The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome

Abstract

Calorie restriction (CR) may extend longevity by modulating the mechanisms involved in aging. Different hypotheses have been proposed for its main mode of action. We quantified hepatic transcripts of male C57BL/6 mice exposed to graded levels of CR (0% to 40% CR) for three months, and evaluated the responses relative to these various hypotheses. Of the four main signaling pathways implied to be linked to the impact of CR on lifespan (insulin/insulin like growth factor 1 (IGF-1), nuclear factor-kappa beta (NF-ĸB), mechanistic target of rapamycin (mTOR) and sirtuins (SIRTs)), all the pathways except SIRT were altered in a manner consistent with increased lifespan. However, the expression levels of SIRT4 and SIRT7 were decreased with increasing levels of CR. Changes consistent with altered fuel utilization under CR may reduce reactive oxygen species production, which was paralleled by reduced protection. Downregulated major urinary protein (MUP) transcription suggested reduced reproductive investment. Graded CR had a positive effect on autophagy and xenobiotic metabolism, and was protective with respect to cancer signaling. CR had no significant effect on fibroblast growth factor-21 (FGF21) transcription but affected transcription in the hydrogen sulfide production pathway. Responses to CR were consistent with several different hypotheses, and the benefits of CR on lifespan likely reflect the combined impact on multiple aging related processes.

Low‐Protein Diets with Fixed Carbohydrate Content Promote Hyperphagia and Sympathetically Mediated Increase in Energy Expenditure

“…However, restriction of both calories and protein in protein‐matched group did not lead to synergistic upregulation of liver and plasma FGF21, and the curtailed secretion of FGF21 may also have contributed to their lower energy expenditure. Our findings are in agreement with some reports on lack of liver FGF21 changes with calorie restriction in mice and a reduction in circulating FGF21 with energy restriction in humans . Prior evidence from intestinal‐derived cell lines implicates the existence of amino acid sensing mechanisms in the intestine; whether similar sensing mechanisms occur in vivo remains largely unknown.…”

Anti-Aging Effects of Calorie Restriction (CR) and CR Mimetics Based on the Senoinflammation Concept

“…Other omics studies provided evidence that CR definitively modulates aging processes and prevents or delays age-associated disease progression. Analysis of hepatic transcriptome showed that CR stimulated pathways involving IGF-1, NF-κB, mTOR, and SIRTs, which collectively contribute to reduced oxidative stress and improved metabolism, further supporting that CR promotes health and could extend lifespan by interfering with age-associated signaling pathways [85]. In addition, CR suppresses adiposity and insulin resistance, consequentially suppressing a proinflammatory status.…”

Aging and the Biological Response to Liver Injury

“…Derous et al studied the effects of caloric restriction (CR) on the increase in lifespan by evaluating four of the main signaling pathways involved in aging. 115 The impact of CR was consistent on IIS, nuclear factor-κB, and mammalian TOR, while sirtuins were not significantly altered (►Fig. 2).…”