Signaling pathway activation drift during aging: Hutchinson-Gilford Progeria Syndrome fibroblasts are comparable to normal middle-age and old-age cells

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.

Early Age-Related Functional Connectivity Decline in High-Order Cognitive Networks

“…While this finding conforms with earlier structural connectivity findings (Salat et al, 2005; Giorgio et al, 2010) as well as with age-related alterations in genetic, biochemical, and neurophysiological variables (Antonini et al, 1993; Kuhn et al, 1996; Mozley et al, 1996; Sheline et al, 2002; Lu et al, 2004; Hattiangady et al, 2005; Rex et al, 2005; Lynch et al, 2006; Hamilton et al, 2013; Aliper et al, 2015), it appears inconsistent with the progressive course of cognitive decline. Although the source for this lifespan FC dynamics cannot be determined by the current study, compensation and dedifferentiation theories might be proposed to account for the apparent late FC plateau.…”

“…Moreover, age-related synaptic plasticity changes, such as long-term potentiation deficits, were evident in middle-aged animals (Rex et al, 2005; Lynch et al, 2006). In humans, signal pathway activation (e.g., ERK-, JNK-, mTOR-, MAPK-, mitochondrial apoptosis, and caspase cascade) in fibroblasts derived from young, middle-aged and old healthy adults as well as Progeria patients showed more pronounced alterations in the transition between the young and middle-aged groups than among other groups (Aliper et al, 2015). Further, a set of genes related particularly to synaptic plasticity, vesicular transport and mitochondrial function showed reduced expression in the frontal cortex after age 40 (Lu et al, 2004).…”

Progerin sequestration of PCNA promotes replication fork collapse and mislocalization of XPA in laminopathy‐related progeroid syndromes

“…A hallmark of premature aging syndromes is the accumulation of DSBs caused by the increased progerin levels, which lead to early replicative senescence; however, the mechanism behind this phenotype has not been fully described. The mechanisms underlying premature aging syndromes are thought to share similarities with normal aging in mammalian cells, in that these cells also accumulate progerin over time (41–43, 50). Our work uncovered an unexpected finding that the nucleotide excision repair protein XPA was localized at DSB sites in HGPS cells instead of the DSB repair proteins, inhibiting DSB repair (14).…”

Insights into the role of immunosenescence during varicella zoster virus infection (shingles) in the aging cell model

“…Recent studies indicate that signaling pathway activation states in cells derived from chronologically young patients with HGPS strongly resemble those in cells from normal middle-aged and elderly individuals [10]. Mutations in the LMNA gene of patients with HGPS results in increased rates of cellular apoptosis, and consequently, a premature loss of functional "young" cells and concomitant premature accumulation of senescent cells [30,31].…”

“…Affected individuals have an average life span of 13 years [8]. Recent studies demonstrate that, similar to certain aspects of premature aging [9], the signaling pathway activation state in cells derived from chronologically young patients with HGPS strongly resembles that in cells from normal middleaged and elderly individuals [10]. A silent point mutation (C1824T) in the LMNA gene results in the production of a truncated form of the lamin A/C protein, known as progerin, which accounts for the accelerated aging phenotype in HGPS.…”