Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 ...signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations.
The free radical theory of aging posits that oxidative stress is among the major mechanisms in aging and age-related disease, including cardiovascular disease (CVD). Numerous in vitro and animal ...studies have supported the role of low-density lipoprotein (LDL) oxidation in atherosclerosis. This has led to the hypothesis that antioxidants could be used as an inexpensive means of prevention and possibly, treatment of coronary artery disease, stroke, peripheral vascular disease, and other CVD-related diseases. Epidemiologic cohort studies with large numbers of men, women, and diverse populations have been largely supportive of this hypothesis. However, interventional trials have been controversial, with some positive findings, many null findings, and some suggestion of harm in certain high-risk populations. Because of the mismatch between the epidemiologic studies and the interventional trials, some researchers have advocated ending antioxidant work. Others have questioned the validity of the LDL oxidative hypothesis itself. Clearly, further research is needed to understand the reasons for the mismatch between the epidemiologic and interventional work. Recent smaller interventional studies with carefully chosen populations, such as those under high levels of oxidative stress, have yielded largely positive results. This suggests that we need more hypothesis-driven and rigorous clinical trial designs. This should help clarify the true potential utility of antioxidants in CVD and may lead to a better understanding of the role of oxidative stress in atherosclerosis.
Epidemiologic studies have linked shortened telomeres with the development of many cancers. However, recent studies have suggested that longer telomeres may lead to prolonged senescence in ...melanocytes, providing increased opportunity for malignant transformation. We therefore examined whether shorter prediagnostically measured relative telomere length in peripheral blood leukocytes (PBL) was associated with a decreased risk of cutaneous melanoma. Telomere length in prospectively collected PBLs was measured in incident melanoma cases and age-matched controls selected from participants in three large prospective cohorts: the Women's Health Initiative Observational Study (WHI-OS), the Health Professionals Follow-up Study (HPFS), and the Nurses' Health Study (NHS). Shorter telomere lengths were associated with decreased risk of melanoma in each cohort. The P(trend) across quartiles was 0.03 in the WHI-OS and 0.008 in the HPFS. When combining these two datasets with published data in the NHS (P(trend), 0.09), compared with individuals in the fourth quartile (the longest telomere lengths), those in the first quartile had an OR of 0.43 (95% CI: 0.28-0.68; P(trend), 0.0003). Unlike findings for other tumors, shorter telomeres were significantly associated with a decreased risk of melanoma in this study, suggesting a unique role of telomeres in melanoma development.
OBJECTIVES: To evaluate the association between protein intake and incident frailty.
DESIGN: Prospective cohort study.
SETTING: Subset of the Women's Health Initiative Observational Study conducted ...at 40 clinical centers.
PARTICIPANTS: Twenty‐four thousand four hundred seventeen women aged 65 to 79 who were free of frailty at baseline with plausible self‐reported energy intakes (600–5,000 kcal/day) according to the Food Frequency Questionnaire (FFQ).
MEASUREMENTS: Baseline protein intake was estimated from the FFQ. Calibrated estimates of energy and protein intake were corrected for measurement error using regression calibration equations estimated from objective measures of total energy expenditure (doubly labeled water) and dietary protein (24‐hour urinary nitrogen). After 3 years of follow‐up, frailty was defined as having at least three of the following components: low physical function (measured using the Rand‐36 questionnaire), exhaustion, low physical activity, and unintended weight loss. Multinomial logistic regression models estimated associations for uncalibrated and calibrated protein intake.
RESULTS: Of the 24,417 eligible women, 3,298 (13.5%) developed frailty over 3 years. After adjustment for confounders, a 20% increase in uncalibrated protein intake (%kcal) was associated with a 12% (95% confidence interval (CI)=8–16%) lower risk of frailty, and a 20% increase in calibrated protein intake was associated with a 32% (95% CI=23–50%) lower risk of frailty.
CONCLUSION: Higher protein consumption, as a fraction of energy, is associated with a strong, independent, dose‐responsive lower risk of incident frailty in older women. Using uncalibrated measures underestimated the strength of the association. Incorporating more protein into the diet may be an intervention target for frailty prevention.
