The age-related decline in regenerative capacity of many tissues constitutes a poorly understood problem that limits human healthspan. As studies in vertebrate systems point to both stem cell (SC) autonomous and non- autonomous causes for this age-related decline, analyzing SC function in an in vivo context is required, preferentially i short-lived, genetically accessible model systems. In recent years, Dr. Jasper's lab has established the fly intestine as a model to explore somatic SC aging, and to identify interventions that modulate SCs to preserve tissue homeostasis and extend lifespan. The Drosophila posterior midgut epithelium is regenerated by intestinal SCs (ISCs), is experimentally accessible, and of sufficient complexity to model the regenerative activity of similar tissues in vertebrates. Studies in the fly midgut have not only discovered mechanisms that promote the age-related regenerative decline in this tissue, but have also established that improving ISC proliferative homeostasis extends lifespan. Dr. Kennedy's lab, in turn, has performed groundbreaking work on aging and progeroid diseases for many years, with a specific recent focus on nutrient-responsive signaling pathways in the control of aging in mice. Here, Dr. Jasper and Dr. Kennedy propose to combine the strength of the fly system with genetic studies in mice to uncover evolutionarily conserved mechanisms of SC aging. Specifically, it will be tested whether the control of SC maintenance by nutrient-responsive signaling, which the applicants have characterized in the ISC lineage, is conserved in the mouse tracheal epithelial SC (Basal Cell, BC) lineage. The BC lineage has significant similarity with the fly ISC lineage, and serves as an accessible model for insight into epithelial regeneration in vertebrates that is likely to impact a major disease of aging: chronic obstructive pulmonary disease (COPD). The proposed work will address the role of TSC/Tor signaling, a conserved regulator of lifespan, on SC maintenance in flies and mice. Based on preliminary results, the applicants propose a conserved role for the negative regulator of Tor, TSC1/2, in shielding somatic SCs from dietary fluctuations, thus preserving SC identity and regenerative capacity in aging tissues. This model will be tested using genetic and pharmacological approaches to perturb the Tor pathway and to assess SC maintenance and regenerative capacity in aging animals. The study, which includes genetic work in mice and flies, as well as pharmacological interventions with new TorC1-specific inhibitors, will be performed in close collaboration between the Kennedy and Jasper labs, making the multi-PI mechanism optimal. The TSC/Tor pathway has emerged as an evolutionarily conserved nutrient sensor that influences life- and healthspan. Characterizing the biological consequences of long-term Tor repression is critical to develop specific intervention protocols that can promote tissue homeostasis and maintain regenerative capacity. The proposed studies will seek to achieve this important goal.

Public Health Relevance

Age-related decline of stem cell function significantly impacts age-related pathologies. The applicants propose genetic studies in flies and mice to characterize the effects of nutrient-response signaling on stem cell maintenance in aging barrier epithelia. The proposed work promises to identify new intervention strategies that will allay stem cell decline and promote regenerative capacity in aging tissues.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Fridell, Yih-Woei
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Buck Institute for Age Research
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Sousa-Victor, Pedro; Jasper, Heinrich; Neves, Joana (2018) Trophic Factors in Inflammation and Regeneration: The Role of MANF and CDNF. Front Physiol 9:1629
Miguel-Aliaga, Irene; Jasper, Heinrich; Lemaitre, Bruno (2018) Anatomy and Physiology of the Digestive Tract of Drosophila melanogaster. Genetics 210:357-396
Neves, Joana; Sousa-Victor, Pedro; Jasper, Heinrich (2017) Rejuvenating Strategies for Stem Cell-Based Therapies in Aging. Cell Stem Cell 20:161-175
Sousa-Victor, Pedro; Ayyaz, Arshad; Hayashi, Rippei et al. (2017) Piwi Is Required to Limit Exhaustion of Aging Somatic Stem Cells. Cell Rep 20:2527-2537
Haller, Samantha; Kapuria, Subir; Riley, Rebeccah R et al. (2017) mTORC1 Activation during Repeated Regeneration Impairs Somatic Stem Cell Maintenance. Cell Stem Cell 21:806-818.e5
Li, Hongjie; Jasper, Heinrich (2016) Gastrointestinal stem cells in health and disease: from flies to humans. Dis Model Mech 9:487-99
Chandel, Navdeep S; Jasper, Heinrich; Ho, Theodore T et al. (2016) Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing. Nat Cell Biol 18:823-32
Adams, Peter D; Jasper, Heinrich; Rudolph, K Lenhard (2015) Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell 16:601-12