Frailty syndrome: an overview

Frailty is a common and important geriatric syndrome characterized by age-associated declines in physiologic reserve and function across multiorgan systems, leading to increased vulnerability for adverse health outcomes. Two major frailty models have been described in the literature. The frailty phenotype defines frailty as a distinct clinical syndrome meeting three or more of five phenotypic criteria: weakness, slowness, low level of physical activity, self-reported exhaustion, and unintentional weight loss. The frailty index defines frailty as cumulative deficits identified in a comprehensive geriatric assessment. Significant progress has recently been made in understanding the pathogenesis of frailty. Chronic inflammation is likely a key pathophysiologic process that contributes to the frailty syndrome directly and indirectly through other intermediate physiologic systems, such as the musculoskeletal, endocrine, and hematologic systems. The complex multifactorial etiologies of frailty also include obesity and specific diseases. Major clinical applications include risk assessment and stratification. This can be applied to the elderly population in the community and in a variety of care settings. Frailty may also be useful for risk assessment in surgical patients and those with cardiovascular diseases, cancer, or human immunodeficiency virus infection, as well as for assessment of vaccine effectiveness in older adults. Currently, exercise and comprehensive geriatric interdisciplinary assessment and treatment are key interventions for frailty. As understanding of the biologic basis and complexity of frailty further improves, more effective and targeted interventional strategies and innovative geriatric-care models will likely be developed.

[1]  S. Bandinelli,et al.  Association of low vitamin D levels with the frailty syndrome in men and women. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[2]  J. Margolick,et al.  Relationship Between a Frailty-Related Phenotype and Progressive Deterioration of the Immune System in HIV-Infected Men , 2009, Journal of acquired immune deficiency syndromes.

[3]  Kenneth Rockwood,et al.  Operationalizing a Frailty Index from a Standardized Comprehensive Geriatric Assessment , 2004, Journal of the American Geriatrics Society.

[4]  J. Iqbal,et al.  Frailty assessment in elderly people , 2013, The Lancet.

[5]  L. Ferrucci,et al.  Nonlinear multisystem physiological dysregulation associated with frailty in older women: implications for etiology and treatment. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[6]  Luigi Ferrucci,et al.  The prognostic value of repeated measures of lower extremity performance: should we measure more than once? , 2014, The journals of gerontology. Series A, Biological sciences and medical sciences.

[7]  G. Wang,et al.  T‐Lymphocytes Expressing CC Chemokine Receptor‐5 Are Increased in Frail Older Adults , 2008, Journal of the American Geriatrics Society.

[8]  K. Patel,et al.  Frailty, HIV Infection, and Mortality in an Aging Cohort of Injection Drug Users , 2013, PloS one.

[9]  W. Bortz,et al.  The physics of frailty. , 1993, Journal of the American Geriatrics Society.

[10]  J. E. Morley,et al.  The I.A.N.A. task force on frailty assessment of older people in clinical practice , 2008, The journal of nutrition, health & aging.

[11]  S. Studenski,et al.  Research Agenda for Frailty in Older Adults: Toward a Better Understanding of Physiology and Etiology: Summary from the American Geriatrics Society/National Institute on Aging Research Conference on Frailty in Older Adults , 2006, Journal of the American Geriatrics Society.

[12]  S. Leng,et al.  IL-6-independent association of elevated serum neopterin levels with prevalent frailty in community-dwelling older adults. , 2011, Age and ageing.

[13]  Kathleen Koenig,et al.  Serum Interleukin‐6 and Hemoglobin as Physiological Correlates in the Geriatric Syndrome of Frailty: A Pilot Study , 2002, Journal of the American Geriatrics Society.

[14]  L. Ferrucci,et al.  Phenotype of frailty: characterization in the women's health and aging studies. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[15]  Anthony A. Vandervoort,et al.  The Effectiveness of Exercise Interventions for the Management of Frailty: A Systematic Review , 2011, Journal of aging research.

[16]  A. Jazaeri,et al.  Frailty: an outcome predictor for elderly gynecologic oncology patients. , 2012, Gynecologic oncology.

[17]  L. Fried,et al.  The Association Between Obesity and the Frailty Syndrome in Older Women: The Women's Health and Aging Studies , 2005, Journal of the American Geriatrics Society.

[18]  C. Caruso,et al.  Zinc and Inflammatory/Immune Response in Aging , 2007, Annals of the New York Academy of Sciences.

[19]  Aaron Aragaki,et al.  Frailty: Emergence and Consequences in Women Aged 65 and Older in the Women's Health Initiative Observational Study , 2005, Journal of the American Geriatrics Society.

[20]  S. Edelman,et al.  Frailty and osteoporosis in older women—a prospective study , 2014, Osteoporosis International.

[21]  M. Makary,et al.  Frailty as a predictor of surgical outcomes in older patients. , 2010, Journal of the American College of Surgeons.

[22]  R. Varadhan,et al.  Higher levels and blunted diurnal variation of cortisol in frail older women. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[23]  R. Kronmal,et al.  The Cardiovascular Health Study: design and rationale. , 1991, Annals of epidemiology.

