This Article Abstract Full Text (PDF) Services Download to citation manager Citing Articles Citing Articles via HighWire PubMed PubMed Citation

Cross-sectional and Prospective Relationships of Interleukin-6 and C-Reactive Protein With Physical Performance in Elderly Persons

MacArthur Studies of Successful Aging

^a The Epidemiology, Demography, and Biometry Program, National Institute on Aging, Bethesda, Maryland
^b Geriatric Department, "I Fraticini," National Research Institute (IN-RCA), Florence, Italy
^c Mount Sinai Medical Center, New York, New York
^d Division of Geriatrics, University of California–Los Angeles School of Medicine

Decision Editor: John E. Morley, MB, BCh

	Abstract

Top Abstract Methods Results Discussion References

 
Background. Chronic inflammation has been proposed as a biological mechanism underlying the decline in physical function that occurs with aging. The purpose of this investigation was to examine the cross-sectional and prospective relationships between markers of inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP), with several measures of physical performance in older persons aged 70 to 79 years.

Methods. Subjects were 880 high-functioning men and women participating in the MacArthur Study of Successful Aging (n = 1189), a subset of the Established Populations for Epidemiologic Studies of the Elderly (n = 4030). Plasma IL-6 and CRP levels were determined by enzyme-linked immunosorbent assay and log transformed to normalize the distributions. Physical function measures included handgrip strength, signature time, chair stands (time to complete five repetitions), and 6-m walk time.

Results. Women had lower (p < .05) IL-6 levels than men, but there was no significant difference between blacks and whites. IL-6 and CRP levels were higher (p < .05) in current smokers than in nonsmokers and in those with a greater body mass index (BMI). Hours per year undertaking moderate and strenuous physical activity were also related to inflammatory markers with higher (p < .001) IL-6 and CRP levels in less active individuals. After adjusting for age, sex, race, BMI, smoking status, use of nonsteroidal anti-inflammatory drugs, and prevalence of morbidity, those in the top two quartiles for walking speed had lower (p = .012) IL-6 levels than those in the bottom quartile. In addition, there was a trend (p = .038) for lower CRP levels in those with higher walking speed. CRP levels were also lower (p = .04) in individuals in the top quartile for grip strength. No significant differences were noted for chair stands or signature time performance. Repeat performance measures obtained on 405 subjects (67% of those eligible at baseline) obtained 7 years later had declined significantly (grip strength, 18%; signature time, 21%; walking speed, 31%; p < .001), except for the chair rise; however, baseline IL-6 and CRP were not associated with a change in performance. However, those who died or who were unable to undergo testing had higher baseline IL-6 and CRP levels (p < .01) and slower walking speed (p < .05).

Conclusions. Although IL-6 has been shown to predict onset of disability in older persons and both IL-6 and CRP are associated with mortality risk, these markers of inflammation have only limited associations with physical performance, except for walking measures and grip strength at baseline, and do not predict change in performance 7 years later in a high-functioning subset of older adults.

AGING is associated with a decline in physical function and performance that negatively impacts quality of life and may eventually compromise independence. A biological mechanism recently proposed to underlie the decline in physical function is chronic inflammation ⁽¹⁾. Aging is associated with an elevation in pro-inflammatory cytokines, such as interleukin-6 (IL-6) ^{(2) (3) (4) (5)}, which play a central role in the hepatic production of C-reactive protein (CRP) and other acute-phase proteins involved in the inflammatory response ⁽⁶⁾. In the absence of infection, injury, or trauma, the cytokines, such as interleukin-1ß (IL-1ß), tumor necrosis factor (TNF-), and IL-6, which act as intracellular signaling polypeptides that stimulate growth, differentiation, and functional development of the immune system, are tightly regulated ^{(4) (5) (6) (7)}. Cytokine production at inflammatory sites by monocytes, macrophages, and other cells results in a cascade of events with multiple targets both locally and systemically via cell receptors ^{(6) (8)}.

