Alzheimer’s disease (AD) is the most common form of dementia and is rapidly growing in prevalence as the population grays. As AD is a disease of aging, and other diseases of aging including diabetes and obesity are risk factors for AD, geroprotective interventions may be use in preventing, treating or delaying the progression of AD. Here, we report our preliminary results of our investigation into the effects of geroprotectors and dietary interventions including protein restriction (PR), acarbose and rapamycin on cognition and disease pathology in the 3xTg mouse model of AD. Six month old male and female 3xTg-AD mice were placed on either 21% protein (control) or 7% protein (PR) diets starting from 6 months and continued until 11 months to determine their effects on AD pathology, metabolic health and cognition. We find that males differed in body weight after only 4 weeks of PR, but females did not differ in body weight even after 12 weeks of PR. Cognitive functioning was analyzed via Novel Object Recognition test. Female’s 3xTg-AD mice on PR diet showed improved long-term memory (LTM), but no significant improvement in short-term memory test (STM), and males showed a positive trend in improved cognitive function compared with their age matched controls. Female and male mice on low protein diets exhibited improvement in glucose tolerance, however females showed a stronger effect in glycemic control than males following a glucose tolerance test (GTT). Following rapamycin or acarbose (from 6 - 9 months) treatment male mice showed decreased AMPK phosphorylation and p62 levels in the brain, as well as a trend toward decreased tau phosphorylation which is a marker for AD progression and reduced expression of mechanistic target of rapamycin complex 1 (mTORC1) signaling in the brain. Our results are promising and suggests that geroprotectors showed beneficial effects on metabolic health, cognitive functioning and a reduction in AD progression markers. However more research is needed and we will further report on ongoing studies, which shows that use of geroprotectors as therapies for AD has significant potential, and can provide additional insights into the mechanisms of action by which geroprotectors function.

Low-protein diets promote metabolic health in humans and rodents. Despite evidence that sex and genetic background are key factors in the response to diet, most protein intake studies examine only a single strain and sex of mice. Using multiple strains and both sexes of mice, we find that improvements in metabolic health in response to reduced dietary protein strongly depend on sex and strain. While some phenotypes were conserved across strains and sexes, including increased glucose tolerance and energy expenditure, we observed high variability in adiposity, insulin sensitivity, and circulating hormones. Using a multi-omics approach, we identified mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype, providing molecular insight into the differential response to protein restriction. Our results highlight the importance of sex and genetic background in the response to dietary protein level, and the potential importance of a personalized medicine approach to dietary interventions.

Low-protein diets promote metabolic health in rodents and humans, and the benefits of low-protein diets are recapitulated by specifically reducing dietary levels of the three branched-chain amino acids (BCAAs), leucine, isoleucine, and valine. Here, we demonstrate that each BCAA has distinct metabolic effects. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity and ketogenesis and increasing energy expenditure, activating the FGF21-UCP1 axis. Reducing valine induces similar but more modest metabolic effects, whereas these effects are absent with low leucine. Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. Finally, we demonstrate that variation in dietary isoleucine levels helps explain body mass index differences in humans. Our results reveal isoleucine as a key regulator of metabolic health and the adverse metabolic response to dietary BCAAs and suggest reducing dietary isoleucine as a new approach to treating and preventing obesity and diabetes.

Our results are promising and suggests that geroprotectors showed beneficial effects on metabolic health, cognitive functioning and a reduction in AD progression markers. However more research is needed and we will further report on ongoing studies, which shows that use of geroprotectors as therapies for AD has significant potential, and can provide additional insights into the mechanisms of action by which geroprotectors function.

Our objective in this comment is to highlight several limitations in an ecological research study that was published in Nutrients by Murphy and Westmark (2020) in January 2020. The study used data from the Food Fortification Initiative (FFI) website, and applying an ecological study design, made an error of "ecologic fallacy" in concluding that "national fortification with folic acid is not associated with a significant decrease in the prevalence of neural tube defects (NTDs) at the population level". We list study limitations that led to their erroneous conclusions, stemming from incorrect considerations regarding NTD prevalence, the average grain availability for a country, the fortification coverage in a country, the population reach of fortified foods within a country, and the absence of the consideration of fortification type (voluntary vs. mandatory), country-specific policies on elective terminations for NTD-affected pregnancies, stillbirth proportions among those with NTDs, and fortification implementation. FFI data are derived from many sources and intended for fortification advocacy, not for hypothesis testing. The flawed study by Murphy & Westmark (2020) in Nutrients promotes a confusing and incorrect message to stakeholders, misguides policy makers, and hinders progress in global NTD prevention through a cost-effective, safe, and effective intervention: the mandatory large-scale folic acid fortification of staple foods.

The United States implemented mandatory fortification of cereal grains with folic acid in 1998 to prevent neural tube defects (NTDs) during pregnancy. The health benefits of folate (vitamin B9) are well documented; however, there are potential risks of exceeding the upper tolerable limit, particularly in vulnerable populations. We conducted a population-based analysis of the Food Fortification Initiative dataset to determine the strength of the evidence regarding reports of decreased NTDs at the national level in response to mandatory folic acid fortification of cereal grains. We found a very weak correlation between NTD prevalence and the level of folic acid fortification, irrespective of the cereal grain fortified (wheat, maize or rice). Stratification of the data based on socioeconomic status (SES) indicated a strong linear relationship between reduced NTDs and better SES. We conclude that national fortification with folic acid is not associated with a significant decrease in the prevalence of NTDs at the population level.