Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver

Yu, Zhen; Wang, Rong; Fok, Wilson C.; Coles, Alexander; Salmon, Adam B.; Pérez, Viviana

doi:10.1093/gerona/glu053

Cited by 35 publications

(23 citation statements)

References 46 publications

(54 reference statements)

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“…Consistent with differences we observe in treatments, two recent reports have highlighted the distinctive effects of RP and CR in the liver after a 6-month treatment (Fok et al ., 2014; Yu et al ., 2014). CR had a larger and mostly opposite effect on the transcriptome compared to RP.…”

Section: Discussionmentioning

confidence: 99%

Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

et al. 2015

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Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10-week RP or 40% CR. Protein abundance and turnover were measured in vivo using 2H3–leucine heavy isotope labeling followed by LC-MS/MS, and translation was assessed by polysome profiling. We observed 35–60% increased protein half-lives after CR and 15% increased half-lives after RP compared to age-matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways, with opposite effects in mitochondrial (mt) dysfunction and eIF2 signaling pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.

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Section: Discussionmentioning

confidence: 99%

Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

et al. 2015

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“…This is not to say that reduced mTOR signalling is not important in the DR response – it might still be indispensable for DR‐mediated lifespan extension in mice and play an important role in the improvement of mouse survival. However, our results indicate that the differential effects of these two treatments on certain aspects of physiology (for example, insulin sensitivity (Fok et al ., ), fat deposition (Fok et al ., ), xenobiotic metabolism (Miller et al ., ), fatty acid oxidation (Yu et al ., ) and mitochondrial biology (Fok et al ., ; Karunadharma et al ., )) are likely influencing at least some of the factors that influence mouse death, either their probability of occurrence or age at onset, generating these distinct mortality patterns that we observe.…”

Section: Discussionmentioning

confidence: 99%

Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction

2016

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SummaryReduced mechanistic target of rapamycin (mTOR) signalling extends lifespan in yeast, nematodes, fruit flies and mice, highlighting a physiological pathway that could modulate aging in evolutionarily divergent organisms. This signalling system is also hypothesized to play a central role in lifespan extension via dietary restriction. By collating data from 48 available published studies examining lifespan with reduced mTOR signalling, we show that reduced mTOR signalling provides similar increases in median lifespan across species, with genetic mTOR manipulations consistently providing greater life extension than pharmacological treatment with rapamycin. In contrast to the consistency in changes in median lifespan, however, the demographic causes for life extension are highly species specific. Reduced mTOR signalling extends lifespan in nematodes by strongly reducing the degree to which mortality rates increase with age (aging rate). By contrast, life extension in mice and yeast occurs largely by pushing back the onset of aging, but not altering the shape of the mortality curve once aging starts. Importantly, in mice, the altered pattern of mortality induced by reduced mTOR signalling is different to that induced by dietary restriction, which reduces the rate of aging. Effects of mTOR signalling were also sex dependent, but only within mice, and not within flies, thus again species specific. An alleviation of age‐associated mortality is not a shared feature of reduced mTOR signalling across model organisms and does not replicate the established age‐related survival benefits of dietary restriction.

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“…However, changes in energetics associated with caloric restriction and metformin treatment (Zhou et al 2001) can increase AMPK activity and inhibit the mTOR pathway. In fact, treatment with rapamycin, an inhibitor of mTOR, and dietary restriction have been shown to decrease hepatic SREBP-1 levels (Yu et al 2015), while inhibition of mTOR complex 1 (mTORC1) can alter expression of genes associated with lipolysis in adipocytes (Chakrabarti et al 2010). It has previously been demonstrated that an 18-h fast and 1 h of metformin treatment can effectively inhibit mTORC1 in murine livers, as indicated by an increase in phospho-Raptor (Gwinn et al 2008).…”

Section: Discussionmentioning

confidence: 99%

Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

Linden

Lopez

Fletcher

et al. 2015

Appl. Physiol. Nutr. Metab.

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Weight loss is recommended for patients with nonalcoholic fatty liver disease (NAFLD), while metformin may lower liver enzymes in type 2 diabetics. Yet, the efficacy of the combination of weight loss and metformin in the treatment of NAFLD is unclear. We assessed the effects of metformin, caloric restriction, and their combination on NAFLD in diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. Male OLETF rats (age 20 weeks; n = 6–8 per group) were fed ad libitum (AL), given metformin (300 mg·kg−1·day−1; Met), calorically restricted (70% of AL; CR), or calorically restricted and given metformin (CR+Met) for 12 weeks. Met lowered adiposity compared with AL but not to the same magnitude as CR or CR+Met (p < 0.05). Although only CR improved fasting insulin and glucose, the combination of CR+Met was needed to improve post-challenge glucose tolerance. All treatments lowered hepatic triglycerides, but further improvements were observed in the CR groups (p < 0.05, Met vs. CR or CR+Met) and a further reduction in serum alanine aminotransferases was observed in CR+Met rats. CR lowered markers of hepatic de novo lipogenesis (fatty acid synthase, acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase-1 (SCD-1)) and increased hepatic mitochondrial activity (palmitate oxidation and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity). Changes were enhanced in the CR+Met group for ACC, SCD-1, β-HAD, and the mitophagy marker BNIP3. Met decreased total hepatic mTOR content and inhibited mTOR complex 1, which may have contributed to Met-induced reductions in de novo lipogenesis. These findings in the OLETF rat suggest that the combination of caloric restriction and metformin may provide a more optimal approach than either treatment alone in the management of type 2 diabetes and NAFLD.

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Rapamycin and Dietary Restriction Induce Metabolically Distinctive Changes in Mouse Liver

Cited by 35 publications

References 46 publications

Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

Comparative idiosyncrasies in life extension by reduced mTOR signalling and its distinctiveness from dietary restriction

Combining metformin therapy with caloric restriction for the management of type 2 diabetes and nonalcoholic fatty liver disease in obese rats

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