Induction of the immune response is beneficial in fighting infection and in tissue repair following trauma. However, cytokines are involved in numerous physiological functions, and both over- and undersecretion are related to a number of disease processes ^{(4) (9)}. It has been proposed that in older adults a chronic inflammatory state may be detrimental by contributing to the pathophysiology of medical conditions that result in functional decline and disability ⁽¹⁰⁾. For instance, an association between cardiovascular disease (CVD) risk and systemic inflammation has been established ^{(11) (12)}. Other age-related conditions, such as osteoporosis ⁽¹³⁾, arthritis ^{(14) (15)}, Alzheimer's disease ⁽¹⁶⁾, cachexia ⁽⁸⁾, type 2 diabetes ⁽¹⁷⁾, and periodontal disease ⁽¹⁸⁾, are associated with elevated markers of inflammation. Immunosenescence is also evident following infection, with older adults having prolonged inflammatory activity compared with their younger counterparts ⁽¹⁹⁾. Moreover, the onset of disability in older persons has been related to higher circulating levels of IL-6 ⁽¹⁰⁾, and both IL-6 and CRP are associated with mortality in healthy nondisabled elderly individuals ⁽⁵⁾. A chronic elevation of inflammatory markers may also underlie sarcopenia, as it does for other muscle-wasting conditions ⁽²⁰⁾. The accompanying reduction in muscle strength associated with the loss of muscle mass may have a profound effect on frailty and disability ⁽²¹⁾.

Although age-related diseases, disability, and mortality are associated with elevated markers of inflammation, little is known of the association of chronic inflammation with subclinical decline in physical performance of well-functioning elderly persons. The purpose of this analysis was to test the hypothesis that in high-functioning, ambulatory, community-dwelling older adults, higher circulating levels of IL-6 and CRP are associated with poorer physical performance, and that these markers of inflammation can be used to predict change in performance with aging. If indices of chronic inflammation are related cross-sectionally and prospectively to physical performance, then these biomarkers may be useful in targeting individuals who require intervention to prevent loss of function and independence.

	Methods

Top Abstract Methods Results Discussion References

 
Subjects
Subjects were 880 men and women participating in the MacArthur Study of Successful Aging, a subset of the Established Populations for Epidemiologic Studies of the Elderly (EPESE). The EPESE comprised four population-based samples of community-dwelling individuals, aged 65 years and older, residing in Durham, North Carolina, East Boston, Massachusetts, New Haven, Connecticut, and rural Iowa. The MacArthur subset were high-functioning individuals from the Durham, East Boston, and New Haven sites aged 70 to 79 years at the 1988 baseline assessment. The determination of "high functioning" was based on the following cognitive and physical function markers: a score of six or more correct answers on the 9-item Pfeiffer Short Portable Mental Status Questionnaire; ability to remember three or more of six elements on a delay recall of a short memory task; report of no disability on the Katz activities of daily living (ADL) scale; report of not more than one disability on the Nagi and Rosow-Breslau scales; ability to hold a semitandem balance stand for 10 seconds; and ability to stand from a seated position five times within 20 seconds ⁽²²⁾. Of the 4030 EPESE participants, 1313 fulfilled the eligibility criteria and 1189 were enrolled in the MacArthur study. The MacArthur study therefore represents the top tertile of cognitive and physical functioning participants in the EPESE cohort and, hence, a narrow portion of the community-dwelling elderly population. Informed consent was obtained from all subjects after the respective human subjects institutional review boards approved the protocols.

IL-6 and CRP
Measures for IL-6 and CRP were obtained from frozen, stored plasma available for 74% of the enrolled MacArthur cohort. Blood samples were obtained in the morning; however, subjects were not required to fast beforehand. Plasma IL-6 levels were measured in duplicate by enzyme-linked immunosorbent assay using a commercial kit (High Sensitivity Quantikine kit, R & D Systems, Minneapolis, MN). The detectable limit for IL-6 was 0.10 pg/ml, with an interassay coefficient of variation of 7%. CRP was also measured in duplicate by ELISA with a detectable limit of 0.08 mg/l and an interassay coefficient of variation of 9% ⁽²³⁾. Circulating IL-6 and CRP levels obtained from one time point have been shown to be reproducible and representative of extended time periods ^{(23) (24)}.

