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Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice.

ABSTRACT: We present genome-wide microarray expression analysis of 11,000 genes in an aging potentially mitotic tissue, the liver. This organ has a major impact on health and homeostasis during aging. The effects of life- and health-span-extending caloric restriction (CR) on gene expression among young and old mice and between long-term CR (LT-CR) and short-term CR (ST-CR) were examined. This experimental design allowed us to accurately distinguish the effects of aging from those of CR on gene expression. Aging was accompanied by changes in gene expression associated with increased inflammation, cellular stress, and fibrosis, and reduced capacity for apoptosis, xenobiotic metabolism, normal cell-cycling, and DNA replication. LT-CR and just 4 weeks of ST-CR reversed the majority of these changes. LT-CR produced in young mice a pattern of gene expression that is a subset of the changes found in old LT-CR mice. It is possible that the early changes in gene expression, which extend into old age, are key to the life- and health-span-extending effects of CR. Further, ST-CR substantially shifted the "normo-aging" genomic profile of old control mice toward the "slow-aging" profile associated with LT-CR. Therefore, many of the genomic effects of CR are established rapidly. Thus, expression profiling should prove useful in quickly identifying CR- mimetic drugs and treatments.

SUBMITTER: Cao SX

PROVIDER: S-EPMC58517 | biostudies-literature | 2001 Sep

REPOSITORIES: biostudies-literature

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Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice.

Cao S X SX Dhahbi J M JM Mote P L PL Spindler S R SR

Proceedings of the National Academy of Sciences of the United States of America 20010904 19

We present genome-wide microarray expression analysis of 11,000 genes in an aging potentially mitotic tissue, the liver. This organ has a major impact on health and homeostasis during aging. The effects of life- and health-span-extending caloric restriction (CR) on gene expression among young and old mice and between long-term CR (LT-CR) and short-term CR (ST-CR) were examined. This experimental design allowed us to accurately distinguish the effects of aging from those of CR on gene expression. ...[more]

PMID: 11535822

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Project description:OBJECTIVE: To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR). BACKGROUND: Lifelong CR has been suggested to reduce the incidence of cardiovascular disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we show how short-term CR protects the mouse heart from ischemia. METHODS: Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food over a period of 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. Prior to MI (d8), the left ventricles (LV) of AL and CR mice were collected for Western blot, DNA and microRNA (miR) analyses. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI. RESULTS: This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). cDNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1?, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CONCLUSIONS: Short-term CR for only 7d represents a preconditioning strategy that limits infarct size. It is associated with a unique gene and miR signature, including the activation of specific pro-survival kinases. These findings may have implications for therapeutic use of short-term CR. . Male 12 wk-old C57Bl/6 mice were obtained from Charles River (Montreal, PQ, Canada) and maintained for at least 2 weeks before experimentation. Animals were randomly assigned to AL, CR and Lira groups with no initial differences in body weights. AL group mice were allowed ad libitum diet. Lira group mice were injected with Liraglutide (Glucagon-like peptide-1 agonist) at a dose of 200 µg/Kg i.p., twice daily for 7 days which is a mild weight-loss inducing dose and had access to ad libitum food and water. CR group mice were put on a Caloric restriction diet (30% less than normal ad libitum caloric intake) for 7 days to induce weight loss comparable to Lira group mice. Mice for CR and AL were individually caged and their food intake was measured everyday between 10-11 am for 1 week to calculate the average daily food intake. CR mice were fed 30% less than the calculated mean daily AL food consumption. CR cages were inspected daily for any remaining food, and transferred to a new cage every day. For CR group, pre-weighed mouse chow pellets were placed in cages between 10-11 am every day. Body weights were recorded between 10-11 am before and after the 7 day study period. For pre-ischemic assessments, animals (n=5/group/assessment) were sacrificed on day-8 (pre-MI), hearts were immediately extracted, washed in sterile phosphate-buffered saline (PBS), with LV free walls dissected, snap frozen in liquid nitrogen and stored at -80o C.

Project description:BackgroundChronic kidney disease and end-stage renal disease are major causes of morbidity and mortality that are seen far more commonly in the aged population. Interestingly, kidney function declines during aging even in the absence of underlying renal disease. Declining renal function has been associated with age-related cellular damage and dysfunction with reports of increased levels of apoptosis, necrosis, and inflammation in the aged kidney. Bioactive sphingolipids have been shown to regulate these same cellular processes, and have also been suggested to play a role in aging and cellular senescence.Methodology/principal findingsWe hypothesized that alterations in kidney sphingolipids play a role in the declining kidney function that occurs during aging. To begin to address this, the sphingolipid profile was measured in young (3 mo), middle aged (9 mo) and old (17 mo) C57BL/6 male mice. Interestingly, while modest changes in ceramides and sphingoid bases were evident in kidneys from older mice, the most dramatic elevations were seen in long-chain hexosylceramides (HexCer) and lactosylceramides (LacCer), with C14- and C16-lactosylceramides elevated as much as 8 and 12-fold, respectively. Increases in long-chain LacCers during aging are not exclusive to the kidney, as they also occur in the liver and brain. Importantly, caloric restriction, previously shown to prevent the declining kidney function seen in aging, inhibits accumulation of long-chain HexCer/LacCers and prevents the age-associated elevation of enzymes involved in their synthesis. Additionally, long-chain LacCers are also significantly elevated in human fibroblasts isolated from elderly individuals.Conclusion/significanceThis study demonstrates accumulation of the glycosphingolipids HexCer and LacCer in several different organs in rodents and humans during aging. In addition, data demonstrate that HexCer and LacCer metabolism is regulated by caloric restriction. Taken together, data suggest that HexCer/LacCers are important mediators of cellular processes fundamental to mammalian aging.

Dataset Information

Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice.

Publications

Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice.

Similar Datasets

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