title: Low mitochondrial DNA content associates with familial longevity: the Leiden Longevity Study.
abstract: Long-lived individuals delay aging and age-related diseases like diabetes, hypertension, and cardiovascular disease. The exact underlying mechanisms are largely unknown, but enhanced mitochondrial biogenesis and preservation of mitochondrial function have been suggested to explain healthy ageing. We investigated whether individuals belonging to long-lived families have altered mitochondrial DNA (mtDNA) content, as a biomarker of mitochondrial biogenesis and measured expression of genes regulating mitochondrial biogenesis. mtDNA and nuclear DNA (nDNA) levels were measured in blood samples from 2,734 participants from the Leiden Longevity Study: 704 nonagenarian siblings, 1,388 of their middle-aged offspring and 642 controls. We confirmed a negative correlation of mtDNA content in blood with age and a higher content in females. The middle-aged offspring had, on average, lower levels of mtDNA than controls and the nonagenarian siblings had an even lower mtDNA content (mtDNA/nDNA ratio = 0.744 ± 0.065, 0.767 ± 0.058 and 0.698 ± 0.074, respectively; p controls-offspring = 3.4 × 10(-12), p controls-nonagenarians = 6.5 × 10(-6)), which was independent of the confounding effects of age and gender. Subsequently, we examined in a subset of the study the expression in blood of two genes regulating mitochondrial biogenesis, YY1 and PGC-1α. We found a positive association of YY1 expression and mtDNA content in controls. The observed absence of such an association in the offspring suggests an altered regulation of mitochondrial biogenesis in the members of long-lived families. In conclusion, in this study, we show that mtDNA content decreases with age and that low mtDNA content is associated with familial longevity. Our data suggest that preservation of mitochondrial function rather than enhancing mitochondrial biogenesis is a characteristic of long-lived families.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Albinusdreef 2, 2333ZA, Leiden, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: van Leeuwen
authors.forename: M
authors.initials: M
authors.lastname: Beekman
authors.forename: J
authors.initials: J
authors.lastname: Deelen
authors.forename: E B
authors.initials: EB
authors.lastname: van den Akker
authors.forename: A J M
authors.initials: AJ
authors.lastname: de Craen
authors.forename: P E
authors.initials: PE
authors.lastname: Slagboom
authors.forename: L M
authors.initials: LM
authors.lastname: 't Hart
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D035781:Siblings; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D050986:YY1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004272:DNA, Mitochondrial; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D050986:YY1 Transcription Factor; C494698:YY1 protein, human