Clonal Mosaicism of Mitochondrial DNA Heteroplasmy as a Molecular Clock of Aging

Abstract

The accumulation of somatic mitochondrial DNA (mtDNA) mutations across life is among the oldest and most debated proposed drivers of aging. A defining, counter‐intuitive feature is that individual mutant molecules, although vanishingly rare when they arise, can come to dominate a cell's multi‐copy mtDNA population through intracellular clonal expansion, producing a mosaic of respiratory‐deficient cells across aging tissues. Here we synthesize current evidence to argue that clonal mosaicism of mtDNA heteroplasmy constitutes a quantifiable, tissue‐specific molecular clock of aging. We trace foundational single‐cell and multi‐tissue observations of somatic mtDNA mutation, examine the causal evidence from mtDNA mutator mice, and dissect the debate between neutral genetic drift and cellular selection that governs clonal expansion. We then integrate recent single‐cell and population‐scale studies that have transformed the field: deep multi‐tissue surveys revealing tissue‐specific accumulation and a biphasic signature, biobank analyses linking heteroplasmy burden to mortality and organ‐specific disease, and a two‐step mechanism in which cryptic replication‐error mutations become detectable through age‐related clonal mosaicism. We discuss technologies such as single‐cell mtDNA genotyping, duplex and long‐read sequencing, and droplet digital PCR that now read the clock at single‐molecule resolution, and we connect mutational accumulation to downstream aging phenotypes through mtDNA‐driven innate immune signaling, cellular senescence and inflammaging. Finally, we position the mitochondrial clock alongside epigenetic and other aging clocks, highlighting concordance, complementarity, and what must be resolved before heteroplasmy can serve as a blood‐based biomarker of biological age.