood, or gait speed.
Bradykinesia; Gait disturbances; Brain MRI
Insulin-like growth factor 1 (IGF-1) stimulates cell proliferation and is crucial for
maintenance of somatic tissues. However, this effect is associated with the inhibition of
FOXO transcription factors and downregulation of antioxidative enzymes. In this study, we
compared the responses of primary dermal fibroblasts and human umbilical vein endothelial
cells with IGF-1 treatment. We found that IGF-1 primarily downregulated enzymatic
antioxidants in skin fibroblasts. However, human umbilical vein endothelial cells were
protected from an IGF-1–mediated decrease in antioxidative capacity. Moreover, IGF-1
also activated endothelial nitric oxide synthase in human umbilical vein endothelial
cells. These observations suggest a dichotomous role for IGF-1, which provides for growth
and repair needs of the soma, while attenuating the effect of oxidative stress on the
vasculature by activating endothelial nitric oxide synthase. This increases the production
of nitric oxide, an antiproliferative and, under certain circumstances, an antioxidant
agent. Findings could help clarify the role of IGF-1 in aging and longevity of lower
organisms, short-lived mammals, and humans.
Insulin/IGF-1 signaling; Oxidative stress; Molecular biology of aging
The application of proteomics methodology for analyzing human blood samples is of
increasing importance as a noninvasive method for understanding, detecting, and monitoring
disease. In particular, glycoproteomic analysis may be useful in the study of age-related
diseases and syndromes, such as frailty. This study demonstrates the use of methodology
for isolating plasma glycoproteins using lectins, comparing the glycoproteome by frailty
status using two-dimensional polyacrylamide gel electrophoresis and identifying
glycoproteins using mass spectrometry. In a pilot study, we found seven glycoproteins to
differ by at least twofold in prefrail compared with nonfrail older adults, including
haptoglobin, transferrin, and fibrinogen, consistent with known inflammatory and
hematologic changes associated with frailty. Enzyme-linked immunosorbent assay analysis
found that plasma transferrin concentration was increased in frail and prefrail older
adults compared with nonfrail, confirming our proteomic findings. This work provides
evidence for using a reproducible methodology for conducting clinical proteomic
comparative studies of age-related diseases.
To validate and extend the findings of a raised cut score of O’Bryant and
colleagues (O’Bryant SE, Humphreys JD, Smith GE, et al. Detecting dementia with
the mini-mental state examination in highly educated individuals. Arch
Neurol. 2008;65(7):963–967.) for the Mini-Mental State Examination in
detecting cognitive dysfunction in a bilingual sample of highly educated ethnically
Archival data were reviewed from participants enrolled in the National
Alzheimer's Coordinating Center minimum data set. Data on 7,093 individuals with 16
or more years of education were analyzed, including 2,337 cases with probable and
possible Alzheimer's disease, 1,418 mild cognitive impairment patients, and 3,088
nondemented controls. Ethnic composition was characterized as follows: 6,296 Caucasians,
581 African Americans, 4 American Indians or Alaska natives, 2 native Hawaiians or
Pacific Islanders, 149 Asians, 43 “Other,” and 18 of unknown origin.
Diagnostic accuracy estimates (sensitivity, specificity, and likelihood ratio) of
Mini-Mental State Examination cut scores in detecting probable and possible
Alzheimer's disease were examined. A standard Mini-Mental State Examination cut
score of 24 (≤23) yielded a sensitivity of 0.58 and a specificity of 0.98 in
detecting probable and possible Alzheimer's disease across ethnicities. A cut score
of 27 (≤26) resulted in an improved balance of sensitivity and specificity (0.79 and
0.90, respectively). In the cognitively impaired group (mild cognitive impairment and
probable and possible Alzheimer's disease), the standard cut score yielded a
sensitivity of 0.38 and a specificity of 1.00 while raising the cut score to 27 resulted
in an improved balance of 0.59 and 0.96 of sensitivity and specificity,
These findings cross-validate our previous work and extend them to an ethnically
diverse cohort. A higher cut score is needed to maximize diagnostic accuracy of the
Mini-Mental State Examination in individuals with college degrees.
