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N Engl J Med. Author manuscript; available in PMC 2017 November 18.
Published in final edited form as:
N Engl J Med. 2017 May 18; 376(20): 1943–1955. doi:10.1056/NEJMoa1616338.

Aerobic or Resistance Exercise, or Both, in Dieting Obese Older
AdultsAuthor Manuscript

Dennis T. Villareal, M.D., Lina Aguirre, M.D., A. Burke Gurney, Ph.D., P.T., Debra L. Waters,
Ph.D., David R. Sinacore, Ph.D., P.T., Elizabeth Colombo, M.D., Ph.D., Reina ArmamentoVillareal, M.D., and Clifford Qualls, Ph.D.
Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, and the Center
for Translational Research on Inflammatory Diseases, Michael E. DeBakey Veterans Affairs (VA)
Medical Center — both in Houston (D.T.V., R.A.-V.); Medicine Care Line, New Mexico VA HealthCare System (L.A., D.L.W., E.C.), and the Department of Internal Medicine (L.A., E.C.), theDivision of Physical Therapy (A.B.G.), and the Department of Mathematics and Statistics (C.Q.),
University of New Mexico School of Medicine — both in Albuquerque; the Department ofMedicine, School of Physiotherapy, University of Otago, Dunedin, New Zealand (D.L.W.); and theProgram in Physical Therapy, Washington University School of Medicine, St. Louis (D.R.S.)

Abstract
BACKGROUND—Obesity causes frailty in older adults; however, weight loss might accelerate
age-related loss of muscle and bone mass and resultant sarcopenia and osteopenia.

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METHODS—In this clinical trial involving 160 obese older adults, we evaluated the effectivenessof several exercise modes in reversing frailty and preventing reduction in muscle and bone massinduced by weight loss. Participants were randomly assigned to a weight-management programplus one of three exercise programs — aerobic training, resistance training, or combined aerobic
and resistance training — or to a control group (no weight-management or exercise program). The
primary outcome was the change in Physical Performance Test score from baseline to 6 months(scores range from 0 to 36 points; higher scores indicate better performance). Secondary outcomes
included changes in other frailty measures, body composition, bone mineral density, and physicalfunctions.

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RESULTS—A total of 141 participants completed the study. The Physical Performance Test
score increased more in the combination group than in the aerobic and resistance groups (27.9 to33.4 points [21% increase] vs. 29.3 to 33.2 points [14% increase] and 28.8 to 32.7 points [14%increase], respectively; P=0.01 and P=0.02 after Bonferroni correction); the scores increased morein all exercise groups than in the control group (P<0.001 for between-group comparisons). Peak
oxygen consumption (milliliters per kilogram of body weight per minute) increased more in the
combination and aerobic groups (17.2 to 20.3 [17% increase] and 17.6 to 20.9 [18% increase],
respectively) than in the resistance group (17.0 to 18.3 [8% increase]) (P<0.001 for bothcomparisons). Strength increased more in the combination and resistance groups (272 to 320 kg

Address reprint requests to Dr. Villareal at Baylor College of Medicine, Michael E. DeBakey VA Medical Center, 2002 Holcombe
Ave., Houston, TX 77030, or at dennis.villareal@bcm.edu.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

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Author Manuscript[18% increase] and 288 to 337 kg [19% increase], respectively) than in the aerobic group (265 to
270 kg [4% increase]) (P<0.001 for both comparisons). Body weight decreased by 9% in all
exercise groups but did not change significantly in the control group. Lean mass decreased less inthe combination and resistance groups than in the aerobic group (56.5 to 54.8 kg [3% decrease]and 58.1 to 57.1 kg [2% decrease], respectively, vs. 55.0 to 52.3 kg [5% decrease]), as did bonemineral density at the total hip (grams per square centimeter; 1.010 to 0.996 [1% decrease] and1.047 to 1.041 [0.5% decrease], respectively, vs. 1.018 to 0.991 [3% decrease]) (P<0.05 for allcomparisons). Exercise-related adverse events included musculoskeletal injuries.
CONCLUSIONS—Of the methods tested, weight loss plus combined aerobic and resistance
exercise was the most effective in improving functional status of obese older adults. (Funded by
the National Institutes of Health; LITOE ClinicalTrials.gov number, NCT01065636.)

