Age-Related Sarcopenia, Muscle Loss
Conditions
Brief summary
The central hypothesis is that higher protein intake and a neutralizing alkaline salt supplement will improve muscle performance and mass, compared to their respective placebos, in older men and postmenopausal women.
Detailed description
With aging, skeletal muscle mass and performance decline leading to an increased risk of falls and physical disability. There is ongoing research on whether increasing dietary protein intake in older adults improves indices of muscle health and thus translates to a reduction in physical disability. A main concern is that high protein results in a large dietary acid load from the breakdown of protein to acidogenic byproducts, which could in turn promote muscle degradation particularly in older adults with age-related declines in renal excretion of acid. The scientific premise of this project is that the balance between the amount of protein in the diet (anabolic component) and the net acid load of the diet (catabolic component) in part determines whether the diet as a whole has a net anabolic or catabolic effect on muscle. Preliminary data have suggested that a daily alkaline salt supplement (potassium bicarbonate, KHCO3) lowered the dietary acid load and improved lower extremity muscle power in postmenopausal women. The investigator's central hypothesis is that higher protein intake and a neutralizing alkaline salt will improve muscle performance and mass, compared to their respective placebos, in older men and postmenopausal women. To test the hypothesis, the investigators conducted a randomized, double-blind, placebo-controlled, 2x2 factorial study in underactive men and women age 65 and older on baseline lower protein diets. Participants were assigned to one of four groups: either a whey protein supplement (to raise protein intake to 1.5 g/kg/d) with or without KHCO3 81 mmol/d or an isocaloric placebo supplement with or without KHCO3 81 mmol/d for 24 wks.
Interventions
DIETARY_SUPPLEMENTwhey protein isolate
one 15-25 gm (based on body weight) protein packet three times a day with each meal
DIETARY_SUPPLEMENTpotassium bicarbonate (KHCO3)
two 13.5 mmol capsules three times a day with each meal
OTHERmicrocrystalline cellulose
identical placebo capsule
OTHERmaltodextrin powder
isocaloric placebo powder
Sponsors
National Institute on Aging (NIA)
Tufts University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
double blind randomized placebo controlled 2x2 factorial design
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. ability to sign informed consent form 2. ambulatory community-dwelling men and women 3. age 65 years and over 4. habitual dietary intake of protein of ≤0.8 g/kg/d 5. underactive 6. estimated glomerular filtration rate ≥ 50 ml/min/1.73 m2
Exclusion criteria
1. participation in a diet or intensive exercise program during the study 2. vegetarian (no animal protein) 3. oral glucocorticoid use for \> 10 days in the last 3 months 4. anabolic and gonadal hormones in the last 6 months 5. Tamoxifen/raloxifene in the last 6 months 6. regular use of alkali-producing antacids (\> 3 times per week) 7. potassium-containing supplements or products 8. non-steroidal anti-inflammatory medications \>3 times per week 9. antacids containing calcium carbonate, aluminum hydroxide, magnesium hydroxide, or calcium acetate 10. insulin 11. sulfonylureas 12. SGLT2 inhibitors 13. a lower extremity fracture in the last year 14. kidney stones in the past 5 years 15. hyperkalemia 16. elevated serum bicarbonate 17. hypercalcemia 18. uncontrolled diabetes mellitus defined as having fasting blood \>150 or hemoglobin A1c \>8% 19. untreated thyroid or parathyroid disease 20. significant immune disorder 21. current unstable heart disease 22. Crohn's disease 23. active malignancy or cancer therapy in the last year 24. alcohol use exceeding 2 drinks/day 25. current peptic ulcers or esophageal stricture 26. other condition or abnormality in screening labs, at discretion of the study physician
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Double Leg Press Peak Power at 70% | 24 weeks | Double leg press peak power at 70% of the 1 repetition maximum |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Double Leg Press Peak Power at 70% | 12 weeks | Double leg press peak power at 70% of the 1-repetition maximum |
| Double Leg Press Peak Power at 40% | 24 weeks | Double leg press peak power at 40% of the 1 repetition maximum |
| Knee Extension Peak Torque | 24 weeks | Knee extension peak torque at 60 degrees/s using Biodex Isokinetic Dynamometer |
| Appendicular Lean Body Mass/Height Squared | 24 weeks | Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs divided by height squared |
| Physical Performance Battery Score | 24 weeks | Performance score (range 0-4 with higher values representing a better performance) based on Health Aging and Body Composition-Physical Performance Battery |
| 24 Hour Urinary Total Nitrogen Excretion | 24 weeks | Measure based on 24 hour urine total nitrogen excretion |
| Handgrip Strength | 24 weeks | Measure maximum handgrip strength in either hand using handheld Jamar+ dynamometer |
Other
| Measure | Time frame | Description |
|---|---|---|
| D3-creatine Muscle Mass/Weight | 24 weeks | measure of total body percent muscle mass by D3-creatine dilution method |
Countries
United States
Participant flow
Recruitment details
From July 2021 to July 2023, ambulatory, community-dwelling men and postmenopausal women aged 65 years and older were recruited from direct mailings to the HNRCA volunteer database and the Tufts Medical Center patient database.
