Though progress has been made, aging remains an unsolved problem in modern biology. A number of mechanisms that lead to cell damage have been identified, but organisms, i.e., living animals and plants, presumably die not because they run out of cells, but because of failures of much larger scale. Cellular failures spread into failure of tissues, organs and ultimately the organism. This project focuses on the first intermediate step of this ordered collapse: the spread of failure from cells to tissues. To this end, the project will theoretically and experimentally establish the role of complex interactions between cells in aging tissues, using tissue engineering strategies to independently control both age and cell interactions. Experiments will be supplemented by mathematical models and computer simulations that will output mortality curves (plots of probability of death with increasing age) and life expectancies of these tissues. Furthermore, the project will be able to quantify the relative importance of cellular scale aging processes compared to those stemming from larger scale interaction effects. In view of broader impacts, aging affects everyone. With steadily increasing life expectancy, there is an immediate need to better understand principles underlying aging to find ways to decrease age-related diseases. This project will offer a fresh view to the scientific and medical community on the multiple scales involved in aging, paving the way for new approaches to delay or reverse aging and help attain healthier old ages. The research findings will be disseminated to a broad audience, from middle school to undergraduate and graduate students, and to the local community, with specific emphasis on underrepresented groups in STEM fields. Activities include workshops for middle school girls, regional science fair projects for high school students and seminars at a local medical center.
Although there exist a number of theories on cell damage, very little is known about how microscopic failures cascade to macro scale failure of tissues, organs and ultimately the organism. The goal of this project is to bridge microscopic cell failure to macroscopic manifestations of aging, by theoretically and experimentally establishing the role of complex interdependence and interactions between cells in aging tissues. Based on strong preliminary data from the investigators' labs, it is hypothesized that aging, defined in terms of an increased probability of death with chronological age, is due to failures cascading through an interdependent network of cells, rather than a series of isolated cell failures. To test this hypothesis, the aims of this project are to 1) Fabricate 3D engineered heart tissues consisting of varying densities of (aged and young) single and multiple cell types of the heart tissue (cardiac fibroblasts, cardiomyocytes and endothelial cells); 2) Age the tissue for a month, both with and without oxidative stress, while measuring the survival statistics of a population of tissues and cells within; and 3) Make inferences regarding the role of interactions using a detailed analytical theory. Specifically, the computational model studies spatial interdependence networks whose edge weights are determined by the diffusion equation and first order reaction kinetics. The nodes fail stochastically depending on their interaction with others, in a percolation-like spread. The computational framework will generate testable hypotheses for the proposed experiments, and in return, experimental measurements will constrain the model parameters. Project findings have the potential to transform aging research by introducing an entirely new view that aging is a universal attribute of any (living or non-living) system that has a sufficient number of components that strongly depend on one other to carry out their microscopic functions. Furthermore, this view enables, for the first time, the ability to quantify and simulate the progression of aging, given a certain interdependence network structure to predict how and when an interdependent system should be expected to catastrophically collapse.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
