Deviations in the body’s energy status trigger corrective mechanisms in various organ systems to return the body back to metabolic homeostasis. Aging is associated with disruptions in these mechanisms, as evidenced by continuing elevation of the body’s weight setpoint up until late middle age. In late age (>65 years old), this dysregulation manifests in an opposing manner with unintentional weight loss and diminished appetite contributing to poor health outcomes. These metabolic changes are not directly linked to disease, as they also occur in healthy individuals during normal aging. Disruptions in the body's ability to regulate energy balance increases the risk of disease development and mortality with aging. Understanding the mechanisms in natural aging that become impaired and contribute to the dysregulation of metabolism is imperative to improve healthspan.
Energy homeostasis is regulated through a complex interplay between peripheral organs and the brain. Metabolic signals from the body prompt the brain to activate either orexigenic or anorexigenic pathways, working to restore balance and maintain stable energy levels. While brain aging is well-characterized in relation to diseases affecting memory and motor function, the changes in central control of metabolic regulation with age remain poorly understood. This dissertation aims to elucidate central mechanisms contributing to age-associated impairments in metabolism.
In the first chapter, we characterize the effect of aging on body weight maintenance, feeding, and the central circuits controlling it. We demonstrate a defect in aged mice to sustain their baseline body weight following stress induced by fasting or neurotoxin treatment. Moreover, the extent of food intake in aged mice was lesser following stimulation of orexigenic neurons compared to young animals. Interestingly, neuronal activity in these orexigenic neurons was comparable between both age groups. One of the key orexigenic cell populations in the brain are Agouti-related peptide (AgRP) neurons located in the hypothalamus. A unique property of these neurons is that a portion of them lie outside the protection of a blood-brain barrier. We found that this exposure to the circulation does not alter the number of AgRP neurons with aging. However, treatment with a blood-restricted neurotoxin led to a greater loss of AgRP cells in aged female mice compared to young. This observation was not seen in male mice, indicating sex-specific differences. Exploration of repair mechanisms following neurotoxin treatment indicate young mice can replenish a portion of lost AgRP neurons, whereas aged mice are unable to do so. Additionally, defects in cell proliferation following injury in hypothalamic stem cells was observed. These results suggest aging impairs multiple pathways involved in maintaining energy status.
In the second chapter, we study changes in the hypothalamic environment of the aging brain in relation to its lack of a blood-brain barrier. We establish there are no changes to baseline permeability with aging. However, we found that neurotoxin treatment in young mice reduced blood penetration, a change not observed in aged animals. Similarly, the number of porous capillaries in this region was discovered to be consistent with these alterations in blood permeability. These findings indicate the dynamic regulation of blood extravasation into the hypothalamus is weakened with aging.
The third chapter explores mechanisms regulating blood-to-hypothalamus permeability. We investigate how tanycytes, specialized glial cells, regulate blood vessels to influence the extent of circulation penetration. During times of decreased permeability, tanycytes reduce their inputs on fenestrated blood vessels and their expression of angiogenic factors. These results reveal potential mechanisms of tanycyte control of blood permeability in this brain region.
