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The role of hepatocyte necroptosis and inflammation in liver-brain crosstalk in aging

Award Number: R01AG059718
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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The role of hepatocyte necroptosis and inflammation in liver-brain crosstalk in aging - Project Summary Chronic, low-grade inflammation (inflammaging) is a hallmark of aging and is one of the ‘seven pillars of aging’ associated with age-related diseases. Liver aging is characterized by an increase in chronic inflammation that is associated with chronic liver diseases (CLD), a leading cause of liver transplantation and mortality in the elderly. Liver inflammation and CLD are proposed to promote neuroinflammation and cognitive impairment in humans, supporting a role of liver in cognitive dysfunction. Despite the link between the liver-brain inflammation axis, pathway(s) promoting liver inflammation or how liver aging contributes to neuroinflammation or cognitive deficit is not known. Necroptosis is a cell death pathway that releases damage associated molecular patterns (DAMPs such as HMGB1) and promote inflammation through the activation innate immune cells. We found that necroptosis increases with age in the liver of mice, and inhibiting necroptosis (using Ripk3-/- or Mlkl-/- mice or pharmacological inhibitor) reduced HMGB1, proinflammatory M1 macrophages, proinflammatory cytokines, and liver pathology (steatosis and fibrosis) in the liver of old mice. Necroptosis inhibition improved autophagy and reduced cellular senescence, key pathways associated with inflammaging and liver pathology. Importantly, activating necroptosis specifically in hepatocytes of adult mice (7-month-old) impaired autophagy and increased cellular senescence, macrophage numbers, and proinflammatory cytokines in the liver. Together, these data support the conclusion that necroptosis is a key factor in liver inflammation and pathology through activation of macrophages and senescence in the liver. Our data show that hepatocyte-specific necroptosis increases neuroinflammation (proinflammatory cytokines and glial cell activation) and levels of circulating HMGB1, a known mediator of neuroinflammation. Neuroinflammation is a significant contributor to cognitive decline, and we found that hepatocyte necroptosis reduced nest building capacity, an early indicator of behavioral deficits in mice. Given that hepatocytes undergo age-related necroptosis and are the primary source to circulating HMGB1 in liver diseases, the central hypothesis of the proposal is that necroptosis activation specifically in hepatocytes will increase HMGB1 release from hepatocytes that will increase liver inflammation by activating macrophages, and liver pathology by increasing cellular senescence. Circulating HMGB1, in turn, will promote neuroinflammation and cognitive impairment through systemic effects. We will test this hypothesis using novel mouse models that allow us to either inhibit or activate necroptosis specifically in hepatocytes. Aim 1. Determine the role of hepatocyte specific necroptosis on macrophage activation and liver inflammation; Aim 2. Determine the role of hepatocyte specific necroptosis on cellular senescence and liver pathology; Aim 3. Determine the effects of hepatocyte specific necroptosis on neuroinflammation and brain function.


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 = $404,946 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	002	7	7/10/2025	NON-COMPETING CONTINUATION	$404,946
2025	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	6	4/8/2025	COMPETING CONTINUATION	$195,521
2025	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	5	4/8/2025	NON-COMPETING CONTINUATION	-$195,521
														Subtotal = $404,946

Issue Date FY: 2024 ( Subtotal = $409,430 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	6	7/3/2024	COMPETING CONTINUATION	$409,430
2024	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	5	6/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $409,430

Issue Date FY: 2023 ( Subtotal = $321,393 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	5	1/24/2023	NON-COMPETING CONTINUATION	$321,393
														Subtotal = $321,393

Issue Date FY: 2022 ( Subtotal = $466,393 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	4	2/17/2022	NON-COMPETING CONTINUATION	$289,253
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	002	4	5/18/2022	SUPPLEMENT FOR EXPANSION	$145,000
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	4	5/17/2022	NON-COMPETING CONTINUATION	$32,140
														Subtotal = $466,393

Issue Date FY: 2021 ( Subtotal = $321,393 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	3	2/16/2021	NON-COMPETING CONTINUATION	$321,393
														Subtotal = $321,393

Issue Date FY: 2020 ( Subtotal = $321,393 )
2020	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	2	2/27/2020	NON-COMPETING CONTINUATION	$321,393
														Subtotal = $321,393

Issue Date FY: 2019 ( Subtotal = $321,393 )
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	000	1	4/29/2019	NEW	$332,256
2019	2019	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Aging Research	001	1	5/15/2019	NEW	-$10,863
														Subtotal = $321,393

Grand Total All Awards = $2,566,341

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The role of hepatocyte necroptosis and inflammation in liver-brain crosstalk in aging

Award Number: R01AG059718

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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