Physical Performance
At baseline, several physical function performance measures were assessed including hand-grip strength, signature time, chair stands, and gait speed. Follow-up physical performance measures were obtained on 405 subjects 7 years later (East Boston and New Haven) in 1995. Hand-grip strength (kg) of the dominant arm was assessed in triplicate using a handheld dynamometer, with the maximal value used for this analysis. A second measure of upper body performance (to assess hand dexterity) was the time required for subjects to sign their name. Lower body function was determined by the 6-m walk time and chair-rise performance. For gait speed, subjects were instructed to quickly walk 3 m, turn, and return. The chair-rise test assessed the time required to rise on command from a standard chair to a full standing position five times.

Potential Confounders
Participants completed a standardized self-report assessment including medical history and use of medications including nonsteroidal anti-inflammatory drugs (NSAIDs), cigarettes, and alcohol. Body mass index (BMI) was calculated by weight in kilograms divided by height in meters squared. Smoking status was classified as either current or nonsmoker. Use of NSAIDs included aspirin. Laboratory markers of CVD and diabetes risk assessed were plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), and glycosylated hemoglobin, which were measured by standard automated techniques. Plasma albumin, an acute phase protein, the level of which decreases with an increase in IL-6, was also measured. Summary scales of self-reported physical activity were reported as strenuous and moderate physical activity hours per year ⁽²²⁾. Physical activity questions were adapted from the Yale Physical Activity Survey ⁽²⁵⁾, which focused on the frequency of current leisure- and work-related activity, with intensity categories determined by energy expenditure ^{(26) (27)}.

Statistical Analysis
Data were analyzed using the SPSS statistical software package (SPSS Inc, Chicago, IL) and included descriptive statistics, correlations, t tests, and analyses of variance and covariance. Where appropriate, the Bonferroni post hoc procedure for multiple comparisons was employed to locate the source of significant differences in means ^{(28) (29)}. When used as a continuous measure, IL-6 and CRP were log transformed (natural logarithm) to normalize the distributions. When used as quartiles, the untransformed IL-6 and CRP value was used. All tests were two-tailed and an alpha level of .05 was considered statistically significant. Data are reported as the mean ± SD, unless stated otherwise.

	Results

Top Abstract Methods Results Discussion References

 
Cross-sectional Analyses
The study population consisted of 468 women and 412 men with a mean age of 74.3 ± 2.7 years and mean BMI of 26.1 ± 4.2 kg/m². The distributions of IL-6 and CRP levels were highly skewed to the right as shown in Fig. 1. Prior to transformation, mean and median values were 4.6 ± 5.5 pg/ml and 2.8 pg/ml for IL-6, and 3.2 ± 5.3 mg/l and 1.8 mg/l for CRP. The distributions were normalized after logarithmic transformation.

View larger version (17K): [in this window] [in a new window]   Figure 1. Distribution of interleukin-6, A, and C-reactive protein, B, values.

	Discussion

Top Abstract Methods Results Discussion References

Participants in the MacArthur study were high-functioning men and women aged 70 to 79 years in the top tertile for both cognitive and physical function of the population-based EPESE. As such, they are a selected population of those who are successfully aging and, hence, are not representative of all elderly individuals. Nevertheless, as expected, IL-6 and CRP levels were associated with smoking and laboratory markers for CVD risk (HDL-C) and glucose control (glycosylated hemoglobin) and with a history of myocardial infarction and stroke. In addition, a gradient existed for higher circulating levels of IL-6 and CRP with body size and in those less physically active. Dysregulation of the inflammatory process was apparent with 56% of the cohort who had IL-6 values above 2.5 pg/ml, which has been found to be associated with an increased risk of functional decline ⁽¹⁰⁾. Forty-one percent had values above 3.2 pg/ml, a value related to an increased risk of mortality in the community-dwelling elderly population ⁽⁵⁾. Fasting blood samples were not required as it was deemed undesirable to potentially have subjects waiting for extended periods of time in the morning for their blood draw in a hypoglycemic state. Cross-sectional and prospective analyses were also performed, adjusted for the time interval between the last meal and the blood draw, and the results were unchanged. Thus, we assume that the nonfasting state was not a significant confounder in our results.

