Research Project: Personalized Nutrition and Healthy Aging

Location: Jean Mayer Human Nutrition Research Center On Aging

2024 Annual Report

Objectives
Objective 1: Conduct and analyze dietary intervention studies to validate gene-diet interactions and identify the underlying mechanisms using omic technologies. Sub-Objective 1A: To characterize the response of cardiometabolic, epigenetics and other age-related biomarkers and the microbiome to diets differing in saturated fat and prebiotics content (animal-based diet versus plant-based diet) in individuals carrying CC and TT genotypes at the common APOA2 -265T>C (rs5082) SNP using a short-term crossover, randomized feeding study, and to elucidate the physiological mechanism(s) by which diet impinges on metabolic pathways through APOA2 genotypes. Sub-Objective 1B: To characterize the TCF7L2-by-diet interaction with respect to those type 2 diabetes (T2D) and cardiovascular disease (CVD) risk factors identified in observational studies for validation in the context of a short-term randomized controlled feeding study (low-fat diet versus Mediterranean diet), and to elucidate the molecular mechanisms responsible for these GxD interactions using epigenetics and metabolomics. Sub-Objective 1C: To develop polygenic risk scores (PRS) predicting the changes in and relationships between cardiovascular disease (CVD) risk factors and disease incidence in response to long-term (>=1 y) dietary interventions [Mediterranean diet (MedDiet) or Low-fat control diet]. Objective 2: Identify genomic, epigenomic, metabolomic, and microbiome-related biomarkers that sustain healthy aging, and define specific personalized dietary, physical activity, and other lifestyle factors associated with optimal health of older adults. Subobjective 2A: To identify genetic and dietary factors that modify CPT1A methylation and cardio-metabolic traits. Subobjective 2B: To identify interactions between the genome, epigenome and diet and lifestyle on lipid profiles that signify CMD risk.

Approach
Promoting healthy aging by tailoring nutritional guidance based on a person's genetic makeup is an emerging science that has great promise. The Nutrition and Genomics lab is a pioneer in this area and focuses its research on the role of precision nutrition and cardiometabolic diseases – the leading cause of death in the United States. Our approach harnesses the availability of tremendous computing power and huge datasets from existing cohorts to study the crosstalk between habitual diets and the genome to identify gene-by-diet interactions that sustain individual optimal health for older adults. This objective will be accomplished using Big Data analytics of omics data (i.e., genome-wide datasets on gene and protein expression, genetic variation, methylation, and metabolite levels). We also conduct short-term feeding studies in people preselected based on particular genotypes to validate gene-by-diet interactions revealed by previous observational studies and, using multi-omic data integration (i.e., genomics, epigenomics, microbiomics, and metabolomics) methods, identifying the mechanisms underlying such interactions. This research will generate new knowledge on how non-modifiable and modifiable factors interact to prevent cardiovascular diseases and type 2 diabetes. Further, it will contribute much-needed evidence and tools to define and implement personalized nutrition as a common practice for the benefit of all stakeholders.

