title: Metformin alleviates ageing cellular phenotypes in Hutchinson-Gilford progeria syndrome dermal fibroblasts.
abstract: Metformin is a popular antidiabetic biguanide, which has been considered as a candidate drug for cancer treatment and ageing prevention. Hutchinson-Gilford progeria syndrome (HGPS) is a devastating disease characterized by premature ageing and severe age-associated complications leading to death. The effects of metformin on HGPS dermal fibroblasts remain largely undefined. In this study, we investigated whether metformin could exert a beneficial effect on nuclear abnormalities and delay senescence in fibroblasts derived from HGPS patients. Metformin treatment partially restored normal nuclear phenotypes, delayed senescence, activated the phosphorylation of AMP-activated protein kinase and decreased reactive oxygen species formation in HGPS dermal fibroblasts. Interestingly, metformin reduced the number of phosphorylated histone variant H2AX-positive DNA damage foci and suppressed progerin protein expression, compared to the control. Furthermore, metformin-supplemented aged mice showed higher splenocyte proliferation and mRNA expression of the antioxidant enzyme, superoxide dismutase 2 than the control mice. Collectively, our results show that metformin treatment alleviates the nuclear defects and premature ageing phenotypes in HGPS fibroblasts. Thus, metformin can be considered a promising therapeutic approach for life extension in HGPS.
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea.
authors.forename: Seul-Ki
authors.initials: SK
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, College of Medicine, Korea University Guro Hospital, Seoul, Republic of Korea.
authors.forename: Ok Sarah
authors.identifier: 0000-0002-3977-2492
authors.initials: OS
authors.lastname: Shin
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D016922:Cellular Senescence / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D034904:Lamin Type A / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D011371:Progeria / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000473:pathology; D013154:Spleen / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism
chemical_list: C468783:H2AX protein, human; D006657:Histones; D007004:Hypoglycemic Agents; D034904:Lamin Type A; D009687:Nuclear Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C090764:prelamin A; D008687:Metformin; D013482:Superoxide Dismutase; D055372:AMP-Activated Protein Kinases
keywords: 
  HGPS
  ; ageing; metformin; progerin; senescence