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Aging and Estrogenic Control of the Bioenergetic System in Brain

Award Number: R37AG053589
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Aging and Estrogenic Control of the Bioenergetic System in Brain - Our earlier mechanistic analyses of estrogen action in brain led to the discovery that estrogen is a master regulator of the bioenergetic system in brain that promotes glucose transport, glucose metabolism, mitochondrial respiration and ATP generation. Collectively, the data provided compelling evidence for estrogen as a systems biology metabolic regulator in brain and illuminated compensatory mechanisms consistent with an aging female brain that is starving. For estrogen to function as master regulator of the bioenergetic system in the female brain, estrogen must be integrating nuclear and mitochondrial genomic responses. Further from a systems level perspective, it would be necessary for estrogen to also regulate cytoplasmic signaling mechanisms for real time feedback on the functional outcomes of nuclear and mitochondrial gene transcription. The fundamental issues to be investigated are the mechanisms whereby estrogen integrates bioenergetic responses across two genomic compartments while simultaneously monitoring energetic demand and performance in real time. The proposed program of research is designed to test two hypotheses. First, estrogenic control of the bioenergetic system in the female brain requires: 1) both nuclear and mitochondrial genomes; 2) integration of gene expression across both genomic compartments and 3) activation of rapid signaling cascades to provide real time feedback on bioenergetic performance. Second, we hypothesize that loss of estrogen in the aging female brain leads to a systematic dis-integration of estrogenic control of nuclear and mitochondrial genomes followed by decline in bioenergetic sensing mechanisms. Estrogenic control of the bioenergetic system of the brain and the dismantling thereof has basic, translational and clinical significance. From a discovery perspective the proposed program of research is unique in exploring the mechanisms underlying estrogenic integration of nuclear and mitochondrial gene expression and the real time feedback mechanisms that control the bioenergetic system of the brain. Further, the process by which this control system is dismantled in the aging female brain is uncharted territory of high significance for understanding bioenergetic aging in brain. Translationally, determining the mechanisms underlying the systematic dismantling of estrogenic integration of bioenergetic compartments in brain has the potential to detect therapeutic targets to sustain bioenergetic function in the aging female brain. Clinically, the aging transition of menopause, unique to the female, is a process that dismantles both reproductive ability and potentially bioenergetic capacity in brain. This is particularly relevant to age-related neurological conditions associated with deficits in glucose hypometabolism such as Alzheimer's, depression and multiple sclerosis which have greater prevalence in postmenopausal women. Research proposed herein aligns with NIA Strategic Research Goals A and C and the “need to better distinguish patterns of brain aging” https://www.nia.nih.gov/about/living-long-well-21st- century-strategic-directions-research-aging and to objectives of Office of Research on Women's Health.


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 = $526,505 )
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	9	3/13/2025	NON-COMPETING CONTINUATION	$483,526
2025	2025	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	001	9	6/18/2025	NON-COMPETING CONTINUATION	$42,979
														Subtotal = $526,505

Issue Date FY: 2024 ( Subtotal = $537,250 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	8	3/19/2024	NON-COMPETING CONTINUATION	$483,526
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	001	8	7/1/2024	NON-COMPETING CONTINUATION	$53,724
														Subtotal = $537,250

Issue Date FY: 2023 ( Subtotal = $537,250 )
2023	2023	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Aging Research	000	7	3/22/2023	NON-COMPETING CONTINUATION	$537,250
														Subtotal = $537,250

Issue Date FY: 2022 ( Subtotal = $537,250 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	6	4/7/2022	EXTENSION WITH OR WITHOUT FUNDS	$537,250
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	002	6	6/13/2022	EXTENSION WITH OR WITHOUT FUNDS	$72,650
2022	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	001	5	6/13/2022	NON-COMPETING CONTINUATION	-$72,650
														Subtotal = $537,250

Issue Date FY: 2021 ( Subtotal = $307,887 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	5	3/23/2021	NON-COMPETING CONTINUATION	$307,887
														Subtotal = $307,887

Issue Date FY: 2020 ( Subtotal = $308,390 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	4	3/6/2020	NON-COMPETING CONTINUATION	$308,390
														Subtotal = $308,390

Issue Date FY: 2019 ( Subtotal = $308,856 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	3	2/25/2019	NON-COMPETING CONTINUATION	$308,856
														Subtotal = $308,856

Issue Date FY: 2018 ( Subtotal = $309,287 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	2	3/12/2018	NON-COMPETING CONTINUATION	$278,358
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	001	2	4/19/2018	NON-COMPETING CONTINUATION	$30,929
														Subtotal = $309,287

Issue Date FY: 2017 ( Subtotal = $309,686 )
2017	2017	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Aging Research	000	1	3/10/2017	NEW	$309,686
														Subtotal = $309,686

Grand Total All Awards = $3,682,361

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Aging and Estrogenic Control of the Bioenergetic System in Brain

Award Number: R37AG053589

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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