In memoriam Bernard Strehler--genomic instability in ageing: a persistent challenge.

Genomic instability comprises a broad spectrum of mutational alterations in the genome, such as point mutations in DNA, microsatellite expansions or contractions, amplifications and deletions of DNA sequences, gene rearrangements and structural or numerical chromosomal aberrations. A substantial body of data demonstrates an increase of genomic instability during normal ageing. This includes cytogenetic changes; loss of rDNA; formation of extrachromosomal circular DNA species; loss of telomeric repeats; increased microsatellite instability; as well as point mutations and deletions in global nuclear and mitochondrial DNA. Evidence has accumulated supporting a causative role of genomic instability in ageing. Genomic instability can be counteracted by a number of proteins including antioxidant enzymes, the WRN protein (deficient in Werner syndrome), telomerase, poly(ADP-ribose) polymerase-1 and a range other others, as well as by multi-protein systems such as DNA mismatch repair, base-excision repair and nucleotide-excision repair. Important research tasks for the future will be to elucidate how and what extent the various expressions of genomic instability contribute to the ageing process and to understand the molecular mechanisms and regulation of the above factors and pathways involved in limiting the induction of ageing-associated genomic instability.