Heterogeneity The Hallmark of Ageing

Ageing is characterized by random accumulation of unrepaired cellular and molecular damage. The mechanisms involved are inherently stochastic, i.e., driven by chance (Kirkwood 2005). In fact, several studies have demonstrated stochastic heterogeneity as an important feature of the ageing process:

Examining the effect of ageing on cell integrity in different tissues of Caenorhabditis elegans by electron microscopy (Herndon et al. 2002), it was found that stochastic factors are clearly involved in the ageing process and that different cell types deteriorate at different rates. Apart from heterogeneity on a tissue and cellular level, the wide interindividual variation in life span of C.elegans nematodes, even in isogenic populations under very homogeneous environmental conditions, indicates the intrinsic randomness of the ageing process (Kirkwood and Finch 2002). This heterogeneity in life span variation of isogenic C. elegans populations has been attributed to chance variation in expression of gene hsp-16.2 (Rea et al. 2005).

Thomas von Zglinicki

Henry Wellcome Laboratory for Biogerontology Research, Institute for Ageing and Health, Center for Integrated Systems Biology of Ageing and Nutrition, University of Newcastle upon Tyne, NE4 6BE, United Kingdom. e-mail: T. [email protected]

K.L. Rudolph (ed.), Telomeres and Telomerase in Ageing, Disease, and Cancer. © 2008 Springer-Verlag Berlin Heidelberg

It has been shown by dissociating single cardiomyocytes from fresh heart samples of both young and old mice that gene expression heterogeneity increased significantly with age (Bahar et al. 2006). In an attempt to attribute a cause to this cell-to-cell variation, the authors tested the involvement of oxidative stress in the process by exposing mouse embryonic fibroblasts to hydrogen peroxide. They found that gene expression variation increased after hydrogen peroxide treatment.

The free radical theory of ageing provided a first approach toward mechanistic insight into the concept of random damage in ageing. Harman's work (Harman 1956) suggested that the random nature of free radical damage could explain the marked heterogeneity in the decline of cells, tissues, and individuals in ageing. Although a large amount of data has been gathered in general support of this idea, the majority of it is still merely correlative and fails to rigidly establish causal connections. So far, mice studies have proven to be inconclusive. For instance, mice carrying a heterozygous deletion of the mitochondrial superoxide dismutase, an enzyme able to convert superoxide anion to water and hydrogen peroxide, showed indications of increased oxidative stress and high cancer incidence but not accelerated ageing (Van Remmen et al. 2003). However, targeting catalase to mitochondria increased the life span of transgenic mice (Schriner et al. 2005) and overexpression of human thioredoxin (TRX) in mice led to increased resistance to oxidative stress and extended median and maximum life spans (Mitsui et al. 2002).

In the model of replicative senescence, i.e., the irreversible loss of division potential of somatic cells after a more or less constant number of cell divisions, the role of oxidative stress is under intense debate. Recently, reports have suggested that oxidative stress might have a role as a tumor suppressor mechanism (Ramsey and Sharpless 2006), and it has been established that oxidative stress has a significant impact on telomere shortening (von Zglinicki 2002). In the remainder of this chapter we will review the role of oxidative stress in replicative senescence, its influence on telomeres, and its contribution to cell-to-cell heterogeneity.

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