Susan B. Racette

Objective: Weight loss is often pursued to improve cardiometabolic health and quality of life. However, weight loss can lead to reductions in lean soft tissue mass and strength, compromising body composition and functional ability. Thus, identifying molecular predictors of muscular strength preservation during weight loss is critical to mitigating these effects. Methods: We conducted a secondary analysis of the CALERIE trial, a 2‐year randomized controlled study of caloric restriction or ad libitum intake in healthy adults without obesity. Changes in whole‐body mass and knee extensor strength were assessed over the first 12 months of the study. Transcriptomic profiling was conducted in a subset who provided skeletal muscle samples. The relationship between strength change and gene expression change was modeled, controlling for whole‐body mass change. Results: Transcriptomics analysis on a subset of 42 individuals revealed 151 genes significantly associated with change in strength after accounting for change in whole‐body mass, including HSP90AA1 and EIF3A . Pathway analyses revealed significant involvement of pathways related to cellular proliferation, immune regulation, and protein secretion. Conclusions: These findings highlight molecular pathways and genes supporting strength retention during caloric restriction‐induced weight loss. Trial Registration: ClinicalTrials.gov identifier: NCT00427194 www.clinicaltrials.gov image

Fasting is part and parcel of the practice of various religious groups. In the scientific literature, the term intermittent fasting (IF) was first reported in a 1946 paper demonstrating its association with increased longevity in rodents. Research has extended IF, particularly time-restricted eating (TRE), to Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by neuritic plaques, neurofibrillary tangles, and neuronal loss. AD manifests in asymptomatic, mild cognitive impairment (MCI), and dementia phases. Delaying progression from MCI to dementia by one year could reduce dementia prevalence by millions. Currently, no pharmacological treatments can reverse or arrest MCI progression to dementia, making exploration of non-pharmacological interventions critical. TRE is a promising approach. AD brains exhibit decreased glucose uptake, while ketone utilization remains intact. Fasting for at least 8–12 h induces a cascade of molecuar events that lead to a metabolic switch from glucose to ketone utilization, providing an alternative energy source for AD brains. Preclinical studies demonstrate that TRE enhances cognitive function via hippocampal neurogenesis, autophagy, and reduced neuroinflammation. Human studies on TRE in MCI are limited but promising, often focusing on cardiometabolic outcomes, with little known about TRE targeting MCI. This review synthesizes current evidence on TRE and cognitive outcomes in humans, non-human primates, and rodents, and describes ongoing trials in MCI patients. We propose a theoretical model of direct and indirect pathways linking TRE with resistance to AD in the brain parenchyma, and identify gaps in knowledge regarding long-term cognitive effects and mechanistic pathways of TRE in MCI, urging rigorous clinical trials to establish TRE as a safe and possibly effective strategy to delay MCI progression to dementia.

There is growing evidence that lifestyle habits influence neurodegenerative disease risk. Dietary strategies and exercise are among the most important lifestyle approaches to promote brain health. This review highlights the primary mechanisms by which three dietary approaches (metabolic switching, calorie restriction, high diet quality) and exercise may promote neuroprotection and inhibit neurodegeneration. Neuroprotective mechanisms induced by a healthful lifestyle include reduced inflammation, increased autophagy, neurogenesis, decreased neuronal cell death, and attenuation of pathological protein burden.

Purpose: Weight loss is often pursued to improve cardiometabolic health and quality of life. However, rapid weight loss can lead to reductions in lean soft tissue mass and strength to compromise body composition and functional ability. Thus, identifying molecular predictors of muscular strength preservation during weight loss is critical to mitigating these effects. Methods: We conducted a secondary analysis of the CALERIE ^TM (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trial, a two-year randomized controlled study of caloric restriction (CR) or ad-libitum intake in healthy adults without obesity. Among 198 participants, changes in whole-body mass and knee extensor strength were assessed over the first 12 months of the study which was primarily characterized by weight loss. Transcriptomic profiling was conducted in a subset of 42 participants who provided skeletal muscle samples. Linear regression was used to model the relationship between strength change and gene expression change, while controlling for changes in whole-body mass. Gene set enrichment analysis (GSEA) was performed using Hallmark pathways. Individual-level pathway analysis was performed via gene set variation analysis (GSVA). Results: We identified 96 out of 198 individuals (48.5%) who maintained or improved strength relative to body mass during weight loss ( i.e. individuals with residuals > 0). Transcriptomics analysis on a subset of 42 individuals revealed 151 genes significantly associated with change in strength after accounting for change in whole-body mass ( p < 0.01). Hub genes were identified as HSP90AA1 (β = 34.45, SE = 7.32, p EIF3A (β = 36.14, SE = 10.27, p < 0.001), EIF5B (β = 49.94, SE = 11.28, p < 0.001), and H3C1 (β = −15.87, SE = 4.85, p < 0.001). GSEA revealed significant involvement of pathways related to cellular proliferation, immune regulation, protein secretion, and checkpoint control processes. GSVA identified a similar set of pathways. Conclusions: These findings highlight molecular pathways supporting strength retention during CR-induced weight loss. Heat-shock protein, HSP90AA1 , warrants further investigation as a candidate target for preserving muscle strength during interventions aimed at weight reduction.

