Main Findings
This prospective study provides the first evidence that higher dietary spermidine intake significantly reduces all-cause mortality in humans. The research demonstrates a strong dose-response relationship, with participants in the highest tertile of spermidine consumption showing mortality risks equivalent to being 5.7 years younger.
Study Design and Population
Primary Cohort: Bruneck Study
- 829 participants aged 45-84 years (49.9% male)
- 20-year follow-up period (1995-2015)
- Population-based cohort from Bruneck, Italy
- 90% participation and follow-up rates
- 341 deaths recorded during 13,019 person-years
Validation Cohort: SAPHIR Study
- 1,770 participants aged 39-67 years
- 12.8-year median follow-up
- 48 deaths recorded
- Confirmed primary findings
Key Mortality Outcomes
Dose-Response Relationship
Spermidine TertileDeaths per 1000 person-years20-year cumulative mortalityLow (<62.2 µmol/d)40.5 (36.1-44.7)48% (45-51%)Medium (62.2-79.8 µmol/d)23.7 (20.0-27.0)41% (38-45%)High (>79.8 µmol/d)15.1 (12.6-17.8)38% (34-41%)
Hazard Ratios
- Unadjusted HR per 1-SD increase: 0.62 (95% CI: 0.55-0.69)
- Fully adjusted HR per 1-SD increase: 0.76 (95% CI: 0.67-0.86)
- Top vs. bottom tertile: 39% lower mortality risk
- Age equivalent: 5.7-year (95% CI: 3.6-8.1) younger chronological age
Dietary Sources and Intake Patterns
Primary Spermidine Sources in Study Population
- Whole grains (13.4% of total intake)
- Apples and pears (13.3%)
- Salad (9.8%)
- Vegetable sprouts (7.3%)
- Potatoes (6.4%)
Other High-Spermidine Foods
- Fresh green pepper, wheat germ, cauliflower, broccoli, mushrooms
- Various cheeses
- Soybean products (natto), shiitake mushrooms, amaranth grain, durian
Population Characteristics by Spermidine Intake
- Higher intake correlated with female sex (63.6% vs. 38.0% in highest vs. lowest tertile)
- Younger age (64.7 vs. 69.0 years)
- Higher physical activity levels
- Lower alcohol consumption and smoking rates
- Better overall diet quality (Alternative Healthy Eating Index: 40.9 vs. 31.2)
Biological Mechanisms
Primary Pathway: Autophagy Enhancement
Spermidine induces autophagy through histone deacetylation, similar to caloric restriction but via different molecular mechanisms:
- Caloric restriction: Sirtuin-mediated histone deacetylase activation
- Spermidine: Direct inhibition of histone acetyltransferase
Cardiovascular Benefits
- Blood pressure reduction
- Enhanced nitric oxide bioavailability
- Reduced arterial advanced glycation end-product deposition
- Antiplatelet effects
- Improved cardiac autophagy and mitophagy
- Protection against hypertensive heart disease
Cancer Protection
- Enhanced anticancer immune surveillance
- Genomic stabilization
- Reduced inflammation
- Lower rates of colon and other tumors in animal studies
Additional Mechanisms
- Restoration of colonic barrier function
- Suppression of low-grade inflammation
- Protection against age-dependent memory impairment
- Improved lipid metabolism
Statistical Robustness
Sensitivity Analyses Confirmed Results
- Exclusion of first 5 years (reverse causation): HR 0.72 (0.62-0.84)
- Baseline intake only: HR 0.78 (0.69-0.88)
- Measurement error correction: HR 0.60 (0.50-0.74)
- Extensive dietary and lifestyle adjustments maintained significance
Specificity to Spermidine
- Spermine: Weak but significant association (HR 0.89, 95% CI: 0.80-0.99)
- Putrescine: No association (HR 1.02, 95% CI: 0.91-1.14)
- Arginine/Methionine: No associations observed
Subgroup Consistency
The mortality reduction was consistent across:
- Both sexes
- All age groups
- Different physical activity levels
- Various dietary quality scores
- Multiple lifestyle factors
Study Limitations
- Population homogeneity: All participants were white Europeans
- Measurement challenges: Self-reported dietary data, food preparation variations not captured
- Residual confounding: Cannot completely rule out unmeasured confounders
- Observational design: Cannot establish causation definitively
Clinical Implications
Dietary Recommendations
- Spermidine intake represents 26% of total polyamine consumption
- Optimal intake appears to be >79.8 µmol/day
- Benefits observed at dietary levels, not requiring supplementation
- Most readily absorbed polyamine from human gut (40-80% absorption)
Public Health Significance
- Mortality benefit comparable to 5.7 years of age difference
- Strongest association among 146 nutrients studied
- Linear dose-response relationship with no apparent threshold
- Effects independent of overall healthy eating patterns
TL;DR: This landmark 20-year study of 829 adults demonstrates that higher dietary spermidine intake reduces all-cause mortality by 24% per standard deviation increase, with the top tertile showing mortality risks equivalent to being 5.7 years younger. The effect is mediated primarily through autophagy enhancement and is independent of other dietary and lifestyle factors, suggesting spermidine-rich foods (whole grains, fruits, vegetables) may be a novel longevity intervention.