Association Between Estimated Net Endogenous Acid Production and Subsequent

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1 Journals of Gerontology: Medical Sciences cite as: J Geron A Biol Sci Med Sci, 2015, doi: /gerona/glu215 Research Article Advance Access publication November 24, 2014 Research Article Association Between Estimated Net Endogenous Acid Production and Subsequent Decline in Muscle Mass Over Four Years in Ambulatory Older Chinese People in Hong Kong: A Prospective Cohort Study Ruth Chan, 1 Jason Leung, 2 and Jean Woo 1 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, China. 2 Jockey Club Centre for Osteoporosis Care and Control, The Chinese University of Hong Kong, Shatin, Hong Kong, China. Address Correspondence to Ruth Chan, PhD, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong, China. ruthchansm@cuhk.edu.hk Abstract Background. Findings regarding dietary acid-base balance and muscle loss were mainly reported in Caucasian populations and seldom documented in Chinese population with different dietary habits. This prospective study examined such association in 3,122 Chinese community-dwelling older people aged 65 and over in Hong Kong. Methods. Baseline dietary intakes were assessed using a validated food frequency questionnaire. Estimated net endogenous acid production (NEAP) was calculated using Frassetto s method based on the diet s protein to potassium ratio. Nutrient intakes and estimated NEAP were energy-adjusted by residual method. Estimated NEAP was divided into sex-specific energy-adjusted quartiles for data analysis. Four-year change in appendicular skeletal muscle mass (ASM) from baseline was assessed using dual-energy X-ray absorptiometry. Analysis of covariance was used to investigate the association between quartiles of estimated NEAP and 4-year change in ASM with adjustments for potential covariates. Results. Median estimated NEAP of the participants was 47.3 (IQR: 35.5, 61) meq/d. Participants in the highest sex-specific quartile of energy-adjusted estimated NEAP lost significantly more ASM over 4-year than those in the lowest sex-specific quartile of energy-adjusted estimated NEAP in both crude and adjusted models (adjusted mean ± SE: ± vs ± kg, p trend =.026). Change in gait speed was not associated with the estimated NEAP. Conclusions. Our findings provide evidence of a slower decline in muscle mass in older adults with a lower dietary acid load. More prospective cohort studies in populations with different dietary habits and randomized controlled trials are warranted to examine the role of dietary acidbase balance in age-related decline in muscle loss. Key words: Acid-base balance Chinese Muscle Nutrition Physical Function. Received March 16, 2014; Accepted October 23, Decision Editor: Stephen Kritchevsky, PhD The Author Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please journals.permissions@oup.com. 905

2 906 Journals of Gerontology: MEDICAL SCIENCES, 2015, Vol. 70, No. 7 The age-related decline in muscle mass and strength has been well documented (1,2), together with its effect on daily functioning, falls, and fractures (3,4). The cause of age-related decline in muscle mass is multifactorial. Accumulating evidence has provided new findings on the impact of nutrition on age-related muscle loss (5,6). There has also been plausible evidence that diet acid-base balance is one of the contributing factors to such muscle loss (6,7). Chronic intake of excess acid-producing nutrients such as meat in combination with a low intake of the alkalizing fruits and vegetables may lead to acidosis and possibly to muscle loss (8). Of particular concern, there is a progressive increase in diet-dependent acidosis with age due to a age-related decline in kidney function (9). Therefore, diet modification or alkaline supplementation to normalize acidosis may benefit elderly health including muscle health (8). Limited studies have investigated the association between dietary acid-base load or alkaline supplementation and muscle loss and performance in older adults. A prospective study showed that diets rich in alkali-producing foods, such as fruits and vegetables were associated with the preservation of lean tissue mass in older adults (7). Two clinical trials demonstrated that alkaline supplementation in the form of potassium bicarbonate reduced urinary nitrogen excretion and thus potentially spared body protein stores in healthy older adults (10,11). A recent trial showed that daily oral administration of bicarbonate over 3 months modestly improved muscle performance and reduced nitrogen excretion in healthy postmenopausal women (12). In view of the scarcity of evidence on this topic, the present study aimed to examine the association of dietary acid-base load with 4-year change in muscle mass and performance in Chinese community-dwelling older adults in Hong Kong. The present work was partly driven by our earlier findings that muscle loss in this sample was associated with vegetable protein intake but was not associated with total or animal protein intake (13). We speculated that dietary acid-base load could be one of the possibilities to explain such association. Methods Study Population Subjects were participants of a prospective cohort study examining the risk factors for osteoporosis in Hong Kong (14). Chinese men 4,000 participants were recruited at baseline between August 2001 and December 2003 (n = 2,000) and women (n = 2,000) aged 65 years or over living in the community were recruited in a health survey between August 2001 and December Participants were volunteers and were able to walk or take public transport to the study site. They were recruited using a stratified sampling method, so that approximately 33% would be in each of these age groups: 65 69, 70 74, 75+. Compared with the general population in this age group, participants had higher educational level (12% 18% vs 3% 9%) with tertiary education in the age groups: 80+, 75 79, 70 74, and years. The 4-year follow-up was held between August 2005 and November Mean (SD) follow-up year was 3.9 (0.1) years. This study was conducted in accordance with the Declaration of Helsinki. This study was approved by the Clinical Research Ethics Committee of the Chinese University of Hong Kong. Written informed consent was obtained from all participants. We excluded participants with incomplete/invalid dietary, or demographic data, or extreme energy intake at baseline, and those with incomplete follow-up data on muscle mass at 4-year. The final analysis was performed on 3,122 participants (Figure 1). Demographic and General Lifestyle Characteristics A standardized, structured interview was performed to collect demographic, lifestyle, and past health information. Information on the duration and level of past and current use of cigarettes, cigars, and pipes was obtained. Smoking history was classified in terms of former smoking (at least 100 cigarettes smoked in a lifetime), current smoking, or never smoking. Participants were also asked about their alcohol use, and drinking status was defined as never, former, or current. Current drinkers were defined as those who drank at least 12 drinks of beer, wine (including Chinese wine), or liquor over the previous 12 months. Self-reported medical history was obtained at baseline based on participants report of their physician s diagnoses, supplemented by the identification of drugs brought to the interviewers. Physical Activity Assessment Physical activity level was assessed using the Physical Activity Scale of the Elderly (PASE [15]). This is a 12-item scale measuring the average number of hours per day spent in leisure, household, and occupational physical activities over the previous 7 days. 3,153 participants attended 4-year follow-up 847 participants discontinued 4-year follow-up: Died (n=248) Lost to follow-up (n=50) Refused (n=549) 3,122 participants were included in the analysis 31 participants were excluded from the analysis due to: Incomplete or invalid dietary or demographic data or extreme energy intake at baseline (n=29) Incomplete 4-year data on muscle mass (n=2) Figure 1. Number of participants included and excluded for analysis.

3 Journals of Gerontology: MEDICAL SCIENCES, 2015, Vol. 70, No Dietary Assessment Dietary intake was assessed at baseline using a validated semi-quantitative food frequency questionnaire (FFQ) (16). Each participant was asked by a trained interviewer to report the frequency and the usual amount of consumption of each food item over the past year. Portion size was explained to participants using a catalogue of pictures of individual food portions. Daily consumption of main food groups, including cereals, egg and egg products, fish and shellfish, fruits and dried fruits, legumes/nuts/seeds, meat and poultry, milk and milk products, and vegetables was calculated. Mean nutrient quantitation per day was calculated using food tables derived from McCance and Widdowson (17) and the Chinese Medical Sciences Institute (18). Intakes were energy-adjusted using the residual method (19). Estimation of Net Endogenous Acid Production Several algorithms have been developed to estimate estimated net endogenous acid production (NEAP) from diet (20). Fassetto et al. (21) calculated the estimated NEAP from the diet s protein to potassium ratio expressed as g/meq, whereas Remer et al. (22) estimated NEAP from average intestinal absorption rates of ingested protein and other minerals as well as an anthropometry-based estimate for organic acid excretion. Each has its rationale and limitations (23). In this study, Frassetto s method was adopted, as in our previous study (24). The rationale and algorithm of this method have been described previously, and the estimated NEAP could account for about 70% of the variation in renal net acid excretion (21). The estimated NEAP was energy-adjusted using residual method (19). Anthropometry Body weight was measured with participants wearing a light gown, using the Physician Balance Beam Scale (Healthometer, Illinois, IL). Height was measured using the Holtain Harpenden stadiometer (Holtain Ltd, Crosswell, UK). Body