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Scheuermaier K.,Brigham and Womens Hospital | Scheuermaier K.,Harvard University | Laffan A.M.,Brigham and Womens Hospital | Laffan A.M.,San Francisco Coordinating Center | Duffy J.F.,Brigham and Womens Hospital
Journal of Biological Rhythms | Year: 2010

Aging is associated with an earlier timing of circadian rhythms and a shorter phase angle between wake time and the timing of melatonin secretion or the core body temperature nadir. Light has a phase-dependent effect on the circadian pacemaker, and modifications of habitual light exposure in older people could contribute to a change in the timing of circadian rhythms or in the phase angle of entrainment. In this study, we compare natural light exposure of community-dwelling older and young subjects studied at the same time of year, focusing on the pattern of light exposure across the waking day. We recorded light exposure data for 3 to 8 days from 22 older (aged 66.01 ± 5.83) and 22 young subjects (aged 23.41 ± 4.57), living at home on self-selected sleepwake schedules, and matched for time of year. All subjects were from New England (latitude 42.3° N to 43° N). We compared the percentage of the waking day spent by older and young subjects at 4 different light levels (from very dim to very bright). We compared hourly averaged light exposure data in each group according to clock time and with respect to each subjects daily sleepwake times. Although both age groups spent more than half of their waking hours in dim or moderate room light intensity (<100 lux), we found that the older subjects spent a significantly greater percentage of their waking day in the brighter light levels (≥1000 lux); their hourly averaged light exposure levels were also significantly greater whether we examined the data with respect to absolute clock time, to wake time, or to bed time, and this was true across all seasons. We found that healthy older people were exposed to significantly higher levels of light throughout their waking day than young people. Differences in natural light exposure may contribute to the age-related phase advance of the circadian pacemaker and its later timing relative to the sleepwake cycle. This hypothesis should be explored further in carefully designed prospective studies. © 2010 SAGE Publications.

Kahn A.J.,San Francisco Coordinating Center | Kahn A.J.,Buck Institute for Research on Aging
Journals of Gerontology - Series A Biological Sciences and Medical Sciences | Year: 2015

In June 2013, a workshop was convened in San Francisco to explore, in depth, the role of the Forkhead transcription factor FOXO3 (and related FOXOs) in development, aging, and, in particular, exceptional longevity. The presentations covered results derived from model systems, computational analysis and bioinformatics, and genomics and genome-wide association studies of a number of cohorts. Although the data collectively strongly reinforce FOXO3 and the FOXO/FOXO3 pathway as very important determinants in aging and life span, much of the detail of how the latter is achieved still remains unknown, in part, because of the very large number of genes (∼2,200 in Caenorhabditis elegans) the transcription factor is involved in helping regulate. Particularly challenging at the present time is understanding the association of apparently nonfunctional specific variants (single nucleotide polymorphisms) of FOXO3 and exceptional longevity in humans, a finding replicated in a number of studies. Nonetheless, as summarized in this report, valuable information and insights were presented at the workshop on the transcription factor including but not limited to its role in determining longevity in C elegans and Drosophila (in flies, eg, an important interaction in aging occurs between dFOXO and the transforming growth factor-β/activin pathway), stem cell function and aging (notably in hematopoiesis), downstream regulatory activity (eg, by binding near sites of RNAse occupancy and altering chromatin structure), and as a potential target for the development a healthy aging drug (in this example, using compounds developed and screened to effect FOXO function in cancer cells). © 2014 The Author.

Premaor M.O.,Federal University of Santa Maria | Ensrud K.,University of Minnesota | Lui L.,California Pacific Medical Center Research Institute | Parker R.A.,University of Cambridge | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2011

Context: A high prevalence of obesity has recently been reported in postmenopausal women with low trauma fracture, suggesting that higher bone mineral density (BMD) in obese individuals may not be protective against fracture. Objective: The aim of this study was to compare BMD and other risk factors for nonvertebral fracture in 1377 obese postmenopausal women. Design: Characteristics of obese women with and without incident nonvertebral fracture were investigated among the prospective cohort in the Study of Osteoporotic Fractures. Setting: The Study of Osteoporotic Fractures is a multicenter study of 9704 women (>99% Caucasian) aged 65 yr and over who were recruited between September 1986 and October 1988 from population-based listings at four U.S. clinical centers. Main Outcome Measure: The main outcome measure was nonvertebral fracture. Results: BMDT-scores in the spine, femoral neck, and total hip were significantly lower in obese women who experienced fractures than in obese women without fracture: mean differences, -0.56 [95% confidence interval (CI) = -0.73 to -0.39], -0.46 (95% CI = -0.57 to -0.36), and -0.51 (95% CI = -0.62 to -0.39), respectively (P < 0.0001 for all). A previous history of fracture [odds ratio = 1.69 (95% CI = 1.33-2.14); P < 0.0001] and femoral neck BMD [1.62 (95% CI = 1.42-1.85) per SD decrease in BMD; P < 0.0001] were independently associated with incident nonvertebral fracture. Conclusions: Obese postmenopausal women who sustain nonvertebral fractures have significantly lower BMD on average than obese women without fracture and are more likely to have a past history of fracture. Fractures in obese postmenopausal women thus exhibit some characteristics of fragility fractures. Copyright © 2011 by The Endocrine Society.

Black D.M.,University of California at San Francisco | Reid I.R.,University of Auckland | Cauley J.A.,University of Pittsburgh | Cosman F.,Helen Hayes Hospital | And 9 more authors.
Journal of Bone and Mineral Research | Year: 2015

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n = 95) and Z6P3 (n = 95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p = 0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. © 2015 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.

Lang T.,University of California at San Francisco | Cauley J.A.,University of Pittsburgh | Tylavsky F.,University of Tennessee Health Science Center | Bauer D.,University of California at San Francisco | And 2 more authors.
Journal of Bone and Mineral Research | Year: 2010

Fatty infiltration of muscle, myosteatosis, increases with age and results in reduced muscle strength and function and increased fall risk. However, it is unknown if increased fatty infiltration of muscle predisposes to hip fracture. We measured the mean Hounsfield unit (HU) of the lean tissue within the midthigh muscle bundle (thigh muscle HU, an indicator of intramuscular fat), its cross-sectional area (CSA, a measure of muscle mass) by computed tomography (CT), bone mineral density (BMD) of the hip and total-body percent fat by dual X-ray absorptiometry (DXA), isokinetic leg extensor strength, and the Short Physical Performance Battery (SPPB) in 2941 white and black women and men aged 70 to 79 years. Sixty-three hip fractures were validated during 6.6 years of follow-up. Proportional hazards regression analysis was used to assess the relative risk (RR) of hip fracture across variations in thigh muscle attenuation, CSA, muscle strength, and physical function for hip fracture. In models adjusted by age, race, gender, body mass index, and percentage fat, decreased thigh muscle HU resulted in increased risk of hip fracture [RR/SD=1.58; 95% confidence interval (CI) 1.10-1.99], an association that continued to be significant after further adjustment for BMD. In models additionally adjusted by CSA, muscle strength, and SPPB score, decreased thigh muscle HU but none of the other muscle parameters continued to be associated with an increased risk of hip fracture (RR/SD=1.42; 95% CI 1.03-1.97). Decreased thigh muscle HU, a measure of fatty infiltration of muscle, is associated with increased risk of hip fracture and appears to account for the association between reduced muscle strength, physical performance, and muscle mass and risk of hip fracture. This characteristic captures a physical characteristic of muscle tissue that may have importance in hip fracture etiology. © 2010 American Society for Bone and Mineral Research.

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