Threonine for Aging

Overseen By Mahroukh Rafii, BSc

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Hospital for Sick Children

Must not be taking: Steroids

Disqualifiers: Chronic disease, Acute illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how a nutrient called threonine might support gut health in older adults. Threonine, an essential dietary component, could play a crucial role in maintaining the body's natural barriers as people age. Researchers aim to determine whether older adults require more threonine to maintain a healthy digestive system. The trial seeks volunteers aged 60 to 90 who are generally healthy and do not have conditions like diabetes or liver disease. As an unphased trial, this study provides a unique opportunity to advance scientific understanding of dietary needs in aging.

Do I have to stop taking my current medications for the trial?

The trial requires that you do not take medications known to affect protein or amino acid metabolism, like steroids. If you're on such medications, you may need to stop them to participate.

What prior data suggests that threonine is safe for older adults?

Research has shown that threonine is generally safe, even in larger amounts. People have safely taken doses up to 4 grams a day for up to a year. Importantly, studies have not identified any major safety concerns, including risks like DNA damage. This evidence suggests that the body tolerates threonine well. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Unlike the standard treatments for aging, such as lifestyle interventions and supplements, threonine is an amino acid that researchers believe could have a direct impact on the aging process itself. Most treatments for aging focus on managing symptoms or improving overall wellness, but threonine may work differently by potentially influencing protein synthesis and cell repair. This unique approach could offer a novel way to address the root causes of aging, which is why researchers are excited about its possibilities.

What evidence suggests that threonine might be an effective treatment for aging?

Research has shown that threonine, an essential amino acid, plays a crucial role in maintaining health as people age. Animal studies have found that threonine can slow aging and extend lifespan. It also supports gut health by increasing mucin production, which protects the gut lining. As animals age, mucin production decreases, increasing vulnerability to issues like bacterial infections. Threonine supplements might help prevent this decline. Although most research has focused on animals, the findings suggest potential benefits for older adults. In this trial, all participants will receive threonine to evaluate its effects on aging in adults over 60. ^{6 7 8 9 10}

Who Is on the Research Team?

Glenda Courtney-Martin, PhD

Principal Investigator

The Hospital for Sick Children

Are You a Good Fit for This Trial?

This trial is for healthy individuals aged 60 to 90 with a BMI under 30, not suffering from chronic diseases or acute illnesses that affect protein metabolism. Participants must not be on medications affecting protein/amino acid metabolism, have no significant recent weight loss or high caffeine/alcohol intake, and must be willing to undergo blood draws.

Inclusion Criteria

Fasting blood glucose, hemoglobin A1c (HbA1c), urea, creatinine

I am willing to participate in the study.

Consent provided

Exclusion Criteria

I am not willing to have blood drawn or undergo specific calorie measurement tests for this study.

Significant caffeine consumption (>2 cups per day)

I have a chronic illness or a recent sickness that can change how my body uses proteins.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive up to 7 threonine test levels in random order to determine threonine requirements

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Threonine

Trial Overview The study aims to determine the dietary requirement of threonine, an essential amino acid important for intestinal health, in older adults. It will assess whether people over age 60 need more threonine than younger adults do to maintain good digestive system function.

How Is the Trial Designed?

Group I: Threonine in Adults > 60 Experimental Treatment 1 Intervention

Threonine: all subjects will receive up to 7 threonine test levels, in random order.

Who Is Running the Clinical Trial?

The Hospital for Sick Children

Lead Sponsor

Trials

724

Recruited

6,969,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Published Research Related to This Trial

A new statistical framework was developed to analyze over 4.5 million drug-adverse event pairs from the FDA Adverse Event Reporting System, identifying 2,523 pairs with significant age-related risks, particularly for children and seniors.

The study highlights the importance of understanding age-specific vulnerabilities to adverse drug events, as demonstrated in a case study on statin-induced adverse effects in children and youth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Computational Framework for Identifying Age Risks in Drug-Adverse Event Pairs. Zhao, Z., Liu, R., Wang, L., et al.[2023]

The accumulation of abnormal enzyme forms with age is linked to posttranslational modifications of proteins and a decline in proteases that normally degrade these modified proteins.

Key modifications include oxidation, deamidation, and isomerization of amino acids, which contribute to the dysfunction of enzymes as we age, highlighting the importance of understanding these processes for potential therapeutic interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protein modification in aging. Stadtman, ER.[2022]

Current drug safety systems often fail to identify certain adverse drug reactions (ADRs) that may mimic age-related chronic diseases, especially in older populations.

