Do Non-Responders to Exercise Exist—and If So, What Should We Do About Them?

Abstract

It is well established that exercise is an important component in the maintenance of good health, and yet recent studies have demonstrated that a sub-section of individuals experience no significant improvements following an exercise training intervention. Such individuals are commonly termed “non-responders”. However, recently a number of researchers have taken a skeptical view as to whether exercise non-response either exists, or is clinically relevant. Here, we explore the research underpinning exercise response, to determine whether non-response to exercise actually exists. We discuss the impact of measurement error and assessment type on the identification of “non-responders”, and whether such non-response is global- or modality-specific. Additionally, we discuss whether, if non-response to an exercise intervention is meaningful and relevant, certain additional interventions—in the form of increasing exercise intensity, volume, or duration—could be made in order to enhance training adaptations. Consequently, based on our interpretations of the available evidence, we suggest that it is unlikely that global non-responders to exercise exist. Furthermore, we suggest this realization effectively counters the perception that some individuals will not positively respond to exercise, and that in turn, this insight serves to encourage health professionals to create more nuanced, efficacious, and individually-focused exercise prescriptions designed to circumvent and overcome apparent non-responsiveness. Adopting a more individually-adaptive approach to exercise prescription could, subsequently, prove a powerful tool in promoting population health.

Full text

Vol.:(0123456789)
Sports Medicine (2019) 49:1–7
https://doi.org/10.1007/s40279-018-01041-1
CURRENT OPINION
Do Non‑Responders toExercise Exist—and If So, What Should We Do
About Them?
CraigPickering1,2 · JohnKiely1
Published online: 17 December 2018
© The Author(s) 2018
Abstract
It is well established that exercise is an important component in the maintenance of good health, and yet recent studies have
demonstrated that a sub-section of individuals experience no significant improvements following an exercise training inter-
vention. Such individuals are commonly termed “non-responders”. However, recently a number of researchers have taken
a skeptical view as to whether exercise non-response either exists, or is clinically relevant. Here, we explore the research
underpinning exercise response, to determine whether non-response to exercise actually exists. We discuss the impact of
measurement error and assessment type on the identification of “non-responders”, and whether such non-response is global-
or modality-specific. Additionally, we discuss whether, if non-response to an exercise intervention is meaningful and relevant,
certain additional interventions—in the form of increasing exercise intensity, volume, or duration—could be made in order
to enhance training adaptations. Consequently, based on our interpretations of the available evidence, we suggest that it is
unlikely that global non-responders to exercise exist. Furthermore, we suggest this realization effectively counters the per-
ception that some individuals will not positively respond to exercise, and that in turn, this insight serves to encourage health
professionals to create more nuanced, efficacious, and individually-focused exercise prescriptions designed to circumvent
and overcome apparent non-responsiveness. Adopting a more individually-adaptive approach to exercise prescription could,
subsequently, prove a powerful tool in promoting population health.
Key Points
“True” exercise non-response is potentially exaggerated
by choice of measurement.
Exercise non-response appears to be mitigated by the
changing of training variables, including increases in
training volume, duration, and intensity.
As a result, it seems unlikely that an individual would
exhibit no positive effects from exercise.
1 Introduction—A Brief History
ofInter‑Individual Variation
Typically, researchers are interested in understanding the
mean response to an intervention in order to determine its
overall efficacy [1]. For example, when determining the
effectiveness of resistance training in improving strength,
subjects will undertake a pre- and post-training interven-
tion one-repetition-maximum (1RM) test, with the average
improvements reported. Similarly, in randomized controlled
trials, the mean pre-post change in the intervention group
is compared to the mean pre-post change in the control
group, and the effectiveness of the intervention determined.
However, whilst sports coaches have long understood there
is variation in how their athletes respond to a given train-
ing stimulus—and researchers often report such variation
through the reporting of standard deviations or standard
error—only relatively recently has interest in both quanti-
fying and understanding this individual variation through
structured research developed [2].
