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Multi-omics approach to frailty resilience

Award Number: R01AG044829
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2014
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Multi-omics approach to frailty resilience - 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 935,000 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 9 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 result in discovery of biomarkers for frailty resilience. Understanding the biologic mechanisms that protect from multi-system failure in older adults is a first step in generating interventions against frailty; while identification of biomarkers will inform us, in the short-term, of the effectiveness of interventions that aim to delay aging and frailty.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $719,587 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	8	8/22/2024	COMPETING CONTINUATION	$719,587
														Subtotal = $719,587

Issue Date FY: 2020 ( Subtotal = -$7,674 )
2020	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	7	9/20/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$7,674
														Subtotal = -$7,674

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	002	6	7/25/2019	NON-COMPETING CONTINUATION	-$41,221
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	6	2/9/2019	NON-COMPETING CONTINUATION	-$210,272
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	001	7	2/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,272
2019	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	003	7	7/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$41,221
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $648,591 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	6	4/23/2018	NON-COMPETING CONTINUATION	$648,591
														Subtotal = $648,591

Issue Date FY: 2017 ( Subtotal = $657,603 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Aging Research	000	5	6/30/2017	NON-COMPETING CONTINUATION	$657,603
														Subtotal = $657,603

Issue Date FY: 2016 ( Subtotal = $666,393 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Aging Research	000	4	4/15/2016	NON-COMPETING CONTINUATION	$666,393
														Subtotal = $666,393

Issue Date FY: 2015 ( Subtotal = $654,761 )
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Aging Research	002	2	9/22/2015	NON-COMPETING CONTINUATION	-$423,242
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Aging Research	001	3	9/22/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$423,242
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Aging Research	000	2	5/11/2015	NON-COMPETING CONTINUATION	$654,761
														Subtotal = $654,761

Issue Date FY: 2014 ( Subtotal = $680,722 )
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Aging Research	000	1	6/18/2014	NEW	$680,722
														Subtotal = $680,722

Grand Total All Awards = $4,019,983

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Multi-omics approach to frailty resilience

Award Number: R01AG044829

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2014

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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