mass index (BMI) was calculated as (body weight in kg / [height in m] 2 ). Physical Performance Measures Physical performance measures, including timed walk, narrow walk balance, and step length were assessed at baseline and at the 4-year follow-up. In the timed walk test, the participants walked 6 m at their usual pace. The duration of the walk and the number of steps were measured. Steps were counted by counting both right and left steps and included the initial starting step and the step that first touched the floor across the finish line. In the 20-cm narrow walking test, the participants walked the 6-m course within a 20-cm narrow path. Two scored trials were performed and the performance was scored for time, if there were no more than two deviations from the path. The best of the results was used. Timing was started when the first footfall crossed over the starting line. The timing was stopped when the first footfall crossed the finish line. Time was recorded within 0.1 s in both tests. Step length was calculated by dividing the distance by the number of steps taken during usual-pace walking over 6 m. Slower times on the gait speed and narrow walk tests and shorter step length reflected worse performance. Appendicular Skeletal Muscle Mass Body composition at baseline and the 4-year follow-up was measured using dual-energy X-ray absorptiometry (Hologic QDR- 4500W, software version 11.2; Hologic, Inc., Waltham, MA). Appendicular skeletal muscle mass (ASM) was calculated by the sum of lean mass measured in the four limbs, with the operator adjusting the cut lines of the limbs according to specific anatomical landmarks as described by Heymsfield et al. (25). Calibration with a Hologic body composition step phantom was performed daily. The coefficient of variation for fat and lean mass measurements is 1.47% and 0.84%, respectively. Statistical Analysis Statistical analyses were performed using the statistical package SPSS version 21.0 (SPSS Inc., Illinois, IL). Data were checked for normality by descriptive analysis. Student s t test and chi-square test were used to examine the baseline differences in mean age, BMI, PASE, and energy intake, and also the differences in the distribution of sex, education level, smoking habit, alcohol use, and number of chronic disease between participants included and participants excluded for data analysis. As energy-adjusted estimated NEAP (continuous) did not follow normal distribution, it was evaluated as a categorical variable by using sex-specific quartile values based on the distribution of included sample. Differences across sex-specific quartiles of energyadjusted estimated NEAP were examined by chi-square test for categorical variables and by analysis of variance for continuous variables unless otherwise stated. Spearman s correlation was used to examine the correlation between energy-adjusted nutrient intakes or food group intakes and estimated NEAP, respectively. Analysis of covariance was used to examine the association between sex-specific quartiles of energy-adjusted estimated NEAP and change in ASM or physical performance measures with adjustment for baseline age (years), BMI (kg/m 2 ), sex, PASE, education level (primary or below, secondary or matriculation, University or above), smoking habit (never, former, current), alcohol use (never, former, current), energy intake, and number of chronic diseases (0, 1 2, 3). Test for trend was examined by entering sex-specific quartiles of energy-adjusted estimated NEAP as a fixed factor and testing the contrast by polynomial option in all models. An α level of 5% was used as the level of significance. Interaction between sex and sex-specific quartiles of energy-adjusted estimated NEAP was tested by addition of cross-product terms to the multivariate models. Interactions were not significant, thus all analyses are presented as combined sex. Results Participants excluded for analysis were older, less physically active, had lower education level, and more likely to be former or current smokers, and suffered from more chronic diseases (p <.05) than participants included for analysis (data not shown). Mean (SD) age of the final sample (1,553 men, 1,569 women) was 71.9 (4.9) years. Mean (SD) BMI was 23.7 (3.2) kg/m 2. Prevalence of self-reported history of diabetes and hypertension was 14.1% and 42.6%, respectively. Mean (SD) baseline ASM and 4-year change in ASM was 16.6 (3.5) kg and 0.3 (0.8) kg respectively. Median estimated NEAP was 47.3 (IQR: 35.5, 61) meq/d. Baseline characteristics of the participants across quartiles of estimated NEAP are shown in Table 1. Participants with higher estimated NEAP were physically less active, had higher education level, were more likely to be nonsmokers, had higher intakes of total protein, animal protein, and plant protein, but lower intakes of vegetables and fruits, and had greater muscle loss. Higher education level and those who were current smokers were also associated with higher intakes of total protein, animal protein, and plant protein (p <.05) (data not shown).