To better detect these 'silent' ADRs that can develop from long-term drug use, a new systematic search strategy is needed alongside existing clinical trials and reporting systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The out-of-focus bias in drug surveillance. Gnädinger, M., Mellinghoff, HU.[2021]

Restoring taurine levels in aged mice has been shown to enhance their lifespan, suggesting a potential link between taurine and longevity.

In addition to increased longevity in mice, the restoration of taurine also positively impacted health markers in monkeys, indicating its potential benefits across species.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Taurine linked with healthy aging. McGaunn, J., Baur, JA.[2023]

In a study involving 12 older men, habituation to a high protein intake (>2.1 g/kg lean body mass per day) resulted in a higher fasting whole-body protein turnover but led to a lower net protein balance, indicating potential negative effects on protein retention.

Despite consuming a protein-rich meal after this high protein habituation, participants did not experience improved protein balance, suggesting that excessive protein intake may not enhance amino acid utilization in the elderly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of habituated dietary protein intake on fasting and postprandial whole-body protein turnover and splanchnic amino acid metabolism in elderly men: a randomized, controlled, crossover trial. Højfeldt, G., Bülow, J., Agergaard, J., et al.[2023]

Restriction of isoleucine in the diet improves metabolic health and promotes leanness and glycemic control in both young and old genetically diverse UM-HET3 mice, indicating its potential benefits for overall health.

Isoleucine restriction not only reduces frailty but also extends lifespan, particularly in male mice, suggesting that this dietary intervention could be a promising approach for enhancing healthspan and longevity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice. Green, CL., Trautman, ME., Chaiyakul, K., et al.[2023]

Low protein intake in mid-life (under 10% of calories) is linked to decreased mortality risk, but in individuals over 65, low protein intake is associated with increased mortality risk, highlighting the need for adequate protein in older adults.

Higher dietary protein may enhance health in the elderly by providing amino acids for glutathione synthesis, which protects against oxidative stress and inflammation; supplementation with N-acetylcysteine (NAC) and lipoic acid could further support this protective effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An increased need for dietary cysteine in support of glutathione synthesis may underlie the increased risk for mortality associated with low protein intake in the elderly. McCarty, MF., DiNicolantonio, JJ.[2022]

A comprehensive review identified 232 plasma proteins that change with age and are linked to health decline, highlighting their potential as biomarkers for aging-related health issues.

The study revealed that these age-associated proteins are involved in key metabolic pathways, such as insulin-like growth factor signaling and cytokine signaling, which could provide insights into the mechanisms of aging and inform future treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proteomics in aging research: A roadmap to clinical, translational research. Moaddel, R., Ubaida-Mohien, C., Tanaka, T., et al.[2022]

Oxidation of methionine and cysteine residues in proteins is reversible, and the enzyme methionine sulfoxide reductase (Msr) plays a crucial role in converting oxidized methionine back to its original form, which is important for cellular health.

Aging is associated with a decrease in Msr activity, leading to increased levels of oxidized methionine in proteins, which may contribute to age-related decline; enhancing Msr activity has been shown to significantly increase lifespan in animal models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methionine oxidation and aging. Stadtman, ER., Van Remmen, H., Richardson, A., et al.[2016]

Cysteine depletion in respiratory chain complexes is a strong predictor of longevity in aerobic animals, suggesting a link between amino acid usage and lifespan.

In contrast, methionine accumulation does not predict longevity but is associated with aerobic metabolic capacity, indicating that the oxidation of cysteine plays a more critical role in aging than methionine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respiratory chain cysteine and methionine usage indicate a causal role for thiyl radicals in aging. Moosmann, B.[2013]

An 8-week study involving 68 sarcopenic older adults showed that supplementation with branched-chain amino acids and vitamin D, combined with low-intensity resistance training, significantly improved muscle strength, muscle mass, and nutritional status compared to a control group.

While both groups experienced improvements in physical function, the intervention group had notably greater enhancements in handgrip strength, calf circumference, and body mass index, indicating the efficacy of the supplementation in supporting rehabilitation outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of branched-chain amino acids and vitamin D supplementation on physical function, muscle mass and strength, and nutritional status in sarcopenic older adults undergoing hospital-based rehabilitation: A multicenter randomized controlled trial. Takeuchi, I., Yoshimura, Y., Shimazu, S., et al.[2019]

In a study of 31,757 Medicare enrollees over 12 months, 1,523 adverse drug events (ADEs) were identified, with 28% of these being preventable, highlighting a significant issue in medication safety for older patients.

