Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The degree of frailty as a translational measure of health in aging

Nature Aging volume 1, pages 651–665 (2021)Cite this article

Subjects

Abstract

Frailty is a multiply determined, age-related state of increased risk for adverse health outcomes. We review how the degree of frailty conditions the development of late-life diseases and modifies their expression. The risks for frailty range from subcellular damage to social determinants. These risks are often synergistic—circumstances that favor damage also make repair less likely. We explore how age-related damage and decline in repair result in cellular and molecular deficits that scale up to tissue, organ and system levels, where they are jointly expressed as frailty. The degree of frailty can help to explain the distinction between carrying damage and expressing its usual clinical manifestations. Studying people—and animals—who live with frailty, including them in clinical trials and measuring the impact of the degree of frailty are ways to better understand the diseases of old age and to establish best practices for the care of older adults.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Frailty is not a disease, but it profoundly influences disease expression.
Fig. 2: Medical interventions, lifestyle factors and social factors have a strong impact on the prevalence of frailty.
Fig. 3: Age-dependent deterioration is heterogeneous and is graded by frailty index scores.
Fig. 4: Age-associated deficits arise at the molecular/cellular level in frail individuals, scaling up to affect function at the organ and system levels.

Similar content being viewed by others

References

  1. Fontana, L., Kennedy, B. K., Longo, V. D., Seals, D. & Melov, S. Medical research: treat ageing. Nature 511, 405–407 (2014). This influential commentary pithily summarized the geroscience agenda: "the problems of old age come as a package".

  2. Epel, E. S. The geroscience agenda: toxic stress, hormetic stress and the rate of aging. Ageing Res. Rev. 28, 101167 (2020). This paper calls to attention the role of hormetic stress in rates of aging.

    Article  CAS  Google Scholar 

  3. Davies, L. E. et al. Adverse outcomes of polypharmacy in older people: systematic review of reviews. J. Am. Med. Dir. Assoc. 21, 181–187 (2020).

    Article  PubMed  Google Scholar 

  4. Eckart, A. et al. Validation of the hospital frailty risk score in a tertiary care hospital in Switzerland: results of a prospective, observational study. BMJ Open 9, e026923 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  5. De Biasio, J. C. et al. Frailty in critical care medicine: a review. Anesth. Analg. 130, 1462–1473 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Campisi, J. et al. From discoveries in ageing research to therapeutics for healthy ageing. Nature 571, 183–192 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019). This paper demonstrates that selectively ablating senescent cells with senolytic drugs can improve physical dysfunction in aging.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Hickson, L. J. et al. Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease. EBioMedicine 47, 446–456 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  9. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013). This paper proposed that aging could be defined by characteristic features termed hallmarks.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kennedy, B. K. et al. Geroscience: linking aging to chronic disease. Cell 159, 709–713 (2014). This paper proposed that aging could be defined by characteristic features termed pillars.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Howlett, S. E. & Rockwood, K. Ageing: develop models of frailty. Nature 512, 253 (2014).

    Article  PubMed  CAS  Google Scholar 

  12. Peters, R. et al. Common risk factors for major noncommunicable disease, a systematic overview of reviews and commentary: the implied potential for targeted risk reduction. Ther. Adv. Chronic Dis. 10, 2040622319880392 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Abeliansky, A. L., Erel, D. & Strulik, H. Aging in the USA: similarities and disparities across time and space. Sci. Rep. 10, 14309 (2020). This paper demonstrates the use of the frailty index as a biological foundation of health economic theory.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Hoogendijk, E. O. et al. Frailty: implications for clinical practice and public health. Lancet 394, 1365–1375 (2019).

    Article  PubMed  Google Scholar 

  15. Rutenberg, A. D., Mitnitski, A. B., Farrell, S. G. & Rockwood, K. Unifying aging and frailty through complex dynamical networks. Exp. Gerontol. 107, 126–129 (2018).

    Article  PubMed  Google Scholar 

  16. Arbeev, K. G. et al. Genetics of physiological dysregulation: findings from the long life family study using joint models. Aging 12, 5920–5947 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Levine, M. E. Assessment of epigenetic clocks as biomarkers of aging in basic and population research. J. Gerontol. A Biol. Sci. Med. Sci. 75, 463–465 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Li, X. et al. Longitudinal trajectories, correlations and mortality associations of nine biological ages across 20-years follow-up. eLife 9, e51507 (2020). This paper compared nine different measures of biological age, concluding that methylation age and frailty are complementary in predicting mortality.

  20. Kameda, M., Mikawa, T., Yokode, M., Inagaki, N. & Kondoh, H. Senescence research from historical theory to future clinical application. Geriatr. Gerontol. Int. 21, 125–130 (2021).

    Article  PubMed  Google Scholar 

  21. Rockwood, K. & Howlett, S. E. Age-related deficit accumulation and the diseases of ageing. Mech. Ageing Dev. 180, 107–116 (2019).

    Article  PubMed  Google Scholar 

  22. Banga, S., Heinze-Milne, S. D. & Howlett, S. E. Rodent models of frailty and their application in preclinical research. Mech. Ageing Dev. 179, 1–10 (2019).

    Article  PubMed  Google Scholar 

  23. Clegg, A., Young, J., Iliffe, S., Rikkert, M. O. & Rockwood, K. Frailty in elderly people. Lancet 381, 752–762 (2013).

    Article  PubMed  Google Scholar 

  24. Andrew, M. K. & Keefe, J. M. Social vulnerability from a social ecology perspective: a cohort study of older adults from the National Population Health Survey of Canada. BMC Geriatr. 14, 90 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gordon, E. H. & Hubbard, R. E. Differences in frailty in older men and women. Med. J. Aust. 212, 183–188 (2020).

    Article  PubMed  Google Scholar 

  26. O’Caoimh, R. et al. Prevalence of frailty in 62 countries across the world: a systematic review and meta-analysis of population-level studies. Age Ageing 50, 96–104 (2021).

    Article  PubMed  Google Scholar 

  27. Trendelenburg, A. U., Scheuren, A. C., Potter, P., Müller, R. & Bellantuono, I. Geroprotectors: a role in the treatment of frailty. Mech. Ageing Dev. 180, 11–20 (2019).

    Article  PubMed  CAS  Google Scholar 

  28. Negm, A. M. et al. Management of frailty: a systematic review and network meta-analysis of randomized controlled trials. J. Am. Med. Dir. Assoc. 20, 1190–1198 (2019).

