Nutrient Metabolites Associated With Low D3Cr Muscle Mass, Strength, and Physical Performance in Older Men.

BACKGROUND: The relationship between amino acids, B vitamins, and their metabolites with D3-creatine (D3Cr) dilution muscle mass, a more direct measure of skeletal muscle mass, has not been investigated. We aimed to assess associations of plasma metabolites with D3Cr muscle mass, as well as muscle strength and physical performance in older men from the Osteoporotic Fractures in Men cohort study. METHODS: Out of 1 425 men (84.2 ±â€…4.1 years), men with the lowest D3Cr muscle mass (n = 100), slowest walking speed (n = 100), lowest grip strength (n = 100), and a random sample (n = 200) serving as a comparison group to the low groups were included. Metabolites were analyzed using liquid chromatography-tandem mass spectrometry. Metabolite differences between the low groups and random sample and their relationships with the muscle outcomes adjusted for confounders and multiple comparisons were assessed using t-test/Mann-Whitney-Wilcoxon and partial correlations, respectively. RESULTS: For D3Cr muscle mass, significant biomarkers (p < .001) with ≥10% fold difference and largest partial correlations were tryptophan (Trp; r = 0.31), kynurenine (Kyn)/Trp; r = -0.27), nicotinamide (Nam)/quinolinic acid (Quin; r = 0.21), and alpha-hydroxy-5-methyl-tetrahydrofolate (hm-THF; r = -0.25). For walking speed, hm-THF, Nam/Quin, and Quin had the largest significance and fold difference, whereas valine (r = 0.17), Trp (r = 0.17), HKyn/Xant (r = -0.20), neopterin (r = -0.17), 5-methyl-THF (r = -0.20), methylated folate (r = -0.21), and thiamine (r = -0.18) had the strongest correlations. Only hm-THF was correlated with grip strength (r = -0.21) and differed between the low group and the random sample. CONCLUSIONS: Future interventions focusing on how the Trp metabolic pathway or hm-THF influences D3Cr muscle mass and physical performance declines in older adults are warranted.

Analysis of the Associations Between the Human Fecal Microbiome and Bone Density, Structure, and Strength: The Osteoporotic Fractures in Men (MrOS) Cohort.

In preclinical models, the composition and function of the gut microbiota have been linked to bone growth and homeostasis, but there are few available data from studies of human populations. In a hypothesis-generating experiment in a large cohort of community-dwelling older men (n = 831; age range, 78-98 years), we explored the associations between fecal microbial profiles and bone density, microarchitecture, and strength measured with total hip dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HRpQCT) (distal radius, distal and diaphyseal tibia). Fecal samples were collected and the 16S rRNA gene V4 hypervariable region sequenced. Sequences were bioinformatically processed through the DADA2 pipeline and then taxonomically assigned using SILVA. Generalized linear models as implemented in microbiome multivariable association with linear models (MaAsLin 2) were used to test for associations between skeletal measures and specific microbial genera. The abundances of four bacterial genera were weakly associated with bone density, structure, or strength (false discovery rate [FDR] ≤ 0.05), and the measured directions of associations of genera were generally consistent across multiple bone measures, supporting a role for microbiota on skeletal homeostasis. However, the associated effect sizes were small (log2 fold change < ±0.35), limiting power to confidently identify these associations even with high resolution skeletal imaging phenotypes, and we assessed the resulting implications for the design of future cohort-based studies. As in analogous examples from genomewide association studies, we find that larger cohort sizes will likely be needed to confidently identify associations between the fecal microbiota and skeletal health relying on 16S sequencing. Our findings bolster the view that the gut microbiome is associated with clinically important measures of bone health, while also indicating the challenges in the design of cohort-based microbiome studies. © 2022 American Society for Bone and Mineral Research (ASBMR).

Secondary analysis of change in physical function after exercise intervention in older adults with hyperkyphosis and low physical function.

