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.
"Genome instability can also result from mechanical stress on the nucleus. So called laminopathies such as Hutchinson–Gilford-progeria-syndrome (HGPS), atypical WS, restrictive dermopathy (RD), and mandibuloacral dysplasia (MAD) are caused by mutations in lamin A and the ZMPSTE24 farnesyltransferase required for lamin A processing (Ramirez et al., 2007). The nuclear instability leads to DNA damage accumulation and evokes a DDR. "
[Show abstract][Hide abstract] ABSTRACT: DNA damage contributes to cancer development and aging. Congenital syndromes that affect DNA repair processes are characterized by cancer susceptibility, developmental defects, and accelerated aging (Schumacher et al., 2008). DNA damage interferes with DNA metabolism by blocking replication and transcription. DNA polymerase blockage leads to replication arrest and can gives rise to genome instability. Transcription, on the other hand, is an essential process for utilizing the information encoded in the genome. DNA damage that interferes with transcription can lead to apoptosis and cellular senescence. Both processes are powerful tumor suppressors (Bartek and Lukas, 2007). Cellular response mechanisms to stalled RNA polymerase II complexes have only recently started to be uncovered. Transcription-coupled DNA damage responses might thus play important roles for the adjustments to DNA damage accumulation in the aging organism (Garinis et al., 2009). Here we review human disorders that are caused by defects in genome stability to explore the role of DNA damage in aging and disease. We discuss how the nucleotide excision repair system functions at the interface of transcription and repair and conclude with concepts how therapeutic targeting of transcription might be utilized in the treatment of cancer.
Frontiers in Genetics 02/2013; 4:19. DOI:10.3389/fgene.2013.00019
"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). "
[Show abstract][Hide abstract] 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 · 10.80 Impact Factor
"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]. "
[Show abstract][Hide abstract] 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 · 2.16 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.