Tryptophan for Healthy Aging

Overseen by Glenda Courtney-Martin, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: The Hospital for Sick Children

Must not be taking: Steroids

Disqualifiers: HIV, Diabetes, Significant weight loss, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

The aging population is growing rapidly. For the first time ever, Canadian seniors outnumbered young adults in 2016. Aging is associated with many physical and metabolic deteriorations including the loss of muscle mass and strength, insulin resistance, increased inflammation and oxidative stress. The muscles of our bodies are composed of proteins and proteins are made of small building blocks called amino acids. Our bodies have the ability to make some amino acids which are called the non-essential amino acids. However, there are certain amino acids that our body's need to make protein but can only be supplied from the foods that we consume. These are called essential amino acids. Tryptophan is one of the essential amino acids that the body needs. Tryptophan is required for protein synthesis and acts as a precursor for serotonin and nicotinic acid. Therefore, there may be a need for more threonine in the diet of older adults. However, the current requirement for threonine is based on studies conducted exclusively in young adults. Thus, the purpose of this study is to find out how much tryptophan older adults need.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are taking medications that affect protein or amino acid metabolism, like steroids.

What evidence supports the effectiveness of the treatment Tryptophan for healthy aging?

Research suggests that higher levels of tryptophan, an essential amino acid, are linked to a lower risk of hip fractures in older adults, which may indicate benefits for bone health. Additionally, tryptophan has shown potential in reducing inflammation and oxidative stress in aging mice, which could be beneficial for overall health during aging. ^{1 2 3 4 5}

Is tryptophan safe for human consumption?

Tryptophan is generally considered safe for humans when taken in appropriate amounts, with a proposed upper limit of 4.5 grams per day for healthy young adults. Some mild side effects like stomach upset may occur at higher doses, but more research is needed on long-term use. ^{2 6 7 8 9}

How does the treatment tryptophan differ from other treatments for healthy aging?

Tryptophan is unique for healthy aging as it may improve gut health and reduce inflammation through its interaction with gut bacteria and its role in producing serotonin and melatonin, which are important for sleep and mood regulation. Unlike other treatments, tryptophan's potential benefits are linked to its ability to enhance neurogenesis and reduce oxidative stress, making it a novel approach to supporting aging health. ^{2 7 10 11 12}

Research Team

Glenda Courtney-Martin, PhD

Principal Investigator

The Hospital for Sick Children

Eligibility Criteria

This trial is for healthy adults aged 60 to 90 who are in good general health as confirmed by medical history, physical exam, and blood tests. Participants must have a BMI under 30 kg/m2 and be willing to participate in the study.

Inclusion Criteria

BMI <30 kg/m2

I am in good health overall.

Consent provided

Exclusion Criteria

I am not willing to have blood drawn or undergo certain tests for this study.

Inability to tolerate the diet (i.e. allergy)

Significant weight loss during the past month or consumption of weight reducing diets

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive varying levels of tryptophan in a controlled diet to determine the requirement in adults over 60 years

up to 24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Tryptophan (Amino Acid)

Trial Overview The study aims to determine the necessary amount of tryptophan (an essential amino acid) for older adults. Tryptophan is crucial for protein synthesis and serves as a precursor for serotonin and nicotinic acid.

Participant Groups

Group I: Tryptophan in Adults >60y Experimental Treatment 1 Intervention

Tryptophan levels, up to 7 levels, will be tested in a random order in all subjects

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

Dr. Ronald D. Cohn

The Hospital for Sick Children

Chief Executive Officer since 2019

MD from University of Düsseldorf, Germany

Dr. Lennox Huang

The Hospital for Sick Children

Chief Medical Officer since 2016

MD from McGill University

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Dr. Paul C. Hébert

Canadian Institutes of Health Research (CIHR)

Chief Executive Officer

MD, University of Ottawa

Dr. Paul C. Hébert

Canadian Institutes of Health Research (CIHR)

Chief Medical Officer

MD, University of Ottawa

Findings from Research

Higher serum levels of the essential amino acid tryptophan (trp) are associated with a lower risk of hip fractures, with a hazard ratio of 0.75 per standard deviation increase in trp levels, based on a study of 262 participants over 12 years.

