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

Zhang, Jin and Asin-Cayuela, Jordi and Fish, Jennifer and Michikawa, Yuichi and Bonafé, Massimiliano and Olivieri, Fabiola and De Benedictis, Giovanna and Passarino, Giuseppe and Franceschi, Claudio and Attardi, Giuseppe (2003) Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Proceedings of the National Academy of Sciences of the United States of America, 100 (3). pp. 1116-1121. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:ZHApnas03

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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 approximate to 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.


Item Type:Article
Additional Information:Copyright © 2003 by the National Academy of Sciences. Contributed by Giuseppe Attardi, November 25, 2002. Published online before print January 21, 2003, 10.1073/pnas.242719399 We are grateful to N. Bresolin and F. Mazzucchelli for providing some of the fibroblast cultures analyzed in the present work. We thank A. Chomyn for valuable discussions and L. Bellavia and M. Del Mar Roldan for expert technical assistance. This work was supported by National Institute on Aging (National Institutes of Health) Grant AG12117 (to G.A.), by Ellison Medical Foundation Senior Scholar Award AG-SS-0622-00 (to G.A.), and by an Associazione Italiana per la Ricerca sul Cancro grant (to C.F.).
Subject Keywords:human mitochondrial-DNA, sequence, cell, region
Record Number:CaltechAUTHORS:ZHApnas03
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:ZHApnas03
Alternative URL:http://dx.doi.org/10.1073/pnas.242719399
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:1340
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:11 Jan 2006
Last Modified:26 Dec 2012 08:43

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