Interorgan communication in aging in Drosophila

Project Summary/Abstract Aging is a complex condition with diverse physiological effects ranging from the cellular to organismal levels, such as the dysregulation of metabolism. While many distinct aspects of aging have been characterized, a wholistic understanding of how these aspects function together will be necessary to define and treat age- associated health decline and diseases more effectively. One way to address this is by better understanding the inter-organ communication (IOC) that coordinates aging mechanisms between tissues. Our proposal focuses on the IOC between aging metabolic tissues and how this communication alters metabolism and impacts biological age. We propose a multi-omics approach of single-cell transcriptomics, tissue-specific proteomics, metabolomics, and bioinformatics to work towards a system-level understanding of IOC, metabolism, and aging in Drosophila melanogaster. We have recently generated the Aging Fly Cell Atlas (AFCA), the most comprehensive single-cell transcriptomic dataset to-date of an entire aging organism. We will exploit and build upon these data to identify novel IOC, tissue-specific metabolic reprogramming, and sex differences during natural fly aging. Additionally, we propose system-level IOC and metabolomic characterization of 1) pro-longevity models of mTOR inhibition in adult flies using tissue-specific FoxO activation and rapamycin feeding and 2) advanced aging models of degenerative muscle stress and human Tau-induced neurodegeneration. We will correlate findings from these models with those from the AFCA to discover anti-aging targets within the IOC network that will modulate aging metabolism in a tissue-specific fashion. This work has the potential to 1) better understand how organismal metabolism is regulated via IOC; 2) develop strategies to enhance anti-aging therapies such as rapamycin; 3) identify disease mechanisms of muscle and neural degeneration that affect otherwise healthy distant tissues; 4) ultimately elucidate fundamental system-level aging biology and accelerate the discoveries of new anti-aging therapies.