Peripheral nervous system aging

Summary Aging alters the function of every organ. An inherent limitation to our understanding of aging is the complexity of the aging process. Thus, fundamental questions remain entirely unanswered: Are there mechanisms that coordinate organ function and how do they deteriorate with age? Could such mechanisms be restored to promote longevity? Previous work has revealed how immune cells and blood factors can impact organ aging and orchestrate organ communication. However, it remains entirely mysterious whether other synchronization systems could regulate organ aging. We are interested in the peripheral nervous system, which connects the brain to all organs, and whether it could coordinate the tempo of aging. This is a challenging problem because aging is a complex process and organ innervation by the peripheral nervous system is extraordinarily diverse. Our lab has recently generated paradigm-shifting methods to study complex aging biology. We have developed machine learning approaches coupled to spatial transcriptomics to determine the age of multiple cell types and to understand the impact cells have on neighboring cells within an organ. In addition, we have recently developed the first in vivo screens for brain aging in mice. Finally, we have established a new vertebrate model system, the African killifish, to perform aging studies at scale. The time is right to leverage these cutting-edge tools and develop new ones to understand how organ innervation responds to aging and to identify targeted approaches to boost the peripheral nervous system to “re-set” organ function and coordination during aging. We are interested in the following high-risk, high-reward questions: What are the age- dependent changes in the peripheral nervous system and how do they differ in diverse organs? How is the activity of peripheral neurons influenced by environmental stimuli that impact longevity? Is the peripheral nervous system functionally implicated in organ aging and how does it coordinate organ aging? Could the tempo of organ aging be “re-set” by restoring organ innervation? Addressing these questions has the potential to revolutionize how we think about aging and could lead to entirely new strategies to counter aging and diseases. More generally, solutions to this challenge could be broadly applied to other biological phenomena where time and organ coordination are critical.