To identify the underlying molecular bases that enable macaque cells to extend their replicative life span (RLS), somatic mutations in p53 were studied in two Japanese macaque (Macaca fuscata) and one long-tailed macaque (Macaca fascicularis) cell strains with extended RLS. Nucleotide sequences of the p53 whole coding region of each species were determined in early passaged cells and somatic mutations were studied in cells with extended RLS. Different type of genomic alteration which may disrupt normal p53 function was observed in each strain: (1) introduction of a premature stop codon in one chromosome and loss of heterozygosity for the other; (2) introduction of a missense mutation into each chromosome independently; (3) generation of a novel splice donor site to delete four amino acid residues in the presence of silencing of the normal p53 gene. Critical roles of p53 in cellular aging among macaques in terms of extention of RLS were demonstrated. (C) 2002 Elsevier Science (USA). All rights reserved.