Thursday, June 7, 2012

Werner Syndrome: Aging in Fast Forward

Let’s face it: Nobody likes to age.  The thought of growing old makes most cringe and scramble to find a miracle cure to halt this process.  Skin care companies make fortunes selling wrinkle creams to make women look ten years younger, hair dyes are sold right and left to get rid of those gray hairs, and Botox has become almost a common procedure in America.  The only thing worse than getting old and wrinkly?  Doing it at an increased rate.  Werner Syndrome is a form of adult progeria, characterized by premature aging, and it is no surprise that telomeres have everything to do with it.

In an article entitled “Essential role of limiting telomeres in the pathogenesis of Werner syndrome”, the researchers test rats in order to find the link that telomeres have in relation to this accelerated aging process.  Werner syndrome is characterized by premature aging, elevated genomic instability, and increased cancer incidence.  In a previous study, “Telomeres, aging and cancer: In searchof a happy ending”, we see that once telomeres (the protective caps at the ends of chromosomes) get too short, the cell has three options.  It can go through senescence, apoptosis, or genomic instability.  When the cell goes through senescence, it is still viable, but unable to proliferate, which is the driving force behind the aging phenotype.  If the cell cannot senesce or go through apoptosis, it will go through genomic instability, making it more susceptible to deleterious mutations.  The cell will keep dividing and keep mutating, making it prone to forming malignant tumors and becoming cancerous.  These three symptoms show that the factors of Werner syndrome are caused by telomere dysfunction and the cell’s inability to keep proliferating in a healthy manner.
In this study, we see that the researchers compared multiple generations of wild type mice (Wrn +/+) to mutant mice that had much shorter telomeres and an increase in telomere dysfunction (Wrn-/-).  Figure 1a shows the overall survival of the mutant and wild type mice over a period of 75 weeks for G1-G3 (the first three generations of mice), where mutants are shown in red and wild type is shows in black.  While the wild types had slightly higher overall survival, most evident in later months, it was still not extremely significant.  In 1b however, where they are testing G4-G6, the difference in survival is much more evident.  This could be due to mice’s lengthened telomeres in comparison to humans.  Since their aging process is different, it takes multiple generations for the telomeres to become as shortened as in older humans, obvious in the more detrimental effects on later generations.
As Wrn-/- is supposed to simulate Werner syndrome, we see the effects of accelerated aging on younger mice as in Fig. 1d, 1e, and 1f.  The three-month-old G5 mouse in 1b is shown with a cataract on its eye, while the eight-week-old G5 mouse and twelve-week-old G6 mouse in 1e and 1f are experiencing alopecia (hair loss) and kyphosis (over curvature in the spine) respectively.  These are all signs of aging, driven by cell senescence due to shortening of the telomeres.  In Fig. 1g, we see loss of bone density by imaging of the femurs of three 32-week-old mice (one W+/+, one W-/- affected, and one W-/- unaffected) and one 4-week-old Wrn-/- mouse.  We see fairly healthy bone densities of all but Wrn-/-, which shows a small fracture as a sign of bone deterioration.
Based on this study, we see the effects of premature aging in age-related diseases such as Werner syndrome, due to the shortening or dysfunction of telomeres.  Knowing the driving factor behind diseases such as this, the next step would theoretically be to fix the problem at the cellular level.  The reactivation of telomerase seems an obvious choice for researchers, but at the same time, there have been studies of the detrimental effects of too much telomerase that could lead to the excessive proliferation of cancer cells as well as normal cells.  It seems that the correct balance of telomeres is the real key, but until we figure out how to achieve that, we will just have to make do with our wrinkly skin and gray hair