The AgingTimer project has developed experimental and computational infrastructure that will enable us to meet our goals - and be the first major study that combines theoretical modeling, cell aging biology and social factors in aging. First, we made major strides in the challenge of quantitating senescent cells in vivo, our prime candidate for the aging timer. To do so, we achieved a breakthrough by developing a FACS-based method to identify senescent cells in tissues using an effective antibody against p16 and two other markers. This method allows using cell-type specific markers to identify and quantify senescent cells in tissues. Our initial experiments using this system have already identified two major therapeutic strategies- using immune checkpoint inhibitors and ribosome biogenesis inhibitors to combat senescent cells. Second, we established a new model organism to study aging, starved E. coli cells. We uncovered a striking universality in the way that damage stochastically accumulates that spans from bacteria to mammals, allowing us accurate modeling of the timer of aging.
Thirdly, we achieved a proof-of concept for measuring the effect of senescent cells on social behavior. To do so, we demonstrated that continuous video monitoring can detect behavioral effects in mice that were manipulated to have excess senescent cells. We were also able to measure the clearance rate of senescent cells in socially isolated versus non-isolated mice, and to understand the role of sex in social hierarchy formation. These studies begin to bridge the gap between molecular studies of aging and studies of social behavior. To tie these themes together, we developed mathematical models that connect senescent cell abundance to disease incidence. To do so, we combined our dynamical equations for senescent cell dynamics with newly available large-scale medical datasets from Israel with incidence of hundreds of age-related diseases in 50 million life-years of data. These models provide a potential link between the AgingTimer project and future applications to human health.
