Fluid Homeostasis is Disrupted by Aging
The body has evolved to balance the levels of many different molecules across different tissues. Multiple systems of signaling, transport, motivation, intake, and excretion interact in order to achieve homeostasis, constantly shifting in response to deficiency or excess. Water is one of the more important molecules managed by this sort of complicated, dynamic balance. As a general rule, all complex systems in the body run awry with aging; the more complex, the more vulnerable it is to damage and dysfunction. The molecular damage of aging changes cell behavior, homeostatic systems stop working as well as they did in youth, and ultimately the failure to achieve homeostasis in the face of stresses that push the system out of normal bounds can prove fatal.
Tight control of fluid balance is essential for life. This is achieved by a physiologic system that monitors the osmolality and volume of the blood and, in response to dehydration, triggers two counterregulatory responses: water consumption, which is motivated by the sensation of thirst, and water reabsorption by the kidney, which is triggered by the hormone vasopressin (AVP). These two responses are controlled by dedicated neural circuits in the forebrain that directly sense changes in fluid balance.
Dysregulation of fluid homeostasis is a common feature of aging. For example, older adults report a reduced perception of thirst and consume less water after many thirst-evoking (dipsogenic) stimuli. In addition, the ability of the kidney to concentrate urine declines with age, leading to greater loss of fluid in older adults. As a result, aging is associated with increased prevalence of chronic dehydration, which is a significant risk factor for morbidity and mortality.
The specific alterations in the fluid homeostasis system that are caused by aging are not well understood. One challenge is that fluid balance involves multiple interacting systems, including a neuroendocrine system that controls water resorption (the AVP-kidney axis); a sensory system that monitors fluid balance and ingestion, which includes subfornical organ (SFO) glutamatergic neurons and their sensory afferents arising from the mouth, throat, and viscera; and a motivational system which drives water seeking and consumption, which includes SFO glutamatergic neurons as well as their downstream targets such as the dopamine system.
It has only recently become possible to monitor and manipulate these fluid homeostasis neurons in behaving animals. Here we have performed a comprehensive analysis of how the fluid homeostasis system is altered by aging in mice. We investigated animals of both sexes, across a range of ages from young to very old, and subjected them to batter of analyses at different levels, including: (1) physiologic measurements of fluid balance, kidney function, and AVP release and sensitivity; (2) behavioral analyses of drinking and motivation in response to diverse thirst stimuli (food, dehydration, hyperosmolality, and hypovolemia); (3) neural recordings from circuit nodes that control drinking, AVP release, and motivation, and (4) optogenetic manipulations to test the sufficiency of circuit nodes. These experiments revealed that a subset of these functions is impaired during aging, whereas others are unexpectedly enhanced.