Circulating miRNA Signature Predicts Cancer Incidence in Lynch Syndrome-A Pilot Study.

Lynch syndrome (LS) is the most common autosomal dominant cancer syndrome and is characterized by high genetic cancer risk modified by lifestyle factors. This study explored whether a circulating miRNA (c-miR) signature predicts LS cancer incidence within a 4-year prospective surveillance period. To gain insight how lifestyle behavior could affect LS cancer risk, we investigated whether the cancer-predicting c-miR signature correlates with known risk-reducing factors such as physical activity, body mass index (BMI), dietary fiber, or NSAID usage. The study included 110 c-miR samples from LS carriers, 18 of whom were diagnosed with cancer during a 4-year prospective surveillance period. Lasso regression was utilized to find c-miRs associated with cancer risk. Individual risk sum derived from the chosen c-miRs was used to develop a model to predict LS cancer incidence. This model was validated using 5-fold cross-validation. Correlation and pathway analyses were applied to inspect biological functions of c-miRs. Pearson correlation was used to examine the associations of c-miR risk sum and lifestyle factors. hsa-miR-10b-5p, hsa-miR-125b-5p, hsa-miR-200a-3p, hsa-miR-3613-5p, and hsa-miR-3615 were identified as cancer predictors by Lasso, and their risk sum score associated with higher likelihood of cancer incidence (HR 2.72, 95% confidence interval: 1.64-4.52, C-index = 0.72). In cross-validation, the model indicated good concordance with the average C-index of 0.75 (0.6-1.0). Coregulated hsa-miR-10b-5p, hsa-miR-125b-5p, and hsa-miR-200a-3p targeted genes involved in cancer-associated biological pathways. The c-miR risk sum score correlated with BMI (r = 0.23, P < 0.01). In summary, BMI-associated c-miRs predict LS cancer incidence within 4 years, although further validation is required. PREVENTION RELEVANCE: The development of cancer risk prediction models is key to improving the survival of patients with LS. This pilot study describes a serum miRNA signature-based risk prediction model that predicts LS cancer incidence within 4 years, although further validation is required.

Physical Behavior Profiles Among Older Adults and Their Associations With Physical Capacity and Life-Space Mobility.

We identified data-driven multidimensional physical activity (PA) profiles using several novel accelerometer-derived metrics. Participants aged 75, 80, and 85 (n = 441) wore triaxial accelerometers for 3-7 days. PA profiles were formed with k-means cluster analysis based on PA minutes, intensity, fragmentation, sit-to-stand transitions, and gait bouts for men and women. Associations with physical capacity and life-space mobility were examined using age-adjusted general linear models. Three profiles emerged: "Exercisers" and "actives" accumulated relatively high PA minutes, with actives engaging in lighter intensity PA. "Inactives" had the highest activity fragmentation and lowest PA volume, intensity, and gait bouts. Inactives showed lower scores in physical capacity and life-space mobility compared with exercisers and actives. Exercisers and actives had similar physical capacity and life-space mobility, except female exercisers had higher walking speed in the 6-min walk test. Our findings demonstrate the importance of assessing PA as multidimensional behavior rather than focusing on a single metric.

Associations of polygenic inheritance of physical activity with aerobic fitness, cardiometabolic risk factors and diseases: the HUNT study.

Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the associations between higher levels of PA and better aerobic fitness and a lower risk for CMDs. We aimed to study how PA genotype associates with self-reported PA, aerobic fitness, cardiometabolic risk factors and diseases. PA genotype, which combined variation in over one million of gene variants, was composed using the SBayesR polygenic scoring methodology. First, we constructed a polygenic risk score for PA in the Trøndelag Health Study (N = 47,148) using UK Biobank single nucleotide polymorphism-specific weights (N = 400,124). The associations of the PA PRS and continuous variables were analysed using linear regression models and with CMD incidences using Cox proportional hazard models. The results showed that genotypes predisposing to higher amount of PA were associated with greater self-reported PA (Beta [B] = 0.282 MET-h/wk per SD of PRS for PA, 95% confidence interval [CI] = 0.211, 0.354) but not with aerobic fitness. These genotypes were also associated with healthier cardiometabolic profile (waist circumference [B = -0.003 cm, 95% CI = -0.004, -0.002], body mass index [B = -0.002 kg/m2, 95% CI = -0.004, -0.001], high-density lipoprotein cholesterol [B = 0.004 mmol/L, 95% CI = 0.002, 0.006]) and lower incidence of hypertensive diseases (Hazard Ratio [HR] = 0.97, 95% CI = 0.951, 0.990), stroke (HR = 0.94, 95% CI = 0.903, 0.978) and type 2 diabetes (HR = 0.94, 95 % CI = 0.902, 0.970). Observed associations were independent of self-reported PA. These results support earlier findings suggesting small pleiotropic effects between PA and CMDs and provide new evidence about associations of polygenic inheritance of PA and intermediate cardiometabolic risk factors.