BACKGROUND: Hyperkyphosis is common in older adults and associated with low physical function and reduced health related quality of life (HrQol). Improved kyphosis has been previously established in kyphosis-targeted interventions in randomized controlled trials in older adults with hyperkyphosis; however, evidence for improved physical function is conflicting. Few studies have investigated change in physical function after a targeted kyphosis intervention in older adults with low physical function. The primary aim in this descriptive study was to explore change in physical function after a progressive high-intensity 3-month targeted kyphosis exercise and posture training intervention in older adults with low physical function and hyperkyphosis. Secondary aims were to explore change in HrQol, spinal strength and spinal curvature, and adherence and safety of the intervention. METHODS: In this secondary analysis of the Specialized Center of Research (SCOR) Kyphosis randomized trial, 101 community dwelling older men and women with hyperkyphosis who completed the intervention were divided into a low function group (LFG) and high function group (HFG). Baseline characteristics were compared between LFG and HFG. Physical function, HrQol, spinal strength and spinal curvature (kyphosis and lordosis) pre/post intervention change scores were explored within and between groups. Adherence and adverse events were examined in the LFG and HFG. RESULTS: Twenty-six (26%) older adults were LFG, mean Short Phyiscal Performance Battery (SPPB) 9.62 (SD = 1.17) points. At baseline, the LFG was older than HFG (p = 0.005), experienced more pain, (p = 0.060), had worse physical function and HrQol (p ≤ 0.001), and comparable kyphosis (p = 0.640). SPPB changed 0.62 (95% CI: - 0.20 to 1.44) points in the LFG and - 0.04 (95%CI: - 0.28 to 0.19) points in the HFG, p = 0.020. Gait speed changed 0.04 (95% CI: - 0.02 to 0.10) m/s in the LFG. Kyphosis improved equally in both groups. Adherence to the intervention was 83% in the LFG and 79% in the HFG. There were no adverse events in either group. CONCLUSIONS: Older adults with low physical function and hyperkyphosis may improve physical function after a kyphosis targeted intervention. Older adults with low physical function may safely participate in targeted high-intensity kyphosis exercise and posture training. This observation needs to be confirmed in larger adequately powered studies. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01766674 .

Long-Term Efficacy of Treatment Effects After a Kyphosis Exercise and Posture Training Intervention in Older Community-Dwelling Adults: A Cohort Study.

BACKGROUND AND PURPOSE: Treatments that prevent worsening kyphosis are important due to the progressive nature of kyphosis with aging. We assessed long-term efficacy of treatment effects after a short-term kyphosis exercise and posture training intervention in a cohort study among older adults with hyperkyphosis, and investigated whether long-term treatment effects differ among males and females. METHODS: In the original kyphosis intervention, 112 older adults enrolled in a waitlist design randomized controlled trial. One hundred three participants, mean age 70.0 (5.7) years and kyphosis 52.0° (7.4°), completed a twice weekly, 3-month, group exercise and posture training intervention, and were eligible to enroll in the follow-up study. We compared (1) change in outcomes pre-/postintervention to change postintervention over the follow-up period, (2) change in outcomes pre-/postintervention and postintervention to follow-up, stratified by sex, and (3) long-term change postintervention to follow-up in males and females. Primary outcome was change in kyphometer-measured thoracic kyphosis. Secondary outcomes were change in lumbar lordosis, objective measures of physical function, self-reported measures of physical activity, and health-related quality of life (HRQoL). RESULTS AND DISCUSSION: Forty-three participants, 42% of the eligible cohort, returned for follow-up, a mean 3.0 (0.7) years after completing the original intervention. Participants (27 females and 16 males) were 73.8 (6.1) years old, with mean kyphosis 48.9° (11.9°) at follow-up. Kyphosis declined -1.5° (95% confidence interval [CI]: -3.9° to 1.0°) postintervention to follow-up and this was no different than change pre-/postintervention, P = .173. Lordosis improved 8.9° (95% CI: 6.2° to 11.6°), more than change pre-/postintervention, P < .001. Gait speed measure of physical function increased 0.08 (95% CI: 0.02 to 0.14) m/s, Physical Activity Scale for the Elderly (PASE) measure of physical activity increased 4 (95% CI: -16 to 24) points, and Patient-Reported Outcomes Measurement Information System (PROMIS) mental health T-score measure of HRQoL increased 1.1 (95% CI: -1.0 to 3.1) points, but these improvements were not significantly more than change pre-/postintervention, P > .050. Other measures of physical function (modified Physical Performance Test [PPT], Timed Up and Go, and 6-minute walk) and HRQoL (Scoliosis Research Society [SRS-30] self-image and PROMIS physical function and physical health) declined at follow-up, significantly more than change pre/postintervention, P ≤ .050. Comparing change in outcomes pre-/postintervention and postintervention to follow-up, stratified by sex, both males and females increased lordosis, and decreased modified PPT and 6-minute walk measures of physical function, P < .050. Males and females differed in long-term change postintervention to follow-up. Time loaded standing and PASE improved in females compared with males, P = .008 and P = .092, respectively, and PROMIS mental health, physical health, and physical function declined in females compared with males, P = .073, P = .025, and P = .005, respectively. CONCLUSIONS: In our follow-up study, a mean of 3.0 (0.07) years after a 3-month kyphosis exercise and posture training intervention, kyphosis maintained and did not progress as expected with age. There was long-term improvement in lordosis. Compared with treatment effects from the short-term intervention, gait speed maintained equally well in males and females, while trunk endurance improved in females. Further investigation of long-term benefits of a short-term kyphosis exercise and posture training intervention is warranted.