No significant associations were found between tryptophan's oxidized or nonoxidized metabolites and hip fractures, mortality, or frailty, indicating that further research, including randomized clinical trials, is needed to explore the potential benefits of increasing trp intake for bone health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study. Carbone, L., Bůžková, P., Fink, HA., et al.[2023]

A diet containing 0.4% tryptophan significantly reduced oxidative stress and inflammation in aging mice, likely through the regulation of AMPK and NF-κB pathways.

The tryptophan diet also increased beneficial gut bacteria (Akkermansia) and improved neurohealth by potentially enhancing brain-derived neurotrophic factor (BDNF) levels, suggesting a link between tryptophan, gut microbiota, and brain health in aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ameliorative Effect of Dietary Tryptophan on Neurodegeneration and Inflammation in d-Galactose-Induced Aging Mice with the Potential Mechanism Relying on AMPK/SIRT1/PGC-1α Pathway and Gut Microbiota. Yin, J., Zhang, B., Yu, Z., et al.[2022]

Rats that were previously fed a tryptophan-deficient diet for 6-22 months showed significant recovery in body weight and improved survival rates after being switched to a normal diet, indicating potential long-term benefits of dietary interventions.

These rats not only had a longer average lifespan (36.31 months) compared to control rats (30.5 months), but also demonstrated enhanced recovery from hypothermia and delayed onset of tumors, suggesting that early dietary deficiencies may influence health outcomes later in life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term tryptophan restriction and aging in the rat. Segall, P.[2013]

In a study involving 1574 participants and 109 cerebrospinal fluid donors, aging was linked to increased levels of kynurenine metabolites (like quinolinic acid) and a decrease in tryptophan, suggesting significant metabolic changes associated with aging.

Higher levels of kynurenine metabolites were correlated with frailty and mortality, indicating that the kynurenine pathway may play a role in adverse health outcomes as people age, although it's unclear if this activation is harmful or beneficial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging. Solvang, SH., Hodge, A., Watne, LO., et al.[2022]

Research indicates that systemic factors, particularly the kynurenine pathway (KP) of tryptophan metabolism, play a significant role in the aging process and the decline of organ function.

Circulating kynurenine levels are associated with higher mortality rates in humans, suggesting that tryptophan derivatives could serve as biomarkers for frailty in the elderly and that targeting the KP may offer therapeutic opportunities for age-related diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical insights into the kynurenine pathway in age-related diseases. Kim, BJ., Lee, SH., Koh, JM.[2021]

A No Observed Adverse Effect Level (NOAEL) of 30 g/d for dietary arginine and an upper limit of safe intake (ULSI) of 4.5 g/d for dietary tryptophan have been established for healthy young adults, indicating safe consumption levels for these amino acids when taken as supplements.

For elderly individuals, a proposed ULSI for leucine is 500 mg · kg-1 · d-1, emphasizing the need for tailored dietary recommendations based on age and health status, which could influence regulatory and nutritional practices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proposals for Upper Limits of Safe Intake for Arginine and Tryptophan in Young Adults and an Upper Limit of Safe Intake for Leucine in the Elderly. Cynober, L., Bier, DM., Kadowaki, M., et al.[2023]

L-Tryptophan (L-Trp) is crucial for growth and can help prevent pellagra, making it an important nutrient, especially in underdeveloped countries.

Research suggests that the urinary excretory ratio of anthranilic acid to kynurenic acid could serve as a sensitive biomarker to predict the safe upper intake level of L-Trp, which is important for ensuring its safe use without adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The metabolites in the tryptophan degradation pathway might be useful to determine the tolerable upper intake level of tryptophan intake in rats. Shibata, K., Fukuwatari, T.[2023]

The EFSA Panel initially could not determine the safety of l-Tryptophan as a feed additive due to insufficient information about its genetic modification, particularly regarding antibiotic resistance genes.