Age But Not Menopausal Status Is Linked to Lower Resting Energy Expenditure.

CONTEXT: It remains uncertain whether aging before late adulthood and menopause are associated with fat-free mass and fat mass-adjusted resting energy expenditure (REEadj). OBJECTIVES: We investigated whether REEadj differs between middle-aged and younger women and between middle-aged women with different menopausal statuses. We repeated the age group comparison between middle-aged mothers and their daughters to partially control for genotype. We also explored whether serum estradiol and FSH concentrations explain REEadj in midlife. METHODS: We divided 120 women, including 16 mother-daughter pairs, into age groups; group I (n = 26) consisted of participants aged 17 to 21, group II (n = 35) of those aged 22 to 38, and group III (n = 59) of those aged 41 to 58 years. The women in group III were further categorized as pre- or perimenopausal (n = 19), postmenopausal (n = 30), or postmenopausal hormone therapy users (n = 10). REE was assessed using indirect calorimetry, body composition using dual-energy X-ray absorptiometry, and hormones using immunoassays. RESULTS: The REEadj of group I was 126 kcal/day [95% confidence interval (CI): 93-160] higher than that of group III, and the REEadj of group II was 88 kcal/day (95% CI: 49-127) higher. Furthermore, daughters had a 100 kcal/day (95% CI: 63-138 kcal/day) higher REEadj than their middle-aged mothers (all P < .001). In group III, REEadj was not lower in postmenopausal women and did not vary by sex hormone concentrations. CONCLUSIONS: We demonstrated that REEadj declines with age in women before late adulthood, also when controlling partially for genetic background, and that menopause may not contribute to this decline.

Menopausal symptoms and cardiometabolic risk factors in middle-aged women: A cross-sectional and longitudinal study with 4-year follow-up.

OBJECTIVE: To study associations of menopausal symptoms with cardiometabolic risk factors. STUDY DESIGN: A cross-sectional and longitudinal study of a representative population sample of 1393 women aged 47-55 years with a sub-sample of 298 followed for four years. The numbers of vasomotor, psychological, somatic or pain, and urogenital menopausal symptoms were ascertained at baseline through self-report. Their associations with cardiometabolic risk factors were studied using linear regression and linear mixed-effect models. Models were adjusted for age, menopausal status, body mass index, the use of hormonal preparations, education, smoking, and alcohol consumption. MAIN OUTCOME MEASURES: Cardiometabolic risk factors included total cholesterol, low-density and high-density lipoprotein cholesterol, blood pressure, glucose, triglycerides, total and android fat mass, and physical activity. RESULTS: All cholesterol and fat mass measures had modest positive associations with menopausal symptoms. The number of vasomotor symptoms, in particular, was associated with total cholesterol (B = 0.13 mmol/l, 95 % CI [0.07, 0.20]; 0.15 mmol/l [0.02, 0.28]) and low-density lipoprotein cholesterol (0.08 mmol/l [0.03, 0.14]; 0.12 mmol/l [0.01, 0.09]) in cross-sectional and longitudinal analyses, respectively. However, these associations disappeared after adjusting for confounders. The number of symptoms was not associated with blood pressure, glucose, triglycerides, and physical activity. Menopausal symptoms at baseline did not predict the changes in the risk factors during the follow-up. CONCLUSIONS: Menopausal symptoms may not be independently associated with cardiometabolic risk, and they do not seem to predict the changes in risk factors during the menopausal transition.

Early adulthood and current physical activity and their association with symptoms of pelvic floor disorders in middle-aged women: An observational study with retrospective physical activity assessment.

