Aging-Induced QT Prolongation as a Potential Contributor to Longevity

The objective of this paper was to review the possibility that the QT interval may be a marker of adult human longevity or life expectancy. Following a literature review, data supporting this possibility was assembled and consists of the following. First, in adults, QT interval increases with increasing age. This is analogous to aging-induced hypertension and diabetes mellitus, both of which are associated with shorter longevity. Second, older persons frequently die suddenly regardless of whether or not they have chronic illnesses for which death is expected. Third, longer QTintervals are associated with increased probability of sudden death. Fourth, patients with two conditions associated with accelerated brain aging, namely dementia and Parkinson's disease, show longer QTcs than age-matched controls. Both of these conditions are associated with sudden cardiac death. Fifth, aging processes may affect the molecular determinants of the QT interval, alter heart composition with increased myocardial fibrosis, or alter the amount of sympathetic and parasympathetic tone, any or all of which can alter myocardial repolarization and the duration of the QTc. Sixth, considering the molecular determinants of the QT interval in the aging heart, which has longer transmembrane action potentials, several factors can account for this change, including changes in late inward Na⁺ current (I_NaL), I_Kr, I_ca, I_to, and K_ATP channels. Transgenic mice overexpressing the Kir6.1 subunit of a K_ATP channel show a prolonged QT interval and reduced longevity, with animals appearing to die suddenly. Seventh, chronic kidney disease, which is associated with a reduced lifespan, is associated with reduced expression of the anti-aging factor Klotho and Klotho-deficient mice have a prolonged QTc and a reduced lifespan. Taken together, there is a cogent case for factors that increase action potential duration in the aging heart, as recognized by increased QTc, to act in concert with other factors to produce fatal arrhythmias leading to sudden cardiac death and shortened longevity.