DNA inherited variants are associated with successful aging and longevity in humans. The study aims to unravel the complex changes associated with aging and age-related diseases. Available data indicate that mutations and deletions accumulate with age in mitochondrial DNA (mtDNA) derived from several tissues, such as the brain and muscle. 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. 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 suggesting that longevity descends chiefly along the maternal line, like the mitochondrial genome. 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, thus giving them a small but continuous advantage that increases the probability of successful aging and longevity. This model is in agreement with the non-additive variance observed in human longevity inheritance, which presupposes epistatic interaction among loci that clearly recalls nuclear-mitochondrial genome interactions.

Successful aging and longevity are the result of the interaction between a variety of genes, environmental conditions, and lifestyles. Because of their critical importance for energy production, mitochondria have attracted the attention of scientists interested in unraveling the complex changes associated with aging and age-related diseases. Mitochondrial DNA (mtDNA) is characterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated polymorphisms 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. MtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests), and the frequency of the J haplogroup was notably higher in 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.

Recently the hypothesis that mtDNA inherited variability plays a role in longevity has been investigated by sequencing the entire mtDNA in 11 centenarians from Japan. Three associated mutations (Mt5178A, Mt8414T, Mt3010A) have been found at higher frequency in centenarians than in 43 controls. One of these mutations (Mt5178A) has also been screened by restriction analysis in an additional 37 centenarians and in 252 controls. However, longevity is strongly affected by environmental factors as well as by the entire genetic background. Different populations are therefore expected to have different gene/longevity associations. On the other hand, sequence analysis of the whole mtDNA is very expensive and time-consuming, and it is unfeasible for large size samples from various populations to be analyzed by this approach.

The novelty of our approach is the use of stable, ancestral, and associated polymorphisms, which are currently used in studies of human evolution, as markers of mtDNA inherited variability. Restriction fragment-length polymorphism studies of mtDNA from a wide range of human populations have revealed sets of ancestral mutations that define groups of mtDNA types (haplogroups) that have common ancestry and, because of uniparental inheritance, evolve independently from each other. Each of these haplogroups, which includes evolutionarily related types of mtDNAs, is defined by specific sets of associated mutations, thus allowing for quick and precise classification of the mtDNA molecules within a certain population. Nine mtDNA haplogroups (H, I, J, K, T, U, V, W, and X) have been identified that are characteristic of Europeans and encompass virtually all mtDNAs in Europe. We used these haplogroups as mtDNA stable markers to explore the role of mtDNA inherited variability on successful aging and longevity in Europeans.

MtDNA analysis was carried out by restriction analyses of mtDNA according to reference (16). For each individual, mtDNA fragments encompassing thenumbers, the observed difference in haplogroup distribution cannot be attributed to chance. The same trend was observed in females, although it did not reach statistical significance.

In southern Italy, no significant differences were found between centenarians and controls in terms of haplogroup distribution. This may indicate that the association between specific mtDNA haplogroups and longevity is not consistent across different geographic regions.

Overall, our results suggest that certain mtDNA haplogroups may be associated with successful aging and longevity. However, further studies are needed to confirm these findings and to investigate the underlying biological mechanisms.