The evolution of ageing is a field flush with misconceptions, misunderstandings, and hiatuses. In this thesis I address the most important misunderstanding and misconceptions, and develop new... Show moreThe evolution of ageing is a field flush with misconceptions, misunderstandings, and hiatuses. In this thesis I address the most important misunderstanding and misconceptions, and develop new theory to fill the gaps. This work directly leads to the restatement of the central question in the evolutionary theory of ageing. Rather than evaluating evolutionary forces in models that are at best weakly rooted in (patho-) physiological mechanisms, usually phrased in terms of __age-specific genes__ that are not further specified, as is the current practice, the most pressing question becomes why an organism cannot, or does not, do in itself what it is perfectly capable of doing outside itself in the form of reproduction, namely producing a perfectly healthy __young__ organism. Evolutionary forces cannot answer this question. If anything, this is a mechanistic question. I suggest investigating __the evolution of unretainability__: why and how has our form of life evolved, in which it is mechanistically impossible to bring ageing to a halt, and what are the responsible mechanistic constraints? Show less
Replicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower... Show moreReplicative ageing of fibroblasts has often been used as a model for organismal ageing. The general assumption that the ageing process is mirrored by cellular senescence in vitro is based on lower replicative capacity of human fibroblasts from donors of higher chronological age, but these inverse relations have not been reported unequivocally. The relation between chronological age and fibroblast growth characteristics was assessed in nonagenarian subjects of the Leiden 85+ Study. A high remaining replicative capacity impressively showed that even in the very elderly a crucial number of cells with high mitotic capacity are left to give rise to fibroblast strains with the capacity for more than 100 population doublings. During the course of fibroblast growth in vitro, beta-galactosidase activity has been shown to be a reliable biomarker for replicative senescence. In myoblast cultures the relation between mixed cultures and clonal cultures was studied, showing marked heterogeneity between clonal cultures that all had a significantly lower replicative capacity when compared to mixed cultures, indicating heterogeneity of cells within one tissue compartment in their in vivo history. In a formal review on the replicative capacity of fibroblasts from patients suffering from accelerated ageing syndromes, age related diseases and donor age it was found that except for premature ageing syndromes, the replicative capacity of fibroblasts in vitro does not mirror key characteristics of human life histories. Show less