Individual and joint trajectories of change in bone, lean mass and physical performance in older men.

BACKGROUND: Declines in bone, muscle and physical performance are associated with adverse health outcomes in older adults. However, few studies have described concurrent age-related patterns of change in these factors. The purpose of this study was to characterize change in four properties of muscle, physical performance, and bone in a prospective cohort study of older men. METHODS: Using repeated longitudinal data from up to four visits across 6.9 years from up to 4681 men (mean age at baseline 72.7 yrs. ±5.3) participating in the Osteoporotic Fractures in Men (MrOS) Study, we used group-based trajectory models (PROC TRAJ in SAS) to identify age-related patterns of change in four properties of muscle, physical performance, and bone: total hip bone mineral (BMD) density (g/m2) and appendicular lean mass/ht2 (kg/m2), by DXA; grip strength (kg), by hand dynamometry; and walking speed (m/s), by usual walking pace over 6 m. We also described joint trajectories in all pair-wise combinations of these measures. Mean posterior probabilities of placement in each trajectory (or joint membership in latent groups) were used to assess internal reliability of the model. The number of trajectories for each individual factor was limited to three, to ensure that the pair-wise determination of joint trajectories would yield a tractable number of groups as well as model fit considerations. RESULTS: The patterns of change identified were generally similar for all measures, with three district groups declining over time at roughly similar rates; joint trajectories revealed similar patterns with no cross-over or convergence between groups. Mean posterior probabilities for all trajectories were similar and consistently above 0.8 indicating reasonable model fit to the data. CONCLUSIONS: Our description of trajectories of change with age in bone mineral density, grip strength, walking speed and appendicular lean mass found that groups identified by these methods appeared to have little crossover or convergence of change with age, even when considering joint trajectories of change in these factors.

Physical Activity Trajectories and Associated Changes in Physical Performance in Older Men: The MrOS Study.

BACKGROUND: Physical activity (PA) is important to maintaining functional independence. It is not clear how patterns of change in late-life PA are associated with contemporaneous changes in physical performance measures. METHODS: Self-reported PA, gait speed, grip strength, timed chair stand, and leg power were assessed in 3,865 men aged ≥ 65 years at baseline (2000-2002) and Year 7 (2007-2009). Group-based trajectory modeling, using up to four PA measures over this period, identified PA trajectories. Multivariate linear regression models (adjusted least square mean [95% confidence interval {CI}]) described associations between-PA trajectories and concurrent changes in performance. RESULTS: Three discrete PA patterns were identified, all with declining PA. Linear declines in each performance measure (baseline to Year 7) were observed across all three PA groups, but there was some variability in the rate of decline. Multivariate models assessing the graded response by PA trajectory showed a trend where the high-activity group had the smallest declines in performance while the low-activity group had the largest (p-for trend < .03). Changes in the high-activity group were the following: gait speed (-0.10 m/s [-0.12, -0.08]), grip strength (-3.79 kg [-4.35, -3.23]), and chair stands (-0.38 [-0.50, -0.25]), whereas changes in the low-activity group were the following: gait speed (-0.16 [-0.17, -0.14]), grip strength (-4.83 kg [-5.10, -4.55]), and chair stands (-0.53 [-0.59, -0.46]). Between-group differences in leg power trajectories across PA patterns were not significant. CONCLUSIONS: Declines in functional performance were higher among those with lower PA trajectories, providing further evidence for the interrelationship between changes in PA and performance during old age.

