DNA inherited variants are with successful aging and longevity in humans

G. DE BENEDICTIS,*,1 G. ROSE,* G. CARRIERI,* M. DE LUCA,*,† E. FALCONE,* G. PASSARINO,* M. BONAFE´,‡ D. MONTI,‡ G. BAGGIO,§ S. BERTOLINI,¶ D. MARI, R. MATTACE,†† AND C. FRANCESCHI†,‡

*Department of Cell Biology, University of Calabria. Rende, Italy; †Italian National Research Center on Aging, Ancona, Italy; ‡Department of Biomedical Sciences, University of Modena, Italy; §Department of Geriatrics, University of Sassari, Italy; ¶Department of Internal Medicine, University of Genova, Italy; Institute of Internal Medicine, IRCCS Maggiore Hospital, University of Milano, Italy; and ††Department of Geriatrics, University of Catanzaro, Italy

interested in unraveling the complex changes asso- ciated with aging and age-related diseases (1). In- deed, available data clearly indicate that mutations and deletions accumulate with age in mitochondrial DNA (mtDNA)2 derived from several tissues, such as brain and muscle (2–5). The hypothesis supporting these investigations predicts that eventually these alterations impair oxidative phosphorylation (OX- PHOS) and energy production below a threshold level incompatible with normal cell functions (6). MtDNA somatic mutations in senescence have been investigated extensively, but a possible role of mtDNA inherited variability on successful aging has not been explored despite some observations sug- gesting that longevity descends chiefly along the maternal line (7), like the mitochondrial genome (8). We could speculate that long-lived individuals have inherited from their mothers mtDNA types that protect mitochondrial functions from damage caused by oxygen free radical production (9), thus giving them a small but continuous advantage that increases the probability of successful aging and longevity. This model is in agreement with the nonadditive variance observed in human longevity inheritance, which presupposes epistatic interaction among loci (10) that clearly recalls nuclear–mito- chondrial genome interactions (11).

ABSTRACT acterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated poly- morphisms whose combination defines groups of mtDNA types (haplogroups) that are currently used to reconstruct human evolution lineages. We used such inherited mtDNA markers to compare mtDNA population pools between a sample of individuals selected for successful aging and longevity (212 subjects older than 100 years and in good clinical condition) and a sample of 275 younger individuals (median age 38 years) carefully matched as to sex and geographic origin (northern and southern Italy). All nine haplogroups that are typical of Europeans were found in both samples, but male centenarians emerged in northern Italy as a particular sample: 1) mtDNA haplogroup frequency distribution was dif- ferent between centenarians and younger individuals P=0 (P 0.017 by permutation tests); and 2) the fre- quency of the J haplogroup was notably higher in P=0 centenarians than in younger individuals (P 0.0052 by Fisher exact test). Since haplogroups are defined on the basis of inherited variants, these data show that mtDNA inherited variability could play a role in successful aging and longevity.—De Benedictis, G., Rose, G., Carrieri, G., De Luca, M., Falcone, E., Passarino, G., Bonafe´, M., Monti, D., Baggio, G., Bertolini, S., Mari, D., Mattace, R., Franceschi, C. Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans. FASEB J. 13, 1532–1536 (1999)

Recently the hypothesis that mtDNA inherited variability plays a role in longevity has been investi- gated by sequencing the entire mtDNA in 11 cente- narians from Japan (12). Three associated mutations (Mt5178A, Mt8414T, Mt3010A) have been found at higher frequency in centenarians than in 43 con- trols. One of these mutations (Mt5178A) has also been screened by restriction analysis in an additional

  Key Words: MtDNA haplogroup mitochondria sex-specific mtDNA/longevity association

Successful aging and longevity are the result of the interaction between a variety of genes, environ- mental conditions, and lifestyles. Because of their critical importance for energy production, mito- chondria have attracted the attention of scientists

1 Correspondence: Department of Cell Biology, University of Calabria. Arcavacata 87030, Italy. E-mail g.debenedictis@ unical.it

2 Abbreviations: mtDNA, mitochondrial DNA; OXPHOS, oxidative phosphorylation;

TABLE 1. Identification of mtDNA haplogroups by restriction analysis of the specific target sequence

Polymorphic restriction sitesa 1715 4577 7025 8249 9052 10394 12308 13366 16065 16389 Haplogroup DdeI NlaIII AluI AvaII HaeII DdeI HinfIb BamHI HinfI BamHI H 0 0 I 0 1 1 1 1 J 1 1 0 K 1 0 1 1 T 1 0 1 U 1 0 1 V 0 1 0 W 1 1 0 X 0 1 0

a Sites are numbered from the first nucleotide of the restriction site according to ref. 17. Presence/absence of the site is indicated as b Restriction site created by mismatched primers (16).

individuals (74 females and 51 males) in northern Italy (Lombardia, Liguria, Veneto, Emilia) and by 150 individuals (76 females and 74 males) in southern Italy (Calabria, Cam- pania, Puglia, Sicilia). The groups of centenarians included only subjects over 100 years old on the day of the blood collection (109 years maximum age) and was made up of 109 subjects (83 females and 26 males) in northern Italy and 103 subjects (67 females and 36 males) in southern Italy. Both groups were composed of people from various social-eco- nomic extraction. All the subjects included in the study were free of clinically manifest pathologies. In particular, the centenarians were self-sufficient, had quite an active lifestyle, and, on the whole, were in a fairly good health status. All the subjects had been invited to participate in the study by an appropriate campaign and had given their informed consent.