Aging as a shrinking margin: the Metabolic Scope Theory

Maximum lifespan varies more than a hundredfold across vertebrates. A bowhead whale and a mouse are built from the same organelles, run the same electron transport chain, and burn the same fuels — yet one gets two centuries and the other gets two years. For most of a century the standard answer was metabolic rate: live fast, die young. That answer has never fit the data well.

In a preprint posted this year, we propose a different accounting. The Metabolic Scope Theory of Aging treats longevity not as a consequence of how fast an animal burns energy, but as the time required to exhaust its mitochondrial bioenergetic reserve.

Three axes

The framework separates that reserve into three physical axes:

1. Scope — the reserve capacity that buffers cumulative damage, for which body mass serves as a proxy.

2. Stability — how well the mtDNA-linked OXPHOS architecture resists erosion, tracked by mtDNA GC content.

3. Pace — the temperature-dependent kinetics of lesion accumulation, tracked by body temperature.

Together these give the Scope–Stability–Pace relation: ln MLS = α·ln BM + β·GC% − γ·Tb + c. Across 379 mammalian species it accounts for roughly 69% of the variance in maximum lifespan.

Two cross-class comparisons matter more to us than the mammalian fit itself, because they test the constraint structure rather than the curve. Birds run hot — high thermal Pace — and should be short-lived by this logic; they are not, and they offset it with elevated mtDNA Stability. And the temperature coefficient derived from mammals alone matches the temperature dependence of lifespan observed in ectotherms. Neither result was fitted; both fall out of the same relation.

Impedance, and what fails first

Mechanistically, we model accumulated mtDNA-linked damage as rising impedance within OXPHOS. The circuit language here is an analogy, not a method — but a productive one, because it predicts an unusual failure signature. As internal resistance climbs, mitochondria drift toward a high-redox-pressure, low-current regime. Basal ATP is largely preserved. What gets squeezed is everything downstream of electron flux: NAD⁺ regeneration, CoQ acceptor availability, and Δp-dependent work.

So the first thing to fail is not energy. It is regenerative scope — NAD⁺-gated TCA flux, aspartate and nucleotide synthesis, one-carbon metabolism, redox-buffered repair. This is why aging presents as a coordinated syndrome across metabolism, immunity, endocrine signaling, cognition and regeneration rather than as a series of unrelated organ failures: those pathologies are tissue-specific projections of one shared upstream constraint.

The distinction we care most about is between two kinds of impedance. One is operational and reversible — redox poise, membrane potential, endocrine tone. The other is informational and fixed: accumulated mtDNA damage, which no regulatory intervention reverses. It is the informational layer that sets the hard ceiling.

That has an uncomfortable implication for the intervention literature. Until we can directly restore mitochondrial conductance, the realistic gains come from relieving redox pressure or bypassing the constrained biosynthetic gates — not from resetting the clock.

The preprint is open: The Metabolic Scope Theory of Aging: Rising Mitochondrial Impedance Compresses Metabolic Reserve to Constrain Lifespan — Lehmann, Greenman, Shtrom, Anis, Lehmann, Stern & Shefer. Comments and objections are welcome, particularly on phylogenetic confounding, which we address directly in the manuscript.