The Marmoset as a Model of Aging and of Age-Related Neurodegenerative Disease
Aging is the greatest risk factor for neurodegenerative diseases such as Alzheimer’s disease, but the reasons for this are poorly understood. We will develop a framework to longitudinally investigate aging in the marmoset through pioneering complementary in vivo and in vitro techniques to significantly enhance the marmoset as a model to study aging and age-associated disorders. Further, we will apply this framework to test a specific hypothesis: that age-related neuronal mitochondrial dysfunction leads to downstream synaptic alterations and consequent cognitive decline. This hypothesis is based on the fact that, while the brain only comprises 2% of human body mass, it accounts for 20% of total energy consumption. This makes the brain especially vulnerable to energetic loss, which can occur when mitochondria undergo significant age-related deterioration.
To address this hypothesis, we will correlate longitudinal cognitive, transcriptomic, neuronal, and mitochondrial changes in young, healthy aging, and cognitively declining marmosets. Marmosets will perform cognitive assessments to track age-related cognitive decline over individual animal lifespans. These tests will be coupled with high-resolution electron microscopy-based analyses to visualize age- and cognition-related mitochondrial and synaptic infrastructure changes. Using non-invasive methods, we will measure age-related changes in gene expression and mitochondrial dynamics. Our combinatorial approach establishes a framework to catalyze future investigation of neuronal components during aging, and our optimized protocols, transcriptomic libraries, and newly developed cell lines will be made available to the research community. Together, we seek to fundamentally advance our understanding of aging mechanisms at the cognitive, genomic, and cellular levels with direct translatability to humans.