Comparing Analytical Methods for the Gut Microbiome and Aging: Gut Microbial Communities and Body Weight in the Osteoporotic Fractures in Men (MrOS) Study.

Determining the role of gut microbial communities in aging-related phenotypes, including weight loss, is an emerging gerontology research priority. Gut microbiome datasets comprise relative abundances of microbial taxa that necessarily sum to 1; analysis ignoring this feature may produce misleading results. Using data from the Osteoporotic Fractures in Men (MrOS) study (n = 530; mean [SD] age = 84.3 [4.1] years), we assessed 163 genera from stool samples and body weight. We compared conventional analysis, which does not address the sum-to-1 constraint, to compositional analysis, which does. Specifically, we compared elastic net regression (for variable selection) and conventional Bayesian linear regression (BLR) and network analysis to compositional BLR and network analysis; adjusting for past weight, height, and other covariates. Conventional BLR identified Roseburia and Dialister (higher weight) and Coprococcus-1 (lower weight) after multiple comparisons adjustment (p < .0125); plus Sutterella and Ruminococcus-1 (p < .05). No conventional network module was associated with weight. Using compositional BLR, Coprococcus-2 and Acidaminococcus were most strongly associated with higher adjusted weight; Coprococcus-1 and Ruminococcus-1 were most strongly associated with lower adjusted weight (p < .05), but nonsignificant after multiple comparisons adjustment. Two compositional network modules with respective hub taxa Blautia and Faecalibacterium were associated with adjusted weight (p < .01). Findings depended on analytical workflow. Compositional analysis is advocated to appropriately handle the sum-to-1 constraint.

Reliability of sagittal vertical axis measurement and association with measures of age-related hyperkyphosis.

[Purpose] Persons with age-related hyperkyphosis often have concomitant sagittal plane imbalance of the spine. This study investigated the reliability of sagittal vertical axis (SVA) measurement of sagittal balance, association between thoracic Cobb angle of kyphosis and SVA measure of sagittal balance, and compared the degree of SVA in males and females with age-related hyperkyphosis. [Participants and Methods] Measurements of SVA and Cobb angle of kyphosis were obtained from baseline radiographs of 112 community-dwelling males and females, mean age 70.0 (SD=5.7) years with kyphosis ≥40 degrees, recruited for a randomized controlled trial. Spearman correlation coefficients were used to determine associations between SVA and kyphosis, and Wilcoxon nonparametric tests to compare SVA between genders. [Results] SVA was acquired with excellent intra-rater [0.95 (95% CI: 0.88, 0.98)] and inter-rater reliability [0.93 (95% CI: 0.83,0.97)]. There was no significant correlation between Cobb angle of thoracic kyphosis and SVA, (r=-0.05). More males than females had sagittal imbalance (SVA≥5 cm). [Conclusion] In older adults with hyperkyphosis, SVA was a reliable measure of sagittal balance, and more extreme in males. SVA was not associated with Cobb angle of thoracic kyphosis, and could be considered an independent phenotype of age-related hyperkyphosis to be targeted in future intervention trials.

The Association Between Trajectories of Physical Activity and All-Cause and Cause-Specific Mortality.

