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Aging: Progeria and the Lamin Connection

2006; Elsevier BV; Volume: 16; Issue: 16 Linguagem: Inglês

10.1016/j.cub.2006.07.029

1879-0445

Brian A. Kudlow, Brian K. Kennedy,

DNA Repair Mechanisms

The relationship between progerias — diseases that resemble premature aging — and the normal aging process has been a source of debate in the aging research community. A recent study finds that LMNA, a gene targeted for mutation in Hutchinson Gilford Progeria Syndrome, may control the onset of aging-associated decline in normal fibroblasts. The relationship between progerias — diseases that resemble premature aging — and the normal aging process has been a source of debate in the aging research community. A recent study finds that LMNA, a gene targeted for mutation in Hutchinson Gilford Progeria Syndrome, may control the onset of aging-associated decline in normal fibroblasts. Gerontologists have long been intrigued by the amazing fidelity with which some pathological conditions, termed progerias, resemble accelerated 'normal' human aging [1Martin G.M. Genetic modulation of senescent phenotypes in Homo sapiens.Cell. 2005; 120: 523-532Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar]. Despite obvious similarities, none of the progeroid syndromes replicate all phenotypes associated with aging, and it remains to be determined whether the determinants of 'accelerated aging' and 'normal aging' overlap. Recent work by Scaffidi and Misteli [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar], however, provides evidence that the gene mutated in Hutchinson-Gilford Progeria Syndrome (HGPS), LMNA, may have a role to play in facilitating cellular senescence and, perhaps, organismal aging. Aging in humans and model organisms is accompanied by a number of characteristic changes at the subcellular, cellular, tissue and organismal level. Among these is a reduction in the proliferative capacity of cells leading to a senescent phenotype [3Campisi J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors.Cell. 2005; 120: 513-522Abstract Full Text Full Text PDF PubMed Scopus (1693) Google Scholar]. As a consequence and although controversial, the study of cell senescence is commonly used as a proxy to understand events associated with normal aging. Underlying the exhaustion of a cell's replicative capacity is a progressive shortening of telomeres, although there are a number of other cellular changes that also contribute to the decline. Among the myriad subcellular changes that accompany aging and senescence are changes to nuclear organization, including irregular nuclear morphology and/or changes in patterns of heterochromatin organization [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar, 4Narita M. Nunez S. Heard E. Narita M. Lin A.W. Hearn S.A. Spector D.L. Hannon G.J. Lowe S.W. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.Cell. 2003; 113: 703-716Abstract Full Text Full Text PDF PubMed Scopus (1545) Google Scholar]. The onset of these nuclear changes is often accelerated in pathological states associated with changes in genes that are linked to premature aging [5Shumaker D.K. Dechat T. Kohlmaier A. Adam S.A. Bozovsky M.R. Erdos M.R. Eriksson M. Goldman A.E. Khuon S. Collins F.S. et al.From the Cover: Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging.Proc. Natl. Acad. Sci. USA. 2006; 103: 8703-8708Crossref PubMed Scopus (498) Google Scholar, 6Scaffidi P. Misteli T. Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome.Nat. Med. 2005; 11: 440-445Crossref PubMed Scopus (421) Google Scholar]. For example, cells derived from Werner Syndrome patients show enhanced changes in nuclear deformation and premature senescence [1Martin G.M. Genetic modulation of senescent phenotypes in Homo sapiens.Cell. 2005; 120: 523-532Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar, 7Adelfalk C. Scherthan H. Hirsch-Kauffmann M. Schweiger M. Nuclear deformation characterizes Werner syndrome cells.Cell Biol. Int. 2005; 29: 1032-1037Crossref PubMed Scopus (22) Google Scholar]. HGPS is perhaps the most severe of the progeroid syndromes, with affected individuals having a mean life span of about 13 years. HGPS is caused by mutations in LMNA, the gene encoding the A-type nuclear lamins, primarily lamin A and C [8De Sandre-Giovannoli A. Bernard R. Cau P. Navarro C. Amiel J. Boccaccio I. Lyonnet S. Stewart C.L. Munnich A. Le Merrer M. et al.Lamin A truncation in Hutchison-Gilford progeria.Science. 