title: 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.
authors.affiliation: Department of Biochemistry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong. ppliew@hku.hk
authors.forename: Baohua
authors.initials: B
authors.lastname: Liu
authors.forename: Shrestha
authors.initials: S
authors.lastname: Ghosh
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Huiling
authors.initials: H
authors.lastname: Zheng
authors.forename: Xinguang
authors.initials: X
authors.lastname: Liu
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wang
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Jin
authors.forename: Bojian
authors.initials: B
authors.lastname: Zheng
authors.forename: Brian K
authors.initials: BK
authors.lastname: Kennedy
authors.forename: Yousin
authors.initials: Y
authors.lastname: Suh
authors.forename: Matt
authors.initials: M
authors.lastname: Kaeberlein
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D034904:Lamin Type A / Q000235:genetics / Q000378:metabolism*; D008136:Longevity; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015530:Nuclear Matrix / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D011371:Progeria / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding; D011498:Protein Precursors / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D034904:Lamin Type A; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011498:Protein Precursors; D011994:Recombinant Proteins; D013267:Stilbenes; C090764:prelamin A; D008666:Metalloendopeptidases; C491250:Zmpste24 protein, mouse; D056564:Sirtuin 1; D000077185:Resveratrol