Associations Between Frailty and Cognitive Outcomes Across the Lifespan of Mice

Abstract Advancements in monitoring biological and brain aging with precise measures of health and longevity have the potential to accelerate research on pharmacological, genetic, and aging-related interventions. Over the past decade, frailty index has been used as an assessment tool for rodents, evaluating more than 30 non-invasive parameters that are strongly associated with chronological age, correlated with mortality, and sensitive to lifespan-altering interventions. However, whether aging phenotypes captured by the frailty index reflect brain aging remains unclear. In this study, 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 and cognitive function. Among 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. Competing Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. For conflicts related to D.A.S., including his ownership and board membership of Life Biosciences, an epigenetic reprogramming company, see: https://genetics.med.harvard.edu/sinclairtest/people/sinclair-other.php