Search

Calorie restriction (CR) typically promotes a reduction in body mass, which correlates with increased lifespan. We evaluated the overall changes in survival, body mass dynamics, and body composition following long-term graded CR (580 days/19 months) in male C57BL/6J mice. Control mice (0% restriction) were fed ad libitum in the dark phase only (12-hour ad libitum [12AL]). CR groups were restricted by 10%–40% of their baseline food intake (10CR, 20CR, 30CR, and 40CR). Body mass was recorded daily, and body composition was measured at 8 time points. At 728 days/24 months, all surviving mice were culled. A gradation in survival rate over the CR groups was found. The pattern of body mass loss differed over the graded CR groups. Whereas the lower CR groups rapidly resumed an energy balance with no significant loss of fat or fat-free mass, changes in the 30 and 40CR groups were attributed to higher fat-free mass loss and protection of fat mass. Day-to-day changes in body mass were less variable under CR than for the 12AL group. There was no indication that body mass was influenced by external factors. Partial autocorrelation analysis examined the relationship between daily changes in body masses. A negative correlation between mass on Day 0 and Day +1 declined with age in the 12AL but not the CR groups. A reduction in the correlation with age suggested body mass homeostasis is a marker of aging that declines at the end of life and is protected by CR. [ABSTRACT FROM AUTHOR]

While the average human life span continues to increase, there is little evidence that this is leading to a contemporaneous increase in "healthy years" experienced by our aging population. Consequently, many scientists focus their research on understanding the process of aging and trialing interventions that can promote healthspan. The 2021 Midwest Aging Consortium consensus statement is to develop and further the understanding of aging and age-related disease using the wealth of expertise across universities in the Midwestern United States. This report summarizes the cutting-edge research covered in a virtual symposium held by a consortium of researchers in the Midwestern United States, spanning topics such as senescence biomarkers, serotonin-induced DNA protection, immune system development, multisystem impacts of aging, neural decline following severe infection, the unique transcriptional impact of calorie restriction of different fat depots, the pivotal role of fasting in calorie restriction, the impact of peroxisome dysfunction, and the influence of early life trauma on health. The symposium speakers presented data from studies conducted in a variety of common laboratory animals as well as less-common species, including Caenorhabditis elegans, Drosophila, mice, rhesus macaques, elephants, and humans. The consensus of the symposium speakers is that this consortium highlights the strength of aging research in the Midwestern United States as well as the benefits of a collaborative and diverse approach to geroscience. [ABSTRACT FROM AUTHOR]

The main purpose of research in mice is to explore metabolic changes in animal models and then predict or propose potential translational benefits in humans. Although some researchers in the brain research field have mentioned that the mouse experiments results still lack the complex neuroanatomy of humans, caution is required to interpret the findings. In mice, we observed in article seventeenth of the series of the effects of graded levels of calorie restriction, metabolomic changes in the cerebellum indicated activation of hypothalamocerebellar connections driven by hunger responses. Therefore, the purpose of the current perspective is to set this latest paper into a wider context of the physiological, behavioral, and molecular changes seen in these mice and to compare and contrast them with previous human studies. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) remains the most robust intervention to extend life span and improve healthspan. Though the cerebellum is more commonly associated with motor control, it has strong links with the hypothalamus and is thought to be associated with nutritional regulation and adiposity. Using a global mass spectrometry-based metabolomics approach, we identified 756 metabolites that were significantly differentially expressed in the cerebellar region of the brain of C57BL/6J mice, fed graded levels of CR (10, 20, 30, and 40 CR) compared to mice fed ad libitum for 12 hours a day. Pathway enrichment indicated changes in the pathways of adenosine and guanine (which are precursors of DNA production), aromatic amino acids (tyrosine, phenylalanine, and tryptophan) and the sulfur-containing amino acid methionine. We also saw increases in the tricarboxylic acid cycle (TCA) cycle, electron donor, and dopamine and histamine pathways. In particular, changes in l-histidine and homocarnosine correlated positively with the level of CR and food anticipatory activity and negatively with insulin and body temperature. Several metabolic and pathway changes acted against changes seen in age-associated neurodegenerative disorders, including increases in the TCA cycle and reduced l-proline. Carnitine metabolites contributed to discrimination between CR groups, which corroborates previous work in the liver and plasma. These results indicate the conservation of certain aspects of metabolism across tissues with CR. Moreover, this is the first study to indicate CR alters the cerebellar metabolome, and does so in a graded fashion, after only a short period of restriction. [ABSTRACT FROM AUTHOR]