Background: Food insecurity is associated with an increased risk of hypertension. Aim: The aim of this study was to evaluate the role of dietary sodium and potassium intake in the setting of food insecurity on hypertension risk. Methods: We performed a cross-sectional analysis of data from 17,015 adults aged 18–65 years who participated in the National Health and Nutrition Examination Survey (2011–2018). We examined the associations between food insecurity, hypertension, and dietary sodium and potassium levels using multivariable logistic regression. Mediation analysis was conducted to explore the potential influence of dietary sodium and potassium intake on the relationship between food insecurity influenced hypertension. Results: Individuals experiencing food insecurity had a significantly lower mean potassium intake (2.5 ± 0.03 g) compared to food-secure counterparts (2.74 ± 0.02 g). Food insecurity status was significantly associated with an increased likelihood of a higher dietary sodium-to-potassium ratio, an established predictor for hypertension. Conclusion: Adults with food insecurity and hypertension were more likely to have lower dietary potassium intake. Increasing access to healthy foods, particularly potassium-rich foods, for individuals facing food insecurity may contribute to reducing the hypertension prevalence and improving cardiovascular outcomes.

Engagement in physical and cognitive activities is associated with a decreased risk of mild cognitive impairment (MCI) and dementia, but the association with Alzheimer disease (AD) neuroimaging biomarkers is less clear. We thus examined associations of physical and cognitive activities with longitudinal trajectories of AD neuroimaging biomarkers among older adults free of dementia. We conducted a longitudinal study within the population-based Mayo Clinic Study of Aging (mean follow-up durations 1.3-3.4 years). Participants were aged 50 years or older and were cognitively unimpaired or had MCI at baseline. Engagement in physical and cognitive activities during 12 months before baseline was assessed through questionnaires. Participants underwent AD neuroimaging biomarker assessments at 1 or more time points. We ran linear mixed-effect models to examine associations between physical and cognitive activity composite scores and trajectories of individual yearly change in amyloid deposition (Pittsburgh compound B [PiB]-PET centiloid), tau burden (tau-PET standardized uptake value ratio [SUVR]), and regional glucose hypometabolism (fluorodeoxyglucose [FDG]-PET SUVR), adjusted for age, sex, APOE ɛ4 carrier status, and medical comorbidity. We included 1,176 participants (47% female; mean [SD] age, 68.7 [9.6] years) for PiB-PET trajectories, 399 participants (49% female; mean [SD] age, 71.9 [11.0] years) for tau-PET trajectories, and 983 participants (46% female; mean [SD] age, 67.9 [9.2] years) for FDG-PET trajectories. PiB-PET and tau-PET measures increased during follow-up (3.4 [SD 4.0] and 1.3 [SD 2.1] years, respectively), whereas FDG-PET values decreased over 2.9 (SD 3.5) years of follow-up. Participants with higher total physical activity (interaction estimate 0.0017; 95% CI 0.0003-0.0031; p = 0.021) and higher moderate-to-vigorous physical activity (interaction estimate 0.0015; 95% CI 0.0001-0.0029; p = 0.040) had a less pronounced decrease in FDG-PET over time. Participants with higher cognitive activity experienced a less pronounced increase in PiB-PET (interaction estimate -0.2253; 95% CI -0.4437 to -0.0070; p = 0.043) and a smaller decrease in FDG-PET (interaction estimate 0.0015; 95% CI 0.0001-0.0028; p = 0.038) over time. Physical activity was associated with less synaptic dysfunction and cognitive activity with less synaptic dysfunction and lower amyloid burden over time, albeit effect sizes were small. Further research is needed to validate findings and clarify causal inference between physical and cognitive activities and AD neuroimaging biomarkers.

The global population is aging rapidly and the prevalence of age-related noncommunicable diseases is increasing. Favorable dietary patterns have the power to reduce the risk or progression of various age-related chronic diseases, including obesity, hypertension, cardiovascular disease, type 2 diabetes, several types of cancer, and some neurodegenerative diseases. In contrast, adverse dietary patterns may contribute to the onset or progression of many chronic diseases or their risk factors. A diet rich in wholesome, nutrient-dense, minimally processed foods, such as a Mediterranean-style diet, may promote health and prevent disease through its abundance of antioxidants, fiber, omega-3 fatty acids, and micronutrients. Conversely, a diet high in nutrient-poor and ultra-processed foods may accelerate disease onset and progression by promoting inflammation and affecting metabolic pathways adversely. This narrative review summarizes the literature from clinical trials and large population-based studies on protective dietary patterns and adverse dietary patterns that influence risk of cardiovascular disease and related risk factors, cancer, Alzheimer’s disease and related dementias, type 2 diabetes, frailty, and liver disease.