The Maintenance of a Genomic Record Is Not Energy-Limited

Abstract

A Stoichiometric Ledger of the Mammalian Nucleus, the Geometry of Its Failure, and What a Longer Life Would Cost Holding a regulatory record in a mammalian nucleus is widely assumed to be energetically expensive. This paper assembles that cost in one currency and finds the assumption wrong. The three maintained records of the interphase nucleus — fast histone acetylation turnover, cohesin-mediated loop extrusion, and active cytosine methylation — together consume about 8.7×1048.7 \times 10^48.7×104 ATP-equivalents per second: roughly 0.06% of a cultured cell’s turnover and 0.003% of a cortical neuron’s. Nuclear record maintenance is therefore not energy-limited in bulk form, and accounts that run from mitochondrial decline through nuclear starvation to epigenetic drift lack a quantitative mechanism of that kind. A stoichiometric ledger further revises two related claims. Chromatin is not an outbid claimant on the acetyl pool: histone acetylation accounts for 74% of acetylated lysine residues in the cell. Nor does a simple cofactor-starvation model explain age-associated loop loss in the expected direction. Geometry constrains failure as sharply as energetics constrains cost. The best-measured maintenance disturbance is domain-bounded; at the lesion counts of the leading inducible system, no published carrier presently has both the reach and the magnitude required for a genome-wide effect. In a post-mitotic neuron the two records converge: trillions of transient chromatin cycles stand against a much smaller number of permanent sequence changes enriched at cell-type-specific regulatory elements. Against that background, a 20–25% gain in median human lifespan corresponds, on a calibrated Gompertz–Makeham construction, to a 3.7- to 5.1-fold reduction in hazard — a priced first rung rather than a forecast. The paper offers no protocol. It offers a ledger, a set of exclusions, and three measurements that would close most of what remains open. Keywords: nuclear maintenance energetics; histone acetylation; cohesin; chromatin architecture; epigenetic drift; post-mitotic neuron; mortality rate doubling time; genomic record; stoichiometric ledger; longevity