2003; 300: 2055Crossref PubMed Scopus (992) Google Scholar, 9Eriksson M. Brown W.T. Gordon L.B. Glynn M.W. Singer J. Scott L. Erdos M.R. Robbins C.M. Moses T.Y. Berglund P. et al.Recurrent de novo point mutations in lamin A cause Hutchison-Gilford progeria syndrome.Nature. 2003; 423: 293-298Crossref PubMed Scopus (1469) Google Scholar]. Of note, over ten other diseases, collectively termed laminopathies have been linked to missense mutations of LMNA[10Jacob K.N. Garg A. Laminopathies: multisystem dystrophy syndromes.Mol. Genet. Metab. 2006; 87: 289-302Crossref PubMed Scopus (95) Google Scholar, 11Smith E.D. Kudlow B.A. Frock R.L. Kennedy B.K. A-type nuclear lamins, progerias and other degenerative disorders.Mech. Ageing Dev. 2005; 126: 447-460Crossref PubMed Scopus (43) Google Scholar]. Although other LMNA mutations have been associated with HGPS, the most frequently occurring mutation is a single nucleotide change that results in activation of a cryptic splice site inside exon 11 and the subsequent loss of 50 amino acids within the carboxyl terminus of the encoded protein [8De Sandre-Giovannoli A. Bernard R. Cau P. Navarro C. Amiel J. Boccaccio I. Lyonnet S. Stewart C.L. Munnich A. Le Merrer M. et al.Lamin A truncation in Hutchison-Gilford progeria.Science. 2003; 300: 2055Crossref PubMed Scopus (992) Google Scholar, 9Eriksson M. Brown W.T. Gordon L.B. Glynn M.W. Singer J. Scott L. Erdos M.R. Robbins C.M. Moses T.Y. Berglund P. et al.Recurrent de novo point mutations in lamin A cause Hutchison-Gilford progeria syndrome.Nature. 2003; 423: 293-298Crossref PubMed Scopus (1469) Google Scholar]. The truncated protein, termed Δ50 lamin A or progerin, retains a carboxy-terminal farnesyl group, which is normally rapidly cleaved off the wild-type lamin A protein. A large body of evidence suggests that LMNA mutations leading to progeria are dominant, gain-of-function alleles [11Smith E.D. Kudlow B.A. Frock R.L. Kennedy B.K. A-type nuclear lamins, progerias and other degenerative disorders.Mech. Ageing Dev. 2005; 126: 447-460Crossref PubMed Scopus (43) Google Scholar]. For example, deletion of Lmna in the mouse leads to muscular dsyrtophy, whereas expression of Δ50 lamin A leads to progeroid phenotypes [12Sullivan T. Escalante-Alcalde D. Bhatt H. Anver M. Bhat N. Nagashima K. Stewart C.L. Burke B. Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy.J. Cell Biol. 1999; 147: 913-920Crossref PubMed Scopus (913) Google Scholar, 13Varga R. Eriksson M. Erdos M.R. Olive M. Harten I. Kolodgie F. Capell B.C. Cheng J. Faddah D. Perkins S. et al.Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome.Proc. Natl. Acad. Sci. USA. 2006; 103: 3250-3255Crossref PubMed Scopus (194) Google Scholar]. Scaffidi and Misteli [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar] found that cells from HGPS patients prematurely display several features in common with cells from aged donors [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar]. This includes nuclear deformation, relocalization of heterochromatin as visualized by staining for tri-methyl-K9 histone H3 and HP1, as well as an upregulated DNA damage response. Some of these findings were expected, as nuclear deformation and alterations in large-scale heterochromatin organization are often associated with mutations in LMNA[11Smith E.D. Kudlow B.A. Frock R.L. Kennedy B.K. A-type nuclear lamins, progerias and other degenerative disorders.Mech. Ageing Dev. 2005; 126: 447-460Crossref PubMed Scopus (43) Google Scholar]. Of note, altering lamin function in Caenorhabditis elegans adults was found to cause both premature mortality and severe nuclear structural abnormalities [14Haithcock E. Dayani Y. Neufeld E. Zahand A.J. Feinstein N. Mattout A. Gruenbaum Y. Liu J. Age-related