Physician-Training Stress and Accelerated Cellular Aging

  • Kathryn K. Ridout
    Department of Psychiatry, Kaiser Permanente, San Jose, California

    Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, Rhode Island
    Search for articles by this author
  • Samuel J. Ridout
    Department of Psychiatry, Kaiser Permanente, San Jose, California
    Search for articles by this author
  • Constance Guille
    Brain Research and Integrative Neuropsychopharmacology Division, Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, South Carolina
    Search for articles by this author
  • Douglas A. Mata
    Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

    Brigham Education Institute, Boston, Massachusetts
    Search for articles by this author
  • Huda Akil
    Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan

    Department of Psychiatry, University of Michigan, Ann Arbor, Michigan
    Search for articles by this author
  • Srijan Sen
    Address correspondence to Srijan Sen, M.D., Ph.D., 1066 Molecular and Behavioral Neuroscience Institute, 205 Zina Pitcher Place, Ann Arbor, MI 48109.
    Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan

    Department of Psychiatry, University of Michigan, Ann Arbor, Michigan
    Search for articles by this author



      Stress is a key precipitant for many common diseases, but established biological markers to track stress and guide investigations into mechanisms linking stress and disease are lacking. Cross-sectional studies have identified correlations between stress and telomere attrition, but no large, longitudinal studies examining the impacts of chronic stress on telomere length exist. Residency training for physicians is a well-established stressful experience and can be used as a prospective stress model.


      In a longitudinal cohort study of 250 interns (first-year residents) at 55 United States hospital systems serving during the 2015–2016 academic year, we examined associations between measures of the residency experience and saliva-measured telomere attrition.


      Telomere length shortened significantly over the course of internship year, from mean ± SD of 6465.1 ± 876.8 base pairs before internship to 6321.5 ± 630.6 base pairs at the end of internship (t246 = 2.69; p = .008). Stressful early family environments and neuroticism were significantly associated with shorter preinternship telomere length. Longer work hours were associated with greater telomere intern telomere loss over the year (p = .002). Of note, the mean telomere attrition during internship year was six times greater than the typical annual attrition rate identified in a recent meta-analysis.


