| Abstrakt: |
Ageing is an issue, which inevitably affects all of us, and conditions that accompany ageing - such as cardiovascular disease, cancer, neurodegenerative disorders and diabetes - account for the majority of healthcare costs. This is a rapidly increasing problem, as, average life expectancy worldwide has increased by 20 years since 1950, to stand at 66 years now and the number of people over 65 is expected to double until 2025 in many industrialized countries in Europe and the US. It can be expected that the trend towards an increased lifespan - independent of the intake of specially designed treatment - has not come to an end yet. Drs. Oeppen and Vaupel (Cambridge University, United Kingdom and Max Planck Institute for Demographic Research, Germany) have observed that maximum life expectancy has steadily increased for the past 160 years. The increase in the record expectation of life should be slowing, when close to a natural maximum, an observation which, however, has not been made. While the magnitude of the consequences of these world-wide demographic changes, however, is not reflected by existing therapeutic options, there is an increasing interest and awareness in the scientific community for the treatment of age-related disorders, dysfunctions and diseases; furthermore, an increasing emphasis is placed on basic research witnessing unprecedented growth and acceptance. Although the fountain of youth certainly is out of reach, the recent past has seen exciting developments bringing us closer to the identification of causes of ageing and to the generation of agents increasing longevity. Exciting innovations have been described in biotechnology including conditions to regrow damaged or diseased tissues and organs, in stem cell technology to permit development of a supply source for human cells, tissues, and organs and genetic engineering advancements. The view dominated by evolutionary research considering ageing as a general deterioration, thus precluding monogenetic causes of longevity, has been changed dramatically within the last decade, which has seen spectacular increases of lifespan in model organisms as a result of single-gene mutations. These findings have fuelled the screening for specifically interfering agents and will prompt the search for further single-gene targets employing timely screening technologies such as high-throughput tests using RNAi. The latter is also being used to correct defective RNA splices that, when expressed, cause disease. Screening for potential treatments, however, requires appropriate models and feasible assays. Whereas lifespan studies are performed in simple organisms like yeast, worms (C. elegans) or flies (Drosophila) requiring several days or weeks, an evaluation in a mouse model may take several months or years. Recent genetic studies on these animals revealed that the lifespan of these species can be dramatically increased by the mutation of one or a few genes. The identification of these genes, however, suggests that ageing can be manipulated, because many genes that affect longevity in model organisms have human homologs. However, it still remains to be shown to which extent these or other gene activities represent drugable targets. With regard to low molecular weight agents, medicinal chemistry has developed efficient toolkits and e.g. Chemical Genetics, a phenotypedriven research targeting the lifespan of model systems and animal models, appears to be fruitful. Given the lack of knowledge on lifeextending mechanisms a random or biased screening approach is reasonable besides attempts to address distinct known targets for interference based on mechanistic considerations. For instance, a lifespan directed screening of agents with known pharmacological activities such as the testing of anticonvulsive drugs by Kerry Kornfeld and colleagues provides highly interesting data pointing to a previously unknown connection between neural function and longevity. Alternative underlying mechanisms are expected to include the preservation or the restoration of important functions in cellular control and repair mechanisms or of pathways affecting the expression and function of proteins controlling the levels of reactive oxygen species and improving stress resistance such as antioxidant enzymes like catalase or administration of the glutathione precursor cysteine, which might reduce age-associated degeneration. Drugs mimicking caloric restriction decrease weight, may decrease oxidative stress, increase insulin sensitivity, modulate the neuroendocrine system and prolong life in ways similar to caloric restriction.... |
