Research Article: 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

Date Published: July 31, 2017

Publisher: Impact Journals LLC

Author(s): Davina Derous, Sharon E. Mitchell, Lu Wang, Cara L. Green, Yingchun Wang, Luonan Chen, Jing-Dong J. Han, Daniel E.L. Promislow, David Lusseau, Alex Douglas, John R. Speakman.


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.

Partial Text

Aging is accompanied by many metabolic changes and elevated risks of metabolic, cardiovascular, neuro-degenerative and other non-communicable diseases. Obesity, insulin resistance, inflammation and hyper-tension are predisposing conditions that increase in prevalence during aging and contribute to the disease state known as the metabolic syndrome of aging [1]. In 1935, evidence emerged that mammalian longevity could be increased by restricting food intake [2]. Nowadays, it is well established that restricting the amount of calories contributes to an increased lifespan and healthspan in many species [3–8], including non-human primates [9]. CR also delays the onset of diseases related to the metabolic syndrome of aging, such as atherosclerosis, type 2 diabetes mellitus and cardiovascular diseases [10–12]. The mechanism(s) by which CR mediates its beneficial effects on aging are yet to be fully comprehended and are likely a result of changes simultaneously in many tissues and pathways. Mathematical models applied to mortality rates have been used to understand if CR postpones or slows the aging process [13]. Here, we analyzed the liver trans-criptome as a part of a systems level description of graded CR responses [14–22]. From a clinical perspective the liver is well protected against aging relative to the other organs, but changes still occur in hepatic structure and function, such as declining liver regeneration, decreasing drug clearance and increasing bile cholesterol production [23]. Interestingly only four weeks of CR was able to reverse the majority of the aging-associated changes observed in murine liver [24]. Due to its central role in energy metabolism and glucose homeostasis, the liver is of great interest for genome-wide analysis to understand whole-body aging.




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