Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans

Abstract

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: 1) mtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests); and 2) 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.—De Benedictis, G., Rose, G., Carrieri, G., De Luca, M., Falcone, E., Passarino, G., Bonafé, 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)

The mitochondrial pharmacogenomics of haplogroup T: MTND2*LHON4917G and antiretroviral therapy-associated peripheral neuropathy

“…This should not be surprising given the vital importance of mitochondria in free radical generation, apoptosis and cellular energy production. [38][39][40] Although this study suggests a relationship between 4917G and NRTI-associated PN based on epidemiological evidence, the underlying biologic mechanisms remain to be elucidated. Functional alterations in protein subunits of the electron transport chain may result in greater electron leakage and increased formation of reactive oxygen species.…”

“…The result may be destruction of critically important biological macromolecules and possibly damage to both mitochondrial and nuclear DNA culminating in mitochondrial dysfunction with, in this case, compromised neuronal function. [38][39][40] Certain mitochondrial polymorphisms, such as those at position 4917, are associated with late-onset neurodegenerative diseases and their relatively high frequency suggests that they do not severely affect reproductive fitness. [24][25][26][27][28] For this reason, there may have been relatively little selective pressure against these potentially deleterious polymorphisms.…”

Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis

“…Some controversial associations of haplogroup J with other diseases, such as an increased penetrance of the milder complex I gene mutations associated with Leber's hereditary optic neuropathy (LHON) (22,42), an increased susceptibility to multiple sclerosis (43), and an association of cluster TJ with type 2 diabetes mellitus (28), have been described. Interestingly, haplogroup J has also been associated with a decreased risk of Parkinson's disease (26) and with increased longevity in several European studies (31,32,33). Haplogroup J mtDNA harbors several missense mutations (Table 5) in both complex I and cytochrome b genes that could alter the oxidative phosphorylation production of ATP (44,45).…”

“…Among Europeans, 95% of the population belongs to 1 of 9 haplogroups: H, I, J, K, T, U, V, W, or X. Given the lines of evidence that describe the contribution of mtDNA to cellular physiology, as well as its critical importance for energy production, a number of studies have investigated the association between mtDNA haplogroups and multifactorial diseases (22)(23)(24)(25)(26)(27)(28), mitochondrial diseases (29,30), and aging (31)(32)(33).…”

The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

“…De Benedictis et al, 1999;Niemi et al, 2003;Tanaka et al, 2000) and degenerative disease (Wallace, 2005). Hence, certain mtDNA lineages from Europe and Asia are protective against the ravages of aging but are population specific.…”