INVITED EDITORIALSA gripping reality: oxidative stress, inflammation, and the pathway to frailtyWilliam B. ErshlerWilliam B. ErshlerPublished Online:01 Jul 2007https://doi.org/10.1152/japplphysiol.00375.2007This is the final version - click for previous versionMoreSectionsPDF (184 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat clinical investigators within the field of geriatric medicine aim to get a handle on “frailty.” That aging is an inevitable consequence of staying alive is irrefutable, but why some people manage to do so and maintain stature and function, while others do not, remains an unresolved question. Frailty is a term commonly used to describe individuals with physical and functional decline that occurs as a consequence of certain diseases (e.g., cancer, chronic infection, etc.) but also even without disease (Fig. 1). The condition has been hard to define because of the seemingly insurmountable heterogeneity inherent in geriatric populations on the basis of variable rates of organ system decline and the presence or absence of any of a number of diseases. Yet, no matter the pathway taken to frailty, the clinical picture has common features, including a reduction in lean body mass (sarcopenia), osteopenia, cognitive impairment, and anemia. On the basis of data derived from large cohorts of elderly individuals, Fried and colleagues (3) have offered an operational definition of frailty incorporating an assessment of five specific characteristics, each of which is ascribed a score of 0 if absent or 1 if present (Table 1). A score of 3 or more has been shown to be independently predictive of a range of adverse clinical outcomes, including acute illness, falls, hospitalization or nursing home placement, and early mortality (1–3).With the phenotype better defined, attention has shifted to pathophysiology. Although frailty may occur in the absence of a diagnosable illness, the fact that some become frail, and others do not, suggests an inherent or acquired variability in homeostatic pathways. Recent evidence from observational studies has raised suspicion that dysregulated inflammatory processes are involved in, if not central to, the variable patterns of aging. Elevated serum levels of certain proinflammatory cytokines, most notably IL-6, are increasingly present with advancing age and to a greater extent with frailty (4). Furthermore, the appearance of this and other inflammatory markers has been associated with a number of adverse clinical outcomes, including decreased strength and mobility, falls, and mortality (5).Of the salient features of frailty, sarcopenia is prominent (6). Weakness, fatigue, imbalance, altered gait, and speed can all be related to diminished skeletal muscle mass (7). Just why this occurs has not been established. Included for consideration is an age-associated reduction in anabolic steroids (testosterone), malnutrition, immobility, lack of exercise, and inflammation. Yet the overlap is remarkable. For example, inflammatory signals, such as TNF-α, viral antigens, bacterial products, or reactive oxidative species (ROS), will stimulate IL-6 and other inflammatory modulators, most commonly by activating NF-κB, resulting in expression of several proteins instrumental in inflammatory and proliferative responses. In addition, increased NF-κB activity might also be the result of postmenopausal estrogen or androgen decline. For example, testosterone has been shown to inhibit IL-6 expression primarily by stabilizing the inhibitor protein-κB (IκB)-NF-κB complex, reducing nuclear translocation and gene activation (8). Estrogen is thought to mediate its anti-inflammatory effects by an analogous manner (9). To the extent that these sex steroids decline with age, increased NF-κB activity may result.That NF-κB overexpression is relevant to muscle wasting is supported by the recent experiments in mice genetically engineered to be deficient in the kinase responsible for inactivating the IκB inhibitor and allowing NF-κB to transcribe its portfolio of inflammatory mediators. In a denervation paradigm, IκB kinase 2 (IKK2) knockout mice had less muscle atrophy and maintained fiber type, size, and strength with less protein degradation than the wild-type controls. Furthermore, in response to muscle damage by toxic chemical injection, IKK2 knockouts had improved skeletal muscle regeneration and reduced fibrosis (10).Thus it appears that the same inflammatory pathways implicated in many of the common features of frailty are also involved in skeletal muscle homeostasis. One specific mechanism whereby this might occur is the inhibition of the transcription factor MyoD by NF-κB. MyoD is a member of the myogenic basic helix-loop-helix transcription factor family, and in experimental animals, its absence is associated with diminished muscle repair after injury (11).Thus, when deciphering the mechanisms of age-related or inflammation-related sarcopenia, one could readily be satisfied that the answer resides with the increased activity of NF-κB, resulting in a metabolic picture of increased catabolic and decreased anabolic forces exerted within muscle cells (Fig. 1). That other explanations are involved, however, is suggested by the work of Howard et al. in this issue of the Journal of Applied Physiology (12). By capitalizing on a well-characterized epidemiological cohort of frail or near-frail individuals (Women's Health and Aging Study I), the hypothesis that sarcopenia present in the more frail participants was related to the extent of ROS-induced direct muscle damage was indirectly tested by the measurement of protein carbonylation (an indicator of ROS muscle damage) and grip strength (as a marker of overall muscle mass). Such simple and logical hypotheses are often difficult to prove. With the caveat that conclusions derived from both observational and cross-sectional data, the findings are quite intriguing and support a “direct-hit” hypothesis. One might argue that protein carbonylation is not an ideal reflection of protein oxidation, or that grip strength