Aging is paradoxical: tissues are constantly renewed, yet the renewal blueprint itself irreversibly deteriorates. Among mammals, lifespan varies 100-fold, even though genes and enzymes are nearly identical. Within a species, different organs age in sync. Existing theories explain why aging exists, but not its coordination or the differences between species. This work stands apart: neighboring studies in the archive look at aging through epigenetic clocks, information loss, or microbial factories, but not through a physical limit on metabolic reserve.
The authors built their theory on a comparative analysis of data from 379 mammal species. They collected information on body mass, maximum lifespan, guanine and cytosine content in mitochondrial DNA (GC%), and body temperature. Then they fitted a log-linear model linking these variables. To test the temperature effect, they used published data on five ectotherm species (insects, crustaceans, nematodes, fish) raised at different temperatures. They also performed a phylogenetic analysis of the stability of the coefficients and compared the model's predictions with human physiology data.
The model explained 69% of the variation in maximum lifespan among mammals (p<10^-90). The coefficients: for body mass α=0.148, for GC% β=+0.105, for temperature γ=+0.091. This means that a 10-fold increase in body mass raises lifespan by about 1.4 times, a 1% increase in GC% raises it by 1.11 times, and a 1°C increase in temperature shortens life by 9%. In birds, GC% does not correlate with lifespan because they have already minimized vulnerable bases in mitochondrial DNA. Fish live no shorter than mammals of the same size, despite having a 30-fold lower metabolism, thanks to slow damage accumulation at low temperature. The activation energy of the temperature dependence was about 73 kJ/mol, which matches data from the five ectotherm species.
This work differs from its neighbors by proposing a single physical mechanism that links the accumulation of mutations in mitochondrial DNA to age-related changes. Neighboring studies focus on epigenetic clocks or information loss, but do not derive them from the energy constraints of the cell. Here, aging appears as a managed retreat under a shrinking metabolic reserve. This shifts the emphasis from preventing damage to buffering it, which changes the strategy for finding interventions.
The theory can be tested by direct measurements of mutation accumulation in mitochondrial DNA and internal resistance in the respiratory chain across different species. It may be possible to create interventions that restore the conductivity of the chain, rather than simply adding fuel or antioxidants. Studying the role of nuclear genes that encode the quality of the respiratory chain is a promising direction, as they may explain the remaining 31% of the variation.
The theory could influence gerontology by offering new biomarkers of age based on dynamic tests rather than static indicators. It also provides a basis for developing therapies aimed at restoring metabolic reserve, rather than fighting individual symptoms.
Longitudinal studies are needed on the accumulation of mutations in mitochondrial DNA and changes in internal resistance of the respiratory chain in model organisms. It is also important to test the theory's predictions using interventions such as expression of LbNOX or alternative oxidase in animal experiments.
The theory ties aging to an unsolved problem in gerontology: why different tissues age in sync despite different renewal rates. It proposes a common mechanism through the accumulation of damage in mitochondrial DNA that may explain this synchrony. It also raises the question of which mutations in mitochondrial DNA are actually causal for aging, rather than merely correlating with age.
The naked mole-rat lives up to 30 years, even though its size matches that of a mouse, which lives 3 years. The secret lies in its low body temperature (about 32°C) and high GC% in mitochondrial DNA, which slows the accumulation of damage.
In H. G. Wells's The Time Machine, the Eloi and the Morlocks represent species with different lifespans, echoing the idea of tuning metabolic reserve through evolution.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.