Alzheimer's disease; Dementia diagnosis; Ethnicity; Language; Mini-Mental State Examination
Readmission is an important quality indicator following acute care hospitalization. We
examined factors associated with hospital readmission in persons with stroke following
postacute inpatient rehabilitation.
Prospective cohort study including 674 persons with stroke who received rehabilitation
at 11 facilities located in eight states and the District of Columbia. Measures included
hospital readmission within 3 months of discharge, sociodemographic characteristics,
length of stay, primary payment source, comorbidities, stroke type, standardized
assessments of motor and cognitive function, depressive symptoms, and social
Mean age was 71.5 years (SD = 10.5). Twenty-five percent of
patients reported high depressive symptoms. Overall, 18% (n =
122) of the sample was rehospitalized. Univariate analyses showed that people who were
rehospitalized were more likely (p < .05) to be non-Hispanic white,
married, demonstrate less functional independence at discharge, experience longer
lengths of stay in rehabilitation, and report more depressive symptoms and lower social
support. In the fully adjusted multivariable hierarchical generalized linear model,
motor functional status (OR = 0.98, 95% CI 0.96–0.99), depressive symptoms
(OR = 1.80, 95% CI 1.06–3.05), and social support (OR = 2.28, 95% CI
1.29–4.03) remained statistically significant. In addition, a
minority-by-depressive symptoms interaction term also reached statistical
Functional status, depressive symptoms, and social support were important predictors of
hospital readmission. These variables are not included in most administrative data sets.
Future research to develop useful risk-adjustment models for rehospitalization following
postacute inpatient rehabilitation services should include large diverse samples and
explore practical sources for additional meaningful information.
Outcomes; Quality indicators; Disability; Postacute
Weight loss in dementia contributes to morbidity and mortality but the distribution of
anthropometric change and its consistency between populations are less clear. Our aim
was to investigate and compare the associations of dementia with waist and upper arm
circumference in elders from seven low- and middle-income nations.
Cross-sectional surveys were conducted of 15,022 residents aged 65 years and older in
Cuba, Mexico, Venezuela, Peru, Dominican Republic, China, and India. Dementia was
assessed using a cross-culturally validated algorithm, and anthropometric measurements
were taken. Associations with dementia and dementia severity (clinical dementia rating
scale) were investigated in linear regression models, with fixed-effects meta-analyses
used to investigate between-country heterogeneity.
Dementia and increased dementia severity were both associated with smaller arm and
waist circumferences with little evidence of confounding by sociodemographic and health
status. Associations between dementia/clinical dementia rating and arm circumference
were homogeneous between countries (Higgins I2 0% and 7%, respectively),
whereas those with waist circumference were more heterogeneous (Higgins I2
67% and 62%, respectively).
Although cross-sectional, our findings are consistent with prospective observations of
weight loss in dementia and suggest loss of both muscle and fat—the former being
consistent across different settings and the latter being more context dependent.
Dementia; Waist circumference; Arm circumference
The redox-sensitive transcription factor NF-E2–related factor 2 (Nrf2) plays a key
role in preserving a healthy endothelial phenotype and maintaining the functional
integrity of the vasculature. Previous studies demonstrated that aging is associated with
Nrf2 dysfunction in endothelial cells, which alters redox signaling and likely promotes
the development of large vessel disease. Much less is known about the consequences of Nrf2
dysfunction at the level of the microcirculation. To test the hypothesis that Nrf2
regulates angiogenic capacity of endothelial cells, we determined whether disruption of
Nrf2 signaling (by siRNA knockdown of Nrf2 and overexpression of Keap1, the cytosolic
repressor of Nrf2) impairs angiogenic processes in cultured human coronary arterial
endothelial cells stimulated with vascular endothelial growth factor and insulin-like
growth factor-1. In the absence of functional Nrf2, coronary arterial endothelial cells
exhibited impaired proliferation and adhesion to vitronectin and collagen. Disruption of
Nrf2 signaling also reduced cellular migration (measured by a wound-healing assay using
electric cell-substrate impedance sensing technology) and impaired the ability of coronary
arterial endothelial cells to form capillary-like structures. Collectively, we find that
Nrf2 is essential for normal endothelial angiogenic processes, suggesting that Nrf2
dysfunction may be a potential mechanism underlying impaired angiogenesis and
microvascular rarefaction in aging.
