IGF-1
Understanding the U-Shaped Risk Profile
The chart illustrates the U-shaped association between IGF-1 levels and all-cause mortality risk, derived from meta-analytic data using dose-response modeling. The nadir occurs at 120-160 ng/ml (HR = 1.0), with increased risks at both extremes.
| IGF-1 Level (ng/ml) | Hazard Ratio (HR) | Associated Risks | Key Evidence (95% CI) |
|---|---|---|---|
| <82 | 2.28 (OR) | Frailty, locomotive syndrome | OR 2.275 (0.993-5.324) |
| <120 | 1.33 | Frailty, sarcopenia, CVD | HR 1.33 (1.14-1.57) |
| 120-160 | 1.0 | Lowest mortality risk | Reference (nadir) |
| >160 | 1.23 | Cancer, NAFLD, mortality | HR 1.23 (1.06-1.44) |
| >200 | ~1.40 (est.) | Cancer, acromegaly complications | Derived from trends |
Risks of Low IGF-1
Low IGF-1 (<120 ng/ml) - HR: 1.33
Low IGF-1 levels are associated with increased risks of frailty, sarcopenia, and cardiovascular mortality, particularly in older adults. A study of 133 elderly individuals found that IGF-1 ≤82 ng/ml increased odds of locomotive syndrome (OR = 2.275).
Key Risk Factors:
- Frailty syndrome: Reduced muscle function and mobility
- Sarcopenia: Age-related muscle mass loss
- Cardiovascular mortality: Increased risk in elderly
- Diabetes risk: Potential correlation in younger adults
- Cognitive decline: Though causality remains uncertain
Excessively low IGF-1 mimics growth hormone deficiency, potentially causing fatigue and poor tissue repair, particularly problematic in aging populations.
Risks of High IGF-1
High IGF-1 (>160 ng/ml) - HR: 1.23
High IGF-1 levels are linked to elevated cancer risk and nonalcoholic fatty liver disease (NAFLD). UK Biobank data with 400,000 participants showed a 69% increased colorectal cancer risk per 100 ng/ml rise in IGF-1.
Key Risk Factors:
- Cancer promotion: 69% increased colorectal cancer risk per 100 ng/ml
- NAFLD: HR = 2.33 (1.75-3.11) for fatty liver disease
- Cell proliferation: Enhanced tumor growth potential
- Acromegaly complications: At extreme levels (>200 ng/ml)
- Overall mortality: Increased all-cause death risk
High levels promote excessive cell proliferation, potentially exacerbating tumor growth and metabolic dysfunction, with extreme levels (>200 ng/ml) further amplifying risks.
Age-Related Modifications
The Curve Shifts with Age
Age significantly modifies the U-shaped curve. In older adults (>70), the risk from low IGF-1 may outweigh high-level risks (HR 1.31 vs. 1.18), reflecting frailty's prominence over cancer concerns.
Age-Specific Considerations:
- Elderly (>70): Low IGF-1 risks become more prominent
- Reference ranges decline: 71-290 ng/ml for ages 55+
- Optimal range may shift: 120-160 ng/ml baseline for general adults
- Genetic factors: Laron syndrome shows protective low IGF-1 effects
- Sex differences: Gender-specific risk patterns
The optimal range of 120-160 ng/ml represents the nadir for general adult populations, but individual interventions should be tailored based on age, health status, and genetic factors.
