Aging-related diseases have been associated with kynurenine pathway dysregulation, which we touched on in issue 3 of our newsletter. Research has shown that with age there are increases in quinolinic acid (QUIN), suggesting that the kynurenine pathway (KP) plays a role in aging-associated diseases. The KP impacts bioenergetic activities through the reduction of nicotinamide adenine dinucleotide (NAD+) levels and ATP production, as well as impacting mitochondria function. Interestingly, longer lifespans have been correlated to suppressed kynurenine activity.
Previous studies have focused on NAD+ levels and how increasing NAD+ through supplementation can impact longevity. Here, Dr. Mariann Gabrawy and colleagues combined KP metabolites with NAD+ precursor supplementation to see the impact on the aging process in Drosophila. In young Drosophila (1 week) the potentially neurotoxic metabolite 3-hydroxykynrenine (3-HK) impacted their physical performance and was associated with an increased failure rate. Feeding 3-hydroxyanthranilic acid (3-HAA) decreased the climbing speed and distance covered in 15s, as well as increased the failure rate of older flies (weeks 5 and 7), which is surprising given that this metabolite has been associated with having an anti-inflammatory effect. Additionally, both 3-HAA and 3-HK supplementation decreased the average lifespan of flies. Suggesting that chronic increases of 3-HAA may have a detrimental effect.
Combining alpha-methyl tryptophan (α-MT) and NAD+ precursors (NAM and NR) significantly improved performance as well as reduced the failure rates of older flies. Additionally, α-MT +NR was associated with increases in dendritic branching within the ventral nerve cord. The combination supplementation also led to significant reductions in kynurenine and 3-HK levels, as well as the kynurenine/tryptophan ratio compared to controls. Furthermore, flies given α-MT, NAM, NR, and combination treatments had an increased lifespan compared to controls, and the longest life span was observed in flies given α-MT + NAM. This research demonstrates that inhibiting the KP and increasing NAD+ levels through supplementation positively affects the aging process in Drosophila. However, this study used life-long alterations, and more research into how this combination therapy affects longevity in aged individuals is warranted.