Is the Frailty of Older Age Related to a Biological Inflammatory Response?

Abstract & Commentary

Synopsis: There is a physiological basis to geriatric frailty characterized by inflammation and elevated markers of blood clotting.

Source: Walston J, et al. Arch Intern Med. 2002;162: 2333-2341.

The findings of this study support the concept that there is a physiological basis to geriatric frailty characterized by inflammation and elevated markers of blood clotting. The objectives of this study were to establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus.

The participants were 4735 community dwelling adults aged 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria.

Of 4735 cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean levels of C-reactive protein (CRP) (5.5 vs 2.7 mg/mg/L), factor VIII 13790 vs 11860 mg/dL and in a smaller subset of subjects, (400 subjects), (D dimer [647 vs 224 ng/mL]) (P = 0.001 for all ´ 2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race.

Walston and colleagues concluded that these findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting. These physiological differences persist when those with cardiovascular disease or diabetes are excluded.

Comment by Ralph R. Hall, MD, FACP

To arrive at a standardized screening tool for frailty, Walston et al previously synthesized the most commonly described attributes of frailty into a definable clinical criteria. These screening criteria consist of weight loss, muscle weakness, fatigue, declines in activity, and slow or unsteady gait. They have evaluated these criteria by showing ability to predict disability, hospitalization, and mortality.1,2

The frail subset had a higher Body Mass Index (BMI) than the intermediate and nonfrail groups despite the weight loss. Walston et al note that although they had no body composition data, the increased BMI and the trend toward glucose intolerance, which was also documented, and the lower walking speed and strength measures suggest a lower percentage of lean body mass.

The increase in D dimer, which has been shown to induce synthesis of biologically active interleukins and plasminogen activator inhibitor, supports the inflammation concept. Walston et al correctly point out, that although these associations are strong, they do not support a causal influence.

Where is this concept of inflammation going to take us? There remains much to explore in regards to the inflammation markers and their influence on atherosclerosis, frailty, and other degenerative diseases. What part do activity and diet play in this process? Studies show that in patients with congestive heart failure and type 2 diabetes, exercise decreases the levels of many, but no all, of the inflammatory and blood clotting markers.3

Two recent studies support the diet and exercise concept. Benjamin Wang working with James Fries at Stanford updated the studies on a group of 370 runners initially aged 50 years and older compared with a group of 249 sedentary control subjects.4 This was a 13-year, prospective, cohort study. Control subjects were without disabilities at the onset of the study. Significantly lower disability levels in the runners vs controls were sustained for at least 13 years. Reaching the objective disability level that was significant was postponed by 8.7 years in the runners. The controls had a 3.3 times higher rate of death than the runners, with higher death rates in all diseases studied.

Stevens and associates at the University of North Carolina evaluated 2506 women and 2860 men between 1972 and 1976.5 Vital statistics were collected through 1998. The mean age was 45.8 years at the start of the study.

They calculated mortality rates, BMI, and fitness levels. The subjects were classified as fit-not fat, fit-fat, unfit-fat, and unfit-not fat. Adjustments were made for age, education, smoking, alcohol intake, and Keys score for dietary intake. For men whose level of fitness and BMI were both in the top quintile, the risk of all-cause mortality was 1.25 compared to those who were fit and not fat. The hazard ratio for the same group of women was 1.32. For women who were not obese but unfit, the hazard ratios for all-cause and cardiovascular disease were 1.30 and 1.53, respectively, and the ratios were 1.44 and 1.55 for men.

Until we have better solutions about how biological inflammation originates and can be controlled, it appears that we have a reasonable way to delay disability and death. Stay fit, non-fat, and eat a reasonable diet. Think of the billions in health care dollars that could be saved.


1. Fried LP, et al. Ann Epidemiol. 1991;1:263-267.

2. Fried LP. J Gerontol. 2001;56A:M1-M11.

3. Conraads VM, et al. European Heart Journal. 2002;23: 1854-1860.

4. Wang WE. Arch Intern Med. 2002;162:2285-2294.

5. Stevens J, et al. Am J Epidemiol. 2002;156:832-841.

Dr. Hall is Emeritus Professor of Medicine at the University of Missouri--Kansas City School of Medicine.