On Extending Life in Mice Via Telomerase Expression

Suitable genetic engineering of telomerase can extend life in mice, but it isn't a straightforward process, and it is unclear as to how this would translate to humans given the complex relationship between telomere biology and aging on the one hand and the differences between humans and mice on the other: "The absence of telomerase [and consequent] telomere shortening in somatic cells plays a controversial role in mammalian aging. On the one hand, genetic knockout of telomerase function in mice has little noticeable effect on the aging of first-generation mutants. Serious phenotypic consequences are seen only in the fourth through sixth generations of such mutants when premature aging-associated phenotypes appear. This is because the normal length of mouse telomeres is sufficient for several mouse life spans, including all of the cell divisions associated with development. On the other hand, ectopic expression of the catalytic subunit of telomerase (telomerase reverse transcriptase, TERT) in epithelial cells has been reported to extend life span by up to 40% in mice engineered to be cancer-resistant. Unfortunately, ectopic expression of TERT in wild-type mice or mutations in human TERT increase cancer risk. There is evidence that active telomerase [and consequently] long telomeres protect cells from the metabolic and mitochondrial compromise that occurs when shortened telomeres induce p53 ... Ironically, shortened telomeres also result in increased cancer rates, probably due to increased genomic instability. Consistent with a homeostatic mechanism is the observation that telomerase reactivation has been shown to partially reverse tissue degeneration in aged telomerase-deficient mice (fourth generation). There is a paradox here: Mouse chromosomes possess enough reserve telomere length to fuel cell divisions for up to six organismal generations, yet mice apparently have at least a subset of cells in which dysfunction is linked to shorter telomeres and/or the absence of telomerase within a single life span. This paradox relates to the critical question of whether sufficient clinical benefit could result from ectopic telomerase expression in human aging and in diseases associated with shortened telomeres ... Of course, one potentially important difference is that humans have significantly shorter telomeres than mice."

Link: http://online.liebertpub.com/doi/full/10.1089/rej.2012.1359


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