Accelerating the clock: Interconnected speedup of energetic and molecular dynamics during aging in cultured human cells

Abstract

AbstractThe allometric theory of metabolism predicts that the rate of biological aging is proportional to an organism’s size and, consequently, its metabolic rate (MR) and partitioning of energetic resources between growth and maintenance/repair processes. Here we test this hypothesis in humans by generating longitudinal, multi-modal signatures of aging in primary human fibroblasts. Relative toin vivo, cells isolated from the human body and grown in culture exhibit markedly elevated growth rates, indicating a shift of finite energetic resources towards growth and away from maintenance/repair processes. Accordingly, isolated cells display reduced lifespan marked by accelerated telomere shortening per cell division, and increased rate of DNA methylation aging. Moreover, despite a marked reduction in division rate towards the end of life, mass-specific MR increases exponentially, reflecting hypermetabolism or increased cost of living. We develop a theoretical-mathematical model that accounts for the partitioning of energetic costs between growth and maintenance/repair, the potential origins of decreased lifespanin vitro, and hypermetabolism with advancing cellular age. Moreover, we define genome-wide molecular rescaling factors that confirm and quantify the systematic acceleration of molecular aging kinetics in cultured fibroblasts. We use this approach to show how metabolic and pharmacological manipulations that increase or decrease MR predictably accelerate or decelerate the rates of biological aging. The interconnected speedup of molecular dynamics with growth and energetic rates in human cells has important theoretical and clinical implications for aging biology.