    Article  PubMed  Google Scholar 

  29. Adja, K. Y. C. et al. The importance of taking a patient-centered, community-based approach to preventing and managing frailty: a public health perspective. Front. Public Health 8, 599170 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Navarrete-Villanueva, D. et al. Frailty and physical fitness in elderly people: a systematic review and meta-analysis. Sports Med. 51, 143–160 (2021).

    Article  PubMed  Google Scholar 

  31. Rezaei-Shahsavarloo, Z., Atashzadeh-Shoorideh, F., Gobbens, R. J. J., Ebadi, A. & Harouni, G. G. The impact of interventions on management of frailty in hospitalized frail older adults: a systematic review and meta-analysis. BMC Geriatr. 20, 526 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Konopka, A. R. et al. Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell 18, e12880 (2019).

    Article  PubMed  CAS  Google Scholar 

  33. Moghtadaei, M. et al. The impacts of age and frailty on heart rate and sinoatrial node function. J. Physiol. 594, 7105–7126 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Jansen, H. J. et al. Atrial structure, function and arrhythmogenesis in aged and frail mice. Sci. Rep. 7, 44336 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Feridooni, H. A. et al. The impact of age and frailty on ventricular structure and function in C57BL/6J mice. J. Physiol. 595, 3721–3742 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Kane, A. E. et al. Age, sex and overall health, measured as frailty, modify myofilament proteins in hearts from naturally aging mice. Sci. Rep. 10, 10052 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Vaupel, J. W., Manton, K. G. & Stallard, E. The impact of heterogeneity in individual frailty on the dynamics of mortality. Demography 16, 439–454 (1979). This paper introduced the notion of variability in the rates of aging as defining frailty.

  38. Vaupel, J. W. et al. Biodemographic trajectories of longevity. Science 280, 855–860 (1998).

    Article  PubMed  CAS  Google Scholar 

  39. Gavrilov, L. A. & Gavrilova, N. S. Late-life mortality is underestimated because of data errors. PLoS Biol. 17, e3000148 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hwang, S. W., Atia, M., Nisenbaum, R., Pare, D. E. & Joordens, S. Is looking older than one’s actual age a sign of poor health? J. Gen. Intern. Med. 26, 136–141 (2011).

    Article  PubMed  Google Scholar 

  41. Fried, L. P. et al.; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 56, M146–M156 (2001). This paper introduced the notion of the frailty syndrome as a phenotype.

  42. Mitnitski, A. B., Mogilner, A. J. & Rockwood, K. Accumulation of deficits as a proxy measure of aging. ScientificWorldJournal 1, 323–336 (2001). This paper introduced the concept of frailty as a state defined by the accumulation of deficits.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Steverink, N., Slaets, J. P. J., Schuurmans, H. & Lis van, M. Measuring frailty. Development and testing of the Groningen Frailty Indicator (GFI). Gerontologist 41, 236–237 (2001).

    Google Scholar 

  44. Dent, E., Kowal, P. & Hoogendijk, E. O. Frailty measurement in research and clinical practice: a review. Eur. J. Intern. Med. 31, 3–10 (2016).

    Article  PubMed  Google Scholar 

  45. Gobbens, R. J., Boersma, P., Uchmanowicz, I. & Santiago, L. M. The Tilburg Frailty Indicator: new evidence for its validity. Clin. Interv. Aging 15, 265–274 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Poh, A. W. Y. & Teo, S. P. Utility of frailty screening tools in older surgical patients. Ann. Geriatr. Med. Res. 24, 75–82 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Searle, S. D., Mitnitski, A., Gahbauer, E. A., Gill, T. M. & Rockwood, K. A standard procedure for creating a frailty index. BMC Geriatr. 8, 24 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Farrell, S. G., Mitnitski, A. B., Rockwood, K. & Rutenberg, A. D. Network model of human aging: frailty limits and information measures. Phys. Rev. E 94, 052409 (2016).

    Article  PubMed  Google Scholar 

  49. Theou, O. et al. Modifications to the frailty phenotype criteria: systematic review of the current literature and investigation of 262 frailty phenotypes in the Survey of Health, Ageing and Retirement in Europe. Ageing Res. Rev. 21, 78–94 (2015).

    Article  PubMed  Google Scholar 

  50. Morley, J. E., Malmstrom, T. K. & Miller, D. K. A simple frailty questionnaire (FRAIL) predicts outcomes in middle-aged African Americans. J. Nutr. Health Aging 16, 601–608 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Panza, F. et al. Cognitive frailty: predementia syndrome and vascular risk factors. Neurobiol. Aging 27, 933–940 (2006).

    Article  PubMed  CAS  Google Scholar 

  52. Bunt, S., Steverink, N., Olthof, J., van der Schans, C. P. & Hobbelen, J. S. M. Social frailty in older adults: a scoping review. Eur. J. Ageing 14, 323–334 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Kukla, M. et al. Irisin in liver cirrhosis. J. Clin. Med. 9, 3158 (2020).

    Article  PubMed Central  CAS  Google Scholar 

  54. Howlett, S. E., Rockwood, M. R., Mitnitski, A. & Rockwood, K. Standard laboratory tests to identify older adults at increased risk of death. BMC Med. 12, 171 (2014). This paper showed that the results of routine laboratory investigations can be combined to produce a frailty index with properties that suggest cellular and tissue deficits precede clinical features of frailty.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Mitnitski, A. et al. Age-related frailty and its association with biological markers of ageing. BMC Med. 13, 161 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Rockwood, K. et al. A global clinical measure of fitness and frailty in elderly people. CMAJ 173, 489–495 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Johnson, R. L., McIsaac, D. I. & Mantilla, C. B. Preoperative frailty assessment: comment. Anesthesiology 133, 468–470 (2020).

    Article  PubMed  Google Scholar 

  58. Kojima, G., Iliffe, S. & Walters, K. Frailty index as a predictor of mortality: a systematic review and meta-analysis. Age Ageing 47, 193–200 (2018).

    Article  PubMed  Google Scholar 

  59. Kojima, G., Taniguchi, Y., Iliffe, S., Jivraj, S. & Walters, K. Transitions between frailty states among community-dwelling older people: a systematic review and meta-analysis. Ageing Res. Rev. 50, 81–88 (2019).

    Article  PubMed  Google Scholar 

  60. Nguyen, Q. D. et al. Health heterogeneity in older adults: exploration in the Canadian Longitudinal Study on Aging. J. Am. Geriatr. Soc. 69, 678–687 (2021).

