Clinical insights into the kynurenine pathway in age-related diseases

Journal Pre-proof Clinical insights into the kynurenine pathway in age-related diseases

Beom-Jun Kim, Seung Hun Lee, Jung-Min Koh PII:

S0531-5565(19)30570-4

DOI:

https://doi.org/10.1016/j.exger.2019.110793

Reference:

EXG 110793

To appear in:

Experimental Gerontology

Received date:

20 August 2019

Revised date:

18 November 2019

Accepted date:

21 November 2019

Please cite this article as: B.-J. Kim, S.H. Lee and J.-M. Koh, Clinical insights into the kynurenine pathway in age-related diseases, Experimental Gerontology(2019), https://doi.org/10.1016/j.exger.2019.110793

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© 2019 Published by Elsevier.

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Clinical insights into the kynurenine pathway in age-related diseases

Beom-Jun Kim*, Seung Hun Lee, Jung-Min Koh

Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of

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Medicine, Seoul, Republic of Korea

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Corresponding author:

Beom-Jun Kim, M.D., Ph.D., Division of Endocrinology and Metabolism, Asan Medical Center,

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University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of

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Korea. Tel.: +82-2-3010-5876; Fax: +82-2-3010-6962; E-mail: [email protected]

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Abstract Accumulating evidence from diverse experiments, including heterochronic parabiosis—the surgical joining of two animals of different ages—has highlighted the importance of systemic factors in the progressive functional decline of various organs and tissues during aging. The major metabolic pathway of tryptophan, an essential amino acid in humans, is the kynurenine pathway (KP) in which indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) catalyze the conversion

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of tryptophan into kynurenine. Importantly, circulating kynurenine produced by this enzymatic breakdown, as a primary driver of the aging process, has been linked to higher mortality in humans.

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This review discusses the potential roles of tryptophan derivatives as biomarkers for the risk of frailty

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in the elderly, based on human observational studies as well as the KP as a therapeutic target for age-

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related diseases.

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Keywords: kynurenine pathway; age-related disease; biomarker; therapeutic target; aging

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1. Introduction Aging is a time-related process of progressive and irreversible decline at the organelle, cellular, tissue, and organismal levels, leading to increased vulnerability and, eventually, death (1, 2). This universal deterioration is known as the most significant risk factor for major debilitating and life-threatening conditions, including many forms of cancer, cardiovascular diseases, and neurodegeneration (3, 4).

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Furthermore, the increased life expectancy with improvement in healthcare and sanitary conditions,

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and the resulting expanded elderly population, have led to worldwide interest in aging research. Tremendous endeavors of researchers have uncovered several major contributors to the aging process,

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such as dysregulation of energy homeostasis, oxidative stress, and cellular senescence (2, 3). However,

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aging and its associated physiological and pathological changes are not as simple as can be explained

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by one key mechanism. Therefore, continuous efforts to further elucidate aging regulators and to prevent age-related diseases are necessary to minimize health problems in older adults.

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Accumulating evidence from diverse experiments, including heterochronic parabiosis, the surgical joining of two animals of different ages, has highlighted the importance of circulating factors

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in age-associated changes in various organs and tissues during aging (5-7). For example, exchange with old blood markedly decreased the maximum muscle strength of young mice (8). Subsequent experiments identified several systemic pro-aging factors (6, 9), and manipulations mitigating the effects of these circulating factors have been proposed as potentially effective approaches for slowing or reversing the aging process (10, 11). The major metabolic pathway of tryptophan, an essential amino acid in humans, is the kynurenine pathway (KP) in which indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3dioxygenase (TDO) catalyze the conversion of tryptophan into kynurenine (12, 13). Importantly, circulating kynurenine produced by the enzymatic breakdown of tryptophan, as a primary driver of the aging process (14-16), has been linked to increased frailty and mortality in humans (17, 18). This 3

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review highlights clinical evidence supporting the importance of the KP in age-related disorders and discusses the potential roles of tryptophan derivatives as biomarkers and therapeutic targets in degenerative diseases (Fig. 1).

