Age-related decline in DNA repair capacity (DRC) is associated with decreased constitutive levels of p53 and other nucleotide excision repair proteins. To determine whether pretreatment of cells with small DNA oligonucleotides compensates for decreased DRC in the elderly, fibroblasts from donors of different ages were pretreated with thymidine dinucleotide (pTT), a 5' phosphorylated 9 base oligonucleotide (p9mer) or diluent alone for 48 h, then UV-irradiated with solar-simulated light. Western blot analysis revealed age-associated decreases of 40%-80% between newborn and old adult donor cells in the constitutive protein levels of p53, p21, XPA, RPA, ERCC1, and PCNA. Treatment with pTT or p9mer up-regulated these proteins by 200%-650% at 24, 48, and 72 h. Moreover, pretreatment with oligonucleotides significantly increased the removal rate of photoproducts as determined by reacting DNA with thymine dimer-specific antibodies: 40+/-5% vs. 20+/-9% and 15+/-11% remained after 24 h in diluent, pTT and p9mer treated cells, respectively. Oligonucleotide-treated adult cells removed thymine dimers at least as rapidly as diluent treated newborn cells, demonstrating that pTT and p9mer completely corrected the age-associated decrease in DRC. Our studies suggest that topical oligonucleotide treatment may enhance DRC in older adults and thus reduce the carcinogenic risk from solar UV irradiation in this age group.