The Curious Case of Ageing


Imagine walking through the corridor of a neonatal intensive care unit (NICU) of a hospital and seeing a 70-year-old baby sleeping in the cradle. Imagine a newborn baby, who looks as aged as your grandparents, having so many diseases that his life begins to shrink even before it blossoms. Well, we all are a big hater of ageing- but when it comes too early, perhaps there is something bigger than the science behind it. Hutchinson-Gilford progeria syndrome (HGPS) is one of the premature ageing disorder characterized by alopecia, bigger head, prominent eyes, atherosclerosis, severe cardiovascular diseases which makes the average lifespan of the patient as much as 12.6 years (2). The disease is so rare that currently there are only 124 cases reported globally (3). While it was thought to be a disease occurred due to heredity, scientists later found that it is the mutation of a single gene that causes the damage. Lamin A is a nuclear membrane protein which is responsible for providing the stability of the cell and it is produced by the LMNA gene (4). Once the protein is produced, then it is farnesylated, moved to the periphery of the nuclear lamina, and the subsequent cut-off of the farnesyl group will allow the protein to provide structural stability in the nucleus of the cell (5). When mutated, these truncated Lamin A proteins are termed as ‘progerin’, that are not only permanently farnesylated, but also they won’t be able to cut-off the farnesyl group and thus will result in the disruption of the nuclear lamina (6). In HGPS, progerin is produced rapidly compared to normal cells. Consequently, the cell will undergo defective DNA repair that will lead to more frequent DNA damage, instability of genome and ultimately ageing at a faster rate (7). Sam Berns, one of the victims, was diagnosed with this disease when he was only 22 months of age. Finding very limited treatment available for this disease, his parents felt the urge to establish an organization which will work solely on this disease. Sam’s parents, along with their friends and colleagues, set up Progeria Research Foundation (PRF) in 1999 to focus on research, disease management and creating awareness about progeria (8). In search of the treatment of this rare autosomal disease, Boston Children’s Hospital, in collaboration with Progeria Research Foundation has finally tested the drug Lonafarnib in 2012 by Merck & Co.- a farnesyltransferase inhibitor (FTI) that blocks the addition of the farnesyl group with progerin, resulting in decrease effects of the harmfulness of progerin (9). Future seems bright since sixty children are currently involved in phase two of the clinical trial. By the end of October 2020 when this trial will finish, we can certainly hope to make things better than they are now (10). At present, scientists are focusing more on the effects of progerin: who knows, if we are able to slow down the production of this ‘ageing culprit’, living hundreds of years without any wrinkles might not be that far away!


References:

(1) Causes - PROGERIA https://progeriagrangebio.weebly.com/causes.html# (accessed Nov 20, 2019).

(2) Kang, H. T.; Park, J. T.; Choi, K.; Choi, H. J. C.; Jung, C. W.; Kim, G. R.; Lee, Y.-S.; Park, S. C. Chemical Screening Identifies ROCK as a Target for Recovering Mitochondrial Function in Hutchinson-Gilford Progeria Syndrome. Aging Cell 2017, 16 (3), 541–550. https://doi.org/10.1111/acel.12584.

(3) Meet the Kids | The Progeria Research Foundation https://www.progeriaresearch.org/meet-the-kids/ (accessed Nov 20, 2019).

(4) Carvalho, A.; Celli, V. O.; Bancke Laverde, A.; Leonardo, B. UC Davis Dermatology Online Journal Title Progeria and the Early Aging in Children: A Case Report Publication Date.

(5) Li, Y.; Zhou, G.; Bruno, I. G.; Zhang, N.; Sho, S.; Tedone, E.; Lai, T.; Cooke, J. P.; Shay, J. W. Transient Introduction of Human Telomerase MRNA Improves Hallmarks of Progeria Cells. Aging Cell 2019, 18 (4). https://doi.org/10.1111/acel.12979.

(6) Prokocimer, M.; Barkan, R.; Gruenbaum, Y. Hutchinson-Gilford Progeria Syndrome through the Lens of Transcription. Aging Cell 2013, 12 (4), 533–543. https://doi.org/10.1111/acel.12070.

(7) Camille, A.; Thompson, S. Mediators and Markers of Mammalian Lifespan Extension: Proteomic, Proliferative and Hormonal Adaptations in Mouse Models of Extended Lifespan; 2014.

(8) The Progeria Research Foundation - YouTube https://www.youtube.com/watch?v=M_V7f4ZLA1s (accessed Nov 20, 2019).

(9) Gordon, L. B.; Kleinman, M. E.; Miller, D. T.; Neuberg, D. S.; Giobbie-Hurder, A.; Gerhard-Herman, M.; Smoot, L. B.; Gordon, C. M.; Cleveland, R.; Snyder, B. D.; et al. Clinical Trial of a Farnesyltransferase Inhibitor in Children with Hutchinson-Gilford Progeria Syndrome. Proc. Natl. Acad. Sci. U. S. A. 2012, 109 (41), 16666–16671. https://doi.org/10.1073/pnas.1202529109.

(10) Gordon, L. B.; Kleinman, M. E.; Massaro, J.; D’Agostino, R. B.; Shappell, H.; Gerhard-Herman, M.; Smoot, L. B.; Gordon, C. M.; Cleveland, R. H.; Nazarian, A.; et al. Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children with Hutchinson-Gilford Progeria Syndrome. Circulation 2016, 134 (2), 114–125. https://doi.org/10.1161/CIRCULATIONAHA.116.022188.



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