Annie Green Howard

Background: The clinical importance of the relationships between cognition and later body composition is unclear and may have important clinical implications. Therefore, we examine the relationship between baseline cognition and later body composition among older adults in China. Methods: Using the China Health and Nutrition Survey (n=1,482, 2006-2015), five body mass/composition subgroups were identified using latent profile analysis. Linear regression model and chi-squared tests were used to test for differences in cognition across profiles using cognitive (2015) and physical function screenings (2006 and 2015). Results: Mean ages ranged from 71.9 (SD 5.7) to 74.1 (SD 7.4) (p=0.0682). The 2015 latent body mass/composition profiles were unrelated to earlier cognitive performance in older adults in China (p=0.76). There was a trend of increased ADL impairment between 2006 to 2015 between and within latent profiles. Conclusions: There was no relationship between baseline cognition and later body composition among older adults in China, addressing the limited evidence base on the relationship between older adult cognitive performance and later body composition.

Aims: Assess changes in lipoprotein(a) [Lp(a)] levels and transitions across ASCVD risk thresholds by menopausal trajectory to inform risk stratification and testing recommendations. Methods and results: We examined changes in Lp(a) between visits 1 and 2 among UK Biobank women. Analyses were examined by menopausal trajectory: those who underwent menopause (N = 415), those who remained premenopausal (N = 532), and those who remained postmenopausal (N = 3615) between visits. Change in Lp(a) between visits was also stratified by visit 1 Lp(a). The primary outcome was incident Lp(a) ≥ 125 nmol/L at visit 2, estimated using Poisson regression. Data were available for 4562 women (mean visit 1 age = 57 years; median visit 1 Lp(a) = 22 nmol/L; median time between visits = 4 years). At visit 1, median Lp(a) was 23 nmol/L in postmenopausal women and 19 nmol/L in premenopausal women. Overall, median changes in Lp(a) between visits were modest. Among women with intermediate visit 1 Lp(a) (75–125 nmol/L), those who transitioned through menopause experienced a median increase of 34.9 nmol/L, approximately fourfold greater than women who remained pre- or postmenopausal. Further, 22 of 39 (56%) of women with intermediate visit 1 Lp(a) who had menopause between visits had incident Lp(a) ≥ 125 nmol/L at visit 2, compared with 29% and 28% of women who remained pre- or postmenopausal, representing a risk ratio of 2.27 (95% CI: 1.36, 3.78) after adjustment for visit 1 age and continuous Lp(a). Conclusion: Relying on a single lifetime Lp(a) measurement may miss reclassification across risk-enhancing thresholds during menopause, particularly for women with intermediate premenopausal levels.

While the earliest pathological signs of cardiovascular–kidney–metabolic disease (CKMD) emerge before age 20, current adult-based risk thresholds fail to identify a substantial fraction of children at high risk. With increasing childhood obesity, early, sensitive detection of CKMD risk is critical to timely intervention. We linked 25 CKMD phenotypes spanning liver, adipose, vascular and dysglycaemia traits to the circulating proteome in 273 Hispanic or Latino children and adolescents (13.1 ± 2.7 years; 53% female). Here we show that proteome signatures of CKMD in children are strongly associated with clinical CKMD outcomes in adults. In 685 adults from the same community and 28,256 adults from UK Biobank, we observe high concordance between the paediatric and adult CKMD phenotype–proteome relationships, related to pancreatic beta-cell health and insulin sensitivity, liver homeostasis, inflammation and cholesterol metabolism. Many proteins linked to paediatric CKMD were modifiable with glucagon-like peptide-1 receptor agonist therapy in adults and are linked to genetic liability to CKMD. These findings support an early origin of CKMD disease liability embedded in the human proteome in children, underscoring the value of precision prevention to forestall metabolic disease long before its clinical manifestation.

Background : While the health benefits of walking are well-established, it is not clear if walking pace is associated with cancer-related outcomes. Purpose : To investigate associations of self-reported walking pace with cancer incidence and mortality among women 62–99 years of age in the Women’s Health Accelerometry Collaboration. Methods : Women self-reported walking pace, classified as brisk (≥3 mph), average (2–2.9 mph), casual ( Results : There were 22,358 women in the analytic sample. During a mean 8.0 years of follow-up, 1891 women developed cancer (n = 615 cancer deaths). Self-reported walking paces were not associated with all site cancer incidence (compared with a brisk walking pace: average walking pace hazard ratio, 1.08 (95% confidence interval, 0.95–1.23); casual walking pace, 1.15 (0.97–1.33), and does not walk regularly 1.14 (0.97–1.34) nor cancer mortality (average walking pace, 0.97 [0.76–1.25], casual walking pace, 0.98 [0.74–1.30], and does not walk regularly 1.20 [0.90–1.60]). Findings were similar when colon, endometrial, and lung cancer were examined, separately. However, casual walking pace was associated with a higher risk of a composite of inactivity-related cancers (1.21 [1.00–1.47]), and breast cancer (1.40 [1.09–1.80]) compared with a brisk walking pace. Conclusions : Slower, compared with faster, self-reported walking paces may be related to a higher risk of some cancers in postmenopausal women. Future research is needed to confirm these findings and investigate mechanisms underlying the associations of walking pace with these cancers.

