Healthy Aging More Doubtful if Nuclear and Mitochondrial Genomes Clash

The two mice shown here are the same age (2 years old), and both were reared under the same conditions. Nonetheless, the mouse on the right has aged normally and shows evident signs of superior health. The only genetic difference between the mice is that they have each inherited a different healthy (nonpathogenic) mitochondrial DNA (mtDNA) variant from their mothers. Distinct mtDNA variants do not have to be pathogenic to have substantially different effects on the quality of aging. [CNIC]

Mitochondrial DNA (mtDNA) doesn’t have to be pathogenic or intrinsically flawed to impair health. It just has to be a poor match with nuclear DNA. According to scientists based at Centro Nacional de Investigaciones Cardiovasculares (CNIC), the quality of the interactions between the two genomes, the nuclear and the mitochondrial, affects the quality of aging, more specifically, the propensity toward developing aging-related conditions such as diabetes, cardiovascular disease, and cancer.

Mitochondrial fitness has been under heightened scrutiny of late, given the rise of mitochondrial donation technology and the production of “three-parent” babies. Mitochondrial donation procedures are designed to prevent the transmission of disease-causing mtDNA. Such procedures might also account for the health impacts of nonpathogenic mtDNA variants.

Studies of nonpathogenic mtDNA variants have been conducted in “conplastic” animals, that is, strains in which the nuclear genome from one strain has been crossed onto the cytoplasm of another. These studies have given equivocal results, partly because they have tended to focus on younger animals. Also, they have not investigated the full scope of physiological and phenotypic variability likely to be influenced by mitochondria.

To improve on these studies, the CNIC scientists systematically characterized conplastic mice throughout their lifespans using transcriptomic, proteomic, metabolomic, biochemical, physiological, and phenotyping studies. The results of this work were presented July 6 in the journal Nature, in an article entitled, “Mitochondrial and Nuclear DNA Matching Shapes Metabolism and Healthy Ageing.”

The article shows that nonpathogenic mtDNA variants have different impacts on organismal metabolism and aging. According to the article’s senior author, the CNIC’s José Antonio Enríquez, Ph.D., nonpathogenic differences in mitochondrial function have direct repercussions on the pace of aging. “Variation in just a few genes,” he asserted, “can determine whether we experience healthy aging.”

“We show,” wrote the authors of the Nature article, “that mtDNA haplotype profoundly influences mitochondrial proteostasis and reactive oxygen species generation, insulin signalling, obesity, and ageing parameters including telomere shortening and mitochondrial dysfunction, resulting in profound differences in health longevity between conplastic strains.”

“The key to this study was understanding how the combination and interaction of our two genomes, the nuclear and the mitochondrial, triggers a cellular adaptation with repercussions throughout our lives,” explained the study’s first author, the CNIC’s Ana Latorre-Pellicer, Ph.D.

The CNIC team obtained robust evidence that the simple measure of changing an animal's mtDNA triggers a series of adaptive cellular mechanisms in young animals that ensure a more healthy aging process. “If we can understand the biology underlying healthy aging that is free of age-associated diseases, we will be in a position to maintain long-lasting health during the aging process,” affirmed Dr. Latorre-Pellicer.