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Regulation of the Autophagy Pathway with Age and in Long-lived Animals

Award Number: R01AG038664
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2011
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Regulation of the Autophagy Pathway with Age and in Long-lived Animals - PROJECT SUMMARY Macroautophagy (referred to as autophagy) is a major cellular recycling process by which cytosolic material is sequestered into double-membrane vesicles or autophagosomes (i.e., early steps of autophagy), which subsequently fuse with lysosomes to ensure cargo degradation (i.e., late steps of autophagy). This complex, multi-step process plays key roles in organismal development and age-related diseases, and numerous direct links exist between autophagy and aging, including that multiple conserved longevity paradigms require autophagy genes for their lifespan extension; the current paradigm suggest that such long-lived animals induce autophagic turnover in a beneficial manner, yet the underlying mechanisms remain elusive. Our research in the previous funding cycle has provided a deeper understanding of the relationship between autophagy and aging in the nematode C. elegans. First, our work using cytological markers has indicated an age-related decline in late-steps of autophagy with variable trajectories in different tissues. Moreover, we have observed a differential regulation of autophagy in long-lived mutants in a tissue-specific fashion. Second, we have discovered unexpected longevity roles for specific autophagy genes in C. elegans neurons, indicating possibly non-canonical functions different from lysosomal degradation, an emerging concept in the autophagy research field which has yet to be investigated in the context of aging. Finally, we have conducted unbiased genetic and biochemical screens to identify new candidate autophagy regulators and receptors, and together with our collaborators identified a small compound that increase autophagy in both mammalian cells and in C. elegans and extends lifespan. Our prior studies provide us with new and specific hypotheses that we aim to test in depth in this renewal. Specifically, we will use a powerful combination of genetic and biochemical approaches to ask if fusion- and/or lysosomal degradation is a limiting step of the autophagy process in relation to organismal aging and longevity (Aim 1); we will ask if neuronal autophagy genes affect aging by cell non-autonomous means (Aim 2); and, finally, we will ask if new candidate autophagy receptors and autophagy-modulating molecules possess roles in longevity and in disease models (Aim 3). Autophagy plays critical roles in many disorders, including age-linked diseases such as neurodegeneration. Understanding the regulation of autophagy and the conserved mechanisms by which autophagy affect aging in multicellular organisms like C. elegans are likely to provide new important insights not only into aging and may also help develop treatments for such age-related diseases, including neurodegenerative disorders.


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 = $575,400 )
2025	2025	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	13	12/10/2024	NON-COMPETING CONTINUATION	$575,400
														Subtotal = $575,400

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	12	11/30/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $618,179 )
2023	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	12	1/5/2023	NON-COMPETING CONTINUATION	$618,179
														Subtotal = $618,179

Issue Date FY: 2022 ( Subtotal = $602,822 )
2022	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	002	11	3/10/2022	COMPETING CONTINUATION	$0
2022	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	001	11	2/4/2022	COMPETING CONTINUATION	$602,822
2022	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	10	12/20/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $602,822

Issue Date FY: 2020 ( Subtotal = $399,750 )
2020	2020	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	10	4/27/2020	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2019 ( Subtotal = $399,750 )
2019	2019	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	9	4/18/2019	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2018 ( Subtotal = $399,750 )
2018	2018	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	8	5/17/2018	NON-COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2017 ( Subtotal = $399,750 )
2017	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	7	4/17/2017	NON-COMPETING CONTINUATION	$359,775
2017	2017	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	7	6/19/2017	NON-COMPETING CONTINUATION	$39,975
														Subtotal = $399,750

Issue Date FY: 2016 ( Subtotal = $399,750 )
2016	2016	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	6	8/31/2016	COMPETING CONTINUATION	$399,750
														Subtotal = $399,750

Issue Date FY: 2015 ( Subtotal = $370,734 )
2015	2015	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	5	5/18/2015	NON-COMPETING CONTINUATION	$370,734
														Subtotal = $370,734

Issue Date FY: 2014 ( Subtotal = $382,200 )
2014	2014	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	4	6/14/2014	NON-COMPETING CONTINUATION	$382,200
														Subtotal = $382,200

Issue Date FY: 2013 ( Subtotal = $361,179 )
2013	2013	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	3	7/25/2013	NON-COMPETING CONTINUATION	$361,179
														Subtotal = $361,179

Issue Date FY: 2012 ( Subtotal = $382,200 )
2012	2012	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	2	7/10/2012	NON-COMPETING CONTINUATION	$382,200
														Subtotal = $382,200

Issue Date FY: 2011 ( Subtotal = $374,360 )
2011	2011	SANFORD-BURNHAM MEDICAL RESEARCH INSTITUTE	10901 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	1	8/3/2011	NEW	$374,360
														Subtotal = $374,360

Grand Total All Awards = $5,665,824

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Regulation of the Autophagy Pathway with Age and in Long-lived Animals

Award Number: R01AG038664

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2011

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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