Background: There are differences in lipid metabolism by sex that are relevant for health, but metabolic pathways are not fully understood. We investigated sex differences in cross-sectional associations between metabolic pathways identified using untargeted metabolomics and clinical lipid measures (total cholesterol [TC], triglycerides [TG], and low- and high-density lipoprotein cholesterol [LDL-c; HDL-c]) from blood plasma in the Coronary Artery Risk Development in Young Adults (CARDIA) study (Year 20; 2005–2006). Our objective was to determine whether associations between metabolic pathways and lipid measures differ by sex and to identify pathways that may underlie sex-specific mechanisms of lipid metabolism. Methods: Using data from 2169 participants, (44% women, mean age = 45, 58% White, 42% Black), we used: (1) Orthogonal partial least squares-regression (OPLS-R) to compare variation in TC, TG, LDL-c, and HDL-c explained by metabolites in men vs. women, (2) linear regression to assess sex-modification of associations between 7255 metabolite peaks and lipid measures using false discovery rate (FDR)-corrected p < 0.1, and (3) pathway enrichment analyses to identify metabolic pathways that differed by sex using Fisher’s exact test (FET) p < 0.05. Results: We found that: (1) untargeted metabolomic data reflected variation in lipid measures better for men compared to women, (2) associations between metabolite peaks and lipid measures differed by sex, and (3) 8 unique pathways differed by sex, particularly primary bile acid biosynthesis, linoleic acid metabolism, and arginine biosynthesis. Conclusions: Our findings suggest distinct lipid-associated metabolic activity by sex that points to potential mechanistic pathways.

While the earliest pathological signs of cardiovascular disease (CVD) emerge before age 20, current adult-based risk thresholds fail to identify a substantial fraction of high-risk children. With the rising prevalence of childhood obesity, the need for early and sensitive detection of cardiovascular-kidney-metabolic disease (CKMD) risk is paramount to enable timely intervention that can prevent the trajectory toward CVD in later life. To identify early accessible molecular biomarkers of CKMD in children, we measured 25 CKMD phenotypes, spanning liver, adipose, vascular, and dysglycemia traits, linked those to the circulating proteome and built a multi-protein signature of composite CKMD, leveraging data from 273 children and adolescents (13.1 ± 2.7 years; 53% females). We compared these results to the adult CKMD proteome, using data from 685 adults from the same community and 28,257 adults from the UK Biobank. The pediatric CKMD proteome was highly concordant with the adult CKMD proteome, reflecting known and novel mechanisms of pancreatic beta-cell health and insulin sensitivity, liver homeostasis, inflammation, and cholesterol metabolism. Similarly, multi-protein signatures of composite CKMD phenotypes in children were strongly associated with CKMD-related outcomes in both adult populations. Importantly, many proteins linked to pediatric CKMD were modifiable with GLP-1 receptor agonist therapy, associated with adult CKMD-related outcomes in a large-scale proteome-wide association study (PWAS), and exhibited significant variability during development (ages 4-24 years). These findings demonstrate that CKMD develops starting early in life-course continuum, with proteomic profiles linked to future irreversible CVD conditions emerging early in life when they may still be reversible. This highlights a critical opportunity to improve CVD-free longevity through precision medicine diagnosis and intervention in children and adolescents.

