(OR22-01-25) Sex- and Diet- Dependent Effects of Microbiome-Derived Metabolite δ-Valerobetaine on Aging

Objectives: We recently found that δ-valerobetaine (δ-VB), a gut microbiome-derived metabolite, inhibits carnitine-dependent mitochondrial fatty acid metabolism and promotes fat accumulation in young mice fed to a Western diet but not in those on a chow diet. Previous studies demonstrated that aged mice have higher δ-VB levels in the brain than young mice, and δ-VB injections impair cognitive performance. Given that δ-VB may have more pronounced effects in aging, this study aimed to evaluate its sex- and diet-dependent effects in aged male and female mice fed either a standard or a Western diet.

Methods: Female and male mice, aged 18-20 months (C57BL/6J), had ad libitum access to either a standard diet (13% kcal from fat) or a Western diet (40% kcal from fat) with water with or without 1.62 mM δ-VB for 12 weeks. We conducted a Y-maze test to measure cognitive function and a grip strength test to assess muscle function, aiming to test whether VB aggravates aging phenotypes.

Results: In mice fed a standard diet, δ-VB significantly increased the body weight gain in females (Control, -0.3±1.3%; δ-VB, 5.7±2.2%; p: 0.02) but not in males. Conversely, in mice fed a Western diet, δ-VB showed a trend toward increased body weight gain in males (Control: 28.1±3.3%; δ-VB: 38.7±5.1%; p: 0.1) but did not reach statistical significance. Under the standard rodent diet condition, δ-VB impaired cognitive function only in males (Control, 66.7±2.2%; δ-VB, 58.8±3.0%; p: 0.04), with no observed effects in females. Under the Western diet condition, a paired t-test comparing initial (Week 0) and final (Week 12) data revealed a significant decrease in cognitive function only in female mice treated with δ-VB (Week 0: 67.7±2.9%; Week 12: 49.8±4.3%; p: 0.02). In contrast, no significant change was observed in female mice with control water (Week 0: 64.7±3.1%; Week 12: 56.6±2.9%; p: 0.1). δ-VB did not influence grip strength in either sex under either dietary condition.

Conclusions: Our data show that δ-VB exacerbates age-related phenotype in a sex- and diet-dependent manner.

Funding Sources: This project was supported by the National Institute on Aging grant R21 AG080247.