OBJECTIVE: To investigate associations of early and middle adulthood physical activity (PA) with symptoms of pelvic floor disorders (PFDs), i.e. stress urinary incontinence (SUI), urge urinary incontinence (UUI), faecal incontinence (FI), constipation or defecation difficulties (CDDs) and feeling of pelvic organ prolapse (POP) among middle-aged women. DESIGN: A cross-sectional, observational study with retrospective PA assessment. SETTING: University Research Laboratory. SAMPLE: A random population sample of 1098 Finnish women aged 47-55 years. METHODS: Early adulthood PA, current PA, and demographic and gynaecological variables were assessed using self-report questionnaires. Logistic regression analyses were applied to study associations of PA variables with symptoms of PFDs. Potential confounding effects of demographic and gynaecological variables were controlled in multiple logistic regression models. MAIN OUTCOME MEASURES: Structured questionnaire-assessed retrospective PA assessment at the age of 17-29 years, current PA at middle age, and prevalence of symptoms of CDD, FI, POP, SUI and UUI. RESULTS: Current PA was not independently associated with the occurrence of the symptoms of PFDs. Middle-aged women with an early adulthood history of competitive sports were more likely to experience symptoms of UUI (OR 2.16, 95% CI 1.10-4.24, p = 0.025) but not symptoms of SUI, FI, CDD or POP, whereas women with a history of regular PA were more likely to experience symptoms of FI (OR 4.41, 95% CI 1.05-18.49, p = 0.043) but no other symptoms of PFDs. CONCLUSIONS: Competitive sports during early adulthood may increase the risk of UUI in middle age. Regular PA during early adulthood may increase the risk of FI.

Associations of resting and peak fat oxidation with sex hormone profile and blood glucose control in middle-aged women.

BACKGROUND AND AIMS: Menopause may reduce fat oxidation. We investigated whether sex hormone profile explains resting fat oxidation (RFO) or peak fat oxidation (PFO) during incremental cycling in middle-aged women. Secondarily, we studied associations of RFO and PFO with glucose regulation. METHOD AND RESULTS: We measured RFO and PFO of 42 women (age 52-58 years) with indirect calorimetry. Seven participants were pre- or perimenopausal, 26 were postmenopausal, and nine were postmenopausal hormone therapy users. Serum estradiol (E2), follicle-stimulating hormone, progesterone, and testosterone levels were quantified with immunoassays. Insulin sensitivity (Matsuda index) and glucose tolerance (area under the curve) were determined by glucose tolerance testing. Body composition was assessed with dual-energy X-ray absorptiometry; physical activity with self-report and accelerometry; and diet, with food diaries. Menopausal status or sex hormone levels were not associated with the fat oxidation outcomes. RFO determinants were fat mass (ß = 0.44, P = 0.006) and preceding energy intake (ß = -0.40, P = 0.019). Cardiorespiratory fitness (ß = 0.59, P = 0.002), lean mass (ß = 0.49, P = 0.002) and physical activity (self-reported ß = 0.37, P = 0.020; accelerometer-measured ß = 0.35, P = 0.024) explained PFO. RFO and PFO were not related to insulin sensitivity. Higher RFO was associated with poorer glucose tolerance (ß = 0.52, P = 0.002). CONCLUSION: Among studied middle-aged women, sex hormone profile did not explain RFO or PFO, and higher fat oxidation capacity did not indicate better glucose control.

Total and regional body adiposity increases during menopause-evidence from a follow-up study.

For women, menopausal transition is a time of significant hormonal changes, which may contribute to altered body composition and regional adipose tissue accumulation. Excess adiposity, and especially adipose tissue accumulation in the central body region, increases women's risk of cardiovascular and metabolic conditions and affects physical functioning. We investigated the associations between menopausal progression and total and regional body adiposity measured with dual-energy X-ray absorptiometry and computed tomography in two longitudinal cohort studies of women aged 47-55 (n = 230 and 148, mean follow-up times 1.3 ± 0.7 and 3.9 ± 0.2 years, mean baseline BMI 25.5 kg/m2 ). We also examined associations between menopausal progression and skeletal muscle fiber characteristics, as well as adipose tissue-derived adipokines. Relative increases of 2%-14% were observed in regional and total body adiposity measures, with a pronounced fat mass increase in the android area (4% and 14% during short- and long-term follow-ups). Muscle fiber oxidative and glycolytic capacities and intracellular adiposity were not affected by menopause, but were differentially correlated with total and regional body adiposity at different menopausal stages. Menopausal progression and regional adipose tissue masses were positively associated with serum adiponectin and leptin, and negatively associated with resistin levels. Higher diet quality and physical activity level were also inversely associated with several body adiposity measures. Therefore, healthy lifestyle habits before and during menopause might delay the onset of severe metabolic conditions in women.

