Abstract
Aging occurs along with multiple pathological problems in various organs. The aged brain, especially, shows a reduction in brain mass, neuronal cell death, energy dysregulation, and memory loss. Brain aging is influenced by altered metabolites both in the systemic blood circulation and the central nervous system (CNS). High levels of ammonia, a natural by-product produced in the body, have been reported as contributing to inflammatory responses, energy metabolism, and synaptic function, leading to memory function in CNS. Ammonia levels in the brain also increase as a consequence of the aging process, ultimately leading to neuropathological problems in the CNS. Although many researchers have demonstrated that the level of ammonia in the body alters with age and results in diverse pathological alterations, the definitive relationship between ammonia and the aged brain is not yet clear. Thus, we review the current body of evidence related to the roles of ammonia in the aged brain. On the basis of this, we hypothesize that the modulation of ammonia level in the CNS may be a critical clinical point to attenuate neuropathological alterations associated with aging.
Highlights
As there are many risk factors for the aging process in the central nervous system (CNS), including various metabolites, aged blood vessels, hyperlipidemia, impaired glucose metabolism, excessive reactive oxygen species (ROS) production, and poor energy metabolism [8,9,10], we investigated brain aging from various viewpoints
The regulation of ammonia levels in the aged brain may be beneficial for attenuating neuroinflammatory responses, which might be helpful for maintaining cognitive function in elderly people
Clinical trials for high ammonia toxicity-induced neuropathological problems include the use of NMDA receptor antagonists, nitric oxide (NO) inhibitors, and acetyl-l-carnitine [120,132,133]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Aging is a substantial global health issue and is markedly increasing in prevalence [1]. Aging changes multiple biochemical and physiological cellular mechanisms, reduces the functions of organs such as the brain [3], and results in a high risk of neurodegenerative diseases, metabolic disorders, and cancer [4,5,6]. As there are many risk factors for the aging process in the CNS, including various metabolites, aged blood vessels, hyperlipidemia, impaired glucose metabolism, excessive reactive oxygen species (ROS) production, and poor energy metabolism [8,9,10], we investigated brain aging from various viewpoints. Level of ammonia in both the blood and the CNS is altered, and altered ammonia levels contribute to multiple neuropathological mechanisms, such as cognitive decline [12]. We review recent evidence on the roles of ammonia in the aged brain, focusing on the breakdown of the blood–brain barrier (BBB), neuroinflammation, and memory function
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