The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific

Nicola Raule; Federica Sevini; Shengting Li; Annalaura Barbieri; Federica Tallaro; Laura Lomartire; Dario Vianello; Alberto Montesanto; Jukka S Moilanen; Vladyslav Bezrukov; Hélène Blanché; Antti Hervonen; Kaare Christensen; Luca Deiana; Efstathios S Gonos; Tom B L Kirkwood; Peter Kristensen; Alberta Leon; Pier Giuseppe Pelicci; Michel Poulain; Irene M Rea; Josè Remacle; Jean Marie Robine; Stefan Schreiber; Ewa Sikora; Peternella Eline Slagboom; Liana Spazzafumo; Maria Antonietta Stazi; Olivier Toussaint; James W Vaupel; Giuseppina Rose; Kari Majamaa; Markus Perola; Thomas E Johnson; Lars Bolund; Huanming Yang; Giuseppe Passarino; Claudio Franceschi

doi:10.1111/acel.12186

The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific

Nicola Raule, Federica Sevini, Shengting Li, Annalaura Barbieri, Federica Tallaro, Laura Lomartire, Dario Vianello, Alberto Montesanto, Jukka S Moilanen, Vladyslav Bezrukov, Hélène Blanché, Antti Hervonen, Kaare Christensen, Luca Deiana, Efstathios S Gonos, Tom B L Kirkwood, Peter Kristensen, Alberta Leon, Pier Giuseppe Pelicci, Michel PoulainIrene M Rea, Josè Remacle, Jean Marie Robine, Stefan Schreiber, Ewa Sikora, Peternella Eline Slagboom, Liana Spazzafumo, Maria Antonietta Stazi, Olivier Toussaint, James W Vaupel, Giuseppina Rose, Kari Majamaa, Markus Perola, Thomas E Johnson, Lars Bolund, Huanming Yang, Giuseppe Passarino, Claudio Franceschi

Research output: Contribution to journal › Article › peer-review

85 Citations (Scopus)

379 Downloads (Pure)

Abstract

To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

Original language	English
Pages (from-to)	401-407
Number of pages	7
Journal	Aging cell
Volume	13
Issue number	3
Early online date	17 Dec 2013
DOIs	https://doi.org/10.1111/acel.12186
Publication status	Published - Jun 2014

Keywords

Ageing Long; Ageing Well; Nonagenarian siblings;
Oxidative Stress
mitochondrial haplogroups
human longevity

ASJC Scopus subject areas

Geriatrics and Gerontology
General Biochemistry,Genetics and Molecular Biology
Ageing
Genetics
Cell Biology

Access to Document

10.1111/acel.12186Licence: CC BY

The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific
Copyright 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 152 KBLicence: CC BY

1 Active

R6229GRM: GEHA.
Rea, M. (PI)
01/08/2004 → …
Project: Research

2 Participation in conference
1 Participation in Festival/Exhibition
1 Invited talk

International Symposium: The Challenges of the Biological Research in Aging in the 21st Century: from the cells to the clinics.
Maeve Rea (Invited speaker)
02 Nov 2014 → 04 Nov 2014
Activity: Participating in or organising an event types › Participation in conference
British Society Research into Ageing
Maeve Rea (Invited speaker)
07 Jul 2014 → 09 Jul 2014
Activity: Participating in or organising an event types › Participation in conference
Super Vivere Exhibition (opening event of the Luminate Scotland's Creative Ageing Festival 2013) on the International Day for Elderly People (UN 1991) in Stirling University. Readings from authored book Super Vivere: Reflections on Long Life and Ageing Well (Rea&Rea 2011) and Introductory Lecture about the Science behind the EU funded Genetics of Healthy Ageing (GeHA) project and artist's overview.
Rea, M. (Speaker)
01 Oct 2013 → 31 Oct 2013
Activity: Talk or presentation types › Invited talk

