Catechol-O-methyltransferase (COMT) polymorphism predicts rapid gait speed changes in healthy older adults.

IMPORTANCE: Adapting one's gait speed to external circumstances is critical for safe ambulation. Dopamine (DA), critical for adapting to increased task demands, predicts usual gait speed and may exert a greater role in complex tasks like rapid gait speed. OBJECTIVE: We hypothesized that a genotypic proxy indicator of greater prefrontal DA signaling would predict significantly faster rapid gait. DESIGN: Longitudinal cohort study over 8 years. SETTING: Community-dwelling adults with no baseline mobility disability. PARTICIPANTS: N = 2353 participants from the Health ABC Study. MEASUREMENTS: Repeated measures of walking speed (meters/sec) were obtained in response to: "walk as fast as possible… (rapid gait) or "walk at your usual pace (usual gait)." Catechol-O-methyltransferase (COMT) val158met polymorphism indicated DA signaling (val/val = higher metabolism, lower DA signaling; met/met = lower metabolism, higher DA signaling). RESULTS: Participants declined in rapid gait from 1.55 (SD = 0.33) to 1.35 m/s (SD = 0.34). Across the full follow-up period, the met/met genotype was associated with significantly greater rapid gait slowing. In mixed effect models, between-group differences were independent of covariates, and remained similar after adjustment for sensorimotor function, cognition, depressive symptoms, and energy. Follow-up analyses indicated the met/met genotype had a significantly faster rapid gait speed compared to the val/val genotype for the first 3 years (p < 0.01) but not years 4-8 (p > 0.05). CONCLUSION: Greater prefrontal DA measured with COMT polymorphism may facilitate short-term adaptation to rapid walking demands that are lost over time. Studies should examine whether these effects are long-term and the underlying mechanistic pathways.

Weight management intervention identifies association of decreased DNA methylation age with improved functional age measures in older adults with obesity.

BACKGROUND: Assessing functional ability is an important component of understanding healthy aging. Objective measures of functional ability include grip strength, gait speed, sit-to-stand time, and 6-min walk distance. Using samples from a weight loss clinical trial in older adults with obesity, we examined the association between changes in physical function and DNA-methylation-based biological age at baseline and 12 weeks in 16 individuals. Peripheral blood DNA methylation was measured (pre/post) with the Illumina HumanMethylationEPIC array and the Hannum, Horvath, and PhenoAge DNA methylation age clocks were used. Linear regression models adjusted for chronological age and sex tested the relationship between DNA methylation age and grip strength, gait speed, sit-to-stand, and 6-min walk. RESULTS: Participant mean weight loss was 4.6 kg, and DNA methylation age decreased 0.8, 1.1, and 0.5 years using the Hannum, Horvath, and PhenoAge DNA methylation clocks respectively. Mean grip strength increased 3.2 kg. Decreased Hannum methylation age was significantly associated with increased grip strength (ß = -0.30, p = 0.04), and increased gait speed (ß = 0.02, p = 0.05), in adjusted models. Similarly, decreased methylation age using the PhenoAge clock was associated with significantly increased gait speed (ß = 0.02, p = 0.04). A decrease in Horvath DNA methylation age and increase in physical functional ability did not demonstrate a significant association. CONCLUSIONS: The observed relationship between increased physical functional ability and decreased biological age using DNA methylation clocks demonstrate the potential utility of DNA methylation clocks to assess interventional approaches to improve health in older obese adults. TRIAL REGISTRATION: National Institute on Aging (NIA), NCT03104192. Posted April 7, 2017, https://clinicaltrials.gov/ct2/show/NCT03104192.

Genome-wide association study of self-reported walking pace suggests beneficial effects of brisk walking on health and survival.