Progress Report
The research conducted over the life of this program has significantly advanced our understanding of gene-diet interactions and their impact on cardiometabolic health and aging. The integration of -omic technologies in our studies has provided more profound insights into the underlying mechanisms of these interactions. Our findings support the development of personalized dietary interventions to promote healthy aging and optimize health outcomes in older adults. A. We investigated the effects of a personalized nutrition program on cardiometabolic health using a randomized controlled trial. Participants [n=347], aged 41–70 years and generally representative of the average U.S. population, were randomized to the personalized dietary program (PDP) [n=177] or control [n=170]. This trial compared the impact of a PDP tailored diet to individual postprandial glucose and triglyceride responses versus general dietary advice. The PDP led to significant reductions in triglycerides and improvements in other health markers, showing how personalized diets can influence type 2 diabetes (T2D) and cardiovascular disease (CVD) risk factors. B. We examined genetic, metabolic, microbiome, and meal composition/context contributions to postprandial metabolic responses in the Personalized Responses to Dietary Composition Trial PREDICT-1 Study, enrolling 1,102 twins and unrelated healthy U.K./U.S. adults. Our analysis revealed significant and consistent differences in blood triglyceride, glucose, and insulin responses to identical meals, influenced by person-specific factors such as the gut microbiome, with genetic variants having a modest impact. Modifiable factors like meal timing significantly affected these responses. We developed a machine learning model that predicts both triglyceride and glycemic responses to food, potentially informing personalized diet strategies. C. In the Coronary Diet Intervention with Olive Oil and Cardiovascular Prevention CORDIOPREV study, a randomized clinical trial including 1002 patients with coronary heart disease (CHD), we investigated the efficacy of a Mediterranean versus low-fat diet over 5 years. We found that the Mediterranean diet significantly preserved kidney function in patients with T2D and obesity. This supports the role of personalized dietary interventions based on genetic variations to manage chronic disease risk. D. We also examined the association between telomere length and diabetes remission in the same cohort. Our findings indicated that patients with longer telomeres at baseline were more likely to achieve diabetes remission following dietary intervention. E. We explored novel factors for inclusion in precision nutrition studies, such as chronobiology and its association with cardiometabolic risk. Our analyses in the CORDIOPREV study showed that evening chronotypes had higher cardiometabolic risk and less robust circadian-related rhythms than morning types, even during nutritional intervention. We also carried out an integrated analysis of sweet taste preference and its modulation by T2D, identifying genetic factors associated with sweet taste preference. F. We investigated the genetic and microbiome contributions to dietary T2D prevention and remission. The CORDIOPREV study assessed T2D risk and remission, finding different baseline gut microbiota associated with dietary patterns and T2D outcomes. Our findings provide evidence of the microbiome as a predictive factor for diet-induced T2D remission. G. We examined the AMY1 gene related to dietary carbohydrate intake and T2D, discovering that low AMY1 copy numbers increase the risk of insulin resistance with age, suggesting dietary modifications to mitigate T2D risk. Additionally, we analyzed the ABCG1 gene for epigenetic changes relating to statin use and the risk of T2D. We found a strong association between statin use and DNA methylation at the ABCG1 gene, leading to an increased risk of T2D. H. We identified associations between dietary intake and DNA methylation at the CPT1A gene, finding that carbohydrate intake directly correlates with DNA methylation, while fat intake shows an inverse relationship. This balance between carbohydrates and fat influences gene activity and has significant health consequences. I. We conducted a prospective observational cohort study in the Boston Puerto Rican Health Study (BPRHS) and the Atherosclerosis Risk in Communities (ARIC) Study, identifying metabolite profiles associated with cardiometabolic stress, all-cause mortality, and CHD. We also investigated clusters of co-regulated metabolites associated with T2D among Puerto Rican adults, identifying several metabolite clusters linked to T2D prevalence. These findings underscore the shared molecular pathophysiology of metabolic dysfunction, cardiovascular disease, and longevity, suggesting pathways for improving prognosis across these conditions J. We developed, validated, and improved dietary and disease risk biomarkers to support precision nutrition approaches. Using continuous glucose monitors (CGM) in the PREDICT-1 Study, we demonstrated strong concordance in measuring postprandial glycemic responses, supporting their potential application in precision nutrition. K. We initiated an effort to discover metabolites correlating with the protective e2 allele of the apolipoprotein E (APOE) gene, identifying a unique signature of 19 metabolites associated with the E2 group. This research provides insights into lipid metabolism, aging, and the gut-brain axis, thereby deepening our understanding of the molecular mechanisms underpinning healthy aging and longevity. L. We identified metabolites associated with cognitive decline and Alzheimer's disease in Puerto Rican adults, linking medium-chain fatty acids and tyrosine metabolism to cognitive health. The findings help identify genetic and dietary factors that modify metabolic traits, aligning with our objective of understanding biomarkers of aging. M. Our research demonstrated that adherence to the Mediterranean diet is associated with longer telomeres, particularly in women. This highlights the role of diet and genetics in influencing aging biomarkers, supporting our goal of identifying factors that promote healthy aging. N. Our study revealed sex-specific variations in gut microbiota linked to CHD. We identified bacterial taxa as key discriminators between sexes and CHD status, contributing to understanding how the genome, epigenome, and diet interact to affect lipid profiles and coronary microvascular dysfunction (CMD) risk.