85 Citations
7 Article

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age
Deelen, J., Beekman, M., Uh, H.-W., Broer, L., Ayers, K. L., Tan, Q., Kamatani, Y., Bennet, A. M., Tamm, R., Trompet, S., Guðbjartsson, D. F., Flachsbart, F., Rose, G., Viktorin, A., Fischer, K., Nygaard, M., Cordell, H. J., Crocco, P., van den Akker, E. B. & Böhringer, S. & 67 others, Helmer, Q., Nelson, C. P., Saunders, G. I., Alver, M., Anderson-Ranberg, K., Breen, M. E., van der Breggen, R., Caliebe, A., Capri, M., Cevenini, E., Collerton, J. C., Dato, S., Davies, K., Ford, I., Gampe, J., Garagnani, P., de Geus, E. J. C., Harrow, J., van Heemst, D., Heijmans, B. T., Heinsen, F.-A., Hottenga, J.-J., Hofman, A., Juene, B., Jonsson, P. V., Lathrop, M., Lechner, D., Martin-Ruiz, C., Mcnerlan, S. E., Mihailov, E., Montesanto, A., Mooijaart, S. P., Murphy, A., Nohr, E. A., Paternoster, L., Postmus, I., Rivadeneira, F., Ross, O. A., Salvioli, S., Sattar, N., Schreiber, S., Stefánsson, H., Stott, D. J., Tiemeier, H., Uitterlinden, A. G., Westendorp, R. G. J., Willemsen, G., Samani, N. J., Galan, P., Sørensen, T. I. A., Boomsma, D. I., Jukema, J. W., Rea, I. M., Passarino, G., de Craen, A. J. M., Christensen, K., Nebel, A., Stefánsson, K., Metspalu, A., Magnusson, P., Blanché, H., Christiansen, L., Kirkwood, T. B. L., van Duijn, C. M., Franceschi, C., Houwing-Duistermaat, J. J. & Slagboom, P. E., 15 Aug 2014, In: Human Molecular Genetics. 23, 6, p. 4420-4432 13 p.
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196 Citations (Scopus)

312 Downloads (Pure)
Health status and 6 years survival of 552 90+ Italian sib-ships recruited within the EU Project GEHA (GEnetics of Healthy Ageing)
Cevenini, E., Cotichini, R., Stazi, M. A., Toccaceli, V., Palmas, M. G., Capri, M., De Rango, F., Dato, S., Passarino, G., Jeune, B., Franceschi, C., GEHA Project Consortium & Rea, I. M., Apr 2014, In: Age (Dordrecht, Netherlands). 36, 2, p. 949-966 18 p.
Research output: Contribution to journal › Article › peer-review
35 Citations (Scopus)
Physical Activity and Cognitive Function in the Elderly: a Systematic Review
Carvalho, A., Rea, M., Parimon, T. & Cusack, B. J., 14 Mar 2014, In: Clinical Interventions in Ageing . 2014:9, p. 661 - 682
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Open Access
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202 Citations (Scopus)

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Cite this

Raule, N., Sevini, F., Li, S., Barbieri, A., Tallaro, F., Lomartire, L., Vianello, D., Montesanto, A., Moilanen, J. S., Bezrukov, V., Blanché, H., Hervonen, A., Christensen, K., Deiana, L., Gonos, E. S., Kirkwood, T. B. L., Kristensen, P., Leon, A., Pelicci, P. G., ... Franceschi, C. (2014). The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific. Aging cell, 13(3), 401-407. https://doi.org/10.1111/acel.12186

@article{77cc81c2313a47c3b00d82e36b40a81c,

title = "The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific",

abstract = "To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.",

keywords = "Ageing Long; Ageing Well; Nonagenarian siblings; , Oxidative Stress, mitochondrial haplogroups, human longevity ",