Although hours spent in strenuous and moderate physical activity were related to inflammation markers, the only performance measures that were associated with IL-6 and CRP were walking speed and grip strength. Several lines of evidence indicate that elevated inflammatory markers may negatively impact muscle function and, hence, physical performance. Multiple cytokines stimulate proteolysis by activating the ubiquitin-proteasome pathway in muscle tissue ⁽²⁰⁾. IL-6 and IL-1 act on the adrenal-pituitary axis to release adrenocorticotropic hormone and subsequently cortisol ⁽³⁰⁾, and animal studies indicate that IL-6 inhibits plasma concentrations of insulin-like growth factor 1 that may impair muscle anabolic processes ⁽³¹⁾. In addition, it has been suggested that cytokines may also alter muscle homeostasis in older persons by impairing tissue repair following injury ⁽³²⁾. In line with this, signature time, a fine motor skill, was not related to IL-6 and CRP.

In contrast to our findings, Cohen and colleagues ⁽⁴⁾ demonstrated a gradient of increasing IL-6 levels with poorer functional ability in community-dwelling elderly persons. For the Katz ADLs (bathing, toileting, dressing, eating, and grooming), mean log IL-6 values increased from 1.05 pg/ml to 1.72 pg/ml in those with a score of 0 and 5, with corresponding log values of 1.01 pg/ml to 1.45 pg/ml for scores of 0 and 5 on the Nagi scale (extend arms above the shoulder, manipulate small objects, stoop, crouch or kneel, and push a large object). However, subjects in the present report are from the top tertile of EPESE participants, reporting no disability on the Katz ADL scale and not more than one disability on the Nagi scale. Consequently, our participants have higher functional ability and are therefore a more select population than that in the study of Cohen and colleagues ⁽⁴⁾. It is therefore possible that had we studied a population representative of all elderly persons (disabled, some degree of functional limitation, nondisabled, and very active) with a wider distribution of performance scores, markers of chronic inflammation may have been associated with all physical performance measures assessed.

Performance measures generally declined in the cohort at 7-year follow-up. The reduction in grip strength was approximately 2.5% per year, while fast walking speed decreased by 4.5% per year. Previous work has shown that aging is associated with an accelerated decline in physical function ⁽³³⁾ and increased morbidity; therefore, declining rates of this magnitude in this age group of survivors were not unexpected. However, in contrast to IL-6 and CRP having prognostic value in several disease states ^{(15) (34) (35)}, including the severity of disease ^{(36) (37)}, there was no association between the magnitude of decline in performance and baseline inflammatory markers in this group of survivors capable of participating. Higher baseline IL-6 and CRP levels were associated with mortality, as previously demonstrated ⁽⁵⁾, and those who died or were unable to undergo follow-up testing had poorer walking performance at baseline. The survivors were thus a restricted group, which could have obscured the ability to detect differences. In addition, although a single measurement in time of plasma IL-6 and CRP has been shown to reflect circulating levels for up to several months ^{(23) (24)}, 7 years separated the performance measures. It is possible that change in cytokines and acute-phase proteins may be associated with change in performance; however, blood samples were not obtained at re-measurement in 1995; therefore, we are unable to address this issue.

The association of physical function and inflammation shown by Cohen and colleagues ⁽⁴⁾ and our finding of lower IL-6 and CRP levels in those more physically active do suggest that moderate physical activity may be beneficial in attenuating chronic inflammation. Lower basal IL-6 ⁽³⁸⁾ and CRP ⁽³⁹⁾ levels have been reported in well-trained swimmers compared with healthy controls, suggesting that chronic exercise has a suppressive effect on mediators of the inflammatory response, and, recently, Smith and colleagues ⁽⁴⁰⁾ reported a 35% reduction in serum levels of CRP following 6 months of supervised moderate exercise in men and women at risk for future heart attack.