[24]  K. Rockwood,et al.  FRAILTY: A Report from the 3rd Joint Workshop of IAGG/WHO/SFGG, Athens, January 2012 , 2012, Canadian geriatrics journal : CGJ.

[25]  J. Margolick,et al.  HIV-1 infection is associated with an earlier occurrence of a phenotype related to frailty. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[26]  L. Fried,et al.  Frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults. , 2011, Vaccine.

[27]  S. Leng,et al.  Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty. , 2009, Cytokine.

[28]  T. Strandberg,et al.  Frailty in elderly people , 2007, The Lancet.

[29]  L. Fried,et al.  Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. , 2002, Archives of internal medicine.

[30]  L. Peng,et al.  Age‐related skeletal muscle mass loss and physical performance in Taiwan: Implications to diagnostic strategy of sarcopenia in Asia , 2013, Geriatrics & gerontology international.

[31]  C. Szoeke,et al.  Pharmacological Treatment of Frailty in the Elderly , 2009 .

[32]  T. Strandberg,et al.  Association of midlife obesity and cardiovascular risk with old age frailty: a 26-year follow-up of initially healthy men , 2012, International Journal of Obesity.

[33]  L. Fried,et al.  Chronic Cytomegalovirus Infection and Inflammation Are Associated with Prevalent Frailty in Community‐Dwelling Older Women , 2005, Journal of the American Geriatrics Society.

[34]  K. Becker,et al.  The physical and biological characterization of a frail mouse model. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[35]  Anne Forster,et al.  Rehabilitation for older people in long-term care. , 2009, The Cochrane database of systematic reviews.

[36]  M. Zunzunegui,et al.  Life course social and health conditions linked to frailty in Latin American older men and women. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[37]  N. Punjabi,et al.  Serum chitotriosidase, a putative marker of chronically activated macrophages, increases with normal aging. , 2013, The journals of gerontology. Series A, Biological sciences and medical sciences.

[38]  G. Savva,et al.  Inflammation and frailty measures in older people , 2009, Journal of cellular and molecular medicine.

[39]  L. Fried,et al.  Frailty in older adults: evidence for a phenotype. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[40]  L. Fried,et al.  Associations of subclinical cardiovascular disease with frailty. , 2001, The journals of gerontology. Series A, Biological sciences and medical sciences.

[41]  Peter N. Murakami,et al.  American Journal of Epidemiology Original Contribution Cytomegalovirus Infection and the Risk of Mortality and Frailty in Older Women: a Prospective Observational Cohort Study , 2022 .

[42]  J. Spagnoli,et al.  Prevalence of frailty in middle-aged and older community-dwelling Europeans living in 10 countries. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[43]  Sathya Karunananthan,et al.  Role of frailty in patients with cardiovascular disease. , 2009, The American journal of cardiology.

[44]  Luigi Ferrucci,et al.  From bedside to bench: research agenda for frailty. , 2005, Science of aging knowledge environment : SAGE KE.

[45]  Erik Buskens,et al.  Measurement properties of the Groningen Frailty Indicator in home-dwelling and institutionalized elderly people. , 2012, Journal of the American Medical Directors Association.

[46]  M. Visser,et al.  Endocrine and inflammatory markers as predictors of frailty , 2005, Clinical endocrinology.

[47]  R. Audisio,et al.  When Reporting on Older Patients with Cancer, Frailty Information is Needed , 2010, Annals of Surgical Oncology.

[48]  Qian-Li Xue,et al.  Association of detectable cytomegalovirus (CMV) DNA in monocytes rather than positive CMV IgG serology with elevated neopterin levels in community-dwelling older adults , 2011, Experimental Gerontology.

[49]  G. Lyman,et al.  Comorbidity and functional status are independent in older cancer patients. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  L. Fried,et al.  Vitamin and carotenoid status in older women: associations with the frailty syndrome. , 2006, The journals of gerontology. Series A, Biological sciences and medical sciences.

[51]  A. LaCroix,et al.  Inflammation and thrombosis biomarkers and incident frailty in postmenopausal women. , 2009, The American journal of medicine.

[52]  B. V. van Munster,et al.  Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: a systematic review. , 2012, The Lancet. Oncology.

[53]  A. Mitnitski,et al.  Nontraditional risk factors combine to predict Alzheimer disease and dementia , 2011, BDJ.

[54]  L. Ferrucci,et al.  Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[55]  T. Gill,et al.  A standard procedure for creating a frailty index , 2008, BMC geriatrics.

[56]  S. Leng,et al.  Serum levels of insulin-like growth factor-I (IGF-I) and dehydroepiandrosterone sulfate (DHEA-S), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty , 2004, Aging clinical and experimental research.

[57]  E. Giltay,et al.  Frailty and malnutrition predictive of mortality risk in older patients with advanced colorectal cancer receiving chemotherapy. , 2013, Journal of geriatric oncology.

[58]  M. Baggiolini,et al.  CCR5 is characteristic of Th1 lymphocytes , 1998, Nature.

