Mitochondria are the power plants of the cell, a herd of bacteria-like organelles that produce the chemical energy store molecule ATP. They have their own DNA, a circular genome distinct from that of the cell nucleus, sometimes several copies per mitochondrion. The number of those mitochondrial DNA copies in a cell is a measure of mitochondrial health that declines with age, as mitochondria become dysfunctional throughout the body. The proximate causes of this dysfunction involve changes in mitochondrial structure and dynamics that inhibit the quality control process of mitophagy, responsible for recycling worn and damaged mitochondria. Connections to deeper causes are not well understood, but these issues must in some way result from the underlying damage of aging.
The DNA methylation (DNAm) based estimator of biological age, DNAm-Age, has become a well-known molecular measure of human aging. DNAm-Age has been associated with cancers, cardiovascular diseases, neurological diseases, and chronic inflammation diseases. Subsequently, another DNAm based marker, DNAm-PhenoAge, was developed to be an improved predictor of mortality and health span using phenotypic age estimated from a range of aging-related clinical measures. Most recently, another metric, DNAm-GrimAge, has been developed to predict all cause mortality and health span.
Unfortunately, the underlying biological and molecular processes that drive these epigenetic age biomarkers are still unknown. Despite the observation that the DNAm-Age is associated with metabolic processes, the relationship between mitochondrial health and DNAm-Age remains understudied. Mitochondria are vital for metabolic processes as they are responsible for ATP production and are known to be involved in the aging process, become larger and less numerous with age. In addition, mitochondrial function may be related to DNAm aging. Activity of DNA methyltransferases (DNMT), as with any cellular enzyme, depend on ATP levels and impaired energy production as a result of mitochondrial dysfunction may influence normal function of DNMTs.
Mitochondrial DNA copy number (mtDNAcn), a measure of mitochondrial genome abundance, is commonly used as a reflection of the mitochondria's response to oxidative stress as well as general dysfunction. Mitochondria DNA (mtDNA) is sensitive to oxidative stress because it lacks a robust DNA repair system to restore oxidative stress induced damage and mtDNA damage persists longer compared to genomic DNA. Typically, mtDNA will increase when the endogenous antioxidant response is no longer able to recover its redox balance, possibly as a compensatory response. Previous studies have shown that mtDNAcn decreases with age and is positively associated with telomere length.
Recently, our group has shown that mtDNAcn is negatively correlated with DNAm-Age and hypothesized mtDNAcn may be a proxy of mitochondrial buffer capacity. Reduced mtDNAcn may be a consequence of exhausted mitochondrial buffering capacity, leading to adverse outcomes such as aging. In a population of 812 aging male veterans, we found contrasting results between cross-sectional and prospective analyses of mtDNAcn with aging biomarkers DNAm-Age, DNAm-PhenoAge, DNAm-GrimAge and leukocyte telomere length. We observed that mtDNAcn is negatively associated with cross-sectional measures of DNAm-Age and DNAm-PhenoAge. We found suggestive evidence that mtDNAcn is positively associated with prospective measures of DNAm-PhenoAge and negatively associated with prospective measures of leukocyte telomere length. These results suggest that while the negative cross-sectional associations reflect the opposing time-trends of mtDNAcn and aging biomarkers, it may be driven by unmeasured confounders such as underlying biological processes that drives both the decrease of mtDNAcn over time and the increase of DNAm-Age and DNAm-PhenoAge over time.