2. Kynurenine pathway in observational studies: a potential biomarker for frailty risk Tryptophan and its metabolites are involved in a wide range of physiologic processes, including cell

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growth and maintenance. In particular, many lines of evidence indicate that the KP plays a critical role

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in tumor progression by diminishing antitumor immune responses and promoting the malignant

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properties of cancer cells (19-21). Because tryptophan metabolism and its clinical implications in cancer have been extensively reviewed elsewhere (22, 23), we focus here on the KP in age-associated

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degenerative diseases (Fig. 2).

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2.1. Kynurenine in human bone and muscle health

Osteoporotic fracture is one of the leading causes of considerable morbidity and disability in older

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people and imposes a substantial economic burden on national healthcare systems (24, 25). Because bone fragility results from an imbalance between osteoblastic bone formation and osteoclastic bone resorption, bone remodeling is finely regulated by systemic or local factors (26). A recent murine study demonstrated the pivotal role of kynurenine in accelerated skeletal aging (15). In brief, tryptophan derivatives were found to increase with age, and exogenous kynurenine treatment induced bone loss by increasing bone marrow adiposity and bone resorption (15). In addition to early research suggesting tryptophan metabolism as a mechanism promoting osteoporosis (27), strong clinical evidence supporting the KP in the pathophysiology of aging bone was provided in 2014. In the Hordaland Health Study, conducted during 1998-2000, Apalset et al. (28) showed that hip bone mineral density was inversely associated with the kynurenine-to-tryptophan 4

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ratio in the older (71-74 years) but not the middle-aged (46-49 years) patient group after multiple adjustments. A subsequent study by the same authors found a higher risk of hip fracture in older adults with higher levels of two kynurenine metabolites: 3-hydroxykynurenine (3-HK) and anthranilic acid (29). The bone marrow (BM) microenvironment consists of various cell types that might affect KP in different ways, and there is thus a possibility that changes in tryptophan derivates with age differ

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between circulating levels and local levels in the BM. Recently, to better define the pathogenic role of kynurenine in age-related bone fragility, we directly measured the tryptophan and kynurenine levels in

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human BM aspirate (16). After adjustment for confounders, including patient sex, age, body mass

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index, smoking history, alcohol use, serum 25-hydroxyvitamin D3, and creatinine clearance, increased

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BM kynurenine levels with age were associated with a higher risk for fragility hip fracture as well as a decrease in femoral bone mass. Interestingly, higher kynurenine concentrations were significantly

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associated with an increase in bone resorption markers, i.e., tartrate-resistant acid phosphatase-5b and receptor activator of nuclear factor-κB ligand, but not in bone formation markers, i.e., bone-specific

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alkaline phosphatase and osteoprotegerin, in BM plasma. These results suggest that increased

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kynurenine levels during aging may contribute to the imbalance in human bone remodeling through increased osteoclastogenesis. Because tryptophan metabolites in BM plasma would more accurately reflect the concentrations to which BM stem cells and osteoclasts are directly exposed, we believe that this study clinically validates the detrimental effects of kynurenine treatment on bone metabolism, as observed in mice. Sarcopenia corresponds to the gradual loss of skeletal muscle mass and function (30). Although sarcopenia has long been regarded as an inevitable outcome of aging, it is now regarded as a disease that should be overcome. Among the various factors affecting muscle homeostasis, nutrition— including the intake of specific amino acids—is acknowledged to be essential for maintaining muscle health in older adults (31, 32), and thus tryptophan and its derivatives are also likely to be involved in 5

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muscle metabolism. An animal study demonstrated that a high-dose kynurenine diet resulted in the loss of muscle mass, whereas mice on tryptophan supplementation had increased lean mass (33). However, despite these experimental results, clinical studies relating kynurenine to muscle phenotypes have not yet been performed. Because osteoporosis and sarcopenia are often present in individuals of similar age groups (34) and synergistically increase the risk for low-trauma fractures (35), further human research regarding the role of kynurenine on muscle health, in addition to bone,

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would contribute to effective prevention of fractures in the elderly.

