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Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

ABSTRACT: Dietary protein has emerged as a key regulator of metabolic health in humans and rodents. Many of the benefits of protein restriction (PR) are mediated by reduced consumption of dietary branched-chain amino acids (BCAAs; leucine, valine and isoleucine), and restriction of BCAAs is sufficient to extend healthspan and lifespan in mice. The metabolic benefits of BCAA restriction are mediated by isoleucine and valine, with isoleucine restriction being sufficient to extend lifespan in male mice. However, the effect of valine restriction on healthy aging remains unknown. In this study, we placed young C57BL/6J mice of both sexes on either control or valine restricted (Val-R) diets and followed them longitudinally as they aged. We found that Val-R-fed male and female mice displayed significantly improved glucose regulation and increased energy expenditure, coinciding with decreased body weight and adiposity. These benefits are independent of FGF21, and mTORC1, signaling pathways associated with metabolism and aging. Further, we performed transcriptomic analysis on the liver, muscle and brown adipose tissue, and found tissue- and sex-specific changes in response to Val-R. Lastly, Val-R reduces frailty and extends the median lifespan of male, but not female, mice by 19%. Our results demonstrate that Val-R improves multiple aspects of health in mice of both sexes and extends lifespan in males, and suggests that interventions that mimic Val-R may have translational potential for aging and age-related diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE298741 | GEO | 2026/05/11

REPOSITORIES: GEO

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Project description:Abstract: Non-alcoholic steatohepatitis (NASH) is associated with a disturbed metabolism in liver and excessive accumulation of ectopic fat. Branched-chain amino acids (BCAAs) may beneficially modulate hepatic lipids, however it remains unclear whether individual BCAAs can attenuate already established NASH and oxidative-inflammatory stress associated with it. Therefore, mice were first put on a run-in fast food diet (FFD) for 26 weeks, these obese mice were then treated with individual BCAAs valine or isoleucine (3% of FFD) for another 12 weeks and compared to FFD controls. Valine and isoleucine treatment did not affect obesity, dyslipidemia, gut permeability or fecal fatty acid excretion, although significantly reduced hyperinsulinemia compared with FFD. Valine and isoleucine significantly reduced ALT, CK-18M30, and liver steatosis with a particularly pronounced effect on the microvesicular component (-61% by valine and -71% by isoleucine). Hepatic 4-hydroxynonenal (4-HNE) immunoreactivity, a marker for oxidative stress-induced lipid peroxidation, was also significantly decreased. Functional genomics analysis demonstrated that valine and isoleucine upregulated BCAA metabolism, deactivated master regulators of anabolic pathways related to steatosis (e.g. SREBPF1) and activated master regulators of mitochondrial biogenesis (e.g. PPARGC1a) and lipid catabolism (e.g. ACOX1, AMPK). The correction of critical metabolic pathways by valine and isoleucine was accompanied by a significant decrease of liver inflammation, and suppression of many FFD-stimulated cytokine and chemokine pathways including IL-1β, TNFα and CCR2 signaling. In conclusion, the dietary intervention with either valine or isoleucine corrected multiple metabolic processes in liver and reduced steatosis and inflammation with profound effects on oxidative stress and inflammatory pathways. Methods: Putative antifibrotic effects of butyrate were studied in Ldlr-/-.Leiden mice fed an obesogenic NASH-inducing diet (HFD) containing 2.5% (w/w) butyrate for 38 weeks and compared to an HFD control group. Antifibrotic mechanisms of butyrate were further investigated in TGF-β-stimulated primary human hepatic stellate cells (HSC). Results: HFD-fed mice developed obesity, insulin resistance, increased levels of plasma leptin, adipose tissue inflammation, gut permeability, dysbiosis and NASH-associated fibrosis. Butyrate corrected hyperinsulinemia, lowered plasma leptin levels and attenuated adipose tissue inflammation, without affecting gut permeability or microbiota composition. Butyrate lowered plasma ALT and CK-18M30 and attenuated hepatic steatosis and inflammation. Butyrate inhibited fibrosis development as demonstrated by decreased hepatic collagen content and Sirius-red-positive area. In TGF-β-stimulated HSC, butyrate dose-dependently reduced collagen deposition and decreased procollagen1α1 and PAI-1 protein expression. Transcriptomic analysis and subsequent pathway and upstream regulator analysis revealed deactivation of specific non-canonical TGF-β signaling pathways RhoA/Rock and PI3K/AKT and other important pro-fibrotic regulators (e.g. YAP/TAZ and MYC) by butyrate, providing a potential rationale for its antifibrotic effects. Conclusions: Butyrate protects against the development of obesity and insulin resistance-associated NASH and liver fibrosis. These antifibrotic effects are at least in part attributable to a direct effect on collagen production in hepatic stellate cells, as a result of inhibiting non-canonical TGF-β signaling.

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Lifelong restriction of dietary valine has sex-specific benefits for health and lifespan in mice

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