Both SIRT1 and mTOR have been linked to age-associated diseases with SIRT1 activation having a protective effect, whereas inhibition of mTOR conferring a beneficial effect. For example, SIRT1 activation confers a therapeutic effect in type 2 diabetes, obesity and neurodegenerative diseases such as Alzheimer's and amyotrophic lateral sclerosis, whereas inhibition of mTOR is protective against cardiovascular and neurological diseases, diet-induced obesity and cancer 
. Autophagy, a mechanism important in regulating stress response and aging is negatively regulated by mTOR 
, whereas SIRT1 has been reported to activate autophagy by deacetylating several essential components of the autophagy machinery 
The inverse relationship between the roles of SIRT1 and mTOR in aging-associated diseases and lifespan extension suggests a functional interrelationship between these two proteins. Our results demonstrate that SIRT1 and mTOR signaling pathways are indeed interconnected in a way that promotes stress sensing pro-survival signals, where the regulation of mTOR is mediated potentially through an interaction of SIRT1 with the TSC1-TSC2 complex.
Stress conditions downregulate mTOR signaling thereby reducing protein synthesis and cell growth. We found that this mechanism is deregulated in the absence of SIRT1 in mouse and human cells. SIRT1 deficiency caused upregulation of mTOR signaling which could not be abolished even under cellular stress caused by leucine starvation and other stress inducible stimuli. Interestingly, SIRT1 has been suggested as a nutrient-sensitive growth suppressor gene 
. Although it was proposed that SIRT1 functions through regulation of telomerase activity, our results suggest that SIRT1 functions as a nutrient-responsive growth suppressor also by regulating mTOR signaling.
SIRT1 has been shown to regulate many metabolic and stress responsive pathways through the regulation of gene expression of critical components. We observed that for mTOR regulation, SIRT1 does not seem to function through regulating expression of mTOR signaling proteins, instead SIRT1 potentially regulates mTOR through an upstream inhibitory complex. Using SIRT1 deficient and TSC2 deficient cells, we observed that SIRT1's inhibitory effect on mTOR was similar to that of the mTOR inhibitory protein TSC2. Further analysis using SIRT1 activator and inhibitor indicated that the mTOR inhibitory effect of SIRT1 was at least partially dependent on TSC2. Resveratrol has been reported to affect insulin signaling through SIRT1 independent pathways. Consistent with these reports, our data demonstrated that at lower doses, resvetratrol regulated the mTOR pathway in a SIRT1 dependent manner. However, at higher doses, reveratrol likely activated SIRT1 independent pathways in parallel, to inhibit mTOR activity.
Based on our data, we propose a model where negative regulation of mTOR signaling by SIRT1 is mediated through its association with TSC2 (). The TSC1-TSC2 complex is the most prominent upstream inhibitor of mTOR signaling, integrating several upstream signals such as growth factor, energy, stress and possibly amino acids. In response to specific stimuli, such as hormones, low energy, low nutrient or hypoxia, specific kinases and regulatory proteins activate or inhibit the TSC2 protein of the TSC1-TSC2 complex, thereby regulating mTOR signaling. By acting through the main mTOR inhibitory complex (TSC1/TSC2 complex), SIRT1 potentially responds to more than one form of stress or growth signal to regulate mTOR signaling.
Importantly, our results demonstrating a role for SIRT1 in mTOR signaling is the first evidence for SIRT1 to directly modulate translation-regulation. Previously, SIRT1's role in regulating cellular stress response was shown to involve various transcription factors such as NF-κB, p53 and the FOXO proteins, and other non-transcription factor proteins such as Ku70 and ATG 
. Consistent with a role for SIRT1 in stress induced translation regulation, we also have demonstrated that SIRT1 interacts with eIF-2alpha, a translation initiation factor, to regulate stress induced translation control (Ghosh et al).
Future studies are needed for insight into the exact mechanism of SIRT1's regulation on the TSC1/TSC2 complex or other potential upstream regulators of mTORC1. Since both SIRT1 and mTOR affect cellular pathways critical in stress response and aging, the regulatory inter-relationship between these proteins will prove to be helpful for designing effective therapeutic strategies for age-associated diseases.