DECIPHERING SEX-SPECIFIC MOLECULAR SIGNATURES OF COGNITIVE DECLINE: AN INTEGRATIVE MULTI-OMICS APPROACH IN AGING MICE

The global increase in life expectancy necessitates a focus on ensuring aging occurs under optimal health conditions. A critical aspect of health, particularly vulnerable to aging, is cognitive function. Age-related cognitive decline is a significant concern, with detrimental impacts on quality of life and independent living. These deficits tend to emerge subtly in early adulthood and progress with age. Despite this general trend, significant sex differences and interindividual differences exist due to factors like cognitive reserve and resilience mechanisms, with steeper declines in general cognitive functions in males compared to females. We have implemented a one-month behavioural phenotyping protocol that includes tests for long-term memory, spatial learning and memory, recognition memory and motor learning and coordination, designed to detect the onset and progression of age-related cognitive decline. Using this approach, we compared the cognitive performance of 3 months-old (mo) with 10 mo and 18 mo male and female mice, where we observed a progressive cognitive decline starting from middle age, with male mice exhibiting a steeper trajectory. The multi-omic analysis (including gene expression and alternative splicing analysis) performed in hippocampal synaptoneurosomes from both male and female mice revealed synaptic impairment and chronic inflammation as key components correlating with the decline, both in its early phase (10 mo vs 3 mo) and in its late phase (18 mo vs 10 mo). Ultimately, this framework provides a robust foundation for evaluating therapeutic interventions targeted towards mitigating cognitive impairment in physiological aging.