Higher circulating levels of uric acid are prospectively associated with better muscle function in older persons

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Abstract

Background

Previous studies have shown that oxidative protein damage is independently associated with low grip strength and that dietary intake and circulating levels of antioxidant vitamins are positive predictors of muscle strength among older persons. Since uric acid (UA), has strong antioxidant properties, we tested the hypothesis that UA levels is cross-sectionaly associated with muscle strength and protective against the decline of strength over the aging process.

Subjects and methods

789 InCHIANTI Study participants underwent baseline serum UA, handgrip and knee extension torque measurements. Of these, 497 participants (226 men and 271 women, mean age 76.0 ± 5.4 years) also had follow-up strength measures. Lifestyle, comorbidities, nutritional profile, inflammatory markers and other laboratory measures were considered as potential confounders.

Results

Follow-up strength measures significantly increased across baseline UA tertiles. After adjusting for potential confounders and analogous baseline strength measures, higher baseline UA levels still remained significantly associated with higher follow-up strength measures.

Conclusions

Our findings suggest that higher levels of UA might represent a protective reaction aimed at counteracting the excessive production of free radicals that cause muscle protein damage and eventually contribute to the decline of muscle mass and strength.

Introduction

The circulating levels of uric acid (UA) are higher and more variable in humans and primates than in any other animals, suggesting that the ability to maintain a high concentration of UA results from a powerful natural selection process associated with some important biological advantage.

Since UA has strong antioxidant properties (Hediger et al., 2005, Reyes, 2005), a number of investigators have suggested that the reason for selection is that circulating UA strongly and positively affects human resistance to oxidative stress (Nieto et al., 2000, Skalska et al., 2005, Reyes, 2005, Waring et al., 2006). In fact, once differential concentrations are accounted for, the antioxidant power of UA is substantially higher than other nonenzymatic antioxidants such as ascorbic acid, α-and γ-tocopherol, β-carotene, and probably also of enzymatic antioxidants such as superoxide dismutase and catalase (Hediger et al., 2005). Interestingly, UA is also produced in the vascular endothelium (Reyes, 2005) and there is evidence that in its antioxidant activity, UA interacts with ascorbic acid (Sevanian et al., 1991).

In spite of the strong theoretical rationale and the evidence from pre-clinical studies, both suggesting a strong positive effect of UA on human health, a number of epidemiological and clinical studies (Jankowska et al., 2007, Shankar et al., 2007, Perlstein et al., 2006, Bos et al., 2006, Sundstrom et al., 2005, Fang and Alderman, 2000) have suggested that UA is an important risk factor for cardiovascular diseases and cardiovascular mortality and has a strong negative effect on the clinical evolution of hypertension and chronic heart failure. Interestingly, while other studies failed to confirm the independent, negative prospective relationship between UA and cardiovascular morbidity and mortality (Forman et al., 2007, Coutinho et al., 2007, Hozawa et al., 2006, Wheeler et al., 2005, Hu et al., 2001, Moriarity et al., 2000, Culleton et al., 1999), evidence that UA is a protective factor or a marker of good health status is limited to few studies on acute cerebral ischemia (Chamorro et al., 2004) and the protective effect of UA on oxidative stress generated during physical activity (Waring et al., 2003). Several mechanisms may explain the hypothetical negative effect of UA on health, including a direct stimulating effect of soluble non-crystalline UA on inflammation, the impairment of endothelial function and the development of pro-oxidant properties in specific metabolic conditions (Maxwell and Bruinsma, 2001, Alderman, 2002, Hediger et al., 2005).

Understanding whether high UA is detrimental to health or is a protective reaction aimed at counteracting the excessive production of free radicals is a difficult task because of the multiple potential sources of confounding. However, this scientific question is clinically relevant because results may reshape attitudes concerning treatment, especially in older persons, who represent an increasing portion of the population in western countries.

Aging is, in fact, associated with a progressive loss of muscle mass and strength (Morley et al., 2001, Nair, 2005) and previous studies have shown that poor muscle strength is a predictor of incident disability and long-term mortality in healthy middle-aged men (Rantanen et al., 1999, Rantanen et al., 2000) and of cause-specific and total mortality among older disabled women (Rantanen et al., 2003).

A previous cross-sectional study, using data from the InCHIANTI Study, has found that dietary intake and circulating levels of antioxidant vitamins are positive predictors of muscle strength in older persons, independent of multiple potential confounders (Cesari et al., 2004). Further, a recent study (Howard et al., 2007), using data from the Women's Health and Aging Study (WHAS) I, has shown that oxidative protein damage is independently associated with low grip strength among older women, suggesting that oxidative stress might contribute to the loss of muscle strength and mass in older adults. Finally, Waring et al. (2003) have shown that UA exerts a protective effect on the oxidative stress generated during physical activity. Accordingly, we hypothesized that the “antioxidant” UA would be a strong, positive correlate of muscle strength, and we tested this hypothesis in longitudinal perspective using data collected in a population-based sample of older persons.

Section snippets

Study sample

The analysis presented in this study is based upon data from the “InCHIANTI” (Invecchiare in Chianti, Aging in the Chianti area) Study, a perspective cohort investigation on factors affecting loss of mobility in late life (Ferrucci et al., 2000). The Ethical Committee of the Italian National Institute of Research and Care of Aging approved the study protocol and all participants signed an informed consent to be included in the study. Using a multistage sampling method, 1453 home-dwelling

Results

Table 1 shows associations of baseline UA tertiles with participants’ characteristics. Independent of the confounding effect of age and sex, BMI, a diagnosis of hypertension and chronic heart failure, plasma levels of triglycerides, HOMA-R index, serum creatinine, α- and γ-tocopherol, hs-C-reactive protein, IL-1RA and IL-6, vitamin C dietary intake, number of medications and use of diuretics were significantly higher across UA tertiles. On the contrary, HDL cholesterol levels were significantly

Discussion

Using data collected in a population-based sample of persons enrolled in the “InCHIANTI” Study we tested the hypothesis that the “antioxidant” UA could be a positive predictor of physical performance and muscle strength in older persons and we found that higher UA levels were prospectively independently associated with better muscle strength.

To our knowledge, this is the first study that has investigated the longitudinal relationship of UA with muscle strength and physical performance.

Funding sources

The InCHIANTI Study was supported as a “targeted project” (ICS 110.1\RS97.71) by the Italian Ministry of Health, by the U.S. National Institute on Aging (Contracts N01-AG-916413, N01-AG-821336 and Contracts 263 MD 9164 13 and 263 MD 821336) and in part by the Intramural Research Program, National Institute on Aging, NIH, USA

Disclosures

The manuscript submitted does not contain information about medical device(s) or drug(s). No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. The authors have reported no conflict of interest.

Statements

All authors have read and approved submission of the manuscript.

Material in the manuscript has not been published and is not being considered for publication elsewhere in whole or in part in any language except as an abstract.

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