The initial studies exploring the individual response to
aerobic training were published in the mid-1980s. The first
* Craig Pickering
craig@dnafit.com
1 Institute ofCoaching andPerformance, School ofSport
andWellbeing, University ofCentral Lancashire, Fylde
Road, PrestonPR12HE, UK
2 Exercise andNutritional Genomics Research Centre, DNAFit
Ltd, London, UK
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2 C.Pickering, J.Kiely
recruited ten monozygotic twin pairs to a 20-week endur-
ance training program, with pre- and post-intervention
measures of maximal aerobic power and ventilatory aerobic
threshold. Whilst training enhanced post-training measures
on average by between 12% (maximal aerobic power) and
20% (ventilatory aerobic threshold), there was considerable
variation, with the magnitude of improvements in maximal
aerobic power ranging from 0 to 41% [3]. Subsequent studies
replicated these initial findings [4, 5], leading to the devel-
opment of the HERITAGE family study. Here, 720 subjects
underwent a 20-week aerobic training program, completing
a battery of pre- and post-intervention tests [6]. Again, the
results showed significant individual variation; whilst the
mean improvement in maximal oxygen uptake (VO2max) was
384 ml O2, some subjects experienced improvements of over
1000 ml O2, and others a reduction in VO2max. Similarly,
whilst the mean heart rate (HR) improvement at a work-
load of 50W was 11 beats per minute (bpm), some subjects
improved by greater than 40 bpm, whilst others became
markedly worse [6]. Similar results have been reported fol-
lowing resistance training. In a classic example, Hubal and
colleagues [7] recruited 585 subjects to a 12-week progres-
sive resistance training program. Although the mean 1RM
improvement was reported as 54%, changes in 1RM ranged
from 0 to +250%. Similarly, changes in maximal voluntary
contraction ranged from −32 to +149%, and changes in
muscle size from −2 to +59%. Such extensive variability
has also been reported in other resistance training studies
[8–10], and those examining other exercise modalities, such
as sprint interval training [11, 12].
As such, there are clear individual variations in post-
training adaptations, with some subjects exhibiting no
meaningful improvements [6, 13], an outcome that conven-
tionally leads to them being labeled as “non-responders”
[13]. Alongside this evidence of no clear improvement from
exercise, pooled data from six different studies suggest that
around 10% of subjects demonstrate an adverse response to
training—i.e., exhibit an increased disease risk—defined as
a change greater than twice the technical error of measure-
ment in the negative direction, whilst 7% of subjects exhibit
an adverse response in at least two variables [14].
Such findings are potentially problematic. If certain indi-
viduals cannot improve—or, more troublingly, worsen—
their health or fitness following exercise, the implications
could be substantial; for some people, exercise may be
ineffective, potentially even increasing their disease risk.
The purpose of this article is, therefore, to closely examine
whether or not exercise non-response exists, and explore the
related question of what, if anything, we can do about it.
2 The Terminology Problem:
“Non‑Responder” Versus “Did Not
Respond”
Given the increased interest in individual variation, along
with the potential for some subjects to exhibit no [6], or
negative [14], responses, the term “non-responder” has
increasingly been employed to describe those who fail to
exhibit positive change in the measured variable following
an intervention [15]. The pejorative connotations implicit
in such a term, however, may promote a damaging and
misleading perception that exercise is perhaps not uni-
versally beneficial. This belief is potentially hugely dam-
aging from a public health perspective, given the well-
established and wide-ranging positive effects of regular
exercise training on reducing obesity risk [16, 17], enhanc-
ing cardiometabolic health [18], increasing function in the
elderly [19], improving mental health [20], and reducing
the risk of various disease states [21–23]. Accordingly, it
is crucial to approach such a term, and its related findings,
with a critical eye.
