To assess whether selenium and carboxymethyl-lysine (CML), two biomarkers of oxidative stress, are independent predictors of anemia in older, community-dwelling adults.
Plasma selenium, CML, folate, vitamin B12, testosterone, and markers of iron status and inflammation were measured at baseline in 1,036 adults, ≥65 years, in the InCHIANTI Study, a population-based cohort study of aging in Tuscany, Italy, and examined in relationship to prevalent anemia and incident anemia over 6 years of follow-up.
At enrollment, 11.6% of participants were anemic. Of 472 participants who were non-anemic at enrollment 72 (15.3%) developed anemia within 6 years of follow-up. At enrollment, plasma CML in the highest quartile (>425 ng/mL) and plasma selenium in the lowest quartile (<66.6 μg/L) predicted incident anemia (Hazards Ratio [H.R.] 1.67, 95% Confidence Interval [C.I.] 1.07–2.59, P = 0.02; H.R. 1.55, 95% C.I.1.01–2.38, P = 0.05, respectively) in a multivariate Cox proportional hazards model that adjusted for age, education, body mass index, cognition, inflammation, red cell distribution width, ferritin, vitamin B12, testosterone, and chronic diseases.
Elevated plasma carboxymethyl-lysine and low plasma selenium are long-term independent predictors of anemia among older community-dwelling adults. These findings support the idea that oxidative stress contributes to the development of anemia.
advanced glycation end products; aging; anemia; carboxymethyl-lysine; oxidative stress; selenium
Older people with type 2 diabetes are at high risk of mobility disability. We investigated the association of diabetes with lower-limb muscle mass and muscle quality to verify whether diabetes-related muscle impairments mediate the association between diabetes and low walking speed.
RESEARCH DESIGN AND METHODS
We performed a cross-sectional analysis of 835 participants (65 years old and older) enrolled in the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) population-based study. Total, muscular, and fat cross-sectional areas of the calf and relative muscle density were measured using peripheral quantitative computerized tomography. Indicators of muscle performance included knee-extension torque, ankle plantar flexion and dorsiflexion strength, lower-extremity muscle power, and ankle muscle quality (ratio of ankle strength to the muscle area [kilograms per centimeters squared]). Gait performance was assessed by 4- and 400-m walking speed. Diabetes was ascertained by standard American Diabetes Association criteria.
Prevalence of diabetes was 11.4%. After adjustment for age and sex, participants with diabetes had lower muscle density, knee and ankle strength, and muscle power and worse muscle quality (all P < 0.05). Diabetic participants were also slower on both 4-m (β: −0.115 ± 0.024 m/s, P < 0.001) and 400-m (β:−0.053 ± 0.023 m/s, P < 0.05) walking tests. In multivariable linear regression models, lower-limb muscle characteristics accounted for 24.3 and 15.1% of walking speed difference comparing diabetic and nondiabetic subjects in the 4- and 400-m walks, respectively.
In older persons, diabetes is associated with reduced muscle strength and worse muscle quality. These impairments are important contributors of walking limitations related to diabetes.
Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample.
We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models.
In genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta=−0.16, p=5.1×10−6, false discovery rate (FDR; q=0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta=−0.16, p=5.1×10−6, q=0.003; and beta=−0.13, p=5.5×10−5, q=0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype.
We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated β-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.
Knee osteoarthritis (kOA) risk is increased by obesity and physical activities (PA) which mechanically stress the joint. We examined the associations of midlife kOA with body mass index (BMI) and activity exposure across adult life and their interaction.
Data are from a UK birth cohort of 2597 participants with a clinical assessment for kOA at age 53. At ages 36, 43 and 53 BMI (kg/m2), self-reported leisure-time PA, and occupational activity (kneeling/squatting; lifting; climbing; sitting; assigned using a job-exposure matrix) were ascertained. Associations were explored using the multiplicative logistic model.