IGF-1 Modification Strategies
| Strategy/Substance | IGF-1 Reduction | Evidence Level | Key Benefits | Potential Risks |
|---|---|---|---|---|
| Fasting | -29 ng/ml | High (meta-analysis) | Metabolic health, cancer risk reduction | Nutrient deficiency, muscle loss |
| Severe Calorie Restriction (>50%) | -37 ng/ml | High (meta-analysis) | Longevity, weight loss | Malnutrition, reduced energy |
| Low-Protein Plant-Based Diet | 50% lower long-term | Moderate-High | Cancer protection, binding protein increase | Protein inadequacy in elderly |
| Ketogenic Diet (>55% fat) | -20% (-25 ng/ml) | High (meta-analysis) | Glucose/insulin reduction | Ketoacidosis, nutrient gaps |
| Selenium Supplementation | 37-65% (animal data) | Moderate (preclinical) | Obesity protection, healthspan | Toxicity at high doses, U-shaped cancer risk |
| Green Tea Extract | Variable (significant in pilots) | Low-Moderate | Antioxidant effects | Limited human confirmation |
| Exercise (Aerobic/Resistance) | Mixed (variable effects) | Moderate | Cognitive gains | May raise IGF-1 in some |
| Metformin/Diazoxide | 20-30% (-95 ng/ml diazoxide) | Moderate (trials) | Antitumor, insulin control | GI side effects, hypoglycemia |
| Acromegaly Drugs (Octreotide) | Substantial (normalizes levels) | High (clinical guidelines) | Tumor shrinkage | Injection site pain, gallstones |
Selenium and Cancer Risk: Another U-Shaped Relationship
Parallel U-Shaped Risk Profile
Recent research from Vietnam (Le et al., 2024) involving 3,758 cancer cases and 2,929 controls demonstrates that selenium intake also exhibits a U-shaped association with cancer risk, remarkably similar to the IGF-1 pattern. This study found a safe selenium intake range of 110.8-124.4 μg/day (mean 117.8 μg/day).
Selenium Risk Profile:
- Low intake (27.8-77.2 μg/day): OR = 3.78 (95% CI: 2.89-4.95) for cancer risk
- Optimal intake (110.8-124.4 μg/day): Lowest cancer risk (reference point)
- High intake (169.1-331.7 μg/day): OR = 1.86 (95% CI: 1.45-2.39) for cancer risk
- Cancer sites affected: Stomach, colon, rectum, and lung cancers
- Population factors: Stronger associations in individuals with BMI <23 kg/m² and never smokers
This finding is particularly relevant since selenium supplementation appears in IGF-1 reduction strategies. The dual U-shaped relationships suggest that optimal health requires balancing both selenium intake and IGF-1 levels within their respective safe ranges, highlighting the complexity of nutritional interventions.
Benefits vs. Risks of IGF-1 Modulation
Benefits of Lowering High IGF-1
- Reduced cancer incidence: Lower tumor promotion and growth
- Vegan diet effects: Correlates with reduced tumor cell promotion
- Longevity gains: 15% lifespan increase in IGF-1 deficient female mice
- Metabolic improvements: Lower triglycerides, better insulin sensitivity
- Calorie restriction/fasting: Extended healthspan in animal models
Risks of Excessively Low IGF-1
- Heightened mortality: HR=1.33 vs. mid-range levels
- Glucose intolerance: Impaired metabolic function
- Reduced bone/muscle maintenance: Particularly problematic in elderly
- Frailty and cirrhosis-related death: Increased risk in older adults
- Growth hormone deficiency-like symptoms: Fatigue and poor tissue repair
Clinical Considerations
Personalized Approach
The optimal IGF-1 range may shift with age, and individual health conditions should guide any interventions. Lowering IGF-1 too far may increase frailty risks, while insufficient reduction may not mitigate cancer risks.
Key Considerations:
- Age-specific targets: Elderly may benefit from higher levels to prevent frailty
- Cancer history: Previous cancer patients may benefit from lower levels
- Metabolic status: Diabetes and metabolic syndrome considerations
- Nutritional status: Ensuring adequate protein intake, especially in elderly
- Monitoring requirements: Regular assessment of IGF-1 levels and health markers
Individual responses vary significantly by age, sex, and health status. Professional consultation is advised for personalized application, especially given the complex U-shaped risk profile.
References
- IGF-1 and mortality risk meta-analysis
- U-shaped relationship in endocrinology
- UK Biobank cancer risk study (400,000 participants)
- IGF-1 and cancer development
- Clinical reference ranges and function
- Dietary interventions and IGF-1
- Aging and cellular longevity research
- Le, N.T., et al. A U-shaped association between selenium intake and cancer risk. Sci Rep 14, 21378 (2024)
Disclaimer: This content is for educational purposes only and should not be considered medical advice. IGF-1 modification strategies should only be undertaken with appropriate medical supervision, particularly given the U-shaped risk profile where both low and high levels carry distinct risks. Individual responses vary significantly by age, health status, and genetic factors.
Last updated: September 2025
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