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2.2. Kynurenine in neurogenerative diseases

Neurodegenerative diseases have become a worldwide public health issue as the size of the aging

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population increases globally (1, 36). The importance of the KP in brain aging was discussed in

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another part of this special issue by Brady. Briefly, 3-HK and quinolinic acid (QA) are neurotoxic KP metabolites, whereas others, such as kynurenic acid (KYNA), are neuroprotective (37, 38).

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neurodegeneration (39).

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Imbalances in these KP metabolites with diverse properties have been shown to result in gradual

Alzheimer’s disease (AD) is the most common cause of dementia and is anatomically characterized by the presence of β-amyloid plaques and neurofibrillary tangles (40). The key feature of this disease is progressive cognitive impairment (41). Several clinical studies that measured circulating tryptophan derivatives have implicated altered activation of the KP in the development of AD. For example, Fekkes et al. (42) reported the increased tryptophan degradation in the plasma of early-stage AD patients, and other scientific groups demonstrated that the kynurenine-to-tryptophan ratio in the blood was increased in AD patients (43, 44) and inversely related to their cognitive performance (43). Furthermore, serum levels of 3-HK were markedly increased in AD patients compared with the comparison groups. All of these results consistently provide clinical evidence regarding the involvement of the KP in the pathogenesis of AD. 6

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Parkinson’s disease (PD) is a common age-related nervous system disorder mainly affecting movement. Although PD is known as a multifactorial disease, accumulating data from in vitro, animal, and pathologic studies indicate a contribution of the KP to the development of PD (45). Human observational studies further support the hypothesis that activation of the KP is associated with a higher risk of PD. Winder et al. (46) reported that PD patients, compared with age-matched controls, had a significantly increased serum kynurenine-to-tryptophan ratio, thus indicating an upregulation of IDO and TDO activity. In a clinical study examining cerebrospinal fluid, which is likely to carry

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direct neuroactive signals, the 3‐HK concentration was increased by one‐third in PD patients (47).

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Huntington’s disease (HD) is a progressive brain disorder that causes uncontrolled

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movements, emotional problems, and cognitive decline (48). As with AD and PD, several tryptophan

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metabolites have an essential role in the development of HD through N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity (49). Specifically, a pioneering report showed that the intrastriatal

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administration of QA, a selective agonist for NMDA receptors, evoked selective neurodegeneration in rodents in a pattern that closely resembles that seen in human HD (50). Consistent with experimental

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research, patients with HD had higher levels of kynurenine, 3-HK, and QA, and lower levels of

HD.

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KYNA in brain or blood samples (51-56), supporting the importance of the KP in the pathogenesis of

In addition to AD, PD, and HD, epidemiologic studies indicate that tryptophan metabolism could be implicated in other neurodegenerative diseases, such as amyotrophic lateral sclerosis and multiple sclerosis (57, 58). Although the specific mechanism causing each disease could be complex and different, it seems to be evident that a clear switch of the KP toward neuroinflammatory and neurotoxic activation during aging can often contribute to the pathogenesis of these various neurodegenerative diseases (37, 39). Interestingly, among the tryptophan metabolites, kynurenine and 3-HK synthesized in the periphery can efficiently penetrate the blood-brain barrier (BBB) (39, 59), whereas QA and KYNA are unable to cross the BBB and thus should be locally generated in the 7

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central nervous system (39, 60). These facts suggest that kynurenine and 3-HK, rather than QA and KYNA, might be more clinically measurable circulating biomarkers relevant to neurodegeneration.

