An enduring human dream is to find the fountain of youth. Although this legendary spring has not yet been discovered, genes that cause early ageing have been found, shedding light on the molecular mechanisms behind how and why we get old.
...genes that cause early ageing have been found, shedding light on the molecular mechanisms behind how and why we get old.
Hutchinson–Gilford progeria syndrome (HGPS) is a rare sporadic early onset disease that is characterized by premature ageing and death from either heart attack or stroke at an average age of 14 years. HGPS is caused by mutations in the LMNA gene, which encodes the nuclear intermediate filament A-type lamins. Most patients with HGPS have a heterozygous mutation at nucleotide 1824 (a C–T substitution), resulting in the expression of progerin — a mutant form of lamin A that lacks 50 residues near its carboxy terminus. Early work headed by Robert Goldman and Francis Collins showed that the premature senescence of fibroblasts from patients with HGPS correlates with progerin levels. These cells also have aberrant nuclear structure, including lobulation of the nuclear envelope, a thick nuclear lamina, loss of peripheral heterochromatin and reduced levels of the silencing markers HP1α and trimethylated Lys9 of the core histone H3.
In a landmark study, Paula Scaffidi and Tom Misteli then showed that morpholino antisense oligonucleotides against the 1824 (C–T) mutation can block the expression of progerin. Surprisingly, not only did these oligonucleotides block the de novo expression of mutant mRNA and the progerin-associated phenotypes, they also rejuvenated cells that were already showing the disease phenotypes, restoring normal nuclear morphology and normal expression of the different chromatin markers.
Interestingly, studies have since shown that progerin accumulates in normal ageing human cells. How progerin affects nuclear shape and chromatin organization, and whether these findings might lead to an elixir of life, remain open questions.
ORIGINAL RESEARCH PAPERS
Goldman, R. D. et al. Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson–Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 101, 8963–8968 (2004)
Scaffidi, P. & Misteli, T. Reversal of the cellular phenotype in the premature aging disease Hutchinson–Gilford progeria syndrome. Nature Med. 11, 440–445 (2005)
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Gruenbaum, Y. The curious case of the ageing cells. Nat Rev Mol Cell Biol 10, 242 (2009). https://doi.org/10.1038/nrm2666