Stochastic mechanisms of gene deregulation in aging

Jan Vijg
Buck Institute for Age Research, Novato, CA

There is extensive variability in age-related degeneration, both among different, genetically identical animals and among cells of the same type within an individual. Such stochasticity can be explained very well in the context of the idea that aging is ultimately caused by the accumulation of somatic damage. As dictated by evolutionary logic, all cellular processes evolve toward procreation, even at the expense of the soma (at least in most metazoans). This logically explains why somatic damage is allowed to accumulate, even to the extent that eventually it will bring life to a close.

While damage can accumulate at all levels of organization, i.e., from DNA to proteins and multimolecular structures, damage to DNA may be most important. Indeed, through errors in its repair, DNA damage can give rise to DNA mutations and epimutations, gradually turning a tissue into a cell functional mosaic. Such genetic and epigenetic drift will randomly reset gene regulatory loops, altering gene expression patterns on a cell by cell basis. (Epi)genetic drift might only slightly compromise cellular function, but in aggregate, more seriously compromise tissues, which function as concerted individual cellular responses and phenotypes. Its consequences would be impossible to correct by pharmacological means, and at present its correction falls outside the realm of current or foreseeable technology.