Walking is a simple form of exercise, widely promoted for its health benefits. Self-reported walking pace has been associated with a range of cardiorespiratory and cancer outcomes, and is a strong predictor of mortality. Here we perform a genome-wide association study of self-reported walking pace in 450,967 European ancestry UK Biobank participants. We identify 70 independent associated loci (P < 5 × 10-8), 11 of which are novel. We estimate the SNP-based heritability as 13.2% (s.e. = 0.21%), reducing to 8.9% (s.e. = 0.17%) with adjustment for body mass index. Significant genetic correlations are observed with cardiometabolic, respiratory and psychiatric traits, educational attainment and all-cause mortality. Mendelian randomization analyses suggest a potential causal link of increasing walking pace with a lower cardiometabolic risk profile. Given its low heritability and simple measurement, these findings suggest that self-reported walking pace is a pragmatic target for interventions aiming for general benefits on health.

The transcript expression levels of HNRNPM, HNRNPA0 and AKAP17A splicing factors may be predictively associated with ageing phenotypes in human peripheral blood.

Dysregulation of splicing factor expression is emerging as a driver of human ageing; levels of transcripts encoding splicing regulators have previously been implicated in ageing and cellular senescence both in vitro and in vivo. We measured the expression levels of an a priori panel of 20 age- or senescence-associated splicing factors by qRT-PCR in peripheral blood samples from the InCHIANTI Study of Aging, and assessed longitudinal relationships with human ageing phenotypes (cognitive decline and physical ability) using multivariate linear regression. AKAP17A, HNRNPA0 and HNRNPM transcript levels were all predictively associated with severe decline in MMSE score (p = 0.007, 0.001 and 0.008 respectively). Further analyses also found expression of these genes was associated with a performance decline in two other cognitive measures; the Trail Making Test and the Purdue Pegboard Test. AKAP17A was nominally associated with a decline in mean hand-grip strength (p = 0.023), and further analyses found nominal associations with two other physical ability measures; the Epidemiologic Studies of the Elderly-Short Physical Performance Battery and calculated speed (m/s) during a timed 400 m fast walking test. These data add weight to the hypothesis that splicing dyregulation may contribute to the development of some ageing phenotypes in the human population.

Meta-analysis identifies mitochondrial DNA sequence variants associated with walking speed.

Declines in walking speed are associated with a variety of poor health outcomes including disability, comorbidity, and mortality. While genetic factors are putative contributors to variability in walking, few genetic loci have been identified for this trait. We examined the role of mitochondrial genomic variation on walking speed by sequencing the entire mitochondrial DNA (mtDNA). Data were meta-analyzed from 1758 Lifestyle Interventions and Independence for Elders (LIFE) Study and replication data from 730 Health, Aging, and Body Composition (HABC) Study participants with baseline walking speed information. Participants were 69+ years old of diverse racial backgrounds (African, European, and other race/ethnic groups) and had a wide range of mean walking speeds [4-6 m (0.78-1.09 m/s) and 400 m (0.83-1.24 m/s)]. Meta-analysis across studies and racial groups showed that m.12705C>T, ND5 variant was significantly associated (p < 0.0001) with walking speed at both short and long distances. Replication and meta-analysis also identified statistically significant walking speed associations (p < 0.0001) between the m.5460.G>A, ND2 and m.309C>CT, HV2 variants at short and long distances, respectively. All results remained statistically significant after multiple comparisons adjustment for 499 mtDNA variants. The m.12705C>T variant can be traced to the beginnings of human global migration and that cells carrying this variant display altered tRNA expression. Significant pooled effects related to stopping during the long-distance walk test were observed across OXPHOS complexes I (p = 0.0017) and III (p = 0.0048). These results suggest that mtDNA-encoded variants are associated with differences in walking speed among older adults, potentially identifying those at risk of developing mobility impairments.

Dopamine-Related Genotypes and Physical Activity Change During an Intervention: The Lifestyle Interventions and Independence for Elders Study.