      This work implicates telomere attrition as a biologically measurable consequence of physician training, with the magnitude of attrition associated with workload. Identification of an objective, biological sequela of residency stress may help to facilitate the development of effective interventions. Further, the findings implicate telomere attrition as an objective biomarker to follow the pathologic effects of stress, in general.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Baker K.
        • Sen S.
        Healing medicine's future: Prioritizing physician trainee mental health.
        AMA J Ethics. 2016; 18: 604-613
        • Mata D.A.
        • Ramos M.A.
        • Bansal N.
        • Khan R.
        • Guille C.
        • Di Angelantonio E.
        • et al.
        Prevalence of depression and depressive symptoms among resident physicians: A systematic review and meta-analysis.
        JAMA. 2015; 314: 2373-2383
        • Wilkinson H.
        • Whittington R.
        • Perry L.
        • Eames C.
        Examining the relationship between burnout and empathy in healthcare professionals: A systematic review.
        Burn Res. 2017; 6: 18-29
        • Yaghmour N.A.
        • Brigham T.P.
        • Richter T.
        • Miller R.S.
        • Philibert I.
        • Baldwin Jr., D.C.
        • et al.
        Causes of death of residents in ACGME-accredited programs 2000 through 2014: Implications for the learning environment.
        Acad Med. 2017; 92: 976-983
        • Dewa C.S.
        • Loong D.
        • Bonato S.
        • Thanh N.X.
        • Jacobs P.
        How does burnout affect physician productivity? A systematic literature review.
        BMC Health Serv Res. 2014; 14: 325
        • Dyrbye L.N.
        • West C.P.
        • Satele D.
        • Boone S.
        • Tan L.
        • Sloan J.
        • et al.
        Burnout among U.S. medical students, residents, and early career physicians relative to the general U.S. population.
        Acad Med. 2014; 89: 443-451
        • Hall L.H.
        • Johnson J.
        • Watt I.
        • Tsipa A.
        • O'Connor D.B.
        Healthcare staff wellbeing, burnout, and patient safety: A systematic review.
        PLoS One. 2016; 11: e0159015
        • Grant F.
        • Guille C.
        • Sen S.
        Well-being and the risk of depression under stress.
        PLoS One. 2013; 8: e67395
        • Sen S.
        • Kranzler H.R.
        • Krystal J.H.
        • Speller H.
        • Chan G.
        • Gelernter J.
        • et al.
        A prospective cohort study investigating factors associated with depression during medical internship.
        Arch Gen Psychiatry. 2010; 67: 557-565
        • Ridout S.J.
        • Ridout K.K.
        • Kao H.T.
        • Carpenter L.L.
        • Philip N.S.
        • Tyrka A.R.
        • et al.
        Telomeres, early-life stress and mental illness.
        Adv Psychosom Med. 2015; 34: 92-108
        • Daneshvar F.
        • Weinreich M.
        • Daneshvar D.
        • Sperling M.
        • Salmane C.
        • Yacoub H.
        • et al.
        Cardiorespiratory fitness in internal medicine residents: Are future physicians becoming deconditioned?.
        J Grad Med Educ. 2017; 9: 97-101
        • Blackburn E.H.
        • Epel E.S.
        • Lin J.
        Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection.
        Science. 2015; 350: 1193-1198
        • Muezzinler A.
        • Zaineddin A.K.
        • Brenner H.
        A systematic review of leukocyte telomere length and age in adults.
        Ageing Res Rev. 2013; 12: 509-519
        • Epel E.S.
        • Blackburn E.H.
        • Lin J.
        • Dhabhar F.S.
        • Adler N.E.
        • Morrow J.D.
        • et al.
        Accelerated telomere shortening in response to life stress.
        Proc Natl Acad Sci U S A. 2004; 101: 17312-17315
        • Li X.
        • Wang J.
        • Zhou J.
        • Huang P.
        • Li J.
        The association between post-traumatic stress disorder and shorter telomere length: A systematic review and meta-analysis.
        J Affect Disord. 2017; 218: 322-326
        • Mathur M.B.
        • Epel E.
        • Kind S.
        • Desai M.
        • Parks C.G.
        • Sandler D.P.
        • et al.
        Perceived stress and telomere length: A systematic review, meta-analysis, and methodologic considerations for advancing the field.
        Brain Behav Immun. 2016; 54: 158-169
        • Oliveira B.S.
        • Zunzunegui M.V.
        • Quinlan J.
        • Fahmi H.
        • Tu M.T.
        • Guerra R.O.
        Systematic review of the association between chronic social stress and telomere length: A life course perspective.
        Ageing Res Rev. 2016; 26: 37-52
        • Ridout K.K.
        • Levandowski M.
        • Ridout S.J.
        • Gantz L.
        • Goonan K.
        • Palermo D.
        • et al.
        Early life adversity and telomere length: A meta-analysis.
        Mol Psychiatry. 2017; 23: 858-871
        • Guille C.
        • Zhao Z.
        • Krystal J.
        • Nichols B.
        • Brady K.
        • Sen S.
        Web-based cognitive behavioral therapy intervention for the prevention of suicidal ideation in medical interns: A randomized clinical trial.
        JAMA Psychiatry. 2015; 72: 1192-1198
        • Mitchell A.J.
        • Yadegarfar M.
        • Gill J.
        • Stubbs B.
