R.T. Mankowski1, K.T. Sibille1,2, C. Leeuwenburgh1, Y. Lin1, F.-C. Hsu4, P. Qiu3, B. Sandesara1, S.D. Anton1
1. Department of Aging and Geriatric Research, University of Florida, Gainesville, FL, USA; 2. Department of Physical Medicine & Rehabilitation, University of Florida, Gainesville, FL, USA; 3. Department of Biostatistics, University of Florida, Gainesville, USA; 4. Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
Corresponding Author: Robert T. Mankowski, PhD, Department of Aging and Geriatric Research, University of Florida, 2004 Mowry Road, Gainesville, FL, 32611, United States. Phone: +1 (352) 294-5055, Fax: +1 (352) 294-5836, E-mail: firstname.lastname@example.org
J Frailty Aging 2022;in press
Published online July 6, 2022, http://dx.doi.org/10.14283/jfa.2022.47
Background: Natural dietary compounds that can modulate the inflammation process have the potential to improve physical function through a number of biological pathways, and thus may represent an alternative approach to avert functional decline compared to more time-burdening lifestyle interventions. In this pilot trial, we tested the feasibility and explored the effect of a nutritional compound, Curcumin C3 Complex® for improving physical function and muscle strength in moderately functioning older adults with low-grade inflammation.
Methods: Moderately functioning (short physical performance battery, SPPB <10) and sedentary older adults (>65 years) with low-grade systemic inflammation (c-reactive protein >1mg/dL) were randomized to receive Curcumin C3 Complex® (n=9) (1000mg/day) or placebo (n=8) groups for 12 weeks. All participants (age range: 66-94 years, 8 females and 9 males) underwent functional testing (SPPB and walking speed by the 400-meter walk test) and lower-limb strength (knee flexion and extension peak torque by the Biodex test) at baseline and 12 weeks. Venous blood was collected at baseline, 4, 8 and 12 weeks for safety blood chemistry analyses and biomarkers of inflammation.
Results: A total of 17 participants were randomized and completed the study. Adherence was high (> 90%) and there were no adverse events reported or abnormal blood chemistries reported. Based on effect sizes, participants in the Curcumin C3 Complex® group demonstrated large effect sizes in the SPPB (Cohen’s effect size d=0.75) and measures of knee extension (d=0.69) and flexion peak torque (d=0.82). Effect sizes for galectin-3 (d=-0.31) (larger decrease) and interleukin-6 (d=0.38) (smaller increase) were small in the Curcumin C3 Complex® group compared to placebo.
Conclusion: This pilot trial suggests that there were no difficulties with recruitment, adherence and safety specific to the study protocol. Preliminary findings warrant a Phase IIb clinical trial to test the effect of Curcumin C3 Complex® on physical function and muscle strength in older adults at risk for mobility disability.
Key words: Muscle strength, nutraceutical, inflammation, clinical trial.
Aging-related functional decline leads to mobility disability (1). One of the hallmarks of aging and contributors of age-related comorbidities and functional decline is low-grade inflammation (2). Lifestyle interventions involving physical activity and caloric restriction have been shown to reduce inflammation and improve physical function in older adults (1, 3), however those interventions pose the time and intensity burden for moderately functioning older adults. Given that chronic inflammation contributes to physical function decline in older adults (4), reducing levels of systemic inflammation may be a strategy to maintain physical function (2).
Natural dietary compounds that can modulate the inflammation process have the potential to improve physical function through a number of biological pathways (5, 6) and may be an alternative to these more time-burdening lifestyle interventions. However, limited evidence exists to support the use of natural dietary compounds for improving function in older adults (5).
Curcumin is the bioactive polyphenolic extract of Turmeric, which has been used to treat inflammatory conditions in India for centuries (7). Findings over the past few decades indicate that curcumin has a broad range of biological effects, including anti-inflammatory and anti-oxidative properties, directly relevant to human health (7). More recently, clinical trials with middle-aged and older adults tested well-tolerated doses between 500 and 2500 mg per day showed mixed results where the effects of curcumin ranged from improvements in physical function to no effects (7-10). The reason for the mixed effects is not clear, but may be related to greater efficacy in comorbid conditions. Thus, curcumin may represent an alternative treatment option for some older adults based on their health status.
