Abstract
The allometric theory of metabolism predicts that the rate of biological aging is proportional to an organism’s size and metabolic rate (MR). 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 markedly elevated MR and operate closer to their maximal energy production capacity. Accordingly, per-cell division, isolated cells display 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 related to both growth or maintenance, quantifying the potential origins of hypermetabolism in vitro, and with advancing age. Moreover, we define genome-wide molecular rescaling factors that confirm and quantify the systematic acceleration of molecular aging kinetics in cultured fibroblasts, and 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 energetic and molecular dynamics across the lifespan of human cells has important theoretical and clinical implications for aging biology.
Competing Interest Statement
The authors have declared no competing interest.