Background: The benefits of physical activity (PA) for health have primarily been evaluated during midlife. Whether patterns of change in late-life PA associate with overall and cause-specific mortality remains unclear. Methods: We examined the association between PA trajectories and subsequent mortality among 3,767 men aged ≥65 years. Men self-reported PA using the Physical Activity Scale for the Elderly (PASE) at up to four time points from 2000 through 2009 (Year 7); mortality was assessed over an average of 7.1 years after the Year 7 contact. Group-based trajectory modeling identified patterns of PA change. Cox proportional hazards models described associations between patterns of change in PA, Year 7 PA, and subsequent mortality risk. Results: Three discrete PA patterns were identified, all with declining PA. Compared to low-activity declining men, moderate (hazard ratio [HR] = 0.78; 95% confidence interval [CI]: 0.70, 0.88) and high-activity (HR = 0.69, 95% CI: 0.57, 0.83) declining groups were associated with lower risk of all-cause mortality. Among models with a single time point, the last time point (Year 7 PA score) was a strong predictor of mortality with HR = 0.85 (95% CI: 0.78, 0.93) per SD increase in PASE score. PA patterns were not a risk factor for mortality after adjustment for the Year 7 PA score. Conclusions: Recent PA levels are a stronger indicator of subsequent mortality risk than PA patterns reported over the prior 7 years or prior PA level, suggesting that current PA rather than history of PA is the most relevant parameter in clinical settings.

APOEε4 and slow wave sleep in older adults.

Slow wave (or stage N3) sleep has been linked to a variety of cognitive processes. However, the role of stage N3 in the elderly is debated. The link between stage N3 and episodic memory may be weakened or changed in the older adult population, possibly due to several altered mechanisms impacting the cellular structure of the brain. The bases for the age-related dissociation between stage N3 and cognition are not understood. Since APOEε4 status is the strongest genetic risk factor for cognitive decline, we assessed whether the ε4 allele is associated with stage N3 sleep. Participants were from the population-based Osteoporotic Fractures in Men (MrOS) cohort with polysomnography and APOEε4 genotype data (n = 2,302, 100% male, mean age 76.6 years). Sleep stages were objectively measured using overnight in-home polysomnography and central electroencephalogram data were used to score stage N3 sleep. Cognitive function was assessed using the Modified Mini Mental State Exam (3MS). The APOE rs429358 single nucleotide polymorphism, which defines the APOEε4 allele, was genotyped using a custom genotyping array. Total time in stage N3 sleep was significantly higher (p<0.0001) among the 40 MrOS participants carrying two copies of the ε4 allele (62±5.2 minutes) compared with 43±1.5 minutes for carriers of one ε4 allele (n = 515) and 40±0.8 minutes for ε4 non-carriers (n = 1747). All results were independent of sleep efficiency, number of sleep cycles, and apnea hypopnea index. These findings support an association between APOEε4 genotype and sleep stage N3 in the elderly. Increased total stage N3 duration among ε4/ε4 carriers does not appear to reflect compensation for prior cognitive decline and may reflect overactive downscaling of synapses during sleep. If confirmed, these results might in part explain the high risk of age-related cognitive decline and AD among APOE ε4/ε4 carriers.

Vertebral Fracture Risk in Diabetic Elderly Men: The MrOS Study.

Type 2 diabetes (T2DM) is associated with a significant increase in risk of nonvertebral fractures, but information on risk of vertebral fractures (VFs) in subjects with T2DM, particularly among men, is lacking. Furthermore, it is not known whether spine bone mineral density (BMD) can predict the risk of VF in T2DM. We sought to examine the effect of diabetes status on prevalent and incident vertebral fracture, and to estimate the effect of lumbar spine BMD (areal and volumetric) as a risk factor for prevalent and incident morphometric vertebral fracture in T2DM (n = 875) and nondiabetic men (n = 4679). We used data from the Osteoporotic Fractures in Men (MrOS) Study, which enrolled men aged ≥65 years. Lumbar spine areal BMD (aBMD) was measured with dual-energy X-ray absorptiometry (DXA), and volumetric BMD (vBMD) by quantitative computed tomography (QCT). Prevalence (7.0% versus 7.7%) and incidence (4.4% versus 4.5%) of VFs were not higher in T2DM versus nondiabetic men. The risk of prevalent (OR, 1.05; 95% CI, 0.78 to 1.40) or incident vertebral-fracture (OR, 1.28; 95% CI, 0.81 to 2.00) was not higher in T2DM versus nondiabetic men in models adjusted for age, clinic site, race, BMI, and aBMD. Higher spine aBMD was associated with lower risk of prevalent VF in T2DM (OR, 0.55; 95% CI, 0.48 to 0.63) and nondiabetic men (OR, 0.66; 95% CI, 0.5 to 0.88) (p for interaction = 0.24) and of incident VF in T2DM (OR, 0.50; 95% CI, 0.41 to 0.60) and nondiabetic men (OR, 0.54; 95% CI, 0.33 to 0.88) (p for interaction = 0.77). Results were similar for vBMD. In conclusion, T2DM was not associated with higher prevalent or incident VF in older men, even after adjustment for BMI and BMD. Higher spine aBMD and vBMD are associated with lower prevalence and incidence of VF in T2DM as well as nondiabetic men. © 2017 American Society for Bone and Mineral Research.

