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Rel 2.7 - 24th December 1997

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J Mol Med 1997 Oct;75(10):715-727

Genetic regulation of aging.

Osiewacz HD

Aging of biological systems is a complex process that is controlled by both environmental factors and the genetic constitution of the individual. Although the molecular mechanisms have not been elucidated for any system in detail, it is clear that various genetic traits are involved in the modulation of life span. In particular, the genetic information located in the mitochondria has been identified as a major genetic component. Instabilities of the mitochondrial DNA (mtDNA) lead to mitochondrial dysfunction and increased oxidative stress. In some cases mtDNA instabilities are related to the activity of mobile genetic elements. In addition, nuclear genes appear to be crucially involved in mtDNA maintenance. Furthermore, the initial analysis of a few cloned nuclear genes affecting life span suggests a cellular machinery dealing with various stress situations as a major component involved in the genetic control of aging. This conclusion may hold true for all biological systems and be related to a unified mechanism of aging. However, in the various lineages this mechanism may be superimposed by other species or lineage-specific mechanisms.


J Mol Med 1997 Oct;75(10):703-714

The membrane hypothesis of aging: its relevance to recent progress in genetic research.

Zs -Nagy I

Department of Gerontology, University Medical School, Debrecen, Hungary.

This review outlines the main concepts of the membrane hypothesis of aging (MHA) developed over the past two decades. MHA offers a general cell biological mechanism to explain the main trends of age-dependent changes in terms of intracellular physicochemistry. An essential point in MHA is that the inevitable plasma membrane alterations result in the accumulation of dry mass in the intracellular space, a process that is essential to cellular development and organismal maturation, but which becomes a rate limiting factor above a certain physical density of the cell colloids. The main statements of the MHA are supported by recent developments in molecular genetics. Specifically, the great majority of the products of oncogenes and antioncogenes are localized to the plasma membrane, indicating a central role of the plasma membrane in mitotic regulation, cell differentiation and senescence.


Science 1997 Aug 29;277(5330):1313-1316

Accelerated aging and nucleolar fragmentation in yeast sgs1 mutants.

Sinclair DA, Mills K, Guarente L

Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

The SGS1 gene of yeast encodes a DNA helicase with homology to the human WRN gene. Mutations in WRN result in Werner's syndrome, a disease with symptoms resembling premature aging. Mutation of SGS1 is shown to cause premature aging in yeast mother cells on the basis of a shortened life-span and the aging-induced phenotypes of sterility and redistribution of the Sir3 silencing protein from telomeres to the nucleolus. Further, in old sgs1 cells the nucleolus is enlarged and fragmented-changes that also occur in old wild-type cells. These findings suggest a conserved mechanism of cellular aging that may be related to nucleolar structure.

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