Abstract
Calorie restriction (CR) promotes longevity. A prevalent mechanistic hypothesis explaining this effect suggests that protein degradation, including mitochondrial autophagy, is increased with CR, removing damaged proteins and improving cellular fitness. At steady state, increased catabolism must be balanced by increasing mitochondrial biogenesis and protein synthesis, resulting in faster protein replacement rates. To test this hypothesis, we measured replacement kinetics and relative concentrations of hundreds of proteins in vivo in long-term CR and ad libitum-fed mice using metabolic 2H2O-labeling combined with the Stable Isotope Labeling in Mammals protocol and LC-MS/MS analysis of mass isotopomer abundances in tryptic peptides. CR reduced absolute synthesis and breakdown rates of almost all measured hepatic proteins and prolonged the half-lives of most (∼80%), particularly mitochondrial proteins (but not ribosomal subunits). Proteins with related functions exhibited coordinated changes in relative concentration and replacement rates. In silico expression pathway interrogation allowed the testing of potential regulators of altered network dynamics (e.g. peroxisome proliferator-activated receptor gamma coactivator 1-alpha). In summary, our combination of dynamic and quantitative proteomics suggests that long-term CR reduces mitochondrial biogenesis and mitophagy. Our findings contradict the theory that CR increases mitochondrial protein turnover and provide compelling evidence that cellular fitness is accompanied by reduced global protein synthetic burden.
Highlights
Calorie restriction (CR)1 is a dietary intervention in which calorie intake is reduced without malnutrition
The second mechanistic theory is supported by studies in yeast and C. elegans that demonstrated that a reduction in the rate of synthesis without a change in total abundance extends the maximal lifespan of these organisms [22,23,24]
ad libitum-fed (AL) mice consumed an average of 5 g, whereas CR mice were administered 3 g daily, as per the National Institutes on Aging (NIA) protocol
Summary
Calorie restriction (CR) is a dietary intervention in which calorie intake is reduced without malnutrition. The second mechanistic theory is supported by studies in yeast and C. elegans that demonstrated that a reduction in the rate of synthesis without a change in total abundance (i.e. reduced protein turnover) extends the maximal lifespan of these organisms [22,23,24]. These reports are consistent with findings that the repression of protein synthetic signaling pathways leads to increased longevity in mice [25]. It is hypothesized that reducing the rate of protein synthesis leads to improved translational fidelity, reduced proteolytic burden, increased chaperone capacity, and, reduced generation of damaged proteins [26]
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