DRUSE

Gustavo Barja discussed the gene cluster hypothesis of ageing and longevity on the journal Biogerontology.

Barja G.
The gene cluster hypothesis of aging and longevity.
Biogerontology. 2008 Feb;9(1):57-66. Epub 2007 Oct 31.

“… 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 … 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 …”

Fig. 1 Scheme representing the gene cluster hypothesis of aging. Target genes producing proteins affecting the endogenous aging rate, degenerative diseases, resistance to external stress, fecundity and other traits can be organized in clusters working through transcriptional cascades and complex interactions. The controller genes (in superior hierarchical levels in space or time) produce regulatory proteins (ovals) that control the graded expression of other genes. Regulatory proteins that would contain similar DNA binding sequences are depicted with the same shading. The grouping of genes controlled by similar regulatory proteins shown in the figure is only one of the many possible combinations, and is arbitrarily shown only as an example. The identification of common sequences in the apparently unrelated genes, or clustering in tandem of some of the genes in the same chromosome region, could serve to identify the cluster. Gene expression would also be influenced by other actors (e.g. upstream promoters, enhancers) not shown in the figure. The graded activation/repression of the target structural genes will finally affect aging rate as well as other traits needed for final expression of a high longevity (e.g., low incidence of degenerative diseases and high resistance to external sources of stress). Interrelations among genes in the cluster are expected to be much complex than depicted, and would include crossed regulations both at horizontal level, and at vertical levels spanning more than one level per relationship. The real number and kinds of final target genes must be much greater than shown in the figure, and the master genes at the upper control level can be multiple, although their number must be much smaller than the number of target genes. This is most interesting for future possible manipulations aimed at greatly increasing maximum longevity. The figure should be considered a highly simplified example of a much more complex net of genetic interrelationships, not a precise scheme. According to present knowledge, the target genes included in the figure should be present in the real cluster, although not necessarily in the sub-clustering tandem positions shown which were arbitrarily selected as one among many possible combinations. The longevity gene cluster, like homeotic genes controlling development, is expected to be highly conserved among animal species, which will strongly facilitate its discovery. For further explanation see text. “a”: horizontal or multilevel (in addition to single level) hierarchical interactions, and overlapping of regulatory elements; “b”: hypothetical example of two genes clustered in tandem in the same region; “m”: master genes