Shared phenotypes among segmental progeroid syndromes suggest underlying pathways of aging.
ABSTRACT Segmental progeroid syndromes are those whose phenotypes resemble accelerated aging. Here we analyze those phenotypes and hypothesize that short telomeres produce the same group of symptoms in a variety of otherwise unrelated progeroid syndromes. Specific findings are the following: (a) short telomeres in some progeroid syndromes cause an alopecia/osteoporosis/fingernail-atrophy group of symptoms; (b) fingernail atrophy in progeroid syndromes resembles the natural slowing of nail growth that occurs in normal aging and nail growth velocity, and may be a marker of replicative aging in keratinocyte stem cells; (c) alopecia and reduced hair diameter parallel the nail results; (d) osteoporosis in Dyskeratosis Congenita resembles age-related osteoporosis, but the same is not true of other progerias; and (e) gray hair is associated with short telomeres, but may also involve reactive oxygen species. On the basis of these results, we make several predictions and discuss how the segmental quality of progeroid syndromes may provide insight into normative aging.
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ABSTRACT: AbstractA major challenge in the elderly is osteoporosis and the high risk of fracture. Telomere dysfunction is a cause of cellular senescence and telomere shortening which occurs with age in cells from most human tissues, including bone. Telomere defects contribute to the pathogenesis of two progeroid disorders characterized by premature osteoporosis, Werner syndrome and dyskeratosis congenital. It is hypothesized that telomere shortening contributes to bone aging. Using mice with disrupted telomere maintenance mechanisms, including mutants in Werner helicase (Wrn(-/-)), telomerase (Terc(-/-)) and Wrn(-/-) Terc(-/-) double mutants, we evaluated their skeletal phenotypes as models for human bone aging. Compared to young wild-type (WT) mice, micro-computerized tomography analysis revealed that young Terc(-/-) and Wrn(-/-)Terc(-/-) mice have decreased trabecular bone volume, trabecular number and trabecular thickness, as well as increased trabecular spacing. In cortical bone, young Terc(-/-) and Wrn(-/-)Terc(-/-) mice have increased cortical thinning, and increased porosity relative to age-matched WT mice. These trabecular and cortical changes were accelerated with age in Terc(-/-) and Wrn(-/-)Terc(-/-) mice compared to older WT mice. Histological quantification of osteoblasts in aged mice showed a similar number of osteoblasts in all genotypes; however, significant decreases in osteoid, mineralization surface, mineral apposition rate and bone formation rate in older Terc(-/-) and Wrn(-/-)Terc(-/-) bone suggest that osteoblast dysfunction is a prominent feature of precocious aging in these mice. Except in the Wrn(-/-) single mutant, osteoclast number did not increase in any genotype. Significant alterations in mechanical parameters (structure model index, degree of anistrophy, and moment of inertia) of the Terc(-/-) and Wrn(-/-)Terc(-/-) femurs compared to WT mice were also observed. Young Wrn(-/-)Terc(-/-) mice had a statistically significant increase in bone marrow fat content compared to young WT mice, which remained elevated in aged double mutants. Taken together, our results suggest that Terc(-/-) and Wrn(-/-)Terc(-/-) mutants recapitulate the human bone aging phenotype and are useful models for studying age-related osteoporosis.Disease Models and Mechanisms 03/2014; DOI:10.1242/dmm.014928 · 5.54 Impact Factor
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ABSTRACT: Fibroblasts from the progeroid Nijmegen breakage syndrome that express a truncated version of the nibrin protein (NBNp70) undergo premature senescence and have an enlarged morphology with high levels of senescence-associated β-galactosidase, although they do not have F-actin stress fibres. Growth of these fibroblasts in the continuous presence of p38 inhibitors resulted in a large increase in replicative capacity and changed the cellular morphology so that the cells resembled young normal fibroblasts. A similar effect was seen using an inhibitor of the p38 downstream effector kinase MK2. These data suggest that NBNp70 expressing cells undergo a degree of stress-induced replicative senescence via p38/MK2 activation, potentially due to increased telomere dysfunction, that may play a role in the progeroid features seen in this syndrome. Electronic supplementary material The online version of this article (doi:10.1007/s10522-014-9530-3) contains supplementary material, which is available to authorized users.Biogerontology 01/2015; 16:43-51. DOI:10.1007/s10522-014-9530-3 · 3.01 Impact Factor
Chapter: DNA INSTABILITY IN PREMATURE AGING[Show abstract] [Hide abstract]
ABSTRACT: DNA damage accumulates with increased chronological age and may contribute to both cell senescence and cancer. However, the importance and role(s) of DNA damage in promoting ageing is difficult to analyze experimentally at the molecular level since ageing results from a complex interplay of genetic and environmental factors. Premature human ageing syndromes offer a route to determining the molecular basis of at least some of the changes in DNA associated with normal ageing, as they are caused by mutation of individual genes whose protein products can be characterized in vitro. Furthermore, experimental manipulation of DNA stability may permit analysis of the contribution of DNA damage to the ageing process. Here, we assess the types of DNA instability observed in premature human ageing, particularly progeroid Hutchison Guilford Progeria and Werner's syndrome, and experimental models of these. The role for RecQ helicases and cognate exonucleases in maintaining DNA stability and preventing premature ageing is discussed in the context of studies in vitro and in model organisms. We conclude that it is by combining studies in various experimental systems that the true in vivo activities of these critical proteins can be elucidated.In: DNA Damage Repair, Repair Mechanisms and Aging, Edited by Allison E Thomas, 10/2010: chapter 1: pages 1-34; Nova Science Publishers.