The research revealed that relying solely on voluntary reporting from healthcare providers is insufficient for detecting ADEs, as only 11% of ADEs were identified through this method; thus, a combination of detection strategies is necessary for better safety monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Strategies for detecting adverse drug events among older persons in the ambulatory setting. Field, TS., Gurwitz, JH., Harrold, LR., et al.[2018]

This study evaluated a safe dosing regimen for olanzapine in older adults with schizophrenia, identifying an optimal dose of 17.8 mg/day that balances therapeutic benefits and risks, based on a population of 34 patients aged 50 and older.

Using advanced modeling and simulation techniques, researchers established a benefit-risk AUC breakpoint of 524.5 ng h/mL, demonstrating a method to minimize adverse drug events in vulnerable older populations while ensuring effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quantitative drug benefit-risk assessment: utility of modeling and simulation to optimize drug safety in older adults. Crentsil, V., Lee, J., Jackson, A.[2018]

Elderly adults face a significant risk of sarcopenia, which is the loss of muscle mass and strength, threatening their independence and quality of life.

Higher levels of protein or essential amino acid intake can effectively stimulate muscle health in elderly adults, compensating for their reduced responsiveness to lower doses compared to younger individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protein Consumption and the Elderly: What Is the Optimal Level of Intake? Baum, JI., Kim, IY., Wolfe, RR.[2022]

In a study analyzing 287 medical records of elderly patients in emergency departments, 8 adverse drug reactions (ADRs) were identified, with 6 classified as serious, highlighting the significant risk of ADRs in this population.

The study found that certain medication classes, particularly those for the alimentary tract and cardiovascular system, were most commonly associated with ADRs, and specific triggers were effective in identifying these issues, especially concerning anticoagulants and antihypertensives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Use of triggers tools to search for adverse drug reactions in the elderly admitted to emergency departments. Nagai, KL., Takahashi, PSK., Pinto, LMO., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9628521/

L-threonine promotes healthspan by expediting ferritin ... Most interestingly, we found that the most elevated amino acid, threonine, delayed the aging process and extended the lifespan of nematodes by ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4254277/

Protein and Amino Acid Restriction, Aging and Disease Studies in yeast have shown that addition of serine, threonine, and valine in media promotes cellular sensitization and aging by activating different but ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1550413118301153

Impairing L-Threonine Catabolism Promotes Healthspan ... Taken together, these results indicate that reduced gcat/T25B9.1 expression increases nematodal lifespan, and improves healthspan-related ...

4. sciencedirect.com sciencedirect.com/topics/medicine-and-dentistry/threonine

Threonine - an overview Simultaneous supplementation of threonine and methionine alleviated the loss of muscle mass in elderly ... data showed the improvement of MPS by threonine alone.

5. researchgate.net researchgate.net/figure/Threonine-declines-with-age-and-threonine-catabolism-disorder-enhances-lifespan-and_fig2_365019632

Threonine declines with age and threonine catabolism ... Supplementation of l-threonine could prevent age-related iron concentration. Ferritin level was positively correlated with aging and l-threonine was up- ...

6. webmd.com webmd.com/vitamins/ai/ingredientmono-1083/threonine

Threonine - Uses, Side Effects, and More Threonine is possibly safe when used in larger amounts as a medicine. Doses of up to 4 grams daily have been used safely for up to 12 months. It seems to be ...

7. fishersci.com fishersci.com/store/msds?partNumber=BP394100&productDescription=L-THREONINE100GM&vendorId=VN00033897&countryCode=US&language=en

SAFETY DATA SHEET Physical State. Powder Solid. Appearance. White. Odor. Odorless. Odor Threshold. No information available. pH. 5.0-6.5. Melting Point/Range.

8. sciencedirect.com sciencedirect.com/science/article/pii/S0002916523061774

Threonine requirement of healthy adults, derived with a 24- ... The 1985 FAO/WHO/UNU threonine recommendation is inadequate, and 15 mg·kg −1 ·d −1 is sufficient to achieve mean indicator (leucine) amino acid balance.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12106564/

Evaluation of safe utilization of l-threonine for ... The objective of this study was to determine in a randomized double blind controlled clinical trial the safety and tolerability of l-threonine used as graded ...

10. vkm.no vkm.no/download/18.645b840415d03a2fe8f25c52/1502801716709/Risk%20assessment%20of%20%22other%20substances%22%20%E2%80%93%20L-threonine.pdf

Risk assessment of "other substances" – L-threonine The available data on threonine do not give rise to safety concerns with respect to genotoxicity. Threonine is expected to be metabolised to ...