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Telomeres - tandem-repeated TTAGGG hexamers at the termini of

mammalian chromosomes - are associated with specific proteins to form

protective caps that prevent the chromosome ends from being recognised

ity and hence the life span of cells [Figure 1]. At the Hayflick

tality stage 1 = senescence) one or more telomeres become cr

They are recognised within the cell as chromosome breaks

cycle is irreversibly arrested.The signal that induces replicativ

is not the shortened telomere sequenceper se

, but rather th

protective telomeric cap (telomere specific proteins binding t

ere), which creates dysfunctional telomeres.At this stage cell

points are activated and replicative senescence or programm

(apoptosis) is induced. However, if these checkpoint system

the cells continue to proliferate and telomere erosion gradual

until nearly all the telomeres reach a critical length and the ce

sis (mortality stage 2). This is characterised by chromosom

because of erroneous DNA damage repair and the pro

genomic errors and DNA breaks. At this point the number

sions is counterbalanced by an equal number of

Chromosomal end fusions and other cytological ab

accumulate [2].

Telomere length: the biologicalclock reviewedAs eukaryotic cells divide, the protective ends of the linearchromosomes, the telomeres, gradually shorten with eachcell division. When a critical telomere length is reached, thecells are signalled into senescence, an irreversible state ofquiescence. Thus, telomere length has emerged as a replica-tive clock within each population of cells and the tissuesand organs they form in vitro. Consequently telomerelength has become accepted as a biomarker for biologicalageing in vivo. Although chronological ageing per se doesnot parallel biological ageing, there are no accurate and reli-able biomarkers to distinguish between both types of age-ing. The question remains whether telomere dynamics is adeterminant or merely a predictor of human biological age

over and above chronological ageing.

by Dr Sofie Bekaert

As published in BTi OctobCELL CYCLE

7/29/2019 Telomere Length the Biological Clock Reviewed

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were developed that used Southern blotting techniques

cence microscopy methods to measure telomere length

cellular and the chromosomal level [4]. Using such assatelomere length was found to decrease progressively d

passages of human fibroblasts. It was also found tha

telomere length was related to the remaining prolifera

and was shorter in samples from older donors.Human l

and haematopoietic stem cells were shown in vivoto lo

repeats with increasing age.More importantly, telomere

in particular, telomere attrition have been proven to be o

in gaining a deeper understanding of the pathophysiolo

human diseases, including age-related disorders and can

Recent findings have provided new insights into both th

of telomere length in normal cells and the phenotypic c

of perturbation of these processes. More specifically rec

has accumulated on the association between telomere

(i.e. cellular ageing) and the implications for human h

particular, accelerated telomere attrition has been imp

growing list of age-related disorders ranging from pro

tions such as the Werner, Bloom, and Hutchinson-

dromes, to conditions such as an increased risk of

osteoarthritis,decreased wound healing and immune fu

Figure 1.Telomere length regulation.Germ cells (a) are telomerase positive and can main-tain telomere length with increasing replicative age. Most normal somatic cells (b) have losttelomerase activity during differentiation.In these cells,telomeres shorten at a rate of 50-100bp/PD until they become critically short and the cells enter senescence (M1). Some specificsomatic cells (c) are telomerase competent and if, like stem cells, they are quiescent, telom-erase is inactive. If they are proliferating,as in progenitor haematopoietic cells,telomerase isactivated, but its presence is not sufficient to maintain telomeres (loss: 30 bp/year).Most cells

enter senescence or die at crisis (M1), but cells transduced with viral oncogenes can bypasssenescence and continue to proliferate with concomitant telomere attrition until crisis ensues(M2). At crisis most cells die but rare survivors can activate telomere-maintenance mecha-nisms, e.g. telomerase (d) or alternative pathways (f), and become immortal. Telomeraseexpression can at this point induce telomere elongation, but sometimes telomeres continuet h t ALT ll t i h t t l l th M t t ll ( ) h

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length does not vary significantly between different cell populations in a given individual and by and large there is no great difference bet

in foetuses and newborns. In light of this, the difference in the telomere erosion rate between children and adults can most probably be

the increased immune cell replication rate that accompanies the characteristic changes of the immune system in newborns and infants.

In elderly (>60 yr) subjects telomere attrition is significantly associated with higher mortality rates, from both infectious and cardiovascular

is assumed that telomere shortening takes place at a rate of approximately 50-100 bp/cell division,this corresponds to 15-30 divisions of stem

first year of postnatal life and 1 stem cell division in the rest of life. Although telomere shortening is not a direct cause of ageing, as seen f

mouse experiments which lack telomerase, impaired telomere length regulation decreases the ability to carry out maintenance and repair sig

well as the capacity to handle acute stress. Whether a direct cause of human ageing or not, telomere length is a valuable biomarker of th

between successful and unsuccessful ageing.

REFERENCES1. Hayflick L and Moorhead PS. Experimental Cell Research 1961;25: 585.

2. Blackburn EH.Nature 2000;408:53.

3. Bodnar AGet al. Science 1998;279: 349.

4. Moyzis RKet al. Proceedings of the National Academy of Sciences USA 1988; 85: 6622.

5. Blasco MA et al. Cell 1997; 91:25.

THE AUTHORSofie Bekaert, Ph.D., Dept. of Molecular Biotechnology, Faculty of Bioscience Engineering,Ghent University, B-9000 Ghent, Belgium, Fax +3

E-mail: sofie.bekaert@UGent.be

As published in BTi OctobCELL CYCLE