Sex differences in response to targeted kyphosis specific exercise and posture training in community-dwelling older adults: a randomized controlled trial.

BACKGROUND: Hyperkyphosis, an excessive anterior curvature in the thoracic spine, is associated with reduced health status in older adults. Hyperkyphosis is highly prevalent, more common in older women than men. There is no standard intervention to reduce age-related hyperkyphosis. Sex differences in response to a kyphosis-specific exercise intervention are not known. METHODS: We conducted a randomized controlled trial of a targeted kyphosis-specific exercise and postural training program on the primary outcome Cobb angle of kyphosis, and investigated whether the magnitude of change differed between men and women. One hundred twelve participants aged ≥60 years with kyphosis ≥40° were enrolled and randomized to exercise or waitlist control, and 101 participants had analyzable baseline and follow-up radiographs for Cobb angle measurements. A group intervention including 10 participants per group was delivered by a physical therapist, 1-h, twice a week for 3-months. Controls were placed on a waitlist for 3 months before receiving a delayed intervention. Primary outcome was change from baseline to 3-months in Cobb angle measured from standing lateral spine radiographs. Secondary outcomes included change over 3-months in kyphometer-measured kyphosis, physical function and quality of life. Groups were combined for analysis after both received the intervention, and sex differences in response to the intervention were tested with ANOVA. RESULTS: Participants (60 women, 41 men) were 70.0 (SD = 5.7) years old with mean Cobb angle 55.9 (SD = 12.2) degrees at baseline. The active group had higher baseline modified Physical Performance Test scores than control, p = 0.03. Men had greater baseline kyphometer-measured kyphosis, p = 0.09, and higher bone mineral density (BMD), spine strength, more vertebral fractures and diffuse idiopathic skeletal hyperostosis (DISH) than women, p ≤ 0.01. There was no statistically significant difference between groups in change in Cobb at 3-months, p = 0.09, however change in kyphometer-measured kyphosis differed by 4.8 (95% CI:-6.8,-2.7) degrees, p < 0.001, favoring the active group. There were no differences between men and women in change in either kyphosis measurement after intervention, p > 0.1. CONCLUSIONS: A 3-month targeted spine strengthening exercise and posture training program reduced kyphometer-measured, but not radiographic-measured kyphosis. Despite sex differences in baseline kyphosis, BMD, spine strength, fractures and DISH, sex did not affect treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01766674.

Trajectories of the relationships of physical activity with body composition changes in older men: the MrOS study.

BACKGROUND: Excess adiposity gains and significant lean mass loss may be risk factors for chronic disease in old age. Long-term patterns of change in physical activity (PA) and their influence on body composition decline during aging has not been characterized. We evaluated the interrelationships of PA and body composition at the outset and over longitudinal follow-up to changes in older men. METHODS: Self-reported PA by the Physical Activity Scale for the Elderly (PASE), clinic body weight, and whole-body lean mass (LM) and fat mass, by dual-energy x-ray absorptiometry (DXA), were assessed in 5964 community-dwelling men aged ≥65 years at baseline (2000-2002) and at two subsequent clinic visits up until March 2009 (an average 4.6 and 6.9 years later). Group-based trajectory modeling (GBTM) identified patterns of change in PA and body composition variables. Relationships of PA and body composition changes were then assessed. RESULTS: GBTM identified three discrete trajectory patterns, all with declining PA, associated primarily with initial PA levelshigh-activity (7.2% of men), moderate-activity (50.0%), and low-activity (42.8%). In separate models, GBTM identified eight discrete total weight change groups, five fat mass change groups, and six LM change groups. Joint trajectory modeling by PA and body composition group illustrated significant declines in total weight and LM, whereas fat mass levels were relatively unchanged among high-activity and low-activity-declining groups, and significantly increased in the moderate-activity-declining group. CONCLUSION: Although patterns of change in PA and body composition were identified, groups were primarily differentiated by initial PA or body composition rather than by distinct trajectories of change in these variables.

