Jamie N. Justice - US grants

Project Summary A key aim of this proposal is to equip the candidate, Dr. Jamie Justice, with the expertise to become an independent investigator who can advance interventions that extend healthy lifespan to randomized, controlled trials in older persons. Specifically, cellular senescence is a biologic hallmark of aging that emerging preclinical evidence indicates could have profound consequences on aging-related disease and function, and removal of senescent cells results in robust improvements in healthspan in rodents. Translation of these interventions to clinical trial has been proposed, yet health consequences of cell senescence and therapeutic potential has not been evaluated in humans. Dr. Justice's preliminary data in a small number of older women are the first to show that cells expressing tumor suppressor protein and senescence biomarker p16INK4a are present in adipose tissue from older adults and related to worse physical function, but exercise and weight loss by caloric restriction may mitigate this burden. The proposed research project represents a critical next step by examining the effects of caloric restriction (CR) on cell senescence in a prospective randomized controlled trial (RCT). The primary hypothesis is that a CR intervention will reduce senescent cell burden and this reduction will be related to improvement in functional and metabolic outcomes. This will be accomplished by capitalizing on a recent NIH-funded RCT (VEGGIE, R01DK103531) and the candidate's engaged inter-disciplinary primary mentoring team (Drs. Nicklas, Ding, Kritchevsky, Kirkland). VEGGIE will determine the effects of CR designed to achieve 10% weight loss vs. health education control in 200 men and women aged 40-65 years with obesity (BMI 30-45 kg/m2), to characterize epigenetic and transcriptomic effects of CR in adipocytes and peripheral blood monocytes and T cells, and associations with physical and metabolic function. We propose an ancillary investigation in a subset of 90 participants (50-65 years, n=45 per grp) to determine the effects of CR on senescent cell burden (Aim 1): a) proportion of p16INK4a expressing senescent cells (immunohistochemistry) in subcutaneous abdominal adipose tissue; b) expression of senescence biomarkers in isolated adipocytes and monocytes (RNAseq) and T cells (p16INK4a expression); and c) SASP biomarkers in plasma (cytokine/chemokine panel). We will also examine cross-sectional associations of age and obesity with cell senescence (Aim 2), and relationships between changes in senescence biomarkers and physical function and metabolic outcomes (Aim 3). The research proposed is aligned with an approved NIA concept to develop markers of aging-related biologic mechanisms for human studies. Additionally, it will provide essential training for the candidate, who will establish expertise in cell senescence and translational research, and develop competencies in leading clinical trials with biological outcomes. This approach provides the ideal platform to advance the candidate's career as an independent investigator, and provide the foundation to establish the role of cell senescence in human age-related functional decline.

PROJECT ABSTRACT/SUMMARY Aging is by far the main risk factor for chronic conditions that jointly account for most morbidity, mortality, and health care costs. Geroscience-guided therapies seeking to alleviate such disorders as a group by targeting basic aging processes are now entering early stage clinical trials. The discovery, validation, and implementation into routine clinical care of such transformational therapies will require the creation of a robust and diverse geroscience workforce and training pipeline. The focus of this application is to address manpower, training, and educational gaps that were identified at a 2017 conference on this topic funded by an earlier Geroscience Network R24 grant (AG044396) with findings published in JAGS (Newman et al., 2019). We are now proposing to create the NIA Geroscience Education and Training (GET) Network through the R25 funding mechanism (PAR-20-095) as a complementary ?sister? network to the Translational Geroscience Network (TGN; R33 AG061456), since educational, curricular, and training goals outlined in this proposal were not suitable for inclusion in a R33 grant. More specifically, we are proposing the creation of a network model designed to leverage and integrate relevant expertise, knowledge, and resources across multiple institutions and organizations to address the following Specific Aims: Aim 1: Develop shared geroscience curricula and educational materials initially targeting: 1A. Medical and 1B. PhD students needing foundational geroscience knowledge irrespective of career plans 1C. Geriatric Medicine Fellows who require a deeper level of geroscience knowledge Aim 2: Develop a Certificate in Geroscience Research Program to train the next generation of geroscience researchers by offering multidisciplinary training in geroscience. Track 1 will address the specific training needs of basic scientists Track 2 will focus on clinicians and others conducting human subject research. This cross-institutional program would be accessible to all eligible trainees wishing to pursue a career in geroscience. Aim 3: Ensure optimal dissemination of the educational materials developed through this award. 3A. Videotaped lectures and other educational materials will be posted on POGOe with feedback surveys 3B. Our longer-range goal is to create a Geroscience Section in UpToDate®?an evidence-based, continually updated resource to ensure sustainability beyond the life of this NIA award