title: Restoring SIRT6 Expression in Hutchinson-Gilford Progeria Syndrome Cells Impedes Premature Senescence and Formation of Dysmorphic Nuclei.
abstract: OBJECTIVE
  Mice overexpressing SIRT6 live longer than wild-type mice while SIRT6 knockout mice exhibit similar degenerative phenotypes as individuals with Hutchinson-Gilford progeria syndrome (HGPS). Thus, we sought to test whether levels of SIRT6 are reduced in cells from individuals with HGPS and whether restored SIRT6 expression may impede premature aging phenotypes.
  
  
  METHODS
  Levels of endogenous SIRT6 and progerin in HGPS and normal fibroblasts were assessed by Western blotting and immunofluorescence. A tetracycline-inducible system was utilized to test whether progerin causes a rapid reduction in SIRT6 protein. SIRT6 was overexpressed in HGPS cells via lentiviral infection with biological endpoints including senescence-associated β-galactosidase (SA-β-gal) positivity, frequency of nuclear atypia, the number of 53BP1-positive DNA damage foci and growth rates.
  
  
  RESULTS
  Typical HGPS fibroblasts express lower levels of SIRT6 than fibroblasts from normal and atypical HGPS donors. Experimental induction of progerin did not cause a detectable reduction of SIRT6 protein. However, overexpression of SIRT6 in HGPS cells was associated with a reduced frequency of SA-β-gal positivity, fewer misshapen nuclei, fewer DNA damage foci, and increased growth rates.
  
  
  CONCLUSIONS
  Typical HGPS fibroblasts exhibit reduced levels of SIRT6 protein via a mechanism that remains to be elucidated. Our findings suggest that restoring SIRT6 expression in HGPS cells may partially impede senescence and the formation of dysmorphic nuclei. © 2015 S. Karger AG, Basel.
authors.affiliation: Department of Pathology, Virginia Commonwealth University, Richmond, Va., USA.
authors.forename: Helal
authors.initials: H
authors.lastname: Endisha
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Merrill-Schools
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.forename: Molly
authors.initials: M
authors.lastname: Bristol
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Nard
authors.initials: N
authors.lastname: Kubben
authors.forename: Lynne W
authors.initials: LW
authors.lastname: Elmore