After reviewing additional data, the EFSA Panel concluded that l-Tryptophan is safe for target animals, consumers, users, and the environment, confirming its efficacy as a nutritional additive for all animal species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of l-tryptophan technically pure, produced by Escherichia&#160;coli CGMCC&#160;3667, for all animal species based on a dossier submitted by GBT Europe GmbH. Rychen, G., Aquilina, G., Azimonti, G., et al.[2020]

A single oral dose of tryptophan at 100 mg/kg body weight is generally well tolerated, with only minor gastric side effects reported, indicating its potential safety for therapeutic use.

There is a lack of comprehensive data on the chronic toxicity and therapeutic index of tryptophan and its metabolites, highlighting the need for further research before clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Toxicity and tolerance of tryptophan and its metabolites]. Montenero, AS.[2015]

In a study involving Fischer 344 rats and B6C3F1 mice, L-Tryptophan showed little toxic effect, with minimal body weight loss and high survival rates in rats, indicating it is safe at the tested doses.

No significant increase in tumor incidence was found in rats, and while some hematopoietic tumors appeared in mice, they were not statistically significant, leading to the conclusion that L-Tryptophan is not carcinogenic under the study conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioassay of L-Tryptophan for Possible Carcinogenicity (CAS No. 73-22-3). [2020]

In a study involving 35 middle-aged to elderly participants, consuming cereals enriched with tryptophan significantly improved sleep quality and reduced symptoms of anxiety and depression over a 3-week period.

The higher tryptophan intake led to increased levels of melatonin and serotonin metabolites in urine, suggesting that this dietary approach may help restore sleep/wake cycles affected by aging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans. Bravo, R., Matito, S., Cubero, J., et al.[2022]

A study on aged mice revealed that a TRP-deficient diet led to significant changes in gut bacteria and increased inflammatory markers, indicating that low tryptophan can negatively impact gut health and inflammation.

Mice fed a high-tryptophan diet showed a healthier gut microbiome and reduced inflammatory responses, suggesting that adequate tryptophan intake is crucial for maintaining gut health and managing inflammation in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Tryptophan-Deficient Diet Induces Gut Microbiota Dysbiosis and Increases Systemic Inflammation in Aged Mice. Yusufu, I., Ding, K., Smith, K., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

The Association of Tryptophan and Its Metabolites With Incident Hip Fractures, Mortality, and Prevalent Frailty in Older Adults: The Cardiovascular Health Study. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Ameliorative Effect of Dietary Tryptophan on Neurodegeneration and Inflammation in d-Galactose-Induced Aging Mice with the Potential Mechanism Relying on AMPK/SIRT1/PGC-1α Pathway and Gut Microbiota. [2022]

3. Germany pubmed.ncbi.nlm.nih.gov

Long-term tryptophan restriction and aging in the rat. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Kynurenine Pathway Metabolites in the Blood and Cerebrospinal Fluid Are Associated with Human Aging. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Clinical insights into the kynurenine pathway in age-related diseases. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Proposals for Upper Limits of Safe Intake for Arginine and Tryptophan in Young Adults and an Upper Limit of Safe Intake for Leucine in the Elderly. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

The metabolites in the tryptophan degradation pathway might be useful to determine the tolerable upper intake level of tryptophan intake in rats. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Safety of l-tryptophan technically pure, produced by Escherichia&#160;coli CGMCC&#160;3667, for all animal species based on a dossier submitted by GBT Europe GmbH. [2020]

9. Italy pubmed.ncbi.nlm.nih.gov

[Toxicity and tolerance of tryptophan and its metabolites]. [2015]

10. United States pubmed.ncbi.nlm.nih.gov

Bioassay of L-Tryptophan for Possible Carcinogenicity (CAS No. 73-22-3). [2020]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Tryptophan-enriched cereal intake improves nocturnal sleep, melatonin, serotonin, and total antioxidant capacity levels and mood in elderly humans. [2022]

12. Switzerland pubmed.ncbi.nlm.nih.gov

A Tryptophan-Deficient Diet Induces Gut Microbiota Dysbiosis and Increases Systemic Inflammation in Aged Mice. [2022]