One issue worthy of exploration is whether this
observed non-response is modality-specific. Whilst the
vast majority of studies reporting exercise non-response
focus on a single training modality, such as aerobic [3,
6] or strength training [7–9], some examine exercise
response across multiple modalities. In one example, 73
subjects completed both endurance and resistance train-
ing interventions in a randomized crossover design, with
improvements in peak oxygen consumption (VO2peak) as
the measured outcome [24]. As expected, there was indi-
vidual variation in VO2peak improvements from both the
aerobic endurance (mean +8%, range −5 to +22) and
resistance training (mean +4%, range −8 to +16) inter-
ventions, such that some subjects did not improve with
a given training modality. Interestingly, however, sub-
jects exhibiting the lowest magnitude of VO2peak response
following the aerobic training intervention exhibited a
positive VO2peak response following the resistance train-
ing intervention, lending credence to the possibility that
changing exercise modality may eliminate, or at least
reduce, exercise non-response. One potential limitation
of this study is that each training intervention lasted only
2 weeks, a duration shorter than most training studies.
Accordingly, it is possible that identified non-responders
might have shown increased responses if the intervention
period was over more standard timeframes, such as 6–8
weeks. In a second study, having undertaken a combined
aerobic endurance and strength training intervention, a
small number of subjects exhibited a negative training
response in either VO2peak or maximum voluntary con-
traction (MVC), but, crucially, not in both [25]. Finally,
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3
Questioning Exercise Non-Response
Bonafiglia and colleagues [12] reported that, whilst there
were non-responders in terms of VO2peak, lactate thresh-
old, and HR improvements following both endurance and
sprint interval training, no subject was a non-responder
to both exercise modalities, and very few were non-
responders across all three measures for a single exercise
intervention. As such, it appears that non-response may be
modality-specific; whilst previous authors have suggested
that global non-responders to exercise are likely to exist
[13], this is not currently supported by experimental data.
A second, less fully appreciated issue relates to the
inherent variability of intra-individual adaptive responses.
Specifically, it remains currently unclear as to whether or
not training responsiveness, to any given intervention, is
a permanent or a temporary phenomenon. In essence, if
a given intervention were to be repeated within the same
population, would the same sub-set of individuals be iden-
tified as non-responders? As exercise intervention studies
tend not to be repeated on identical subjects, we cannot
definitively answer this question. Additionally, as aspects
such as baseline fitness, along with dietary factors, training
history, and between-session recovery modify the adaptive
response to training [26, 27], the individual taking part in
an exercise intervention for a second time is likely not in the
same adaptive state as when undertaking the initial exercise
intervention—further hampering our ability to derive firmer
conclusions. As a result, it is not clear whether exercise non-
response to a given stimulus is static and unchangeable,
remaining uniform when repeated, or dynamic, with “non-
responders” showing increased adaptations when repeating a
training program. As such, it may be preferable to label indi-
viduals exhibiting no measurable improvement in a given
variable as those who “did not respond”, representing our
uncertainty as to the time-course of such a label, rather than
“non-responders”.
3 Exercise Non‑Response: Methodological
Insights
Given the increased interest in exercise non-response and
individual variation, a number of researchers have cast a
welcome skeptical eye on the underpinning data [28–31].
When determining whether a subject has responded to
training, research designs typically require a pre- and post-
intervention test, with the difference between the two test
scores determining responsiveness [29]. However, inher-
ent within any measurement are both technical error and
random within-subject variation [28, 29]; such confounders
are said to represent “false” individual variation [28], poten-
tially leading to the mis-identification of individuals as non-
responders. To guard against this, a method to determine
“true” individual variation has been proposed, whereby the
standard deviations of the intervention group are compared
to a control/comparator group, as both groups will have
similar measurement error and random within-subject vari-
ations [28, 30]. Many of the studies supporting the concept
of exercise non-response, particularly with regard to aerobic
training, lack such a comparator arm [30]. Accordingly, the
“true” occurrence of exercise non-response may be over-
stated, and is currently unclear.