OBJECTIVES: To determine whether intervention-induced physical activity (PA) changes in sedentary older adults differed according to dopamine-related genotype. DESIGN: Randomized clinical trial (Lifestyle Interventions and Independence for Elders Trial (2010-13)). SETTING: Multicenter study, 8 U.S. PARTICIPANTS: Volunteer sample of sedentary adults aged 70 to 89 at risk of disability (N=1635). INTERVENTIONS: Structured PA versus health education (HE) for an average of 2.6 years. MEASUREMENTS: Single-nucleotide polymorphisms of dopamine-related genes (dopamine receptor (DR) D1, DRD2, DRD3, and catechol-O-methyltransferase (COMT)) were assessed. Average moderate to vigorous PA (MVPA) was calculated using accelerometry (min/d) at baseline and 6, 12, and 24 months. Between-arm MVPA differences according to genotype and genotype with square root-transformed MVPA separately according to arm were tested, stratified according to race, and adjusted for multiple comparisons. RESULTS: White participants in the PA arm (n=513) had higher average square root transformed MVPA (4.91±1.91)than those in the HE arm (n=538) (4.51±1.82) (p=.001). Between-arm differences were greater for DRD2 Met/Met (high dopamine; HE: 4.76±1.80, PA: 5.53±1.60, p=.03) than Val/Val (low dopamine; HE: 4.58±1.92, PA: 4.81±1.83, p=.16); results were similar for COMT. In the PA arm, DRD2 Met/Met was associated with higher average MVPA (5.39±2.00) than Met/Val (4.46±2.51) (p=.01) and Val/Val (4.65±2.71) (p=.01). There were no associations for other genes. Associations were not significant in blacks but followed similar trends. CONCLUSION: Higher dopamine signaling may support changes in PA during an intervention. The role of dopamine-related pathways in promoting PA participation and enhancing response to interventions in sedentary older adults should be studied. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01072500.

Genetic variants associated with physical performance and anthropometry in old age: a genome-wide association study in the ilSIRENTE cohort.

Unraveling the complexity of aging is crucial for understanding its mechanisms and its role as a risk factor for most chronic conditions. Advancements marked by genome-wide association studies (GWASs) have sparked interest in gene cataloguing in the context of aging and age-related conditions. Here, we used GWAS to explore whether single nucleotide polymorphisms (SNPs) were associated with functional and anthropometric parameters in a cohort of old community-dwellers enrolled in the ilSIRENTE study. Analyses were carried out in men and women aged 80+ years enrolled in the ilSIRENTE study (n = 286) and replicated in the inCHIANTI study (n = 1055). Genotyping was accomplished on Infinium Human610-QUAD version 1. In the ilSIRENTE population, genetic variants in ZNF295 and C2CD2 (rs928874 and rs1788355) on chromosome 21q22.3, were significantly associated with the 4-meter gait speed (rs928874, p = 5.61 × 10-8; rs1788355, p = 5.73 × 10-8). This association was not replicated in the inCHIANTI population. Our findings suggest that specific SNPs may be associated with a key measure of physical performance in older adults. GWASs using larger samples are needed to confirm these preliminary results to enhance our comprehension of complex age-associated phenomena.

Higher heritabilities for gait components than for overall gait scores may improve mobility in ducks.

BACKGROUND: Genetic progress in selection for greater body mass and meat yield in poultry has been associated with an increase in gait problems which are detrimental to productivity and welfare. The incidence of suboptimal gait in breeding flocks is controlled through the use of a visual gait score, which is a subjective assessment of walking ability of each bird. The subjective nature of the visual gait score has led to concerns over its effectiveness in reducing the incidence of suboptimal gait in poultry through breeding. The aims of this study were to assess the reliability of the current visual gait scoring system in ducks and to develop a more objective method to select for better gait. RESULTS: Experienced gait scorers assessed short video clips of walking ducks to estimate the reliability of the current visual gait scoring system. Kendall's coefficients of concordance between and within observers were estimated at 0.49 and 0.75, respectively. In order to develop a more objective scoring system, gait components were visually scored on more than 4000 pedigreed Pekin ducks and genetic parameters were estimated for these components. Gait components, which are a more objective measure, had heritabilities that were as good as, or better than, those of the overall visual gait score. CONCLUSIONS: Measurement of gait components is simpler and therefore more objective than the standard visual gait score. The recording of gait components can potentially be automated, which may increase accuracy further and may improve heritability estimates. Genetic correlations were generally low, which suggests that it is possible to use gait components to select for an overall improvement in both economic traits and gait as part of a balanced breeding programme.

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.