author = "Nicola Raule and Federica Sevini and Shengting Li and Annalaura Barbieri and Federica Tallaro and Laura Lomartire and Dario Vianello and Alberto Montesanto and Moilanen, {Jukka S} and Vladyslav Bezrukov and H{\'e}l{\`e}ne Blanch{\'e} and Antti Hervonen and Kaare Christensen and Luca Deiana and Gonos, {Efstathios S} and Kirkwood, {Tom B L} and Peter Kristensen and Alberta Leon and Pelicci, {Pier Giuseppe} and Michel Poulain and Rea, {Irene M} and Jos{\`e} Remacle and Robine, {Jean Marie} and Stefan Schreiber and Ewa Sikora and {Eline Slagboom}, Peternella and Liana Spazzafumo and {Antonietta Stazi}, Maria and Olivier Toussaint and Vaupel, {James W} and Giuseppina Rose and Kari Majamaa and Markus Perola and Johnson, {Thomas E} and Lars Bolund and Huanming Yang and Giuseppe Passarino and Claudio Franceschi",

note = "{\textcopyright} 2013 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",

year = "2014",

month = jun,

doi = "10.1111/acel.12186",

language = "English",

volume = "13",

pages = "401--407",

journal = "Aging cell",

issn = "1474-9718",

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Raule, N, Sevini, F, Li, S, Barbieri, A, Tallaro, F, Lomartire, L, Vianello, D, Montesanto, A, Moilanen, JS, Bezrukov, V, Blanché, H, Hervonen, A, Christensen, K, Deiana, L, Gonos, ES, Kirkwood, TBL, Kristensen, P, Leon, A, Pelicci, PG, Poulain, M, Rea, IM, Remacle, J, Robine, JM, Schreiber, S, Sikora, E, Eline Slagboom, P, Spazzafumo, L, Antonietta Stazi, M, Toussaint, O, Vaupel, JW, Rose, G, Majamaa, K, Perola, M, Johnson, TE, Bolund, L, Yang, H, Passarino, G & Franceschi, C 2014, 'The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific', Aging cell, vol. 13, no. 3, pp. 401-407. https://doi.org/10.1111/acel.12186

TY - JOUR

T1 - The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific

AU - Raule, Nicola

AU - Sevini, Federica

AU - Li, Shengting

AU - Barbieri, Annalaura

AU - Tallaro, Federica

AU - Lomartire, Laura

AU - Vianello, Dario

AU - Montesanto, Alberto

AU - Moilanen, Jukka S

AU - Bezrukov, Vladyslav

AU - Blanché, Hélène

AU - Hervonen, Antti

AU - Christensen, Kaare

AU - Deiana, Luca

AU - Gonos, Efstathios S

AU - Kirkwood, Tom B L

AU - Kristensen, Peter

AU - Leon, Alberta

AU - Pelicci, Pier Giuseppe

AU - Poulain, Michel

AU - Rea, Irene M

AU - Remacle, Josè

AU - Robine, Jean Marie

AU - Schreiber, Stefan

AU - Sikora, Ewa

AU - Eline Slagboom, Peternella

AU - Spazzafumo, Liana

AU - Antonietta Stazi, Maria

AU - Toussaint, Olivier

AU - Vaupel, James W

AU - Rose, Giuseppina

AU - Majamaa, Kari

AU - Perola, Markus

AU - Johnson, Thomas E

AU - Bolund, Lars

AU - Yang, Huanming

AU - Passarino, Giuseppe

AU - Franceschi, Claudio

PY - 2014/6

Y1 - 2014/6

N2 - To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

AB - To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

KW - Ageing Long; Ageing Well; Nonagenarian siblings;

KW - Oxidative Stress

KW - mitochondrial haplogroups

KW - human longevity

U2 - 10.1111/acel.12186

DO - 10.1111/acel.12186

M3 - Article

C2 - 24341918

SN - 1474-9718

VL - 13

SP - 401

EP - 407

JO - Aging cell

JF - Aging cell

IS - 3

ER -

The co-occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Fingerprint

Projects

R6229GRM: GEHA.

Activities

International Symposium: The Challenges of the Biological Research in Aging in the 21st Century: from the cells to the clinics.

British Society Research into Ageing

Research output

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

Health status and 6 years survival of 552 90+ Italian sib-ships recruited within the EU Project GEHA (GEnetics of Healthy Ageing)

Physical Activity and Cognitive Function in the Elderly: a Systematic Review

Cite this