    Article  PubMed  Google Scholar 

  61. Fan, J. et al. China Kadoorie Biobank Collaborative Group. Frailty index and all-cause and cause-specific mortality in Chinese adults: a prospective cohort study. Lancet Public Health 5, e650–e660 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Kulminski, A. M. et al. Cumulative deficits better characterize susceptibility to death in elderly people than phenotypic frailty: lessons from the Cardiovascular Health Study. J. Am. Geriatr. Soc. 56, 898–903 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sathyan, S. & Verghese, J. Genetics of frailty: a longevity perspective. Transl. Res. 221, 83–96 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Ukraintseva, S., Yashin, A. I. & Arbeev, K. G. Resilience versus robustness in aging. J. Gerontol. A Biol. Sci. Med. Sci. 71, 1533–1534 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Rolfson, D. B., Majumdar, S. R., Tsuyuki, R. T., Tahir, A. & Rockwood, K. Validity and reliability of the Edmonton Frail Scale. Age Ageing 35, 526–529 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Parks, R. J. et al. A procedure for creating a frailty index based on deficit accumulation in aging mice. J. Gerontol. A Biol. Sci. Med. Sci. 67, 217–227 (2012). This paper demonstrated that the concept of a frailty index could be applied to animal models.

    Article  PubMed  Google Scholar 

  67. Whitehead, J. C. et al. A clinical frailty index in aging mice: comparisons with frailty index data in humans. J. Gerontol. A Biol. Sci. Med. Sci. 69, 621–632 (2014).

    Article  PubMed  Google Scholar 

  68. Liu, H., Graber, T. G., Ferguson-Stegall, L. & Thompson, L. V. Clinically relevant frailty index for mice. J. Gerontol. A Biol. Sci. Med. Sci. 69, 1485–1491 (2014).

    Article  PubMed  Google Scholar 

  69. Hua, J. et al. Assessment of frailty in aged dogs. Am. J. Vet. Res. 77, 1357–1365 (2016).

    Article  PubMed  Google Scholar 

  70. Banzato, T. et al. A Frailty Index based on clinical data to quantify mortality risk in dogs. Sci. Rep. 9, 16749 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Yamada, Y. et al. Caloric restriction and healthy life span: frail phenotype of nonhuman primates in the Wisconsin national primate research center caloric restriction study. J. Gerontol. A Biol. Sci. Med. Sci. 73, 273–278 (2018).

    Article  PubMed  Google Scholar 

  72. McNally, M. & Lahey, W. Frailty’s place in ethics and law: some thoughts on equality and autonomy and on limits and possibilities for aging citizens. Interdiscip. Top. Gerontol. Geriatr. 41, 174–185 (2015).

    Article  PubMed  Google Scholar 

  73. Han, L., Clegg, A., Doran, T. & Fraser, L. The impact of frailty on health care resource use: a longitudinal analysis using the Clinical Practice Research Datalink in England. Age Ageing 48, 665–671 (2019). This representative study suggests that per person cost to the health care system increases with the degree of frailty.

    Article  PubMed  Google Scholar 

  74. Granger, K., Ninan, S. & Stopford, E. The patient presenting with ‘acopia’. Acute Med. 12, 173–177 (2013).

    Article  PubMed  CAS  Google Scholar 

  75. Vermeiren, S. et al. Gerontopole Brussels Study group. Frailty and the prediction of negative health outcomes: a meta-analysis. J. Am. Med. Dir. Assoc. 17, 1163.e1–1163.e17 (2016).

    Article  Google Scholar 

  76. Shi, S. M., McCarthy, E. P., Mitchell, S. L. & Kim, D. H. Predicting mortality and adverse outcomes: comparing the frailty index to general prognostic indices. J. Gen. Intern. Med. 35, 1516–1522 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Sillner, A. Y. et al. The association of a frailty index and incident delirium in older hospitalized patients: an observational cohort study. Clin. Interv. Aging 15, 2053–2061 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Pérez-Zepeda, M. U., Carrillo-Vega, M. F., Theou, O., Jácome-Maldonado, L. D. & García-Peña, C. Hospital complications and frailty in Mexican older adults: an emergency care cohort analysis. Front. Med. 7, 505 (2020).

    Article  Google Scholar 

  79. Bowman, K. et al. Predicting incident delirium diagnoses using data from primary-care electronic health records. Age Ageing 49, 374–381 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Hollinghurst, J. et al. External validation of the electronic Frailty Index using the population of Wales within the Secure Anonymised Information Linkage Databank. Age Ageing 48, 922–926 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Kim, D. H. Measuring frailty in health care databases for clinical care and research. Ann. Geriatr. Med. Res. 24, 62–74 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Simo, N. et al. Frailty index, hospital admission and number of days spent in hospital in nursing home residents: results from the INCUR study. J. Nutr. Health Aging 25, 155–159 (2021).

    Article  PubMed  CAS  Google Scholar 

  83. Know, C. S., Hasan, S. S., Thiruchelvam, K. & Aldeyab, M. Association of frailty and mortality in patients with COVID-19: a meta-analysis. Br. J. Anaesth. 126, e108–e110 (2021).

    Article  CAS  Google Scholar 

  84. Pranata, R. et al. Clinical Frailty Scale and mortality in COVID-19: a systematic review and dose–response meta-analysis. Arch. Gerontol. Geriatr. 93, 104324 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Hägg, S. et al. Age, frailty, and comorbidity as prognostic factors for short-term outcomes in patients with Coronavirus Disease 2019 in geriatric care. J. Am. Med. Dir. Assoc. 21, 1555–1559 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  86. Izurieta, H. S. et al. Natural history of COVID-19: risk factors for hospitalizations and deaths among >26 million US Medicare beneficiaries. J. Infect. Dis. 223, 945–956 (2021).

    Article  PubMed  CAS  Google Scholar 

  87. Cosco, T. D. et al. What is the relationship between validated frailty scores and mortality for adults with COVID-19 in acute hospital care? a systematic review. Age Ageing 50, 608–616 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Petermann-Rocha, F. et al. Comparison of two different frailty measurements and risk of hospitalisation or death from COVID-19: findings from UK Biobank. BMC Med. 18, 355 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Ma, Y. et al. The association between frailty and severe disease among COVID-19 patients aged over 60 years in China: a prospective cohort study. BMC Med. 18, 274 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Vilches-Moraga, A. et al. COPE Study. Increased care at discharge from COVID-19: the association between pre-admission frailty and increased care needs after hospital discharge; a multicentre European observational cohort study. BMC Med. 18, 408 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Marengoni, A., Zucchelli, A., Grande, G., Fratiglioni, L. & Rizzuto, D. The impact of delirium on outcomes for older adults hospitalised with COVID-19. Age Ageing 49, 923–926 (2020).

