Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.

MCK-PGC1α transgenic mice had significantly higher kynurenine aminotransferase (KAT) expression compared with wildtype littermates.

• KAT expression was approximately 2-5-fold higher in MCK-PGC1α mice compared with wildtype littermates.
• The difference was statistically significant for all KAT isoforms (p < 0.0001 for all isoforms).
• KATs degrade L-Kynurenine into kynurenic acid and are regulated by PGC1α.
• This finding supports the mechanism by which PGC1α overexpression increases skeletal muscle capacity for L-Kyn metabolism.

Dietary elevation of L-Kynurenine decreased treadmill endurance capacity and daily physical activity in male mice.

• A main effect of L-Kyn diet was observed for decreasing treadmill endurance capacity in male mice (p ≤ 0.002).
• A main effect of L-Kyn diet was observed for decreasing daily physical activity in male mice (p ≤ 0.002).
• Physical function was assessed longitudinally from 16 to 24 months of age.
• The cohort included both MCK-PGC1α transgenic mice and wildtype littermates of both sexes (n = 262).

Dietary elevation of L-Kynurenine decreased maximal walking speed in female mice.

• A main effect of L-Kyn diet for decreasing maximal walking speed was found in female mice (p = 0.037).
• This effect was observed only for walking speed and not for other physical function measures in females.
• Physical function measures assessed included treadmill endurance capacity, grip strength, walking speed, and daily physical activity.
• The sex-specific pattern of physical function decline differed between males and females in response to L-Kyn diet.

Elevated circulating L-Kynurenine increased frailty prevalence in both male and female wildtype mice, and this effect was mitigated by MCK-PGC1α.

• L-Kyn increased frailty prevalence in male wildtype mice by 17% (p = 0.025).
• L-Kyn increased frailty prevalence in female wildtype mice by 26% (p = 0.0001).
• The increase in frailty prevalence was mitigated by MCK-PGC1α transgenic expression in both sexes.
• This finding supports a causal role of elevated circulating L-Kyn in promoting frailty during aging.

Soleus muscle strength and power were not impacted by L-Kyn diet or genotype in either sex.

• Muscle function was assessed in situ using nerve-mediated contraction of the soleus muscle.
• No significant effect of diet or genotype on soleus muscle strength and power was observed in either sex (p > 0.5).
• This indicates that the physical function changes associated with L-Kyn diet were not driven by impairments in intrinsic muscle contractile function.

Mitochondrial oxidative phosphorylation function was greater in MCK-PGC1α mice than in wildtype mice regardless of diet.

• The difference in mitochondrial oxidative phosphorylation function between MCK-PGC1α and wildtype mice was significant in both males and females (p < 0.04).
• This effect was observed regardless of L-Kyn diet condition.
• The authors attributed this finding to upregulated expression of mitochondrial biogenesis-related genes.
• Mitochondrial energetics were assessed using high resolution respirometry and fluorescence spectroscopy.

L-Kynurenine levels increase with age and have been associated with reduced physical function and increased frailty in humans.

• L-Kynurenine is a product of tryptophan catabolism.
• KATs, which degrade L-Kyn, are robustly expressed in skeletal muscle.
• KAT expression is regulated by the transcriptional co-regulator PGC1α.
• The study investigated whether elevating L-Kyn levels via dietary intervention exacerbates age-related decline in physical, muscle, and mitochondrial functions.