Mini ReviewTelomerase and the aging process
Introduction
Telomeres are the specialized repetitive DNA sequences at the ends of the linear chromosomes, and associated proteins, that serve to maintain the integrity of the chromosomes. Telomerase is a ribonucleoprotein DNA polymerase complex that maintains telomere length. The complex comprises the protein telomerase reverse transcriptase (TERT, or hTERT in humans) and a catalytic RNA (TERC) (Shay and Wright, 2007). In the absence of telomerase activity telomeres progressively shorten. Telomerase activity is absent in most normal human somatic cells because of the lack of expression of TERT; TERC is usually present. On the other hand most mouse cells have telomerase activity (Blasco, 2005). Without telomerase, telomere shortening eventually limits the growth of cells, either by senescence, in cells with intact cell cycle checkpoints (a G1 cell cycle block), or by crisis, in cells with inactivated checkpoints (telomeric end-to-end fusions cause chromosome breakage and mitotic catastrophe) (Shay and Wright, 2007). Expression of TERT in cells that otherwise lack telomerase activity causes cells to bypass senescence and crisis, and such cells are usually termed “immortalized”. The significance of senescence, crisis and immortalization is explored further in this revew (see Fig. 1).
Section snippets
Do telomere biology and telomerase activity determine aging?
The first aspect to this question is whether differences in aging rates among mammalian species are caused in whole or in part by species-specific differences in telomerase/telomere biology. A very brief consideration of this question will show that this is unlikely. Mice are short-lived compared to humans, yet mice have long telomeres and adult mouse somatic cells often have telomerase activity (Blasco, 2005). On the other hand, humans have relatively short telomeres, even when compared to
Telomeres, telomerase and tumor suppression
The second major question posed at the beginning of this review is whether high telomerase activity could be a factor causing shorter life span. In fact there is evidence that short telomeres and a lack of telomerase can exert a longevity-promoting effect via prevention of cancer. Of course, this does not mean that short telomeres/lack of telomerase cause a slower rate of aging. Instead it is reasonable to hypothesize that any species which has evolved a slower rate of aging will also need to
The potential role of telomerase in cell therapy in aging
Beginning with the first reports of hTERT-immortalization, it was speculated that this technology could be used to expand populations of cells for subsequent therapeutic transplantation (Bodnar et al., 1998). This was thought of as particularly important for the replacement of tissues and organs damaged during aging (Shay and Wright, 2000). In one proposed form of this therapy, cells with shortened telomeres would be isolated from a patient and telomere length restored by hTERT expression. The
Conclusions
Telomerase is probably not a factor in determining the differences in aging rate among species. Telomere shortening resulting from the absence of telomerase activity may be a factor in determining some age-related properties of organs in humans. Reactivation of telomerase could be useful in some forms of cell therapy and does not appear to present a problem with safety. However, activation of telomerase removes a barrier to the continued growth of developing cancers; lack of telomerase activity
Acknowledgement
Work from the author’s lab cited here was supported by grants from the National Institute on Aging (AG12287 and AG20752) and by a Senior Scholar Award from the Ellison Medical Foundation.
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