Location: Jean Mayer Human Nutrition Research Center On Aging
2025 Annual Report
Objectives
Objective 1: Investigate metabolic and nutritional mechanisms of cellular aging that can be targeted to promote healthy aging and prevent age-related pathology. (NP 107 4A,5A)
Subobjective 1.A: To assess the induction of ferroptosis as a mechanism for senescent cell elimination in mouse models of aging and age-related pathology.
Objective 2: Determine the mechanistic and physiological roles of dietary components in tissues that regulate systemic metabolism such as brown and white adipose tissue, liver, skeletal muscle, immune responses, and their contribution to aging and age-related obesity.
Subobjective 2.A: To determine the role of adipocyte interferon-related factor 8 in the regulation of adipose and systemic metabolism, obesity, and metabolic complications across the lifespan.
Subobjective 2.B: To determine the mechanistic understanding of the health benefits of tomato carotenoid to protect against high refined carbohydrate diet/age-related nonalcoholic fatty liver disease (NAFLD) across the lifespan.
Objective 3: Determine the mechanisms by which diet and/or physical activity regulate the microbiomes and intestinal homeostasis to promote healthy aging and prevent age-associated diseases. (NP 107 4A, 4B, 5A)
Subobjective 3.A: To determine the impact of a high-soluble fiber diet on the gut-muscle axis in older adult humans and in aged mice.
Subobjective 3.B: To determine the effects of different standard rodent chow diets on normative aging processes (gut homeostasis, microbiome function, neurocognition, and host metabolism) in mice.
Approach
Our goal is to improve the healthspan of individuals. Our approach is to elucidate the metabolic and molecular mechanisms that regulate healthspan. Many of our studies utilize mouse models of aging which will provide the foundation for future clinical studies to facilitate long-lived healthspan.
Our team of researchers for this project will work together and provide synergy in our approach. A significant detrimental consequence of aging is that cells undergo senescence and do not function properly. Elimination of senescent cells has been shown to improve health. In one project, researchers will investigate if induction of a process called ferroptosis in senescent cells can cause removal of these cells and improve health span. A second project investigates the identification of a protein, called interferon regulatory protein 8 (IRF8), expressed in fat cells which is increased in adipocytes and promotes diet-induced obesity and dysregulated glucose metabolism and whether reductions of the expression of IRF8 protects against obesity and improve regulation of glucose metabolism. A third project is investigating whether when the nutrient carotenoids are isolated from tomatoes it can protect against the development of fatty liver disease. Another project is investigating the role of dietary fiber on beneficially modulating the gut microbiota and their effects on regulating skeletal muscle function and health in aging mice and humans. Diet quality plays an important role in mediating host metabolism across the lifespan in humans but is a commonly overlooked experimental factor in rodent diets. Standard rodent diet composition is highly variable, and this may have potential long-term effects on regulating normative aging processes in mice. Here, we aim to determine the effect of three commonly used rodent diets on biological aging processes, including senescence, gut and glucose homeostasis, and neurocognition, in normatively aging mice.
The research proposed is consistent with the research goals of the Jean Mayer USDA Human Nutrition Research Center on Aging. The results of the proposed studies will be integrated into the Center’s approach to elucidating nutrition that can improve healthspan.
Progress Report
Our first objective is to investigate the metabolic and nutritional mechanisms of cellular aging that can be targeted to promote healthy aging. To achieve our goal, we continued breeding mouse models for various studies, focusing primarily on creating a cohort of aged mice. We made substantial progress in expanding our mouse lines, including generating mice with specific protein deficiencies in fat cells to prepare for future mechanistic studies.
As part of our second objective, we fed two-month-old male mice, both wild type and those lacking the enzymes responsible for carotenoid cleavage, a high-refined carbohydrate diet with or without carotenoid (specifically phytoene) supplementation for six months. The dosage of phytoene in the diet approximates a human equivalent intake of 2-3 medium-sized tomatoes daily. We also explored different strategies to lower levels of old (senescent) cells or prevent liver disease in a liver damage mouse model. We have concluded that use of an omega-6 fatty acid found in soybeans shows the most promise in lowering markers of liver disease during chronological aging.
Our third objective is to determine the mechanism by which diet and/or physical activity regulate mechanisms underlying healthy aging. In our human studies, we completed the recruitment and enrollment of participants for a dietary fiber study. We have started measuring and analyzing outcomes from collected samples, including body composition, gut bacteria composition, gut bacteria-derived small molecules, and fecal pH. Concurrently, we also have established cohorts of aging female and male mice fed different rodent diets and initiated metabolic phenotyping assays, which include measuring glucose levels, blood hormone levels, body weight, and fat mass.
This data will be used to inform future research directions, develop new therapeutic strategies, and improve our understanding of aging and metabolic health.
Accomplishments
1. Serotonin from fat cells contributes to obesity and regulation of blood glucose. ARS-funded researchers in Boston, Massachusetts, investigated gene and protein expression in fat cells of obese mice and humans. They found that an enzyme's increased expression in these cells led to the release of serotonin into the bloodstream. Elevated serotonin levels were linked to promoting obesity and negative changes in glucose and liver metabolism. These findings lay the groundwork for strategies to improve fat cell function in obese humans.
2. Phytoene, a plant-derived precursor of lycopene in tomatoes, reduced the development of nonalcoholic fatty liver disease. The health benefits of consuming tomatoes largely have been attributed to a carotenoid called lycopene. However, little is known about the role of phytoene, a colorless precursor of lycopene that is abundant in tomatoes. ARS-funded researchers in Boston, Massachusetts, investigated whether dietary phytoene, equivalent to 2-3 medium-sized tomatoes per day, contributes to protective effects against high refined carbohydrate diet-induced nonalcoholic fatty liver disease (NAFLD) in mice. Results showed that phytoene significantly reduced liver fat by regulating sirtuin 1 and enhancing mitochondrial fatty acid oxidation, thereby contributing to the health benefits of consuming tomatoes in preventing NAFLD.
3. Normatively aging chow-fed mice are metabolically healthy. Little has been done to understand how variations in nutrient content of rodent chow diets afffect health outcomes. ARS-funded researchers in Boston, Massachusetts, investigated this area by studying the effects of these diets on glucose homeostasis and the metabolic health of aged mice. They found that aging female and male mice fed different chow diets have different body compositions, glucose metabolism, and indices of gut health. These results emphasize the important and overlooked role of the variation in nutrient content of individual rodent chow diets used widely in nutrition research.
Review Publications
Coleman, C.R., Pallos, J., Arreola-Bustos, A., Wang, L., Raftery, D., Promislow, D., Martin, I. 2024. Natural variation in age-related dopamine neuron degeneration is glutathione dependent and linked to life span. Proceedings of the National Academy of Sciences (PNAS). https://doi.org/10.1073/pnas.2403450121.
Hilsabeck, T., Narayan, V.P., Wilson, K.A., Carrera, E., Raftery, D., Promislow, D., Brem, R.B., Campisi, J., Kapahi, P. 2024. Systems biology approaches identify metabolic signatures of dietary lifespan and healthspan across species. Nature Communications. https://doi.org/10.1038/s41467-024-52909-y.
Zhu, Y., Yeo, E.N., Smith, K.M., Greenberg, A., Rowan, S. 2024. Aging modulates the effect of dietary glycemic index on gut microbiome composition in mice. Journal of Nutrition. https://doi.org/10.1016/j.tjnut.2024.07.014.