Table 3

FFS and mitochondrial haplogroupdodds ratio (95% confidence interval) of being in a frailer Fried category (pre-frail versus robust or frail versus pre-frail) by mitochondrial haplogroupa

Haplogroup Model 1, odds ratio Model 1, Model 2, odds ratio Model 2, Model 3, odds ratio Model 3, (95% confidence interval) p value (95% confidence interval) p value (95% confidence interval) p value H 1.05 (0.73e1.50) 0.790 1.10 (0.77e1.57) 0.608 1.04 (0.71e1.53) 0.832 Non-H Reference Reference Reference T 1.10 (0.61e1.96) 0.752 0.93 (0.52e1.68) 0.815 0.80 (0.43e1.51) 0.498 Non-T Reference Reference Reference J 0.72 (0.41e1.27) 0.262 0.74 (0.42e1.31) 0.305 0.99 (0.54e1.81) 0.968 Non-J Reference Reference Reference U 0.95 (0.59e1.52) 0.816 0.95 (0.59e1.52) 0.820 0.85 (0.51e1.41) 0.526 Non-U Reference Reference Reference K 0.66 (0.33e1.32) 0.248 0.70 (0.35e1.37) 0.293 0.79 (0.38e1.64) 0.532 Non-K Reference Reference Reference X 4.45 (0.91e21.71) 0.065 4.32 (0.87e21.52) 0.074 3.64 (0.68e19.61) 0.132 Non-X Reference Reference Reference W 2.58 (0.88e7.57) 0.084 2.30 (0.78e6.81) 0.131 2.90 (0.89e9.49) 0.078 Non-W Reference Reference Reference I 0.95 (0.10e9.10) 0.967 0.89 (0.09e8.53) 0.918 1.14 (0.11e11.78) 0.913 Non-I Reference Reference Reference V 1.20 (0.43e3.32) 0.729 1.29 (0.46e3.58) 0.630 1.20 (0.38e3.71) 0.757 Non-V Reference Reference Reference

a Ordinal logistic regression models were fitted with Fried status as the dependent variable and mitochondrial haplogroup as the independent variable. Seven binary variableswerecreatedof“inhaplogroupH”versus“notinhaplogroupH”type,and7modelswererunenteringeachbinaryvariableseparately.Model1isunadjusted,model2 adjusted for sex only, and model 3 adjusted for sex, years of education, smoking status, and count of chronic diseases.

relatively small size of these study groups led to false-positive associations because mtDNA haplogroup studies are particularly sensitive to population stratification. In keeping with this, none of the previously reported positive findings have been replicated directly, and it is not clear why a particular haplogroup would be associated with longevity in one context and not the other. Like- wise, we were unable to replicate previous findings of a gender- specific association with aging. If present, such an association would be difficult to explain mechanistically.

informative biomarker of aging (Martin-Ruiz et al., 2011), and the overall distribution of mtDNA haplogroups closely resembled ethnically matched cohorts from 3 different younger age groups. Our findings do not support a role for mtDNA in promoting healthy aging or longevity. The absence of an age-associated stratification of mtDNA haplogroups is in agreement with previous findings in large European cohorts (Benn et al., 2008; Dato et al., 2004). On the other hand, our findings contrast with the results of several smaller European (De Benedictis et al., 1999; Dominguez-Garrido et al., 2009; Ivanova et al., 1998; Niemi et al., 2003; Ross et al., 2001) and Far-Eastern studies (Feng et al., 2011; Zhang et al., 2003). Although it is conceivable that these geographic differences reflect different environmental constraints, or ethnic differences in the nuclear genetic background, it is perhaps more likely that the

Although we cannot exclude the possibility that a larger study cohort would reveal an association between mtDNA and longevity and/or healthy aging phenotypes, our findings of a lack of an association with 2 sensitive and reliable measures of frailty and no direct evidence of an effect on survival suggest that any contribu- tion from mtDNA would be modest at best. Our results, therefore, turn the spotlight away from mtDNA back to the nuclear genome, in the search for genes predisposing to longevity and healthy aging.

it is conceivable that these geographic differences reflect environmental constraints, or ethnic differences in the genetic background, it is perhaps more likely that the

Table 4

Hazard ratios for mortality by mitochondrial haplogroupa

Haplogroup Model 1, hazard Model 1, Model 2, hazard Model 2, ratio (95% p value ratio (95% p value confidence interval) confidence interval) H 1.10 (0.89e1.36) 0.380 1.04 (0.82e1.31) 0.748 Non-H Reference Reference T 1.00 (0.70e1.43) 0.988 1.04 (0.72e1.50) 0.852 Non-T Reference Reference J 0.92 (0.65e1.30) 0.625 0.95 (0.66e1.36) 0.762 Non-J Reference Reference U 0.97 (0.72e1.31) 0.841 1.13 (0.83e1.55) 0.425 Non-U Reference Reference K 0.61 (0.38e0.98) 0.041 0.52 (0.30e0.91) 0.023 Non-K Reference Reference X 2.05 (1.09e3.86) 0.025 1.91 (0.96e3.83) 0.066 Non-X Reference Reference W 0.85 (0.42e1.72) 0.652 0.90 (0.42e1.92) 0.790 Non-W Reference Reference I 0.99 (0.41e2.38) 0.973 0.71 (0.26e1.93) 0.506 Non-I Reference Reference V 1.28 (0.75e2.19) 0.360 1.22 (0.68e2.19) 0.497 Non-V Reference Reference

Disclosure statement

The authors report no conflicts of interest.

The data contained in the manuscript being submitted have not been previously published, have not been submitted elsewhere, and will not be submitted elsewhere while under consideration at Neurobiology of Aging. All authors have reviewed the contents of the manuscript being submitted, approved of its contents, and vali- dated the accuracy of the data.

Ethical approval for the study is in place.

Acknowledgements

This work was supported by the Medical Research Council and the Biotechnology and Biological Sciences Research Council (G0500997 and G0601333) and The Wellcome Trust (084980/Z/08/ Z, 096919Z/11/Z). P.F.C. is an Honorary Consultant Neurologist at Newcastle upon Tyne Foundation Hospitals National Health Service (NHS) Trust, a Wellcome Trust Senior Fellow in Clinical Science, and a UK National Institute for Health Research (NIHR) Senior Investigator. This work was also supported by NIHR