BMI was strongly and positively associated with kOA in men and women. Men and women in manual occupations also had greater odds of kOA; there was a weak suggestion that kOA risk was higher among men exposed to lifting or kneeling at work. For men, the only evidence of a multiplicative interaction between BMI and activities was for lifting (p = 0.01) at age 43; BMI conferred higher kOA risk among those most-likely to lift at work (OR per increase in BMI z-score: 3.55, 95% CI: 1.72-7.33). For women, the only evidence of an interaction was between BMI and leisure-time PA (p = 0.005) at age 43; BMI conferred higher kOA risk among those at higher PA levels (OR per increase in BMI z-score: 1.59, 95% CI: 1.26-2.00 in inactive; 1.70, 95% CI: 1.14-2.55 (less-active); and 4.44; 95% CI: 2.26-8.36 (most-active).
At the very least, our study suggests that more active individuals (at work and in leisure) may see a greater reduction in risk of kOA from avoiding a high BMI than those less active.
Knee osteoarthritis; Body mass index; Physical activity; Occupational activity
The relationship between menopausal characteristics and later life mortality is unclear. We tested the hypotheses that women with surgical menopause would have increased all-cause and cardiovascular mortality compared with women with natural menopause, and that women with earlier ages at natural or surgical menopause would have greater all-cause and cardiovascular mortality than women with later ages at menopause.
Women who participated in the Iowa cohort of the Established Populations for the Epidemiologic Study of the Elderly (n=1684) reported menopausal characteristics and potential confounding variables at baseline and were followed up for up to 24 years. Participants were aged 65 years or older at baseline and lived in rural areas. We used survival analysis to examine the relationships between menopausal characteristics and all-cause and cardiovascular mortality.
A total of 1477 women (87.7% of respondents) died during the study interval. Women with an age at natural menopause ≥55 years had increased all-cause and cardiovascular disease mortality compared with women who had natural menopause at younger ages. Type of menopause and age at surgical menopause were not related to mortality. These patterns persisted after adjustment for potential confounding variables.
Among an older group of women from a rural area of the United States, later age at natural menopause was related to increased all-cause and cardiovascular mortality. Monitoring the cardiovascular health of this group of older women may contribute to improved survival times.
An important challenge in epidemiology is the difficulty in inferring causality from observational studies. Even the best longitudinal studies have limitations in this regard, and when clinical trials are feasible they will provide more definite evidence of causality. However, even when clinical trials are feasible, we can learn a great deal about the disease process, assessment techniques, subject selection criteria, and the impact of potential interventions from longitudinal studies. This review covers the theoretical issues supporting the value and limitations of longitudinal studies, the practical utilization in clinical trials of different aspects of knowledge that can be gained from longitudinal studies, critical issues in the translation of longitudinal observational studies into clinical trials, and the value of observational studies in broadening the applicability of specific trials. Relevant issues are illustrated with examples of both unsuccessful and successful trials, with a major emphasis on clinical trials of physical activity in older persons.
longitudinal studies; observational studies; clinical trials
Low vitamin B12 and high homocysteine (Hcy) levels are common in older adults and may be associated with worse neurological function. The aim of this study is to determine whether changes in B12 or Hcy levels are associated with longitudinal changes in peripheral nerve function and clinical neurological signs and symptoms.
Participants aged 60 years and older at baseline (n = 678; 72.2 ± 6.2 years; 43.5% male) were from the InCHIANTI Study. Low B12 (<260 pmol/L) and high Hcy (≥13 μmol/L) were measured at baseline and 3-year follow-up. Neurological function was assessed by peroneal nerve conduction amplitude (compound motor action potential) and velocity, neurological examination, and peripheral neuropathy symptoms at baseline, 3-year, and 6-year follow-up.
At baseline, 43.8% had low B12 levels and 58.6% had high Hcy levels. Over 6 years, 12.4% declined to poor compound motor action potential (<1 mV) and 42.1% declined to poor nerve conduction velocity (<40 m/s). In mixed models analyses, sustained high Hcy was associated with worse compound motor action potential compared with sustained normal Hcy (p = .04), adjusting for demographics, diabetes, and folate level. Participants whose Hcy level became high at follow-up were more likely to become unable to detect monofilament at 6-year follow-up compared with those with sustained normal Hcy (odds ratio: 5.4; 95% CI: 1.5–19.0), adjusting for demographics, diabetes, body mass index, and peripheral arterial disease. There was no association with vitamin B12 level or with symptoms.
