Environmental Modulation of Behavioral and Molecular Aging in Genetically Identical Mice

Trajectories of age-related declines in tissue function, cognition, health, and survival are strongly shaped by environmental exposures. Yet, the vast majority of what we know about the biology of aging comes from animals studied under constant, simplified laboratory conditions that poorly reflect the complex environments in which mammalian physiology evolved. This project aims to determine which aspects of aging biology are robust across environments and which are environmentally contingent and at risk of being mischaracterized in the lab. To address this challenge, I will use a naturalistic outdoor enclosure system that allows genetically identical C57BL/6J mice to live in semi-natural social and ecological conditions that much better capture the challenges, complexity, and dynamism of the environments in which mammalian physiology evolved. I have shown that animals reared in these environments experience more rapid epigenetic aging and broad transcriptomic remodeling, indicating that real-world complexity fundamentally alters physiological trajectories. My preliminary data confirm the feasibility and power of this approach, with findings already published in Science and Aging Cell. During the mentored K99 phase, I will expand these findings by testing how environmental realism affects the pace and profile of aging across biological levels—including behavior and cognition, gene expression, DNA methylation, mitochondrial function, and gut microbiome composition. During the R00 phase, I will test whether a leading pro-longevity intervention (rapamycin) is effective under naturalistic conditions. This novel system represents the first sustained effort to bring ecological validity to a tractable aging model, merging evolutionary and biomedical perspectives to examine how real-life complexity influences known hallmarks of aging. This work will identify which biomarkers and interventions retain their relevance outside the lab and will help build a more generalizable foundation for aging biology. Findings will improve the design and interpretation of preclinical studies by revealing context-dependent effects on molecular aging pathways. The proposed career development plan will provide advanced training in molecular and computational tools—including DNA methylation profiling, RNA-seq analysis, mitochondrial functional assays, and microbiome sequencing—critical for my long-term goal of establishing an independent research program at the interface of ecological and biomedical aging research. My training will be supported by a highly collaborative environment at Cornell University, with direct mentorship from Dr. Michael Sheehan, as well as through cross-institutional training from Drs. Wanding Zhou (U. of Pennsylvania), Andrew Moeller (Princeton U.), and Steven Austad (U. of Alabama at Birmingham). Through this integrated training plan, I will gain the interdisciplinary expertise needed to lead a research program that combines molecular gerontology and environmental realism in aging models. Project Number: 1K99AG101696-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Matthew Zipple | Institution: CORNELL UNIVERSITY, ITHACA, NY | Award Amount: $136,350 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 AN-N (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11352122