Declines in mRNA synthesis set the rate of organismal aging
Abstract
The abundance of mRNA sets a ceiling on a cell's capacity to produce protein and carry out its functions. Here, we describe a pathological decline in absolute mRNA abundance that occurs in most cell types during invertebrate and mammalian aging, caused by decreases in mRNA synthesis capacity. In C. elegans, decreases in mRNA abundance are tightly coupled to declines in RNA Polymerase II (Pol II) protein abundance. Measuring Pol II abundance dynamics in vivo, we find that individuals enter adulthood with a four-fold excess of Pol II, whose kinetic equilibration towards its homeostatic set point drives reductions in mRNA abundance and, in turn, organismal aging. Briefly accelerating Pol II declines produces permanent, dose-dependent reductions in healthspan and lifespan, whereas deceleration extends both. Although disrupted cellular homeostasis is conventionally seen as a consequence of aging, our results reveal how an out-of-equilibrium state established during development provides a driving force for aging.
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Research summary
The paper proposes that the kinetic equilibration of RNA Polymerase II abundance from a developmental excess to a homeostatic set point is a primary driver of organismal aging, rather than merely a consequence of cellular damage. This work is relevant because it identifies a fundamental mechanistic cause of aging (declining mRNA synthesis capacity) and demonstrates that modulating this specific process can extend healthspan and lifespan, addressing the root causes of aging rather than just treating symptoms.
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