High Hcy may be associated with worse sensory and motor peripheral nerve function. Because poor nerve function has been associated with lower strength and physical performance, these results have important implications for disability in older adults.
Vitamin B12; Homocysteine; Peripheral nerve function; Neurological signs
To determine whether higher body mass index (BMI) is associated with more adverse lower extremity muscle characteristics at baseline and more adverse changes in muscle over time among participants with lower extremity peripheral arterial disease (PAD).
Longitudinal, observational study.
Academic medical center in Chicago.
Participants were 425 men and women with PAD and 261 without PAD.
Computed Tomography was used to measure calf muscle characteristics at baseline and every two years. Knee extension isometric strength, power, and six-minute walk were measured at baseline and annually. Baseline BMI categories were ideal (20-25 kg/m2), overweight (>25-30 kg/m2), and obese (>30 kg/m2). Analyses adjust for age, race, gender, ankle brachial index (ABI), comorbidities, and other covariates.
At baseline, among participants with PAD, higher BMI was associated with greater calf muscle area (ideal BMI: 5181 mm2, overweight: 5513 mm2, obese: 5695 mm2, p trend=0.0009), higher calf muscle percent fat (6.38%, 10.28%, 17.44% respectively, p trend<0.0001), lower calf muscle density (p trend<0.0001), and higher isometric knee extension strength (p trend=0.015). Among participants with PAD, higher BMI was associated with greater declines in calf muscle area p trend=0.030) and greater increases in calf muscle percent fat (p trend=0.023). Among participants without PAD, there were no significant associations of baseline BMI with changes in lower extremity muscle outcomes over time.
Among PAD participants, higher BMI is associated with greater calf muscle area at baseline. However, higher BMI is associated with more adverse calf muscle density and percent fat at baseline and greater declines in calf muscle area over time.
We studied whether lower calf muscle density and poorer upper and lower extremity strength are associated with higher mortality rates in men and women with PAD.
Men and women with lower extremity peripheral arterial disease (PAD) have lower calf muscle density and reduced lower extremity strength compared to individuals without PAD.
At baseline, participants underwent measurement of calf muscle density with computed tomography in addition to knee extension power, and isometric knee extension, plantar flexion, and hand grip strength measures. Participants were followed annually for up to four years. Results are adjusted for age, sex, race, body mass index, the ankle brachial index (ABI), smoking, physical activity, and comorbidities.
Among 434 PAD participants, 103 (24%) died during a mean follow-up of 47.6 months. Lower calf muscle density was associated with higher all-cause mortality (lowest density tertile-hazard ratio (HR)=1.80 (95% Confidence Interval (CI)-1.07-3.03), 2nd tertile-HR=0.91 (95% CI-0.51-1.62); highest density tertile (HR=1.00), P trend=0.020) and higher cardiovascular disease mortality (lowest density tertile-HR=2.39 (95% CI-0.90-6.30), 2nd tertile-HR=0.85 (95% CI-0.27-2.71); highest density tertile (HR=1.00), P trend=0.047). Poorer plantar flexion strength (P trend=0.004), lower baseline leg power (P trend=0.046), and poorer handgrip (P trend=0.005) were associated with higher all-cause mortality.
These data demonstrate that lower calf muscle density and weaker plantar flexion strength, knee extension power, and hand grip are associated with increased mortality in participants with PAD, independently of the ABI and other confounders.
Mortality; intermittent claudication; prognosis; Physical functioning
We hypothesized that natural menopause would be related to better physical functioning compared to surgical menopause and that later age at menopause would be related to better physical functioning.
Our sample comprised 1765 women aged ≥ 60 years who participated in the National Health and Nutrition Examination Survey III, a cross-sectional study representative of the United States population. Women recalled age at final menstrual period and age at removal of the uterus and ovaries and reported age, race and ethnicity, height, weight, educational attainment, smoking status, number of children, and use of estrogen therapy. Respondents completed a walk trial and chair rises and reported functional limitations.
