What geriatricians should know about the Werner syndrome

Geriatricians want to know the extent to which inborn genetic variations influence health span and life span in their patients. Current research on this subject is largely confined to the very basic issues of identifying, mapping, and cloning relevant genes and of investigating their modes of action. Here we summarize the status of such basic research on a gene (WRN), null mutations at which cause a striking segmental progeroid syndrome, the Werner syndrome (WS). The views of clinicians and basic scientists concerning the significance of WRN gene action for normal aging are polarized. Some regard it as the most important aging gene and refer to the syndrome explicitly as one of premature aging. Others regard WS as an entirely inappropriate model for aging because WS exhibits many clinical and cell biological discordances with normal aging. Moreover, WS has a major impact on reproductive fitness and, hence, does not escape the forces of natural selection. By contrast, senescent phenotypes of normal (usual) aging can be defined as those that do escape the forces of natural selection. We here give a more balanced view. Work has only just begun on the potential significance of a range of variants at the WS locus, including "leaky" mutations, heterozygosity for null mutations, and polymorphisms, some of which may indeed escape the force of natural selection and thus contribute to the burden of illness in old age. We are also at a very early stage of knowledge concerning genes coding for WRN interacting proteins, variations at which may also be of significance for gerontology and geriatric medicine.