4 908 Journals of Gerontology: MEDICAL SCIENCES, 2015, Vol. 70, No. 7 Table 1. Baseline Participant s Characteristics and Change in ASM by sex-specific quartiles of energy-adjusted estimated NEAP (n = 3,122) Variable Sex-Specific Quartile of Energy-adjusted Estimated NEAP (g/meq) p* Q1 (n = 779) Q2 (n = 783) Q3 (n = 780) Q4 (n = 780) Mean (SD)/(%) Mean (SD)/(%) Mean (SD)/(%) Mean (SD)/(%) Estimated NEAP (g/meq) Original , , , , 78.9 <0.001 Energy adjusted , , , , 78.8 <0.001 Estimated PRAL (meq/d) Original , , , , 29.3 <0.001 Energy adjusted , , , , 29.1 <0.001 Age (years) BMI (kg/m 2 ) Male (%) Education level (%) Primary or below <0.001 Secondary / Matriculation University or above Smoking habit (%) Never smoke Former smoker Current smoker Alcohol use (%) Never Former drinker Current drinker No. of chronic disease (%) Baseline 6-m walking speed (m/s) Narrow walk speed (m/s) Average step length (m) ASM (kg) Absolute change 6-m walking speed (m/s) Narrow walk speed (m/s) Average step length (m) ASM (kg) Energy intake (kcal/d) Total protein intake (g/d) <0.001 Animal protein intake (g/d) <0.001 Plant protein intake (g/d) <0.001 Vegetables intake (g/d) <0.001 Fruits and dried fruits intake (g/d) <0.001 PASE score *Differences between groups were assessed by chi-square test and ANOVA. Data are presented as median (IQR) and differences between groups were assessed by Kruskal Wallis test. Baseline value 4-year value. ASM, appendicular skeletal muscle mass; NEAP, estimated net endogenous acid production. Estimated NEAP was positively associated with total protein, animal protein, plant protein, calcium and phosphorus intake, and was negatively associated with vitamin C, fiber, magnesium, vitamin K, and potassium intake (p <.05, Table 2). Higher estimated NEAP was associated with higher consumption of meat and fish, and lower consumption of cereals, fruits, and vegetables (p <.05, Table 2). The association between estimated NEAP and 4-year change in ASM or physical performance measures is shown in Table 3. Participants in the highest quartile of estimated NEAP lost significantly more ASM over 4-year than those in the lowest quartile of estimated NEAP in both crude and adjusted models (p trend <0.05). None of the physical performance measures was associated with the estimated NEAP in all models. Discussion In this study among 3,122 older Chinese adults, higher estimated NEAP was associated with greater muscle loss. To our knowledge,

5 Journals of Gerontology: MEDICAL SCIENCES, 2015, Vol. 70, No this is the first prospective study to report an association between estimated NEAP and muscle loss in older Chinese adults. Substantial evidence supports that acidosis promotes muscle protein loss, both by enhancing protein degradation and by inhibiting Table 2. Spearman s Correlation Between Estimated NEAP and Selected Nutrients and Main Food Groups (n = 3,122) Energy-adjusted Nutrients / Main Food Groups Energy-adjusted Estimated NEAP (meq/d) Total protein (g) 0.25 <0.001 Animal protein (g) 0.17 <0.001 Plant protein (g) 0.10 <0.001 Vitamin C (mg) 0.27 <0.001 Calcium (mg) Phosphorus (mg) 0.16 <0.001 Fiber (g) 0.22 <0.001 Magnesium (mg) 0.20 <0.001 Vitamin K (mcg) 0.17 <0.001 Potassium (mg) 0.69 <0.001 Cereals (g) Egg and egg products (g) Fish and shellfish (g) 0.07 <0.001 Fruits and dried fruits (g) 0.31 <0.001 Legumes, seeds, and nuts (g) Meat and poultry (g) 0.12 <0.001 Milk and milk products (g) Vegetables (g) 0.18 <0.001 NEAP, estimated net endogenous acid production. r s P protein synthesis (26). Several studies have shown the influence of acidosis on whole body protein turnover and muscle protein degradation (27 30), and muscle protein synthesis (31,32). Acidosis promotes muscle protein loss possibly through an upregulation of the muscle proteolytic pathways and a down-regulation of muscle protein synthetic pathways (33,34). In contrast, findings regarding the impact of alkalosis on protein kinetics are inconclusive. Alkalosis could possibly inhibit protein degradation (35,36), but the influence of alkalosis on protein synthesis remains to be investigated. While respiratory alkalosis resulted from hyperventilation increased muscle protein synthesis in critically ill patients with traumatic brain injury (37), raising blood ph did not affect muscle protein synthesis in dialysis patients (38). Adequate protein intake is needed to counter age-related sarcopenia and current recommendations are towards increasing protein intake to at least 1.2 g/kg/body weight for older people (39). However, our findings and previous literature show that increasing protein intake which raises the acidic environment may be counterproductive (26). Our previous findings demonstrated that muscle loss in our sample was associated with vegetable protein intake but was not associated with total or animal protein intake (13). Limited observational study and clinical trials also suggested the possible role of alkaline diet or supplementation in preserving muscle mass and performance (7,10 12), although the underlying mechanisms remains