The impact of age on ketogenesis and the liver-GUT axis

The National Institute on Aging awarded Palo Alto Veterans Institute For Research a $596,400 Project Grant (CFDA 93.866, Aging Research) on August 1, 2026, to investigate the impact of age on ketogenesis and the liver-gut axis in metabolic disease. The research examines mechanistic factors underlying liver-gut cross-talk in aging, including the role of meta-inflammation, mitochondrial dysfunction, and ketogenesis in young versus old age groups. The recipient will focus on SHC protein modulation to increase ketogenesis and assess resulting improvements in liver and gut outcomes through multiple aims: evaluating SHC deletion effects in the liver and ketone body (beta-hydroxybutyrate) production and downstream effects on macrophage immunophenotype, enteric neuron structure, gastrointestinal motility, and intestinal permeability; exploring how beta-hydroxybutyrate reverses age-dependent changes in gut immunometabolism through FOXO3 signaling to preserve gastrointestinal and liver function in older age; and additional mechanistic studies to be conducted through the project period. Work will be performed in Palo Alto, California, with a period of performance from August 1, 2026, through July 31, 2031.

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.