Women with a surgical menopause had chair rise times that were an average of 4.4% slower than those of women with natural menopause (95% CI 0.56, 8.27). Women with natural menopause at age ≥ 55 years had an average walking speed 0.05 meters/second (95% CI 0.01, 0.10) faster than women with natural menopause at age < 45 years. Later ages at natural and surgical menopause were also related to lower self-reported functional limitation. Women with surgical menopause at age ≥ 55 years had odds of functional limitation 0.52 times (95% CI 0.29, 0.95) those of women with surgical menopause at age < 40 years, with similar patterns for natural menopause.
Women with surgical menopause and earlier age at menopause had worse physical function in older adulthood. These groups of women may benefit from interventions to prevent functional decline.
menopause; physical functioning; women’s health
The effect of dietary protein intake on muscle strength in older persons is unknown. The objective of this study was to examine whether protein intake is associated with change in muscle strength in older persons. Because systemic inflammation has been associated with protein catabolism, we also evaluated whethera synergistic effect exists between protein intake and inflammatory markers on change in muscle strength using a longitudinal study of community-dwelling persons aged 65 years or older.
The InCHIANTI Study.
Five hundred and ninety-eight persons.
Knee extension strength was measured at baseline (1998–2000) and during 3-year follow-up (2001–2003) using a hand-held dynamometer. Protein intake was assessed using a very detailed food frequency questionnaire. The inflammatory markers included in this study were C-reactive protein (CRP), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α).
The main effect of protein intake on change in muscle strength was not significant, but we found a significant interaction between protein intake and CRP, IL-6 and TNF-α (p=0.003, p=0.049 and p=0.019, respectively), indicating thata lower protein intake was associated with a greater decline in muscle strength in persons with high levels of inflammatory markers.
Selectively in older persons with a pro-inflammatory state, low protein intake was associated with accelerated decline in muscle strength. These results may help to understand the factors contributing to decline in muscle strength and to identify the target population of older persons who may benefit from nutritional interventions aimed at preventing or reducing age-associated muscle impairments and its detrimental consequences.
Muscle Strength; Protein Intake; Inflammatory markers
Vitamin D deficiency is associated with cardiovascular disease, osteoporosis, poor muscle strength, falls, fractures, and mortality. Although older adults are at a high risk of vitamin D deficiency, the relationship of serum 25(OH)D with all-cause and cardiovascular disease mortality has not been well characterized in the elderly. We hypothesized that low serum 25(OH)D predicted mortality in older adults.
Serum 25(OH)D and all-cause and cardiovascular disease mortality were examined in 1006 adults, ≥65 years, who participated in the InCHIANTI study, a population-based, prospective cohort study of aging in Tuscany, Italy. Serum 25(OH)D was measured at enrollment in 1998-1999, and participants were followed for mortality.
During 6.5 years of follow-up, 228 (22.7%) participants died, of whom 107 died from cardiovascular disease. Compared with participants in the highest quartile of serum 25(OH)D (>26.5 ng/mL)(to convert to nmol/L, multiply by 2.496), those in the lowest quartile (<10.5 ng/mL) had increased risk of all-cause mortality (Hazards Ratio [H.R.] 2.11, 95% Confidence Interval [C.I.] 1.22 – 3.64, P = 0.007) and cardiovascular disease mortality (H.R. 2.64, 95% C.I. 1.14 – 4.79, P = 0.02), in multivariate Cox proportional hazards models that adjusted for age, sex, education, season, physical activity, and other potential confounders.
Older community-dwelling adults with low serum 25(OH)D are at higher risk of all-cause and cardiovascular disease mortality.
Aging; all-cause mortality; cardiovascular disease mortality; vitamin D
Accidents (including motor vehicle accidents) are a leading cause of death among American Indians/Alaskan Natives (AI/AN). The purpose of this study was to examine geographic variation and the existence of a seatbelt law on seatbelt use among AI/AN and non-Hispanic Whites (NHW).