Accomplishments
1. Targeting diets based on genetics may improve weight loss. ARS-funded researchers in Boston, Massachusetts, examined whether people with different versions of a specific gene called APOA2 lose weight differently when following a low-carbohydrate diet or a low-fat diet. The researchers found that people with a certain version of the APOA2 gene, known as TT, lost more weight on a low-carb diet compared to a low-fat diet. Conversely, people with other versions of the gene (CT or CC) lost more weight on a low-carb diet compared to a low-fat diet in the first three months. However, the differences disappeared by six months on each diet. This study suggests that tailoring diets based on genetic makeup, particularly the APOA2 gene type, could help improve weight loss outcomes. However, individuals with certain genetic makeups may need more educational and behavioral reinforcement to maintain long-term weight loss. This approach, known as precision nutrition, can lead to significant health benefits.

Review Publications
Coltell, O., Asensio, E.M., Sorli, J.V., Ortega-Azorin, C., Fernandez-Carrion, R., Pascual, E.C., Barragan, R., Gonzalez, J.I., Estruch, R., Alzate, J.F., Perez-Fidalgo, A., Portoles, O., Ordovas, J.M. 2023. Associations between the new DNA-methylation-based telo-mere length estimator, the Mediterranean diet, and genetics in a Spanish population at high cardiovascular risk. Antioxidants. https://doi.org/10.3390/antiox12112004.
Guan, Y., Cheng, C., Bellomo, L.I., Narain, S., Bigornia, S., Garelnabi, M., Scott, T., Ordovas, J.M., Tucker, K.L., Bhadelia, R., Koo, B. 2023. APOE4 allele-specific associations between diet, multimodal biomarkers, and cognition among Puerto Rican adults in Massachusetts. Frontiers in Aging Neuroscience. https://doi.org/10.3389/fnagi.2023.1285333.
Coltell, O., Asensio, E.M., Sorli, J.V., Ortega-Azorin, C., Fernandez-Carrion, R., Pascual, E.C., Barragan, R., Gonzalez, J.I., Estruch, R., Alzate, J.F., Perez-Fidalgo, A., Portoles, O., Ordovas, J.M., Corella, D. 2023. Associations between the new DNA-methylation-based telomere length estimator, the mediterranean diet and genetics in a Spanish population at high cardiovascular risk. Antioxidants. https://doi.org/10.3390/antiox12112004.
Parnell, L.D., Magadmi, R., Zwanger, S., Shukitt Hale, B., Lai, C., Ordovas, J.M. 2023. Dietary responses of dementia-related genes encoding metabolic enzymes. Nutrients. 15(3):644. https://doi.org/10.3390/nu15030644.
Sanchez-Cabo, F., Fuster, V., Silla, J., Gonzalez, G., Lorenzo-Vivas, E., Alvarez, R., Callejas, S., Benguria, A., Gil, E., Nunez, E., Oliva, B., Mendiguren, J.M., Cortes-Canteli, M., Bueno, H., Andres, V., Ordovas, J.M., Fernandez-Freira, L., Quesada, A.J., Garcia, J.M., Rossello, X., Vasquez, J., Dopazo, A., Fernandez-Ortiz, A., Ibanez, B., Fuster, J.J., Lara-Pezzi, E. 2023. A multi-omics approach unveils an association between subclinical atherosclerosis and epigenetic age acceleration mediated by systemic inflammation. European Heart Journal. https://doi.org/10.1093/eurheartj/ehad361.
Rivas-Garcia, L., Quintana-Navarro, G.M., Torres-Pena, J.D., Arenas-de Larriva, A.P., Alcala-Diaz, J.F., Yubero-Serrano, E.M., Perez-Caballero, A.I., Ortiz-Morales, A.M., Rangel-Zuniga, O., Lopez-Moreno, A., Ordovas, J.M., Perez-Martinez, P., Lopez-Miranda, J., Delgado-Lista, J. 2023. Dietary antioxidant intake reduces carotid intima-media thickness in coronary heart disease patients: From the CORDIOPREV study. Free Radicals in Biology and Medicine. https://doi.org/10.1016/j.freeradbiomed.2023.11.026.
