Age-related alterations of DNA repair could be involved in the accumulation of genetic damage with age. Few data suggest a possible alteration with age of the mismatch repair system, evidenced by the acquisition of microsatellite instability. We aimed to point out a possible implication of this repair system in the accumulation of genetic damage with age. Peripheral blood cell DNA from 226 participants, 110 young (25–35 years), 58 old (85–97 years), and 58 centenarian was analyzed at five polymorphic microsatellite loci (CD4, p53, VWA31, TPOX, and FES/FPS) to point out age-related instabilities or modifications in allele frequencies. FES/FPS microsatellite was the most instable, showing both the appearance of trizygosis in DNA from old participants and differences in allele patterns among age groups, thus indicating an association between increased microsatellite instability and aging, one of the possible causes of which being an impairment of mismatch repair system capacity with age.