In the present study, haplogroup F is significantly associated with exceptional longevity in women of an isolated Bama Chuang popula- tion in southern China, conferring approximately 2.0 times of the pro- tective effect (OR: 2.010, 95%:1.263–3.197, in Table 3). There are three potential explanations for this observation. First, previous stud- ies have suggested that haplogroup F may have a protective effect on several deleterious traits. For example, there were trends towards a lower prevalence of Leber's hereditary optic neuropathy (LHON) in patients with haplogroup F in southern Chinese and Thai populations (Ji et al., 2008; Tharaphan et al., 2006), and the association of hap- logroup F with low penetrance of idiopathic sensorineural hearing loss was shown in a Taiwanese population (Wu et al., 2007). There- fore, haplogroup F would be associated negatively with disorders and positively with longevity. Paradoxically, haplogroup F in a Japa- nese population was reported to be associated with the risk of type 2 diabetes mellitus which could increase mortality and is associated with decreased longevity. The discrepancy could be ascribable to the difference in the haplogroup frequencies between populations. Haplogroup F was widespread in Southeast Asian and at moderate frequencies in Northeast Asian (Li et al., 2007). Alternatively, to ex- plain the difference, we hypothesize certain interactions between mi- tochondrial haplogroups and nuclear polymorphisms and/or environmental factors.

Second, the association of the haplogroup F with longevity might be specific in the isolated Bama population. Bama is surrounded by steep mountains, resulting in poor transportation and communica- tion with outside territories throughout history. These external fac- tors resulted in social isolation. And it is quite likely that this

Note: Data in italics indicates pb0.05, OR=odds ratio, 95%CI=confidence interval. ⁎ C issubhaplogroup ofM8, ⁎ M7b′cand⁎ M7b1′2are subhaplogroups ofM7,⁎ D4and⁎ D4a are subhaplogroups of D, ⁎ F3 is subhaplogroup of F. “#Others” haplogroup categories include all other haplotypes except four haplogroups (M8, M7, D and F).

Table 3

Distribution of mtDNA haplogroups and variants between long-lived subjects and controls in female and male Chuang population.

Haplogroups Women p value OR 95%CI Men p value OR 95%CI Longevity Controls Longevity Controls % (n=269) % (n=264) % (n=98) % (n=107) M8 6.3 9.1 0.230 0.675 0.354–1.287 6.1 11.2 0.198 0.516 0.186–1.433 ⁎ C 5.2 4.9 0.883 1.060 0.488–2.300 5.1 3.7 0.634 1.384 0.361–5.310 M7 17.5 15.2 0.469 1.186 0.748–1.879 16.3 15.9 0.932 1.033 0.490–2.177 ⁎ M7b′c 17.5 14.0 0.273 1.299 0.813–2.076 16.3 15.9 0.932 1.033 0.490–2.177 ⁎ M7b1′2 16.4 12.5 0.205 1.369 0.841–2.228 15.3 15.0 0.944 1.028 0.478–2.208 D 8.2 10.6 0.337 0.751 0.418–1.349 10.2 7.5 0.491 1.406 0.531–3.721 ⁎ D4 7.4 7.6 0.951 0.980 0.514–1.867 10.2 6.5 0.342 1.623 0.593–4.446 ⁎ D4a 1.5 1.9 0.715 0.782 0.208–2.944 2.0 1.9 0.929 1.904 0.151–7.917 F 22.3 12.5 0.003 2.010 1.263–3.197 17.3 15.9 0.779 1.111 0.532–2.320 ⁎ F3 5.2 1.9 0.039 2.844 1.010–8.011 4.1 3.7 0.899 1.096 0.266–4.505 #Others 45.7 52.7 0.110 0.758 0.539–1.065 50.0 49.5 0.947 1.019 0.589–1.763 Variants 10400CNT 41.6 47.7 0.157 0.781 0.555–1.100 46.9 47.7 0.917 0.971 0.561–1.682 15487ANT 6.3 9.1 0.230 0.675 0.354–1.287 6.1 11.2 0.198 0.516 0.186–1.433 13263ANG 5.2 4.9 0.883 1.060 0.488–2.300 5.1 3.7 0.634 1.384 0.361–5.310 6455CNT 17.5 15.2 0.469 1.186 0.748–1.879 16.3 15.9 0.932 1.033 0.490–2.177 4071CNT 17.5 15.2 0.469 1.186 0.748–1.880 16.3 15.9 0.932 1.033 0.490–2.177 4048GNA 17.5 14.4 0.332 1.259 0.790–2.006 16.3 16.8 0.924 0.965 0.462–2.017 12811TNC 16.4 12.1 0.162 1.418 0.868–2.316 15.3 15.0 0.944 1.028 0.478–2.208 5178CNA 8.2 11.0 0.271 0.722 0.403–1.292 10.2 7.5 0.491 1.406 0.531–3.721 3010GNA 7.4 7.6 0.951 0.98 0.514–1.867 10.2 6.5 0.342 1.623 0.593–4.446 14979TNC 1.5 1.9 0.715 0.782 0.208–2.944 2.0 1.9 0.929 1.094 0.151–7.917 3970CNT 29.4 17.4 0.001 1.970 1.305–2.976 22.4 23.4 0.876 0.949 0.494–1.823 13928GNC 30.1 19.3 0.004 1.799 1.204–2.689 23.5 24.3 0.889 0.955 0.502–1.817 10310GNA 22.3 12.5 0.003 2.010 1.263–3.197 17.3 15.9 0.779 1.111 0.532–2.320 10320GNA 5.2 1.9 0.039 2.844 1.010–8.011 4.1 3.7 0.899 1.096 0.266–4.505 5585GNA 5.6 3.0 0.148 1.890 0.787–4.535 4.1 3.7 0.899 1.096 0.266–4.505

Note: Data in italics indicates pb0.05, OR=odds ratio, 95%CI=confidence interval. ⁎ C is subhaplogroup of M8, ⁎ M7b′c and ⁎ M7b1′2 are subhaplogroups of M7, ⁎ D4 and ⁎ D4a are subhaplogroups of D, ⁎ F3 is subhaplogroup of F. “#Others” haplogroup categories include all other haplotypes except four haplogroups (M8, M7, D and F).

Table 5). In a previous study, pathogenic mutations in ND5 gene that cause LHON are speculated to increase reactive oxygen species (ROS) production from complex I (Lenaz et al., 2006). With respect to successful aging, the amino acid Ser531Thr replacement in ND5 subunits could account for specific phenotypes related to less coupled reactions, leading to lower levels of oxidative damage. If this is the case, we speculate that the accumulation of mtDNA deletions and point mutations would be slower in subjects with haplogroup F than in subjects with other haplogroups, resulting in less oxidative damage to the mtDNA. Thus, the protective effect of haplogroup F

has had few opportunities for gene flow. In the isolated population, haplogroup F might be a protective factor for per- with successful aging. The present results need to be replicated additional populations.

Third, there were three mtSNPs (3970CNT, 13928GNC, and 10310GNA) in haplogroup F that were consistently associated with longevity in the women of the Bama Zhuang population. Among hap- logroup F-specific mtSNPs m.13928GNC, which causes an amino acid change Ser531Thr in the MT-ND5 protein, would potentially seem to be a functionally relevant polymorphism (see Supplementary

Table 4