Furthermore, exercise non-response has no set definition;
it can refer to the lack of a clinically meaningful change, the
lack of a measurable change, a value above the technical
error of the test, or to the lowest set percentage of subjects
in terms of response [14, 29, 32, 33]. This obviously makes
comparisons between trials difficult, as individuals classed
as responders in one trial may be classed as non-responders
in another, thereby hampering our discernment of the true
rate of non-response.
There is also the potential that the type of evaluation
utilized may cause differences in test performance that
masquerade as individual response. For example, maximal
VO2max tests are often used to determine improvements in
cardiovascular fitness following training. These tests impose
significant physical stress and discomfort, ensuring test per-
formance is modulated by subject motivation [34]. Hence,
an individual may have undergone significant physiological
adaptations from a training program, but performed poorly
on the quantifying test due to motivational, non-physiolog-
ical reasons. Whilst this individual would have responded
positively to training, this improvement would not be
reflected in test performance. This obviously has important
implications for gene association studies exploring exercise
non-response; for example, is a particular single nucleotide
polymorphism associated with enhanced improvements
in aerobic fitness, or does it merely predispose to greater
exercise discomfort tolerance [35]? Such a problem could
be overcome by more accurate quantification of volitional
exhaustion during the pre- and post-intervention exercise
testing. For example, the triangulation of relevant objective
and subjective measures could provide a more fine-grained
estimation of the true extent of fatigue at the point of volun-
tary cessation, thereby providing a more accurate indication
of whether true exhaustion has occurred. Any such improve-
ments in measurement accuracy may well serve to reduce
the likelihood of potential mis-labelling of individuals as
non-responders to a specific intervention.
Finally, the selection of tested variables appears to
affect the identification of exercise non-responders. Typi-
cally, non-responders are identified on the basis of one
measure, such as 1RM change or improvements in VO2max.
However, when data on more than one variable are col-
lected, exercise non-response seems to disappear. For
example, Scharhag-Rosenberger and colleagues [36] had
18 subjects undergo a year-long aerobic training program.
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4 C.Pickering, J.Kiely
Pre- and post-measures were collected for four variables;
VO2max, resting HR, exercise HR, and individual anaero-
bic threshold. Ten subjects showed no improvement on at
least one variable, but, crucially, every subject improved
on at least one metric. Similarly, Churchward-Venne etal.
[8] retrospectively analyzed subject data collected follow-
ing 12–24 weeks of resistance training, exploring changes
in lean body mass, type I and II fiber size, chair-rise time,
leg press, and leg extension 1RM. Again, there were non-
responders for each individual measure, but no one sub-
ject exhibited non-response across all measures.
4 Should We be Concerned About Exercise
Non‑Response?
At this point, it appears that individual variation in
response to exercise is a normal and natural occurrence.
This non-response has a statistical component, with the
definition of non-response [29], and the variables meas-
ured [36], impacting whether an individual is labelled as
a non-responder. However, at a population-wide level, by
measuring only a few variables and labelling an individ-
ual as a non-responder, we run the risk of taking a reduc-
tionist approach to exercise. If we accept that exercise
is a “polypill”, exerting a plethora of positive benefits
[22, 23], then by focusing on a small number of measures
of response, we likely miss the bigger picture; exercise
works through so many different pathways and mecha-
nisms, that the chances of an individual exhibiting no
single biological benefit is highly unlikely. Additionally,
exercise clearly exerts benefits above the physiological,
reducing stress and improving mental health [20], as well
as serving as a social aid [37].
Nevertheless, some physiological measures appear to
be more important than others. Timmons [13] referred
to this as a “hierarchy of health benefits”, with improve-
ments in aerobic fitness likely to have a greater bearing
on health [38] and longevity [39, 40] than other meas-
ures. As such, exercise non-response in these higher-tier
aspects is clearly important, as maximizing the respon-
siveness of larger numbers of individuals to exercise
could drive important improvements in population health.
