Mitochondrial determinants of cognitive aging outcomes: A longitudinal study in marmosets - PROJECT SUMMARY Aging is the greatest risk factor for cognitive decline and Alzheimer's disease (AD), yet some individuals remain cognitively resilient into advanced age. The brain's exceptional energy demand makes it especially sensitive to energy disruptions, placing mitochondria, the central regulators of cellular energy metabolism, as a primary vulnerability. The overall hypothesis of this project is that mitochondria are upstream indicators of cognitive aging outcomes. Although the mitochondrial aging field has identified distinct but interconnected mechanisms that govern ATP generation (respiration, membrane potential stability, and ROS control) and network maintenance (motility, fusion/fission, and mitophagy), what mechanisms drive cognitive decline, when they emerge, and how best to measure them remain critical knowledge gaps. These gaps are best addressed with longitudinal designs that allow within-subject measurement of cognition and mitochondrial mechanisms on the same timeline. Yet human longitudinal studies are scarce due to lifespan and logistics; cross-sectional designs capture single time points; rodent models have limited translational validity; and postmortem/terminal sampling precludes functional assays in living cells. Induced pluripotent stem cell models enable access to neurons but erase subject aging signatures, limiting their utility for studying aging. This project overcomes these barriers using a short-lived (~12 year) non-human primate, the common marmoset, to integrate longitudinal cognitive testing with repeated, minimally invasive skin biopsies that yield fibroblasts directly converted to age-retaining induced neurons (iNs). Direct conversion avoids rejuvenation, preserving age-linked molecular features essential for mitochondrial aging studies and, with matched fibroblast assays, distinguishes neuron-specific from systemic mitochondrial changes. Because fibroblasts and iNs are derived from the same biopsy, this approach provides matched, longitudinal neuron-periphery pairs on the same timeline as behavior. Aim 1 defines individual cognitive aging trajectories via semiannual cognitive tests, using statistical modeling to classify resilience vs decline and to pinpoint age of onset. Aim 2 quantifies ATP-generating mechanisms at baseline, during challenge, and in recovery to identify those most consequential for cognitive decline and whether effects are neuron-specific. Aim 3 measures mitochondrial maintenance pathways with live-cell imaging and molecular markers to determine whether network upkeep deficits predict cognitive decline and whether they are neuron-specific. Together, this project delivers: (i) a within-subject, time-resolved, mechanistic map linking cognitive decline to discrete energy- governing and maintenance pathways, (ii) the earliest, most informative metrics of impending decline, and (iii) validation of minimally-invasive, scalable biomarker candidates. By establishing mitochondrial mechanisms as upstream indicators of cognitive outcomes, this work will enable mechanism-based screening and inform targeted strategies to preserve mitochondrial health, maintain cognition, and reduce AD risk.