Self-reported seatbelt behavior data from the 1997 and 2002 Behavioral Risk Factor Surveillance System (BRFSS) were analyzed in 2006–2007 and were restricted to AI/AN (n=4,310 for 2002, and n=1,758 for 1997) and NHW (n=193,617 for 2002, and n=108,551 for 1997) aged 18 years and older.
Seatbelt non-use varied significantly across geographic regions for both AI/AN and NHW. For example, AI/AN living in the Northern Plains [odds ratio (OR)=12.4 (95% confidence interval (CI): 6.5, 23.7)] and Alaska [OR=10.3 (95%CI: 5.3, 19.9)] had significantly higher seatbelt non-use compared to AI/AN living in the West. In addition, compared to those residing in urban areas, those living in rural areas were 60% more likely in NHW and 2.6 times more likely in AI/AN not to wear a seatbelt. Both AI/AN and NHW living in states without primary seatbelt laws were approximately twice as likely to report seatbelt non-use in 2002 as those living in states with primary laws. In states with primary laws enacted between 1997 and 2002, AI/AN experienced greater decline in seatbelt non-use than NHW.
Seatbelt use among AI/AN and NHW varied significantly by region and urban-rural residency in 2002. Primary seatbelt laws appear to help reduce regional and racial disparities in seatbelt non-use.
Background & Aims
Red cell distribution width (RDW), a measure of heterogeneity in the size of circulating erythrocytes, is associated with some chronic diseases and predicts mortality. Although oxidative damage and inflammation have been theorized to affect RDW, the relationships of antioxidants and inflammation with RDW have not been well characterized. The aims were to determine whether total serum carotenoids, α-tocopherol, selenium, protein carbonyls, and interleukin-6 (IL-6) are associated with RDW and predict RDW over time.
RDW was measured at baseline, 12 months, and 24 months follow-up in 786 moderately to severely disabled community-dwelling women, aged ≥65 years, in the Women’s Health and Aging Study I in Baltimore, Maryland.
Selenium was significantly associated with RDW at baseline and predicted RDW over two years’ follow-up in separate multivariate mixed effects models that adjusted for other covariates. As expected, the addition of IL-6 to the models attenuated the association of serum selenium with RDW, as low antioxidant levels are known to upregulate IL-6. Total carotenoids were associated with RDW at baseline and one year follow-up. Protein carbonyls and α-tocopherol were not significantly associated with RDW.
Serum selenium is an independent predictor of RDW and may potentially mediate effects on RDW through IL-6.
carotenoids; interleukin-6; oxidative stress; red cell distribution width; selenium; vitamin E
Older women and those of lower socioeconomic position (SEP) consistently constitute a larger portion of the disabled population than older men or those of higher SEP, yet no studies have examined when in the life course these differences emerge.
Prevalence of self-reported limitations in the upper body (gripping or reaching) and lower body (walking or stair climbing) at 43 and 53 years were utilized from 1,530 men and 1,518 women from the British 1946 birth cohort. Generalized linear models with a binomial distribution were used to examine the effects of gender, childhood and adult SEP, and the differences in the SEP effects by gender on the prevalence of limitations at age 43 years and changes in prevalence from 43 to 53 years.
For both genders, the prevalence of upper and lower body limitations were reported at 3%–5% at age 43 years. However, by age 53 years, women’s upper body limitations had increased to 28% and lower body limitations to 21%, whereas men’s limitations had only increased to 12% and 11%, respectively. Men and women whose father’s occupation was manual or whose adult head of household occupation was manual had higher prevalence of both limitations compared with those with non-manual backgrounds. These differences widened with age, especially in women. The effect of adult SEP on the prevalence of limitations was stronger than that of childhood SEP and was partly mediated by educational attainment.
Our findings provide the first evidence that prevention of disability in old age should begin early in midlife, especially for women from manual occupation households.
Gender; Social class; Functional limitations; Longitudinal studies; Middle aged
Muscle weakness and obesity are two significant threats to mobility facing the increasing number of older adults. To date, there are no studies that have examined the association of strength and body mass index (BMI) on event rates on a widely used performance measure of major mobility disability.