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More than a third of persons 65 years of age or older in the United States are obese,1 andthis group constitutes a population vulnerable to adverse outcomes, because obesity
exacerbates the age-related decline in physical function and causes frailty.2–5 However,appropriate management of obesity in older adults remains controversial, given the reported
reduction in relative health risks associated with increasing body-mass index in this group.6
Moreover, an important concern is that weight loss could worsen frailty by accelerating the
age-related decline in muscle and bone mass and resultant sarcopenia and osteopenia.7,8Author Manuscript

Given the positive effects of exercise on physical function, healthy aging in obese older
adults might require an intervention that involves regular exercise.9 We reported previouslythat exercise (combined aerobic and resistance training) in combination with weight loss was
associated with greater improvement in physical function than weight loss alone or exercise
alone.10 However, exercise attenuated but did not prevent loss in muscle and bone massinduced by weight loss and ameliorated but did not reverse frailty. The physiologic
adaptations to aerobic and resistance exercise are distinctly different: aerobic exercise
improves cardiovascular adaptations that increase peak oxygen consumption without
significantly changing strength, whereas resistance exercise improves neuromuscular
adaptations that increase strength without significantly changing peak oxygen
consumption.11 These physiologic adaptations may interfere with each other when the two
types of training are performed together.12–14 In the current clinical trial, we compared theeffectiveness of aerobic exercise, resistance exercise, and combined exercise in reversing
frailty and preserving muscle and bone mass during weight loss in obese older adults. We
hypothesized that weight loss plus resistance exercise would improve physical function morethan weight loss plus aerobic exercise or weight loss plus combined aerobic and resistance
exercise.

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METHODSSTUDY OVERSIGHT
We conducted the Lifestyle Intervention Trial in Obese Elderly (LITOE) from April 2010
through June 2015 at the University of New Mexico School of Medicine and New Mexico
Veterans Affairs Health Care System. The study was approved by the institutional review
board of the University of New Mexico School of Medicine and was monitored by an

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independent data and safety monitoring board; all participants provided written informed
consent. All the authors had access to the data and vouch for the integrity, accuracy, andcompleteness of the data and analyses and for the fidelity of the study to the protocol. The
first author wrote the first draft of the manuscript; all the authors participated in subsequent
drafts and made the decision to submit the manuscript for publication. No commercial
support was received.
PARTICIPANTS

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Participants were recruited through advertisements and underwent comprehensive medical
screening. Persons were eligible for inclusion if they were 65 years of age or older, wereobese (body-mass index [the weight in kilograms divided by the square of the height inmeters] ≥30), were sedentary (regular exercise <1 hour per week), and had had a stable bodyweight (loss or gain of no greater than 2 kg) and stable medication use for 6 months before
enrollment. All participants had mild-to-moderate frailty, as defined by a score of 18 to 31
on the modified Physical Performance Test (scores range from 0 to 36 points, with higherscores indicating better performance).15 Persons who had severe cardiopulmonary disease(e.g., recent myocardial infarction or unstable angina), musculoskeletal or neuromuscular
impairments that precluded exercise training, or cognitive impairments or who used drugs
that affect bone metabolism were excluded.
STUDY OUTCOMES
The primary outcome was the change in score on the Physical Performance Test frombaseline to 6 months. Secondary outcomes were changes in other frailty measures, bodycomposition, bone mineral density, specific physical functions, and quality of life.

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INTERVENTION
In this 26-week study, participants were randomly assigned, with stratification according tosex, to one of four groups — a control protocol that included neither a weight-management
nor an exercise intervention, an aerobic group that participated in a weight-management
program and aerobic exercise training, a resistance group that participated in a weightmanagement program and resistance exercise training, and a combination group thatparticipated in a weight-management program and combined aerobic and resistance exercise
training.
The control group was asked not to participate in external weight-loss or exercise programs.
However, this group attended group educational sessions about a healthful diet duringmonthly visits.

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The aerobic group participated in a weight-management program, in which the participants
were prescribed a balanced diet that provided an energy deficit of 500 to 750 kcal per day
and contained approximately 1 g of high-quality protein per kilogram of body weight per
day.2 Participants met weekly with a dietitian for dietary adjustments and behavioral therapy(diet therapy). They were instructed to set weekly behavioral goals and attend weigh-in
sessions. Food diaries were reviewed, and goals were set on the basis of diary reports. The
goal was to achieve a weight loss of approximately 10% at 6 months. They also participated

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in aerobic exercise training sessions three times weekly. The sessions were approximately 60
minutes long and included 10 minutes of flexibility exercises, followed by 40 minutes ofaerobic exercises and 10 minutes of balance exercises. The aerobic exercises consisted oftreadmill walking, stationary cycling, and stair climbing. Participants exercised at
approximately 65% of their peak heart rate, which was gradually increased to 70 to 85%.

