Gene network stability and aging: evolutionary trade-off with grave consequencies
Будем выступать на Aging and Diseases of Aging конференции в Токио (октябрь, 2012). Скоро будет препринт, а пока абстракт:
There is a growing number of examples among the very different animal species yielding ever increasing number of animals exhibiting what can be called a negligible senescence (see e.g. the pioneering work Buffenstein et al, 2005). The reported age dynamics of mortality data followed by the recent transcriptomics studies, suggest that the genetic networks of at least some of the animals can extremely stable on very long time scales. On the contrary, most of the animals including humans show a catastrophic (exponential) increase of mortality with age, which could be a signature of underlying genetic regulatory network instability.
In this work we show that there may be two distinctly different types of aging. To do that we provide a minimalistic, possibly the simplest mathematical model of aging in a genetic network and analyze the gene expression levels stability in the presence of environmental or metabolic perturbations. Under a very generic set of assumptions we establish a possibility of a dynamic instability (in the simplified model scenario, or a full fledged phase transition in a more realistic model of a gene network) associated with the gene network connectivity, leading to exponential accumulation of the genome regulation errors and, subsequently, to a very fast aging in organisms where the efficiency of the reparation systems is insufficient to correct errors. On the other end of the spectrum the model predicts existence of organisms capable of boosting the repairs strong enough to stabilize the gene network and establish a very different aging dynamics, much closer to that observed in naked mole types.
We work through the model solutions to compare the findings with some of the available experiments, analyze the results and trade-offs involved in the possible lifespan extension strategies. Finally we speculate on plausible explanations behind evolutionary advantages and frequency of occurrence of the both aging phenotypes in Nature.
There is a growing number of examples among the very different animal species yielding ever increasing number of animals exhibiting what can be called a negligible senescence (see e.g. the pioneering work Buffenstein et al, 2005). The reported age dynamics of mortality data followed by the recent transcriptomics studies, suggest that the genetic networks of at least some of the animals can extremely stable on very long time scales. On the contrary, most of the animals including humans show a catastrophic (exponential) increase of mortality with age, which could be a signature of underlying genetic regulatory network instability.
In this work we show that there may be two distinctly different types of aging. To do that we provide a minimalistic, possibly the simplest mathematical model of aging in a genetic network and analyze the gene expression levels stability in the presence of environmental or metabolic perturbations. Under a very generic set of assumptions we establish a possibility of a dynamic instability (in the simplified model scenario, or a full fledged phase transition in a more realistic model of a gene network) associated with the gene network connectivity, leading to exponential accumulation of the genome regulation errors and, subsequently, to a very fast aging in organisms where the efficiency of the reparation systems is insufficient to correct errors. On the other end of the spectrum the model predicts existence of organisms capable of boosting the repairs strong enough to stabilize the gene network and establish a very different aging dynamics, much closer to that observed in naked mole types.
We work through the model solutions to compare the findings with some of the available experiments, analyze the results and trade-offs involved in the possible lifespan extension strategies. Finally we speculate on plausible explanations behind evolutionary advantages and frequency of occurrence of the both aging phenotypes in Nature.