X-Message-Number: 25664 Date: Sat, 5 Feb 2005 12:21:18 -0800 (PST) From: Doug Skrecky <> Subject: the great divide between in-vitro & in-vivo aging [This is a great deal of doubt about the applicability of the in-vitro aging to its real life counterpart. For example, drastic telomere shortening can limit the replication capacity of cells grown in a test tube. A more limited shortening that occurs in-vivo is also associated with proliferative defects. However there is some evidence that it is non-telomere driven P16 that is driving these defects, since telomeres themselves are still too long to be a major aging driver.] Exp Cell Res. 2004 Oct 15; 300(1):1-10 From cells to ageing: a review of models and mechanisms of cellular senescence and their impact on human ageing. Given the duration of ageing in humans, cell culture studies are a promising approach to the study of human ageing. It is reasonable to assume that human ageing has, at least partly, a cellular origin. The question is how we can replicate in vitro the age-related changes that occur in human cells in vivo. In this review, widely used models for studying ageing in cell culture, such as Hayflick's, are interpreted in the context of the human ageing process. The mechanisms behind cellular senescence such as telomere disruption and DNA damage are reviewed and their relation to human ageing debated. A system-level examination of these mechanisms suggests that cell culture models are useful for studying cancer and certain age-related pathologies. There is little evidence, however, that cellular senescence is a significant factor in human ageing or that the mechanisms responsible for in vitro cellular senescence are a causative factor in human ageing in vivo. Therefore, novel approaches for studying human ageing at a cellular level are necessary and some suggestions are put forward. Mol Cell. 2004 May 21;14(4):501-13 Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21(CIP1), but not p16(INK4a). Cellular senescence can be triggered by telomere shortening as well as a variety of stresses and signaling imbalances. We used multiparameter single-cell detection methods to investigate upstream signaling pathways and ensuing cell cycle checkpoint responses in human fibroblasts. Telomeric foci containing multiple DNA damage response factors were assembled in a subset of senescent cells and signaled through ATM to p53, upregulating p21 and causing G1 phase arrest. Inhibition of ATM expression or activity resulted in cell cycle reentry, indicating that stable arrest requires continuous signaling. ATR kinase appears to play a minor role in normal cells but in the absence of ATM elicited a delayed G2 phase arrest. These pathways do not affect expression of p16, which was upregulated in a telomere- and DNA damage-independent manner in a subset of cells. Distinct senescence programs can thus progress in parallel, resulting in mosaic cultures as well as individual cells responding to multiple signals. [Telomerase exerts a mild anti-aging effect in transgenic mice, but this is not mediated by telomeres themselves.] Oncogene. 2005 Jan 31; [Epub ahead of print] Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Many degenerative diseases that occur with aging, as well as premature aging syndromes, are characterized by presenting cells with critically short telomeres. Telomerase reintroduction is envisioned as a putative therapy for diseases characterized by telomere exhaustion. K5-mTert transgenic mice overexpress telomerase in a wide spectrum of tissues. These mice have a higher incidence of both induced and spontaneous tumors, resulting in increased mortality during the first year of life. Here, we show that in spite of this elevated tumor incidence and the initial lower survival, K5-mTert mice show an extension of the maximum lifespan from 1.5 to 3 months, depending on the transgenic line, which represents up to a 10% increase in the mean lifespan compared to wild-type littermates. This longer lifespan is coincidental with a lower incidence of certain age-related degenerative diseases, mainly those related to kidney function and germline integrity. Importantly, these effects of telomerase overexpression cannot be attributed to dramatic differences in telomere length in aged K5-Tert mice compared to wild-type mice, as shown by quantitative telomeric FISH. These findings indicate that telomerase overexpression extends the maximum lifespan of mice.Oncogene advance online publication, 31 January 2005; doi:10.1038/sj.onc.1208413. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=25664