In a new research study, scientists from Vision Genomics, LLC, Insilico Medicine, Inc., and Howard University showed that Hutchinson-Gilford Progeria Syndrome (HGPS or Progeria) is comparable to normal aging with respect to cellular signaling pathways, and that HGPS truly recapitulates the normal aging process. This study was accomplished by the analysis of microarray gene expression datasets of fibroblasts from normal individuals (young and aging) and HGPS patients using a newly-developed pathway analysis and drug discovery tool named ‘GeroScopeTM’.
HGPS is an accelerated aging disease typically caused by a de novo mutation leading to autosomal dominant single base substitution in the Lamin A gene. The expression of this mutated Lamin A gene results in a truncated protein known as ‘Progerin’. In HGPS there is an excessive accumulation of Progerin that is toxic to cells, causing DNA damage and genomic instability. Since normal lamins also participate as relays for intracellular signaling pathways in the nucleus, as well as interact with chromatin, its mutated version, Progerin can have serious implications in normal aging and disease.
The team of scientists used GeroScopeTM to analyze and compare microarray datasets from replicatively senescent cell lines, cohorts of normally-aging individuals and individuals with HGPS. Analysis of 65 major cellular signaling pathways revealed that signaling pathway activation states in fibroblasts derived from chronologically young HGPS patients strongly resemble those taken from normal middle-aged and old individuals.
Dr. Antonei Benjamin Csoka, CEO of Vision Genomics and assistant Professor at Howard University, said “Although Progeria is primarily caused by accumulation of Progerin, we believe it truly represents accelerated aging. That is because what we commonly refer to as aging is a macroscopic effect rather than a cause. For example shortening of telomeres can be a cause of aging, damage to mitochondria can be a cause of aging, aneuploidy can be a cause of aging, stem cell depletion can be a cause of aging, and so forth. All of these microscopic cellular pathologies, and more, can be causative in normal aging, and what we call aging is the macroscopic consequence, or effect of these incidents that we define as cause. In Progeria, the Progerin accumulation component is dramatically increased, but our results show that Progeria nevertheless represents aging at the effect levels of cellular senescence and organismal aging.”
The innovative tool GeroScope analyzes gene expression datasets from multiple platforms with low error rate and has the ability to elucidate and precisely define altered features of intracellular regulation using mathematical computations. The results are noted as Pathway Activation Strength (PAS) values, where positive and negative PAS values indicate pathway up- and down-regulation, respectively.
Alex Aliper, co-leader of the study, said, “We divided our analysis into two phases: in phase 1, we analyzed the pathway changes during increasing cell passage number representing in vitro cellular senescence, and we found an increase in cellular pathway activation with increasing number of passages. We call this the “Pathway Activation Drift”. In phase 2, we analyzed pathway changes in different age groups (chronological aging) as well as Progeria patients. We found that signaling pathways activation in chronologically young patients with Progeria strikingly resembled normal middle-aged and old individuals rather than normal young individuals.”
With the findings from Phase 2 analysis, the team could conclude that HGPS actually represents accelerated aging rather than being a mere simulacrum of aging. Further, HGPS, Middle-age and Old-age groups share 13 similarly activated signaling pathways. Specifically, AR, IGF1R, HGF, HIF1A, IP3, PAK, SMAD, TNF and TGF-beta main pathways are up-regulated, whereas the mitochondrial apoptosis pathway is down-regulated. Thus, this study clearly demonstrates that the process of aging and the pathophysiology of the accelerated aging syndrome HGPS are regulated through similar signaling pathways.
Some of the significantly altered pathways that reveal the similarity between Progeria and normal aging are the Caspase cascade main pathway, Growth Hormone main pathway, MAPK main pathway, and Transcription main pathway. Some of these altered pathways have a major effect on DNA repair and chromatin organization in particular. The results from this comparative study suggest potential pathways that could be targeted to develop drugs and drug combinations for HGPS as well as normal aging.
The broad message behind this initiative is that cellular aging is the precondition for anatomical aging, and the overall aging phenotype of the organism is the final outcome of cellular aging. With this initial step towards studying and comparing aging and aging-related diseases, the team plans to study Werner’s Syndrome (WS), Bloom syndrome (BS) and xeroderma pigmentosum (XP) (to name a few) in order to identify common aging PAS patterns in near future.