Resource Core 2 (RC2) Biological Mechanisms Core: Project Summary The identification of the etiologies of frailty and age-related vulnerability remains a crucial challenge for gerontological research. Key to this challenge are the development of a better understanding of the underlying biological basis that contributes to frailty and the identification of key biological pathways for the development of interventions that might help prevent or alleviate frailty and loss of independence. The goal of Johns Hopkins Older Americans Independence Center (OAIC) Biological Mechanisms Core (RC-2) is to enable the next generation of frailty-related etiological discovery and to promote the translation of these discoveries into clinically relevant diagnostic, preventive, and treatment modalities. This will be achieved through the provision of high-quality biological and bioengineering measurement expertise, incorporation of new technologies, analytical and computational expertise for genetics and omics analyses, and infrastructure necessary to attain this goal. In order to comprehensively encompass the biological expertise necessary to study frailty-related etiology, we have engaged a leadership team and internal consultants with complementary and synergistic biological and translational expertise needed to unravel the complex biological mechanisms that underpin frailty. They also all bring mentorship skills for trainees, and infrastructure to RC-2 and national prominence to frailty research. The specific aims of RC-2 are to: 1) provide state of the art scientific expertise, infrastructure, and technology necessary to advance biological and etiological research related to frailty, 2) provide access to biological samples from human subjects and from animal models necessary to test hypotheses related to frailty, 3) facilitate the translation of biological findings into interventions or prevention-focused clinical studies, 4) provide training, mentorship, and guidance to promising junior investigators around biological mechanisms that impact frailty, and 5) provide institutional and external visibility for RC-2 related science and activities. Our aims will be accomplished through close communication between the core leaders and their laboratories, close partnership with the other OAIC cores, and the engagement of expert consultants in the highly relevant areas of mitochondrial measurement, metabolomics, epigenetics, mouse model development, nanotechnologies for diagnostic and treatment development, and the development of multi-omic analyses related to frailty. By providing these resources, RC-2 will foster high quality research that elucidates clinically relevant biological pathways that underlie frailty and related interventions that hold promise to attenuate frailty, related conditions, and the loss of independence.