Research
Negotiating with biological aging.
Forty years of bench and clinical work on the cellular drivers of cardiovascular aging — oxidative stress, mitochondrial dysfunction, NADPH oxidase (NOX4), Plasminogen Activator Inhibitor-1 (PAI-1) — converging on a multi-omic Michigan initiative that links epigenetic clocks, cardiorespiratory fitness, and maternal mtDNA inheritance to healthspan.
Current Research & Publications
Living Longer, Living Better: Epigenetic Aging & Inflammaging
An initiative investigating how mitochondrial dysfunction and epigenetic modifications drive the "vicious cycle" of inflammaging and age-related disease. The project links cardiorespiratory fitness phenotypes to multi-omic epigenetic biomarkers, with the goal of building a "Longevity & Cardiovascular Health Index."
Scientific focus: ROS-induced mtDNA damage → DAMP release → cGAS-STING activation → chronic inflammation → cellular senescence. Reading the same axis in fitness phenotypes, methylation arrays, and mtDNA inheritance is the bet behind the longevity index.
Research Leaders: Steven Kunkel, PhD (UM), Brian Athey, PhD (UM), Sachin Kheterpal, MD, MBA (UM), Marschall Runge, MD, PhD (UM)
Translational Research Epigenetics Longevity
Telomere Maintenance Mechanisms in Cancer & Aging
Long-read telomere sequencing for Telomere Maintenance Mechanism (TMM) profiling in liposarcoma. The platform combines Telo-seq on Oxford Nanopore, PacBio HiFi, Cas9-targeted enrichment, and SMA-seq reference standards to resolve Alternative Lengthening of Telomeres (ALT), arm-specific dynamics, and native subtelomeric methylation.
Key insight: Long-read sequencing reads native 5mC/5hmC marks, so aging signatures map directly onto the telomeric sequence, putting cancer biology and aging biology in one dataset.
Collaborators: Brian D. Athey, PhD (UM), Dennis Kappei, PhD (CSI Singapore), Rogel Cancer Center (UM)
Cancer Genomics Long-Read Sequencing Aging & Oncology
NADPH Oxidase, Oxidative Stress & Cardiovascular Aging
Key finding: Reactive oxygen species (ROS) damage mtDNA, and that damage tracks with atherosclerosis progression. The work established mitochondria as an independent genetic contributor to vascular health, not just an energy-supply organelle.
Mechanism: NOX4-derived superoxide → mtDNA damage → metabolic reprogramming of macrophages → inflammatory response. The chain links oxidative metabolism to immune activation, and points to therapeutic targets in cardiovascular aging.
Frontiers in Immunology Antioxidants & Redox Signaling Vascular Biology
Vascular Fibrosis, PAI-1 & Hypertension
Key finding: NIA-funded work on Plasminogen Activator Inhibitor-1 (PAI-1) and its role in vascular aging, fibrosis, and hypertension. The papers worked out the molecular mechanism behind plaque formation and vascular remodeling.
Mechanism: PAI-1 overexpression → impaired fibrinolysis → extracellular matrix accumulation → vascular fibrosis. PAI-1 sits at the intersection of cellular stress, mitochondrial dysfunction, and vascular aging, which is part of why age is the dominant risk factor for cardiovascular disease.
Hypertension (AHA) Circulation Research Aging & Fibrosis