Pre-assignment details
Exclusion criteria included use of oral glucocorticoids, anabolic and gonadal hormones, alkali-producing antacids, potassium-containing supplements, insulin, uncontrolled diabetes mellitus, kidney stones, advanced chronic kidney disease, cirrhosis, gastroesophageal or intestinal disease, immune disorders, unstable heart disease, untreated thyroid or parathyroid disease, active malignancy or cancer therapy, recent fracture, milk protein allergy, and relevant laboratory abnormalities.
Participants by arm
| Arm | Count |
|---|---|
| Whey Protein Isolate + KHCO3 1.5 gm/kg/day of whey protein and 81 mmol/day of KHCO3
whey protein isolate: one 15-25 gm (based on body weight) protein packet three times a day with each meal
potassium bicarbonate (KHCO3): two 13.5 mmol capsules three times a day with each meal | 29 |
| Whey Protein Isolate + Microcrystalline Cellulose 1.5 gm/kg/day of whey protein and identical placebo microcrystalline cellulose capsules
whey protein isolate: one 15-25 gm (based on body weight) protein packet three times a day with each meal
microcrystalline cellulose: identical placebo capsule | 34 |
| Maltodextrin Powder + KHCO3 isocaloric placebo maltodextrin powder and 81 mmol/day of KHCO3
potassium bicarbonate (KHCO3): two 13.5 mmol capsules three times a day with each meal
maltodextrin powder: isocaloric placebo powder | 31 |
| Maltodextrin Powder + Microcrystalline Cellulose isocaloric placebo maltodextrin powder and identical placebo microcrystalline cellulose capsules
microcrystalline cellulose: identical placebo capsule
maltodextrin powder: isocaloric placebo powder | 34 |
| Total | 128 |
Baseline characteristics
| Characteristic | Whey Protein Isolate + Microcrystalline Cellulose | Whey Protein Isolate + KHCO3 | Maltodextrin Powder + KHCO3 | Maltodextrin Powder + Microcrystalline Cellulose | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 34 Participants | 29 Participants | 31 Participants | 34 Participants | 128 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 74.5 years STANDARD_DEVIATION 6.3 | 75.1 years STANDARD_DEVIATION 6.4 | 74.1 years STANDARD_DEVIATION 5.3 | 72.7 years STANDARD_DEVIATION 5.5 | 74.1 years STANDARD_DEVIATION 5.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants | 28 Participants | 31 Participants | 33 Participants | 126 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants | 5 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 25 Participants | 25 Participants | 28 Participants | 107 Participants |
| Region of Enrollment United States | 34 participants | 29 participants | 31 participants | 34 participants | 128 participants |
| Sex: Female, Male Female | 15 Participants | 14 Participants | 16 Participants | 16 Participants | 61 Participants |
| Sex: Female, Male Male | 19 Participants | 15 Participants | 15 Participants | 18 Participants | 67 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 36 | 0 / 35 | 1 / 35 |
| other Total, other adverse events | 22 / 35 | 14 / 36 | 18 / 35 | 14 / 35 |
| serious Total, serious adverse events | 3 / 35 | 2 / 36 | 3 / 35 | 3 / 35 |
Outcome results
Primary
Double Leg Press Peak Power at 70%
Double leg press peak power at 70% of the 1 repetition maximum
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Double Leg Press Peak Power at 70% | 260.3 Watts |
| Placebo-WP | Double Leg Press Peak Power at 70% | 255.6 Watts |
| Potassium Bicarbonate (KHCO3) | Double Leg Press Peak Power at 70% | 251.1 Watts |
| Placebo-KHCO3 | Double Leg Press Peak Power at 70% | 264.8 Watts |
Secondary
24 Hour Urinary Total Nitrogen Excretion
Measure based on 24 hour urine total nitrogen excretion
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | 24 Hour Urinary Total Nitrogen Excretion | 13.1 g |
| Placebo-WP | 24 Hour Urinary Total Nitrogen Excretion | 9.8 g |
| Potassium Bicarbonate (KHCO3) | 24 Hour Urinary Total Nitrogen Excretion | 11.2 g |
| Placebo-KHCO3 | 24 Hour Urinary Total Nitrogen Excretion | 11.7 g |
Secondary
Appendicular Lean Body Mass/Height Squared
Dual energy X-ray absorptiometry (DXA) lean mass of arms plus legs divided by height squared
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Appendicular Lean Body Mass/Height Squared | 7.0 kg/m^2 |
| Placebo-WP | Appendicular Lean Body Mass/Height Squared | 7.1 kg/m^2 |
