Resveratrol Rescues SIRT1-Dependent Adult Stem Cell Decline and Alleviates Progeroid Features in Laminopathy-Based Progeria

Abstract

Abnormal splicing of LMNA gene or aberrant processing of prelamin A results in progeroid syndrome. Here we show that lamin A interacts with and activates SIRT1. SIRT1 exhibits reduced association with nuclear matrix (NM) and decreased deacetylase activity in the presence of progerin or prelamin A, leading to rapid depletion of adult stem cells (ASCs) in Zmpste24(-/-) mice. Resveratrol enhances the binding between SIRT1 and A-type lamins to increases its deacetylase activity. Resveratrol treatment rescues ASC decline, slows down body weight loss, improves trabecular bone structure and mineral density, and significantly extends the life span in Zmpste24(-/-) mice. Our data demonstrate lamin A as an activator of SIRT1 and provide a mechanistic explanation for the activation of SIRT1 by resveratrol. The link between conserved SIRT1 longevity pathway and progeria suggests a stem cell-based and SIRT1 pathway-dependent therapeutic strategy for progeria.

Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol

“…This is in agreement with several previous reports (Borra et al 2005;Kaeberlein et al 2005;Beher et al 2009;Pacholec et al 2010;Liu et al 2012) and contrasts with some others (Dai et al 2010;Hubbard et al 2013). Significantly, the two native peptides used in our experiments all have an aromatic residue at the +1 position, and the PGC-1α peptide also contains an additional aromatic residue at the +6 position, which has been suggested to further stimulation of SIRT1 activity by STACs (Hubbard et al 2013).…”

“…However, it is not unprecedented that an NTD of sirtuin harbors an allosteric activation mechanism toward native substrates. For example, binding of Sir4, principally through the NTD of Sir2, stimulates deacetylation of H4K16 by Sir2 (Tanny et al 2004;Hsu et al 2013), and binding by AROS and Lamin A, suggested via the NTD of SIRT1, potentiates the activity of SIRT1 toward p53 (Kim et al 2007;Liu et al 2012). Therefore, it is possible that, by modeling the protein-protein interaction effect with small molecules, allosteric activation of SIRT1 activation may be achieved.…”

“…The structural information obtained here may facilitate a computational search of such compounds. The structural property of SIRT1, together with further information on protein-protein interaction, should also benefit the understanding of new activation mechanisms of SIRT1 involving additional binding factors, such as Lamin A, which is reported to synergize with resveratrol to stimulate SIRT1 activity (Liu et al 2012). …”

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

“…Furthermore, HDAC2 has been shown to suppress p21 expression in human hepatocellular carcinoma via its binding to an Sp1‐binding site (Noh et al, 2011). On the other hand, it has been demonstrated that lamin A/C establishes direct interactions with histone deacetylases including SIRT1 (Cenni et al, 2014; Liu et al, 2012), SIRT6 (Ghosh, Liu, Wang, Hao, & Zhou, 2015), and HDAC1 (Kubben et al, 2016), while lamin partners at the nuclear envelope such as emerin, BAF, and LAP2beta interact with HDAC3 (Demmerle, Koch, & Holaska, 2013) or HDAC2 (Tsai et al, 2015). Moreover, lamin A/C has been demonstrated to bind gene promoters or neighboring domains and this binding has been linked to distinct transcriptional outcomes (Lee, Welton, Smith, & Kennedy, 2009; Lund & Collas, 2013; Mattout et al, 2011).…”

SIRT6, oxidative stress, and aging

“…Moreover, this regulatory pathway may be altered in human progeria and should be assessed in progeroid mouse models. In one such model, Zmpste24 −/− mice, a model for Hutchinson-Gilford progeria associated with mutations in A-type lamins, loss of SIRT1 function has already been noted in MSC populations [11]. SIRT6 was not assessed in that study; however, another recent study showed that A-type lamins are required for SIRT6 activation and support SIRT6-mediated DNA repair [12].…”