    Article  PubMed  Google Scholar 

  92. Kennedy, M. et al. Delirium in older patients with COVID-19 presenting to the emergency department. JAMA Netw. Open 3, e2029540 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Persico, I. et al. Frailty and delirium in older adults: a systematic review and meta-analysis of the literature. J. Am. Geriatr. Soc. 66, 2022–2030 (2018).

    Article  PubMed  Google Scholar 

  94. Aucoin, S. D. et al. Accuracy and feasibility of clinically applied frailty instruments before surgery: a systematic review and meta-analysis. Anesthesiology 133, 78–95 (2020).

    Article  PubMed  Google Scholar 

  95. Wilson, J. E. et al. Delirium. Nat. Rev. Dis. Primers 6, 90 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Geriatric Medicine Research Collaborative. Delirium is prevalent in older hospital inpatients and associated with adverse outcomes: results of a prospective multi-centre study on World Delirium Awareness Day. BMC Med. 17, 229 (2019).

  97. McElhaney, J. E. et al. The immune response to influenza in older humans: beyond immune senescence. Immun. Ageing 17, 10 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Soiza, R. L., Scicluna, C. & Thomson, E. C. Efficacy and safety of COVID-19 vaccines in older people. Age Ageing 50, 279–283 (2021).

    Article  PubMed  Google Scholar 

  99. Andrew, M. K. & McElhaney, J. E. Age and frailty in COVID-19 vaccine development. Lancet 396, 1942–1944 (2021).

    Article  PubMed  Google Scholar 

  100. McKhann, G. M. et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging and the Alzheimer’s Association Workgroup. Alzheimers Dement. 7, 263–269 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Landau, S. M. et al. Amyloid deposition, hypometabolism and longitudinal cognitive decline. Ann. Neurol. 72, 578–586 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Cummings, J. The National Institute on Aging-Alzheimer’s Association framework on Alzheimer’s disease: application to clinical trials. Alzheimers Dement. 15, 172–178 (2019).

    Article  PubMed  Google Scholar 

  103. Nicoll, J. A. R. et al. Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer’s disease. Brain 142, 2113–2126 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Holmes, C. et al. Long-term effects of Aβ42 immunisation in Alzheimer’s disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 372, 216–223 (2008).

    Article  PubMed  CAS  Google Scholar 

  105. Lim, A. et al. Clinico-neuropathological correlation of Alzheimer’s disease in a community-based case series. J. Am. Geriatr. Soc. 47, 564–569 (1999).

    Article  PubMed  CAS  Google Scholar 

  106. Matthews, F. E. et al. Epidemiological pathology of dementia: attributable risks at death in the Medical Research Council Cognitive Function and Ageing Study. PLoS Med. 6, e1000180 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Brenowitz, W. D. et al. Alzheimer’s disease neuropathologic change, Lewy body disease and vascular brain injury in clinic- and community-based samples. Neurobiol. Aging 53, 83–92 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Boyle, P. A. et al. Attributable risk of Alzheimer’s dementia attributed to age-related neuropathologies. Ann. Neurol. 85, 114–124 (2019).

    Article  PubMed  CAS  Google Scholar 

  109. Savva, G. M. et al. Age, neuropathology and dementia. N. Engl. J. Med. 360, 2302–2309 (2009).

    Article  PubMed  CAS  Google Scholar 

  110. Wallace, L. M. K. et al. Investigation of frailty as a moderator of the relationship between neuropathology and dementia in Alzheimer’s disease: a cross-sectional analysis of data from the Rush Memory and Aging Project. Lancet Neurol. 18, 177–184 (2019). This paper demonstrates that frailty moderates the risk of Alzheimer neuropathology in relation to Alzheimer dementia in late life.

    Article  PubMed  Google Scholar 

  111. Mitnitski, A., Fallah, N., Rockwood, M. R. & Rockwood, K. Transitions in cognitive status in relation to frailty in older adults: a comparison of three frailty measures. J. Nutr. Health Aging 15, 863–867 (2011).

    Article  PubMed  CAS  Google Scholar 

  112. Song, X., Mitnitski, A. & Rockwood, K. Nontraditional risk factors combine to predict Alzheimer disease and dementia. Neurol 77, 227–234 (2011). This paper introduced the notion of ‘traditional’ and ‘nontraditional’ risk factors for evaluating risk in relation to age-associated deficits.

    Article  Google Scholar 

  113. Wallace, L. M. K. et al. Neuropathological burden and the degree of frailty in relation to global cognition and dementia. Neurology 95, e3269–e3279 (2020).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  114. Sathyan, S. et al. Frailty and risk of incident motoric cognitive risk syndrome. J. Alzheimers Dis. 71, S85–S93 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Livingston, G. et al. Dementia prevention, intervention and care: 2020 report of the Lancet Commission. Lancet 396, 413–446 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Wallace, L. M. et al. Accumulation of nontraditional risk factors for coronary heart disease is associated with incident coronary heart disease hospitalization and death. PLoS ONE 9, e90475 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Dewan, P. et al. The prevalence and importance of frailty in heart failure with reduced ejection fraction—an analysis of PARADIGM-HF and ATMOSPHERE. Eur. J. Heart Fail. 22, 2123–2133 (2020).

    Article  PubMed  Google Scholar 

  118. Farooqi, M. A. M., Gerstein, H., Yusuf, S. & Leong, D. P. Accumulation of deficits as a key risk factor for cardiovascular morbidity and mortality: a pooled analysis of 154,000 individuals. J. Am. Heart Assoc. 9, e014686 (2020). This large-scale independent reanalysis of several clinical trials demonstrated the inseparability of deficit-driven, variable rates of aging from cardiovascular mortality.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Aguayo, G. A. et al. Comparative analysis of the association between 35 frailty scores and cardiovascular events, cancer and total mortality in an elderly general population in England: an observational study. PLoS Med. 15, e1002543 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Wilkinson, C., Todd, O., Clegg, A., Gale, C. P. & Hall, M. Management of atrial fibrillation for older people with frailty: a systematic review and meta-analysis. Age Ageing 48, 196–203 (2019).

    Article  PubMed  Google Scholar 

  121. Clegg, A. et al. Development and validation of an electronic frailty index using routine primary care electronic health record data. Age Ageing 45, 353–360 (2016). This paper introduced an electronic frailty index collected from routine primary care practice visits, offering proof-of-concept of routine screening of the degree of frailty.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Wilkinson, C. et al. Atrial fibrillation and oral anticoagulation in older people with frailty: a nationwide primary care electronic health records cohort study. Age Ageing 50, 772–779 (2021).