Based on its mechanisms of action and safe history of use in normally functioning middle-aged and older populations (8, 11), curcumin may represent a dietary compound that is uniquely capable of improving physical function and muscle strength via reduction of inflammation levels. To our knowledge, no study to date has tested the effects of curcumin in older adults with elevated levels of systemic inflammation. Therefore, the purpose of this pilot study was to test the feasibility of 1000 mg/day of Curcumin C3 Complex® supplementation for 12 weeks in moderately functioning older adults with low-grade inflammation (c-reactive protein > 1.0 mg/dL). We hypothesized that the study would be feasible in regard to recruitment, adherence, and safety. Additionally, we anticipated exploratory analyses would indicate that Curcumin C3 Complex® treatment would improve physical function, walking speed and lower-limb strength in this population of older adults.
Study procedures and design
This pilot randomized trial was designed to test feasibility of a 12-week supplementation with Curcumin C3 Complex®, compared to placebo, in moderately functioning older adults with low-grade systemic inflammation. Temporary exclusion criterial included bacterial/viral infection in the last 2 weeks and a major surgery in the last 6 months.
The University of Florida’s Institutional Review Board approved the study, and a Data Safety Monitoring Board reviewed the study bi-annually. Prior to enrollment, all participants provided verbal and written informed consent. This study follows CONSORT reporting guidelines (12) and was pre-registered on ClinicalTrials.gov (NCT03085680).
Participants, recruitment and study entry
Participants were moderately functioning (short physical performance battery, SPPB<10) older adults 65-90 years old in the Gainesville, FL area with low-grade chronic inflammation (C-reactive protein, CRP > 1mg/dL).
We reached potential participants by mailing postcards and via newspaper advertisements. Interested individuals were pre-screened during an initial telephone screening form, and invited for in-person screening, if eligible. At this visit, after signing an informed consent, participants were screened for cardiovascular and other major chronic diseases. The health review consisted of a medication inventory, medical and hospital admission history, a review of the telephone screen, a Mini Mental Status Exam, and a physical exam which included blood pressure, radial pulse, weight, and waist circumference. Participants also completed the SPPB assessment at this visit to ensure that they were not high functioning (SPPB<10).
Curcumin C3 Complex® supplementation and placebo
The Curcumin C3 Complex® (500mg of curcumin, demethoxycurcumin and bisdemethoxycurcumin in each capsule) and placebo (nitrocellulose) were alike looking capsules for this trial were provided by Sabinsa Corporation, Piscataway, NJ. Participants in both the Curcumin C3 Complex® and placebo conditions were instructed to consume one oral capsule twice daily, immediately following breakfast and dinner. We obtained the investigational new drug (IND) exemption granted by the Food and Drug Administration (FDA) At participants’ monthly clinic visits, pill counts and diaries were used to check the adherence to supplement use.
Adverse event evaluation
Potential adverse events for study related activities and interventions were explained to each participant by trained study personnel during the informed consent process. Each participant was instructed to report the occurrence of an adverse event at scheduled data collection times (scheduled research visits at 4, 8 and 12 weeks or phone interviews).
Venous blood was collected at baseline, 4-, 8- and 12-week follow-up visits for safety blood chemistries by Quest Analytics Laboratories then processed for plasma and stored frozen in an -80C environment for further laboratory analyses. The safety blood chemistry results were evaluated for abnormal values by the study physician. In case of abnormal values, the PI and study physician decided on whether to exclude a participant from the trial.
Physical function was assessed objectively by the SPPB, which is comprised of a 4-meter walk, repeated chair stands, and three increasingly difficult standing balance tests. Each task received a score from 0 (worst performance) to 4 (best performance). The total score ranges from 0 to 12 and was computed by summing the three component scores (13).