uncertain. These previous findings as well as our findings therefore suggest that adopting a diet with adequate protein intake and rich in alkaline-producing foods, such as vegetables and fruits to counter the acidic environment resulted from the increasing protein intake may be one of the nutritional strategies for improving skeletal muscle health in the elderly population. However, considering that older people may have difficulties to consume sufficient portion Table 3. Adjusted Mean (SE) of Change* in ASM and Physical Performance Measures by Sex-specific Quartiles of Energy-adjusted Estimated NEAP Using Analysis of covariance (n = 3,122) ASM / Physical Performance Sex-specific Quartiles of Energy-adjusted Estimated NEAP (meq/d) p trend Measures Q1 (n = 779) Q2 (n = 783) Q3 (n = 780) Q4 (n = 780) Mean SE Mean SE Mean SE Mean SE ASM (kg) Unadjusted Model Model Model m walking speed (m/s) Unadjusted Model Model Model Narrow walk speed (m/s) Unadjusted Model Model Model Average step length (m) Unadjusted Model Model Model *Baseline value 4 year value. p trend by entering sex-specific quartiles of energy-adjusted NEAP as a fixed factor in the ANCOVA model based on the polynomial option. Model 1: Age and sex. Model 2: Age, sex, and BMI. Model 3: Age, sex, education level, PASE, BMI, smoking status, alcohol use, and number of chronic diseases. ASM, appendicular skeletal muscle mass; NEAP, estimated net endogenous acid production.

6 910 Journals of Gerontology: MEDICAL SCIENCES, 2015, Vol. 70, No. 7 of vegetables and fruits, the potential use of alkaline supplement in improving acid-base balance and muscle mass and performance in the elderly population remains to be explored (11). Our data showed that participants with high estimated NEAP had lower PASE. Less active lifestyle may be one of the factors confounding the relationship between NEAP and muscle loss, as exercise is shown to be beneficial to skeletal muscle health in older people (39). However, the association between estimated NEAP and ASM change remained significant in our study after adjustment for PASE, suggesting an independent association between NEAP and muscle loss in this sample. More studies are therefore warranted to determine the interplay among NEAP, protein intake, exercise and muscle mass in the elderly population. Further studies examining the effect of acid-base balance on protein kinetics, especially the impact of alkalosis on protein synthesis are also recommended. Our study had several limitations. Dietary assessment by FFQ is subject to recall bias, thus the measurement error may attenuate associations between diet and outcome measures. Furthermore, we did not have dietary data at the 4-year follow-up whereas diet may have changed between baseline and follow-up. Moreover, residual confounding from other factors related to muscle loss, such as vitamin D status and renal function status might exist. Chronic renal failure is associated with metabolic acidosis, which could promote muscle catabolism in the body (40). Excluding participants with impaired renal function by inclusion of biomarkers of kidney functions, such as cystatin C will allow to examine a direct association between diet acid-base load and muscle decline in future studies. In addition, the clinical relevance of the differences in ASM change remains uncertain. While we detected statistically significant differences in ASM change along quartiles of NEAP, such differences between the lowest quartile and the highest quartile of NEAP were small in terms of percentage decline in ASM over 4 years (mean: 1.5% for the lowest quartile vs 2.2% for the highest quartile). Besides, our sample as a whole was of a higher education compared with the general Hong Kong population. Participants were volunteers and were able to walk or take public transport to the study site, thus they may be more health conscious and have good baseline muscle mass and functions. There were also differences in demographic and lifestyle characteristics between those included and those excluded for the analysis. Therefore, the results may not be generalized to the general population. In conclusion, our findings provide evidence of a reduced muscle loss in older adults with a lower dietary acid load. More prospective cohort studies in populations with different dietary habits and randomized controlled trials are warranted to examine the role of dietary acid-base balance in age-related decline in muscle loss and performance. Funding The work was supported by grants from the Research Grants Council of Hong Kong (CUHK 4101/02M); the Hong Kong Jockey Club Charities Trust; the SH Ho Centre for Gerontology and Geriatric; and the Centre for Nutritional Studies, the Chinese University of Hong Kong. Acknowledgments We wish to thank all participants for their participation and Dr Edith Lau for her contribution in setting up the cohort. Conflict of Interest None of the authors had a conflict of interest. References 1. Stookey JD, Adair L, Stevens J, Popkin BM. 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