The gene cluster hypothesis of aging and longevity.
The maximum longevity of different species can vary by 100-fold in mammals and by 1,000-fold or more from invertebrates to mammals. However, the life extension effect of single gene mutations or dietary restriction converges on a comparatively minute 1.3- to 1.6-fold difference with controls. It is proposed that this can be due to organization of genes affecting maximum life span in large clusters functionally linked by complex interactions analogously to homeotic genes during development. A relatively small number of master genes would control the activity of the structural target genes of the whole cluster, strongly facilitating changes in longevity during species evolution. Experimentally manipulating the expression of those master genes would have the potential to increase maximum longevity to a much higher extent than the options available nowadays. The present availability of the full genome sequence of various organisms including rats, mice and men can greatly help to discover such clustering and to identify those master genes. Fortunately for gerontology, the first highly reliable completed genomes were those of the laboratory rodents and humans, mammals with strongly different maximum longevities, 3-4 years and 122 years, respectively. Comparing them focusing on longevity will help to discover the longevity gene cluster and many other relevant aspects concerning aging rate, and should be encouraged. The gene cluster hypothesis of aging can be tested at least: (a) using bioinformatics tools allowing to look for common sequences in known genes that, based on the evidence available, are expected to be part of the longevity gene cluster; (b) looking for spatial clustering of some of these genes in particular chromosome regions. The huge benefits that could be obtained discovering the longevity gene cluster will amply outweigh the comparatively small research effort involved.
Barja
Gustavo
G
Departamento de Fisiología Animal-II, Facultad de Ciencias Biológicas, Universidad Complutense, Madrid, Spain. gbarja@bio.ucm.es
D000375:Aging / Q000235:genetics*; D006801:Humans; D008136:Longevity / Q000235:genetics*; D005810:Multigene Family