We assessed gait speed on the 400-meter walk test (14). Participants were asked to walk at their usual pace, without over-exerting. They could stop for up to 1 min due to fatigue or other symptoms. Participants were allowed to use a cane, but not a walker, to complete this test. Walking speed, as assessed by the 400 m walk, has been shown to be directly related to whole body aerobic capacity (15), which has been found to be strongly associated (r > 0.70) with mitochondrial function in both younger and older adults (16).
Tests of isolated muscle function by performing unilateral knee extension, flexion maximal strength and endurance tests were done using the Biodex system. These tests involve using an isokinetic dynamometer set at 90 degrees per second (17, 18). Participants performed 50 maximal knee extension and flexion concentric repetitions, which were administered by trained and certified research coordinators. Maximal muscle strength was summarized as peak torque achieved in Newton-meters.
Plasma galectin-3 and interleukin-6 (IL-6) biomarkers were measured using an enzyme-linked immunosorbent assay (ELISA) using commercial kits (R&D Systems, Minneapolis, MN). These measures were selected based on the previous reports on selected biomarkers of systemic inflammation in older adults (19). However, these selected biomarkers need to be interpreted with caution due to multiple functions beyond inflammation.
The primary physical function outcomes of interest were changes in SPPB, 400-meter walking speed, and peak torque at week 12 from baseline. Each outcome was summarized by mean ± standard error and standard deviation by the intervention group. The 12-week changes in safety variables (AEs and blood chemistries) were compared between intervention groups using the two-sample t-test. To compare changes in physical function and muscle strength for the two groups, the two-sample t-test was also used. Additionally, we calculated Cohen’s d effect size to identify the standardized mean difference of an effect. This is beneficial to the determination of sample size for future larger studies (20). We used Spearman’s correlation coefficients to test an association between muscle strength with the inflammation biomarkers. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC) and R 3.6.1.
Eighteen moderately functioning, sedentary, otherwise healthy older adults (SPPB) <10) with low-grade systemic inflammation (CRP >1mg/dL), were randomized to either 1000mg (n=9) of Curcumin C3 Complex® or placebo (nitrocellulose) (n=9) for 12 weeks. Only one participant withdrew; thus, a total of 17 participants completed the study (Figure 1).
Baseline characteristics of participants in both groups are depicted in Table 1. These characteristics were not different between the randomized treatment and placebo groups.
C= Curcumin C3 Complex® group; P=placebo group; BMI=body mass index; SBP=systolic blood pressure, DBP=diastolic blood pressure; GLS=global longitudinal strain; SPPB=short physical performance battery; MMSE=mini mental status exam; CRP=C-reactive protein. Bpm=beats per minute; Nm=Newton-meters. Values are mean (SD) or number (%), and statistical significance (p<0.05) marked with *.
Recruitment and Retention. Participant retention rate was 94% in terms of participants who were randomized to an intervention, attended study visits, and completed measures.
Adherence and Acceptability
There were no difficulties collecting measures across all sessions. Adherence to study protocol was >90%.
Tolerance and Safety
Participants tolerated the Curcumin C3 Complex® and placebo capsules. Mean compliance rates to the Curcumin C3 Complex® (95%) and placebo (96%) supplement regimens were high. In our population of older adults with low-grade inflammation, no abnormal values among the safety blood chemistries were identified (data not shown). Study participants did not report any serious adverse events associated with participation in the study. Three participants in the Curcumin C3 Complex® group reported adverse events during the course of the study, and one participant in the placebo group reported an adverse event, all unrelated to the intervention.
Although there were no statistically significant differences between groups, participants in the Curcumin C3 Complex® group demonstrated a large change in the SPPB compared to placebo (Cohen’s d=0.75). Figure 2 displays the comparison of the mean change from baseline (one score point) between Curcumin C3 Complex® and placebo in the total SPPB score. After analyzing separate components of the SPPB, the change from baseline in total balance and chair stand test had large effect sizes (d=0.88 and d=0.74, respectively), whereas the gait speed test had a small effect size (d=0.32).
