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.

Fig. 1

mtDNA content associates with age in controls and offspring of nonagenarians. For each participant in the control and offspring group, mtDNA/nDNA ratios are shown at the age of DNA collection. Controls are shown as black squares and the linear regression as a solid black line. Offspring of the nonagenarians are shown as a cross and the linear regression as a dashed line

Fig. 2

mtDNA content in the nonagenarian siblings, their offspring, and controls. MtDNA content is given as the mtDNA/nDNA ratio in arbitrary units corrected for age, gender, DNA isolation location, and family relatedness. Error bars represent the SEM

Fig. 3

Difference in mtDNA content across different age categories in male and female controls and offspring of nonagenarians. Data represent mean mtDNA content given as the mtDNA/nDNA ratio±SEM across age tertiles in men and women separately. The number in each column represents the number of subjects in each group. The age tertiles were defined as follows: for men, first age ≤57.05, second age >57.05 and ≤62.97, and third age tertile >62.97; for women, first age ≤55.88, second age >55.88 and ≤61.53, and third age tertile >61.53. Open bars reflect mtDNA content in controls and gray bars represent the offspring