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	FUNDP Faculté des Sciences Unité de Recherche en Biologie Cellulaire Animale Rue de Bruxelles, 61 B-5000 Namur Belgique
Modelling human ageing: role of telomeres in stress-induced premature senescence and design of anti-ageing strategies
Modélisation du vieillissement humain: rôle des télomères dans la sénescence induite prématurément par les stress et design de stratégies anti-vieillissement
João Pedro de Magalhães
Promoteur : Dr. O. Toussaint	Dissertation présentée pour l'obtention du diplôme de docteur en sciences

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Summary

Due to the duration of human ageing, researchers must rely on models such as animals and cells. Replicative senescence and stress-induced premature senescence (SIPS) are two cellular models sharing many features. Although telomeres play a major role in replicative senescence, their involvement in SIPS is unclear.

In this work, we first wanted to investigate how accurate models of ageing are. We published a new model of the evolution of human ageing, which offers a refined view of the evolution of ageing in humans and suggests that human models should be favoured. Though studying other mammals, reptiles, and birds may also be useful, we conclude that lower life forms such as yeast and invertebrates are not representative of the human ageing process.

Secondly, we wanted to elucidate the importance of telomeres in SIPS and study gene expression and regulatory networks. Using a telomerase-immortalized cell line, we found no evidence that damage specific to the telomeres is at the origin of SIPS. In our published model, neither the TGF-β1 pathway nor telomeres appear to play a crucial role in SIPS. We suggest that widespread damage to the DNA causes SIPS and propose a rearrangement of gene expression networks as a result of stress. Moreover, we advise caution in using telomerase in anti-ageing therapies since telomerase expression may alter the normal cellular functions and promote tumorogenesis.

Lastly, we published strategies to integrate the modern computational approaches to research ageing. Although we find it unlikely that a full understanding of ageing may be achieved within a near future, we argue that understanding the structure and finding key regulatory genes of the human ageing process is possible.

Table of Contents

Summary	ii
Abbreviations	ix
Introduction	1
Chapter 1: Human ageing	2
1.1. Definition and history	2
1.2. The ageing phenotype	2
1.3. Theories of ageing	3
1.3.1. Energy consumption hypothesis	4
1.3.2. Free radical theory	6
1.3.3. DNA damage theory	9
1.4. Evolutionary theory of ageing	11
1.5. Models of human ageing	14
Chapter 2: Replicative senescence and stress	16
2.1. Hayflick's limit	16
2.1.1. Biomarkers of RS	17
2.2. The theory of stress	18
2.3. Stress-induced premature senescence	19
2.3.1. Biomarkers of SIPS induced by oxidative stress	21
2.4. Relation between ageing, RS, and SIPS	21
Chapter 3: Cell cycle regulation by the telomeres	24
3.1. Telomere shortening and RS	24
3.2. How telomere dysfunction induces senescence	25
3.2.1. Uncapped telomeres recognized as DNA damage	27
3.3. Ageing, cancer, and the telomeres	31
Chapter 4: Mechanisms of SIPS	34
4.1. From DNA damage to SIPS	34
4.2. The telomeres	36
Chapter 5: Computational methods	39
5.1. From genes to ageing	39
5.1.1. Comparative genomics	40
5.1.2. Transcriptional regulation	41
5.1.3. Gene expression studies	44
5.2. Systems biology	45
Aim of the Work	47
Results	49
Chapter 6: Human ageing: evolution and research models	50
6.1. Article 1: The evolution of mammalian aging (Experimental Gerontology, volume 37, pages 769-775, 2002)	50
Chapter 7: Role of the telomeres in SIPS	59
7.1. Article 2: Stress-induced premature senescence in BJ and hTERT-BJ1 human foreskin fibroblasts (FEBS Letters, volume 523, pages 157-162, 2002)	59
Chapter 8: Gene expression in SIPS	67
8.1. Article 3: All roads lead to Rome: How gene expression networks reorganize in premature senescence of human skin fibroblasts expressing or not telomerase (submitted for publication)	67
Discussion	90
Chapter 9: Models of human ageing	91
9.1. Lessons from the evolution of ageing	91
9.2. Animal models	93
9.3. Human models	95
9.3.1. Centenarians	95
9.3.2. Werner's syndrome	96
9.4. Cellular models	97
9.4.1. Senescence, RS, and SIPS	98
9.4.2. Comparative biology	99
9.5. Computer models	100
9.6. Developing anti-ageing therapies	102
9.6.1. Telomerase alters the normal cellular functions	105
Chapter 10: DNA damage, ageing, and SIPS	107
10.1. Critical telomere shortening is not necessary for SIPS	107
10.2. DNA damage induces cellular senescence through complementary pathways	109
10.3. RS versus SIPS	112
10.4. DNA metabolism and ageing	113
Chapter 11: How bioinformatics can help reverse engineer human aging	116
11.1. Introduction	116
11.2. Data-mining methods	117
11.2.1. Comparative genomics of ageing	117
11.2.2. Transcriptional regulation of ageing	119
11.2.3. DNA microarrays	120
11.3. Modelling human ageing	124
11.3.1. System structure and identification	124
11.3.2. System-level perturbations in model organisms	125
11.3.3. Reconstructing the genetic network of human aging	127
11.4. Conclusion: is it possible to reverse engineer human aging?	128
General Conclusion	130
Appendix: How the genome regulates aging: development of a comparative genomics method to study human aging and a test of theories of aging (submitted for publication)	133
Bibliography	150

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