Data presented as mean ± 1 SEM. Statistical significance was set at p<0.05.
Participants in the Curcumin C3 Complex® group demonstrated large effect sizes in the knee extension (Figure 3A) (d=0.69) and flexion (Figure 3B) (d=0.82) peak torque compared to participants receiving placebo. Figure 3 shows the comparison of the mean change from baseline between Curcumin C3 Complex® and placebo on the knee extension and flexion peak torque tests.
Data presented as mean ± 1 SEM. Statistical significance was set at p<0.05. Nm=Newton-meters.
The mean change in walking speed measured during the 400-meter walk test trended to be lower among participants in the Curcumin C3 Complex® group (0.01±0.1 m/s) compared to participants receiving the placebo (0.1±0.1 m/s). The effect size was d=0.96.
Effect sizes for galectin-3 (d=-0.31) (small decrease) and IL-6 (d=0.38) (smaller increase) were small in the Curcumin C3 Complex® group compared to placebo. Additionally, we noted a negative correlations between the change in extension peak torque with galectin-3 (r=-0.65, p=0.009) and IL-6 (r=-0.50, p=0.06).
CO2=carbon dioxide; ALT= alanine aminotransferase; AST= aspartate aminotransferase; MCV= mean corpuscular volume; MCH= mean corpuscular hemoglobin; MCHC= mean corpuscular hemoglobin concentration; RDW= red cell distribution width; MPV= mean platelet volume. Values are mean (SD) or number (%), and statistical significance (p<0.05) marked with *.
To our knowledge, this was the first pilot study to test the feasibility of an intervention and the effect of Curcumin C3 Complex® supplementation on physical function and muscle strength in moderately functioning older adults with low-grade systemic inflammation. The main findings of our study were that 12 weeks of Curcumin C3 Complex® supplementation without a lifestyle intervention in this population was feasible, and also resulted in large improvements (based on effect sizes) in physical function and lower-limb muscle strength, and with small changes in inflammation levels.
Feasibility indicators for the study were strong. Participants in the study were recruited through community advertisements. Randomization resulted in balanced groups, and the compliance with supplementation for the Curcumin C3 Complex® and placebo capsules and study measures were high. No adverse events or abnormal changes in blood chemistry related to the intervention were observed.
The findings of our study also suggest Curcumin C3 Complex® is safe and well tolerated by moderately functioning older adults with elevated levels of inflammation. Our findings are in line with previous clinical trials, which have found that doses up to 2500 mg of curcumin per day to be safe and well-tolerated among healthy older adults and in disease conditions such as osteoarthritis, metabolic syndrome, and chronic kidney disease (7, 9, 10, 21). Supplementation duration in previous studies has varied from 12 weeks to 18 months, with 12 weeks being reported as the most common intervention period (22).
Findings have been mixed on the effects of curcumin on physical function in middle-aged and older adults. For example, Santos-Parker et al. did not demonstrate improvements in physical function and muscle strength in response to 12 weeks of 2000mg of curcumin per day in normally functioning middle-aged and older adults (9). In contrast, in middle-aged and overweight adults with limited physical function due to osteoarthritis, 12 weeks of 1000mg of curcumin per day improved walking speed by 0.1m/s and the Chair Stand Test score by 1.44 compared to placebo (10). One factor that may have led to the disparate findings may have been the participants’ level of baseline function prior to the curcumin supplementation. Our population consisted of moderately functioning (SPPB < 10) and sedentary adults, age 65 years and older with low-grade systemic inflammation, which could be a more responsive population to Curcumin C3 Complex®.
