Rate-limiting enzymes in cardiometabolic health and aging in humans

Authors: Parnell, Laurence; MCCAFFREY, KIRA - University Of Konstanz; BROOKS, ATHENA - Carleton College; SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; Lai, Chao Qiang; CHRISTENSEN, JACOB - University Of Oslo; WILEY, CHRISTOPHER - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Lifestyle Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/24/2023
Publication Date: 7/20/2023
Citation: 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.
DOI: https://doi.org/10.1159/000531350

Interpretive Summary: Food fuels our metabolism and enzymes are the proteins that convert food into molecules vital for health. Although the number of different enzymes in each human cell amounts to several thousand, some enzymes can be called rate-limiting, natural slow points in metabolic processes. However, these rate-limiting enzymes are incompletely characterized in humans, and how they might function in cardiovascular disease is heretofore not known. Thus, we selected a set of 380 such enzymes that we then assessed for their functions in common measures of cardiovascular health, including blood pressure and blood cholesterol levels. We discovered that many rate-limiting enzymes participate in basic metabolic features of cardiovascular health but few are sensitive to aging. This suggests that imbalances in metabolism that occur with aging involve other faster-acting types of enzymes. We also noted that some components of the specific biochemical processes that these enzymes facilitate were observed at high frequency. In particular, we observed new connections between certain diet-derived molecules and blood pressure, cholesterol levels and waist circumference. As these molecular components are derived from food, this is a finding that suggests carefully designed feeding studies to test specific changes to the diet in order to contribute to maintaining a healthy cardiovascular system.

Technical Abstract: Background. Many age-related diseases, and especially those of the cardiovascular system, arise from the combination of sub-optimal nutrition and metabolic imbalances. Rate-limiting enzymes (RLEs) are innate slow points in metabolic pathways, and many function in bioprocesses related to nutrient sensing. However, the activity of RLEs in cardiovascular health is poorly characterized. Thus, the objective of this study was to conduct a comprehensive survey of RLEs and their involvement in cardiometabolic health and disease. Methods. A dataset of 380 human RLEs was compared to protein and gene datasets for mitochondrial proteins, proteins showing significant age-related altered expression in blood, inherited metabolic disorders, and genetic loci with variants that associate with common cardiometabolic phenotypes: waist circumference, blood pressure, and plasma triglycerides, HDL-cholesterol, LDL-cholesterol and glucose. The biochemical reactions catalyzed by RLEs were evaluated for molecular entities that were enriched in subsets of RLEs associating with each cardiometabolic phenotype. Results. 112 RLEs function in mitochondria, and 53 RLEs have the attribute of contributing to an inherited metabolic disorder. There was a substantial depletion of RLE proteins that showed age-related altered expression in human plasma (P = 2.2x10-8), and of those that exhibited this behavior, 65% were downregulated. At the gene level, RLEs were assessed for common genetic variants that associated with important cardiometabolic traits of LDL-cholesterol or any of the five outcomes pertinent to metabolic syndrome. This revealed several RLEs with links to cardiometabolic traits, from a minimum of 26 for HDL-cholesterol to a maximum of 45 for plasma glucose. An analysis of these GWAS-linked RLEs for enrichment of the molecular constituents of the catalyzed reactions disclosed a number of significant phenotype-metabolite links. These included blood pressure with acetate (P = 2.2x10-4) and NADP+ (P = 0.0091), plasma HDL-cholesterol and triglyceride with diacylglycerol (P 2.6x10-5, 6.4x10-5, respectively) and diolein (P = 2.2x10-6, 5.9x10-6), and waist circumference with diolein (P = 1.8x10-4) and D-glucosamine 6-phosphate (P = 1.8x10-4). Discussion. In the context of cardiometabolic health, aging and disease, these results highlight key diet-derived metabolites that are central to specific rate-limited processes that are linked to cardiometabolic health. These metabolites include acetate and diacylaglycerol, pertinent to blood pressure and triglycerides, respectively. Although RLEs show extensive overlap with mitochondrial proteins and loci associated with cardiometabolic outcomes, RLEs are rarely found among standard sets of of aging-related genes. This suggests that age-related metabolic imbalance occurs at other points in pathways where RLEs operate.