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  • Genetic predisposition, modifiable lifestyles, and their joint effects on human lifespan: evidence from multiple cohort studies

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Original research
Genetic predisposition, modifiable lifestyles, and their joint effects on human lifespan: evidence from multiple cohort studies
  1. Zilong Bian1,2,
  2. Lijuan Wang1,3,
  3. Rong Fan1,2,
  4. Jing Sun1,
  5. Lili Yu1,
  6. Meihong Xu4,
  7. Paul R H J Timmers3,5,
  8. Xia Shen6,
  9. James F Wilson3,5,
  10. Evropi Theodoratou3,7,
  11. Xifeng Wu1,8,
  12. Xue Li1,3
    1. 1 Department of Big Data in Health Science, School of Public Health and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
    2. 2 Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China
    3. 3 Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK
    4. 4 Department of Nutrition and Food Hygiene, School of Public Health, Peking University, Beijing, China
    5. 5 MRC Human Genetics Unit, MRC Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
    6. 6 Department of Biostatistics, School of Public Health and The Key Laboratory of Public Health Safety of Ministry of Education, Fudan University, Shanghai, China
    7. 7 Cancer Research UK Edinburgh Centre, Medical Research Council Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
    8. 8 The Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province, Hangzhou, China
    1. Correspondence to Professor Xifeng Wu, Department of Big Data in Health Science, School of Public Health and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; xifengw{at}zju.edu.cn; Dr Xue Li, Department of Big Data in Health Science, School of Public Health and Center of Clinical Big Data and Analytics of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; xueli157{at}zju.edu.cn

    Abstract

    Objective To investigate the associations across genetic and lifestyle factors with lifespan.

    Design A longitudinal cohort study.

    Setting UK Biobank.

    Participants 353 742 adults of European ancestry, who were recruited from 2006 to 2010 and were followed up until 2021.

    Exposures A polygenic risk score for lifespan with long (<lowest quintile), intermediate (quintiles 2 to 4), and short (>highest quintile) risk categories and a weighted healthy lifestyle score, including no current smoking, moderate alcohol consumption, regular physical activity, healthy body shape, adequate sleep duration, and a healthy diet, categorised into favourable, intermediate, and unfavourable lifestyles.

    Main outcome measures Lifespan defined as the date of death or the censor date minus the date of birth.

    Results Of the included 353 742 participants of European ancestry with a median follow-up of 12.86 years, 24 239 death cases were identified. Participants were grouped into three genetically determined lifespan categories including long (20.1%), intermediate (60.1%), and short (19.8%), and into three lifestyle score categories including favourable (23.1%), intermediate (55.6%), and unfavourable (21.3%). The hazard ratio (HR) of death for individuals with a genetic predisposition to a short lifespan was 1.21 (95% CI 1.16 to 1.26) compared to those with a genetic predisposition to a long lifespan. The HR of death for individuals in the unfavourable lifestyle category was 1.78 (95% CI 1.71 to 1.85), compared with those in the favourable lifestyle category. Participants with a genetic predisposition to a short lifespan and an unfavourable lifestyle had 2.04 times (95% CI 1.87 to 2.22) higher rates of death compared with those with a genetic predisposition to a long lifespan and a favourable lifestyle. No multiplicative interaction was detected between the polygenic risk score of lifespan and the weighted healthy lifestyle score (p=0.10). The optimal combination of healthy lifestyles, including never smoking, regular physical activity, adequate sleep duration, and a healthy diet, was derived to decrease risk of premature death (death before 75 years).

    Conclusion Genetic and lifestyle factors were independently associated with lifespan. Adherence to healthy lifestyles could largely attenuate the genetic risk of a shorter lifespan or premature death. The optimal combination of healthy lifestyles could convey better benefits for a longer lifespan, regardless of genetic background.

    • PUBLIC HEALTH

    Data availability statement

    Data are available in a public, open access repository. NHANES data are available at http://www.cdc.gov/nchs/nhis/index.htm. UK Biobank study was under Application Number 66354. The UK Biobank is an open access resource and bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/. Further information is available from the corresponding author upon request.

    https://doi.org/10.1136/bmjebm-2023-112583

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      Data availability statement

      Data are available in a public, open access repository. NHANES data are available at http://www.cdc.gov/nchs/nhis/index.htm. UK Biobank study was under Application Number 66354. The UK Biobank is an open access resource and bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/. Further information is available from the corresponding author upon request.

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      Footnotes

      • ZB, LW and RF are joint first authors.

      • Contributors ZB and XL conceived and designed the study. All authors contributed to acquisition, analysis, or interpretation of data. ZB, LW and RF drafted the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version of the manuscript. XW and XL contributed to supervision and administrative, technical, or material support. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. XW and XL are joint last authors. XL is the guarantor for the full content.

      • Funding XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019). XFW is supported by the Key Laboratory of Intelligent Preventive Medicine of Zhejiang Province (2020E10004), the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (2019R01007), the Key Research and Development Program of Zhejiang Province (2020C03002), and Healthy Zhejiang One Million People Cohort (K-20230085). ZLB is supported by China Scholarship Council (201909067018). ET is supported by a CRUK Career Development Fellowship (C31250/A22804). PRHJT and JFW are supported by the MRC Human Genetics Unit program grant, Quantitative traits in health and disease (U. MC_UU_00007/10). The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

      • Competing interests PRHJT is an employee of BioAge Labs, Inc; there are no other relationships or activities that could appear to have influenced the submitted work.

      • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

      • Provenance and peer review Not commissioned; externally peer reviewed.

      • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.