The Second Law of Thermodynamics dictates that heat, not resulting in work, will increase a system’s state of entropy, and very simply all systems—both animate and inanimate—will proceed toward a state of disorder. This phenomenon is somewhat outside the purview of biology and is more often dealt with within the realm of physics, yet it is undeniable that as a function of both time and temperature, biological systems are fated to an increased state of entropy. From an organismal perspective, this can speed the steady accumulation of dysfunctional biomolecules exceeding the threshold of what can be adequately maintained. These changes can have a secondary effect on other systems, and this increasing systemic failure is thought by some to be the phenomenon of aging. A recent Nature Metabolism paper has sought to address this fundamental feature of aging and whether or not core body temperature can modulate lifespan.

Commonly referred to as warm-blooded, homeothermic organisms maintain a set body temperature independent of most changes in environmental conditions. Previous studies have shown that genetic alterations to the brain’s “thermostat” can lower this set point and significantly extend the lifespan of mice; however, the attribution of this effect to reductions in body temperature alone is questionable as metabolic rate and body temperature are closely intertwined, and reductions in metabolic rates are also associated with increased lifespan. To address this conundrum, experiments were designed to take advantage of a dissociation that occurs between metabolic rate and body temperature as animals approach the high end of what is known as the thermal neutral zone.

Thermograms of male and female humansThe thermal neutral zone is the ambient temperature range requiring a nominal amount of energy to maintain an organism’s prescribed core body temperature. As ambient temperatures fall below the lower limit of this range, homeotherms will generate heat through increased metabolism. At the upper limit of this thermoneutral zone, there is a point at which an animal’s body temperature will increase without a concordant change in metabolic rate. Taking advantage of this phenomenon allowed researchers to interrogate differing body temperatures independent of metabolic changes.

Animals that were kept at this critical temperature threshold experienced an average increase in body temperature of approximately 0.5°C. This temperature differential varied slightly between gender and species but was always significantly greater when compared to counterpart animals housed at temperatures below the thermoneutral zone. As a result, animals with increased body temperatures showed a reduction in lifespan ranging between 21% and 41%; lifespan reductions also varied in a manner similar to the gender- and species-dependent variations with regard to body temperature increases.

Importantly, the core body temperature of animals housed at the upper limit of the thermoneutral zone can be lowered with exposure to a continuous circulation of air. This resulted in the elimination of increased core body temperatures and completely reversed the reduced lifespan seen in their overheated counterparts, demonstrating that body temperature independent of metabolic alterations can be a potent modulator of lifespan.

Since the development of technologies that have allowed humanity to outlive the “normal” period an organism is fit to survive in the natural world, the tragedy of old age and decrepitude has frustrated researchers and driven them to seek out a root cause. Progress has been achieved, for the most part, by addressing the discrete age-related pathologies; however, taking a first-principles approach focused on temperature has allowed researchers to investigate a basic temperature-dependent facet of aging and perhaps affect an underlying driver of many, if not all, age-related phenomena.