Date Approved

7-6-2026

Embargo Period

7-6-2027

Document Type

Dissertation

Degree Name

Ph.D. Neuroscience

Department

Cell Biology and Neuroscience

College

Rowan-Virtua School of Translational Biomedical Engineering & Sciences

Advisor

Benjamin Rood, Ph.D.

Committee Member 1

Jeremy Francis, Ph.D.

Committee Member 2

Jessica Loweth, Ph.D.

Committee Member 3

Rachel Navarra, Ph.D.

Committee Member 4

Brian Weiser, Ph.D.

Keywords

Aspartoacylase;Biomarkers;Mitochondria energy metabolism;N-acetylaspartate;N-acetyltransferase 8-like;Neurodegenerative disease

Abstract

N-acetylaspartate (NAA) is a highly abundant neuronal metabolite tightly linked to mitochondrial function and energy metabolism. Reduced NAA is an early biomarker of multiple neurodegenerative diseases and has also been observed in cognitively intact aging, suggesting a potential role as an indicator of age-related metabolic vulnerability. Because NAA synthesis depends on mitochondrial aspartate, it may compete with oxidative phosphorylation for substrates required for ATP production. We hypothesized that age-related changes in the NAA metabolic cycle reflect an adaptive response to neuronal energetic status and remain responsive to positive environmental modulation. The current study demonstrates that expression of two genes, rate-limiting for the synthesis (Nat8L) and catabolism (ASPA) of NAA, is dynamically regulated during normal aging in mice, particularly in the hippocampus and fornix—regions most affected by age-related dementia. Age-related changes in Nat8L and ASPA expression are not due to cell loss but are associated with an increased prominence of oxidative phosphorylation with age, likely reflecting alterations in mitochondrial energy metabolism during aging. Additionally, environmental enrichment restores Nat8L and ASPA expression in older animals to baseline levels, further demonstrating the responsiveness of both arms of NAA metabolism to shifts in cellular energy metabolism. These findings support a model in which NAA metabolism undergoes adaptive, multicompartmental regulation during normal aging and remains modifiable in midlife. Coordinated regulation of Nat8L and ASPA emerges as a sensitive indicator of neuronal energetic status and a potential biomarker framework for the transition between healthy aging and neurodegenerative risk.

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Available for download on Tuesday, July 06, 2027

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