Drink up! (Water please)

Dehydration is a major risk factor for bad things in older adults – including death.

With summer’s high heat hitting parts of our country (and the world) it’s more important than ever to pay attention to how much liquid we take in.  Buck faculty member Jennifer Garrison, PhD, addressed the topic toward the end of a recent community seminar.  “Dehydration is a major risk factor for death.  If you are over 65 and dehydrated, you are at an increased risk for fracture and delirium.  Being well hydrated is at the top of the list if you want to age well.”

Our bodies are 60 to 70 percent water. Those are big numbers considering the aging process conspires against us when it comes to maintaining the correct balance of fluids in our various physiological systems. “Our drive to drink water, our thirst mechanisms go down with age,” says Garrison. “Plus, our kidneys don’t work as well as we age. They don’t concentrate urine as well and they are worse at filtering things out.”   

Garrison says maintaining fluid balance, or fluid homeostasis, is complicated.  Surprisingly the process is controlled in the brain. One of the projects in her lab, which is focused on understanding how the breakdown in homeostatic brain currents leads to aging, takes aim at dehydration. The ultimate goal of the project is to develop interventions that would shore up the neuronal wiring in the brain for fluid homeostasis that goes awry with aging.  

Postdoc Heeun Jang, PhD, leads the work and brings a particular skill to the research which involves a mouse model of dehydration.  This neuroscientist is able to do live imaging at the neuronal level to track what happens in the brain of aging wild-type mice as they eat and drink.  The fact that she is able to link brain activity with specific behaviors is groundbreaking research. “This is an area that is really understudied,” says Jang. “Right now, the only treatment for dehydration is to either drink more water or get an IV. My hope is that understanding the mechanisms behind fluid homeostasis such as feeling thirsty and the drive to drink will result in interventions that will help older adults maintain good health.”

Jang’s major focus is on input – how much and how often we drink when we eat.  She is interested in osmolality receptors in our mouth and in the brain. Osmolality refers to the concentration of particles dissolved in a fluid.  How salty is the water or food we eat? What is the concentration of other minerals circulating in our body? The osmolality of serum is used to diagnose several medical conditions such as dehydration, diabetes, and shock.

Jang says those osmolality receptors in the mouth send a signal to the brain, specifically to an area called the subfornical organ or SFO.  The SFO is a small structure located deep in the brain, along the wall of one of the brain’s cavities. Located outside the blood brain barrier and exposed to circulation, the SFO plays a crucial role in sensing and integrating circulating signals related to body fluid balance and blood pressure. While the SFO has its own osmolality receptors, these receptors sense slower changes in the blood after salt and nutrients are absorbed. It is the primary thirst-sensing organ in the brain. “The SFO gets feedback immediately as we eat and drink and makes us ‘feel thirsty’ or ‘quenched’” says Jang. “Using live imaging we see that this signaling mechanism is impaired in aging mice, especially as they eat. In other words, older mice feel less thirsty as they eat”

Jang says in turn, the SFO neurons signal downstream to another brain structure which drives drinking behavior.  The nucleus accumbens (NAc), a key component of the brain's reward circuit, receives input from various structures which regulate basic instincts, including thirst, and sends projections to motor areas, playing a crucial role in translating emotional and motivational signals into action. “If the SFO is not sending the proper signals, then the motivation to drink declines. Surprisingly, we found SFO is doing a good job sending signals to NAc in aged mice.” she says.

The dehydration story doesn’t end there. It also involves output largely via urination.  Jang says the SFO also signals the hypothalamus, a grape-sized brain structure that plays a crucial role in maintaining homeostasis when it comes to body temperature, hormone function, appetite and sleep-wake cycles.  Jang is particularly interested in a region of the hypothalamus that is important for fluid retention. It produces a hormone called vasopressin which travels from the hypothalamus to the kidneys via the blood. Vasopressin primarily regulates water balance in the body by increasing water reabsorption in the kidneys.  It also plays a role in blood vessel constriction and blood pressure regulation.

Aging impacts vasopressin. While vasopressin levels fluctuate in older adults, the body’s ability to respond to it, particularly in the kidneys, diminishes, leading to a reduced ability to concentrate urine and conserve water.  It’s one reason why older adults make more trips to the bathroom. Jang pushed vasopressin into the blood of her aging mice; their kidneys did not respond that well. “Using live imaging, we also found that activity in the part of the hypothalamus that produces vasopressin was impaired in aged mice".

Jang is a neuroscientist; she is not a kidney expert – but her research has the potential to impact health at every level.  “Water is essential for life. Dehydration impacts all cellular functions. It is a risk factor for diabetes and delirium,” she says. Severe dehydration can lead to complications like heat exhaustion, seizures, kidney failure, low blood volume shock, and even death.  Dehydration accelerates aging.  “Just look at what happens in the dry skin,” says Jang.

Jang came to the Buck after completing her PhD at the Rockefeller University, where she began developing the tools she now uses for her research in dehydration.  “I got excited about studying dehydration when I saw what a huge problem it is in the older population. I want to do research that could have a direct clinical impact on human health. I’m very eager to see how my project continues to play out.”