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fl and mortality are not in uenced by mitochondrial DNA haplotypes in the old

a b a b b Joanna Collerton , Deepthi Ashok , Carmen Martin-Ruiz , Angela Pyle , Gavin Hudson , a a a a Mohammad Yadegarfar , Karen Davies , Carol Jagger , Thomas von Zglinicki , Thomas B.L. Kirkwood Patrick F. Chinnery b,*

aInstitute for Ageing and Health, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK bWellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 4LP, UK



Inherited genetic variation of mitochondrial DNA (mtDNA) could account for the missing heritability of human longevity and healthy aging. Here, we show no robust association between common genetic variants of mtDNA and frailty (an “unhealthy aging” phenotype) or mortality in 700, more than 85-year- old, participants of the Newcastle 85þ study. Conflicting data from different populations underscore our conclusion that there is currently no compelling link between inherited mtDNA variants and aging.

1. Introduction

In an attempt to resolve these issues, we carried out a compre- hensive study of mtDNA haplogroups in the Newcastle 85þ study. Ten mtDNA haplogroup markers effectively tag the most common subgroups of mtDNA found in 95% of the local population. The Newcastle 85þ study provides a unique opportunity to study the effects of these haplogroups both on survival up to and beyond age 85 and on frailty, an “unhealthy aging” phenotype, in a represen- tative population-based cohort of the very old.

Human longevity shows heritability of w25%, but large-scale, nuclear, genome-wide association studies have not yet clearly established all the responsible genes (Beekman et al., 2013;

nuclear, genome-wide association studies have not yet clearly established all the responsible genes (Beekman et al., 2013; Kirkwood et al., 2011). In addition to nuclear genes, there may also be contributions from the maternally inherited, extranuclear, mitochondrial genome (mitochondrial DNA [mtDNA]). mtDNA codes for 13 respiratory chain proteins that are essential for the production of adenosine triphosphate, which is required for all active intracellular processes. There is an emerging evidence that mitochondrial dysfunction plays a key role in cellular aging, and the accumulation of somatic mutations of mtDNA is associated with an aging phenotype in mice and humans (Schon et al., 2012). It is, therefore, of great interest that different polymorphic variants of mtDNA appear to be enriched in cohorts of healthy older individ- uals, raising the possibility that our mitochondrial genome may influence how we age and how long we live. However, although several studies support this hypothesis (Niemi et al., 2003, 2005; Yang et al., 2012), there are conflicting findings and a lack of consistency (Courtenay et al., 2012; De Benedictis et al., 1999; Feng et al., 2011; Finnila et al., 2000; Ivanova et al.,1998; Ross et al., 2001;

2. Experimental procedures

2.1. Study cohort

The Newcastle 85þ study has been reported and includes a sociodemographically representative 1921 birth cohort recr- uited at age w85 through general practice patient lists (n ¼ 845) (Collerton et al., 2009). An assessment of frailty was performed at baseline using 2 robust and validated measures: the Rockwood frailty index (RFI) (Rockwood and Mitnitski, 2007) and the Fried frailty status (FFS) (Fried et al., 2009), as described (Collerton et al., 2012). RFI was available for 811 (96.0%) of the cohort and FFS for 552 (65.3%). The cohort has been followed for mor- tality from baseline assessment (June 2006 to Sept 2007) until April 30, 2012.

* Corresponding author at: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 4LP, UK. Tel.: +44 191 241 8611; fax: +44 191 241 8666. E-mail address: patrick.chinnery@ncl.ac.uk (P.F. Chinnery).

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J. Collerton et al. / Neurobiology of Aging xxx (2013) 1e4

healthy older subjects (n ¼ 93, 35% male; mean age 69, standard deviation ¼ 8.5).

Table 1

Comparison of haplogroup frequencies across cohorts, percent

Mitochondrial Newcastle Local older 1958 MRC Local birth haplogroup 85þ study cohort age birth cohort, cohort age 85.5 y 68.9 y (SD 8.5), n ¼ 2889 neonates, (SD 0.4), n ¼ 93 n ¼ 344 n ¼ 700 H 46.0 (322) 36.6 (34) 44.2 (1278) 39.8 (137) V 3.6 (25) 3.2 (3) 3.0 (87) 3.5 (12) J 11.0 (77) 8.6 (8) 11.6 (336) 9.9 (34) T 10.3 (72) 3.2 (3) 10.0 (289) 13.1 (45) U 15.4 (108) 15.1 (14) 12.9 (374) 15.1 (52) K 7.3 (51) 7.5 (7) 9.3 (269) 7.8 (27) Other (W, X, I, M 6.4 (45) 25.8 (24) 8.9 (256) 10.8 (37) classified here)

Mitochondrial haplogroup data were available for 85.8% (696/ 811) of those with RFI available and 91.4% (477/552) of those with FFS available. These were the samples used in the principal anal- yses. Linear regression was used to determine the relationship between mtDNA haplogroups and RFI, and ordinal logistic regres- sion was used to determine the relationship between mtDNA haplogroups and FFS, both before and after controlling for sex, years of education, and smoking status. A count of chronic diseases was used as an additional control for the FFS. The relationship between mtDNA haplogroups and survival was determined by Cox propor- tional hazards analysis, both before and after controlling for sex, total cholesterol, body mass index, hypertension, diabetes, ethnicity, and smoking status. The median follow-up period was 58 months during which 336 deaths occurred.

Key: SD, standard deviation; MRC, Medical Research Council.