Meta Information
ID:mots-c
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-20
Model
agent_curation_2026_05_20_peptides
Interactions
Target id:
/condition/fda-compounding-risk
Target name:
FDA 503A Bulk Drug Substances List
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
MOTS-c is listed on the FDA's 503A Bulk Drug Substances List (2023), meaning licensed compounding pharmacists may use it under 503A, but it has no FDA-approved indication. Quality standards for compounded MOTS-c are not externally verified by the FDA. Human safety data are very limited, with only a single Phase I/IIa clinical trial of a MOTS-c analog (CohBar CB4211) having been conducted.
Actionable advice:
MOTS-c has no FDA-approved formulation. Any compounded MOTS-c product lacks verified quality and safety standards. Human efficacy and safety data are extremely sparse.
Validation status:
validated_via_regulatory
Evidence tier:
tier_b
Evidence basis:
regulatory_advisory_verbatim
Evidence anchors:
Exact phrase from label:
Certain Bulk Drug Substances for Use in Compounding That May Present Significant Safety Risks
Label source:
US FDA compounding advisory. CORRECTION: MOTS-c was among the 12 peptides FDA REMOVED from Category 2 on 2026-04-15 (the row's '503A list 2023' framing is outdated). MOTS-c has no FDA-approved indication.
Action type:
informational_none
Target id:
/class/antidiabetic-medications
Target name:
Antidiabetic Medications (Insulin, Metformin, SGLT2 Inhibitors)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
MOTS-c activates AMPK and enhances GLUT-4-mediated glucose uptake in skeletal muscle through folate pathway modulation. These mechanisms overlap with those of metformin (AMPK activation) and SGLT2 inhibitors (glucose clearance). Additive glucose-lowering effects could cause hypoglycemia, particularly in patients with diabetes on pharmacological treatment or in fasted individuals.
Actionable advice:
Blood glucose is best monitored closely when combining MOTS-c with any antidiabetic medication. The risk of hypoglycemia is amplified in fasted individuals and those on insulin or sulfonylureas.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance
Label source:
Lee et al. 2015, PMID 25738459. MOTS-c activates AMPK and improves insulin sensitivity; additive glucose-lowering with metformin/SGLT2 is a class-level extension - monitor for hypoglycemia.
Action type:
monitor
Target id:
/condition/active-cancer
Target name:
Active Cancer / Malignancy
Severity:
moderate
Interaction type:
adverse
Nature:
conditional
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The MOTS-c monograph notes that patients with active malignancies should exercise caution despite anti-cancer effects observed in specific models. MOTS-c's effects on cellular metabolism and proliferation are complex: preclinical data show both pro-apoptotic effects in some cancer cell lines and metabolic effects that could theoretically affect cancer cells unpredictably. Until comprehensive oncology safety data are available, conservative use is warranted.
Actionable advice:
Exercise caution in patients with active cancer. MOTS-c has not been studied in oncology contexts in humans. Disclose use to oncologist.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
No-data precaution: no human data on MOTS-c in active malignancy; the previously cited paper showed anti-tumor effects, so caution rests on unknown long-term effects only (contradicting citation removed).
Action type:
informational_none
Target id:
/intervention/exercise
Target name:
Aerobic Exercise / Physical Activity
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
MOTS-c levels increase endogenously in response to exercise and cold exposure. Exogenous MOTS-c and exercise both activate AMPK and improve mitochondrial function via overlapping pathways. The combination may have synergistic metabolic benefits, but also amplifies AMPK-mediated glucose uptake, potentially increasing hypoglycemia risk in fasted individuals.
Actionable advice:
If using MOTS-c, be aware that its effects on glucose metabolism are amplified during and after exercise. Monitor blood glucose if diabetic or on glucose-lowering medications during exercise.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation.
Label source:
Reynolds et al. 2021 (Nat Commun), PMID 33473109. MOTS-c rises with exercise and both activate AMPK/mitochondrial function - complementary.
Action type:
monitor
Target id:
/condition/pregnancy
Target name:
Pregnancy
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Pregnancy is listed as a contraindication for MOTS-c until comprehensive reproductive safety data are established. No human safety data exist for MOTS-c during pregnancy or lactation.
Actionable advice:
MOTS-c should not be used during pregnancy or breastfeeding. No safety data exist.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
No-data precaution: no human reproductive-safety data for MOTS-c; the previously cited animal study showed fetal PROTECTION, so avoidance in pregnancy rests on absence of human data (contradicting citation removed).
Action type:
avoid
Target id:
/condition/lactation
Target name:
Breastfeeding (Lactation)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
null
Description:
It is unknown if MOTS-c is excreted in breast milk or what its effects on a nursing infant might be. Its use is contraindicated while breastfeeding.
Actionable advice:
This should be strictly avoided while breastfeeding.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
avoid
Target id:
/intervention/methotrexate
Target name:
Methotrexate
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
null
Description:
MOTS-c regulates the folate-one-carbon metabolism pathway, which is the direct target of the antifolate drug methotrexate. Co-administration could lead to unpredictable and severe cellular toxicity.
Actionable advice:
It should be avoided completely while taking methotrexate.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
avoid
Target id:
/class/ampk-activators
Target name:
AMPK Activators (e.g., Metformin, Berberine)
Severity:
moderate
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
null
Description:
MOTS-c activates the AMPK pathway, similar to metformin and berberine. Combining these agents can lead to additive effects on glucose metabolism and cellular energy sensing.
Actionable advice:
Additive effects are possible; it is a good idea to monitor blood glucose closely when combining with other AMPK activators.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
monitor
Target id:
/biomarker/folate-b12-status
Target name:
Folate (B9) and Vitamin B12 Status
Severity:
moderate
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
null
Description:
Optimal function of MOTS-c depends on the folate-one-carbon metabolism cycle, for which folate and vitamin B12 are essential cofactors. Deficiency may impair its efficacy.
Actionable advice:
It is a good idea to maintain adequate folate and vitamin B12 levels through diet or supplementation.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
monitor
Target id:
/biomarker/cgm-glucose-levels
Target name:
Blood Glucose Levels
Severity:
moderate
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
null
Description:
Due to its potent effects on glucose metabolism, regular monitoring of blood glucose is crucial to ensure safety and track efficacy, especially when combined with diet, exercise, or other medications.
Actionable advice:
Regularly monitor blood glucose, ideally with a CGM, to track response and prevent hypoglycemia.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
monitor
Target id:
/circadian/wake
Target name:
Waking Up
Severity:
minor
Interaction type:
synergistic
Nature:
temporal
Temporal spacing:
Hours before target:
null
Hours after target:
1
Description:
Endogenous MOTS-c levels exhibit a circadian rhythm. Administering it in the morning may better synchronize with the body's natural metabolic clock.
Actionable advice:
Administer in the morning shortly after waking to align with natural circadian rhythms.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
informational_none
Target id:
/intervention/ss-31
Target name:
SS-31 (Elamipretide)
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
null
Description:
Both MOTS-c and SS-31 are peptides that enhance mitochondrial function, though through different mechanisms. Their combination is theoretical but may provide complementary benefits for mitochondrial health.
Actionable advice:
This combination is theoretical and should be approached with caution, as clinical data is lacking.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
Action type:
informational_none