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The resistance group participated in the same weight-management program as the aerobic
group, as well as resistance exercise training sessions three times weekly; the sessions wereapproximately 60 minutes long and included 10 minutes of flexibility exercises, followed by
40 minutes of resistance exercises and 10 minutes of balance exercises. The resistancetraining consisted of nine upper-body and lower-body exercises using weight-liftingmachines. The initial sessions were 1 to 2 sets of 8 to 12 repetitions at 65% of the onerepetition maximum. This was increased progressively to 2 to 3 sets at approximately 85%of the one-repetition maximum.
The combination group participated in the same weight-management program as the otherexercise groups, as well as combined aerobic and resistance exercise training sessions threetimes weekly. The sessions were 75 to 90 minutes long and included 10 minutes offlexibility exercises, followed by 30 to 40 minutes of aerobic exercises, 30 to 40 minutes ofresistance exercises, and 10 minutes of balance exercises. To test the interference effect,12–14
aerobic and resistance training were balanced between groups: the longer duration of
exercise in the combination group allowed the participants to perform an amount of aerobic
exercise that was equivalent to that of the aerobic group and an amount of resistance exercisethat was equivalent to that of the resistance group.

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Exercise sessions were supervised by exercise trainers. Participants were advised to maintaintheir usual physical activity outside of exercise sessions. All participants received
supplements to ensure an intake of approximately 1500 mg of calcium per day andapproximately 1000 IU of vitamin D per day.2
BASELINE ASSESSMENTS

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Physical Function—Frailty was assessed with the Physical Performance Test. The
Physical Performance Test includes seven standardized tasks (walking 15.2 m [50 ft],putting on and removing a coat, picking up a penny, standing up from a chair, lifting a book,climbing one flight of stairs, and performing a progressive Romberg test) plus two additionaltasks (going up and down four flights of stairs and making a 360-degree turn). The score foreach task ranges from 0 to 4, with higher scores indicating better physical performance; aperfect score would be 36.15 Frailty was also assessed by measurement of peak oxygen
consumption and by administration of the Functional Status Questionnaire. Peak oxygen
consumption was assessed during graded treadmill walking, as described previously.3
Ability to perform activities of daily living was assessed with the use of the Functional
Status Questionnaire (scores range from 0 to 36, with higher scores indicating better
functional status).16 We also assessed strength, balance, gait speed, and one-repetition
maximum (the maximum weight a participant can lift, in one attempt, in the biceps curl,bench press, seated row, knee extension, knee flexion, and leg press). We assessed staticbalance by measuring the time a participant could stand on a single leg3 and dynamic
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Author Manuscriptbalance by measuring the time needed to complete an obstacle course.15 Fast gait speed wasassessed by measurement of the time needed to walk 7.6 m (25 ft).
Body Composition and Bone Mineral Density—Fat mass, lean mass, and bonemineral density of the whole body and at the lumbar spine and total hip were measured withthe use of dual-energy x-ray absorptiometry (Lunar DPX [General Electric] or Discovery A[Hologic] scanner), as described previously.3,17 For each participant, baseline and follow-up
scans were obtained with the use of the same instrument. Thigh muscle and fat volumes
were measured by magnetic resonance imaging (Magnetom Avanto [Siemens]), as described
previously.18

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Quality of Life—We used the physical and mental component subscales of the Medical
Outcomes Study 36-Item Short-Form Health Survey (SF-36), version 2, to evaluate qualityof life.19 Scores on the physical and mental component subscales of the SF-36 range from 0
to 100, with higher scores indicating better health status; the minimal clinically importantdifference is 2 points.20
FOLLOW-UP ASSESSMENTS
All baseline assessments were repeated at 6 months. The Physical Performance Test wasalso repeated at 3 months. Assessors were unaware of the study-group assignments.
STATISTICAL ANALYSIS

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We estimated that a sample size of 40 participants per group would provide 80% power todetect a mean (±SD) clinically important difference between groups of 1.8±2.5 in the change
in score on the Physical Performance Test, at an alpha level of 0.05. Intention-to-treat
analyses were performed with SAS software, version 9.4 (SAS Institute). Baselinecharacteristics were compared with the use of analysis of variance or Fisher’s exact test.
Longitudinal changes between groups were tested with the use of mixed-model repeatedmeasures analysis of variance, with adjustment for baseline values and sex. The primary
focus of the analyses was the 6-month change in outcome in the four groups. When theoverall P value for the interaction between group and time was less than 0.05, prespecified
comparisons were used to test five hypotheses: that changes in the aerobic group would
differ from those in the control group, that changes in the resistance group would differ fromthose in the control group, that changes in the aerobic group would differ from those in theresistance group, and that changes in the combination group would differ from those in the
aerobic group and from those in the resistance group. For the Physical Performance Test
score, Bonferroni correction was used to adjust for these comparisons. Within-groupchanges were analyzed with the use of repeated-measures analysis of variance. Secondary
outcomes were grouped into five domains. In accordance with a gatekeeping strategy,21 asignificant group-by-time interaction (P<0.01) and at least one significant difference
between an exercise group and the control group and at least one significant difference
among the exercise groups in the change in score on the Physical Performance Test wererequired to continue to testing of secondary outcomes; comparisons of the exercise groups
with the control group were performed with Dunnett’s test and comparisons among theintervention groups were performed with the Fisher–Hayter test22 (Fig. S1 in the