| Potassium Bicarbonate (KHCO3) | Appendicular Lean Body Mass/Height Squared | 7.0 kg/m^2 |
| Placebo-KHCO3 | Appendicular Lean Body Mass/Height Squared | 7.1 kg/m^2 |
Secondary
Double Leg Press Peak Power at 40%
Double leg press peak power at 40% of the 1 repetition maximum
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Double Leg Press Peak Power at 40% | 223.8 Watts |
| Placebo-WP | Double Leg Press Peak Power at 40% | 219.5 Watts |
| Potassium Bicarbonate (KHCO3) | Double Leg Press Peak Power at 40% | 225.3 Watts |
| Placebo-KHCO3 | Double Leg Press Peak Power at 40% | 218.1 Watts |
Secondary
Double Leg Press Peak Power at 40%
Double leg press peak power at 40% of the 1 repetition maximum
Time frame: 12 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Double Leg Press Peak Power at 40% | 221.9 Watts |
| Placebo-WP | Double Leg Press Peak Power at 40% | 215.8 Watts |
| Potassium Bicarbonate (KHCO3) | Double Leg Press Peak Power at 40% | 220.7 Watts |
| Placebo-KHCO3 | Double Leg Press Peak Power at 40% | 215.3 Watts |
Secondary
Double Leg Press Peak Power at 70%
Double leg press peak power at 70% of the 1-repetition maximum
Time frame: 12 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Double Leg Press Peak Power at 70% | 252.8 Watts |
| Placebo-WP | Double Leg Press Peak Power at 70% | 253.8 Watts |
| Potassium Bicarbonate (KHCO3) | Double Leg Press Peak Power at 70% | 246.9 Watts |
| Placebo-KHCO3 | Double Leg Press Peak Power at 70% | 259.7 Watts |
Secondary
Handgrip Strength
Measure maximum handgrip strength in either hand using handheld Jamar+ dynamometer
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Handgrip Strength | 29.0 kg |
| Placebo-WP | Handgrip Strength | 28.3 kg |
| Potassium Bicarbonate (KHCO3) | Handgrip Strength | 28.7 kg |
| Placebo-KHCO3 | Handgrip Strength | 28.5 kg |
Secondary
Knee Extension Peak Torque
Knee extension peak torque at 60 degrees/s using Biodex Isokinetic Dynamometer
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Knee Extension Peak Torque | 99.5 Newton-meters |
| Placebo-WP | Knee Extension Peak Torque | 101.5 Newton-meters |
| Potassium Bicarbonate (KHCO3) | Knee Extension Peak Torque | 102.4 Newton-meters |
| Placebo-KHCO3 | Knee Extension Peak Torque | 98.6 Newton-meters |
Secondary
Knee Extension Peak Torque
Knee extension peak torque at 60 degrees/s using Biodex Isokinetic Dynamometer
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Knee Extension Peak Torque | 96.2 Newton-meters |
| Placebo-WP | Knee Extension Peak Torque | 100.8 Newton-meters |
| Potassium Bicarbonate (KHCO3) | Knee Extension Peak Torque | 95.2 Newton-meters |
| Placebo-KHCO3 | Knee Extension Peak Torque | 97.7 Newton-meters |
Secondary
Physical Performance Battery Score
Performance score (range 0-4 with higher values representing a better performance) based on Health Aging and Body Composition-Physical Performance Battery
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | Physical Performance Battery Score | 2.1 score on a scale |
| Placebo-WP | Physical Performance Battery Score | 2.2 score on a scale |
| Potassium Bicarbonate (KHCO3) | Physical Performance Battery Score | 2.2 score on a scale |
| Placebo-KHCO3 | Physical Performance Battery Score | 2.1 score on a scale |
Other Pre-specified
D3-creatine Muscle Mass/Weight
measure of total body percent muscle mass by D3-creatine dilution method
Time frame: 24 weeks
Population: Analysis used an at-the-margins approach to evaluate the superiority of whey protein (WP) against placebo-WP and of potassium bicarbonate (KHCO3) against placebo-KHCO3
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | D3-creatine Muscle Mass/Weight | 27.9 percentage of muscle mass |
| Placebo-WP | D3-creatine Muscle Mass/Weight | 29.1 percentage of muscle mass |
| Potassium Bicarbonate (KHCO3) | D3-creatine Muscle Mass/Weight | 28.9 percentage of muscle mass |
| Placebo-KHCO3 | D3-creatine Muscle Mass/Weight | 28.1 percentage of muscle mass |
Post Hoc
IGF-1
Serum insulin-like growth factor 1 (IGF-1) level
Time frame: 24 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Whey Protein (WP) | IGF-1 | 118.5 ng/mL |
| Placebo-WP | IGF-1 | 104.3 ng/mL |
| Potassium Bicarbonate (KHCO3) | IGF-1 | 115.0 ng/mL |
| Placebo-KHCO3 | IGF-1 | 107.8 ng/mL |