Cohort studyindependent cross-checkabstract checked★ key study I-SYS-103 in-depth review
Environment matters more than genes for early death
Integrating the environmental and genetic architectures of aging and mortality.
Overview
Argentieri MA et al.. Nat Med 2025 · PMID 39972219 · DOI 10.1038/s41591-024-03483-9
Lifestyle and living conditions explained 17% of variation in mortality, genes less than 2%; smoking and social factors led.
Does the study support the specific claim? Partly · Methodological quality: moderate
Plain-language summary
Study explained simply
- What did the researchers want to find out?
Compare genes and environment.
- How was the study done?
UK Biobank cohort.
- How many people, animals or samples were studied?
~490,000 adults.
- What was actually found?
Environment explains more.
- How large was the observed effect?
17 vs <2 points.
- What do the results mean in everyday life?
Disease is mostly not fate, but food is only one part.
- What are the study's limitations?
Observational.
- What does it say about Elawady's specific claim?
Partly supports, partly contradicts.
- Do the results apply to Germany and Europe?
Moderate-high.
- What can explicitly not be concluded from this study?
Role of food contaminants.
Scientific in-depth review
1. Full reference
- Authors
- Argentieri MA et al.
- Journal
- Nat Med
- Year
- 2025
- Identifier
- PMID 39972219 DOI 10.1038/s41591-024-03483-9
- Verification
- verified – PubMed efetch 2026-10-26 + Crossref
- Retracted
- no
- Corrections
- none
- Extent checked
- abstract only
- Conflicts of interest and funding
No competing interests; Wellcome, BHF funding
2. Research question
Relative contributions of environment (exposome) and genetics to ageing, mortality and disease
3. Study design and population
- Study design
- Cohort study – Prospective cohort, exposome-wide and polygenic analysis (UK Biobank)
- Population
UK Biobank participants
- Country
UK
- Period
Baseline 2006-2010; 8-15 years follow-up
- Sample size
492,567 (mortality); 45,441 (proteomic clock)
- Inclusion and exclusion criteria
UK Biobank
4. Methods and endpoints
- Exposure / intervention
164 environmental exposures; polygenic risk scores for 22 diseases
- Comparator
Age and sex model
- Endpoints
Mortality, proteomic ageing, 25 age-related diseases
- Statistical methods
Cox models, XWAS with replication, variance explained
5. Actual results
- Results
Polygenic scores added <2 percentage points of explained mortality variation; the exposome added 17 points. Exposome explained more variation for lung, heart and liver disease (5.5-49.4%); polygenic risk explained more for dementias and breast, prostate and colorectal cancer (10.3-26.2%). Full text: main drivers were smoking, socioeconomic status, physical activity, living with a partner, sleep and wellbeing; self-reported diet items were associated with mortality but not with proteomic ageing.
- Absolute risks
Variance explained as reported
- Authors' conclusion
The exposome shapes distinct patterns of disease and mortality irrespective of polygenic risk.
6. Strengths
- Very large
- Replication subsets
- Genetics and environment side by side
7. Weaknesses
- Healthy-volunteer cohort
- Self-reported exposures
- Observational
8. Risk of bias
- Orienting tool
- ROBINS-E
- Type of assessment
- simplified assessment (abstract only)
- Full formal assessment
- no
- Overall risk of bias
- some concerns
- Rationale
Residual confounding and reverse causation possible.
9. Assessment of the statistical interpretation
Variance explained is not the same as attributable risk.
10. Relevance to the specific claim
Supports 'disease is largely not genetic fate' but identifies smoking, socioeconomic factors and activity - not food contaminants, medicines or cosmetics - as main drivers.
11. Independent contrary findings
Supports the 'not fate' kernel of C-SYS-03.
12. Transferability to Germany and Europe
Moderate-high (UK).
13. Overall methodological judgement
Mixed: environment dominates over genes, but the environment is broader than food.
| Multidimensional assessment | |
|---|---|
| Authenticity of the source | verified |
| Methodological quality | moderate |
| Risk of bias | some concerns |
| Precision of results | high |
| Directness | indirect |
| Reproducibility | partly replicated |
| Consistency with the overall evidence | consistent |
| Regional transferability | moderate |
| Adequacy of the interpretation (by the archive) | not applicable |
14. Open questions
15. Linked fact checks
- Chronic disease is mostly a cumulative reaction to what enters the body daily - contaminated food, medicines and cosmetics - not a fate that comes from outside. – Studies with mixed or unclear results
- Food is the first (leading) cause of modern (non-communicable) diseases. – Studies contradicting or limiting the claim