    Article  PubMed  Google Scholar 

  123. Wilkinson, C. et al. Clinical outcomes in patients with atrial fibrillation and frailty: insights from the ENGAGE AF-TIMI 48 trial. BMC Med. 18, 401 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Warwick, J. et al. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over. BMC Med. 13, 78 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Pajewski, N. M. et al.; SPRINT Study Research Group. Characterizing frailty status in the systolic blood pressure intervention trial. J. Gerontol. A Biol. Sci. Med. Sci. 71, 649–655 (2016).

  126. Russo, G. et al. Impact of SPRINT results on hypertension guidelines: implications for ‘frail’ elderly patients. J. Hum. Hypertens. 32, 633–638 (2018).

    Article  PubMed  Google Scholar 

  127. Benetos, A., Petrovic, M. & Strandberg, T. Hypertension management in older and frail older patients. Circ. Res. 124, 1045–1060 (2019).

    Article  PubMed  CAS  Google Scholar 

  128. Giffin, A., Madden, K. M. & Hogan, D. B. Blood pressure targets for older patients—do advanced age and frailty really not matter? Can. Geriatr. J. 23, 205–209 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Bartosch, P., McGuigan, F. E. & Akesson, K. E. Progression of frailty and prevalence of osteoporosis in a community cohort of older women-a 10-year longitudinal study. Osteoporos. Int. 29, 2191–2199 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Guaraldi, G. et al. A frailty index predicts survival and incident multimorbidity independent of markers of HIV disease severity. AIDS 29, 1633–1641 (2015).

    Article  PubMed  Google Scholar 

  131. Legge, A. et al. Prediction of damage accrual in systemic lupus erythematosus using the systemic lupus international collaborating clinics frailty index. Arthritis Rheumatol. 72, 658–666 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Herrera, A. P. et al. Disparate inclusion of older adults in clinical trials: priorities and opportunities for policy and practice change. Am. J. Public Health 100, S105–S112 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Rich, M. W. et al.; American Heart Association Older Populations Committee of the Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, and Stroke Council; American College of Cardiology; and American Geriatrics Society. Knowledge gaps in cardiovascular care of the older adult population: a scientific statement from the American Heart Association, American College of Cardiology and American Geriatrics Society. J. Am. Coll. Cardiol. 67, 2419–2440 (2016).

  134. Walker, D. M. et al. Frailty and the management of patients with acute cardiovascular disease: a position paper from the Acute Cardiovascular Care Association. Eur. Heart J. Acute Cardiovasc. Care. 7, 176–193 (2018).

    Article  PubMed  CAS  Google Scholar 

  135. Hanlon, P. et al. Identifying frailty in trials: an analysis of individual participant data from trials of novel pharmacological interventions. BMC Med. 18, 309 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Motta, F., Sica, A. & Selmi, C. Frailty in rheumatic diseases. Front. Immunol. 11, 576134 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Andrew, M. K., Mitnitski, A., Kirkland, S. A. & Rockwood, K. The impact of social vulnerability on the survival of the fittest older adults. Age Ageing 41, 161–165 (2012). This paper proposes that the outcomes of the fittest people define the characteristics of a population or group, demonstrated here by the impact of social vulnerability on health and mortality.

  138. Theou, O. et al. Exploring the relationship between national economic indicators and relative fitness and frailty in middle-aged and older Europeans. Age Ageing 42, 614–619 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Shamliyan, T., Talley, K. M., Ramakrishnan, R. & Kane, R. L. Association of frailty with survival: a systematic literature review. Ageing Res. Rev. 12, 719–736 (2013).

    Article  PubMed  Google Scholar 

  140. Ellis, H. L. et al. Complementing chronic frailty assessment at hospital admission with an electronic frailty index (FI-Laboratory) comprising routine blood test results. CMAJ 192, E3–E8 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Abeliansky, A. L. & Strulik, H. Hungry children age faster. Econ. Hum. Biol. 29, 211–220 (2018).

    Article  PubMed  Google Scholar 

  142. Marshall, A., Nazroo, J., Tampubolon, G. & Vanhoutte, B. Cohort differences in the levels and trajectories of frailty among older people in England. J. Epidemiol. Community Health 69, 316–321 (2015).

    Article  PubMed  Google Scholar 

  143. Bäckman, K. et al. Changes in the lethality of frailty over 30 years: evidence from two cohorts of 70-year-olds in Gothenburg, Sweden. J. Gerontol. A Biol. Sci. Med. Sci. 72, 945–950 (2017).

    PubMed  Google Scholar 

  144. Mousa, A. et al. Is frailty a stable predictor of mortality across time? evidence from the cognitive function and ageing studies. Age Ageing 47, 721–727 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Yu, R. et al. Trajectories of frailty among Chinese older people in Hong Kong between 2001 and 2012: an age–period–cohort analysis. Age Ageing 47, 254–261 (2018).

    Article  PubMed  Google Scholar 

  146. Hoogendijk, E.O. et al. Trends in frailty and its association with mortality: results from the Longitudinal Aging Study Amsterdam, 1995–2016. Am. J. Epidemiol. https://doi.org/10.1093/aje/kwab018 (2021).

  147. Haapanen, M. J. et al. Infant and childhood growth and frailty in old age: the Helsinki Birth Cohort Study. Aging Clin. Exp. Res. 31, 717–721 (2019).

    Article  PubMed  CAS  Google Scholar 

  148. Welstead, M. et al. Inflammation as a risk factor for the development of frailty in the Lothian Birth Cohort 1936. Exp. Gerontol. 139, 111055 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Rockwood, K., Song, X. & Mitnitski, A. Changes in relative fitness and frailty across the adult life span: evidence from the Canadian National Population Health Survey. CMAJ 183, E487–E494 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Blodgett, J. M., Rockwood, K. & Theou, O. Changes in the severity and lethality of age-related health deficit accumulation in the USA between 1999 and 2018: a population-based cohort study. Lancet Healthy Longev. 2, E96–E104 (2021).

    Article  Google Scholar 

  151. Brothers, T. D., Theou, O. & Rockwood, K. Frailty and migration in middle-aged and older Europeans. Arch. Gerontol. Geriatr. 58, 63–68 (2014).

    Article  PubMed  Google Scholar 

  152. Franse, C. B. et al. Ethnic differences in frailty: a cross-sectional study of pooled data from community-dwelling older persons in the Netherlands. BMJ Open. 8, e022241 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Pradhananga, S. et al. Ethnic differences in the prevalence of frailty in the United Kingdom assessed using the electronic Frailty Index. Aging Med. 2, 168–173 (2019).