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Supplementary Appendix, available with the full text of this article at NEJM.org). Sensitivity
analyses that validated the statistical results included multiple imputation for missing fitness
data. Data for change scores and percentage changes are presented as least-squares–adjusted
means (±SE).

RESULTSSTUDY POPULATION
A total of 160 participants underwent randomization, and 141 participants (88%) completed
the study (Fig. 1). Nineteen participants discontinued the intervention and were included in
the intention-to-treat analyses (follow-up data were obtained for all 19 participants at 3
months but not at 6 months). There were no significant differences among the groups inbaseline characteristics (Table 1).

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Median attendance at the diet-therapy sessions was 96% (interquartile range, 87 to 100) in
the aerobic group, 100% (interquartile range, 90 to 100) in the resistance group, and 97%(interquartile range, 89 to 100) in the combination group. Median attendance at exercise
sessions was 96% (interquartile range, 84 to 100) in the aerobic group, 98% (interquartile
range, 81 to 100) in the resistance group, and 93% (interquartile range, 83 to 100) in the
combination group.
ADVERSE EVENTS

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Exercise-related adverse events included falling, shoulder pain, and back pain in the aerobic
group; atrial fibrillation, shoulder pain, and knee pain in the resistance group; and shoulder
injury, knee pain, back pain, and hip pain in the combination group. There were no other
differences in adverse events relative to the control group (Table S1 and S2 in the
Supplementary Appendix).
PHYSICAL PERFORMANCE TEST AND OTHER FRAILTY MEASURES

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The scores on the Physical Performance Test increased more in the combination group thanin aerobic or resistance groups: 27.9 to 33.4 points (a change of 5.5±0.4 points [21%increase from the least-squares adjusted mean at baseline]) versus 29.3 to 33.2 points (achange of 3.9±0.4 points [14% increase]) and 28.8 to 32.7 points (a change of 3.9±0.4 points[14% increase]), respectively; scores in all three exercise groups increased more than scoresin the control group (4% increase) (Table 2 and Fig. 2A). Peak oxygen consumption(measured as milliliters per kilogram of body weight per minute) increased more in the
combination and aerobic groups than in the resistance group: 17.2 to 20.3 (a change of
3.1±0.3 [17% increase]) and 17.6 to 20.9 (a change of 3.3±0.3 [18% increase]), respectively,
versus 17.0 to 18.3 (a change of 1.3±0.3 [8% increase]) (Table 2 and Fig. 2B). Functional
Status Questionnaire scores increased more in the combination group than in the aerobic andresistance groups: 29.8 to 33.4 points (a change of 3.6±0.3 points [14% increase]) versus
30.1 to 32.1 points (a change of 2.0±0.3 points [7% increase]) and 29.3 to 31.6 points (achange of 2.3±0.3 points [8% increase]), respectively (Table 2 and Fig. 2C).

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BODY COMPOSITION

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Body weight decreased in the aerobic group (96.9 to 87.9 kg; a change of −9.0±0.6 kg, [9%decrease]), in the resistance group (101.8 to 93.3 kg; a change of −8.5±0.5 kg [9%decrease]), and in the combination group (99.0 to 90.5 kg; a change of −8.5±0.5 kg [9%decrease]), but there was no significant change in body weight in the control group (97.9 to
97.0 kg; a change of −0.9±0.5 kg [<1% decrease]) (Table 2). The time course of weight loss
is shown in Figure 3. Lean mass decreased less in the combination group (56.5 kg to 54.8
kg; a change of −1.7±0.3 kg [3% decrease]) and in the resistance group (58.1 to 57.1 kg; achange of −1.0±0.3 kg [2% decrease]) than in the aerobic group (55.0 to 52.3 kg; a changeof −2.7±0.3 kg [5% decrease]) (Table 2 and Fig. 2D). Fat mass decreased by −6.3±0.5 kg in
the aerobic group (41.9 to 35.6 kg [16% decrease]), −7.3±0.4 kg in the resistance group(44.3 to 37.0 kg [17% decrease]), and −7.0±0.5 kg in the combination group (42.5 to 35.5 kg[17% decrease]). The changes in thigh muscle and thigh fat among the exercise groups weresimilar to those observed for lean mass and fat mass, respectively.
BONE MINERAL DENSITY
Bone mineral density at the total hip did not change significantly in the resistance group(1.047 to 1.041 g per square centimeter; a change of −0.006±0.004 g per square centimeter[<1% decrease]), whereas it decreased in the aerobic group (1.018 to 0.991 g per squarecentimeter; a change of −0.027±0.004 g per square centimeter [2.6% decrease]) and in the
combination group (1.010 to 0.996 g per square centimeter; a change of −0.014±0.004 g per
square centimeter [1.1% decrease]) (Table 2 and Fig. 2E). Bone mineral density of the wholebody and at the lumbar spine did not change significantly in any of the study groups (Table
S3 in the Supplementary Appendix).

