Frailty is a complex clinical condition that is characterized by increased vulnerability to disability and high risk for mortality in older adults. Identifying biological mechanisms that protect from frailty is an important step in the development of effective therapies that protect from and delay frailty. Aging is a major risk factor for frailty; thus, studying biological mechanisms and populations that delay aging may lead to the identification of molecular factors that can protect from frailty. The biological approaches thus far have mainly focused on descriptive phenotypes, such as inflammatory plasma profile and candidate gene approaches, looking for risk factors for frailty. It is apparent, however, that frailty is a complex syndrome, akin to other complex disorders; thus, simplistic approaches that focus on one genetic variant or inflammatory biomarker at a time are unlikely to yield satisfactory progress. Moreover, to date, few attempts have been made to identify protective biological components of resilience to frailty. This proposal brings together a multidisciplinary team of experts who will tackle these barriers by applying state-of-the-art multi-omics approach to test the hypothesis that unique genomic, epigenomic and proteomic profiles, which are enriched among families with exceptional longevity, are associated with resilience to frailty. Frailty resilience will be quantified using a newly devised and validated measure, the Frailty Resilience Score (FRS), that incorporates the complex biology of frailty by integrating genetic risk in the form of frailty- specific polygenic risk score (PRS), age, and sex. The FRS will be studied in the context of a multi-omics approach to identify the genomic (Aim 1), epigenomic (Aim 2), and proteomic (Aim 3) components that protect from frailty. Whole exome sequencing and SNP arrays will be used to identify gene variants and gene sets associated with frailty resilience (Aim 1). DNA methylation across 850,000 CpG sites will be used for epigenomic discovery (Aim 2) and approximately 5,000 plasma proteins for the proteomic discovery (Aim 3) of resilience markers and pathways. Additionally, integration of proteomics with genomics and epigenomics will be performed to identify common mechanisms and pathways of frailty resilience. These approaches will be applied to a longitudinal cohort of older adults (n=1,400; mean age 76, median follow-up 8 years) from the ongoing LonGenity study, who are annually evaluated with frailty measures, have banked DNA, and whose samples have already been subjected to WES and proteomic analysis. This unique cohort is (1) enriched with protective genes, as half of them are offspring of centenarians and is (2) relatively homogeneous genetically, as all subjects are from an Ashkenazi Jewish founder population, a feature that increases the power for genetic and biological discovery. This multi-omics approach has the potential to both expand our understanding of biology and resul...