Although preliminary, our results on the medium to large effect size of the knee extension and flexion peak torque representing lower-limb muscle strength are novel. To our knowledge, this is the first study to report strength improvement in response to Curcumin C3 Complex® supplementation in older adults. Pre-clinical studies on molecular changes in response to curcumin indicate a potential mechanism of muscle strength improvement (23, 24). For example, reduced skeletal muscle strength is dependent on impaired mitochondrial function, muscle atrophy and a shift from type I to type II muscle fibers, and decreased muscle force induced by ongoing systemic inflammation and oxidative stress (25, 26). Mice with heart failure had downregulation of the nuclear factor erythroid2-related factor 2 (Nrf2)/anti-oxidant enzymes as well as myogenin/myoblast determination protein 1 (MyoD). Downregulation of these pathways is associated with decreased anti-oxidant regulation, increased inflammation, protein stability and muscle degeneration, and these impairments were substantially attenuated by short and long-term treatments with curcumin (23, 25, 27). Taken together, the pre-clinical studies on biological mechanisms contributing to improved skeletal muscle strength by anti-oxidative and anti-inflammatory effects of curcumin support our clinical findings, however future studies are needed to confirm this mechanism by muscle specimen analyses in a fully powered clinical trial.
Low-grade inflammation has been demonstrated as one of the mediators of functional decline in older adults. Anti-inflammatory agents, such as curcumin, could potentially alleviate low-grade inflammation and facilitate functional improvements in older adults. Our results showed a low effect size of reductions in galectin-3 and IL-6 inflammatory biomarkers. In a previous study in young and middle-aged adults, eight weeks of curcumin supplementation (1000mg/day) reduced systemic inflammation biomarkers (tumor necrosis factor alpha, IL-6 and monocyte chemoattractant protein-1) (28). In this study, the same type and dose of curcumin was used as in our study, with a difference of adding 5mg of piperine to each 500mg of curcumin to improve bioavailability (28). Additionally, in our study, we noted negative associations between muscle strength and inflammatory biomarkers, which may suggest that trends in muscle strength improvements may have been mediated by anti-inflammatory effects of Curcumin C3 Complex®, which needs to be studied in more detail in future projects.
Although participants in the Curcumin C3 Complex® showed larger improvements on measures of physical function and strength (based on effect size), walking speed did not change from baseline (based on effect size). A large and clinically meaningful increase in walking speed was observed among participants in the placebo group compared to the intervention group. This finding was unexpected and in contrast to our hypothesis. Such findings may have been an artifact of our small sample size and highlight the importance of a fully powered clinical trial to investigate the effects of Curcumin C3 Complex® and other compounds on walking speed.
Among the strengths of this pilot study were high levels of adherence (>90%) and retention (94%) of the study participants during this 12-week intervention. Additionally, we have demonstrated the feasibility of recruiting moderately functioning, sedentary older adults with elevated levels of systemic inflammation.
The sample size was small and consisted only of Caucasian participants. Additionally, participants were followed for a short period of time (three months) and one dose of Curcumin C3 Complex® was tested. We also evaluated one biological pathway (inflammation) that could affect physical function. These measures were selected based on the previous reports on selected biomarkers of systemic inflammation in older adults. However, these selected biomarkers need to be interpreted with caution due to multiple functions beyond inflammation. It is likely that Curcumin C3 Complex® affects a number of biological mechanisms that may be related to physical function in older adults. We did not measure other important potential biological mechanisms, such as mitochondrial function and expression of hypertrophy proteins, which could help explain our functional findings.
Conclusions and Future Directions
In conclusion, the findings of this pilot trial suggest that the study protocol tested is feasible. Additionally, the pattern of findings regarding Curcumin C3 Complex® and physical functioning were encouraging and warrant further investigation. Thus, these preliminary results warrant a Phase IIb clinical trial over a longer-term period in a diverse population of older adults. Such trials are needed to determine whether use of Curcumin C3 Complex® can improve physical function and muscle strength in older adults, as well as to identify the potential mechanisms through which this compound works.
Acknowledgement: Support was provided by the University of Florida’s McKnight Brain Institute, Claude D. Pepper Older Americans Independence Center (NIH/NIA P30AG028740), and Clinical and Translational Science Institute (NIH/NCRR UL1TR000064). The product for this trial was provided by Sabinsa Corporation, Piscataway, NJ.
Conflict of interest: none.
Ethical standards: The study was approved by the local Institutional Review Board and all study participants signed a written informed consent.
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