My last major post traced developments related to a form of progeria (premature aging) known as Hutchinson-Gilford progeria syndrome, or HGPS, for short. The discussion and comments on this post are leading us down new paths, such as exploring the role of progerin and FTI therapies and seemingly away from the usual theories of aging. There is also a different rare form of progeria known as Werner Syndrome (WS) that is worth looking at for what it might tell us about normal aging.
WS, sometimes called adult progeria, is characterized by the premature onset of age-related diseases, including inflammatory diseases, atherosclerosis and cancer. People with WS may develop the symptoms of very old age by the time they turn 30 or 40, including “wrinkled skin, baldness, cataracts, muscular atrophy and a tendency to diabetes mellitus, among others(ref).” Cells from people with WS when cultured have shorter life spans than cells from normal people. “In culture, cells obtained from patients with WS are genetically unstable, characterized by an increased frequency of nonclonal translocations and extensive DNA deletions(ref).” It has recently been shown that WS is due to a mutation in a gene called WRN. It is a hellicase deficiency disease. Hellicases are enzymes important for many cellular processes including “DNA replication, transcription, translation, recombination, DNA repair, and ribosome biogenesis.” Normally, the WRN gene “ functions as a key factor in resolving aberrant DNA structures that arise from DNA metabolic processes such as replication, recombination and/or repair, to preserve the genetic integrity in cells(ref).”
Unlike the case for HGPS, there appears to be a direct link between the aging mechanisms operating in WS patients and at least one of the usual theories of aging, the telomere shortning and damage theory. For example, regarding study of a mouse model of WS the authors write “Recent studies of the telomerase-Werner double null mouse link telomere dysfunction to accelerated aging and tumorigenesis in the setting of Werner deficiency. This mouse model thus provides a unique genetic platform to explore molecular mechanisms by which telomere dysfunction and loss of WRN gene function leads to the onset of premature aging and cancer(ref).” Some researchers highlight the roles of cell senescence and telomeres in WS: “Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts(ref).” Normal hellicase structures can be very important for assuring normal telomere structures(ref), a situation not present in WS. Other researchers believe WS operates primarily through other than telomere erosion or damage: “– our data suggest that the abbreviated replicative life span of WS cells is due to a stress-induced, p38-mediated growth arrest that is independent of telomere erosion(ref).”
Looking for bridges between the genetic mechanisms operating in HGPS and those operating in WS: 1 It is easy to find commonality of end-results, specifically premature aging phenotypes like baldness, wrinkled skin and cardiovascular disease, and 2. The underlying genomic mechanisms themselves are in the first instance quite different; they involve activation of different genes and the actions of different protein products. I do not see any easy “Ah hah, here is the common mechanism of aging involved in HGPS, WS and normal aging.” Both HGPS and WS suggest means by which normal aging might work and possibly be slowed down, having to do with accumulation of progerin and possible treatment with FTIs in the case of HGPS, and having to do with P38, telomere shortening and telomerase activation in the case of WS.
Another progeria disease Cockayne syndrome has a drug now called prodarsan