    Article  Google Scholar 

  154. Herr, M., Robine, J. M., Aegerter, P., Arvieu, J. J. & Ankri, J. Contribution of socioeconomic position over life to frailty differences in old age: comparison of life-course models in a French sample of 2,350 old people. Ann. Epidemiol. 25, 674–680 (2015).

    Article  PubMed  Google Scholar 

  155. Van der Linden, B. W. A. et al. Life-course socioeconomic conditions and frailty at older ages. J. Gerontol. B Psychol. Sci. Soc. Sci. 75, 1348–1357 (2020).

    Article  PubMed  Google Scholar 

  156. Young, A. C., Glaser, K., Spector, T. D. & Steves, C. J. The identification of hereditary and environmental determinants of frailty in a cohort of UK twins. Twin Res. Hum. Genet. 19, 600–609 (2016). This twin study suggests that about half of the interindividual variation in frailty is heritable.

    Article  PubMed  Google Scholar 

  157. Li, X. et al. The frailty index is a predictor of cause-specific mortality independent of familial effects from midlife onwards: a large cohort study. BMC Med. 17, 94 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Raymond, E. et al. Drivers of frailty from adulthood into old age: results from a 27-year longitudinal population-based study in Sweden. J. Gerontol. A Biol. Sci. Med. Sci. 75, 1943–1950 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Sathyan, S. et al. Plasma proteomic profile of age, health span and all-cause mortality in older adults. Aging Cell 19, e13250 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Livshits, G. et al. Multi-omics analyses of frailty and chronic widespread musculoskeletal pain suggest involvement of shared neurological pathways. Pain 159, 2565–2572 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Taneja, S., Mitnitski, A. B., Rockwood, K. & Rutenberg, A. D. Dynamical network model for age-related health deficits and mortality. Phys. Rev. E 93, 022309 (2016). The paper introduced a framework for modeling deficit accumulation and its relationship to mortality.

    Article  PubMed  CAS  Google Scholar 

  162. Jazwinski, S. M. & Kim, S. Examination of the dimensions of biological age. Front. Genet. 10, 263 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Araújo Carvalho, A. C. et al. Telomere length and frailty in older adults—a systematic review and meta-analysis. Ageing Res. Rev. 54, 100914 (2019).

    Article  PubMed  CAS  Google Scholar 

  164. Hägg, S., Jylhävä, J., Wang, Y., Czene, K. & Grassmann, F. Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance. Hum. Genet. 40, 849–861 (2021). This paper demonstrates that mitochondrial dysfunction is related to the degree of frailty in a sex-specific fashion.

    Article  CAS  Google Scholar 

  165. Hao, Q. et al. Prediction of mortality in Chinese very old people through the frailty index based on routine laboratory data. Sci. Rep. 9, 221 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. King, K. E., Fillenbaum, G. G. & Cohen, H. J. A cumulative deficit laboratory test-based frailty index: personal and neighborhood associations. J. Am. Geriatr. Soc. 65, 1981–1987 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Mitnitski, A. & Rockwood, K. The rate of aging: the rate of deficit accumulation does not change over the adult life span. Biogerontology 17, 199–204 (2016).

    Article  PubMed  Google Scholar 

  168. Hoogendijk, E. O. et al. Tracking changes in frailty throughout later life: results from a 17-year longitudinal study in the Netherlands. Age Ageing 47, 727–733 (2018).

    Article  PubMed  Google Scholar 

  169. Stolz, E., Hoogendijk, E.O., Mayerl, H. & Freidl, W. Frailty changes predict mortality in four longitudinal studies of aging. J. Gerontol. A Biol. Sci. Med. Sci. https://doi.org/10.1093/gerona/glaa266 (2020).

  170. Stolz, E. et al. Acceleration of health deficit accumulation in late life: evidence of terminal decline in frailty index three years before death in the US Health and Retirement Study. Ann. Epidemiol. 58, 156–161 (2021).

    Article  PubMed  Google Scholar 

  171. Lu, W. et al. Relationship between employment histories and frailty trajectories in later life: evidence from the English Longitudinal Study of Ageing. J. Epidemiol. Community Health 71, 439–445 (2017).

    Article  PubMed  Google Scholar 

  172. Noppert, G. A., Aiello, A. E., O’Rand, A. M. & Cohen, H. J. Race/ethnic and educational disparities in the association between pathogen burden and a laboratory-based cumulative deficits index. J. Racial Ethn. Health Disparities 7, 99–108 (2020).

    Article  PubMed  Google Scholar 

  173. Miller, M. G., Thangthaeng, N. & Shukitt-Hale, B. A clinically relevant frailty index for aging rats. J. Gerontol. A Biol. Sci. Med. Sci. 72, 892–896 (2017).

    Article  PubMed  Google Scholar 

  174. Rockwood, K. et al. A frailty index based on deficit accumulation quantifies mortality risk in humans and in mice. Sci. Rep. 7, 43068 (2017). This paper demonstrates that deficits accumulate in similar patterns across the life course in humans and in mice.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Baumann, C. W., Kwak, D. & Thompson, L. V. Assessing onset, prevalence and survival in mice using a frailty phenotype. Aging 10, 4042–4053 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Kwak, D., Baumann, C. W. & Thompson, L. V. Identifying characteristics of frailty in female mice using a phenotype assessment tool. J. Gerontol. A Biol. Sci. Med. Sci. 75, 640–646 (2020).

    Article  PubMed  CAS  Google Scholar 

  177. Yorke, A., Kane, A. E., Hancock Friesen, C. L., Howlett, S. E. & O’Blenes, S. Development of a rat clinical frailty index. J. Gerontol. A Biol. Sci. Med. Sci. 72, 897–903 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Pandey, A., Kitzman, D. & Reeves, G. Frailty is intertwined with heart failure: mechanisms, prevalence, prognosis, assessment and management. JACC Heart Fail. 7, 1001–1011 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Bibas, L. et al. Implications of frailty in elderly patients with electrophysiological conditions. JACC Clin. Electrophysiol. 2, 288–294 (2016).

    Article  PubMed  Google Scholar 

  180. Yabuuchi, J. et al. Association of advanced glycation end products with sarcopenia and frailty in chronic kidney disease. Sci. Rep. 10, 17647 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Antoch, M. P. et al. Physiological frailty index: quantitative in-life estimate of individual biological age in mice. Aging 9, 615–626 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Keller, K., Kane, A. E., Heinze-Milne, S., Grandy, S. A. & Howlett, S. E. Chronic treatment with the ACE inhibitor enalapril attenuates the development of frailty and differentially modifies pro- and anti-inflammatory cytokines in aging male and female C57BL/6 mice. J. Gerontol. A Biol. Sci. Med. Sci. 74, 1149–1157 (2019). This paper shows that long-term treatment of older mice with a drug that reduces inflammation improves health span.