The complex genetics of gait speed: genome-wide meta-analysis approach.

Emerging evidence suggests that the basis for variation in late-life mobility is attributable, in part, to genetic factors, which may become increasingly important with age. Our objective was to systematically assess the contribution of genetic variation to gait speed in older individuals. We conducted a meta-analysis of gait speed GWASs in 31,478 older adults from 17 cohorts of the CHARGE consortium, and validated our results in 2,588 older adults from 4 independent studies. We followed our initial discoveries with network and eQTL analysis of candidate signals in tissues. The meta-analysis resulted in a list of 536 suggestive genome wide significant SNPs in or near 69 genes. Further interrogation with Pathway Analysis placed gait speed as a polygenic complex trait in five major networks. Subsequent eQTL analysis revealed several SNPs significantly associated with the expression of PRSS16, WDSUB1 and PTPRT, which in addition to the meta-analysis and pathway suggested that genetic effects on gait speed may occur through synaptic function and neuronal development pathways. No genome-wide significant signals for gait speed were identified from this moderately large sample of older adults, suggesting that more refined physical function phenotypes will be needed to identify the genetic basis of gait speed in aging.

Association of Polymorphisms in Connective Tissue Growth Factor and Epidermal Growth Factor Receptor Genes With Human Longevity.

Growth pathways play key roles in longevity. The present study tested single-nucleotide polymorphisms (SNPs) in the connective tissue growth factor gene (CTGF) and the epidermal growth factor receptor gene (EGFR) for association with longevity. Comparison of allele and genotype frequencies of 12 CTGF SNPs and 41 EGFR SNPs between 440 American men of Japanese ancestry aged ≥95 years and 374 men of average life span revealed association with longevity at the p < .05 level for 2 SNPs in CTGF and 7 in EGFR. Two in CTGF and two in EGFR remained significant after Bonferroni correction. The SNPs of both CTGF and EGFR were in a haplotype block in each respective gene. Haplotype analysis confirmed the suggestive association found by χ2 analysis. We noted an excess of heterozygotes among the longevity cases, consistent with heterozygote advantage in living to extreme old age. No associations of the most significant SNPs were observed in whites or Koreans. In conclusion, the present findings indicate that genetic variation in CTGF and EGFR may contribute to the attainment of extreme old age in Japanese. More research is needed to confirm that genetic variation in CTGF and EGFR contributes to the attainment of extreme old age across human populations.

Longevity-Associated FOXO3 Genotype and its Impact on Coronary Artery Disease Mortality in Japanese, Whites, and Blacks: A Prospective Study of Three American Populations.

BACKGROUND: We recently reported that protection against coronary artery disease (CAD) mortality is the major contributor to longer life associated with FOXO3 genotype. The present study examined this relation in more detail. METHODS: We performed a 15-year observational study of 3,584 older American men of Japanese ancestry from the Kuakini Honolulu Heart Program cohort and 1,595 White and 1,067 Black elderly individuals from the Health Aging and Body Composition study. RESULTS: Multivariate Cox regression models demonstrated that carriage of the longevity-associated G allele of FOXO3 single nucleotide polymorphisms rs2802292 was a protective factor against CAD mortality in all three populations. In Japanese and Whites, but not in Blacks, the protective effect of the G allele was little changed in models adjusted for other major risk factors. Population-attributable risk (PAR) models found that the nonprotective TT genotype contributed 15%, 9%, and 3% to CAD mortality risk in Japanese, White, and Black Americans, respectively, and was one of the top three contributing factors to CAD mortality. In Japanese, this effect size was comparable with hypertension (15%), but in Whites and Blacks PAR for hypertension was higher (29% and 26%, respectively). G-allele carriers had lower plasma TNF-α than noncarriers, suggesting inflammation as a potential mediating factor for CAD mortality risk. CONCLUSION: FOXO3 genotype is an important risk factor for CAD mortality in older populations. More research is needed to identify potential mechanisms and targets for intervention.