In summary, IL-6 and CRP levels in the MacArthur cohort of high-functioning elderly persons were related to physical activity and walking speed, but not to other physical performance measures, nor to change in performance over 7 years in those surviving and able to undergo testing. Nevertheless, recent evidence suggests that chronic inflammation may be attenuated by regular physical exercise ⁽⁴⁰⁾. Therefore, long-term exercise interventions in the elderly population, apart from improving physical function and performance, may prove useful in correcting age-related immune dysregulation, thereby reducing disease risk. However, clinical trials addressing this issue will be required before definitive conclusions and recommendations can be made.

	Acknowledgments

 
Address correspondence to Dennis R. Taaffe, PhD, National Institute on Aging, Epidemiology, Demography, and Biometry Program, Gateway Building, Room 3C-309, 7201 Wisconsin Avenue, Bethesda, MD 20892-9205. E-mail:

Received March 30, 2000

Accepted June 1, 2000

	References

Top Abstract Methods Results Discussion References

 

1. Kuller LH, 1999[editorial]. Serum levels of IL-6 and development of disability in older persons. J Am Geriatr Soc 47:755-756. [Medline]
2. Hager K, Machein U, Krieger S, Platt D, Seefried G, Bauer J, 1994. Interleukin-6 and selected plasma proteins in healthy persons of different ages. Neurobiol Aging 15:771-772. [Medline]
3. McKane WR, Khosla S, Peterson JM, Egan K, Riggs BL, 1994. Circulating levels of cytokines that modulate bone resorption: effects of age and menopause in women. J Bone Miner Res 9:1313-1318. [Medline]
4. Cohen HJ, Pieper CF, Harris T, Rao KMK, Currie MS, 1997. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol Med Sci 52A:M201-M208. [Abstract]
5. Harris TB, Ferrucci L, Tracy RP, et al. 1999. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med 106:506-512. [Medline]
6. Gabay C, Kushner I, 1999. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340:448-454. [Free Full Text]
7. Venkatraman JT, Fernandes G, 1997. Exercise, immunity and aging. Aging Clin Exp Res 9:42-56.
8. Yeh S-S, Schuster MW, 1999. Geriatric cachexia: the role of cytokines. Am J Clin Nutr 70:183-197. [Abstract/Free Full Text]
9. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP, 1998. The pathophysiologic roles of interleukin-6 in human disease. Ann Intern Med 128:127-137. [Abstract/Free Full Text]
10. Ferrucci L, Harris TB, Guralnik JM, et al. 1999. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 47:639-646. [Medline]
11. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH, 1997. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973-979. [Abstract/Free Full Text]
12. Tracy RP, Lemaitre RN, Psaty BM, et al. 1997. Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. Arterioscler Thromb Vasc Biol 17:1121-1127. [Abstract/Free Full Text]
13. Pacifici R, 1996. Estrogen, cytokines, and pathogenesis of postmenopausal osteoporosis. J Bone Miner Res 11:1043-1051. [Medline]
14. Sipe JD, 1995. Acute-phase proteins in osteoarthritis. Semin Arthritis Rheum 25:75-86. [Medline]
15. Spector TD, Hart DJ, Nandra D, et al. 1997. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthritis Rheum 40:723-727. [Medline]
16. Hull M, Fiebich BL, Lieb K, et al. 1996. Interleukin-6 associated inflammatory processes in Alzheimer's disease: new therapeutic options. Neurobiol Aging 17:795-800. [Medline]
17. Tracy RP, Psaty BM, Macy E, et al. 1997. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. Arterioscler Thromb Vasc Biol 17:2167-2176. [Abstract/Free Full Text]
18. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S, 1996. Periodontal disease and cardiovascular disease. J Periodontal 67:1123-1137.