Additionally, for those at risk of certain diseases, chas-
ing a response in a specific variable may be important.
For example, when aiming to reduce type-II diabetes risk
in a cohort of at-risk individuals, we seek reductions in
fasting glucose and body mass index (BMI) [41]. In this
case, non-response to critical variables, and the target-
ing of effective exercise interventions to overcome non-
response, demand greater attention.
5 “Did Not Respond”—Potential
Interventions
The measurable differences in the magnitude of adapta-
tions following an exercise training program, if clinically
relevant, raise the question “what should we do about it?”
Findings from a small number of studies provide poten-
tially important information on how best to mitigate, and
potentially eliminate, exercise non-response. The simplest
approach would be to undertake the training program for
longer; Churchward-Venne and colleagues [8] reported
that the longer a resistance training intervention lasted, the
less prevalent non-response was, and, after 24 weeks, all
subjects exhibited a positive response in at least one out-
come measure. Sisson etal. [42] demonstrated that the rate
of non-response decreased as exercise volume increased,
from 45% at a total training exercise expenditure of 4 kcal/
kg per week (the lowest volume) to 19% at 12 kcal/kg
per week (the highest training volume). Similarly, Ross
and colleagues [43] randomly assigned obese subjects to
different exercise protocols over a 24-week intervention;
low-intensity, low-volume exercise (180–300 kcal per ses-
sion at 50% VO2peak); low-intensity, high-volume exercise
(360–600 kcal per session at 50% VO2peak); or high-vol-
ume, high-intensity exercise (360–600 kcal per session
at 75% VO2peak). On average, all groups increased their
aerobic fitness, although there were a number of subjects
deemed to exhibit no response. Interestingly, there were
no non-responders in the high-intensity training group,
demonstrating that increasing exercise intensity represents
a viable method of reducing exercise non-response. Addi-
tionally, in the two low-intensity training groups, the group
undertaking higher total volumes had fewer non-respond-
ers (18%) compared to the group with the lower volume
(39%). Furthermore, Astorino and Schubert [11] reported
that, following 2 weeks of low-volume sprint interval
training, the frequency of non-response was greater than
following prolonged, high-volume high-intensity train-
ing, again suggesting that exercise intensity is important.
Finally, in a paper entitled “Refuting the myth of non-
response to exercise training”, Montero and Lundby [44]
reported that exercise non-response is dose dependent,
finding that it was more likely to occur in subjects exer-
cising 1–2 times per week than in those exercising 4–5
times per week; indeed, there were no non-responders in
this latter group. Furthermore, when the subjects identi-
fied as non-responders to the initial exercise intervention
underwent a second intervention, identical to the first but
with two additional weekly training sessions, there were
no non-responders. As such, increasing exercise intensity
and/or duration appear to be useful strategies for reducing,
or perhaps even eliminating, exercise non-response.
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5
Questioning Exercise Non-Response
A further option for enhancing training outcomes is
changing training modality. Because the molecular pathways
and gene networks underpinning adaptations to aerobic and
resistance exercise are often distinct (although there can be
overlap) [13, 45–48], undertaking exercise-types that an
individual can more favorably adapt to holds promise. This
has been illustrated by Hautala and colleagues [24], whereby
individuals termed non-responders following aerobic train-
ing enhanced their cardiovascular fitness following resist-
ance training. Additionally, Bonafiglia and colleagues [12]
reported that non-response to either typical endurance train-
ing or sprint interval training largely abated when subjects
undertook the other exercise intervention.
