Abstract
For the past several decades, research in understanding the molecular basis of human aging has progressed significantly with the analysis of premature aging syndromes. Progerin, an altered form of lamin A, has been identified as the cause of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), and may be a contributing causative factor in normal aging. However, the question of whether HGPS actually recapitulates the normal aging process at the cellular and organismal level, or simply mimics the aging phenotype is widely debated. In the present study we analyzed publicly available microarray datasets for fibroblasts undergoing cellular aging in culture, as well as fibroblasts derived from young, middle-age, and old-age individuals, and patients with HGPS. Using GeroScope pathway analysis and drug discovery platform we analyzed the activation states of 65 major cellular signaling pathways. Our analysis reveals that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble cells taken from normal middle-aged and old individuals. This clearly indicates that HGPS may truly represent accelerated aging, rather than being just a simulacrum. Our data also points to potential pathways that could be targeted to develop drugs and drug combinations for both HGPS and normal aging.
Highlights
IntroductionPremature aging disorders as models to understand human aging
Premature aging disorders as models to understand human agingThe complexity of human aging has eluded biologists and physicians for decades, leading to a concerted effort to unravel the physiological, cellular and molecular mechanisms of aging
Key findings of various altered pathways outlined above are consistent with previously characterized gene expression alterations in various cell lines, primary cultures of Hutchinson‐Gilford Progeria Syndrome (HGPS) patients as well as those from normally aging control individuals
Summary
Premature aging disorders as models to understand human aging. The complexity of human aging has eluded biologists and physicians for decades, leading to a concerted effort to unravel the physiological, cellular and molecular mechanisms of aging. Premature aging is manifested in the rare genetic condition, HutchinsonGilford Progeria Syndrome or HGPS [3], which is a disease with major phenotypic features of accelerated www.impactaging.com. Progerin has been detected in normal individuals throughout their lifespan beginning at 1 month of age [8]; its accumulation leads to DNA damage and is manifested in the molecular response of ATR and ATM activation as well as phosphorylation of Chk, Chk and p53 [9, 10]. Fibroblasts from HGPS patients are slower in recruitment of DNA damage response proteins such as p53 binding protein 1(53BP1), thereby indicating defective DNA repair pathways [11]
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