Metabolic health, menopause, and physical activity-a 4-year follow-up study.

BACKGROUND: In women, metabolic health deteriorates after menopause, and the role of physical activity (PA) in mitigating the change is not completely understood. This study investigates the changes in indicators of metabolic health around menopause and evaluates whether PA modulates these changes. METHODS: Longitudinal data of 298 women aged 48-55 years at baseline participating in the ERMA and EsmiRs studies was used. Mean follow-up time was 3.8 (SD 0.1) years. Studied indicators of metabolic health were total and android fat mass, waist circumference, waist-to-hip ratio (WHR), systolic (SBP) and diastolic (DBP) blood pressure, blood glucose, triglycerides, serum total cholesterol, and high- (HDL-C) and low-density (LDL-C) lipoprotein cholesterol. PA was assessed by accelerometers and questionnaires. The participants were categorized into three menopausal groups: PRE-PRE (pre- or perimenopausal at both timepoints, n = 56), PRE-POST (pre- or perimenopausal at baseline, postmenopausal at follow-up, n = 149), and POST-POST (postmenopausal at both timepoints, n = 93). Analyses were carried out using linear and Poisson mixed-effect models. RESULTS: At baseline, PA associated directly with HDL-C and inversely with LDL-C and all body adiposity variables. An increase was observed in total (B = 1.72, 95% CI [0.16, 3.28]) and android fat mass (0.26, [0.06, 0.46]), SBP (9.37, [3.34, 15.39]), and in all blood-based biomarkers in the PRE-POST group during the follow-up. The increase tended to be smaller in the PRE-PRE and POST-POST groups compared to the PRE-POST group, except for SBP. The change in PA associated inversely with the change in SBP (-2.40, [-4.34, -0.46]) and directly with the change in WHR (0.72, [0.05, 1.38]). CONCLUSIONS: In middle-aged women, menopause may accelerate the changes in multiple indicators of metabolic health. PA associates with healthier blood lipid profile and body composition in middle-aged women but does not seem to modulate the changes in most of the studied metabolic health indicators during the menopausal transition.

Predicting the age at natural menopause in middle-aged women.

OBJECTIVE: To predict the age at natural menopause (ANM). METHODS: Cox models with time-dependent covariates were utilized for ANM prediction using longitudinal data from 47 to 55-year-old women (n = 279) participating in the Estrogenic Regulation of Muscle Apoptosis study. The ANM was assessed retrospectively for 105 women using bleeding diaries. The predictors were chosen from the set of 32 covariates by using the lasso regression (model 1). Another easy-to-access model (model 2) was created by using a subset of 16 self-reported covariates. The predictive performance was quantified with c-indices and by studying the means and standard deviations of absolute errors (MAE ±â€ŠSD) between the predicted and observed ANM. RESULTS: Both models included alcohol consumption, vasomotor symptoms, self-reported physical activity, and relationship status as predictors. Model 1 also included estradiol and follicle-stimulating hormone levels as well as SD of menstrual cycle length, while model 2 included smoking, education, and the use of hormonal contraception as additional predictors. The mean c-indices of 0.76 (95% CI 0.71-0.81) for model 1 and 0.70 (95% CI 0.65-0.75) for model 2 indicated good concordance between the predicted and observed values. MAEs of 0.56 ±â€Š0.49 and 0.62 ±â€Š0.54 years respectively for model 1 and 2 were clearly smaller than the MAE for predicted sample mean (1.58 ±â€Š1.02). CONCLUSIONS: In addition to sex hormone levels, irregularity of menstrual cycle, and menopausal symptoms, also life habits and socioeconomic factors may provide useful information for ANM prediction. The suggested approach could add value for clinicians' decision making related to the use of contraception and treatments for menopausal symptoms in perimenopausal women.

Video Summary:http://links.lww.com/MENO/A743 .

Accelerometer-measured and self-reported physical activity in relation to extraversion and neuroticism: a cross-sectional analysis of two studies.