Finally, by understanding the mediators of inter-individ-
ual variation, we may be able to enhance the probability of
enhanced outcomes, arising from any given training pro-
gram, for all individuals. At present, research has illustrated
that factors such as genotype, baseline fitness, training his-
tory, nutritional intake, psycho-emotional states, between-
session recovery, age, weight, and ability to meet prescribed
training workloads all influence the magnitude of subsequent
adaptive responses to exercise [26, 27, 49, 50]. As such, if an
individual exhibits a lower response to exercise, correction
of some of these factors, such as implementing enhanced
sleep hygiene [51] or moderating background psycho-
emotional stressors [52], may enhance subsequent training
adaptations. Additionally, there remains the possibility that,
as the magnitude of exercise response is partially governed
by various molecular drivers [13], and as these drivers are
partially genetically determined [2, 53], use of genetic infor-
mation may assist in the selection of more individually-opti-
mal training prescription [27, 54]. The potential influence
of genotype on training outcomes is an emerging, currently
contentious field, with both early promise [55, 56] and null
results [57]. As such, the utility of using genotype to guide
training interventions requires further research.
6 Conclusion—Do Non‑Responders
toExercise Exist?
Based on available evidence, we can conclude that:
1. There is an individual variation in response to exercise,
with some subjects experiencing larger improvements
than others [6, 10, 24].
2. This individual response is a combination of “true” and
“false” variation, with “false” variation referring to both
technical measurement error and random within-subject
biological variation [26], and “true” variation to real,
between-subject differences, comprised of differences
in both genotype and individual history, amongst other
influencing factors [26, 27, 58].
3. There is often a sub-group of individuals who appear to
exhibit either no [6, 10] or a negative [14] response to
specific exercise training programs.
4. The extent to which this non-response is “true” or
“false” within each study currently remains unclear, as
is whether this non-response is static (i.e., the individual
will always be a non-responder to that particular exercise
training program), or merely a temporary reflection of
the adaptive capacity of specific individuals at a given
time (i.e., the individual did not respond to that exer-
cise training program, but might if the intervention was
repeated).
5. Exercise response is often determined by measurement
of one, or at most a small number, of all the potential
variables that can typically change with exercise. Thus,
just because an individual does not improve their VO2max
or 1RM with training, this does not mean that they have
not derived a multitude of other benefits from exercise,
many of which, such as increased social interaction seen
in community exercise settings [37], are non-physiolog-
ical in nature.
6. Increasing the number of measured variables can elimi-
nate the prevalence of exercise non-response [36], as
can increasing training volume, intensity, or duration [8,
42–44].
As a result, we might, therefore, be better off stating
that people “did not respond” to a particular intervention
in a given measure, as opposed to labelling them as “non-
responders”, because it seems likely that a different train-
ing programme (in terms of intensity, volume, duration, or
modality) would elicit a positive response. This is similar
to the ideas of Booth and Laye [15], who believed the
term “non-responder” should be replaced by “low sensitiv-
ity”; in this case, these low-sensitivity individuals merely
require increased volumes and/or intensity to drive favour-
able response. Undoubtedly, this is good news, given the
wide-ranging benefits of exercise on health and wellbe-
ing; however, further research is required to identify the
optimal way to align individuals to the training type most
likely to elicit the greatest adaptations, especially given
the limited time many people perceive they have available
to exercise, along with concerns about the applicability
of increased exercise intensities for all exercisers [59].
Furthermore, future research should focus on identifying
those expected to exhibit a lower response to exercise,
so that they can be given an alternative, more efficacious
training intervention. Such research has the potential to
have a huge impact on the health of populations, increas-
ing the health and fitness of time-poor individuals in a
more effective manner.
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6 C.Pickering, J.Kiely
Compliance with Ethical Standards
Funding No sources of funding were used to assist in the preparation
of this article.
Conflict of interest Craig Pickering is an employee of DNAFit Ltd, a
genetic testing company. He received no financial incentives for the
preparation of this manuscript. John Kiely declares that he has no con-
flict of interest relevant to the content of this article.
OpenAccess This article is distributed under the terms of the Crea-
tive Commons Attribution 4.0 International License (http://creat iveco
mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribu-
tion, and reproduction in any medium, provided you give appropriate
credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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