Background: Obesity perturbs metabolism, resulting in differential diet–disease associations, but metabolic pathways that differ by obesity remain unclear. We investigated whether cross‐sectional associations between metabolites and diet quality differ by obesity status in 2832 participants in the CARDIA (Coronary Artery Risk Development in Young Adults) cohort study. Methods: We used untargeted metabolomics (7255 metabolite peaks) and an a priori diet quality score (APDQS) to (1) compare model accuracy and prediction, stratified by body mass index (BMI); (2) assess modification of APDQS‐metabolite associations by BMI in linear regression models; (3) identify pathways with differential metabolic activity by BMI; and (4) assess the strength and direction of associations with identified/annotated metabolites. Results: In BMI‐stratified models, metabolite peaks had higher model accuracy but similar APDQS predictive ability among participants with lower versus higher BMI (BMI2 =0.52; 25≤BMI2 =0.41; BMI≥30: Q ² =0.21). Of the 7255 metabolite peaks, 180 peaks were associated with APDQS and differed by BMI (false discovery rate<0.1). From pathway enrichment analyses, 6 pathways had differential metabolic activity by BMI (Fisher's exact test <0.05) including primary bile acid biosynthesis; steroid biosynthesis; steroid hormone biosynthesis; caffeine metabolism; valine, leucine, and isoleucine biosynthesis; linoleic acid metabolism. Strength of associations were strongest for those without overweight or obesity. Conclusions: Diet‐metabolite associations were best detected among participants who did not have overweight/obesity. We identified associated diet–metabolic pathways that differ by obesity, suggesting potential metabolic‐related mechanisms perturbed for those with obesity.

Background: The influence of physical activity (PA) and sedentary behavior (SB) on survival to late age with intact mobility is unclear. This study investigated associations between accelerometer-measured daily PA, SB, and survival to age 90 birthyear with and without intact mobility in the Women’s Health Accelerometry Collaboration (WHAC). Methods: Postmenopausal US women aged 78-89 years without mobility disability were followed for an average of 6.1 years. At age 90 birthyear, participants were categorized as: (1) surviving with intact mobility, (2) surviving with mobility disability, or (3) deceased. Participants wore an accelerometer on the hip for up to 7 days at baseline from 2011 to 2015. Covariate-adjusted multinomial logistic regression models estimated odds ratios (ORs) of PA (light, moderate-to-vigorous [MVPA], total, steps) and SB (sitting time, mean sitting bout duration) with survival outcomes relative to dying. Results: Among 2656 women (mean baseline age 83.1 years), 62.8% survived with intact mobility, 22.3% with mobility disability, and 15.0% died. Compared to dying before age 90, the OR (95% confidence intervals [CI]) for every 1-SD increment in accelerometer variables and survival with intact mobility were 1.36 (1.20, 1.54) for light PA, 1.69 (1.47, 1.96) for MVPA, 1.51 (1.33, 1.71) for total PA, 1.75 (1.51, 2.03) for steps, 0.70 (0.61, 0.80) for sitting time, and 0.79 (0.70, 0.89) for sitting bouts. Similar, weaker trends were present for mobility disability. Conclusions: These findings corroborate the potential role of increasing physical activity in preserving physical functioning as an important element of healthy longevity.

Purpose: Few studies have explored whether accelerometer-measured sedentary behavior increases cancer risk. We examined the associations of accelerometer-measured daily sitting time and mean sitting bout duration classified by the Convolutional Neural Network Hip Accelerometer Posture (CHAP) machine-learned algorithm with incidence of any cancer, incidence of 13 physical activity-related cancers, and cancer mortality among postmenopausal women. Methods: We used data from 22,097 women (mean age = 73.3 years, standard deviation [SD] = 6.7) in the Women’s Health Accelerometry Collaboration, a consortium of two US-based cohort studies of postmenopausal women: the Women’s Health Study and the Women’s Health Initiative Objective Physical Activity and Cardiovascular Health Study. Women who completed hip-worn triaxial accelerometry for ≥ 4 of 7 consecutive days were included. Associations between sedentary behaviors and physician-adjudicated invasive cancer incidence and mortality were tested using Cox regression. Results: Women were followed on average 8.0 years to identify cancer cases ( n = 1,861) and deaths ( n = 601). Overall, mean sitting time was 567 (SD = 113) min/day and mean sitting bout duration was 12.8 (SD = 4) min/bout. In covariate-adjusted models, one-SD increment higher in sitting time was associated with a 6% increased risk of incident cancer (hazard ratio [HR] = 1.06, 95% CI: 1.01–1.11); associations were similar for bout duration (HR = 1.05, 95% CI: 1.00–1.10). Estimates were similar for the 13 physical activity-related cancers (sitting time: HR = 1.10, 95% CI: 1.04–1.17; bout duration: HR = 1.08, 95% CI: 1.02–1.14) and for cancer mortality (sitting time: 1.06, 95% CI: 0.98–1.16; bout duration: HR = 1.05, 95% CI: 0.97–1.13). Conclusion: Among postmenopausal women, sedentary behavior was associated with increased cancer risk, particularly for physical activity-related cancers and cancer mortality.