Aging is the leading risk factor for the disorders that account for the bulk of the nation's morbidity, mortality, and health costs. Recent findings suggest it is feasible to alleviate such disorders as a group by targeting fundamental aging processes. Several such interventions are near the point of entering human proof-of-concept clinical trials. Since interventions that increase lifespan and healthspan in mammals now exist, we hypothesize that clinical interventions targeting fundamental mechanisms of aging may delay, prevent, or treat age-related diseases and disabilities as a group, instead of one at a time. To accelerate testing this hypothesis, we propose a Translational Geroscience Network (TGN). Planning began 4 years ago through an NIA R24 grant involving 122 investigators in the biology of aging and clinical geriatrics. Our goal is to mature this network into a national resource starting with a subgroup of centers committed to working together using common measures and protocols allowing network-wide learning from complementary, small-scale, proof-of- concept ?use case? clinical studies. Aim 1 is to establish a TGN to develop, implement, test, and harmonize methods and standard operating protocols (SOPs) for translational early phase trials of agents that target fundamental aging processes. The TGN will support development, coordination, and infrastructure around independently-funded ?use case? trials (2-3 per year) using re-purposed drugs for which preclinical or clinical data already exist, such as a multicenter trial of senolytics for idiopathic pulmonary fibrosis, a trial of a different drug to reduce senescent cell burden and alleviate frailty in older women, and a trial of metformin to enhance immune responses to influenza vaccination. Based on these ?use case? trials, we will streamline and harmonize approvals, recruitment, sample collection, SOPs, and analytic procedures across the TGN. Aim 2 is to select, optimize, and validate ancillary measures of fundamental aging processes to be assayed across all trials to establish reference analytical capabilities. An existing cell senescence assay facility will be expanded to analyze blood, other body fluids, cells, and biopsies from trials across and beyond the TGN to serve as a national resource. New assays will be developed and optimized. The facility will expand to include laboratories beyond the TGN and incorporate assays of key basic aging mechanisms, including mTOR activity, proteostasis, autophagy, mitochondrial function, and epigenetics. Aim 3 is to provide statistical and data management support to select efficient study designs, provide sample size estimates and support a TGN-wide data entry platform to facilitate cross-study comparisons. Aim 4 is to develop a biobanking and repository network for samples from the clinical trials to permit future analyses as new ancillary research questions are developed and assays become available. A system for disseminating samples to the basic biology of aging community, biobanking protocols, and operating manuals will be developed. Translating agents targeting basic aging processes into interventions for the major chronic diseases and age-related disabilities could be transformative.

R33AG061456

2019-02-01

2023-11-30