BACKGROUND: Personality reflects relatively stable and pervasive tendencies in feeling, thinking and behaving. While previous studies have found higher extraversion and lower neuroticism to be linked to higher self-reported physical activity levels, larger studies using accelerometer-measured physical activity are lacking. This study investigated the cross-sectional associations of extraversion and neuroticism with both accelerometer-measured and self-reported physical activity and the role of these personality traits in possible discrepancies between these two measures of physical activity among Finnish adults. METHODS: Two community-dwelling samples were used in this study: a) 47-55-yr-old women (n = 1098) and b) 70-85-yr-old women and men (n = 314). In both samples, extraversion and neuroticism were assessed by the 19-item short form of the Eysenck Personality Inventory. Physical activity was assessed with hip-worn tri-axial accelerometers and self-reported questions. Regression analyses were adjusted by age, BMI and education. RESULTS: In the middle-aged women, neuroticism was negatively associated with accelerometer-measured leisure time moderate-to-vigorous physical activity (ß = -.07, p = .036) and with self-reported physical activity (ß = -.08, p = .021), while extraversion was positively associated with self-reported physical activity (ß = .10, p = .005). No associations of extraversion or neuroticism with physical activity were found in the older men and women. Older adults who scored high in neuroticism reported less physical activity than what was measured by accelerometers (ß = -.12, p = .039). Extraversion was not associated with discrepancy between self-reported and accelerometer-measured leisure time physical activity in either sample. CONCLUSIONS: Neuroticism was associated with lower leisure-time physical activity levels and extraversion with higher self-reported physical activity among middle-aged women. Neuroticism and extraversion were unrelated to physical activity among older adults, but older adults with high neuroticism seemed to underreport their physical activity level. The role of personality in the discrepancy between self-reported and device-based physical activity warrants further research.

Validity and Reliability of a Single Question for Leisure-Time Physical Activity Assessment in Middle-Aged Women.

PURPOSE: To investigate the validity and test-retest reliability of a single seven-level scale physical activity assessment question (SR-PA L7) and its three-level categorization (SR-PA C3). METHODS: The associations of SR-PA L7 and C3 with accelerometer-measured leisure-time physical activity (ACC-LTPA) and with the results of four different physical performance tests (6-min walk [n = 733], knee extension [n = 695], vertical jump [n = 731], and grip force [n = 780]) were investigated among women aged 47-55 years participating in the Estrogenic Regulation of Muscle Apoptosis study (n = 795). The reliability was studied using Spearman correlations with 4-month test-retest period (n = 152). RESULTS: SR-PA L7 and C3 had low correlations with ACC-LTPA (rs = .105-.337). SR-PA L7, SR-PA C3, and ACC-LTPA explained comparable but small amount of variance of the physical performance test results. The reliability analysis provided moderate agreement (rs = .707 and .622 for SR-PA L7 and C3, respectively). CONCLUSIONS: SR-PA L7 and C3 demonstrated limited validity and reasonable repeatability.

Menopausal Status and Physical Activity Are Independently Associated With Cardiovascular Risk Factors of Healthy Middle-Aged Women: Cross-Sectional and Longitudinal Evidence.

Cardiovascular disease (CVD) is the primary cause of mortality in women in developed countries. CVD risk rises with age, yet for women there is a rapid increase in CVD risk that occurs after the onset of menopause. This observation suggests the presence of factors in the middle-aged women that accelerate the progression of CVD independent of chronological aging. Leisure time physical activity (LTPA) is a well-established protective factor against CVD. However, its role in attenuating atherogenic lipid profile changes and CVD risk in post-menopausal women has not been well-established. The present study is part of the Estrogenic Regulation of Muscle Apoptosis (ERMA) study, a population-based cohort study in which middle-aged Caucasian women (47-55) were classified into pre-menopausal, peri-menopausal, and post-menopausal groups based on follicle stimulating hormone levels and bleeding patterns. Comprehensive questionnaires, laboratory visits, anthropometric measurements, and physical activity monitoring by accelerometers were used to characterize the menopausal groups and serum lipid profiles were analyzed to quantify CV (cardiovascular) risk factors. Based on our findings, LTPA may attenuate menopause-associated atherogenic changes in the serum CV risk factors of healthy middle-aged women. However, LTPA does not seem to entirely offset the lipid profile changes associated with the menopausal transition.