Accumulation of genetic impairment over a lifetime is a common feature of aging. Indeed, the human genome is under continual challenges by DNA-destructive attacks, which endanger cellular homeostasis. These include various exogenous physical, chemical, and biological threats such as viruses, UV damage, and chemicals, as well as endogenous hazards such as DNA replication inaccuracies, spontaneous hydrolytic reactions, and reactive oxygen species (ROS). Thus, somatic mutations of the nuclear DNA accumulate within cells of aged organisms. 125 Mutations and deletions in mitochondrial DNA may also contribute to aging. Accumulated defects in the nuclear lamina are another possible source of genomic instability, except for the genomic damage affecting nuclear or mitochondrial DNA. Further, cell cycle stress, alterations in gene expression and gene regulation take place as a direct consequence of genomic instability. Eventually, it results in age-related cellular degeneration and functional decay. Aging and degenerative disease happen as the ultimate outcome of genomic instability. 128 Thus, there is extensive evidence that genomic damage accompanies and is causatively related to aging. The produced genetic damages are diverse, including impairments such as point mutations, translocations, telomere shortening, and others. To counteract these DNA damages, organisms have developed repair mechanisms such as specific processes for maintaining the appropriate length and functionality of telomeres and for ensuring the integrity of mitochondrial DNA. • Telomere attrition Although DNA damage accumulation with age involve the genome generally, certain regions of the chromosomes, such as telomeres, are especially vulnerable to age-associated deterioration (Figure ). Telomeres are chromatin structures at the distal ends of chromosomes, including conserved microsatellite repeats TTAGGG, which cap and protect the end of a chromosome from recombination and degradation. They allow the chromosome to replicate properly during cell division. The telomere length in humans at birth is ~10,000 -19,000 base pairs. 134 They are known to shorten during cell division, as a result of imperfect replication, losing ~50 -200 base pairs per cell division. Such gradual telomere shortening restricts the number of times a cell can divide. It is considered to act as a 'molecular clock' correlated to organism aging. Telomere length is one of the biomarkers of aging and biological age. Specifically, telomere shortening below a critical length causes telomere protection deficiency, chromosomal instability, and weakened cell viability. This excludes germ cells and certain cancerous cells which are known to express high levels of telomerase, thus avoiding significant telomere shortening and supporting cell viability. Telomerase is a specialized DNA polymerase with the ability to replicate the distal ends of DNA molecules. Telomerase is highly expressed in embryonic stem cells, however, it is not expressed in most mammalian somatic cells, which results in cumulative loss of telomere-shielding sequences at the chromosome ends. Such telomere exhaustion explicates the limited proliferation ability of some cells cultured in vitro, the so-called Hayflick limit specified as the number of times a normal somatic cell population will keep dividing until cell division halts. Studies on genetically modified animals have reported causative relationships between telomere loss, cellular senescence, and aging, indicating that aging can be reverted by telomerase activation. Thus, normal aging is associated with telomere attrition, while pathological telomere dysfunction accelerates aging. 140 Telomeres are particularly predisposed to age-associated deterioration because of the existence of complexes termed shelterins. The key function of shelterins is forming T-loops at the ends of chromosomes, which safeguard telomeres by avoiding them being identified as DNA damage by the DNA polymerase. This has the undesirable effect though of making it difficult for DNA polymerase to repair telomere damage. Thus, both extending telomeres and developing a mechanism to repair DNA damage in telomeres is required in order to deal with this aging pathway.