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STRENGTH, BALANCE, GAIT, AND QUALITY OF LIFE

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Total one-repetition maximum strength increased in the resistance group (288 to 337 kg; achange of 49±5 kg [19% increase]) and in the combination group (272 to 320 kg; a changeof 48±5 kg [18% increase]), whereas it was maintained in the aerobic group (265 to 270 kg;
a change of 5±5 kg [4% increase]) (Table 2 and Fig. 2F). Time needed to complete the
obstacle course decreased more in the combination group (17.0 to 14.1 seconds; a change of−2.9±0.3 seconds [13% decrease]) than in the aerobic group (15.5 to 14.0 seconds; a changeof −1.5±0.4 seconds [7% decrease]). Gait speed increased more in the combination group(68.8 to 80.9 m per minute; a change of 12.1±1.3 m per minute [14% increase]) than in the
aerobic group (74.6 to 82.7 m per minute; a change of 8.1±1.3 m per minute [9% increase]).
The SF-36 physical-component score increased more in the combination group (45.9 to 55.4
points; a change of 9.5±0.7 points [24% increase]) than in the aerobic group (48.6 to 55.1
points; a change of 6.5±0.7 points [14% increase]) and the resistance group (51.0 to 58.4
points; a change of 7.4±0.8 points [17% increase]) (Table S3 in the Supplementary
Appendix).

DISCUSSION
Our randomized, controlled trial involving obese adults 65 years of age or older indicatedthat weight loss plus a combination of aerobic and resistance exercise improved physicalN Engl J Med. Author manuscript; available in PMC 2017 November 18.

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function and reduced frailty more than weight loss plus aerobic exercise or weight loss plus
resistance exercise. Evidence-based data to guide treatment of older adults with obesity are
limited5,23,24 and tend to rely on studies involving younger adults.2 Our study directlycompared aerobic, resistance, and combined (aerobic and resistance) training during weightloss in obese older adults. The matched weight loss across groups facilitated the assessmentof the independent and combined effects of aerobic and resistance training. Despite anegative energy balance, aerobic training improved cardiovascular fitness and resistancetraining improved strength. Contrary to our hypothesis, combined aerobic and resistancetraining improved cardiovascular fitness to the same extent as aerobic training alone andstrength to the same extent as resistance training alone. Therefore, combined aerobic andresistance training resulted in additive effects that translated into the greatest improvement
among the interventions in physical function and reduction of frailty. Both resistancetraining and combined resistance and aerobic training attenuated the loss of lean mass during
aerobic training. Moreover, although only resistance training prevented the weight-loss–
induced reduction in bone mineral density at the total hip, combined aerobic and resistancetraining nonetheless attenuated the loss of bone mineral density at the total hip during
aerobic training. Our data suggest that obese older adults can adapt and respond to exercise
training during an energy deficit and that combined aerobic and resistance training provides
the greatest benefits with respect to physical function, with relative preservation of leanmass.

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Our findings in obese older adults expand observations of the positive effects of exercise
training without weight loss in nonobese older adults25,26 and support the results of previous
studies that showed that exercise training was most beneficial in frail older adults in theearlier stages of frailty.27 Given the exercise goals for our frail and obese participants,28 we
designed the aerobic and resistance training to be moderate to vigorous in intensity to induce
exercise adaptations29 while keeping exercise volumes moderate.27 Using these exercise
strategies, we found additive effects of aerobic and resistance training without interference
effect from concurrent training.12–14 Adherence to exercise was high despite frailty, andadverse events were relatively few and consistent with coexisting medical conditions. Ourfindings suggest that the recommendation by the American Heart Association and American
College of Sports Medicine to combine aerobic exercise with resistance exercise for overall
health30 extends to obese older adults undertaking weight loss.

