Molecular Mechanisms And Models Of Aging

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Download or read book Task Group 7B written by and published by . This book was released on 2007 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: The degree to which an individual organism maintains healthspan and lifespan is a function of complex interactions between genetic inheritance ('nature'), environment, including cultural inheritance (nurture) and stochastic events ('luck' or 'chance'). This task group will focus upon the role of chance because it is so poorly understood and because it appears to be of major importance in the determination of individual variations in healthspan and lifespan within species. The major factor determining variations in healthspan and lifespan between species is genetic inheritance. Broader aspects of cellular and molecular mechanisms of biological aging will also be considered, given their importance for understanding the cellular and molecular basis of successful aging. The task force will consider the cellular and molecular basis for nature, nurture and chance in healthspan and life span determination. On the basis of comparisons between identical and non-identical twins, geneticists have estimated that genes control no more than about a quarter of the inter-individual differences in lifespan (Herskind 1996). Twin studies of very old individuals, however, show substantially greater genetic contributions to Healthspan (McClearn 2004; Reed 2003). The environment clearly plays an important role in the length and the quality of life. Tobacco smoke, for example has the potential to impact upon multiple body systems in ways that appear to accelerate the rates at which those systems age (Bernhard 2007). To document the role of chance events on aging, one must rigorously control both the genetic composition of an organism and its environment. This has been done to a remarkable degree in a species of nematodes, Caenorhabditis elegans (Vanfleteren 1998). The results confirm hundreds of previous studies with a wide range of species, especially those with inbred rodents housed under apparently identical but less well controlled environments. One observes wide variations in lifespan in all these studies. For the C. elegans experiments, the distributions of lifespan fit best with two parameter or three parameter logistic models and not with the classical Gompertz model nor the Weibull model. Many mutations have been shown to substantially increase lifespan in C. elegans. It is of interest, however, that the ranges of the lifespan variations among such mutant strains overlap with those of wild type strains (Kirkwood 2002). Many of these long-lived mutant strains exhibit enhanced resistance to a variety of stressors, notably heat shock. It was therefore predicted that variable degrees of response to heat shock stress might form a basis, or a partial basis, for individual variations in longevity. An initial set of experiments demonstrated that is indeed the case, at least for a transgenic construct that includes the promoter of a small heat shock gene (Rea 2005). There was a very strong correlation between the response to a heat stress and longevity, with good responding worms living longer. Strikingly, this phenotype was not heritable. The progeny of a worm showing a strong heat stress reaction exhibited the broad distribution of lifespans shown by the starting population. The heat stress reaction was therefore stochastic. The nature of the chance events that determine the reaction remains unknown. They could be related to the intrinsic instability of the transgene, making it important to repeat such experiments utilizing endogenous genes as reporters of the response to heat shock and other stressors. It could be due to epigenetic drifts in gene expression, perhaps involving random changes in gene promoters or in the state of chemical modifications to histone proteins that coat chromosomes. Such changes have indeed been observed in aging human identical twins (Fraga 2005). While those changes have been interpreted as being driven by the environment, one cannot at present rule out random variations unrelated to environmental influences. Variations in gene expression in genetically identical organisms examined under environmentally identical conditions have also been attributable to intrinsic 'noise' in fundamental molecular processes such as the transcription and translation of genes. Most such observations have been made using microorganisms (Elowitz 2002), but stochastic bursts of transcription have also been noted in mammalian cells (Raj 2006). Moreover, substantial variation in the levels at which genes are transcribed have shown to occur in mouse tissues, and that variation was shown to increase with age (Bahar 2006). Chance events are also of major significance in the determination of diseases of aging. For the case of cancer, mutations have been shown to be of major importance. A likely key to malignancy, however, is the chance event of suffering a mutation in a gene which, when mutated, now greatly enhances the general frequency of mutation.