Aging of Hutchinson–Gilford progeria syndrome fibroblasts is characterised by hyperproliferation and increased apoptosis

Abstract

Hutchinson -Gilford progeria syndrome is a rare genetic disorder that mimics certain aspects of aging prematurely. Recent work has revealed that mutations in the lamin A gene are a cause of the disease. We show here that cellular aging of Hutchinson -Gilford progeria syndrome fibroblasts is characterised by a period of hyperproliferation and terminates with a large increase in the rate of apoptosis. The occurrence of cells with abnormal nuclear morphology reported by others is shown to be a result of cell division since the fraction of these abnormalities increases with cellular age. Similarly, the proportion of cells with an abnormal or absent A-type lamina increases with age. These data provide clues as to the cellular basis for premature aging in HGPS and support the view that cellular senescence and tissue homeostasis are important factors in the normal aging process. q 2004 Elsevier Inc. All rights reserved.

The R527H mutation in LMNA gene causes an increased sensitivity to ionizing radiation

“…36 Interestingly, MADA cell homozygous the R527H mutation showed the highest rates of apoptosis and micronuclei formation compared to other MADA cell carrying different types of mutation in the lamin A gene. 7 Due to the connection of micronucleation with apoptosis and considering that apoptosis could potentially account for tissue degeneration in progeria, 37 it can be speculated that the high level of phosphorylated ATM and p53 in R527H MADA cells, is responsible for the high percentage of apoptotic cells and, consequently, for the senescent phenotype. 7 The p53-associated DNA damage repair pathway constitutes a complicated network.…”

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

“…Consistent with this hypothesis, CR in rodents results in dramatic reductions in global cell proliferation rates as well as the preservation of the proliferative capacity of many cell types later in life (Lok et al ., 1990; Wolf et al ., 1995; Bruss et al ., 2011). In contrast, premature aging and shortened maxLS are associated with early‐life hyperproliferation and premature loss of the proliferative capacity of cells in both mice and humans (Pendergrass et al ., 1993; Bridger & Kill, 2004). …”

Blocking farnesylation of the prelamin A variant in Hutchinson-Gilford progeria syndrome alters the distribution of A-type lamins

“…3,4,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] This prominent morphological abnormality appears to be caused by expression of farnesylated progerin at the nuclear envelope, as blocking protein prenylation significantly restores normal nuclear shape. [16][17][18][19][20][21][25][26][27]30 The normalization of nuclear shape induced by blocking progerin prenylation correlates with an amelioration of disease phenotypes in mouse models of HGPS.…”