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The improvements in objective measures of frailty in our participants may have important
implications for preserving independent living. The Physical Performance Test assesses
multiple domains of physical function15 and predicts disability, loss of independence, anddeath.31,32 The peak oxygen consumption relative to body weight is the best indicator of
cardiovascular endurance33 and is important for performing daily tasks with increased bodyweight.3,34 Improvements in the objective Physical Performance Test score and peak oxygen
consumption were consistent with improvements in Functional Status Questionnaire andSF-36 scores, which indicate subjective improvements in functional ability.
Although combined aerobic and resistance training improved physical function the mostamong the interventions, the reductions in lean mass and bone mineral density that wereattenuated but not prevented might represent an adverse effect in that these reductions

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further diminish tissue reserves superimposed on age-related losses. However, resistancetraining improved strength despite muscle loss induced by weight loss. Conversely, whether
improved physical function lowers the risks of falls and fractures despite the decline in bonemineral density is currently unclear. In future studies, additional strategies to preserve leanmass might include improving the efficiency of vitamin D and protein intake, increasing
weight-bearing exercises, and perhaps administering anabolic hormone therapy.35,36 Anotheradverse effect was exercise-related musculoskeletal injuries, which could be minimized
through individualized exercises.

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Strengths of our study include the randomized, controlled trial design, the comprehensive
lifestyle programs, the high rate of adherence to the trial interventions, the similar weightloss management that allowed for unbiased group comparisons, and the use of objective andsubjective measures of physical function. Because this was an efficacy study, the 6-month
duration was appropriate to determine which exercise was most efficacious in improving
physical function during weight loss. Data from long-term studies that show whether weightloss plus combined aerobic and resistance training prolongs physical independence in obese
older adults are currently lacking. The findings from our study may have pragmatic
implications, because Medicare currently covers behavioral therapy for weight loss,37 and a
growing number of Medicare plans now offer gym memberships.38 Data from a previous
trial show that older adults may be more successful in achieving long-term weight loss than
younger adults.39

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Our study has limitations. First, in accordance with the exclusion criteria, the participants inour study were physically able to participate in a lifestyle program and thus may not be fully
representative of the general obese older adult population. Second, our sample was not large
enough to analyze differences according to sex. Finally, most of the participants were
women, white, and well educated, which limits broader generalization.
In conclusion, our study showed that weight loss plus resistance training or aerobic training
improved physical function and ameliorated frailty; however, weight loss plus combined
aerobic and resistance training provided greater improvement in physical function andreduction of frailty than either intervention alone and was associated with relative
preservation of lean mass.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

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Acknowledgments
The content is solely the responsibility of the authors and does not necessarily represent the official views of the
National Institutes of Health and the Department of Veterans Affairs (VA).
Supported by grants from the National Institutes of Health (RO1-AG031176, UL1-TR000041, and P30DK020579).
We thank the participants for their cooperation, Kenneth Fowler for study coordination, Brandy Martinez and Erik
Faria for exercise training, and Ronni Farris and Reed Vawter for weight-loss training. We also thank the membersof the Alkek Foundation for their support. The findings reported in this article are the result of work supported withN Engl J Med. Author manuscript; available in PMC 2017 November 18.

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resources and the use of facilities at the New Mexico VA Health Care System and Michael E. DeBakey VA Medical
Center.

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Figure 1. Screening, Randomization, and Follow-up

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The study groups included a control group that received neither a weight-management nor
an exercise intervention and three exercise groups: a group that received aerobic exercise
training (aerobic group), a group that received resistance exercise training (resistance group),
and a group that received combined aerobic and resistance exercise training (combinationgroup); all three exercise groups also participated in a weight-management program.

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Figure 2. (facing page). Mean Percentage Changes in Physical Function, Lean Mass, and BMD at
the Total Hip during the Interventions

Measures of physical function included the Physical Performance Test (PPT; scores range
from 0 to 36, with higher scores indicating better functional status), peak oxygen
consumption, Functional Status Questionnaire (FSQ; scores range from 0 to 36, with higherscores indicating better functional status), and strength (measured as total one-repetition
maximum [i.e., the total of the maximum weight a participant can lift, in one attempt, in thebiceps curl, bench press, seated row, knee extension, knee flexion, and leg press]). Scores on
the PPT were used as an objective measure of frailty (primary outcome), and scores on the
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FSQ were used as a subjective measure of frailty. The asterisk indicates P<0.05 for thecomparison with the control group, the dagger P<0.05 for the comparison with the aerobic
group, and the double dagger P<0.05 for the comparison with the resistance group.
Percentage changes are presented as least-squares–adjusted means; T bars indicate standard
errors. BMD denotes bone mineral density.

