A Membrane Lipid Peroxidation Mechanism for the Age-Dependent Linear Decline in Maximal Heart Rate Subtitle: Sinoatrial HCN4 channel activation is constrained by progressive membrane lipid peroxidation

Background: The linear decline in maximal heart rate with age is well established but lacks a molecular explanation. After controlling for autonomic factors, the decline is largely attributable to sinoatrial node function. Hypothesis: We propose that age-dependent membrane lipid peroxidation in sinoatrial pacemaker cells reduces membrane fluidity and impairs HCN4 channel voltage sensor rearrangement, thereby slowing diastolic depolarization and lowering maximal heart rate. Evidence: Four independent lines of evidence support this hypothesis: HCN4 channels are sensitive to membrane lipid domains; cultured cardiomyocytes show reversible beating-rate decline with membrane lipid changes; aged skeletal muscle shows reduced membrane fluidity; and lipid peroxidation products accumulate with age. Conclusion: This hypothesis generates three testable predictions and provides a mechanistic basis for the clinically observed 220 − age formula.