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If I read the following correctly, it seems to indicate that gross = oxidative stress (free radical damage?) leads to 5 1/2 times the rate of = telomeric shortening than normal cell doubling would. If true, doesn't = this suggest a direct causal connection between the free radical theory = of aging, and the telomeric/proliferative senesence apoptosis model? I = had been thinking that the rate of telomeric shortening was a constant, = and that the NUMBER of doublings was the only thing which invoked the = Hayflick limit. Now, if I interpret the below correctly, there is a = quintuple whammy when cell doubling occurs under free radical oxidative = stress such as in crush injuries etc. Am I getting this right?
Exp Cell Res 1995 Sep;220(1):186-93=20
Mild hyperoxia shortens telomeres and inhibits proliferation of = fibroblasts: a model for senescence?
von Zglinicki T, Saretzki G, Docke W, Lotze C Institute of Pathology, Humboldt University, Berlin, Germany.=20
Mild oxidative stress as exerted by culture of human WI-38 fibroblasts = under 40% oxygen partial pressure blocks proliferation irreversibly = after one to three population doublings. Hyperoxically blocked cells are = similar to senescent ones in terms of general morphology and lipofuscin = accumulation. Moreover, they, like senescent fibroblasts, are blocked = preferentially in G1 as evident from DNA content measurements by flow = cytometry. Southern blotting of AluI- and HinfI-restricted genomic DNA = shows an increase of the rate of telomere shortening from 90 bp per = population doubling under normoxia to more than 500 bp per population = doubling under hyperoxia. In every case, proliferation is blocked if a = telomere cutoff length of about 4 kb is arrived at. The fact that = telomere length correlates with the final inhibition of proliferation = under conditions of varied oxidative stress, while the population = doubling level does not, suggests that telomere shortening provides the = signal for cell cycle exit in senescence. In postmitotic cells, no = further telomere shortening occurs. However, the sensitivity of terminal = restriction fragments to S1 nuclease increases, indicating the = accumulation of single-strand breaks in telomeres of nondividing = fibroblasts. This effect is found both under normoxic and hyperoxic = culture, although it is more pronounced under conditions of higher = oxidative stress. It might be speculated that accumulation of = single-strand breaks and the resultant loss of distal single-stranded = fragments during replication could be a major cause of telomere = shortening, possibly more important than incomplete replication per se
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