19. Bruunsgaard H, Skinhoj P, Qvist J, Pedersen BK, 1999. Elderly humans show prolonged in vivo inflammatory activity during pneumococcal infections. J Infect Dis 180:551-554. [Medline]
20. Mitch WE, Goldberg AL, 1997. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med 335:1897-1905. [Free Full Text]
21. Fiatarone MA, Evans WJ, 1993. The etiology and reversibility of muscle dysfunction in the aged. J Gerontol Med Sci 48: (special issue) M77-M83.
22. Berkman LF, Seeman TE, Albert M, et al. 1993. High, usual, and impaired functioning in community-dwelling older men and women: findings from the MacArthur Foundation Research Network on successful aging. J Clin Epidemiol 46:1129-1140. [Medline]
23. Macy EM, Hayes TE, Tracy RP, 1997. Variability in the measurement of C-reactive protein in healthy subjects: implications for reference intervals and epidemiological applications. Clin Chem 43:52-58. [Abstract/Free Full Text]
24. Rao KMK, Pieper CS, Currie MS, Cohen HJ, 1994. Variability of plasma IL-6 and crosslinked fibrin dimers over time in community dwelling elderly subjects. Am J Clin Pathol 102:802-805. [Medline]
25. DiPietro L, Caspersen CJ, Ostfeld AM, Nadel ER, 1993. A survey for assessing physical activity among older adults. Med Sci Sports Exerc 25:628-642. [Medline]
26. Paffenbarger RS, Jr Wing AL, Hyde RT, 1978. Physical activity as an index of heart attack risk in college alumni. Am J Epidemiol 108:161-175. [Abstract/Free Full Text]
27. Taylor HL, Jacobs DR, Jr Schucker B, Knudsen J, Leon AS, Debacker G, 1978. A questionnaire for the assessment of leisure time physical activities. J Chron Dis 31:741-755. [Medline]
28. SPSS Inc. SPSS Base 8.0: User's Guide. Chicago: SPSS Inc; 1998.
29. Miller RG Jr. Simultaneous Statistical Inference. 2nd ed. New York: Springer-Verlag; 1981.
30. Bauman H, Gauldie J, 1994. The acute phase response. Immunol Today 15:74-80. [Medline]
31. De Benedetti F, Alonzi T, Moretta A, et al. 1997. Interleukin 6 causes growth impairment in transgenic mice through a decrease in insulin-like growth factor-I: a model for stunted growth in children with chronic inflammation. J Clin Invest 99:643-650. [Medline]
32. Cannon JG, 1995. Cytokines in aging and muscle homeostasis. J Gerontol Med Sci 50A: (special issue) M120-M123.
33. Kallman DA, Plato CC, Tobin JD, 1990. The role of muscle loss in the age-related decline in grip strength: cross-sectional and longitudinal perspectives. J Gerontol Med Sci 45:M82-M88.
34. Liuzzo G, Biasucci LM, Gallimore JR, et al. 1994. The prognostic value of C-reactive protein and serum amyloid a protein in severe unstable angina. N Engl J Med 331:417-424. [Abstract/Free Full Text]
35. Biasucci LM, Vitelli A, Liuzzo G, et al. 1996. Elevated levels of interleukin-6 in unstable angina. Circulation 94:874-877. [Abstract/Free Full Text]
36. Badolato R, Oppenheim JJ, 1996. Role of cytokines, acute-phase proteins, and chemokines in the progression of rheumatoid arthritis. Semin Arthritis Rheum 26:526-538. [Medline]
37. Mach F, Lovis C, Gaspoz JM, et al. 1997. C-reactive protein as a marker for acute coronary syndromes. Eur Heart J 18:1897-1902. [Abstract/Free Full Text]
38. Espersen GT, Elbaek A, Schmidt-Olsen S, Ejlersen E, Varming K, Grunnet N, 1996. Short-term changes in the immune system of elite swimmers under competition conditions. Different immunomodulation induced by various types of sport. Scand J Med Sci Sports 6:156-163. [Medline]
39. Dufaux B, Order U, Geyer H, Hollmann W, 1984. C-reactive protein serum concentrations in well-trained athletes. Int J Sports Med 5:102-106. [Medline]
40. Smith JK, Dykes R, Douglas JE, Krishnaswamy G, Berk S, 1999. Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. JAMA 281:1722-1727. [Abstract/Free Full Text]