This study was a secondary analysis of a randomized controlled trial in which sedentary functionally limited participants (70–89 years, Short Physical Performance Battery ≤ 9) who were able to complete a 400-m walk test at baseline were randomized to a physical activity or health education intervention and reassessed for major mobility disability every 6 months for up to 18 months. We evaluated whether baseline grip strength and BMI predicted failure to complete the 400-m walk test in 15 minutes or less (major mobility disability).
Among N = 406 participants with baseline measures, lower grip strength was associated with an increased risk for developing major mobility disability, with and without covariate adjustment (p < .01): The hazard ratio (95% confidence interval) for the lowest versus high sex-specific quartile of grip strength was 6.11 (2.24–16.66). We observed a U-shaped relationship between baseline BMI and the risk of developing major mobility disability, such that the risk for participants with a BMI of 25–29 kg/m2 was approximately half that of participants with BMI less than 25 or 30 kg/m2 or more (p = .04 in fully adjusted analyses).
Our data highlight the importance of muscle weakness, low BMI, and obesity as risk factors for major mobility disability in older adults. Being overweight may be protective for major mobility disability.
Physical disability; Physical activity; Older adults
We examined the cross-sectional and longitudinal relationship between plasma carotenoids and depressive symptoms over a six-year follow-up in older persons.
Methods and Materials
This research is part of the InCHIANTI Study, a prospective population-based study of older persons in Tuscany, Italy. The sample for this analysis included 958 women and men aged 65 years and older. Plasma total carotenoids were assessed at baseline. Depressive symptoms were assessed at baseline and at the 3- and 6-year follow-up using the Center for Epidemiological Studies-Depression Scale (CES-D). Depressed mood was defined as CES-D≥20.
At baseline, higher total carotenoids level were associated with lower probability of depressed mood (OR=0.82, 95%CI=0.68–0.99, p=0.04) after adjustment for sociodemographic, health and inflammation. After the exclusion of participants with baseline depressed mood and use of antidepressants, higher total carotenoids level were associated with lower risk of incident depressed mood (OR=0.72, 95%CI=0.52–0.99, p=0.04) at 6-year follow-up, after adjustment for confounders plus baseline CES-D. Inflammatory marker Interleukin-1 receptor antagonist partially mediated this association.
Low plasma concentrations of carotenoids are associated with depressive symptoms and predict the development of new depressive symptoms in older persons. Understanding the mechanism of this association may reveal potential targets for prevention and treatment.
Carotenoids; antioxidants; depression; inflammation; aging
Assessment of mobility in geriatric hospital units relies primarily on subjective observation or patient self-reports. We objectively examined the gait speed of hospitalized older patients.
Prospective study of 322 patients 65 years or older admitted from the community to a geriatric hospital unit between March 2008 and October 2009. Associations of gait speed (in meters per second) and activities of daily living with length of stay and home discharge were examined in multivariable logistic and generalized linear regression models.
In total, 206 of 322 patients completed the gait speed walk, with a mean gait speed of 0.53 m/s. A strong association was found between faster gait speed and shorter length of stay. Patients unable to complete the walk and patients having gait speeds of less than 0.40 m/s had significantly longer lengths of stay by 1.9 and 1.4 days, respectively, compared with patients having gait speeds of at least 0.60 m/s. Similarly, patients unable to complete the walk (odds ratio, 0.03; 95% CI, 0.003–0.21) and patients having gait speeds of less than 0.40 m/s (odds ratio, 0.07; 95% CI, 0.001–0.63) had significantly decreased odds of home discharge compared with patients having gait speeds of at least 0.60 m/s. Activities of daily living were less robust than gait speed in discriminating the risk of length of stay or home discharge.
Gait speed is a clinically relevant indicator of functional status and is associated with important geriatric health outcomes, including length of stay and home discharge. Gait speed could be used to complement information obtained by self-reported activities of daily living.
To determine whether plasma klotho, a recently discovered hormone that has been implicated in atherosclerosis, is related to prevalent cardiovascular disease in adults.
