Telomere Shortening

A major cause of replicative senescence in human cells is progressive telomere shortening and eventual telomere dysfunction. Telomeres are the repetitive DNA sequences and specialized proteins at the ends of linear chromosomes (17). Vertebrate telomeres comprise the double-stranded sequence 5'TTAGGG3', repeated a few hundred to many thousand times (depending on the species), a 3' single stranded overhang of a few hundred bases, and a host of associated proteins that facilitate the formation of large loops, termed t-loops, that cap the chromosome ends (18,19). Telomeres protect chromosome ends from degradation or fusion by cellular DNA repair processes. Thus, they prevent loss of genetic information and genomic instability, which can result in cell death or malignant transformation.

Owing to the biochemistry of DNA replication, the 3' ends of duplex DNA molecules cannot be completely replicated. This end-replication problem causes the loss of 50 to 200 bp from each chromosome 3' end during every S phase (20). Thus, telomeres shorten progressively with each cell cycle (Fig. 2).

When critically short, telomeres may fail to form a proper t-loop and become uncapped. Dysfunctional, or perhaps near-dysfunctional, telomeres trigger the senescence response. Thus, telomere shortening limits the number of cell divisions—that is, causes replicative senescence. The senescence response prevents further cell division, thereby avoiding the risk of genomic instability and malignant transformation.

How do short dysfunctional telomeres trigger a senescence response? Although there are many gaps in our knowledge, recent results show that dysfunctional telomeres trigger senescence because they induce a classic DNA damage response (21,22). The responses to both dysfunctional telomeres and nontelomeric DNA damage require activation of the p53 tumor-suppressor protein, which arrests cell proliferation either transiently or permanently (senescence), depending on the level of damage. Uncapped, dysfunctional telomeres are thought to resemble DNA double-strand breaks.

Telomeres shorten as many human cell types proliferate in culture (23-26). Telomeres also shorten with age and as a function of proliferative history in vivo (26-28). These findings have led to the hypothesis that telomeres are determinants of longevity. However, there is no correlation between longevity and telomere length per se. For example, laboratory mice have long telomeres (30 to >50 kb) compared to humans (15-20 kb) (29). Yet, mouse cells generally have a shorter replicative life span in culture, and, of course, mice are shorter lived than humans. Mouse cells undergo replicative senescence in culture due to mechanisms other than telomere shortening. These mechanisms are incompletely understood, but include stressful culture conditions, such as the ambient and supraphysiological oxygen in which mammalian cells are typically cultured (5,8,16). Thus, replicative and cellular senescence can be caused by many stimuli, of which dysfunctional telomeres are but one.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

Get My Free Ebook


Post a comment