        Case finding and screening clinical utility of the Patient Health Questionnaire (PHQ-9 and PHQ-2) for depression in primary care: A diagnostic meta-analysis of 40 studies.
        BJPsych Open. 2016; 2: 127-138
        • van Ockenburg S.L.
        • de Jonge P.
        • van der Harst P.
        • Ormel J.
        • Rosmalen J.G.
        Does neuroticism make you old? Prospective associations between neuroticism and leukocyte telomere length.
        Psychol Med. 2014; 44: 723-729
        • Savolainen K.
        • Eriksson J.G.
        • Kajantie E.
        • Pesonen A.K.
        • Räikkönen K.
        Associations between the five-factor model of personality and leukocyte telomere length in elderly men and women: The Helsinki Birth Cohort Study (HBCS).
        J Psychosom Res. 2015; 79: 233-238
        • Lahey B.B.
        Public health significance of neuroticism.
        Am Psychol. 2009; 64: 241-256
        • Costa Jr., P.T.
        • McCrae R.R.
        Stability and change in personality assessment: the revised NEO Personality Inventory in the year 2000.
        J Pers Assess. 1997; 68: 86-94
        • Taylor S.E.
        • Lerner J.S.
        • Sage R.M.
        • Lehman B.J.
        • Seeman T.E.
        Early environment, emotions, responses to stress, and health.
        J Pers. 2004; 72: 1365-1393
        • Rogers N.L.
        • Cole S.A.
        • Lan H.C.
        • Crossa A.
        • Demerath E.W.
        New saliva DNA collection method compared to buccal cell collection techniques for epidemiological studies.
        Am J Hum Biol. 2007; 19: 319-326
        • Lin J.
        • Epel E.
        • Cheon J.
        • Kroenke C.
        • Sinclair E.
        • Bigos M.
        • et al.
        Analyses and comparisons of telomerase activity and telomere length in human T and B cells: insights for epidemiology of telomere maintenance.
        J Immunol Methods. 2010; 352: 71-80
        • Entringer S.
        • Epel E.S.
        • Lin J.
        • Blackburn E.H.
        • Buss C.
        • Shahbaba B.
        • et al.
        Maternal folate concentration in early pregnancy and newborn telomere length.
        Ann Nutr Metab. 2015; 66: 202-208
        • Goglin S.E.
        • Farzaneh-Far R.
        • Epel E.S.
        • Lin J.
        • Blackburn E.H.
        • Whooley M.A.
        Change in leukocyte telomere length predicts mortality in patients with stable coronary heart disease from the Heart and Soul Study.
        PLoS One. 2016; 11: e0160748
        • Ridout K.K.
        • Carpenter L.L.
        • Tyrka A.R.
        The cellular sequelae of early stress: Focus on aging and mitochondria.
        Neuropsychopharmacology. 2016; 41: 388-389
        • Rotenstein L.S.
        • Ramos M.A.
        • Torre M.
        • Segal J.B.
        • Peluso M.J.
        • Guille C.
        • et al.
        Prevalence of depression, depressive symptoms, and suicidal ideation among medical students: A systematic review and meta-analysis.
        JAMA. 2016; 316: 2214-2236
        • Dzau V.J.
        • Kirch D.G.
        • Nasca T.J.
        To care is human—Collectively confronting the clinician-burnout crisis.
        N Engl J Med. 2018; 378: 312-314
        • Ridout K.K.
        • Ridout S.J.
        • Price L.H.
        • Sen S.
        • Tyrka A.R.
        Depression and telomere length: A meta-analysis.
        J Affect Disord. 2016; 191: 237-247
        • Arsenis N.C.
        • You T.
        • Ogawa E.F.
        • Tinsley G.M.
        • Zuo L.
        Physical activity and telomere length: Impact of aging and potential mechanisms of action.
        Oncotarget. 2017; 8: 45008-45019
        • Astuti Y.
        • Wardhana A.
        • Watkins J.
        • Wulaningsih W.
        • Network P.R.
        Cigarette smoking and telomere length: A systematic review of 84 studies and meta-analysis.
        Environ Res. 2017; 158: 480-489
        • Perez L.M.
        • Amaral M.A.
        • Mundstock E.
        • Barbe-Tuana F.M.
        • Guma F.
        • Jones M.H.
        • et al.
        Effects of diet on telomere length: Systematic review and meta-analysis.
        Public Health Genomics. 2017; 20: 286-292
        • Rafie N.
        • Golpour Hamedani S.
        • Barak F.
        • Safavi S.M.
        • Miraghajani M.
        Dietary patterns, food groups and telomere length: A systematic review of current studies.
        Eur J Clin Nutr. 2017; 71: 151-158
        • Mundstock E.
        • Zatti H.
        • Louzada F.M.
        • Oliveira S.G.
        • Guma F.T.
        • Paris M.M.
        • et al.
        Effects of physical activity in telomere length: Systematic review and meta-analysis.
        Ageing Res Rev. 2015; 22: 72-80
        • Stout S.A.
        • Lin J.
        • Hernandez N.
        • Davis E.P.
        • Blackburn E.
        • Carroll J.E.
        • et al.
        Validation of Minimally-Invasive Sample Collection Methods for Measurement of Telomere Length.
        Front Aging Neurosci. 2017; 9: 397

      Linked Article

      • Telomeres, Trauma, and Training
        Biological PsychiatryVol. 86Issue 9
        • Preview
          There was no glamour in this. My first patient of the New Year was a 5-year-old found in a clothes dryer, face bloodied. She had been hit by her pregnant mother, hit over and over with a bludgeon of pantyhose stuffed with shards of broken glass. How could I survive? —Samuel Shem, The House of God
        • Full-Text
        • PDF