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Role of estrogen receptor-a in aging and sex-specific responses to 17a-estradiol

Award Number: R01AG070035
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: 06/30/2026

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Role of estrogen receptor-a in aging and sex-specific responses to 17a-estradiol - PROJECT SUMMARY/ABSTRACT Several pharmacological compounds have shown promise as interventional strategies for extending longevity. One recently studied compound shown to improve healthspan and longevity is 17α-estradiol (17α-E2). 17α-E2 is a diastereomer of 17β-estradiol (17β-E2) with considerably less binding affinity for classical estrogen receptors than 17β-E2. The NIA Interventions Testing Program has shown that 17α-E2 extends lifespan in male, but not female, mice at two doses. The mechanisms that promote sexually divergent responses to 17α-E2 are poorly understood and are aligned with the increasing recognition that aging and the incidence of specific diseases often differ between the sexes. This project will explore potential mechanisms by which 17α-E2 modulates aging and metabolism in a sex-specific manner. Successful completion of this project will determine: 1) if estrogen receptor α (ERα) is required for 17α-E2 to elicit benefits on healthspan, disease pathology, and lifespan, 2) if 17α-E2 modulates metabolic parameters predominantly through hypothalamic ERα-mediated signaling, 3) if the beneficial effects of 17α-E2 on metabolic parameters can be mimicked by activating hypothalamic ERα through chemogenetic approaches, and 4) if the elimination of endogenous estrogen production render female mice responsive to 17α-E2-mediated effects on metabolism, and if this is ERα dependent. We hypothesize that 17α- E2 signals through ERα in male mice to enhance healthspan and longevity and that these effects are at least partially mediated through the hypothalamus. We also hypothesize that female mice lacking endogenous estrogens will beneficially respond to 17α-E2 in an ERα-dependent manner. Aim 1: Determine if 17α-E2 improves healthspan and lifespan in an ERα-dependent manner. We will evaluate the effects of chronic 17α-E2 treatment on indices of healthspan and lifespan in wild-type and global ERαKO mice. Aim 2: Determine if 17α- E2 elicits metabolic benefits through ERα in the hypothalamus. We will evaluate the effects of 17α-E2 treatment on metabolic and healthspan parameters in mice with a hypothalamus-specific deletion of ERα using stereotaxic delivery of adeno-associated virus (AAV) that drives expression of Cre in ERα-flox mice. Aim 3: Determine if chemogenetic activation of hypothalamic ERα-expressing cells can mimic the health benefits observed with 17α- E2 treatment. We will evaluate the effects of stimulating hypothalamic ERα-expressing cells on metabolic and healthspan outcomes via site-specific expression of AAV Gq-coupled Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in ERα-flox mice. Aim 4: Determine if the elimination of endogenous estrogen production renders female mice responsive to 17α-E2 treatment. We will evaluate the effects of 17α-E2 treatment on metabolic and healthspan parameters in wild-type and global ERαKO female mice undergoing ovariectomy or 4-vinylcyclohexene diepoxide-induced ovarian insufficiency. The ultimate goal of this research is to develop sex-specific pharmacological interventions for attenuating aging and chronic 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: 2025 ( Subtotal = $505,160 )
2025	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	5	6/11/2025	NON-COMPETING CONTINUATION	$41,239
2025	2025	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	5	5/7/2025	NON-COMPETING CONTINUATION	$463,921
														Subtotal = $505,160

Issue Date FY: 2024 ( Subtotal = $514,469 )
2024	2024	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	4	6/14/2024	NON-COMPETING CONTINUATION	$514,469
														Subtotal = $514,469

Issue Date FY: 2023 ( Subtotal = $515,190 )
2023	2023	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	3	7/10/2023	NON-COMPETING CONTINUATION	$515,190
														Subtotal = $515,190

Issue Date FY: 2022 ( Subtotal = $514,994 )
2022	2022	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	2	7/8/2022	NON-COMPETING CONTINUATION	$514,994
														Subtotal = $514,994

Issue Date FY: 2021 ( Subtotal = $514,707 )
2021	2021	OKLAHOMA MEDICAL RESEARCH FOUNDATION	825 NE 13TH ST	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	8/14/2021	NEW	$514,707
														Subtotal = $514,707

Grand Total All Awards = $2,564,520

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Role of estrogen receptor-a in aging and sex-specific responses to 17a-estradiol

Award Number: R01AG070035

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: 06/30/2026

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