The role of tryptophan metabolism in aging and longevity has been an ongoing and intriguing topic. One end product of tryptophan metabolism, NAD, has been a major focus in the study of aging and longevity. However, recent years have brought forth emerging evidence suggesting that other metabolites of the kynurenine pathway (KP) may also play a crucial role in aging and longevity. For example, metabolites of the KP have been linked to use as predictors of biological age, frailty (see April 2023 highlight), and Alzheimer’s Disease (see June 2022 highlight). These clinical findings underscore a strong motivation to delve deeper into understanding how alterations to tryptophan metabolism impact the aging process. Indeed, previous studies have already demonstrated that modifying the KP can affect aging. Notably, restricting the activities of TDO-2, KYNU-1, and ACSD-1 has been shown to promote longevity. In this issue, let’s explore another KP enzyme and its intermediate, HAAO and 3HAA, as a potential target for extending the lifespan of C. elegans and mice. The implications of these findings may extend to humans, providing valuable insights into the intricate relationship between tryptophan metabolism and longevity.
Dang and Castro-Portuguez et al. (2023) demonstrated that the 3HAA-producing enzyme, HAAO, promotes aging. Inhibiting HAAO function genetically results in lifespan extension in C. elegans. Importantly, their study revealed that interference with HAAO function had minimal impact on the essential development and survival of C. elegans. Conversely, exogenous supplementation of 3HAA at a level (1μM) comparable to the condition where HAAO function is disrupted also conferred lifespan extension in C. elegans. Moreover, treatment with a 3HAA analog (4CL-3HAA) yielded similar findings. Notably, the researchers established that 3HAA exhibits antioxidant activity. These findings were validated in mammals using a mouse model, which showed similar outcomes.
These findings contribute to existing research suggesting that modulation of the kynurenine pathway (KP) may hold the key to slowing aging. Previously, it was believed that longevity was primarily linked to the KP as the metabolic determinant of NAD production, and it was NAD that had a direct effect on aging. However, it is becoming increasingly clear that, aside from NAD, various targets within the KP are directly responsible for modulating the aging process. Given that NAD is a relatively unstable molecule and is present in very low amounts in biofluids, these findings present a significant opportunity for biomarker discovery in aging, in addition to identifying therapeutic targets.
While the knockdown of HAAO and 3HAA supplementation extends lifespan with minimal disruption to normal function in C. elegans and mouse models, the results from human studies are less favorable. A study published in the New England Journal of Medicine demonstrated that two families with loss-of-function in HAAO and increased 3HAA experienced congenital malformations. When replicated in a mouse model to mimic the same pathogenic gene variant, similar results were observed. Clearly, some disparities need to be resolved before the findings by Dang and Castro-Portuguez et al. can be translated into human studies.