Baccarelli, A., Ordovas, J.M. 2023. The epigenetics of early cardiovascular and metabolic diseases development: From mechanisms to precision medicine. Circulation Research. 132(12):1648-1662. https://doi.org/10.1161/CIRCRESAHA.123.322135.
Runblad, A., Sandoval, V., Holven, K., Ordovas, J.M., Ulven, S. 2023. Omega-3 fatty acids and individual variability in plasma triglyceride response: A mini-review. Redox Biology. https://doi.org/10.1016/j.redox.2023.102730.
Graniel, I.P., Babio, N., Becerra-Tomas, N., Toledo, E., Camacho-Barcia, L., Corella, D., Castaner-Nino, O., Romaguera, D., Vioque, J., Alonso-Gomez, A.M., Warnberg, J., Martinez, J.A., Serra-Majem, L., Estruch, R., Tinahones, F., Fernandez-Aranda, F., Lapertra, J., Pinto, X., Tur, J.A., Garcia-Rios, A., Bueno-Cavanillas, A., Gaforio, J.J., Matia-Martin, P., Daimiel, L., Sanchez, V.M., Prieto-Sanchez, L., Ros, E., Razquin, C., Mestres, C., Sorli, J.V., Cuenca-Royo, A., Rios, A., Torres-Collado, L., Vaquero-Luna, J., Perez-Farinos, N., Zulet, M.A., Sanchez-Villegas, A., Casas, R., Bernal-Lkopez, M., Santos-Lozano, J., Corbella, X., Mateos, D., Buil-Cosiales, P., Jimenez-Murcia, S., Fernandez-Carrion, R., Forcano-Gamazo, L., Lopez, M., Sempere-Pascual, M.A., Moreno-Rodriquez, A., Gea, A., de la Torre-Fornell, R., Salas-Salvado, J., Ordovas, J.M. 2020. Association between coffee consumption and total dietary caffeine intake with cognitive functioning: Cross-sectional assessment in an elderly Mediterranean population. European Journal of Nutrition. https://doi.org/10.1007/s00394-020-02415-w.
Parnell, L.D., McCaffrey, K.S., Brooks, A., Smith, C.E., Lai, C., Christensen, J.J., Wiley, C.D., Ordovas, J.M. 2023. Rate-limiting enzymes in cardiometabolic health and aging in humans. Lifestyle Genomics. 16:124-138. https://doi.org/10.1159/000531350.
Lai, C., Parnell, L.D., Lee, Y., Zeng, H., Smith, C., Mckeowan, N.M., Ordovas, J.M. 2023. The impact of alcoholic drinks and dietary factors on epigenetic markers associated with triglyceride levels. Frontiers in Genetics. https://doi.org/10.3389/fgene.2023.1117778.
Bermingham, K.M., Mazidi, M., Franks, P.W., Maher, T., Valdes, A.M., Linenberg, I., Wolf, J., Hadjigeorgiou, G., Spector, T.D., Menni, C., Ordovas, J.M., Berry, S.E., Hall, W.L. 2023. Characterisation of fasting and postprandial NMR metabolites: Insights from the ZOE PREDICT 1 study. Nutrients. https://doi.org/10.3390/nu15112638.
Fernandez-Carrion, R., Sorli, J.V., Asensio, E.M., Pascual, E.C., Portoles, O., Alvarez Sala, A., Frances, F., Ramirez Sabio, J.B., Perez Fidalgo, A., Villamil, L., Tinahones, F.J., Estruch, R., Ordovas, J.M., Coltell, O., Corella, D. 2023. DNA methylation signatures of tobacco smoking in a high cardiovascular risk population: Modulation by the mediterranean diet. International Journal of Environmental Research and Public Health. https://doi.org/10.3390/ijerph20043635.
Guitierrez Mariscal, F., Alcala Diaz, J., Quintana Navarro, G., de la Cruz, A.S., Torres Pena, J.D., Cardelo, M.P., Arenas Larriva, A.P., Malagon, M.M., Romero Cabrera, J.L., Ordovas, J.M., Perez Martinez, P., Delgado Lista, J., Yubero Serrano, E., Lopez Miranda, J. 2023. Changes in quantity plant based protein intake on type 2 diabetes remission in coronary heart disease patients: From the CORDIOPREV study. European Journal of Nutrition. https://doi.org/10.1007/s00394-022-03080-x.
Garcia-Fernandez, H., Arenas-De Larriva, A.P., Lopez-Moreno, J., Gutierrez Mariscal, F., Romero Cabrera, J.L., Molina-Abril, H., Torres Pena, J.D., Rodriguez-Cano, D., Malagon, M.M., Ordovas, J.M., Delgado Lista, J., Perez Martinez, P., Lopez Miranda, J., Camargo, A. 2024. Sex-specific differences in intestinal microbiota associated with cardiovascular disease. Biology of Sex Differences. https://doi.org/10.1186/s13293-024-00582-7.