Abstract
Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, TNF-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.
Highlights
Chronic inflammation, as measured by persistently elevated serum levels of inflammatory cytokines, has long been hypothesized to play a role in the development of multiple adverse conditions related to aging, including disability, physical frailty, mild cognitive impairment, and early mortality [1,2,3]
Using an in vivo assessment of nerve-evoked plantar flexor function, we evaluated the force versus frequency relationship between aged control (n = 7) and IL 10tm1Cgn/J (IL-10tm) (n = 8) mice
We show that total isometric force was reduced in the IL-10tm at frequencies greater than 60 Hz (Figure 1A)
Summary
As measured by persistently elevated serum levels of inflammatory cytokines, has long been hypothesized to play a role in the development of multiple adverse conditions related to aging, including disability, physical frailty, mild cognitive impairment, and early mortality [1,2,3]. Aging is known to affect all components of the neuromuscular system, including brain, spinal neurons, peripheral axons, and muscle tissues, which contribute to functional decline in older adults These findings suggest a potential etiologic role for chronic inflammation in frailty and functional decline, the mechanism that connects inflammation to these conditions has not been elucidated. With chronic systemic activation of inflammatory pathways early in life, these mice undergo accelerated changes consistent with late-life decline, including decreased muscle mass, muscle and bone weakness, and altered skeletal muscle gene profile [5,6,7,8,9,10, 14] This mouse model could be used to help identify metabolomic signatures of chronic inflammation–related changes that could help inform the mechanisms that connect chronic inflammation to physical frailty and functional decline in older adults
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