Age associated decline in the conversion of leucine to β-Hydroxy-β-Methylbutyrate in rats

• Endogenous plasma levels of HMB decline with age in rats.
• A significant negative correlation was seen between plasma HMB levels and age.
• Levels of liver 4-HPPD, the enzyme involved in the conversion of keto-iso caproate to HMB were down-regulated with age.
• The conversion efficiency of leucine to HMB was reduced in older compared to younger rats.

BackgroundThe loss of muscle mass is considered to be a major factor contributing to strength decline during aging. β-Hydroxy-β-Methylbutyrate (HMB), a metabolite of leucine has been shown to enhance muscle protein synthesis and attenuate loss of muscle mass by multiple pathways. However, the production and regulation of endogenous levels of HMB over the lifespan have not been investigated.ObjectiveThe objective of the present study was to do a cross-sectional analysis of the basal plasma levels of HMB in male Sprague–Dawley rats of different ages and to compare the efficiency of conversion of leucine to HMB in young versus older rats.MethodsPlasma levels of HMB and α-ketoisocaproate (KIC) were analyzed in rats of different age groups (3, 9, 12 and 24 months old, n = 10 per group). Levels of 4-HPPD, the enzyme involved in the conversion of KIC to HMB in the liver were determined by ELISA. The conversion efficiency of leucine to HMB was compared between 3 and 24 month rats after an oral bolus dose of leucine.ResultsEndogenous circulating levels of HMB were significantly reduced in older age rats compared to young rats (100 ± 3.7 vs 156 ± 10 (mean ± SEM), ng/mL, p < 0.001). A significant negative correlation was seen between HMB levels and age. The liver levels of 4-HPPD were found to be significantly lower in old versus young rats. Consistent with this, the conversion efficiency of leucine to HMB was significantly lower in the aged versus young cohorts.ConclusionsIn summary, this study depicts for the first time that the basal levels of HMB, a metabolite of amino acid leucine, declines with age, and that this decline is due to perturbations in the key enzyme 4-HPPD which catalyzes the conversion of KIC to HMB. As a consequence, the efficiency of conversion of leucine to HMB is diminished in older rats compared to younger rats.