Mitochondrial Dysfunction in Circulating Blood Cells and Biological Aging: A Review of Mechanisms and Evidence

Chronological age tells us how long a person has lived-but not how well. Two individuals of the same age can differ dramatically in their cellular health, disease risk, and functional capacity. This gap between calendar age and biological age has driven growing interest in biomarkers that reflect true cellular aging rather than years lived. Mitochondria sit at the heart of this problem. Far more than cellular power plants, these organelles govern energy production, oxidative stress, immune signaling, and programmed cell death. As the body ages, mitochondria deteriorate in consistent and measurable ways-and crucially, these changes can be detected in circulating blood cells, offering a minimally invasive window into the body's biological age. This narrative review synthesizes two decades of research (2005-2025) on three blood-based mitochondrial markers: mitochondrial DNA copy number (mtDNA-CN) in peripheral blood mononuclear cells, mitochondrial membrane potential (MMP), and cell-free mitochondrial DNA (cf-mtDNA) in plasma. Across 68 carefully selected studies, we evaluate the strength, consistency, and clinical relevance of each marker, alongside their associations with cardiovascular disease, metabolic dysfunction, cognitive decline, and mortality. The evidence is promising but still maturing. Significant methodological variation across studies limits direct comparisons, and robust prospective outcome data remain limited. We propose a four-phase framework for responsible clinical translation and identify specific research investments needed-from measurement standardization to large cohort studies and intervention trials-before these markers can responsibly inform patient care.