Restoring SIRT6 Expression in Hutchinson-Gilford Progeria Syndrome Cells Impedes Premature Senescence and Formation of Dysmorphic Nuclei

Abstract

Objectives: 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.

Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases

“…T2D metabolic defects are also ameliorated by increased activation of SIRT6, possibly through suppression of IGF1 signalling 92 . SIRT6 levels are decreased in patients with HGPS, and SIRT6 over-expression partially rescues the senescent phenotype of fibroblasts from patients with HGPS and extends the lifespan of wild-type male mice 101,102 .…”

SIRT6: Novel Mechanisms and Links to Aging and Disease

“…Intriguingly, recent studies have suggested that impaired heterochromatin maintenance due to reduced SIRT6 activity could contribute to pathogenesis of Hutchinson-Gilford Progeria Syndrome (HGPS), a human premature aging disorder [31]. HGPS patient cells express an abnormal Lamin A protein, a scaffold protein that is important for heterochromatin maintenance.…”

“…Recently, Lamin A was found to activate SIRT6-dependent histone deacetylation and ADP-ribosylation (see Box 1), but this function is lost in the HGPS mutant Lamin A protein [33]. Moreover, other work revealed that SIRT6 levels were reduced in HGPS cell lines, and SIRT6 re-expression in these cells attenuated their premature senescence [31]. It will be interesting to determine whether the underlying mechanisms involve SIRT6-dependent re-silencing of heterochromatin at pericentric or other genomic regions.…”

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

“…Suppression of SIRT6 protein levels mediates premature senescence-like phenotype in cells under H 2 O 2 -induced oxidative stress [99]. Premature cell senescence in Hutchinson–Gilford progeria syndrome (HGPS) and chronic obstructive pulmonary disease is linked with lower SIRT6 expression; its restoration remedies a number of senescence-linked traits, in the latter case through modulation of IIS–mTor signaling [100, 101]. The restoration of falling SIRT6 levels also rescues the diminished efficiency of DNA base excision repair in human foreskin fibroblasts from aged donors [102].…”