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Proteostasis and metabolism in brain aging

Award Number: R01AG057353
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Proteostasis and metabolism in brain aging - PROJECT SUMMARY Age-related neurodegenerative diseases like Alzheimer’s Disease exhibit a breakdown in neuronal protein homeostasis (proteostasis). The relationship between age-related metabolic dysfunctions and protein aggregation in such diseases remains poorly understood. Elucidating the molecular basis for the age-related loss of proteostasis is expected to inspire new therapeutic approaches, not only for diseases like Alzheimer’s, but more broadly for a wide range of age-related diseases. Increasingly, this promise of “Geroscience” is being recognized as critical for extending our healthspan. Among the most productive experimental approaches in Geroscience is the use of genetically accessible model systems for the study of longevity. These models have allowed the identification of single gene mutations and of interventions that extend lifespan, highlighting the plasticity of the aging process and suggesting avenues to significantly alter its course. The cellular events impacted by such interventions and causing the lifespan extension, however, remain largely unclear. In many cases, the effect on longevity is associated with changes in proteostasis and metabolism. To understand the relationship between proteostasis and longevity in detail, however, requires an integrated approach that investigates the effects of lifespan extending perturbations on global protein homeostasis and metabolic flux in a well-defined genetic system. Here, the applicants propose such integration by combining the expertise of groups using genetic approaches (Jasper), proteomic and bioinformatic approaches (Schilling and Ghaemmaghami), and metabolomic approaches (Ramanathan) to develop models for protein and metabolic homeostasis in long-lived mutants of Drosophila. Recent technological advances in the field of mass spectrometry have enabled global analyses of protein turnover rates and metabolic flux in complex organisms. Combining these technologies with detailed analysis of lifespan-extending genetic perturbations is expected to provide transformative new insights into molecular changes required for longevity. The aims proposed by the applicants are to (i) assess age-related changes in global protein turnover and metabolic flux, (ii) determine if changes in energy metabolism downstream of the Jun-N-terminal Kinase and Insulin signaling pathways influence protein turnover, and (iii) perform genetic studies to explore the causes of aging and longevity. It is anticipated that combining the strengths of the Drosophila system with state-of-the-art proteomic and metabolomic approaches will significantly accelerate the discovery of fundamental mechanisms influencing physiology and cell function with age, providing new therapeutic avenues for age-related diseases.


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 = $0 )
2024	2021	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	1/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $626,560 )
2021	2021	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	001	5	6/16/2021	NON-COMPETING CONTINUATION	$626,560
2021	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	4	12/29/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $626,560

Issue Date FY: 2020 ( Subtotal = $626,560 )
2020	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	4	6/4/2020	NON-COMPETING CONTINUATION	$626,560
														Subtotal = $626,560

Issue Date FY: 2019 ( Subtotal = $626,560 )
2019	2019	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	3	5/23/2019	NON-COMPETING CONTINUATION	$626,560
														Subtotal = $626,560

Issue Date FY: 2018 ( Subtotal = $626,560 )
2018	2018	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	5/21/2018	NON-COMPETING CONTINUATION	$626,560
														Subtotal = $626,560

Issue Date FY: 2017 ( Subtotal = $636,140 )
2017	2017	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	9/8/2017	NEW	$636,140
														Subtotal = $636,140

Grand Total All Awards = $3,142,380

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Proteostasis and metabolism in brain aging

Award Number: R01AG057353

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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