[59]  David A Bennett,et al.  Physical Frailty Is Associated with Incident Mild Cognitive Impairment in Community‐Based Older Persons , 2010, Journal of the American Geriatrics Society.

[60]  L. Fried,et al.  White blood cell counts, insulin-like growth factor-1 levels, and frailty in community-dwelling older women. , 2009, The journals of gerontology. Series A, Biological sciences and medical sciences.

[61]  L. Ferrucci,et al.  Upregulated ex vivo expression of stress-responsive inflammatory pathway genes by LPS-challenged CD14+ monocytes in frail older adults , 2009, Mechanisms of Ageing and Development.

[62]  S B Roberts,et al.  Exercise training and nutritional supplementation for physical frailty in very elderly people. , 1994, The New England journal of medicine.

[63]  I. Lang,et al.  Frailty, body mass index, and abdominal obesity in older people. , 2010, The journals of gerontology. Series A, Biological sciences and medical sciences.

[64]  Kenneth Rockwood,et al.  Frailty defined by deficit accumulation and geriatric medicine defined by frailty. , 2011, Clinics in geriatric medicine.

[65]  L. Fried,et al.  Inflammation and Frailty in Older Women , 2007, Journal of the American Geriatrics Society.

[66]  L. Lipsitz Dynamics of stability: the physiologic basis of functional health and frailty. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[67]  A. Forster,et al.  Do home-based exercise interventions improve outcomes for frail older people? Findings from a systematic review. , 2012, Reviews in clinical gerontology.

[68]  J. Yesavage,et al.  One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women. , 2001, The Journal of clinical endocrinology and metabolism.

[69]  A. Jette,et al.  Adverse events associated with testosterone administration. , 2010, The New England journal of medicine.

[70]  David A Bennett,et al.  Frailty is Associated With Incident Alzheimer’s Disease and Cognitive Decline in the Elderly , 2007, Psychosomatic medicine.

[71]  L. Fried,et al.  Inflammatory Markers and Frailty , 2018, Handbook of Immunosenescence.

[72]  J. Margolick,et al.  T cell subsets and mortality in older community-dwelling women , 2005, Experimental Gerontology.

[73]  L. Ferrucci,et al.  Relationship between cytomegalovirus (CMV) IgG serology, detectable CMV DNA in peripheral monocytes, and CMV pp65495–503-specific CD8+ T cells in older adults , 2011, AGE.

[74]  L. Fried,et al.  Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: Results from the Women’s Health and Aging Studies I , 2009, Experimental Gerontology.

[75]  Charles Kooperberg,et al.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. , 2002, JAMA.

[76]  H. Allore,et al.  A program to prevent functional decline in physically frail, elderly persons who live at home. , 2002, The New England journal of medicine.

[77]  A. Goldberger,et al.  Loss of 'complexity' and aging. Potential applications of fractals and chaos theory to senescence. , 1992, JAMA.

[78]  S. Leng,et al.  Frailty, inflammation, and immunity. , 2011, Aging and disease.

[79]  Suzanne G. Leveille,et al.  Change in Muscle Strength Explains Accelerated Decline of Physical Function in Older Women With High Interleukin‐6 Serum Levels , 2002, Journal of the American Geriatrics Society.

[80]  T. Takebayashi,et al.  Adipose endocrine function, insulin-like growth factor-1 axis, and exceptional survival beyond 100 years of age. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[81]  J. A. Bennett,et al.  Frailty in older breast cancer survivors: age, prevalence, and associated factors. , 2013, Oncology nursing forum.

[82]  S. Leng,et al.  Decreased cell proliferation and altered cytokine production in frail older adults , 2004, Aging clinical and experimental research.

[83]  S. Leng,et al.  Inflammation and immune system alterations in frailty. , 2011, Clinics in geriatric medicine.

[84]  Rose Anne Kenny,et al.  A Frailty Instrument for primary care: findings from the Survey of Health, Ageing and Retirement in Europe (SHARE) , 2010, BMC geriatrics.

[85]  A. LaCroix,et al.  Statin use and incident frailty in women aged 65 years or older: prospective findings from the Women's Health Initiative Observational Study. , 2008, The journals of gerontology. Series A, Biological sciences and medical sciences.

[86]  S. Iliffe,et al.  Frailty in elderly people , 2013, The Lancet.

[87]  A. Newman,et al.  Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. , 2002, The journals of gerontology. Series A, Biological sciences and medical sciences.

[88]  L. Ferrucci,et al.  Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. , 2004, The journals of gerontology. Series A, Biological sciences and medical sciences.

[89]  M. Catt,et al.  Frailty and the role of inflammation, immunosenescence and cellular ageing in the very old: Cross-sectional findings from the Newcastle 85+ Study , 2012, Mechanisms of Ageing and Development.

[90]  A. Mitnitski,et al.  Frailty in relation to the accumulation of deficits. , 2007, The journals of gerontology. Series A, Biological sciences and medical sciences.

[91]  Matteo Cesari,et al.  Frailty consensus: a call to action. , 2013, Journal of the American Medical Directors Association.

[92]  C. Macintyre,et al.  Immunological responses to pneumococcal vaccine in frail older people. , 2009, Vaccine.