Date of Award
2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy in Pharmaceutical Sciences
Department
Biomedical and Pharmaceutical Sciences
First Advisor
Jaime Ross
Second Advisor
Giuseppe Coppotelli
Abstract
In response to an increased accessibility to health care, improved medical treatment, and enhanced hygiene and nutrition, the human lifespan has significantly increased. While this expansion of lifespan is positive, it is also accompanied by a rising prevalence of age-related disorders, with neurodegenerative diseases at the forefront. This increased incidence of age-related diseases can have a catastrophic impact on our society. Thus, we must understand the underlying mechanisms of the aging process to aid in the treatment of age-related disorders and the improvement of health span.
In recent years there has been a dramatic advance in monitoring biological age, versus chronological age, by using the methylation clock. In addition, researchers have worked to develop non-invasive and cost-effective measures, such as the frailty index (FI) scoring system. Although this measure is reliable in predicting biological age, no studies have been conducted to determine its efficiency in predicting how the brain ages in mice. To investigate this, we examined the relationship between frailty index and cognitive ability in young (3-4 months), middle-aged (12 months), and old (24 months) male and female C57BL/6J mice using a battery of behavioral and locomotor assays to determine whether frailty index scores can predict performance in tasks evaluating behavioral cognitive function. Of the behavioral assays tested, frailty index scores had good correlation with the percentage of time spent in the center of the open-field apparatus, the duration spent in the open arms of the elevated plus maze, and the time spent in the target hole of the Barnes maze. These findings indicate that the frailty index not only reflects general physiological aging but may also serve as a reliable predictor of age-related cognitive decline in mice, providing a valuable tool for studies of interventions targeting brain aging.
Alongside developing methods to measure aging, scientists have also worked diligently to understand its underlying mechanisms. To systematically explain the aging process, Carlos López-Otín and colleagues categorized nine “common denominators” of aging in 2013 and expanded these hallmarks to include twelve processes a decade later. Although these hallmarks have been highlighted as playing a key role in the aging process, minimal progress has been made to study the interconnectedness of these hallmarks. To investigate the interplay between two hallmarks of aging, epigenetic alterations and mitochondrial dysfunction, we examined the impact of DNA damage-induced epigenetic changes on mitochondrial morphology and function. To assess how different levels of DNA damage affected mitochondrial function, we used fibroblasts derived from a mouse model with Inducible Changes to the Epigenome (ICE mouse model) where DNA-damage causes erosion of the epigenome. Cells were exposed to DNA-damaging conditions for 24, 48, or 72 hours, followed by a one-week recovery period before analyzing mitochondrial morphology, dynamics, membrane potential, and cellular respiration. Our results demonstrate that DNA damage reshapes the mitochondrial network by altering mitochondrial dynamics, increasing the number of mitochondrial branches, and elevating the levels of proteins involved in oxidative phosphorylation and respiration. These findings highlight the intricate interdependence between DNA damage-induced epigenetic remodeling and mitochondrial function, underscoring the complexity of the aging process and offering insights into potential therapeutic targets for aging and age-related diseases.
Alongside mitochondrial functioning, we were also interested in observing the effect of DNA-damage induced epigenetic alterations on brain aging disorders, such as Alzheimer’s disease (AD). AD is currently the most common brain aging disorder and leading form of dementia world-wide and is characterized by the accumulation of extracellular amyloid-beta plaques, intracellular neurofibrillary tangles and widespread neurodegeneration. While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift. We hypothesized that DNA damage-induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess Aβ pathology and neuroinflammatory markers. Our findings reveal that DNA damage-induced epigenetic alterations significantly affected cognitive behavior and altered Aβ plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage-induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.
As the global population continues to age, it remains increasingly important to deepen our understanding of the aging process, particularly brain aging and neurodegeneration. Given the established relationship between DNA damage, mitochondrial dysfunction, and the pathogenesis of Alzheimer’s disease, future investigations should further delineate these interconnections to advance our understanding of aging, and neurodegenerative diseases.
Recommended Citation
Bartman, Sydney, "MECHANISMS OF BRAIN AGING: LINKING FRAILTY, EPIGENOMIC ALTERATIONS, AND MITOCHONDRIAL DYSFUNCTION TO COGNITIVE DECLINE AND ALZHEIMER’S DISEASE PATHOLOGY" (2025). Open Access Dissertations. Paper 4521.
https://digitalcommons.uri.edu/oa_diss/4521