Vascular aging; Microcirculation; Capillary density; Angiogenesis; Heart
The present study was conducted to test predictions of the oxidative stress theory of aging assessing reactive oxygen species production and oxidative stress resistance in cultured fibroblasts from 13 primate species ranging in body size from 0.25 to 120 kg and in longevity from 20 to 90 years. We assessed both basal and stress-induced reactive oxygen species production in fibroblasts from five great apes (human, chimpanzee, bonobo, gorilla, and orangutan), four Old World monkeys (baboon, rhesus and crested black macaques, and patas monkey), three New World monkeys (common marmoset, red-bellied tamarin, and woolly monkey), and one lemur (ring-tailed lemur). Measurements of cellular MitoSox fluorescence, an indicator of mitochondrial superoxide (O2·−) generation, showed an inverse correlation between longevity and steady state or metabolic stress–induced mitochondrial O2·− production, but this correlation was lost when the effects of body mass were removed, and the data were analyzed using phylogenetically independent contrasts. Fibroblasts from longer-lived primate species also exhibited superior resistance to H2O2-induced apoptotic cell death than cells from shorter-living primates. After correction for body mass and lack of phylogenetic independence, this correlation, although still discernible, fell short of significance by regression analysis. Thus, increased longevity in this sample of primates is not causally associated with low cellular reactive oxygen species generation, but further studies are warranted to test the association between increased cellular resistance to oxidative stressor and primate longevity.
Primates; Comparative biology; Free radical; Oxidative stress
Growth hormone receptor gene–disrupted (GHR−/−) mice are dwarf, insulin sensitive, and long lived despite being obese. In order to identify characteristics associated with their increased longevity, we studied age-related plasma proteomic changes in these mice. Male and female GHR−/− mice and their littermate controls were followed longitudinally at 8, 16, and 24 months of ages for plasma proteomic analysis. Relative to control littermates, GHR−/− mice had increased levels of apolipoprotein A-4 and retinol-binding protein-4 and decreased levels of apolipoprotein E, haptoglobin, and mannose-binding protein-C. Female GHR−/− mice showed decreased inflammatory cytokines including interleukin-1β and monocyte chemotactic protein-1. Additionally, sex differences were found in specific isoforms of apolipoprotein E, RBP-4, haptoglobin, albumin, and hemoglobin subunit beta. In conclusion, we find plasma proteomic changes in GHR−/− mice that favor a longer life span as well as sex differences indicative of an improved health span in female mice.
Growth hormone receptor; Plasma; Proteomics; Sex; Aging
Studies of drug-related hospitalizations have focused on adverse drug reactions, but
few data are available on therapeutic failures (TFs) and adverse drug withdrawal events
(ADWEs) leading to hospitalization among community-dwelling older adults. Thus, we
sought to describe the prevalence of unplanned hospitalizations caused by TFs and ADWEs.
In addition, we evaluated factors associated with these events in a nationally
representative sample of older Veterans.
This study included 678 randomly selected unplanned hospitalizations of older (age ≥
65 years) Veterans between December 1, 2003, and November 9, 2006. The main outcomes
were hospitalizations caused by a TF and/or an ADWE as determined by a pair of health
professionals from review of medication charts and application of the Therapeutic
Failure Questionnaire and/or Naranjo ADWE algorithm, respectively. Preventability (ie,
medication error) of the admission was also assessed.