    Article  PubMed  CAS  Google Scholar 

  183. Kane, A. E., Keller, K. M., Heinze-Milne, S., Grandy, S. A. & Howlett, S. E. A murine frailty index based on clinical and laboratory measurements: links between frailty and pro-inflammatory cytokines differ in a sex-specific manner. J. Gerontol. A Biol. Sci. Med. Sci. 74, 275–282 (2019).

    Article  PubMed  CAS  Google Scholar 

  184. Wilson, D. et al. Frailty is associated with neutrophil dysfunction which is correctable with phosphoinositol-3-kinase inhibitors. J. Gerontol. A Biol. Sci. Med. Sci. 75, 2320–2325 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Fulop, T. et al. Frailty, inflammation and immunosenescence. Interdiscip. Top. Gerontol. Geriatr. 41, 26–40 (2015).

    Article  PubMed  Google Scholar 

  186. Graber, T. G., Ferguson-Stegall, L., Liu, H. & Thompson, L. V. Voluntary aerobic exercise reverses frailty in old mice. J. Gerontol. A Biol. Sci. Med. Sci. 70, 1045–1058 (2015).

    Article  PubMed  Google Scholar 

  187. Gomez-Cabrera, M. C. et al. A new frailty score for experimental animals based on the clinical phenotype: inactivity as a model of frailty. J. Gerontol. A Biol. Sci. Med. Sci. 72, 885–891 (2017).

    Article  PubMed  Google Scholar 

  188. Seldeen, K. L. et al. High-intensity interval training improves physical performance and frailty in aged mice. J. Gerontol. A Biol. Sci. Med. Sci. 73, 429–437 (2018).

    Article  PubMed  CAS  Google Scholar 

  189. Seldeen, K. L. et al. High-intensity interval training improves physical performance in aged female mice: a comparison of mouse frailty assessment tools. Mech. Ageing Dev. 180, 49–62 (2019).

    Article  PubMed  Google Scholar 

  190. Kane, A. E. et al. Impact of longevity interventions on a validated mouse clinical frailty index. J. Gerontol. A Biol. Sci. Med. Sci. 71, 333–339 (2016).

    Article  PubMed  CAS  Google Scholar 

  191. Correia-Melo, C. et al. Rapamycin improves health span but not inflammaging in Nfκb1−/− mice. Aging Cell. 18, e12882 (2019).

    Article  PubMed  CAS  Google Scholar 

  192. Yu, D. et al. Calorie-restriction-induced insulin sensitivity is mediated by adipose mTORC2 and not required for life span extension. Cell Rep. 29, 236–248 (2019).

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  193. Newman, J. C. et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab. 26, 547–557 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Richardson, N. E. et al. Lifelong restriction of dietary branched-chain amino acids has sex-specific benefits for frailty and life span in mice. Nat. Aging 1, 73–86 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Henderson, Y.O. et al. Late-life intermittent fasting decreases aging-related frailty and increases renal hydrogen sulfide production in a sexually dimorphic manner. Geroscience https://doi.org/10.1007/s11357-021-00330-4 (2021).

  196. Guderyon, M. J. et al. Mobilization-based transplantation of young-donor hematopoietic stem cells extends life span in mice. Aging Cell 19, e13110 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Schultz, M. B. et al. Age and life expectancy clocks based on machine-learning analysis of mouse frailty. Nat. Commun. 11, 4618 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  198. Liu, Y. et al. Allicin reversed the process of frailty in aging male Fischer 344 rats with osteoporosis. J. Gerontol. A Biol. Sci. Med. Sci. 75, 821–825 (2020).

    Article  PubMed  CAS  Google Scholar 

  199. Asadi Shahmirzadi, A. et al. Alpha-ketoglutarate, an endogenous metabolite, extends life span and compresses morbidity in aging mice. Cell Metab. 32, 447–456 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  200. Chellappa, K. et al. Hypothalamic mTORC2 is essential for metabolic health and longevity. Aging Cell. 18, e13014 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  201. Mach, J. et al. Chronic polypharmacy with increasing Drug Burden Index exacerbates frailty and impairs physical function, with effects attenuated by de-prescribing, in aged mice. J. Gerontol. A Biol. Sci. Med. Sci. 76, 1010–1018 (2020).

  202. Fielder, E. et al. Sublethal whole-body irradiation causes progressive premature frailty in mice. Mech. Ageing Dev. 180, 63–69 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Darvall, J. N. et al. Frailty and outcomes from pneumonia in critical illness: a population-based cohort study. Br. J. Anaesth. 125, 730–738 (2020).

    Article  PubMed  CAS  Google Scholar 

  204. Pulok, M. H., Theou, O., van der Valk, A. M. & Rockwood, K. The role of illness acuity on the association between frailty and mortality in emergency department patients referred to internal medicine. Age Ageing 49, 1071–1079 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Rockwood, K. & Mitnitski, A. Limits to deficit accumulation in elderly people. Mech. Ageing Dev. 127, 494–496 (2006).

    Article  PubMed  Google Scholar 

  206. McIsaac, D. I., MacDonald, D. B. & Aucoin, S. D. Frailty for perioperative clinicians: a narrative review. Anesth. Analg. 130, 1450–1460 (2020).

    Article  PubMed  Google Scholar 

  207. Carli, F., Bessissow, A., Awasthi, R. & Liberman, S. Prehabilitation: finally utilizing frailty screening data. Eur. J. Surg. Oncol. 46, 321–325 (2020).

    Article  PubMed  Google Scholar 

  208. Coelho-Júnior, H. J. et al. Evidence-based recommendations for resistance and power training to prevent frailty in community-dwellers. Aging Clin. Exp. Res. 33, 2069–2086 (2021).

  209. Guralnik, J. et al. Clinically meaningful change for physical performance: perspectives of the ICFSR Task Force. J. Frailty Aging 9, 9–13 (2020).

