Dataset Information

Acarbose improves late-life physical function in mice of both sexes, but rejuvenates cardiac structure and lipid profile in males only

ABSTRACT: With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat Type 2 diabetes (T2DM) can extend mouse lifespan, with greater effect in males than in females. Utilizing a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological and biochemical changes that occur during aging, and determined which of the effects of age and drug were sex-dependent. In both sexes, ACA prevented age-dependent loss of body mass, in addition to improving grip strength, balance/coordination on an accelerating rotarod, and rotarod endurance. Age-related cardiac hypertrophy was seen only in male mice, and this male-specific aging effect was attenuated by ACA. ACA-sensitive cardiac changes were associated with reduced activation of cardiac growth promoting pathways and decreased abundance of peroxisomal proteins involved in lipid metabolism. ACA further ameliorated age-associated changes in cardiac lipid species, particularly lysophospholipids – changes which have previously been associated with aging, cardiac dysfunction and cardiovascular disease in humans. In the liver, ACA had pronounced effects on lipid handling in both sexes, reducing hepatic lipidosis during aging and shifting the liver lipidome in adulthood, particularly favoring reduced triglyceride accumulation. Our results demonstrate that ACA, already in clinical use for T2DM, has broad-ranging anti-aging effects in multiple tissues, and may have the potential to increase physical function and alter lipid biology to preserve or improve health at older ages.

ORGANISM(S): Mus Musculus

SUBMITTER: Gennifer Merrihew

PROVIDER: PXD017706 | panorama | Wed Mar 03 00:00:00 GMT 2021

REPOSITORIES: PanoramaPublic

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Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology.

Herrera Jonathan J JJ Louzon Sean S Pifer Kaitlyn K Leander Danielle D Merrihew Gennifer E GE Park Jea H JH Szczesniak Kate K Whitson Jeremy J Wilkinson John E JE Fiehn Oliver O MacCoss Michael J MJ Day Sharlene M SM Miller Richard A RA Garratt Michael M

JCI insight 20201105 21

With an expanding aging population burdened with comorbidities, there is considerable interest in treatments that optimize health in later life. Acarbose (ACA), a drug used clinically to treat type 2 diabetes mellitus (T2DM), can extend mouse life span with greater effect in males than in females. Using a genetically heterogeneous mouse model, we tested the ability of ACA to ameliorate functional, pathological, and biochemical changes that occur during aging, and we determined which of the effec ...[more]