Thirty-four TFs and eight ADWEs involving 54 drugs were associated with 40 (5.9%)
Veterans’ hospitalizations; of these admissions, 90.0% (36/40) were rated as
potentially preventable mostly due to medication nonadherence and suboptimal
prescribing. The most common TFs that occurred were heart failure exacerbations
(n = 8), coronary heart disease symptoms (n
= 6), tachyarrhythmias (n = 3), and chronic obstructive
pulmonary disease exacerbations (n = 3). Half (4/8) of the ADWEs
that occurred were cardiovascular in nature. Multivariable logistic regression modeling
indicated that black Veterans (adjusted odds ratio 2.92, 95% CI
1.25–6.80) were significantly more likely to experience a TF-related admission
compared with white Veterans.
TF-related unplanned hospitalizations occur more frequently than ADWE-related
admissions among older Veterans. Almost all TFs and/or ADWEs are potentially
Drug-related problems; Hospitalizations; Veterans;
There is increasing evidence that age-associated chronic low-grade inflammation promotes
the development of both large-vessel disease (myocardial infarction, stroke, peripheral
arterial disease) and small-vessel pathologies (including vascular cognitive impairment)
in older persons. However, the source of age-related chronic vascular inflammation remains
unclear. To test the hypothesis that cell-autonomous mechanisms contribute to the
proinflammatory changes in vascular phenotype that accompanies advancing age, we analyzed
the cytokine secretion profile of primary vascular smooth muscle cells (VSMCs) derived
from young (∼13 years old) and aged (∼21 years old) Macaca
mulatta. Aged VSMCs cultured in the absence of systemic factors exhibited
significantly increased secretion of interleukin-1β, MCP-1, and tumor necrosis
factorα compared with young control cells. Secretion of interleukin-6 also tended to
increase in aged VSMCs. This age-associated proinflammatory shift in the cellular
secretory phenotype was associated with an increased mitochondrial O2
− production and nuclear factor κ-light-chain-enhancer of activated
B cells activation. Treatment of aged VSMCs with a physiologically relevant concentration
of resveratrol (1 μM) exerted significant anti-inflammatory effects, reversing
aging-induced alterations in the cellular cytokine secretion profile and inhibiting
nuclear factor κ-light-chain-enhancer of activated B cells. Resveratrol also
attenuated mitochondrial O2
− production and upregulated the transcriptional activity of Nrf2 in aged
VSMCs. Thus, in non-human primates, cell-autonomous activation of nuclear factor
κ-light-chain-enhancer of activated B cells and expression of an inflammatory
secretome likely contribute to vascular inflammation in aging. Resveratrol treatment
prevents the proinflammatory properties of the aged VSMC secretome, an effect that likely
contributes to the demonstrated vasoprotective action of resveratrol in animal models of
Vascular aging; Inflammation; Oxidative stress; Cytokine; 3,5,4’-trihydroxy-trans-stilbene
Age-related changes in neural circuits, neural networks, and their plasticity are central to our understanding of age changes in cognition and brain structure and function. This paper summarizes selected findings on these topics presented at the Cognitive Aging Summit II. Specific areas discussed were synaptic vulnerability and plasticity, including the role of different types of synaptic spines, and hormonal effects in the dorsolateral prefrontal cortex of nonhuman primates, the impact of both compensatory processes and dedifferentiation on demand-dependent differences in prefrontal activation in relation to age and performance, the role of vascular disease, indexed by white matter signal abnormalities, on prefrontal activation during a functional magnetic resonance imaging-based cognitive control paradigm, and the influence of amyloid-β neuropathology on memory performance in older adults and the networks of brain activity underlying variability in performance. A greater understanding of age-related changes in brain plasticity and neural networks in healthy aging and in the presence of underlying vascular disease or amyloid pathology will be essential to identify new targets for intervention. Moreover, this understanding will assist in promoting the utilization of existing interventions, such as lifestyle and therapeutic modifiers of vascular disease.
cognitive changes; aging; Neural networks