is an insufficient reflection of overall muscle mass. Yet, both seem to be quite accurate. We have known that protein carbonyl levels increase with age and that grip strength declines. Howard and colleagues provide evidence that these occurrences are related. Those with the highest protein carbonyl level were demonstrably lowest on the grip strength test.Gerontologists have focused on oxidative stress for decades, and most agree that with time there is an accumulation of DNA, muscle, and lipid damage sufficient to impair cellular and organ function. What is neat about the Howard study is the simple correlation of a measure of protein oxidation and muscle strength in a well-characterized elderly population, many of whom were frail. Thus the “free radical” gerontologists do not necessarily have to implicate inflammatory mechanisms to account for sarcopenia (although such are likely to be contributory). Furthermore, the results imply that environmental and nutritional efforts to modify oxidative damage may, in the long run, reduce the likelihood of developing this important component of frailty. Fig. 1.Pathways to sarcopenia. Reactive oxygen species increase with age, as does the presence of inflammatory processes, resulting in both catabolic and anabolic effects on muscle. Oxidative stress may also directly injure muscle, as suggested by Howard et al. (12), contributing to the composite picture of sarcopenia and frailty in some, but not all, elderly. AP-1, activator protein 1; CRP, C-reactive protein.Download figureDownload PowerPoint Table 1. Criteria of Fried et al. for an operational definition of frailty incorporating an assessment of five specific characteristicsDomainCriterionFrailtyNutritional statusUnintentional weight loss, last 12 mo>5% body weightMuscle strengthGrip strength/stratified by sex and BMIMen <29–32 kg/m2; women <17–21 kg/m2Lower extremity performanceWalking speed, 15-ft walk/stratified by height>6–7 sPhysical activityBased on the short version to the Minnesota Leisure Time Activity questionnaire, kcal/wk calculatedMen <383 kcal/wk; women <270 kcal/wkExhaustionUsing CES-D Scale; the following statements are read: a) I felt that everything that I did was an effort; b) I could not get going. The question is asked, “How often in the last week did you feel this way?” 0 = rarely; 1 = some or a little of the time (1–2 days); 2 = a moderate amount of time (3–4 days); 3 = most of the timeSubjects answering “2” or “3” to either of these questionsBMI, body mass index; CES-D Scale, Center for Epidemiological Studies-Depression Scale. See text for further description of scoring. Adapted from Fried et al. (3).REFERENCES1 Bandeen-Roche K, Xue QL, Ferrucci L, Walston J, Guralnik JM, Chaves P, Zeger SL, Fried LP. Phenotype of frailty: characterization in the women's health and aging studies. J Gerontol A Biol Sci Med Sci 61: 262–266, 2006.Crossref | ISI | Google Scholar2 Fried LP, Hadley EC, Walston JD, Newman AB, Guralnik JM, Studenski S, Harris TB, Ershler WB, Ferrucci L. From bedside to bench: research agenda for frailty. Sci Aging Knowledge Environ 2005(31): pe24, 2005 [August 3, 2005].Google Scholar3 Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA; 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.Crossref | PubMed | ISI | Google Scholar4 Leng S, Chaves P, Koenig K, Walston J. Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study. J Am Geriatr Soc 50: 1268–1271, 2002.Crossref | ISI | Google Scholar5 Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 51: 245–270, 2000.Crossref | PubMed | ISI | Google Scholar6 Morley JE, Baumgartner RN, Roubenoff R, Mayer J, Nair KS. Sarcopenia. J Lab Clin Med 137: 231–243, 2001.Crossref | PubMed | Google Scholar7 Greenlund LJ, Nair KS. Sarcopenia—consequences, mechanisms, and potential therapies. Mech Ageing Dev 124: 287–299, 2003.Crossref | PubMed | ISI | Google Scholar8 Keller ET, Chang C, Ershler WB. Inhibition of NFκB activity through maintenance of IκBα levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. J Biol Chem 271: 26267–26275, 1996.Crossref | PubMed | ISI | Google Scholar9 Ray P, Ghosh SK, Zhang DH, Ray A. Repression of interleukin-6 gene expression by 17β-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-κB by the estrogen receptor. FEBS Lett 409: 79–85, 1997.Crossref | PubMed | ISI | Google Scholar10 Mourkioti F, Kratsios P, Luedde T, Song YH, Delafontaine P, Adami R, Parente V, Bottinelli R, Pasparakis M, Rosenthal N. Targeted ablation of IKK2 improves skeletal muscle strength, maintains mass, and promotes regeneration. J Clin Invest 116: 2945–2954, 2006.Crossref | PubMed | ISI | Google Scholar11 Guttridge DC, Mayo MW, Madrid LV, Wang CY, Baldwin AS Jr. NF-κB-induced loss of MyoD messenger RNA: possible role in muscle decay and cachexia. Science 289: 2363–2366, 2000.Crossref | PubMed | ISI | Google Scholar12 Howard C, Ferrucci L, Sun K, Fried LP, Walston J, Varadhan R, Guralnik JM, Semba RD. Oxidative protein damage is associated with poor grip strength among older women living in the community. J Appl Physiol; doi:10.1152/japplphysiol.00133.2007.Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByAnalysis of the Effects of Ninjin’yoeito on Physical Frailty in Mice23 September 2022 | International Journal of Molecular Sciences, Vol. 23, No. 19Increased Omega-3 Fatty Acid Intake Is Associated with Low Grip Strength in Elderly Korean Females8 June 2022 | Nutrients, Vol. 14, No. 12Dietary Quality, Sleep Quality and Muscle Mass Predicted Frailty among Chinese Postmenopausal Women in Malaysia23 February 2022 | International Journal of Environmental Research and Public Health, Vol. 19, No. 5FRailty and Arterial stiffness – the role of oXidative stress and Inflammation (FRAXI study)18 October 2022 | Biomarker Insights, Vol. 17Associations between low muscle mass, blood-borne nutritional status and mental health in older patients6 March 2020 | BMC Nutrition, Vol. 6, No. 1 Association Between Body Composition and Frailty in Elder Inpatients 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