Thoughts on Mechanisms Linking Body Temperature and Aging
A fair number of papers have been published on various aspects of the link between body temperature and pace of aging. Calorie restriction in mammals both slows aging and lowers body temperature, for example. Mice with lower body temperatures due to altered temperature regulation mechanisms in the hypothalamus live a little longer. Body temperature tends to fall with advancing age in mammals, and some unusually long-lived mammals stand out for having particularly low body temperatures. When it comes to looking at the mechanisms involved in these relationships, the cellular biochemistry is very complex, and most of the relevant research has been carried out in flies and nematode worms rather than in mammals - though noted here, researchers are working their way up to the identification of interesting mechanisms in mice.
In 1916, researchers demonstrated that lower temperatures could dramatically extend the lifespan of the fruit fly, Drosophila. Other poikilothermic animals, whose internal temperature varies considerably, including C. elegans, also present increased lifespan upon modest temperature reduction. Additionally, lowering the core body temperature of homeothermic animals, such as mice, also increases lifespan, highlighting a general role of temperature reduction in lifespan extension in both poikilotherms and homeotherms. Reduction in core body temperature has been proposed to mediate the longevity benefits of dietary restriction. Conversely, raising the culturing temperature (e.g., to 25°C) greatly shortens nematode lifespan.
How is the cold-dependent lifespan extension mediated? One prominent model assumes that lowering the body temperature would reduce the rate of chemical reactions, thereby leading to a slower pace of living. This model suggests that the extended lifespan observed at low temperatures is simply a passive thermodynamic process. However, a more attractive hypothesis suggests that specific genetic programs might be engaged to actively promote longevity at cold temperatures, as observed upon dietary restriction or other paradigms.
Researchers reasoned that a cold sensor of the TRP channel family might be recruited in this process. The best-known mammalian cold sensors are TRPA1 and TRPM8; however, TRPM8 does not have a C. elegans homolog, thus ruling this receptor out of the candidate-based approach. But, TRPA1 has one ortholog in C. elegans referred to as TRPA-1, which becomes active under 20°C and therefore constitutes an attractive candidate to mediate the longevity extension observed under cold temperature.
Three temperatures (15°C, 20°C, and 25°C) are common laboratory conditions for culturing worms. If TRPA-1 is involved in promoting longevity at low temperatures, one would expect that mutant worms lacking TRPA-1 should have a shorter lifespan at 15°C and 20°C than wild-type worms, but not at 25°C. This is because this cold-sensitive channel is expected to be functional at 15°C and 20°C but remains closed at 25°C. Consistent with this prediction, trpa-1 null mutant worms showed a significantly shorter lifespan than wild-type worms at 15°C and 20°C but not 25°C. Similarly, transgenic expression of TRPA-1 under its own promoter increased lifespan at 15°C and 20°C but not at 25°C.
The ability to affect aging by manipulation of TRP channels in invertebrate models such as C. elegans provides evidence for evolutionary conservation and argues for the investigation of homologous and analogous circuits in mammalian models. Recently, evidence of the conserved function of chemosensory neurons in the regulation of longevity has been provided through the study of the capsaicin receptor TRPV1.
Impairment of TRPV1 sensory receptors is sufficient to extend mouse lifespan and improve many aspects of health in aging mice. Under normal fed ad libitum conditions, the TRPV1 mutation is not sex specific in its effects: longevity in both genders was extended to a similar extent, with 11.9% increase in male TRPV1 mutants and 15.9% increase in median female lifespan compared to wild-type controls. The longevity increase observed in these animals is not due to previously established mouse longevity paradigms such as reduced growth hormone (GH) and/or insulin growth factor (IGF-1) signaling. TRPV1 mutants show no growth delay and do not differ in body composition compared to control animals. TRPV1 mutant mice also do not present core body temperature differences with controls, arguing that their long lifespan is not due to a dietary restriction mimetic mechanism. How can a mutation in a sensory TRPV result in increased lifespan? TRPV1 mutation results in enhanced insulin secretion with age and a youthful metabolic profile that leads to increased lifespan in mice.