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

The 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 energy resources between growth and maintenance processes. Here we test this hypothesis in humans by generating longitudinal, multi-modal signatures of aging in primary human fibroblasts. Relative to metabolic rates in the human body, isolated cells exhibit similar MR but markedly elevated growth rates indicating a shift of finite energetic resources away from molecular maintenance and repair processes. Accordingly, per-cell division, isolated cells display reduced lifespan marked by accelerated telomere shortening 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. We develop a theoretical-mathematical model that accounts for a partitioning of energetic costs between growth and maintenance, the potential origins of decreased lifespan in 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.