Thermodynamic scaling of canine aging and reversible clock deceleration by a reverse transcriptase inhibitor

Aging was tracked in a cohort of 99 “retired” sled dogs over four years to characterize the latent dynamics of physiological decline. Animals were randomized to receive either placebo or the reverse transcriptase inhibitor lamivudine for ∼30 months. We employed a variational autoregressive model to integrate longitudinal blood parameters and DNA methylation (DNAm) profiles. The model defines Biological Age (BA) as a signature of irreversible damage with Poissonian statistics, a feature conserved across mammalian scales. Lamivudine modulated age-independent latent variables and temporarily decelerated the DNAm clock in females, but these effects were reversible upon treatment discontinuation and did not alter the long-term BA trajectory. Critically, we show that physiological fluctuations are governed by a single systemic factor – an effective or phenotypic temperature representing an emergent (macroscopic) property. We show that while the rate of damage accumulation (the BA slope) is independent of this temperature, actuarial aging parameters (initial mortality and the Gompertz exponent) are strongly temperature dependent. This supports a model where mortality arises from effective activation across a protective free energy barrier that erodes with age. These findings identify phenotypic temperature as an important control variable governing the kinetics of organism-level failure, offering a compelling target for interventions aimed at extending healthspan by “squaring” the survival curve.