Werner syndrome resembles normal aging

The mechanisms and genetic programs underlying human aging remain elusive. Some of the most powerful models for understanding aging are the use of progeroid syndromes caused by monogenic defects. There are several known progeroid syndromes, or accelerated aging syndromes, and there is a constant dispute regarding the extent to which these conditions resemble normal aging or represent diseases. They probably represent both. Amongst these conditions, Werner syndrome (WS) stands out as the one that resembles normal aging most although the patients also display many features that differ from normal aging. Numerous studies have focused on various aspects of the WS molecular pathology, cell biology and clinical features and while much progress has been made, there is still limited understanding about the mechanisms involved. Biochemical studies on the function of the Werner syndrome protein suggest that it functions in several DNA metabolic pathways.¹

In Volume 8 Issue 13 of Cell Cycle, Turaga et al.² takes a fresh look at the role of Werner protein (WRN) using siRNA to specifically reduce WRN expression, then assesses the effects on genome wide gene expression by cDNA micro arrays. Microarray studies can provide a more global understanding of aging related processes than traditional molecular studies. However, a number of studies in human³ and non-human⁴ species have revealed complex age-associated expression patterns, which thus far point to no single mechanism that explains the aging process. This is in part probably due to the fact that WS and aging are dynamic processes.

In 2003 we demonstrated that transcriptional changes in WS are strikingly similar to those in normal aging.⁵ The conclusions drawn by Turaga et al. support and extend our initial findings on a number of levels. A main common conclusion from both studies is that WRN deficiency markedly resembles normal old age. Our earlier studies were performed on primary fibroblasts from clinically affected WS patients whereas the current study by Turaga et al. used short term temporary siRNA knockdown. Mechanistically, siRNA inhibition is advantageous in that it filters out transcription alterations secondary to aneuploidy, chromosomal rearrangements and genetic background. Thus, siRNA WRN inhibition can potentially shed new light on the direct mechanistic consequences of WRN deficiency. However, in WS patients the phenotype evolves with symptoms not appearing until the second or third decade of life. Thus a short term knockdown provides a useful but limited perspective. Given the nature of microarray studies, with varying experimental conditions and sensitive statistics involved, results often compare poorly between studies on a gene-to-gene basis. When looking at pathways and groups of genes however, different experiments can point to common conclusions. Therefore, addressing the same problem from multiple angles greatly increases the validity of the conclusions drawn, and in that sense the current study by Turaga et al. represents a significant step forward.

The authors cement the previously established transcriptional role of WRN in DNA repair, DNA replication, cell cycle regulation, DNA damage response and other pathways. An important conclusion from both studies is that WRN appears to be widely involved in many cellular processes and play many important roles in the cell. This conclusion is supported by cellular and biochemical studies that show a wide spectrum of different functions for WRN protein.¹ In comparing the Turaga et al. results directly to ours, the authors find ten genes identified in both datasets, nine of which are downregulated in both WS and aging.² These genes are involved in crucial cellular processes including mRNA nuclear export, mRNA surveillance (RNSP1), ER-to-Golgi transport of selected proteins (DPM1 defect, which is known to cause severe developmental delay, seizures and dysmorphic features; MCFD2 mutations found in combined coagulation factor V and VIII deficiency),⁶ tumor suppression and transcription regulation (MIA3, SAV1), mitochondrial function, cancer (UQCRFS1)⁷ and DNA structure (CBX3). The present study also highlights the pro-inflammatory gene expression pattern observed in WRN siRNA transfected cells, consistent with previous studies⁸ and several of our earlier findings which were only published as supplementary material.⁵ WS and aging are dynamic processes and much information is missed when only examining unchallenged cells. We have examined how WS and cells from old donors react to DNA damage on a global genome expression level and found that there is an age-associated aberration of gene expression responses to DNA damage in WS.⁹

The Turaga et al. study also revealed an as yet unappreciated role of WRN on adipocyte differentiation.² Specifically, in WRN siRNA transfected cells they observed down-regulation of genes involved in cell cycle regulation during adipocyte differentiation. They further show that WRN siRNA treated cells have a slight decrease in lipid accumulation. Combining this paper’s observations with the previous demonstration that WS patients have high levels of visceral fat,¹⁰ suggests that WS patients may have altered lipid metabolism. Adipogenesis regulation in WS was also suggested by our earlier finding that APOB, the main apolipoprotein of chylomicrons and low density lipoproteins, was up-regulated in both WS and aging.³

It’s clear from the Turaga et al.² work and others that WRN appears to be widely involved in many cellular functions and its loss contributes to a wide spectrum of deleterious consequence. This paper supports the idea that WS resembles normal aging and while much remains to be understood, it is yet another step towards unveiling the complex mechanism underlying Werner syndrome and aging.