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Figure 3. Mean Percent Changes in Body Weight during the Interventions

Percent changes are presented as least-squares–adjusted means; I bars indicate standard
errors.

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Table 1

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Baseline Characteristics of the Participants.*
Characteristic

Control(N = 40)

Aerobic(N = 40)

Resistance(N = 40)

Combination(N = 40)

Age — yr

70±5

70±4

70±5

70±5

Male

12 (30)14 (35)15 (38)16 (40)Female28 (70)26 (65)25 (62)24 (60)White

36 (90)36 (90)33 (82)35 (88)

Black

1 (2)

0

3 (8)

2 (5)

Other

3 (8)

4 (10)

4 (10)

3 (8)Hispanic or Latino

13 (32)13 (32)

12 (30)12 (30)Not Hispanic or Latino

27 (68)27 (68)27 (68)28 (70)

0

0

1 (2)

0

Less than a college degree

14 (35)

13 (32)15 (38)10 (25)

College degree

20 (50)20 (50)12 (30)19 (48)

Graduate school

6 (15)

7 (18)

13 (32)11 (28)Single8 (20)

4 (10)

9 (22)

5 (12)

Married15 (38)25 (62)22 (55)23 (58)

Divorced

9 (22)

7 (18)

6 (15)

8 (20)

Widowed8 (20)

4 (10)3 (8)

4 (10)

Body-mass index‡

36.7±5.0

35.9±4.436.7±5.835.8±4.5

Chronic diseases — no.§3.2±3.4

2.6±2.7

3.6±3.92.7±2.0

Routine medications — no.¶5.5±4.3

5.7±3.4

6.2±5.7

5.7±4.0

Sex — no. (%)

Race — no. (%)†

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Ethnic group — no. (%)†

Unknown
Education — no. (%)

Marital status — no. (%)

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Plus-minus values are means ±SD. There were no significant between-group differences in baseline characteristics. The study groups included acontrol group that received neither a weight-management nor an exercise intervention and three exercise groups: a group that received aerobic
exercise training (aerobic group), a group that received resistance exercise training (resistance group), and a group that received combined aerobic
and resistance exercise training (combination group); all three exercise groups also participated in a weight-management program. Percentages may
not total 100 because of rounding.

†Race and ethnic group were reported by the participants.

‡

The body-mass index is the weight in kilograms divided by the square of the height in meters.

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Chronic diseases included hypertension, diabetes, coronary artery disease, congestive heart failure, arthritis, and chronic lung disease.

¶

Routine medications included antihypertensive, antidiabetic, antidyspeptic, antianginal, diuretic, antiarthritic, antilipidemic, and antidepressant
medications.

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0.4±0.3
1.0±0.4

Change at 3 mo

Change at 6 mo

0.1±0.3

Change at 6 mo

0.4±0.3

Change at 6 mo

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−0.9±0.5

Change at 6 mo

0.0±0.2

Change at 6 mo

43.0±1.5−0.9±0.4

Baseline

Change at 6 mo

Fat mass (kg)54.9±2.3

Baseline

Lean mass (kg)97.9±2.9

Baseline

Body weight (kg)Body composition

29.8±0.5

Baseline

FSQ score

17.0±0.5

Baseline

VO2peak (ml/kg/min)Other frailty measures

Secondary outcomes

28.6±0.5

Control(N =40)Baseline

PPT score

Primary outcome

Outcome44.3±1.5−7.3±0.4‡−6.3±0.5‡−1.0±0.3¶−2.7±0.3‡

41.9±1.3

58.1±2.3−8.5±0.5‡−9.0±0.6‡

55.0±1.9

101.8±2.9

2.3±0.3‡

2.0±0.3‡

96.9±2.3

29.3±0.630.1±0.5

1.3±0.3‡

3.3±0.3‡

3.9±0.4‡

3.9±0.4‡

17.0±0.6

3.2±0.4‡

2.9±0.4‡

17.6±0.528.8±0.4

Resistance(N = 40)29.3±0.3

Aerobic(N = 40)−7.0±0.5‡42.5±1.6−1.7±0.3‡56.5±1.8−8.5±0.5‡

99.0±2.9

3.6±0.3‡29.8±0.6

3.1±0.3‡

17.2±0.6

5.5±0.4‡

4.0±0.4‡27.9±0.4

Combination(N =40)<0.001<0.001<0.001<0.001<0.001<0.001

Group–TimeInteraction<0.001<0.001<0.001

0.002<0.001<0.001

Aerobic
vs.
Control<0.0010.03<0.001<0.0010.007<0.001

0.18§

0.001

0.76§

0.46

<0.001

0.87

Aerobic
vs.
ResistanceP Value†
Resistancevs.
Control

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Effect of Specific Exercise Modes, Added to Diet-Induced Weight Loss, on Outcomes.*