2.3. Kynurenine as a clinical biomarker of frailty Frailty is a geriatric syndrome characterized by decreased reserve and resistance to stressors, resulting from cumulative declines across multiple physiologic systems and causing vulnerability to adverse

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outcomes (61). This condition can lead to increasing disability, hospitalization, and even mortality in

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the elderly (62). Therefore, awareness of frailty and associated risk factors for adverse outcomes can

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improve the care for this most vulnerable subset of patients and thus reduce the burden on the healthcare system. From this perspective, there is an increasing need to identify novel clinical

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biomarkers for frailty (63, 64). Importantly, musculoskeletal weakness and progressive

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neurodegeneration during aging are major manifestations of frailty (65), and, as described above, have been significantly associated with blood levels of tryptophan derivatives, especially kynurenine, in

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humans. These findings raise the possibility that specific KP metabolites could serve as circulating biomarkers related to the risk of frailty. However, frailty is a heterogeneous condition consisting of

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various clinical components. Therefore, the “biomarker risk score” generated by combining systemic factors potentially related to age-associated decline in multiple organs, in addition to KP metabolites, may enhance the frailty assessment.

3. Kynurenine pathway as a therapeutic target for age-related degenerative diseases With increasing knowledge that KP metabolites can directly and indirectly affect the pathogenesis of diverse human diseases, interest in drug development based on these roles has been rapidly expanding. In general, the inhibition of key enzymes in KP, including IDO, TDO, and kynurenine 3monooxygenase (KMO), has received the most attention for pharmacological manipulations. In 8

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particular, targeting IDO1 with various biological functions in immune suppression and tumor progression has become an attractive approach in cancer therapeutic development (23), and relevant preclinical and clinical data on this topic have been well-covered in recent reviews (22, 66). Although the termination of recent phase III trials with negative results has raised concerns regarding the role of IDO1 in cancer immunology (23, 67), experts in the field agree that a better understanding regarding the regulation and downstream mediators of tryptophan metabolism would realize the druggability of

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the KP in cancer treatment. Despite the clinical significance of osteoporosis and sarcopenia in the elderly, interventional

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research targeting the KP in terms of the musculoskeletal system is relatively limited, and most of the

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related studies have been focused on only tryptophan per se as a component of amino acids (33, 68-70)

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and not on its derivatives. The lack of relevant research modulating the KP might be attributable to the fact that its roles regarding bone and muscle metabolism have only recently been clarified. However,

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as it is evident that the accumulation of KP metabolites, especially kynurenine, have been implicated in the pathogenesis of osteoporosis and sarcopenia (15, 16), we, therefore, believe that the reduction

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of kynurenine by inhibiting IDO or TDO could be therapeutically beneficial for maintaining

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musculoskeletal health in older adults.

A growing body of evidence indicates that the shift in tryptophan metabolism toward the direction of neurotoxic 3-HK and QA synthesis and the relative reduction of neuroprotective KYNA provides the key mechanism causing the age-related, neurodegenerative diseases (37, 38). Therefore, it is clear that rebalancing these KP metabolites may serve as a potentially successful therapeutic approach. Two main strategies have been suggested to achieve this goal: 1) production of the BBBpenetrant KYNA prodrugs or analogs and 2) modulation of KP activity to favor neuroprotection by targeting involved enzymes. The therapeutic potential of KYNA prodrugs or analogs in the treatment of age-related neurodegenerative diseases has been studied in animal models. The systemic administration of L9

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kynurenine, the precursor of KYNA, together with probenecid, an inhibitor of organic acid transport, increased brain KYNA levels in a dose-dependent manner and markedly reversed glutamate excitotoxicity in 6-hydroxydopamine-induced PD rats (71). 4-chlorokynurenine, the BBB-penetrant prodrug of 7-chlorokynurenic acid—which is the halogenated KYNA analog exerting a selective glycine site antagonism of NMDA receptors—reduced levodopa-induced dyskinesia in a PD monkey model (49). Additionally, Zadori et al. (72) reported that intraperitoneal injections of a KYNA analog, N-(2-N,N-dimethylaminoethyl)-4-oxo-1H-quinoline-2-carboxamide hydrochloride, in an HD mouse

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model, ameliorated their hypolocomotion, completely prevented the atrophy of striatal neurons, and

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prolonged survival by approximately 31%.

