Department of Molecular Biology, Laboratory of Molecular and Cellular Biology, Ruder Bosković Institute, 10000 Zagreb, Croatia.
Exp Gerontol. 2010 Mar;45(3):235-42. doi: 10.1016/j.exger.2010.01.009. Epub 2010 Jan 18.
Aging is one of the most basic properties of living organisms. Abundant evidence supports the idea that cell senescence underlies organismal aging in higher mammals. Therefore, examining the molecular mechanisms that control cell and replicative senescence is of great interest for biology and medicine. Several discoveries strongly support telomere shortening as the main molecular mechanism that limits the growth of normal cells. Although cultures gradually approach their growth limit, appearance of individual senescent cells is sudden and stochastic. A theoretical model of abrupt telomere shortening has been proposed in order to explain this phenomenon, but until now there was no reliable experimental evidence supporting this idea. Here, we have employed novel methodology to provide evidence for the generation of extrachromosomal circular telomeric DNA as a result of abrupt telomere shortening in normal human fibroblasts. This mechanism ensures heterogeneity in growth potential among individual cells, which is crucial for gradual progression of the aging process.
衰老是生物体最基本的特性之一。大量证据支持这样一种观点，即在高等哺乳动物中，细胞衰老是机体衰老的基础。因此，研究控制细胞和复制性衰老的分子机制对生物学和医学具有重要意义。有几个发现强烈支持端粒缩短是限制正常细胞生长的主要分子机制。尽管培养物逐渐接近其生长极限，但个别衰老细胞的出现是突然和随机的。为了解释这一现象，提出了一个关于端粒突然缩短的理论模型，但直到现在还没有可靠的实验证据支持这一观点。在这里，我们采用了新的方法学来提供证据，证明正常人类成纤维细胞中端粒突然缩短会产生额外的染色体环状端粒 DNA。这种机制确保了单个细胞之间生长潜力的异质性，这对于衰老过程的逐渐进展至关重要。
