Human progeroid syndromes, aging and cancer: New genetic and epigenetic insights into old questions
ABSTRACT Disorders in which individuals exhibit certain features of aging early in life are referred to as segmental progeroid syndromes. With the progress that has been made in understanding the etiologies of these conditions in the past decade, potential therapeutic options have begun to move from the realm of improbability to initial stages of testing. Among these syndromes, relevant advances have recently been made in Werner syndrome, one of several progeroid syndromes characterized by defective DNA helicases, and Hutchinson-Gilford progeria syndrome, which is characterized by aberrant processing of the nuclear envelope protein lamin A. Although best known for their causative roles in these illnesses, Werner protein and lamin A have also recently emerged as key players vulnerable to epigenetic changes that contribute to tumorigenesis and aging. These advances further demonstrate that understanding progeroid syndromes and introducing adequate treatments will not only prove beneficial to patients suffering from these dramatic diseases, but will also provide new mechanistic insights into cancer and normal aging processes.
- SourceAvailable from: José MP Freije
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- "An exaggerated accumulation of cellular damage or the inefficient ability to respond to stress causes progeroid syndromes, characterized by a precocious manifestation of several features related to human aging (Burtner and Kennedy 2010). Most progeroid syndromes are caused by defective DNA repair mechanisms or by alterations in the nuclear lamina (Ramirez et al. 2007; Hoeijmakers 2009). The nuclear lamina is a complex structure that surrounds and protects the nuclear content, playing important roles in genome regulation, organization, and maintenance (Dechat et al. 2008). "
ABSTRACT: Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-κB activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and Lmna(G609G/G609G) mice). Causal involvement of NF-κB in accelerated aging was demonstrated by the fact that both genetic and pharmacological inhibition of NF-κB signaling prevents age-associated features in these animal models, significantly extending their longevity. Our findings provide in vivo proof of principle for the feasibility of pharmacological modulation of the NF-κB pathway to slow down the progression of physiological and pathological aging.Genes & development 09/2012; 26(20):2311-24. DOI:10.1101/gad.197954.112 · 12.64 Impact Factor
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- "However, they are segmental in nature, as only a subset of tissues seems to age prematurely [Burtner and Kennedy, 2010]. Understanding the differences between progeroid syndromes with different manifestations may help to dissect the normal aging process [Ramirez et al., 2007]. "
ABSTRACT: Progeria syndromes are rare disorders that involve premature aging. Mutations in BANF1 have been recently reported to cause a new hereditary progeroid syndrome that we now propose to call the Néstor-Guillermo progeria syndrome (NGPS). We describe herein the clinical features of the first two NGPS patients, who phenocopy features of classic progerias (i.e., Hutchinson-Gilford progeria syndrome or mandibuloacral dysplasia), such as aged appearance, growth retardation, decreased subcutaneous fat, thin limbs, and stiff joints. However, these NGPS patients have a distinctive phenotype. In their early adulthood (32 and 24 years of age), they have no signs of cardiovascular impairment, diabetes mellitus, or hypertriglyceridemia. In contrast, they suffer profound skeletal abnormalities that affect their quality of life. The observed differences are of utmost importance to patients and their families and palliation of osseous manifestations is a priority, given their relatively long lifespan. We define NGPS as a chronic progeria because of its slow clinical course and relatively long survival, despite its early onset. Understanding the differences between progeria syndromes might contribute to the development of treatment strategies for common skeletal conditions, as well as aging itself.American Journal of Medical Genetics Part A 11/2011; 155A(11):2617-25. DOI:10.1002/ajmg.a.34249 · 2.05 Impact Factor
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- "For example, by annotating known protein mutations with disease terms, Mort et al. identified a class of diseases—blood coagulation disorders—that are associated with a significant depletion in substitutions at Olinked glycosylation sites . Similarly, by identifying other disease associations for the genes involved in a certain disease of interest we can gain insight into how the causation of seemingly unrelated diseases might be related, e.g., Werner's syndrome, Cockayne syndrome, Burkitt's lymphoma, and Rothmund-Thomson Syndrome    . We can also apply the enrichment analysis methodology to other sets of interest—such as patient cohorts. "
ABSTRACT: Advanced statistical methods used to analyze high-throughput data such as gene-expression assays result in long lists of "significant genes." One way to gain insight into the significance of altered expression levels is to determine whether Gene Ontology (GO) terms associated with a particular biological process, molecular function, or cellular component are over- or under-represented in the set of genes deemed significant. This process, referred to as enrichment analysis, profiles a gene set, and is widely used to make sense of the results of high-throughput experiments. Our goal is to develop and apply general enrichment analysis methods to profile other sets of interest, such as patient cohorts from the electronic medical record, using a variety of ontologies including SNOMED CT, MedDRA, RxNorm, and others. Although it is possible to perform enrichment analysis using ontologies other than the GO, a key pre-requisite is the availability of a background set of annotations to enable the enrichment calculation. In the case of the GO, this background set is provided by the Gene Ontology Annotations. In the current work, we describe: (i) a general method that uses hand-curated GO annotations as a starting point for creating background datasets for enrichment analysis using other ontologies; and (ii) a gene-disease background annotation set - that enables disease-based enrichment - to demonstrate feasibility of our method.Journal of Biomedical Informatics 04/2011; 44 Suppl 1:S31-8. DOI:10.1016/j.jbi.2011.04.007 · 2.48 Impact Factor