The joint effects of frailty and telomere length for predicting mortality in older adults: the National Health and Nutrition Examination Survey 1999–2002

  • Dan Liu
  • Zhuoting Zhu
  • Long Zhou
  • Ming YangEmail author
Original Article



Frailty and short telomere length, which address different aspects of biological aging, are separately associated with mortality in older adults.


To evaluate whether the combination of these two biomarkers would be a better predictor of mortality than either alone.


This present study included participants 60 years of age or older from the National Health and Nutrition Examination Survey in the 1999–2002 phase. The frailty phenotype was identified based on the Fried definition. Telomere length relative to standard reference DNA (T/S ratio) was assessed using quantitative polymerase chain reaction (PCR). Cox proportional hazards regression models were used to estimate the individual and combined effects of frailty phenotype and telomere length on all-cause and cardiovascular mortality.


Compared with participants with neither impairment, the mortality risks increased slightly among participants with short telomere length only (hazard ratio [HR] 1.19, 95% confidence interval [CI]: 1.00–1.42) or pre-frailty only (HR 2.16, 95% CI 1.80–2.60) and gradually elevated approximately 3 folds with both short telomere length and pre-frailty (HR 2.23, 95% CI 1.81–2.74) or frailty (HR 3.57, 95% CI 2.56–4.98). Moreover, participants with both short telomere length and frailty had the highest increased all-cause mortality (HR 5.16, 95% CI 3.38–7.85) and cardiovascular mortality (HR 4.67, 95% CI 2.02–10.82).

Discussion and conclusions

The combined predictor had more capability of predicting mortality, which suggested that integrating both molecular biomarkers and physiological functional parameters would be a more informative measure of biological aging.


Frailty phenotype Telomere length Mortality 



We appreciated all the NHANES participants and staff for their efforts and contributions.

Compliance with ethical standards

Conflict of interest

We declare that we have no competing interests.

Ethical approval

The National Center for Health Statistics (NCHS) Research Ethics Review Board approved the NHANES protocol.

Statement of human and animal rights

All procedures performed in the study were in accodance with recommendations of the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) standards (ICH-GCP) and the Declaration of Helsinki.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

40520_2019_1376_MOESM1_ESM.docx (90 kb)
Supplementary material 1 (DOCX 99 kb)