CONTEXT The Women's Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the ...balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported. OBJECTIVE To examine health outcomes associated with randomization to treatment with conjugated equine estrogens (CEE) among women with prior hysterectomy after a mean of 10.7 years of follow-up through August 2009. DESIGN, SETTING, AND PARTICIPANTS The intervention phase was a double-blind, placebo-controlled, randomized clinical trial of 0.625 mg/d of CEE compared with placebo in 10 739 US postmenopausal women aged 50 to 79 years with prior hysterectomy. Follow-up continued after the planned trial completion date among 7645 surviving participants (78%) who provided written consent. MAIN OUTCOME MEASURES The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. A global index of risks and benefits included these primary outcomes plus stroke, pulmonary embolism, colorectal cancer, hip fracture, and death. RESULTS The postintervention risk (annualized rate) for CHD among women assigned to CEE was 0.64% compared with 0.67% in the placebo group (hazard ratio HR, 0.97; 95% confidence interval CI, 0.75-1.25), 0.26% vs 0.34%, respectively, for breast cancer (HR, 0.75; 95% CI, 0.51-1.09), and 1.47% vs 1.48%, respectively, for total mortality (HR, 1.00; 95% CI, 0.84-1.18). The risk of stroke was no longer elevated during the postintervention follow-up period and was 0.36% among women receiving CEE compared with 0.41% in the placebo group (HR, 0.89; 95% CI, 0.64-1.24), the risk of deep vein thrombosis was lower at 0.17% vs 0.27%, respectively (HR, 0.63; 95% CI, 0.41-0.98), and the risk of hip fracture did not differ significantly and was 0.36% vs 0.28%, respectively (HR, 1.27; 95% CI, 0.88-1.82). Over the entire follow-up, lower breast cancer incidence in the CEE group persisted and was 0.27% compared with 0.35% in the placebo group (HR, 0.77; 95% CI, 0.62-0.95). Health outcomes were more favorable for younger compared with older women for CHD (P = .05 for interaction), total myocardial infarction (P = .007 for interaction), colorectal cancer (P = .04 for interaction), total mortality (P = .04 for interaction), and global index of chronic diseases (P = .009 for interaction). CONCLUSIONS Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality. A decreased risk of breast cancer persisted. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611
A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause ...mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality.
Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71–93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models.
Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68·3, 48·9, 41·1, and 43·3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0·72 (95% CI 0·60–0·87), 0·60 (0·49–0·74), and 0·65 (0·53–0·80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1·64, 95% CI 1·13–2·36).
We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4·65 mmol/L) in elderly people.
OBJECTIVE:--Experimental and epidemiologic studies suggest that calcium and vitamin D may reduce the risk of developing diabetes. We examined the effect of calcium plus vitamin D supplementation on ...the incidence of drug-treated diabetes in postmenopausal women. RESEARCH DESIGN AND METHODS--The Women's Health Initiative Calcium/Vitamin D Trial randomly assigned postmenopausal women to receive 1,000 mg elemental calcium plus 400 IU of vitamin D3 daily, or placebo, in a double-blind fashion. Among 33,951 participants without self-reported diabetes at baseline, we ascertained by treatment assignment new diagnoses of diabetes treated with oral hypoglycemic agents or insulin. Effects of the intervention on fasting measurements of glucose, insulin, and insulin resistance were examined among a subset of participants. RESULTS:--Over a median follow-up time of 7 years, 2,291 women were newly diagnosed with diabetes. The hazard ratio for incident diabetes associated with calcium/vitamin D treatment was 1.01 (95% CI 0.94-1.10) based on intention to treat. This null result was robust in subgroup analyses, efficacy analyses accounting for nonadherence, and analyses examining change in laboratory measurements. CONCLUSIONS:--Calcium plus vitamin D3 supplementation did not reduce the risk of developing diabetes over 7 years of follow-up in this randomized placebo-controlled trial. Higher doses of vitamin D may be required to affect diabetes risk, and/or associations of calcium and vitamin D intake with improved glucose metabolism observed in nonrandomized studies may be the result of confounding or of other components of foods containing these nutrients.
