Sirt1 ameliorates systemic sclerosis by targeting the mTOR pathway

Abstract

The modulation of Sirt1 activity may represent a potential therapeutic method for SSc. The mechanism may involve the inhibition of mTOR phosphorylation, whereas mTOR activity was shown to be a pathogenic culprit of SSc.

Sirtuins and Accelerated Aging in Scleroderma

“…In some cases, the observed mechanistic effects of SIRTs are so diverse, that it is difficult to narrowly classify them [69, 88, 91, 120]. Specific intracellular signaling molecules or pathways interacting functionally with or targeted directly by SIRTs include adenosine monophosphate-activated protein kinase (AMPK) – angiotensin-converting enzyme 2 (ACE2) signaling [69, 104], peroxisome proliferator-activated receptor (PPAR)γ [97], signal transducer and activator of transcription (STAT)3 [108], mammalian target of rapamycin (mTOR) [99, 102], nuclear factor erythroid 2-related factor 2 (Nrf2) [91, 117], Krüppel-like factor (KLF)15 [110], forkhead fox O1 (FOXO1) [66] and O3 (FOXO3) [67, 68], nuclear factor κB (NF-κB) [115], Notch1 [95], matrix metalloproteinase (MMP)-14 [92], manganese superoxide dismutase (MnSOD) [65, 87], and c-Jun [13]. …”

“…At the time of preparation of this review, there are only a handful of reports that have directly addressed the involvement of SIRTs in SSc [99–102, 111, 112, 121]. Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121].…”

“…Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121]. The prevailing message from these studies is that SIRTs play an antifibrotic role in SSc and engage in mutual negative feedback with the TGF-β signaling pathway, the most potent known driver of fibrosis.…”

“…Contradicting these findings, increased SIRT1 levels were found in SSc skin fibroblasts [102] and IPF lung tissues [98], as well as in bleomycin-treated mice [98, 102]. Another report showed increased SIRT6 expression in epithelial cells lining dilated cysts in patients with IPF, but not in normal lung, and upregulation of SIRT6 by TGF-β in primary human bronchial epithelial cells [118].…”

“…A subsequent study by this group found increased inflammatory and fibrogenic factors and increased mTOR levels in skin fibroblasts from patients with SSc and lesional skin in bleomycin-challenged mice compared to controls [102]. Activation of SIRT1 with resveratrol had a protective effect in the bleomycin model, which the authors ascribed to downregulation of mTOR and subsequent attenuation of multiple pro-inflammatory and profibrotic responses.…”