Mitochondria and ageing: winning and losing in the numbers game.
ABSTRACT Mitochondrial dysfunction has long been considered a key mechanism in the ageing process but surprisingly little attention has been paid to the impact of mitochondrial number or density within cells. Recent reports suggest a positive association between mitochondrial density, energy homeostasis and longevity. However, mitochondrial number also determines the number of sites generating reactive oxygen species (ROS) and we suggest that the links between mitochondrial density and ageing are more complex, potentially acting in both directions. The idea that increased density, especially when combined with mitochondrial dysfunction, might accelerate ageing is supported by a negative correlation between mitochondrial density and maximum longevity in an interspecies comparison in mammals, and by evidence for an intimate interconnection between cellular ROS levels, mitochondrial density and cellular ageing. Recent data suggest that retrograde response, which activates mitochondrial biogenesis, accompanies cellular ageing processes. We hypothesise that increased mitochondrial biogenesis, and possibly also impaired degradation and segregation of mitochondria, if occurring as adaptation to pre-existing mitochondrial dysfunction, might aggravate ROS production and thus actively contribute to ageing.
Article: Ageing as a price of cooperation and complexity: self-organization of complex systems causes the gradual deterioration of constituent networks.[show abstract] [hide abstract]
ABSTRACT: The network concept is increasingly used for the description of complex systems. Here, we summarize key aspects of the evolvability and robustness of the hierarchical network set of macromolecules, cells, organisms and ecosystems. Listing the costs and benefits of cooperation as a necessary behaviour to build this network hierarchy, we outline the major hypothesis of the paper: the emergence of hierarchical complexity needs cooperation leading to the ageing (i.e. gradual deterioration) of the constituent networks. A stable environment develops cooperation leading to over-optimization, and forming an 'always-old' network, which accumulates damage, and dies in an apoptosis-like process. A rapidly changing environment develops competition forming a 'forever-young' network, which may suffer an occasional over-perturbation exhausting system resources, and causing death in a necrosis-like process. Giving a number of examples we demonstrate how cooperation evokes the gradual accumulation of damage typical to ageing. Finally, we show how various forms of cooperation and consequent ageing emerge as key elements in all major steps of evolution from the formation of protocells to the establishment of the globalized, modern human society.BioEssays 06/2009; 31(6):651-64. · 4.95 Impact Factor
Article: Mitonuclear match: optimizing fitness and fertility over generations drives ageing within generations.[show abstract] [hide abstract]
ABSTRACT: Many conserved eukaryotic traits, including apoptosis, two sexes, speciation and ageing, can be causally linked to a bioenergetic requirement for mitochondrial genes. Mitochondrial genes encode proteins involved in cell respiration, which interact closely with proteins encoded by nuclear genes. Functional respiration requires the coadaptation of mitochondrial and nuclear genes, despite divergent tempi and modes of evolution. Free-radical signals emerge directly from the biophysics of mosaic respiratory chains encoded by two genomes prone to mismatch, with apoptosis being the default penalty for compromised respiration. Selection for genomic matching is facilitated by two sexes, and optimizes fitness, adaptability and fertility in youth. Mismatches cause infertility, low fitness, hybrid breakdown, and potentially speciation. The dynamics of selection for mitonuclear function optimize fitness over generations, but the same selective processes also operate within generations, driving ageing and age-related diseases. This coherent view of eukaryotic energetics offers striking insights into infertility and age-related diseases.BioEssays 09/2011; 33(11):860-9. · 4.95 Impact Factor
Article: A stochastic step model of replicative senescence explains ROS production rate in ageing cell populations.[show abstract] [hide abstract]
ABSTRACT: Increases in cellular Reactive Oxygen Species (ROS) concentration with age have been observed repeatedly in mammalian tissues. Concomitant increases in the proportion of replicatively senescent cells in ageing mammalian tissues have also been observed. Populations of mitotic human fibroblasts cultured in vitro, undergoing transition from proliferation competence to replicative senescence are useful models of ageing human tissues. Similar exponential increases in ROS with age have been observed in this model system. Tracking individual cells in dividing populations is difficult, and so the vast majority of observations have been cross-sectional, at the population level, rather than longitudinal observations of individual cells.One possible explanation for these observations is an exponential increase in ROS in individual fibroblasts with time (e.g. resulting from a vicious cycle between cellular ROS and damage). However, we demonstrate an alternative, simple hypothesis, equally consistent with these observations which does not depend on any gradual increase in ROS concentration: the Stochastic Step Model of Replicative Senescence (SSMRS). We also demonstrate that, consistent with the SSMRS, neither proliferation-competent human fibroblasts of any age, nor populations of hTERT overexpressing human fibroblasts passaged beyond the Hayflick limit, display high ROS concentrations. We conclude that longitudinal studies of single cells and their lineages are now required for testing hypotheses about roles and mechanisms of ROS increase during replicative senescence.PLoS ONE 01/2012; 7(2):e32117. · 4.09 Impact Factor