Inflammatory responses are associated with cardiovascular disease and may be associated with dementing disease. We evaluated the long‐term prospective association between dementia and ...high‐sensitivity C‐reactive protein, a nonspecific marker of inflammation. Data are from the cohort of Japanese American men who were seen in the second examination of the Honolulu Heart Program (1968–1970) and subsequently were reexamined 25 years later for dementia in the Honolulu‐Asia Aging Study (1991–1996). In a random subsample of 1,050 Honolulu‐Asia Aging Study cases and noncases, high‐sensitivity C‐reactive protein concentrations were measured from serum taken at the second examination; dementia was assessed in a clinical examination that included neuroimaging and neuropsychological testing and was evaluated using international criteria. Compared with men in the lowest quartile (<0.34mg/L) of high‐sensitivity C‐reactive protein, men in the upper three quartiles had a 3‐fold significantly increased risk for all dementias combined, Alzheimer's disease, and vascular dementia. For vascular dementia, the risk increased with increasing quartile. These relations were independent of cardiovascular risk factors and disease. These data support the view that inflammatory markers may reflect not only peripheral disease, but also cerebral disease mechanisms related to dementia, and that these processes are measurable long before clinical symptoms appear.
Objectives
To determine how the number of geriatric syndromes is associated with incident disability in community‐based populations of older adults.
Design
Longitudinal analysis from the Women's ...Health Initiative Observational Study (WHI‐OS).
Setting
Community.
Participants
Twenty‐nine thousand five hundred forty‐four women aged 65 and older enrolled in the WHI‐OS and free of disability in activities of daily living (ADLs) at baseline.
Measurements
Geriatric syndromes (high depressive symptoms, dizziness, falls, hearing or visual impairment, osteoporosis, polypharmacy, syncope, sleep disturbance, and urinary incontinence) were self‐reported at baseline and 3‐year follow‐up. Disability was defined as dependence in any ADL and was assessed at baseline and follow‐up. Chronic diseases were measured according to a modified Charlson Index.
Results
Geriatric syndromes were common in this population of women; 76.3% had at least one syndrome at baseline. Greater number of geriatric syndromes at baseline was significantly associated with greater risk of incident ADL disability at follow‐up (P ≤ .001). Adjusted risk ratios were 1.21 (95% confidence interval (CI) = 0.78–1.87) for a single syndrome and 6.64 (95% CI = 4.15–10.62) for five or more syndromes compared with no syndromes. These results were only slightly attenuated after adjustment for number of chronic diseases or pain.
Conclusion
Geriatric syndromes are significantly associated with onset of disability in older women; this association is not simply a result of chronic disease or pain. A better understanding of how these conditions contribute to disablement is needed. Geriatric syndrome assessment should be considered along with chronic disease management in the prevention of disability in older women.
OBJECTIVE: To examine whether lower serum levels of serum 25-hydroxyvitamin (OH) D 25(OH)D are associated with increased risk of developing type 2 diabetes. RESEARCH DESIGN AND METHODS: A post hoc ...analysis of three nested case-control studies of fractures, colon cancer, and breast cancer that measured serum 25(OH)D levels in women participating in the Women's Health Initiative (WHI) Clinical Trials and Observational Study who were free of prevalent diabetes at baseline. Diabetes was defined as self-report of physician diagnosis or receiving insulin or oral hypoglycemic medication. We used inverse probability weighting to make the study population representative of the WHI population as a whole. Weighted logistic regression models compared 25(OH)D levels (divided into quartiles, clinical cut points <50, 50-<75, ≥75 nmol/L, or as a continuous variable) using the distribution of control subjects and adjusted for multiple confounding factors. RESULTS: Of 5,140 women (mean age 66 years) followed for an average of 7.3 years, 317 (6.2%) developed diabetes. Regardless of the cut points used or as a continuous variable, 25(OH)D levels were not associated with diabetes incidence in either age or fully adjusted models. Nor was any relationship found between 25(OH)D and incident diabetes when evaluated by strata of BMI, race/ethnicity, or randomization status in the Calcium Vitamin D trial. CONCLUSIONS: Lower serum 25(OH)D levels were not associated with increased risk of developing type 2 diabetes in this racially and ethnically diverse population of postmenopausal women.
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