Animals undergoing calorie restriction (CR) often lower their body temperature to conserve energy. Brown adipose tissue (BAT) is stimulated through norepinephrine when rapid heat production is needed, as it is highly metabolically active due to the uncoupling of the electron transport chain from ATP synthesis. To better understand how BAT metabolism changes with CR, we used metabolomics to identify 883 metabolites that were significantly differentially expressed in the BAT of C57BL/6 mice, fed graded CR (10%, 20%, 30%, and 40% CR relative to their individual baseline intake), compared with mice fed ad libitum (AL) for 12 hours a day. Pathway analysis revealed that graded CR had an impact on the TCA cycle and fatty acid degradation. In addition, an increase in nucleic acids and catecholamine pathways was seen with graded CR in the BAT metabolome. We saw increases in antioxidants with CR, suggesting a beneficial effect of mitochondrial uncoupling. Importantly, the instigator of BAT activation, norepinephrine, was increased with CR, whereas its precursors l-tyrosine and dopamine were decreased, indicating a shift of metabolites through the activation pathway. Several of these key changes were correlated with food anticipatory activity and body temperature, indicating BAT activation may be driven by responses to hunger. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) remains the most robust intervention to extend life span and improve health span. Using a global mass spectrometry-based metabolomics approach, we identified metabolites that were significantly differentially expressed in the plasma of C57BL/6 mice, fed graded levels of calorie restriction (10% CR, 20% CR, 30% CR, and 40% CR) compared with mice fed ad libitum for 12 hours a day. The differential expression of metabolites increased with the severity of CR. Pathway analysis revealed that graded CR had an impact on vitamin E and vitamin B levels, branched chain amino acids, aromatic amino acids, and fatty acid pathways. The majority of amino acids correlated positively with fat-free mass and visceral fat mass, indicating a strong relationship with body composition and vitamin E metabolites correlated with stomach and colon size, which may allude to the beneficial effects of investing in gastrointestinal organs with CR. In addition, metabolites that showed a graded effect, such as the sphinganines, carnitines, and bile acids, match our previous study on liver, which suggests not only that CR remodels the metabolome in a way that promotes energy efficiency, but also that some changes are conserved across tissues. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) leads to a remarkable decrease in adipose tissue mass and increases longevity in many taxa. Since the discovery of leptin, the secretory abilities of adipose tissue have gained prominence in the responses to CR. We quantified transcripts of epididymal white adipose tissue of male C57BL/6 mice exposed to graded levels of CR (0-40% CR) for 3 months. The numbers of differentially expressed genes (DEGs) involved in NF-κB, HIF1-α, and p53 signaling increased with increasing levels of CR. These pathways were all significantly downregulated at 40% CR relative to 12 h ad libitum feeding. In addition, graded CR had a substantial impact on DEGs associated with pathways involved in angiogenesis. Of the 497 genes differentially expressed with graded CR, 155 of these genes included a signal peptide motif. These putative signaling proteins were involved in the response to ketones, TGF-β signaling, negative regulation of insulin secretion, and inflammation. This accords with the previously established effects of graded CR on glucose homeostasis in the same mice. Overall these data suggest reduced levels of adipose tissue under CR may contribute to the protective impact of CR in multiple ways linked to changes in a large population of secreted proteins. [ABSTRACT FROM AUTHOR]