Population-based sample of adults residing in Tuscany, Italy.
One thousand and twenty-three men and women, aged 24–102, participating in the Invecchiare in Chianti (InCHIANTI) study.
Anthropometric measures, plasma klotho, fasting plasma total, high-density lipoprotein (HDL) cholesterol, triglycerides, glucose, creatinine, C-reactive protein. Clinical measures: medical assessment, diabetes mellitus, hypertension, coronary heart disease, heart failure, stroke, peripheral artery disease, cancer, chronic kidney disease. Logistic regression models were used to examine the relationship between plasma klotho and prevalent cardiovascular disease.
Of 1023 participants, 259 (25.3%) had cardiovascular disease. Median (25th, 75th percentile) plasma klotho concentrations were 676 (530, 819) pg/mL. Plasma klotho was correlated with age (r = −0.14, P <0.0001), HDL cholesterol (r = 0.11, P = 0.0004), C-reactive protein (r = −0.10, P = 0.0008), but not systolic blood pressure, fasting plasma glucose, or renal function. Plasma klotho age-adjusted geometric means (95% Confidence Interval [C.I.]) were 626 (601, 658) in participants with cardiovascular disease and 671 (652, 692) pg/mL in those without cardiovascular disease (P = 0.0001). Adjusting for traditional cardiovascular risk factors (age, sex, smoking, total cholesterol, HDL cholesterol, systolic blood pressure, and diabetes), log plasma klotho was associated with prevalent cardiovascular disease (Odds Ratio per 1 standard deviation increase = 0.85, 95% C.I. 0.72, 0.99).
In community-dwelling adults, higher plasma klotho concentrations are independently associated with a lower likelihood of having cardiovascular disease.
aging; atherosclerosis; cardiovascular disease; C-reactive protein; klotho
Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β) triggered macrophage-mediated muscle fibre regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in-vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population.
We undertook a genome wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (ages 30–104 yrs). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery score (SPPB) tested walk speed, chair stand and balance.
CEBPB expression levels were associated with muscle strength (beta coefficient = 0.20560, p=1.03*10−6, false discovery rate q=0.014). The estimated handgrip strength in 70 year old men in the lowest CEBPB expression tertile was 35.2 kg compared to 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle and shoulder strength and the SPPB performance score (p=0.018). Near study-wide associations were also noted for TGFB3 (p=3.4*10−5, q=0.12) and CEBPD expression (p=9.67E−5, q=0.18) but not for CEBPA expression.
We report here a novel finding that raised CEBPB expression in circulating leukocyte derived RNA samples in-vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB triggered muscle repair: if this mechanism is confirmed it may provide a target for intervention to protect and enhance aging muscle.
macrophage; inflammation; transcription; regeneration; population; mechanism
Aging is a major risk factor for chronic disease in the human population, but there is little human data on gene expression alterations that accompany the process. We examined human peripheral blood leucocyte in-vivo RNA in a large-scale transcriptomic microarray study (subjects aged 30 to 104 years). We tested associations between probe expression intensity and advancing age (adjusting for confounding factors), initially in a discovery set (n = 458), following-up findings in a replication set (n=240). We confirmed expression of key results by real-time PCR. Of 16,571 expressed probes, only 295 (2%) were robustly associated with age. Just six probes were required for a highly efficient model for distinguishing between young and old (Area Under the Curve in replication set; 95%). The focussed nature of age-related gene expression may therefore provide potential biomarkers of aging. Similarly, only 7 of 1065 biological or metabolic pathways were age-associated, in Gene Set Enrichment Analysis (GSEA), notably including the processing of messenger RNAs (mRNAs); (p<0.002, FDR q<0.05). This is supported by our observation of age-associated disruption to the balance of alternatively-expressed isoforms for selected genes, suggesting that modification of mRNA processing may be a feature of human aging.
Aging; Gene expression; mRNA processing; Cell senescence; predictive model
To determine whether poor lower extremity nerve function is associated with more adverse calf muscle characteristics and greater functional impairment in people with and without peripheral arterial disease (PAD).
