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]

Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans. [ABSTRACT FROM AUTHOR]

Mitochondrial NAD+‐dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)‐dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR‐mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole‐body aerobic capacity but is dispensable for CR‐dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3−/−) yielded a longer overall and maximum lifespan as compared to Sirt3+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3−/−CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging. [ABSTRACT FROM AUTHOR]

Dietary macronutrient composition influences both hepatic function and aging. Previous work suggested that longevity and hepatic gene expression levels were highly responsive to dietary protein, but almost unaffected by other macronutrients. In contrast, we found expression of 4005, 4232, and 4292 genes in the livers of mice were significantly associated with changes in dietary protein (5%–30%), fat (20%–60%), and carbohydrate (10%–75%), respectively. More genes in aging‐related pathways (notably mTOR, IGF‐1, and NF‐kappaB) had significant correlations with dietary fat intake than protein and carbohydrate intake, and the pattern of gene expression changes in relation to dietary fat intake was in the opposite direction to the effect of graded levels of caloric restriction consistent with dietary fat having a negative impact on aging. We found 732, 808, and 995 serum metabolites were significantly correlated with dietary protein (5%–30%), fat (8.3%–80%), and carbohydrate (10%–80%) contents, respectively. Metabolomics pathway analysis revealed sphingosine‐1‐phosphate signaling was the significantly affected pathway by dietary fat content which has also been identified as significant changed metabolic pathway in the previous caloric restriction study. Our results suggest dietary fat has major impact on aging‐related gene and metabolic pathways compared with other macronutrients. [ABSTRACT FROM AUTHOR]

As the aging population on a global and national scale reaches ever increasing highs, research is essential to reduce the burden of aging and age-related diseases. I Vav-iCre i SP ± sp I ;Ercc1 i SP I -/fl i sp mice are healthy into adulthood, but then display premature onset of immunosenescence characterized by senescence of specific immune cell populations and impaired immune function, similar to changes that occur with aging in wild-type mice. B Dr. Claire Richardson b , University of Wisconsin-Madison, investigated how aging affects neuron cell biology by exploiting the ability of the nematode I Caenorhabditis i elegans to de-couple the symptoms of aging from chronological age [[61]]. They discovered that morphological aging is cell-intrinsically controlled by focusing on features of neuron morphological aging. LSD1 also targets non-histone proteins p53 and RelA/p65, which contribute to senescence and the secretory phenotype of senescent cells (senescence-associated secretory phenotype or SASP). [Extracted from the article]

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 evolutionary context of why caloric restriction (CR) activates physiological mechanisms that slow the process of aging remains unclear. The main goal of this analysis was to identify, using metabolomics, the common pathways that are modulated across multiple tissues (brown adipose tissue, liver, plasma, and brain) to evaluate two alternative evolutionary models: the "disposable soma" and "clean cupboards" ideas. Across the four tissues, we identified more than 10,000 different metabolic features. CR altered the metabolome in a graded fashion. More restriction led to more changes. Most changes, however, were tissue specific, and in some cases, metabolites changed in opposite directions in different tissues. Only 38 common metabolic features responded to restriction in the same way across all four tissues. Fifty percent of the common altered metabolites were carboxylic acids and derivatives, as well as lipids and lipid-like molecules. The top five modulated canonical pathways were L-carnitine biosynthesis, NAD (nicotinamide adenine dinucleotide) biosynthesis from 2-amino-3-carboxymuconate semialdehyde, S-methyl-5'-thioadenosine degradation II, NAD biosynthesis II (from tryptophan), and transfer RNA (tRNA) charging. Although some pathways were modulated in common across tissues, none of these reflected somatic protection, and each tissue invoked its own idiosyncratic modulation of pathways to cope with the reduction in incoming energy. Consequently, this study provides greater support for the clean cupboards hypothesis than the disposable soma interpretation. [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) remains the most robust intervention to extend lifespan and improve health span. Using a global mass spectrometry-based metabolomic approach, we identified 193 metabolites that were significantly differentially expressed ( SDE) in the livers of C57 BL/6 mice, fed graded levels of CR (10, 20, 30 and 40% CR) compared to mice fed ad libitum for 12 h a day. The differential expression of metabolites also varied with the different feeding groups. Pathway analysis revealed that graded CR had an impact on carnitine synthesis and the carnitine shuttle pathway, sphingosine-1-phosphate (S1P) signalling and methionine metabolism. S1P, sphingomyelin and L-carnitine were negatively correlated with body mass, leptin, insulin-like growth factor- 1 ( IGF-1) and major urinary proteins ( MUPs). In addition, metabolites which showed a graded effect, such as ceramide, S1P, taurocholic acid and L-carnitine, responded in the opposite direction to previously observed age-related changes. We suggest that the modulation of this set of metabolites may improve liver processes involved in energy release from fatty acids. S1P also negatively correlated with catalase activity and body temperature, and positively correlated with food anticipatory activity. Injecting mice with S1P or an S1P receptor 1 agonist did not precipitate changes in body temperature, physical activity or food intake suggesting that these correlations were not causal relationships. [ABSTRACT FROM AUTHOR]