MECHANISMS OF BRAIN AGING: LINKING FRAILTY, EPIGENOMIC ALTERATIONS, AND MITOCHONDRIAL DYSFUNCTION TO COGNITIVE DECLINE AND ALZHEIMER’S DISEASE PATHOLOGY

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 telomere(definition) attrition, cellular senescence(definition))." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">hallmarks of aging(definition), epigenetic alterations and mitochondrial dysfunction(definition), 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