This article has been cited by other articles:

				H. K. Neilson, C. M. Friedenreich, N. T. Brockton, and R. C. Millikan Physical Activity and Postmenopausal Breast Cancer: Proposed Biologic Mechanisms and Areas for Future Research Cancer Epidemiol. Biomarkers Prev., January 1, 2009; 18(1): 11 - 27. [Abstract] [Full Text] [PDF]

				T. N Hilton, L. J Tuttle, K. L Bohnert, M. J Mueller, and D. R Sinacore Excessive Adipose Tissue Infiltration in Skeletal Muscle in Individuals With Obesity, Diabetes Mellitus, and Peripheral Neuropathy: Association With Performance and Function Physical Therapy, November 1, 2008; 88(11): 1336 - 1344. [Abstract] [Full Text] [PDF]

				A. E. Aiello, M. N. Haan, C. M. Pierce, A. M. Simanek, and J. Liang Persistent Infection, Inflammation, and Functional Impairment in Older Latinos J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2008; 63(6): 610 - 618. [Abstract] [Full Text] [PDF]

				J. R. Ruiz, F. B. Ortega, J. Warnberg, L. A. Moreno, J. J. Carrero, M. Gonzalez-Gross, A. Marcos, A. Gutierrez, and M. Sjostrom Inflammatory Proteins and Muscle Strength in Adolescents: The AVENA Study Arch Pediatr Adolesc Med, May 1, 2008; 162(5): 462 - 468. [Abstract] [Full Text] [PDF]

				M. Asghar, L. George, and M. F. Lokhandwala Exercise decreases oxidative stress and inflammation and restores renal dopamine D1 receptor function in old rats Am J Physiol Renal Physiol, September 1, 2007; 293(3): F914 - F919. [Abstract] [Full Text] [PDF]

				B. K. Pedersen State of the Art Reviews: Health Benefits Related to Exercise in Patients With Chronic Low-Grade Systemic Inflammation American Journal of Lifestyle Medicine, August 1, 2007; 1(4): 289 - 298. [Abstract] [PDF]

				K. H. Schmitz, A. R. Cappola, C. T. Stricker, C. Sweeney, and S. A. Norman The Intersection of Cancer and Aging: Establishing the Need for Breast Cancer Rehabilitation Cancer Epidemiol. Biomarkers Prev., May 1, 2007; 16(5): 866 - 872. [Abstract] [Full Text] [PDF]

				M. G. Flynn, B. K. McFarlin, and M. M. Markofski State of the Art Reviews: The Anti-Inflammatory Actions of Exercise Training American Journal of Lifestyle Medicine, May 1, 2007; 1(3): 220 - 235. [Abstract] [PDF]

				J. K. Kiecolt-Glaser, M. A. Belury, K. Porter, D. Q. Beversdorf, S. Lemeshow, and R. Glaser Depressive Symptoms, omega-6:omega-3 Fatty Acids, and Inflammation in Older Adults Psychosom Med, April 1, 2007; 69(3): 217 - 224. [Abstract] [Full Text] [PDF]

				M. A. Schrager, E. J. Metter, E. Simonsick, A. Ble, S. Bandinelli, F. Lauretani, and L. Ferrucci Sarcopenic obesity and inflammation in the InCHIANTI study J Appl Physiol, March 1, 2007; 102(3): 919 - 925. [Abstract] [Full Text] [PDF]

				K. L. Campbell and A. McTiernan Exercise and Biomarkers for Cancer Prevention Studies J. Nutr., January 1, 2007; 137(1): 161S - 169S. [Abstract] [Full Text] [PDF]

				F. Lally and P. Crome Understanding frailty Postgrad. Med. J., January 1, 2007; 83(975): 16 - 20. [Abstract] [Full Text] [PDF]