Three Chicago-area medical centers
413 participants with PAD (ankle-brachial index (ABI) <0.90) and 271 participants without PAD.
Electrodiagnostic testing of the peroneal nerve was performed. Calf muscle cross-sectional area and percent fat were measured using computed tomography at 66.7% of the distance between the distal and proximal tibia. 6-minute walk performance was measured.
Adjusting for age, sex, race, ABI, leg symptoms, smoking, physical activity, comorbidities, and other covariates, lower peroneal nerve conduction velocity (NCV) was associated with lower calf muscle area (1st quartile: 5571.1 mm2, 4th quartile: 4770.3 mm2, p-value<0.001) and poorer 6-minute walk distance (1st quartile: 989.2 ft, 4th quartile: 1210.8 ft, p-value<0.001) in non-diabetic PAD participants. Lower peroneal NCV was associated with lower calf muscle area (1st quartile: 5166.0 mm2, 4th quartile: 6003.8 mm2, p-value=0.014) and poorer 6-minute walk distance (1st quartile: 866.4 ft, 4th quartile: 1082.5 ft, p-value=0.012) in diabetic PAD participants as well. Among non-PAD participants, lower peroneal NCV was not associated with lower calf muscle area but was associated with poorer 6-minute walk distance in non-diabetic participants only (1st quartile 1317.0 ft, 4th quartile 1570.4 ft; p-trend<0.001).
Lower peroneal nerve function is associated with smaller calf muscle area in individuals with PAD and greater functional impairment in individuals with PAD. Future study is needed to determine whether improving peroneal NCV prevents loss of calf muscle and functional decline in PAD.
Claudication; Muscles; Peripheral Nervous System; Peripheral Vascular Disease; Physical functioning
Handgrip strength is a strong indicator of total body muscle strength and is a predictor of poor outcomes in older adults. The aging suppressor gene klotho encodes a single-pass transmembrane protein that is secreted as a circulating hormone. In mice, disruption of klotho expression results in a syndrome that includes sarcopenia, atherosclerosis, osteoporosis, and shortened lifespan, and conversely, overexpression of klotho leads to a greater longevity. The objective was to determine whether plasma klotho levels are related to skeletal muscle strength in humans. We measured plasma klotho in 804 adults, ≥65 years, in the InCHIANTI study, a longitudinal population-based study of aging in Tuscany, Italy. Grip strength was positively correlated with plasma klotho at threshold <681 pg/mL. After adjusting for age, sex, education, smoking, physical activity, cognition, and chronic diseases, plasma klotho (per 1 standard deviation increase) was associated with grip strength (beta = 1.20, standard error = 0.35, P = 0.0009) in adults with plasma klotho <681 pg/mL. These results suggest that older adults with lower plasma klotho have poor skeletal muscle strength.
aging; klotho; muscle strength; sarcopenia
Higher levels of inflammation are associated with adverse outcomes in persons with lower extremity peripheral arterial disease (PAD). This study evaluated associations of physical activity during daily life with levels of inflammatory biomarkers, D-dimer, and homocysteine in persons with PAD. Participants were 244 men and women (mean age 74.4 years ± 8.2) with PAD (ankle brachial index (ABI) < .90). C reactive protein (CRP), Interleukin-6 (IL-6), soluble Intracellular Adhesion Molecule-1 (sICAM-1), soluble Vascular Cellular Adhesion Molecule-1 (sVCAM-1), D-dimer, and homocysteine were assessed at study entry. Physical activity was objectively assessed via a vertical accelerometer, which participants wore continuously for 7 days. After adjusting for age, sex, race, body mass index, smoking, comorbidities, ABI, and other potential confounders, higher physical activity levels were associated linearly and significantly with lower levels of all measured circulating biomarkers: sVCAM-1 (p trend = 0.001); D-Dimer (p trend = 0.005); homocysteine (p trend = 0.006); IL-6 (p trend = 0.010); CRP, (p trend = 0.028); sICAM-1 (p trend = 0.033). In conclusion, higher levels of physical activity were associated independently with lower levels of inflammatory markers, homocysteine, and D-dimer in PAD patients.