Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes

Jin Zhang, Jordi Asin-Cayuela, Jennifer Fish, Yuichi Michikawa, Massimiliano Bonafé, Fabiola Olivieri, Giuseppe Passarino, Giovanna De Benedictis, Claudio Franceschi, Giuseppe Attardi

Research output: Contribution to journalArticle

Abstract

The presence of a genetic component in longevity is well known. Here, the association of a mtDNA mutation with a prolonged life span in humans was investigated. Large-scale screening of the mtDNA main control region in leukocytes from subjects of an Italian population revealed a homoplasmic C150T transition near an origin of heavy mtDNA-strand synthesis in ≈17% of 52 subjects 99-106 years old, but, in contrast, in only 3.4% of 117 younger individuals (P = 0.0035). Evidence was obtained for the contribution of somatic events, under probable nuclear genetic control, to the striking selective accumulation of the mutation in centenarians. In another study, among leukocyte mtDNA samples from 20 monozygotic and 18 dizygotic twins, 60-75 years old, 30% (P = 0.0007) and 22% (P = 0.011), respectively, of the individuals involved exhibited the homoplasmic C150T mutation. In a different system, i.e., in five human fibroblast longitudinal studies, convincing evidence for the aging-related somatic expansion of the C150T mutation, up to homoplasmy, was obtained. Most significantly, 5′ end analysis of nascent heavy mtDNA strands consistently revealed a new replication origin at position 149, substituting for that at 151, only in C150T mutation-carrying samples of fibroblasts or immortalized lymphocytes. Considering the aging-related health risks that the centenarians have survived and the developmental risks of twin gestations, it is proposed that selection for a remodeled replication origin, inherited or somatically acquired, provides a survival advantage and underlies the observed high incidence of the C150T mutation in centenarians and twins.

Original languageEnglish
Pages (from-to)1116-1121
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number3
DOIs
Publication statusPublished - Feb 4 2003

ASJC Scopus subject areas

  • Genetics
  • General

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