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Respiratory Control in Old Age

Award Number: R01AG044615
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2013
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Respiratory Control in Old Age - By 2030, ~70 million people in the USA will be >65 years old with ~10 million >85 years old. The studies proposed in this competitive renewal application are motivated by our previous finding that larger phrenic motor neurons (PhMNs) are selectively lost in old age and the work of others implicating mitochondrial disruption in motor neuron death. BDNF/TrkB signaling mediates CREB phosphorylation at serine 133 (pCREBs133), which promotes mitochondrial remodeling via gene targeting of PGC1a. Activity dependent pAMPK signaling also mediates pCREBs133 phosphorylation and PGC1a expression. It appears that BDNF/TrkB signaling in PhMNs is reduced in old age, but activity of smaller PhMNs persists to support breathing, which may underlie their sparing in old age. It is also well established that circulating TNFa is elevated with aging. In other cell types, we found that TNFa selectively activates the IRE1a/sXBP1 ER stress pathway, which induces mitochondrial fragmentation and mitophagy. Our experimental design involves a comprehensive array of novel techniques already established and validated in our lab. The results of the proposed studies will guide development of novel therapeutic approaches targeting BDNF/TrkB or pCREBs133 phosphorylation (e.g., quercetin) and/or TNFa induced IRE1a/sXBP1 ER stress (e.g., infliximab) to promote PhMN survival. Conceptual Framework: We hypothesize that mitochondrial volume density (MVD) and respiratory capacity (SDHmax) in PhMNs are affected by the balance between mitochondrial biogenesis and mitophagy. Mitochondrial biogenesis is regulated via pCREBs133 phosphorylation and PGC1a expression, which is triggered by both activity (via pAMPK – Aim 1) and BDNF/TrkB.FL signaling (Aim 2). In old age, the influence of BDNF/TrkB.FL signaling is diminished especially in larger PhMNs, while activity of smaller PhMNs persists. Furthermore, serum TNFa is elevated in old age, which induces pIRE1a/sXBP1 ER stress leading to mitophagy (Aim 3). Aim 1: Determine the role of pAMPK/pCREB/PGC1a signaling in maintaining mitochondrial volume density in smaller PhMNs.. Aim 2: Determine the impact of reduced BDNF/TrkB/pCREB signaling in age-related remodeling of mitochondria in PhMNs. Aim 3: Determine the impact of TNFa induced activation of the IRE1a/sXBP1 ER stress pathway in age-related remodeling of mitochondria in PhMNs.


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 = $602,958 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	13	7/31/2025	NON-COMPETING CONTINUATION	$602,958
2025	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	11	2/19/2025	COMPETING CONTINUATION	$79,933
2025	2022	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	10	2/19/2025	NON-COMPETING CONTINUATION	-$79,933
														Subtotal = $602,958

Issue Date FY: 2024 ( Subtotal = $615,263 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	12	7/9/2024	NON-COMPETING CONTINUATION	$615,263
														Subtotal = $615,263

Issue Date FY: 2023 ( Subtotal = $615,263 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	11	7/18/2023	COMPETING CONTINUATION	$615,263
2023	2022	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	10	7/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $615,263

Issue Date FY: 2022 ( Subtotal = $605,695 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	10	4/21/2022	NON-COMPETING CONTINUATION	$605,695
														Subtotal = $605,695

Issue Date FY: 2021 ( Subtotal = $605,695 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	9	3/17/2021	NON-COMPETING CONTINUATION	$605,695
														Subtotal = $605,695

Issue Date FY: 2020 ( Subtotal = $605,695 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	8	3/31/2020	NON-COMPETING CONTINUATION	$605,695
														Subtotal = $605,695

Issue Date FY: 2019 ( Subtotal = $605,695 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	7	3/18/2019	NON-COMPETING CONTINUATION	$605,695
2019	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	6	3/11/2019	COMPETING CONTINUATION	$125,546
2019	2017	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	5	3/11/2019	NON-COMPETING CONTINUATION	-$125,546
														Subtotal = $605,695

Issue Date FY: 2018 ( Subtotal = $605,695 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	002	6	8/30/2018	COMPETING CONTINUATION	$26,647
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	6	6/15/2018	COMPETING CONTINUATION	$579,048
2018	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	5	6/14/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $605,695

Issue Date FY: 2017 ( Subtotal = $414,788 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	001	5	6/20/2017	NON-COMPETING CONTINUATION	$41,479
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	5	4/28/2017	NON-COMPETING CONTINUATION	$373,309
														Subtotal = $414,788

Issue Date FY: 2016 ( Subtotal = $414,788 )
2016	2016	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	4	4/30/2016	EXTENSION WITH OR WITHOUT FUNDS	$414,788
														Subtotal = $414,788

Issue Date FY: 2015 ( Subtotal = $402,345 )
2015	2015	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	3	5/6/2015	NON-COMPETING CONTINUATION	$402,345
														Subtotal = $402,345

Issue Date FY: 2014 ( Subtotal = $414,788 )
2014	2014	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	2	6/14/2014	NON-COMPETING CONTINUATION	$414,788
														Subtotal = $414,788

Issue Date FY: 2013 ( Subtotal = $414,788 )
2013	2013	MAYO CLINIC	200 FIRST STREET, S. W.	ROCHESTER	MN	55905	OLMSTED	USA	Aging Research	000	1	5/24/2013	NEW	$414,788
														Subtotal = $414,788

Grand Total All Awards = $6,923,456

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Respiratory Control in Old Age

Award Number: R01AG044615

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2013

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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