changes of nuclear architecture in Caenorhabditis elegans.Proc. Natl. Acad. Sci. USA. 2005; 102: 16690-16695Crossref PubMed Scopus (183) Google Scholar]. Finally, Scaffidi and Misteli [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar] report an age-dependent redistribution of A-type lamins from the nuclear interior to the nuclear periphery, consistent with findings that lamins are concentrated at the periphery in HGPS fibroblasts [15Goldman R.D. Shumaker D.K. Erdos M.R. Eriksson M. Goldman A.E. Gordon L.B. Gruenbaum Y. Khuon S. Mendez M. Varga R. et al.Accumulation of mutant lamin A causes progressive in nuclear architecture in Hutchinson-Gilford progeria syndrome.Proc. Natl. Acad. Sci. USA. 2004; 101: 8963-8968Crossref PubMed Scopus (746) Google Scholar]. The surprising finding of Scaffidi and Misteli [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar] is that all human cell lines and tissues observed, despite having normal LMNA genes, express a small amount of Δ50 lamin A. Their findings show that the normal LMNA gene, albeit with considerably lower efficiency, can be spliced in the same way as the HGPS allele of LMNA, thus producing the same Δ50 lamin A protein. Importantly, they found that treating fibroblasts from old donors with morpholinos designed to specifically reduce expression of Δ50 lamin A led to a reversal of the age-associated nuclear phenotypes. This result suggests that some nuclear changes accompanying aging require the presence of some threshold level of Δ50 lamin A, which is present in high levels in HGPS cells (Figure 1). When the authors [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar] compared cells from young and old donors, or cells passaged in culture over time, they were surprised to find that the levels of Δ50 lamin A did not increase with age. In contrast, it is known that in cells from HGPS patients, the abundance of Δ50 lamin A increases markedly with passage number, and this accumulation is correlated with a decline in nuclear organization [15Goldman R.D. Shumaker D.K. Erdos M.R. Eriksson M. Goldman A.E. Gordon L.B. Gruenbaum Y. Khuon S. Mendez M. Varga R. et al.Accumulation of mutant lamin A causes progressive in nuclear architecture in Hutchinson-Gilford progeria syndrome.Proc. Natl. Acad. Sci. USA. 2004; 101: 8963-8968Crossref PubMed Scopus (746) Google Scholar]. Scaffidi and Misteli [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar] propose that, in cells with normal LMNA genes, it is the prolonged exposure to low levels of Δ50 lamin A that leads to its deleterious effects in aged cells. Another, non-exclusive possibility is that other, unknown changes that lead to the nuclear alterations occur with age, but that the deleterious effects of these changes are enabled by the presence of Δ50 lamin A. In this view, the alternative splice product is not the primary determinant of age-related decline, but is required for the decline to occur. In HGPS patients, it may be that the dramatically elevated levels of Δ50 lamin A sensitize cells to the changes that occur with normal aging, leading to a more rapid decline in proliferative potential and premature senescence. As with many novel findings, this study [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar] raises several questions and directions of future research. For instance, will prolonged exposure to the splice-specific morpholino delay the onset of cellular senescence in normal fibroblasts? What are the functional differences in Δ50 lamin A compared to normal lamin A that promote the onset of nuclear aging phenotypes? Finally, if Δ50 lamin A expression is conserved in the mouse, can life span extension be achieved by reducing the expression of this Lmna splice variant in vivo? While the study by Scaffidi and Misteli [2Scaffidi P. Misteli T. Lamin A-dependent nuclear defects in human aging.Science. 2006; 312: 1059-1063Crossref PubMed Scopus (784) Google Scholar] does not unambiguously establish mechanistic overlap between progeria and normal aging, it succeeds in establishing a line of experimentally tractable questions whose answers could resolve the debate.