Combined treatment of rapamycin and dietary restriction has a larger effect on the transcriptome and metabolome of liver

Abstract

Rapamycin (Rapa) and dietary restriction (DR) have consistently been shown to increase lifespan. To investigate whether Rapa and DR affect similar pathways in mice, we compared the effects of feeding mice ad libitum (AL), Rapa, DR, or a combination of Rapa and DR (Rapa + DR) on the transcriptome and metabolome of the liver. The principal component analysis shows that Rapa and DR are distinct groups. Over 2500 genes are significantly changed with either Rapa or DR when compared with mice fed AL; more than 80% are unique to DR or Rapa. A similar observation was made when genes were grouped into pathways; two-thirds of the pathways were uniquely changed by DR or Rapa. The metabolome shows an even greater difference between Rapa and DR; no metabolites in Rapa-treated mice were changed significantly from AL mice, whereas 173 metabolites were changed in the DR mice. Interestingly, the number of genes significantly changed by Rapa + DR when compared with AL is twice as large as the number of genes significantly altered by either DR or Rapa alone. In summary, the global effects of DR or Rapa on the liver are quite different and a combination of Rapa and DR results in alterations in a large number of genes and metabolites that are not significantly changed by either manipulation alone, suggesting that a combination of DR and Rapa would be more effective in extending longevity than either treatment alone.

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

“…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.…”

Aberrant mTOR activation in senescence and aging: A mitochondrial stress response?

“…However, the effects of rapamycin on mitochondrial homeostasis appear to be more complex than a simple increase in clearance. For example, transcriptional profiling of mice fed rapamycin revealed significant changes in genes associated with mitochondrial function (Fok et al, 2014a; Fok et al, 2014b; Fok et al, 2014c). Additionally, acute treatment with rapamycin induces a rapid shift in metabolism, reducing metabolic intermediates of mitochondrial function (Ramanathan and Schreiber 2009) and acute treatment of myoblast cells with rapamycin inhibits mitochondrial biogenesis (Cunningham et al, 2007).…”

Short-term rapamycin treatment in mice has few effects on the transcriptome of white adipose tissue compared to dietary restriction

“…However using C57BL/6 mice, we showed that rapamycin had no effect on total fat mass or fat depots (Figure 1) in contrast to DR treatment, which resulted in ∼30% reduction in body weight that largely arose from a loss of adipose weight across all fat deposits (Fok et al, 2013b). Our group showed that male or female mice fed rapamycin for 6 months or 21 months had body weight and fat mass similar to mice fed a control diet (Fok et al, 2013a; Fok et al, 2014; Fok et al, 2013b; Zhang et al, 2013). …”

“…Initially, we compared the effect of DR and rapamycin on the liver transcriptome (Fok et al, 2013a) because the liver is one the first tissue to be exposed to rapamycin and it expresses a diverse number of metabolomics pathways. We found that less than 20% of 2724 transcripts that changed significantly by either DR or rapamycin were shared by both treatments.…”

“…We found that less than 20% of 2724 transcripts that changed significantly by either DR or rapamycin were shared by both treatments. Fok et al (2013a) also compared the liver metabolome of mice fed rapamycin and a DR-diet. An even greater difference between DR and rapamycin was observed in the 546 metabolites detected in liver.…”