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This research article presents one of the largest This research article presents one of the largest and most comprehensive Mendelian Randomization (MR) analyses ever conducted to uncover which environmental exposures (the exposome) have a causal impact on human longevity. Using 461,000+ UK Biobank participants and genetic instruments from 4,587 environmental exposures, the study integrates exposome science with MR methods to identify which factors genuinely cause longer or shorter lifespans, instead of merely being associated.
The study uses genetic variants as unbiased proxies for exposures, allowing the researchers to overcome typical problems in observational studies such as confounding and reverse causation. Longevity is defined by survival to the 90th or 99th percentile of lifespan in large European-ancestry cohorts.
🔶 1. Purpose of the Study
The article aims to:
Identify which components of the exposome causally affect longevity.
Distinguish between real causes of longer life and simple correlations.
Highlight actionable targets for public health and aging research.
It is the first study to systematically test thousands of environmental exposures for causal effects on human lifespan.
🔶 2. Methods
A. Exposures
4,587 environmental exposures were initially screened.
704 exposures met strict quality criteria for MR.
Exposures were grouped into:
Endogenous factors (internal biology)
Exogenous individual-level factors (behaviors, lifestyle)
Exogenous macro-level factors (socioeconomic, environmental)
B. Outcomes
Longevity was defined as survival to:
90th percentile age (≈97 years)
99th percentile age (≈101 years)
C. Analysis
Two-sample Mendelian Randomization
Sensitivity analyses: MR-Egger, weighted median, MR-PRESSO
False discovery rate (FDR) correction applied
Investigating causal relationsh…
🔶 3. Key Results
After rigorous analysis, 53 exposures showed evidence of causal relationships with longevity. These fall into several categories:
⭐ A. Diseases That Causally Reduce Longevity
Several age-related medical conditions strongly decreased the odds of surviving to very old age:
Coronary atherosclerosis
Ischemic heart disease
Angina (diagnosed or self-reported)
Hypertension
Type 2 diabetes
High cholesterol
Alzheimer’s disease
Venous thromboembolism (VTE)
For example:
Ischemic heart disease → 34% lower odds of longevity
Hypertension → 30–32% lower odds of longevity
Investigating causal relationsh…
These findings confirm cardiovascular and metabolic conditions as major causal barriers to long life.
⭐ B. Body Fat and Anthropometric Traits
Higher body fat mass, especially centralized fat, had significant causal negative effects on longevity:
Trunk fat mass
Whole-body fat mass
Arm fat mass
Leg fat mass
Higher BMI
Lean mass, height, and fat-free mass did not causally influence longevity.
Investigating causal relationsh…
This underscores fat accumulation—particularly visceral fat—as a biologically damaging factor for lifespan.
⭐ C. Diet-Related Findings
Unexpectedly, the trait “never eating sugar or sugary foods/drinks” was linked to lower odds of longevity.
This does not mean sugar prolongs life; instead, it likely reflects:
Illness-driven dietary restriction
Reverse causation captured genetically
Investigating causal relationsh…
This finding needs further investigation.
⭐ D. Socioeconomic and Behavioral Factors
One of the strongest protective factors was:
Higher educational attainment
College/university degree → causally increased longevity
Investigating causal relationsh…
This supports the idea that education improves health literacy, income, lifestyle choices, and access to medical care, all contributing to longer life.
⭐ E. Early-Life Factors
Greater height at age 10 was causally associated with lower longevity.
High childhood growth velocity has been linked to metabolic stress later in life.
⭐ F. Family History & Medications
Genetically proxied traits like:
Having parents with heart disease or Alzheimer’s disease
Use of medications like blood pressure drugs, metformin, statins, aspirin
showed causal relationships that mostly mirror their disease categories.
Medication use was negatively associated with longevity, likely reflecting underlying disease burden rather than drug harm.
🔶 4. Validation
Independent datasets confirmed causal effects for:
Myocardial infarction
Coronary artery disease
VTE
Alzheimer’s disease
Body fat mass
Education
Lipids (LDL, HDL, triglycerides)
Type 2 diabetes
Investigating causal relationsh…
This strengthens the reliability of the findings.
🌟 5. Core Conclusions
✔️ Some age-related diseases are true causal reducers of lifespan, especially:
Cardiovascular disease, diabetes, Alzheimer’s, hypertension, and lipid disorders.
✔️ Higher body fat is a causal risk factor for reduced longevity, especially central fat.
✔️ Education causally increases lifespan, pointing to the importance of socioeconomic factors.
✔️ New potential targets for improving longevity include:
Managing VTE
Childhood growth patterns
Healthy body fat control
Optimal sugar intake
Investigating causal relationsh…
⭐ Perfect One-Sentence Summary
This paper uses Mendelian Randomization on thousands of environmental exposures to identify which factors truly cause longer or shorter human lifespans, revealing that cardiovascular and metabolic diseases, high body fat, and low education are major causal reducers of longevity... |