  1. 1.
    Khan SS, Singer BD, Vaughan DE (2017) Molecular and physiological manifestations and measurement of aging in humans. Aging Cell 16:624–633CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Jylhava J, Pedersen NL, Hagg S (2017) Biological age predictors. EBioMedicine 21:29–36CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Lara J, Cooper R, Nissan J et al (2015) A proposed panel of biomarkers of healthy ageing. BMC Med 13:222CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Belsky DW, Moffitt TE, Cohen AA et al (2018) Eleven telomere, epigenetic clock, and biomarker-composite quantifications of biological aging: do they measure the same thing? Am J Epidemiol 187:1220–1230CrossRefGoogle Scholar
  5. 5.
    World Report on Ageing and Health (2015) World Health Organization, LuxembourgGoogle Scholar
  6. 6.
    Cesari M, Prince M, Thiyagarajan JA et al (2016) Frailty: an emerging public health priority. J Am Med Dir Assoc 17:188–192CrossRefGoogle Scholar
  7. 7.
    Saum KU, Dieffenbach AK, Muller H et al (2014) Frailty prevalence and 10-year survival in community-dwelling older adults: results from the ESTHER cohort study. Eur J Epidemiol 29:171–179CrossRefGoogle Scholar
  8. 8.
    Fried LP, Tangen CM, Walston J et al (2001) Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56:M146–M156CrossRefGoogle Scholar
  9. 9.
    Babizhayev MA, Savel’yeva EL, Moskvina SN et al (2011) Telomere length is a biomarker of cumulative oxidative stress, biologic age, and an independent predictor of survival and therapeutic treatment requirement associated with smoking behavior. Am J Ther 18:e209–e226CrossRefGoogle Scholar
  10. 10.
    Armanios M, Blackburn EH (2012) The telomere syndromes. Nat Rev Genet 13:693–704CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Rizvi S, Raza ST, Mahdi F (2014) Telomere length variations in aging and age-related diseases. Curr Aging Sci 7:161–167CrossRefGoogle Scholar
  12. 12.
    Sanders JL, Newman AB (2013) Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol Rev 35:112–131CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Levine ME (2013) Modeling the rate of senescence: can estimated biological age predict mortality more accurately than chronological age? J Gerontol A Biol Sci Med Sci 68:667–674CrossRefGoogle Scholar
  14. 14.
    Breitling LP, Saum KU, Perna L et al (2016) Frailty is associated with the epigenetic clock but not with telomere length in a German cohort. Clin Epigenet 8:21CrossRefGoogle Scholar
  15. 15.
    Haapanen MJ, Perala MM, Salonen MK et al (2018) Telomere length and frailty: the Helsinki Birth cohort study. J Am Med Dir Assoc 19:658–662CrossRefGoogle Scholar
  16. 16.
    Saum KU, Dieffenbach AK, Muezzinler A et al (2014) Frailty and telomere length: cross-sectional analysis in 3537 older adults from the ESTHER cohort. Exp Gerontol 58:250–255CrossRefGoogle Scholar
  17. 17.
    Yu R, Tang N, Leung J et al (2015) Telomere length is not associated with frailty in older Chinese elderly: cross-sectional and longitudinal analysis. Mech Ageing Dev 152:74–79CrossRefGoogle Scholar
  18. 18.
    Crow RS, Lohman MC, Titus AJ et al (2018) Mortality risk along the frailty spectrum: data from the National Health and Nutrition Examination Survey 1999 to 2004. J Am Geriatr Soc 66:496–502CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Zhang X, Dou Q, Zhang W et al (2019) Frailty as a predictor of all-cause mortality among older nursing home residents: a systematic review and meta-analysis. J Am Med Dir Assoc 20:657–663CrossRefGoogle Scholar
  20. 20.
    Wang Q, Zhan Y, Pedersen NL et al (2018) Telomere length and all-cause mortality: a meta-analysis. Ageing Res Rev 48:11–20CrossRefGoogle Scholar
  21. 21.
    NHANES. National Health and Nutrition Examination Survey Laboratory ProtocolGoogle Scholar
  22. 22.
    Hyattsville (2005) Centers for Disease Control and Prevention, National Center for Health Statistics. National Health and Nutrition Examination Survey Data. In: US Department of Health and Human Services CfDCaP, editorGoogle Scholar
  23. 23.
    Barreto Pde S, Greig C, Ferrandez AM (2012) Detecting and categorizing frailty status in older adults using a self-report screening instrument. Arch Gerontol Geriatr 54:e249–e254CrossRefGoogle Scholar
  24. 24.
    Blodgett J, Theou O, Kirkland S et al (2015) Frailty in NHANES: comparing the frailty index and phenotype. Arch Gerontol Geriatr 60:464–470CrossRefGoogle Scholar
  25. 25.
    Fernandez-Garrido J, Ruiz-Ros V, Buigues C et al (2014) Clinical features of prefrail older individuals and emerging peripheral biomarkers: a systematic review. Arch Gerontol Geriatr 59:7–17CrossRefGoogle Scholar
  26. 26.
    Shamliyan T, Talley KM, Ramakrishnan R et al (2013) Association of frailty with survival: a systematic literature review. Ageing Res Rev 12:719–736CrossRefGoogle Scholar
  27. 27.
    Montiel Rojas D, Nilsson A, Ponsot E et al (2018) Short telomere length is related to limitations in physical function in elderly european adults. Front Physiol 9:1110CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hemann MT, Strong MA, Hao LY et al (2001) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell 107:67–77CrossRefPubMedGoogle Scholar
  29. 29.
    Ortiz-Ramirez M, Sanchez-Garcia S, Garcia-Dela Torre P et al (2018) Telomere shortening and frailty in Mexican older adults. Geriatr Gerontol Int 18:1286–1292CrossRefGoogle Scholar
  30. 30.
    Blackburn EH, Epel ES, Lin J (2015) Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection. Science 350:1193–1198CrossRefGoogle Scholar
  31. 31.
    Muezzinler A, Zaineddin AK, Brenner H (2013) A systematic review of leukocyte telomere length and age in adults. Ageing Res Rev 12:509–519CrossRefGoogle Scholar
  32. 32.
    Kong CM, Lee XW, Wang X (2013) Telomere shortening in human diseases. FEBS J 280:3180–3193CrossRefGoogle Scholar
  33. 33.
    Starr JM, Shiels PG, Harris SE et al (2008) Oxidative stress, telomere length and biomarkers of physical aging in a cohort aged 79 years from the 1932 Scottish Mental Survey. Mech Ageing Dev 129:745–751CrossRefGoogle Scholar
  34. 34.
    Wong JY, De Vivo I, Lin X et al (2014) The relationship between inflammatory biomarkers and telomere length in an occupational prospective cohort study. PLoS One 9:e87348CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cassidy A, De Vivo I, Liu Y et al (2010) Associations between diet, lifestyle factors, and telomere length in women. Am J Clin Nutr 91:1273–1280CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    McGrath M, Wong JY, Michaud D et al (2007) Telomere length, cigarette smoking, and bladder cancer risk in men and women. Cancer Epidemiol Biomark Prev 16:815–819CrossRefGoogle Scholar
  37. 37.
    Collerton J, Martin-Ruiz C, Davies K et al (2012) Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: cross-sectional findings from the Newcastle 85 + Study. Mech Ageing Dev 133:456–466CrossRefGoogle Scholar
  38. 38.
    Laudisio A, Navarini L, Margiotta DPE et al (2019) The association of olfactory dysfunction, frailty, and mortality is mediated by inflammation: results from the InCHIANTI Study. J Immunol Res 2019:3128231CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Brown PJ, Roose SP, Zhang J et al (2016) Inflammation, depression, and slow gait: a high mortality phenotype in later life. J Gerontol A Biol Sci Med Sci 71:221–227CrossRefGoogle Scholar
  40. 40.
    Fougere B, Boulanger E, Nourhashemi F et al (2017) Chronic inflammation: accelerator of biological aging. J Gerontol A Biol Sci Med Sci 72:1218–1225CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE)BonnGermany
  2. 2.State Key Laboratory of OphthalmologyZhongshan Ophthalmic Center, Sun Yat-sen UniversityGuangzhouChina
  3. 3.School of Public HealthXi’an Jiaotong University Health Science CenterXi’anChina
  4. 4.The Center of Gerontology and Geriatrics, West China HospitalSichuan UniversityChengduChina
  5. 5.Precision Medicine Research CenterWest China Hospital, Sichuan UniversityChengduChina

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