increase in the number of mtDNA copies and elevated ATP production.54

Human research has shown an association between rs1937 and neurodegenerative diseases characterized by distur- bance of mtDNA integrity and mitochondrial dysfunction, i.e., late-onset36–38 or sporadic Alzheimer disease,39 with the rare CC genotype conferring a protective effect38 and the GG being a risk genotype.36,39 Furthermore, the rare C allele has been recently associated with an ‘aerobic’ or ‘endurance- oriented phenotype’, with elite endurance athletes showing higher frequency of the C allele than non-athletic controls.47 Regarding this, a shift toward a more ‘aerobic phenotype’ could have a beneficial influence on health-related pheno- types and longevity, with classic studies in rats by Koch’s and Britton’s groups showing improved mitochondrial fit- ness may be a common factor linking physical fitness and decreased disease risk.55,56

Acknowledgment

This study was funded by the Fondo de Investigaciones Sanitarias (FIS, ref. PS09/00194 and PI12/00914).

Author Disclosure Statement

No competing financial interests exist

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References

The renewal of mitochondria through the process of bio- genesis is vital for maintaining mitochondrial integrity, and a diminished capacity for organelle biogenesis has been im- plicated in the pathogenesis of several diseases as well as in the aging process.57,58 A role for mitochondrial dysfunction in aging is evidenced by mtDNA mutator mice that express a proofreading-deficient mitochondrial DNA polymerase gamma.59 These mutant mice have increased mtDNA mu- tations and display age-related phenotypes, including severe sarcopenia that is likely due to defects in the assembly of functional electron chain transport complexes.60 Similar findings of increased mtDNA mutagenesis and reduced mitochondrial enzyme activities have been reported in hu- man skeletal muscle with age.61 However, our findings and those recently reported by our group with part of the present centenarians’ cohort do not support a major role of genetic variants in mtDNA62 or in the PPARD-PPARGC1A-NRF- TFAM mitochondriogenesis pathway on extreme longevity. Other genetic variants not studied here or other non-genetic factors that are known to influence mitochondriogenesis, such as exercise or calorie restriction,1,63 might be more in- fluential to extreme longevity.

cause all of the following criteria were met64: The phenotype ‘exceptional longevity’ was properly defined with all cases being centenarians (living 100+ years is still a rare phenotype, i.e., £1 every 10,000 people9), both groups of cases and con- trols were ethnically matched, genetic assessment was unbi- ased, all genotype distributions were in Hardy–Weinberg equilibrium in the control group, and we adjusted our statis- tical analyses for multiple comparisons. The relatively low sample size of the centenarians’ cohort is a limitation. Future research is needed with larger sample sizes, especially with more centenarian men, to corroborate the existence of an as- sociation between rs1937 and extreme longevity or whether this association is sex-dependent. The lack of data in a ‘rep- lication’ cohort of a different ethnic background also limits the ‘external validity’ (and therefore generalizability) of our re- sults. On the other hand, while keeping in mind the afore- mentioned limitations, we believe the major strength of our study stems in its novelty and in the rationale for studying genetic variants in the mitochondriogenesis pathway.