PMID: 32990683

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Project description:McAuley2012 - Whole-body Cholesterol Metabolism Lipid metabolism has a key role to play in human longevity and healthy aging. A whole-body mathematical model of cholesterol metabolism that explores the changes in both the rate of intestinal cholesterol absorption and the hepatic rate of clearance of LDL-C from the plasma, has been presented here. The model showed that of these two mechanisms, changes to the rate of LDL-C removal from the plasma with age had the most significant effect on cholesterol metabolism. The original SBML model file was generated using MathSBML 2.5.1. This model is described in the article: A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation. Mc Auley MM, Wilkinson DJ, Jones JJ, Kirkwood TT. BMC Syst Biol. 2012 Oct 10;6(1):130. Abstract: BACKGROUND: Global demographic changes have stimulated marked interest in the process of ageing. There has been, and will continue to be, an unrelenting rise in the number of the oldest old ( >85 years of age). Together with an ageing population there comes an increase in the prevalence of age related disease. Of the diseases of ageing, cardiovascular disease (CVD) has by far the highest prevalence. It is regarded that a finely tuned lipid profile may help to prevent CVD as there is a long established relationship between alterations to lipid metabolism and CVD risk. In fact elevated plasma cholesterol, particularly Low Density Lipoprotein Cholesterol (LDL-C) has consistently stood out as a risk factor for having a cardiovascular event. Moreover it is widely acknowledged that LDL-C may rise with age in both sexes in a wide variety of groups. The aim of this work was to use a whole-body mathematical model to investigate why LDL-C rises with age, and to test the hypothesis that mechanistic changes to cholesterol absorption and LDL-C removal from the plasma are responsible for the rise. The whole-body mechanistic nature of the model differs from previous models of cholesterol metabolism which have either focused on intracellular cholesterol homeostasis or have concentrated on an isolated area of lipoprotein dynamics. The model integrates both current and previously published data relating to molecular biology, physiology, ageing and nutrition in an integrated fashion. RESULTS: The model was used to test the hypothesis that alterations to the rate of cholesterol absorption and changes to the rate of removal of LDL-C from the plasma are integral to understanding why LDL-C rises with age. The model demonstrates that increasing the rate of intestinal cholesterol absorption from 50% to 80% by age 65 years can result in an increase of LDL-C by as much as 34mg/dL in a hypothetical male subject. The model also shows that decreasing the rate of hepatic clearance of LDL-C gradually to 50% by age 65 years can result in an increase of LDL-C by as much as 116mg/dL. CONCLUSIONS: Our model clearly demonstrates that of the two putative mechanisms that have been implicated in the dysregulation of cholesterol metabolism with age, alterations to the removal rate of plasma LDL-C has the most significant impact on cholesterol metabolism and small changes to the number of hepatic LDL receptors can result in a significant rise in LDL-C. This first whole-body systems based model of cholesterol balance could potentially be used as a tool to further improve our understanding of whole-body cholesterol metabolism and its dysregulation with age. Furthermore, given further fine tuning the model may help to investigate potential dietary and lifestyle regimes that have the potential to mitigate the effects aging has on cholesterol metabolism. This model is hosted on BioModels Database and identified by: MODEL1206010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Project description:To determine the effects of age and lipoic acid supplementation on hepatic gene expression, we fed young (3 months) and old (24 months) male Fischer 344 rats a diet with or without 0.2% (w/w) R-?-lipoic acid (LA) for two weeks. Total RNA isolated from liver tissue was analyzed by Affymetrix microarray to examine changes in transcriptional profile. Results showed an increase in pro-inflammatory gene expression in the aging liver, with increased immune cell function and tissue remodeling genes, representing 45% of the age-related transcriptome changes. Increased inflammation was corroborated by increases in soluble ICAM1 levels with age. There were also observed age-related increases in transcription of genes related to lipid and cholesterol synthesis including Acetyl CoA Carboxylase (Acacb) and Fatty acid Synthase (Fasn). Supplementation of old animals with LA did not reverse this necro-inflammatory phenotype, yet limited age-associated hepatic dyslipidemia. Dietary LA further affected a small but concerted number of hepatic genes regardless of age. These included declines in lipid and bile synthesis genes. Decline in lipid synthesis genes was further corroborated by a decrease in Fasn and Acc protein levels. Intriguingly, LA also altered the expression of genes governing circadian rhythm, most notably Bmal1, Npas2, and Per2, which changed in a coordinated manner with respect to their rhythmic transcription. Thus, advanced age is associated with a necro-inflammatory phenotype and increased lipid synthesis, while chronic LA supplementation influences hepatic genes associated with energy metabolism and circadian rhythm regardless of age. Young (3 months) and old (24 months) Fischer 344 male rats were fed an AIN-93M diet ± 0.2% (w/w) R-?-lipoic acid for two weeks prior to sacrifice. Total RNA was extracted from the median lobe of the liver and analyzed using Affymetrix Rat Genome 230 2.0 Genechips. There were hybridizations for 8 animals in each of the young control, young LA-supplemented, and old control groups, and 6 animals in the old LA-supplemented group. There are only 6 animals in the old LA group because two animals died during the two-week feeding period. This is the reason for nonsequential numbering of animals in this group.

Dataset Information

Acarbose improves late-life physical function in mice of both sexes, but rejuvenates cardiac structure and lipid profile in males only

Publications

Acarbose has sex-dependent and -independent effects on age-related physical function, cardiac health, and lipid biology.

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