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Development of a Predictive Frailty Clock & Longitudinal Investigation of its Epigenetic Determinants

Award Number: R00AG070102
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Development of a Predictive Frailty Clock & Longitudinal Investigation of its Epigenetic Determinants - Project summary/abstract Longevity studies in mice are expensive and time-consuming, and there are currently no measures that can predict mortality in a mouse at an earlier time-point. Additionally, there are very few measures of the overall health of mice that can be assessed longitudinally. In humans, frailty can predict mortality with greater power than the DNA methylation clock. In my early postdoctoral work I have validated a mouse frailty index, that increases with age, is associated with mortality and age-related pathologies, and is sensitive to interventions. In the Sinclair lab I have used machine learning modelling of this mouse frailty index to make the Analysis of Frailty in Death (AFRAID) clock that can predict the lifespan of male C57BL/6 mice aged 21 months or older with accuracy of approximately 1.7 months. We hypothesis that frailty clocks that include a range of measures including physiological and molecular measures (blood-based Analysis of Frailty in Death, bAFRAID) will accurately predict lifespan in younger, female mice and different strains. To test this hypothesis I will use previously collected longitudinal health and molecular data from C57BL/6 mice, as well as collect lifelong health data, plus blood and stool samples, from UM-HET3 mice. I will use regression modelling of all measured outcomes to develop optimized ‘bAFRAID clocks’ that predict time to death in mice of both strains, and both sexes. For Aim 2, I will test the hypothesis that epigenetic dysregulation underlies the development of frailty in mice. I will use longitudinal assessments, and cutting-edge epigenetic tools (including TIMEseq for DNA methylation and CUT&Tag for histone modifications) to investigate the relationship between epigenetic changes and the bAFRAID clocks. Completion of this project will provide important tools for the field, and allow us to understand whether epigenetic changes precede the development of frailty in mice.


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: 2025 ( Subtotal = $375,620 )
2025	2025	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	003	5	7/18/2025	SUPPLEMENT FOR EXPANSION	$131,600
2025	2025	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	000	5	5/1/2025	NON-COMPETING CONTINUATION	$224,100
2025	2025	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	002	5	6/20/2025	NON-COMPETING CONTINUATION	$19,920
2025	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	001	4	5/14/2025	TERMINATION	$0
														Subtotal = $375,620

Issue Date FY: 2024 ( Subtotal = $497,373 )
2024	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	002	4	5/2/2024	NON-COMPETING CONTINUATION	$249,000
2024	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	000	3	12/15/2023	SUPPLEMENT FOR EXPANSION	$37,277
2024	2024	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	003	4	5/6/2024	SUPPLEMENT FOR EXPANSION	$111,830
2024	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	001	3	12/20/2023	EXTENSION WITH OR WITHOUT FUNDS	$99,266
														Subtotal = $497,373

Issue Date FY: 2023 ( Subtotal = $249,000 )
2023	2023	INSTITUTE FOR SYSTEMS BIOLOGY	401 TERRY AVE N	SEATTLE	WA	98109	KING	USA	Aging Research	000	3	5/8/2023	EXTENSION WITH OR WITHOUT FUNDS	$249,000
														Subtotal = $249,000

Grand Total All Awards = $1,121,993

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Development of a Predictive Frailty Clock & Longitudinal Investigation of its Epigenetic Determinants

Award Number: R00AG070102

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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