One common denominator of aging is the accumulation of genetic damage throughout life.

Moreover, numerous premature aging diseases, integrity and stability of DNA are continuously challenged by exogenous physical, chemical, and biological agents, as well as by endogenous threats, including DNA replication errors, spontaneous hydrolytic reactions, and reactive oxygen species.

The genetic lesions arising from extrinsic or intrinsic damages are highly diverse and include point mutations, translocations, chromosomal gains and losses, telomere shortening, and gene disruption caused by the integration of viruses or transposons.

To minimize these lesions, organisms have evolved a complex network of DNA repair mechanisms that are collectively capable of dealing with most of the damages inflicted to nuclear DNA.

The genomic stability systems also include specific mechanisms for maintaining the appropriate length and functionality of telomeres and for ensuring the integrity of mitochondrial DNA.

Increased clonal mosaicism for large chromosomal anomalies has also been reported. All of these forms of DNA alterations may affect essential genes and transcriptional pathways, resulting in dysfunctional cells that, if not eliminated by apoptosis or senescence, may jeopardize tissue and organismal homeostasis.

Mutations and deletions in aged mtDNA may also contribute to aging. mtDNA has been considered a major target for aging-associated somatic mutations due to the oxidative microenvironment of the mitochondria, the lack of protective histones in the mtDNA, and the limited efficiency of the mtDNA repair mechanisms compared to those of nuclear DNA.

Defects in the nuclear lamina can also cause genome instability. Nuclear lamins constitute the major components of the nuclear lamina and participate in genome maintenance by providing a scaffold for tethering chromatin and protein complexes that regulate genomic stability.

Telomere dysfunction also promotes progerin production in normal human fibroblasts upon prolonged in vitro culture, suggesting intimate links between telomere maintenance and progerin expression during normal aging.

There is extensive evidence that genomic damage accompanies aging and that its artificial induction can provoke aspects of accelerated aging. In the case of the machinery that ensures faithful chromosomal segregation, there is genetic evidence that its enhancement can extend longevity in mammals.

Moreover, in the particular case of progerias associated with nuclear architecture defects, there is proof of principle for treatments that can delay premature aging. Similar avenues should be explored to find interventions that reinforce other aspects of nuclear and mitochondrial genome stability, such as DNA repair, that could have a positive impact on normal aging since telomeres constitute a particular case and are discussed separately.