Utilizing Heterogeneous Mouse Models to Discover Mechanisms Underlying Caloric Restriction (CR) on Cognitive Outcomes

/ABSTRACT Our work and others, suggest that interactions between genetic and modifiable dietary factors are key determinants of cognitive aging trajectory. We propose to conduct the first comprehensive analysis of the genetic determinants of cognitive resilience under conditions of caloric restriction (CR) using a systems genetics resource—the Diversity Outbred (DO) panel of mice. The DO mice were specifically designed to discover complex genetic and environmental interactions that control variation of cognitive outcomes observed in human populations. The goal of this project is to identify genetic factors and mechanisms underlying variation in cognitive outcomes following adult-onset CR, one of the most robust and reproducible dietary interventions for extending lifespan. We previously found that this highly robust and reproducible dietary intervention for extending lifespan (40% CR) in aging DO mice causes an increased incidence of memory impairment. This is considered a ‘worst case’ outcome for individuals, caregivers, and health care systems looking for interventions that ultimately reduce the time patients require dementia care. There are currently no CR studies in humans powered for genome-wide discovery of modifiers of cognitive outcomes. This proposal will use innovative mouse models to identify genetic mechanisms that modify the age at onset and severity of cognitive performance in a cohort of male and female aging DO mice (Aim 1). Candidate genes and networks will be tested for associations against the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) CR longitudinal trial in humans, as well as in ‘normal’ aging and Alzheimer’s disease (AD) cohorts to identify resilience factors conserved in humans (Aim 2). We will test the role of these candidate genes predicted to promote healthy brain aging (resilience), as well as those associated with a negative shift from normal cognitive aging toward AD pathophysiology (Aim 3). Specific innovations include the use of multi- scale neural network methods to identify resilience genes that are capable of distinguishing perturbations and latent factors that initiate cognitive resilience from those that merely correlate; our cross-species translational platform for testing candidates identified in mice in multiple human cohorts; the mouse resources and expertise of The Kaczorowski Laboratory, which will be leveraged for gene validation and creation of precision AD models; and our team of experts in human and mouse genetics, multi-omics, computational modeling, electrophysiology and genome editing for functional validation. IMPACT: We will discover and validate targets for promoting healthy brain aging in response to CR, and test their relevance in the context of resilience to AD. The identification of genetic factors and mechanisms underlying variation in normal cognitive aging in response to adult-onset CR in, and that may lead to pathologic brain aging (e.g. AD/ADRD), will likely point to novel therapeutic strategies in humans. Project Number: 1R01AG094704-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: CATHERINE KACZOROWSKI (+1 co-PI) | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $1,732,842 | Activity Code: R01 | Study Section: Cognitive Disorders and Brain Aging Study Section[CDBA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11201430