Cross-Sectional and Longitudinal Associations of Diffuse Idiopathic Skeletal Hyperostosis and Thoracic Kyphosis in Older Men and Women.

OBJECTIVE: To investigate cross-sectional and longitudinal associations of diffuse idiopathic skeletal hyperostosis (DISH) and thoracic kyphosis in older persons. METHODS: DISH and kyphosis were assessed in 1,500 men from the Osteoporotic Fractures in Men (MrOS) study and in 1,267 women from the Study of Osteoporotic Fractures (SOF). DISH was assessed using baseline lateral spine radiographs, and Cobb angle of kyphosis was measured from baseline and followup radiographs, a mean 4.6 years later in men, and 3.7 and 15 years later in women. Linear regression was used to analyze associations of DISH with baseline Cobb angle and with percent annualized change in Cobb angle. We tested for heterogeneity among studies. RESULTS: DISH was identified in 222 participants in MrOS (15%) and in 156 participants in SOF (12%). Participants with DISH in both cohorts had higher baseline Cobb angles (P < 0.05), after adjustment for covariates. After approximately 4 years of followup, there was no significant difference in annualized percent change in Cobb angle in those with DISH compared to those without DISH (P > 0.05) for men or women. Women with DISH had less kyphosis progression over 15 years (0.25% less annualized change in Cobb) than those without DISH. CONCLUSION: Prevalent DISH is associated with greater kyphosis in older men and women, and is not significantly associated with a change in kyphosis over 4-5 years. However, in women followed over 15 years, DISH was associated with less progression of kyphosis. These results suggest that DISH influences kyphosis and may slow progression over the long term. Additional studies of DISH/kyphosis associations are warranted to understand the functional implications of this finding.

Association of Sleep Disordered Breathing with Erectile Dysfunction in Community Dwelling Older Men.

PURPOSE: We investigated the association between sleep disordered breathing and erectile dysfunction in older men. MATERIALS AND METHODS: We performed a cross-sectional analysis of community dwelling men age 67 years or older enrolled in the Osteoporotic Fractures in Men Sleep Study. Participants underwent overnight polysomnography (2003 to 2005) and completed sexual health questionnaires (2005 to 2006). We defined sleep disordered breathing using the apnea-hypopnea index or nocturnal hypoxemia. Erectile dysfunction was defined using the MMAS (Massachusetts Male Aging Study) scale and, in sexually active men, the International Index of Erectile Function. We used logistic regression to examine the association between sleep disordered breathing and erectile dysfunction. RESULTS: Mean participant age was 76±5 years. Of the 2,676 men completing the MMAS, 70% had moderate to complete erectile dysfunction. Among 1,099 sexually active men completing the IIEF-5 (5-item International Index of Erectile Function), 26% had moderate to severe erectile dysfunction. A higher apnea-hypopnea index was associated with greater odds of MMAS defined moderate to complete erectile dysfunction after adjusting for age and study site (OR 1.39, 95% CI 1.00-1.92 for severe sleep disordered breathing vs none, p trend=0.008), but not after further adjustment for body mass index, socioeconomic status and comorbidities (OR 1.05, 95% CI 0.75-1.49, p trend=0.452). Greater nocturnal hypoxemia was associated with increased odds of MMAS defined moderate to complete erectile dysfunction (unadjusted OR 1.36, 95% Cl 1.04-1.80 vs none) but this was attenuated after adjustment for age and study site (OR 1.24, 95% CI 0.92-1.66). Sleep disordered breathing was not associated with erectile dysfunction by 5-item International Index of Erectile Function. CONCLUSIONS: In this cross-sectional analysis in older men sleep disordered breathing was associated with higher odds of erectile dysfunction in unadjusted analyses that was largely explained by higher body mass index and increased comorbidity among men with sleep disordered breathing. Prospective studies accounting for obesity and multimorbidity would further clarify the association of sleep disordered breathing and erectile dysfunction.