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Telomere loss and skin aging

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The ends of the chromosomes are termed telomeres, are comprised of tracts of hexanucleotide sequences (TTAGGG in vertebrates) and together with specific proteins, protect the chromosome against degradation, fusion events and as being recognized as ‘damaged’ DNA. This non-coding ‘dispensable’ DNA is essential because during replication of the DNA only leading strand synthesis is straight forward. Bases can be added in 5′ to 3′ direction in a serial fashion. During lagging strand synthesis, however, the DNA is replicated in Okazaki fragments. For initiation, RNA primers are used which are finally replaced by DNA in order to allow a continuous DNA strand. Since the outermost primer can not be replaced, the last gap remains unreplicated. This phenomenon, known as end-replication problem, therefore, causes telomere shortenings with each round of DNA replication.

In addition it is believed that telomeres have a reduced repair capacity. Thus damage caused by, e.g. oxidative stress leading to DNA double strand breaks can additionally contribute to accelerated telomere shortening. To counteract this continuous telomere loss, germ line- and embryonic cells express telomerase, a ribonucleoprotein complex that habors reverse transcriptase activity and therefore can extend and maintain the telomere length by de novo addition of hexameric telomere repeats. In agreement with the fact that cells from older individuals generally replicate fewer times in culture than cells from younger individuals, referred to as the Hayflick limit of replication, it was observed that the telomeres had shortened significantly and it is now believed that the replication-dependent telomere shortening is the internal clock, the counting mechanism of cellular aging. In addition, one or few critically short telomeres finally provide the signal for the cell to stop dividing and to enter a state of irreversible growth arrest, i.e. senescence.

While telomerase is active in all cells during embryonic development, telomerase is inhibited in most human adult tissues. Exceptions are cells from regenerative tissues such as the hematopoietic system or the epidermis of the skin [ 1, 2]. In these tissues, a population of stem cells guarantee their life long proliferation capacity. These quasi immortal cells are thought to be the telomerase-positive cells and telomerase, although not able to completely prevent, may help to slow down replication-dependent telomere erosion in order to ensure the large expansion demands. While this would suggest a constitutive expression of telomerase in the stem cells, we have evidence that in epidermal stem cells telomerase is extremely low but up-regulated in the more actively proliferating transit amplifying cells [ 3, 4]. Although this up-regulation seems to correlate with c-Myc regulation, it is not proliferation-dependent [ 5]. Furthermore, we have evidence that telomerase needs to be inhibited in order to allow complete epidermal differentiation and that calcium is involved in the differentiation-dependent inhibition [ 3, 6]. Thus, in skin keratinocytes telomerase is not constitutively expressed but expression seems tightly regulated during epidermal maturation and it remains to be seen whether telomerase is active in maintaining the capacity for sufficient stem cell renewal or has another as yet unidentified function.

What does the telomere/telomerase hypothesis mean for aging of the skin? Interestingly, aging phenomena are predominantly visible in the dermis as exemplified by changes in the extracellular matrix and/or expression pattern of the dermal fibroblasts. However, fibroblasts hardly ever proliferate and consequently do not suffer from critical telomere shortening [ 7]. Instead, the cells remain in the tissue for long-term and are, therefore, more prone to damage- and age-dependent deficiencies. Thus, it remains questionable whether de novo activation of telomerase in these cells would help to prevent or at least postpone aging of the skin. On the other hand, when telomerase-positive keratinocytes from older donors were pre-selected for stem cells and then taken into culture, these cells still exhibited a proliferation potential similar to that of infant cells, indicating that in the keratinocytes age-dependent changes may only be secondary. Despite the fact that some aged donors still had rather long telomeres, the level of telomerase varied significantly [ 4]. Continuous high expression of telomerase may, therefore, not be essential for life-long proliferation of skin keratinocytes.
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Document Type: Abstract

Affiliations: DKFZ, Heidelberg, Germany

Publication date: April 1, 2004

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