Research Paper Volume 16, Issue 6 pp 4980—4999
CMS121: a novel approach to mitigate aging-related obesity and metabolic dysfunction
- 1 Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
- 2 Neurobiology Research Laboratory, Atta ur Rahman School of Applied Biosciences, National University of Sciences and Technology (NUST), Islamabad, Pakistan
- 3 Department of Biochemistry, Federal University of Santa Catarina, Florianópolis, SC 88040-900, Brazil
- 4 The Razavi Newman Integrative Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Received: October 10, 2023 Accepted: February 23, 2024 Published: March 20, 2024
https://doi.org/10.18632/aging.205673How to Cite
Copyright: © 2024 Dafre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Background: Modulated by differences in genetic and environmental factors, laboratory mice often show progressive weight gain, eventually leading to obesity and metabolic dyshomeostasis. Since the geroneuroprotector CMS121 has a positive effect on energy metabolism in a mouse model of type 2 diabetes, we investigated the potential of CMS121 to counteract the metabolic changes observed during the ageing process of wild type mice.
Methods: Control or CMS121-containing diets were supplied ad libitum for 6 months, and mice were sacrificed at the age of 7 months. Blood, adipose tissue, and liver were analyzed for glucose, lipids, and protein markers of energy metabolism.
Results: The CMS121 diet induced a 40% decrease in body weight gain and improved both glucose and lipid indexes. Lower levels of hepatic caspase 1, caspase 3, and NOX4 were observed with CMS121 indicating a lower liver inflammatory status. Adipose tissue from CMS121-treated mice showed increased levels of the transcription factors Nrf1 and TFAM, as well as markers of mitochondrial electron transport complexes, levels of GLUT4 and a higher resting metabolic rate. Metabolomic analysis revealed elevated plasma concentrations of short chain acylcarnitines and butyrate metabolites in mice treated with CMS121.
Conclusions: The diminished de novo lipogenesis, which is associated with increased acetyl-CoA, acylcarnitine, and butyrate metabolite levels, could contribute to safeguarding not only the peripheral system but also the aging brain. By mimicking the effects of ketogenic diets, CMS121 holds promise for metabolic diseases such as obesity and diabetes, since these diets are hard to follow over the long term.