				R. von Kanel, J. E. Dimsdale, P. J. Mills, S. Ancoli-Israel, T. L. Patterson, B. T. Mausbach, and I. Grant Effect of Alzheimer caregiving stress and age on frailty markers interleukin-6, C-reactive protein, and d-dimer. J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2006; 61(9): 963 - 969. [Abstract] [Full Text] [PDF]

				M. K. Figaro, S. B. Kritchevsky, H. E. Resnick, R. I. Shorr, J. Butler, A. Shintani, B. W. Penninx, E. M. Simonsick, B. H. Goodpaster, A. B. Newman, et al. Diabetes, Inflammation, and Functional Decline in Older Adults: Findings from the Health, Aging and Body Composition (ABC) study. Diabetes Care, September 1, 2006; 29(9): 2039 - 2045. [Abstract] [Full Text] [PDF]

				M. Maggio, J. M. Guralnik, D. L. Longo, and L. Ferrucci Interleukin-6 in aging and chronic disease: a magnificent pathway. J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2006; 61(6): 575 - 584. [Abstract] [Full Text] [PDF]

				M. M. McDermott, K. Liu, J. M. Guralnik, L. Ferrucci, D. Green, P. Greenland, L. Tian, M. H. Criqui, C. Lo, N. Rifai, et al. Functional decline in patients with and without peripheral arterial disease: predictive value of annual changes in levels of C-reactive protein and d-dimer. J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2006; 61(4): 374 - 379. [Abstract] [Full Text] [PDF]

				H.-K. Kuo, J. F. Bean, C.-J. Yen, and S. G. Leveille Linking C-Reactive Protein to Late-Life Disability in the National Health and Nutrition Examination Survey (NHANES) 1999-2002. J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2006; 61(4): 380 - 387. [Abstract] [Full Text] [PDF]

				B. K. McFarlin, M. G. Flynn, W. W. Campbell, B. A. Craig, J. P. Robinson, L. K. Stewart, K. L. Timmerman, and P. M. Coen Physical activity status, but not age, influences inflammatory biomarkers and toll-like receptor 4. J. Gerontol. A Biol. Sci. Med. Sci., April 1, 2006; 61(4): 388 - 393. [Abstract] [Full Text] [PDF]

				C. Kasapis and P. D. Thompson The Effects of Physical Activity on Serum C-Reactive Protein and Inflammatory Markers: A Systematic Review J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1563 - 1569. [Abstract] [Full Text] [PDF]

				A. M. W. Petersen and B. K. Pedersen The anti-inflammatory effect of exercise J Appl Physiol, April 1, 2005; 98(4): 1154 - 1162. [Abstract] [Full Text] [PDF]

				J. K. Kiecolt-Glaser, K. J. Preacher, R. C. MacCallum, C. Atkinson, W. B. Malarkey, and R. Glaser Chronic stress and age-related increases in the proinflammatory cytokine IL-6 PNAS, July 22, 2003; 100(15): 9090 - 9095. [Abstract] [Full Text] [PDF]

				T.S. Church, C.E. Barlow, C.P. Earnest, J.B. Kampert, E.L. Priest, and S.N. Blair Associations Between Cardiorespiratory Fitness and C-Reactive Protein in Men Arterioscler Thromb Vasc Biol, November 1, 2002; 22(11): 1869 - 1876. [Abstract] [Full Text] [PDF]

				J. E. Morley Editorial: Drugs, Aging, and the Future J. Gerontol. A Biol. Sci. Med. Sci., January 1, 2002; 57(1): M2 - 6. [Full Text] [PDF]

				J. K. Kiecolt-Glaser, L. McGuire, T. F. Robles, and R. Glaser Psychoneuroimmunology and Psychosomatic Medicine: Back to the Future Psychosom Med, January 1, 2002; 64(1): 15 - 28. [Abstract] [Full Text] [PDF]

				H. J. Cohen Editorial: In Search of the Underlying Mechanisms of Frailty J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2000; 55(12): 706M - 708. [Full Text]

This Article Abstract Full Text (PDF) Services Download to citation manager Citing Articles Citing Articles via HighWire PubMed PubMed Citation