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KMO is a class A flavoprotein monooxygenase that catalyzes the hydroxylation of

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kynurenine to 3-HK (73). Because it lies at a key branching point of the KP, at which kynurenine is converted into either 3-HK or KYNA, the ratio of neurotoxic to neuroprotective metabolites is largely

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determined by this enzyme (39). Consequently, a number of investigators have attempted to reverse neurodegeneration through the inhibition of KMO, which can divert kynurenine toward increased

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neuroprotective KYNA production. For example, the chronic oral administration of JM6, a KMO

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inhibitor, prevented spatial memory deficits, anxiety-related behavior, and synaptic loss in a transgenic AD mouse model, and reduced synaptic loss and microglial activation in an HD mouse model (74). Findings from experiments using other KMO inhibitors, such as Ro-61-8048 and CHDI340246, also provided preclinical evidence supporting the therapeutic potential of targeting KMO in neurodegenerative diseases (75, 76). Although no candidates modulating the KP have reached the point of pivotal clinical trials confirming the achievement of neuroprotection, existing data from animal models combined with plausible mechanisms indicate that the KP is likely a viable target for treating neurodegenerative disorders in older adults.

4. Conclusion 10

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Clinical observations indicate that functional decline in one organ system, such as muscle or bone, may occur alongside degenerative changes in other tissues, such as the brain. For example, muscle atrophy and bone loss with aging are often present in patients with cognitive impairment and AD (7779). Considered together with the results of heterochronic parabiosis experiments (5-7), these observations support the concept that increased circulating factors with age could play a critical role in the degenerative changes that occur in multiple tissues in the elderly. Furthermore, the data from in vitro, animal, and human studies consistently suggest that several tryptophan derivatives could be

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among such systemic pro-aging factors.

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In a rapidly aging global society, many people wish to live longer and healthier lives. This

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wish may be achieved via the early detection of vulnerabilities to age-related degenerative diseases,

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followed by their effective treatment. The present review discusses not only the possible use of KP metabolites as circulating biomarkers for frailty risk but manipulation of the KP as a potential

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therapeutic target for age-associated degenerative diseases. However, despite the merits of targeting the KP, many challenges should be addressed before applying it to actual clinical practice. Regarding

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the role of KP components as biomarkers, a causal relationship among variables has not been

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determined because most of the previous epidemiologic studies investigating the KP in relation to aging phenotypes have been cross-sectional. The usefulness of circulating tryptophan metabolites as a predictor of frailty should be proven using longitudinal cohorts. The other important issue to be solved is the safety of drug candidates targeting the KP. From the physician’s point of view, the safety of a drug is regarded as much more important than its therapeutic efficacy. Unfortunately, the KP involves a complex enzyme cascade and generates diverse metabolites with distinct action. When certain routes in the KP are activated or inhibited for therapeutic purposes, the net effect by which other factors compensate remains unclear. Therefore, at this point, concerns remain regarding the offtarget effects and unexpected adverse outcomes of such a pharmacological intervention. However, KP researchers recognize these limitations and are endeavoring to minimize them. Because there is no doubt that the KP is an attractive target for diagnosis and treatment of age-associated degenerative 11

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diseases, future efforts are expected to increase the clinical applicability of this pathway.

Acknowledgments This work was supported by a National Research Foundation of Korea (NRF) grant funded by the

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Korean government (MSIT) [grant number 2019R1A2C2006527].

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Conflict of interest

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The authors declare no conflicts of interest.

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Figure Legends

Figure 1. The potential roles of kynurenine pathway metabolites as biomarkers and therapeutic targets

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for age-related diseases.

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Figure 2. Schematic overview of tryptophan metabolites and their association with age-related degenerative diseases based on human observational studies. IDO, indoleamine 2,3-dioxygenase;

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TDO, tryptophan 2,3-dioxygenase; KAT, kynurenine aminotransferase; KMO, kynurenine 3-

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monooxygenase; NAD, nicotinamide adenine dinucleotide; CNS, central nervous system; AD,

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Alzheimer’s disease; PD, Parkinson’s disease; HD, Huntington’s disease.

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Highlights

Systemic factors have important roles in the development of age-related diseases.

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Circulating kynurenines may serve as biomarkers related to the risk of frailty.

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The kynurenine pathway is a viable therapeutic target for age-related diseases

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Figure 1

Figure 2