ThermoTRPs: Role in Aging

An organism's health depends on the integrity of molecular and biochemical networks responsible for ensuring homeostasis within its cells and tissues. However, upon aging, a progressive failure in the maintenance of this homeostatic balance occurs in response to various insults, allowing the accumulation of damage, the physiological decline of individual tissues, and susceptibility to diseases. Despite the complex nature of the aging process, simple genetic and environmental alterations can cause an increase in healthy lifespan or “healthspan” in laboratory model organisms. Genetic manipulations of model organisms including yeast, worms, flies, and mice have revealed signaling elements involved in DNA damage, stem cells maintenance, proteostasis, energy, and oxidative metabolism (Riera et al., 2016). However, one of the most intriguing discoveries made in these models resides in the ability of environmental factors to profoundly alter the aging process by remodeling some of the genetic programs mentioned above (Riera and Dillin, 2016). The first line of evidence that an external cue could powerfully regulate longevity was obtained by performing dietary restriction in rodents, a reduction in food intake without malnutrition. Dietary restriction is the most robust intervention to increase lifespan in model organisms including rodents and primates, and delays the emergence of age-related diseases (Mair and Dillin, 2008). How dietary restriction extends lifespan remains an open question, but decades of research are evidencing molecular pathways embedded in the response to reduce energy availability, resulting in the emergence of an altered metabolic state that promotes health and longevity. Nonetheless, the discovery of dietary restriction opened a new avenue of research in the aging field, and in particular in the understanding of how animals deal with fluctuating energy levels in their natural environment, and how their longevity is affected by such factors. This is particularly relevant for the nematode , which survives in a changing environment and must be able to coordinate energy-demanding processes including basal cellular functions, growth, reproduction, and physical activity with available external resources. In order to sense their environment, possess ciliated sensory neurons located primarily in sensory organs in the head and tail regions. Cilia function as sensory receptors, expressing many G protein-coupled receptors (GPCRs) and transient receptor potential (TRP) channels, and mutants with defective sensory cilia have impaired sensory perception (Bargmann, 2006). Cilia are membrane-bound microtubule-based structures and in are only found at the dendritic endings of sensory neurons. Sensory neurons provide nematodes with a remarkable form of developmental plasticity, allowing them to assess food availability, temperature, and crowding information (worm density) in order to arrest their development if required, thus forming long-lived and stress-resistant dauer larvae (Bargmann, 2006; Golden and Riddle, 1982). When favorable times return, worms assess the same cues to recover and resume normal development. As the entry and exit of the dauer larval stage suggest, worm sensory neurons truly function as neuroendocrine organs, being implicated in many physiological functions in addition to their behavioral role (Bargmann, 2006). Much information on these neurons has been gathered from laser ablation experiments and analysis of mutants presenting defects in sensory cilia. A seminal discovery in the aging field was achieved when the laboratory of Cynthia Kenyon showed in 1999 that mutations that cause various defects in cilia formation, including the absence of cilia, deletion of middle and distal segments, or impair chemosensory signal transduction increase longevity profoundly (Apfeld and Kenyon, 1999). Later, this group also demonstrated that laser ablation of specific pairs of gustatory and olfactory chemosensory neurons was sufficient to extend lifespan (Alcedo and Kenyon, 2004). What is the role of TRP channels in modulating these neuroendocrine processes, and what kind of stimuli are these receptors detecting to control aging? This chapter summarizes relevant discoveries that clarify some of the roles of TRP channels in the aging process.