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Biomedical subjects

A Kowald

Publications and source records attributed to A Kowald.

6 recordsLinked to original sources
PubMed1996

A network theory of ageing: the interactions of defective mitochondria, aberrant proteins, free radicals and scavengers in the ageing process.

Evolution theory indicates that ageing is caused by progressive accumulation of defects, since the evolutionary optimal level of maintenance is always below the minimum required for indefinite survival. Evolutionary theories also suggest that multiple processes are operating in parallel, but unfortunately they make no predictions about specific mechanisms. To understand and evaluate the many different mechanistic theories of ageing which have been proposed, it is therefore important to understand and study the network of maintenance processes which control cellular homeostasis. In this paper we describe a Network Theory of Ageing which integrates the contributions of defective mitochondria, aberrant proteins, and free radicals to the ageing process, and which includes the protective effects of antioxidant enzymes and proteolytic scavengers. The model simulations not only confirm and explain many experimental, age related findings like an increase in the fraction of inactive proteins, a significant rise in protein half-life, an increase in the amount of damaged mitochondria, and a drop in the energy generation per mitochondrion, but they also show interactions between the different theories which could not have been observed without the network approach. In some simulations, for example, the mechanism of the final breakdown seems to be a consequence of the cooperation of mitochondrial and cytoplasmic reactions, the mitochondria being responsible for a long term, gradual change which eventually triggers a short lived cytoplasmic error loop.

Aging↗
PubMed1994

Towards a network theory of ageing: a model combining the free radical theory and the protein error theory.

Many different theories of ageing have been proposed, based often on highly specific molecular causes. Recent advances in evolutionary theory support the idea that ageing is caused by progressive accumulation of defects, but indicate that multiple processes are likely to operate in parallel. This calls for an understanding of ageing and longevity in terms of a network of maintenance processes that controls the capability of the system to preserve homeostasis. Here we develop a theoretical model which begins the task of implementing a Network Theory of Ageing. To do this the model integrates the ideas of the Free Radical Theory, describing the reactions of free radicals, antioxidants and proteolytic enzymes, with the Protein Error Theory, describing the error propagation loops within the cellular translation machinery. The simulations show that an increased radical production and/or insufficient radical protection can destabilize an otherwise stable translation system. The model supports the idea that caloric restriction prolongs life via a reduction of the generation of radicals. Another result of the model is that protein half-life increases with time as a natural consequence of the interaction between proteolytic enzymes and radicals. Finally the model strengthens certain evolutionary ageing theories by showing that there is a positive correlation between maintenance related energy consumption and lifespan.

Aging↗
PubMed1994

Growing a classification tree using the apparent misclassification rate.

A method to determine the size of a classification tree is proposed. This method is based on the change of the apparent misclassification rate (AMR) of the tree at each growing stage. The method is simple and fast compared to the other classification tree methods, which are based on minimizing a cost complexity function. To test the method, it was used to classify species of fungi, and the results are in good agreement with those obtained by linear discriminant analysis. Also, 21 proteins with known structures and functions were classified using the proposed method. For this purpose the coefficient of variation for several properties of the secondary structures of these proteins has been used. Again, the results were in good agreement with the classification obtained previously using dynamic programming.

Algorithms↗
PubMed1993

Accuracy of tRNA charging and codon: anticodon recognition; relative importance for cellular stability.

Cellular homeostasis and the mechanisms which control homeostasis are important for understanding such fundamental processes as ageing and the origin of life. Several models have studied the importance of accurate protein synthesis for cellular stability, but these models have not considered the complexities of the translation process in any detail. Here we develop a new model which describes the interplay between aminoacyl-tRNA (aatRNA) synthetases, the cellular pool of charged tRNAs and the process of codon: anticodon recognition. We also take the processive character of the ribosomes into account. In common with previous work, our model predicts that the cellular translation apparatus can either be stable or deteriorate progressively with time. However, because our model explicitly describes different subreactions of the overall translation process, we are also able to assess the relative importance of accurate tRNA charging and codon: anticodon recognition for cellular stability. It appears that the tRNA charging by the aatRNA synthetases plays the key role in controlling the long-term stability of the cell. Ribosomal errors are less important because error-prone ribosomes, being processive, produce mainly inactive proteins which do not contribute to error propagation within the translation machinery.

Amino Acyl-tRNA Synthetases↗
PubMed1993

Mitochondrial mutations, cellular instability and ageing: modelling the population dynamics of mitochondria.

All eukaryotic cells rely on mitochondrial respiration as their major source of metabolic energy (ATP). However, the mitochondria are also the main cellular source of oxygen radicals and the mutation rate of mtDNA is much higher than for chromosomal DNA. Damage to mtDNA is of great importance because it will often impair cellular energy production. However, damaged mitochondria can still replicate because the enzymes for mitochondrial replication are encoded entirely in the cell nucleus. For these reasons, it has been suggested that accumulation of defective mitochondria may be an important contributor to loss of cellular homoeostasis underlying the ageing process. We describe a mathematical model which treats the dynamics of a population of mitochondria subject to radical-induced DNA mutations. The model confirms the existence of an upper threshold level for mutations beyond which the mitochondrial population collapses. This threshold depends strongly on the division rate of the mitochondria. The model also reproduces and explains (i) the decrease in mitochondrial population with age, (ii) the increase in the fraction of damaged mitochondria in old cells, (iii) the increase in radical production per mitochondrion, and (iv) the decrease in ATP production per mitochondrion.

Aging↗