    PubMed  PubMed Central  CAS  Google Scholar 

  210. Jang, I. Y. et al. Evaluation of clinically meaningful changes in measures of frailty. J. Gerontol. A Biol. Sci. Med. Sci. 75, 1143–1147 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Theou, O. et al. Exploring clinically meaningful changes for the frailty index in a longitudinal cohort of hospitalized older patients. J. Gerontol. A Biol. Sci. Med. Sci. 75, 1928–1934 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  212. Hshieh, T. T., Yang, T., Gartaganis, S. L., Yue, J. & Inouye, S. K. Hospital elder life program: systematic review and meta-analysis of effectiveness. Am. J. Geriatr. Psychiatry 26, 1015–1033 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  213. Curtis, M. S., Forman, N. A., Donovan, A. L. & Whitlock, E. L. Postoperative delirium: why, what and how to confront it at your institution. Curr. Opin. Anaesthesiol. 33, 668–673 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  214. Khachaturian, A. S. et al. International drive to illuminate delirium: a developing public health blueprint for action. Alzheimers Dement. 16, 711–725 (2020).

    Article  PubMed  Google Scholar 

  215. Rockwood, K. et al. CCCDTD5: reducing the risk of later-life dementia. Evidence informing the Fifth Canadian Consensus Conference on the Diagnosis and Treatment of Dementia (CCCDTD-5). Alzheimers Dement. 6, e12083 (2020).

    Google Scholar 

  216. Kirkland, J. L. & Tchkonia, T. Senolytic drugs: from discovery to translation. J. Intern. Med. 288, 518–536 (2020).

    Article  PubMed  CAS  Google Scholar 

  217. Williams, D. M., Jylhävä, J., Pedersen, N. L., N.L. & Hägg, S. A frailty index for UK Biobank participants.J. Gerontol. A Biol. Sci. Med. Sci. 74, 582–587 (2019).

    Article  PubMed  Google Scholar 

  218. Wang, Q. et al. Genetically predicted life-long lowering of low-density lipoprotein cholesterol is associated with decreased frailty: a Mendelian randomization study in UK biobank. EBioMedicine 45, 487–494 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Mekli, K. Frailty Index associates with GRIN2B in two representative samples from the United States and the United Kingdom. PLoS ONE 13, e0207824 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Espeland, M. A. et al.; Multimorbidity Clinical Trials Consortium. Clinical trials targeting aging and age-related multimorbidity.72, 355–361 (2017). J. Gerontol. A Biol. Sci. Med. Sci. 72, 355–361 (2017).

  221. Warner, H. R. et al. Program for testing biological interventions to promote healthy aging. Mech. Ageing Dev. 115, 199–207 (2000).

    Article  PubMed  CAS  Google Scholar 

  222. Nadon, N. L. et al. Design of aging intervention studies: the NIA interventions testing program. Age 30, 187–199 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  223. Farrell, S., Mitnitski, A., Rockwood, K. & Rutenberg, A. Generating synthetic aging trajectories with a weighted network model using cross-sectional data. Sci. Rep. 10, 19833 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. García-Peña, C. et al. Network analysis of frailty and aging: empirical data from the Mexican Health and Aging Study. Exp. Gerontol. 128, 110747 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  225. Stubbings, G., Farrell, S., Mitnitski, A., Rockwood, K. & Rutenberg, A. Informative frailty indices from binarized biomarkers. Biogerontology 70, 1–11 (2020).

    Google Scholar 

  226. Farrell, S., Stubbings, G., Rockwood, K., Mitnitski, A. & Rutenberg, A. The potential for complex computational models of aging. Mech. Ageing Dev. 193, 111403 (2021).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to acknowledge the influence of Arnold Mitnitski to how we think about frailty. Arnold died after a brief illness on 26 May 2021. We will miss him both as a friend and colleague, and one who has had an enormous influence on our field. Work in the laboratory of S.E.H. is supported the Canadian Institutes of Health Research (PJT 162462 and 155961) and the Heart and Stroke Foundation of Canada (G-19–0026260). Work in the laboratory of A.D.R. is supported by grants from the Natural Sciences and Engineering Research Council of Canada (RGPIN-2019–05888). Work in the Geriatric Medicine Research Unit (GMRU; K.R.) is supported by grants from the Canadian Institutes of Health Research (PJT 156114), Research Nova Scotia (RNS-SIG-2021–1640) and the Canadian Frailty Network (CFN-CSA-2019 and NSHA-2020). The GMRU has received long-term philanthropic support from the Fountain Family Innovation Fund of the QEII Health Sciences Foundation. The figures were created with BioRender.com.

Author information

Authors and Affiliations

  1. Geriatric Medicine Research Unit, Department of Medicine, Dalhousie University & Nova Scotia Health, Halifax, Nova Scotia, Canada

    Susan E. Howlett & Kenneth Rockwood

  2. Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

    Susan E. Howlett

  3. Department of Physics and Atmospheric Science, Dalhousie University, Halifax, Nova Scotia, Canada

    Andrew D. Rutenberg

Authors
  1. Susan E. Howlett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew D. Rutenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kenneth Rockwood
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.E.H. and K.R. conceived the review and wrote the first version of the manuscript. A.D.R. provided constructive input and wrote additional sections in subsequent revisions of the manuscript. All authors approved the final version of the article and figures.

Corresponding author

Correspondence to Kenneth Rockwood.

Ethics declarations

Competing interests

K.R. has asserted copyright of the Clinical Frailty Scale through Dalhousie University’s Industry, Liaison and Innovation Office. Use is free for education, research and not-for-profit health care. Users agree not to change or commercialize the scale. In addition to academic and hospital appointments, K.R. is cofounder of Ardea Outcomes, which (as DGI Clinical) in the last 3 years has contracts with pharma and device manufacturers (Biogen, Hollister, Novartis, Nutricia, Roche and Takeda) on individualized outcome measurement. In 2019, K.R. was paid an honorarium for an interview with Biogen. In 2020, he attended an advisory board meeting with Nutricia on dementia, and chaired a scientific workshop and technical review panel on frailty for the Singapore National Research Foundation. Otherwise, any personal fees were for invited guest lectures, rounds and academic symposia, received directly from event organizers, for presentations on frailty. K.R. is associate director of the Canadian Consortium on Neurodegeneration in Aging, which is funded by the Canadian Institutes for Health Research, the Alzheimer Society of Canada and several other charities. S.E.H. has a paid consulting role with Ardea Outcomes. A.D.R. has no competing interests to declare.

Additional information

Peer review information Nature Aging thanks Simon Conroy, Luigi Ferrucci, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Howlett, S.E., Rutenberg, A.D. & Rockwood, K. The degree of frailty as a translational measure of health in aging. Nat Aging 1, 651–665 (2021). https://doi.org/10.1038/s43587-021-00099-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43587-021-00099-3

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research