0.36§

0.047

0.72§

0.005

0.63

0.002

Combination
vs.
Aerobic

0.67§

0.20

0.96§

0.03

0.001

0.004

Combination
vs.
Resistance

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0.0±0.3

Change at 6 mo

75.0±2.6−0.5±1.3

Baseline

Change at 6 moGait speed (m/min)

15.9±0.7

2±5Baseline

Obstacle course (sec)Change at 6 moBaseline

Total 1RM (kg)║269±210.004±0.004

Change at 6 moStrength, balance, and gait

1.031±0.025−2±36

1774±13210±71302±63

Baseline

BMD at total hip (g/cm2)

Change at 6 moBaseline

Thigh fat (cm3)

Change at 6 moBaseline

74.3±2.3
9.3±1.3‡

8.1±1.3‡−2.2±0.3‡−1.5±0.4‡74.6±2.0

16.4±0.6

12.1±1.3‡68.8±2.2−2.9±0.3‡

17.0±1.0

48±5‡

49±5‡

15.5±0.85.0±5272±16−0.014±0.004¶

1.010±0.025−288±35‡

1784±125−40±7‡

1186±66288±30−0.006±0.004−0.027±0.004‡265±201.047±0.022−280±35‡−260±35‡

1.018±0.019

1848±108−23±7¶−77±7‡

1700±981190±481234±62

Combination(N =40)<0.001<0.001<0.0010.001<0.001<0.001

Group–TimeInteraction<0.001

0.02

0.99

<.001

<0.001<0.001

Aerobic
vs.
Control<0.001<0.001<0.0010.37<0.001

0.008

Resistancevs.
Control

0.56

0.20

<0.001

0.005

0.64§

<0.001

Aerobic
vs.
ResistanceP Value†

0.03

0.01

<0.001

0.04

0.61§

0.005

Combination
vs.
Aerobic

0.09

0.20

0.82

0.43

0.97§

0.21

Combination
vs.
ResistanceP values for the changes from baseline to 6 months in between-group comparisons were calculated with the use of mixed-model repeated-measures analyses of variance (with baseline values and sex ascovariates) and are reported when the overall P value was lower than 0.05 for the interaction among the four groups over time. In a Bonferroni correction to adjust for the multiple comparisons in the PPTscore (in which the P values were multiplied by 5 for the comparison with an alpha level of 0.05), the corrected P values were 0.01 for the combination group versus the aerobic group and 0.02 for the
combination group versus the resistance group. In accordance with a gatekeeping strategy, a significant group-by-time interaction (P<0.01) and at least one significant difference between an exercise groupand the control group and at least one significant difference among the exercise groups in the change in PPT score were required to continue to testing of the secondary outcomes; comparisons of the†bone mineral density.

Plus-minus values for the change scores are the least-squares adjusted means ±SE from the repeated-measures analyses of variance; plus-minus values for the baseline values are the observed means ±SE.
Scores on the Physical Performance Test (PPT) (primary outcome) range from 0 to 36, with higher scores indicating better physical function; the minimal clinically important difference is 1.8. Peak oxygen
consumption (VO2peak) was assessed during graded treadmill walking. Scores on the Functional Status Questionnaire (FSQ) range from 0 to 36, with higher scores indicating better function. BMD denotes*

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Thigh muscle (cm3)Resistance(N = 40)

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Aerobic(N = 40)

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Control(N =40)

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P<0.001 for the comparison of the value at the follow-up time with the baseline value within the group, as calculated with the use of mixed-model repeated-measures analysis of variance.

Total one-repetition maximum (1RM) is the total of the maximum weight a participant can lift, in one attempt, in the biceps curl, bench press, seated row, knee extension, knee flexion, and leg press.

P<0.01 for the comparison of the value at the follow-up time with the baseline value within the group, as calculated with the use of mixed-model repeated-measures analysis of variance.

║¶

The between-group differences were not significant in the last three columns because the group-by-time interaction for the three intervention groups (step 1 of the Fisher–Hayter test) was not significant;the family-wise error rate of 0.05 or less is maintained for the Fisher–Hayter multiple comparison procedure.

§‡

exercise groups with the control group were performed with Dunnett’s test and comparisons among the intervention groups were performed with the Fisher–Hayter test. Secondary analyses included acomparison between the combination group and the control group; all P values were less than 0.05.

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