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The Impact of Age on Ketogenesis and the Liver-Gut Axis

Award Number: R01AG092825
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2031

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The Impact of Age on Ketogenesis and the Liver-Gut Axis - PROJECT SUMMARY/ABSTRACT The prevalence of metabolic disease affecting the liver and gut is steadily increasing during aging, significantly contributing to morbidity and mortality in the elderly. The hepatic consequences (MASLD/MASH) and gut dysfunction are recognized, however, there are paucity of data on how these entities are interlinked. Specifically, the mechanistic factors that underlie the liver-gut cross talk are not well understood, and the role of meta- inflammation, dysregulation of mitochondrial function and ketogenesis have not been adequately evaluated in the young vs. old age groups. We demonstrated that targeting the Src homology 2 domain containing (Shc) proteins provides several benefits with an increase in ketogenesis and improvement in lipid peroxidation. On the other hand, age-dependent decrease in Foxo3 in the gut is connected to neuro-inflammation and decreased motility. We propose a novel paradigm that, in aging, a dysregulated liver-gut axis promotes a feed-forward loop whereby meta-inflammatory processes in both organs are accelerated. We hypothesize that increasing ketogenesis during aging could translate into reducing liver and gut inflammatory cascades, improving their function. To address this hypothesis, we will focus on the mechanistic aspects of Shc deletion in the liver (Aim 1), in full or hepatocyte-specific Shc knockdowns, as well as by in vivo p46Shc induction or deletion models, to modulate ketogenesis, and assess liver and gut outcomes (young vs. old mice). We will investigate how beta hydroxybutyrate (BHB) production is modulated and the downstream effects it has on the gut, including macrophage immunophenotype, enteric neuron structure, GI motility, and intestinal permeability. In Aim 2, we will explore how BHB can reverse age-dependent changes in gut immunometabolism via Foxo3 signaling and preserve GI and liver function in old age. In Aim 3, we will undertake studies focusing on the liver and gut effects of the Shc inhibitor Idebenone that has ketogenic effects, in young and old mice in treatment protocols. These studies will help to understand the age-specific dysregulated circuitry between these organs and establish a framework for developing effective treatment options for the elderly.


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: 2026 ( Subtotal = $596,400 )
2026	2026	PALO ALTO VETERANS INSTITUTE FOR RESEARCH	3801 MIRANDA AVE	PALO ALTO	CA	94304	SANTA CLARA	USA	Aging Research	000	1	7/20/2026	NEW	$596,400
														Subtotal = $596,400

Grand Total All Awards = $596,400

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The Impact of Age on Ketogenesis and the Liver-Gut Axis

Award Number: R01AG092825

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2031

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