An Illustrative Consideration of Mitochondrial Haplogroup Differences in Human Longevity

In the open access paper quoted here, researchers suggest that variations in the MOTS-c peptide encoded in mitochondrial DNA may have some effect on life expectancy in at least some human populations. The present landscape of statistical data for human gene variants and longevity points to a complex array of many, many individually tiny contributions to longevity, these contributions interacting with one another so that the patterns and relationships are very different in different populations. The correlations found in one study of genetics and longevity are very rarely replicated in others. Only a few gene variants are reliably associated with longevity in multiple human study populations, and their effects are dwarfed by the contribution of exercise and calorie intake to long-term health.

To a first approximation we all age in the same way, for the same underlying reasons, which is to say the accumulation of unrepaired damage produced as a side-effect of the normal operation of cellular metabolism. Effective treatments for aging will be mass-produced, repairing exactly the same forms of damage in every patient in exactly the same way. That is the path to real results in healthy life extension, not trying to find genetic alterations that might slightly, trivially slow down the damage, or slightly, trivially change the response to damage, and thus slightly, trivially alter the odds of living in suffering and pain for an extra year or two. Deciphering the enormously complex relationship between genes and aging is a worthy goal for the scientific community, but it isn't the path to useful therapies for degenerative aging.

If you were looking for genetic variants associated with longevity, however, then there are far worse places to start than mitochondrial DNA. Unlike nuclear DNA, there are only a handful of different mitochondrial genomes, haplogroups defined by accumulated mutations that spread throughout populations in the generations since the recent common ancestor, Mitochondrial Eve. Each haplogroup is carried by an enormous human population, and many existing sets of epidemiological data include haplogroup identification. This makes obtaining data and running statistical analyses a much easier prospect than is the case for the alternatives, and is one of the reasons why there are numerous studies on whether or not some mitochondrial haplogroups are modestly better than others, linked to small statistical advantages in health or longevity.

The research linked below is a good example of this sort of thing, and gives some insight into the types of investigation underway at the border between relentless genetic information gathering on the one hand and the struggle to understand the details of the progression of degenerative aging on the other. It is a rich mix of data analysis, modeling, inference, collaboration, and genetics:

The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity?

The number of people aged ≥60 years is expected to almost triple by 2050, with the 'oldest old' group (older than 85 years) being the most rapidly expanding segment in Western societies. Among long-lived individuals, those who reach exceptional longevity (EL, i.e., centenarians (≥100 years) and supercentenarians (SCs, ≥110 years)) are arguably the paradigm of successful aging. Several genetic factors might contribute to EL, as suggested by the differences found in the frequency distribution of several genetic variants among centenarians compared with their ethnic-matched referents of younger ages. Factors related to inflammation, metabolism or nutrition, among others, can also influence the likelihood of reaching EL. Japan has clearly the longest life expectancy in the world, as well as the highest number of SCs, as we recently reviewed. Thus, Japanese long-lived people represent an interesting model to study the biology of EL, and to gain insight into the nature vs. nurture debate.

Mitochondrial DNA (mtDNA) can influence EL. Human mtDNA contains 13 genes that codify proteins involved in mitochondrial oxidative phosphorylation (OXPHOS), as well as 2 rRNA and 22 tRNA genes that are necessary for protein synthesis within mitochondria. Mitochondria are one of the most important players to understand the aging process at the cellular level as they are both the main source and target of oxidative damage. Mitochondrial dysfunction is in fact a main hallmark of aging, which is partly caused by accumulation of mtDNA damage as we age. Thus, because mtDNA haplotypes or haplogroups (i.e., characteristic clusters of tightly linked mtDNA polymorphisms that form continent-specific genotypes) might influence individual susceptibility to mtDNA damage, they could also influence EL in a continent- or ethnic-specific manner.

For instance, the association between mtDNA and EL is controversial in Spanish people, with researchers reporting no association between mtDNA haplogroups and EL but others find that the Caucasian haplogroup J (which would be associated with lower mtDNA damage) might confer a higher chance to attain high longevity (85+ years) compared with other haplogroups in Northern Spaniards. On the other hand, although mtDNA haplogroups D4b2b, D4a, and D5 are not associated with type 2 diabetes, they are linked with EL in Japanese population. We also showed that the mtDNA m.1382A>C polymorphism, which is specific for the ancestor haplogroup D4b2, is associated with EL in the Japanese population.

Mitochondrial-derived peptides (MDP) are encoded by functional short open reading frames in the mtDNA. These include humanin, a 24-amino acid peptide encoded in the 16S rRNA region with strong cytoprotective actions and the recently discovered mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), which is a 16-amino acid peptide that regulates insulin sensitivity and metabolic homeostasis. We have recently suggested that MOTS-c might also be involved in the aging process.

The aforementioned m.1382A>C polymorphism is located in the MOTS-c encoding mtDNA, a short open reading frame in the 12S rRNA region. The m.1382A>C variation causes a Lys14Gln replacement in the MOTS-c peptide equivalent to nucleotide position 1382 of the mtDNA; this is likely to have functional consequences, as the physicochemical difference between the original and the altered amino acid residues is relatively high, with a Grantham value of 53, that is, above the average value (=50) that differentiates radical from conservative single amino acid replacements. This amino acid replacement is also predicted to have a functional effect with the PROVEAN (PROtein Variation Effect ANalyzer) tool, that is, yielding a score of −4.000, below the specifically predicted cutoff score (=−2.5) above which the variant would be 'neutral'. The m.1382A>C polymorphism is specific for the Northeast Asian population and may be among the putative biological mechanisms explaining the high longevity of Japanese people. Further, MOTS-c is an important 'mitokine', with this term referring to mitochondrial-derived signals that impact other cells in an endocrine-like manner.

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