Association of Mitochondrial DNA Haplogroups with Exceptional Longevity in a Chinese Population

Cai, Xiao-feng Wang, Shi-lin Li, Ji Qian, De-gui Qian, Fei Chen, Ya-jun Yang, Zi-yu Jun Xu, Yidong Bai, Shun-zhang Yu, and Li Jin*

State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai, China; Longevity Research Institute of Rugao, Jiangsu, China; Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; School of Public Health, Fudan University, Shanghai, China

Abstract:

To explore the effects of mtDNA haplogroups on the prevalence of extreme longevity (EL), a population-based case-control study was conducted in Rugao - a prefecture city in Jiangsu, China. Case subjects include 463 individuals aged 95 years or older (EL group). Control subjects include 926 individuals aged 60-69 years (elderly group) and 463 individuals aged 40-49 years (middle-aged group) randomly recruited from Rugao. We observed a significant reduction of M9 haplogroups in longevity subjects (0.2%) when compared with both elderly subjects (2.2%) and middle-aged subjects (1.7%). Linear-by-linear association test revealed a significant decreasing trend of N9 frequency from middle-aged subjects (8.6%), elderly subjects (7.2%), and longevity subjects (4.8%) (p=0.018). In subsequent analysis stratified by gender, linear-by-linear association test revealed a significant increasing trend of D4 frequency from middle-aged subjects (15.8%), elderly subjects (16.4%), and longevity subjects (21.7%) in females (p=0.025). Conversely, a significant decreasing trend of B4a frequency was observed from middle-aged subjects (4.2%), elderly subjects (3.8%), and longevity subjects.

Conclusions:

Our observations support the association of mitochondrial DNA haplogroups with exceptional longevity in a Chinese population. These authors contributed equally to this work.

Introduction:

Mutations [10] have been linked to age-associated accumulations of mtDNA mutations [2,3]. In particular, haplogroup D4a, D5, and D4b2b were observed to be enriched in centenarians in Japan [11,12]. Haplogroup J was detected as overrepresented in male long-living subjects and centenarians in northern Italy [13], an observation that was replicated in Irish and Finnish populations [14,15], although contradicted in southern Italy [16]. These data suggest that the association between mtDNA variants and longevity could be highly geographically or population dependent, as seen from other genetic studies on longevity [17].

Individuals vary widely in their health status over their life course and in age at death. Longevity is thought to be a complex puzzle of interplay of environmental, behavioral, genetic, and stochastic factors. There is increasing evidence that exceptional longevity is a familial trait that is at least partially genetic. However, the magnitude of the genetic contribution is still controversial [13], and the inherited biological factors that promote longevity in humans remain undetermined.

Mitochondrial DNA (mtDNA) is a maternally inherited genome [4]. Human populations carry several mtDNA haplogroups defined by unique sets of mtDNA polymorphisms, reflecting mutations accumulated by a discrete maternal lineage [5,6]. Thus, haplogroup association studies have been used to assess the effect of mtDNA variants on various complex diseases such as diabetes, cancer, and Alzheimer's disease [7-9]. Decades of evolution of the mitochondrial theory of aging have not yet clarified the possible contribution of mtDNA haplogroup-specific mutations to the prevalence of longevity. Therefore, we performed a population-based case-control study in a Chinese Han population residing in Rugao, Jiangsu Province. It is worth noting that Rugao has long been claimed as a longevity town in China since ancient times.

Materials and Methods:

We selected 33 mtSNPs to define 28 major mitochondrial haplogroups (D*, D4, D4a, D4b, D4b2, D4b2b, D5, M12,G*, G2, M7*, M7b, M8*, M8a, C, M9, M10, N9, N9a, A, F*, F1, B*, B5, B5a, B5b, B4a and B4b) found in the Chinese population as shown in Table 1 [20]. These SNPs allow allocating common mitochondrial East Asian haplotypes and following the suggestion of association of Histories and cognitive function appraisals were conducted, along with physical examinations. Fasting blood specimens were drawn for laboratory examination, including lipid, glucose, and liver function. To ensure quality control, all field staff involved in data collection and handling were trained. All interviews were recorded, and 5 percent of these interviews were evaluated for quality. Approximately 35 percent of subjects were re-contacted by phone to evaluate the interviewers' work. Written informed consent was obtained from each participant or a member of their immediate family. The Human Ethics Committee of Fudan University School of Life Sciences approved the research.

Experimental procedures: Genomic DNA was extracted using a method described by Boom et al., with minor modifications [19]. In order to examine the correlations between haplogroups and longevity, we observed a decreasing trend of N9 haplogroups from middle-aged subjects (8.6%), elderly (7.1%), and EL subjects (5.3%) in female samples; however, the statistical significance originally observed in all subjects diminished, which may be due to a lack of statistical power (Table 3).