Ageing Research Reviews 38 (2017) 1–5

Contents lists available at ScienceDirect

Ageing Research Reviews

journal homepage: www.elsevier.com/locate/arr

Review

A viewpoint on considering physiological principles to study stress

resistance and resilience with aging
Benjamin F. Miller a,∗ , Douglas R. Seals b , Karyn L. Hamilton a
a
Department of Health and Exercise Science, 201 Moby B Complex, Colorado State University, Fort Collins, CO, 80523-1582, USA
b
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, 80309,USA

a r t i c l e i n f o a b s t r a c t

Article history: Adaptation to stress is identified as one of the seven pillars of aging research. Our viewpoint discusses
Received 9 May 2017 the importance of the distinction between stress resistance and resilience, highlights how integration of
Received in revised form 22 June 2017 physiological principles is critical for further understanding in vivo stress resistance and resilience, and
Accepted 23 June 2017
advocates for the use of early warning signs to prevent a tipping point in stress resistance and resilience.
Available online 1 July 2017
© 2017 Elsevier B.V. All rights reserved.

Keywords:
Stress resistance
Resilience
Physiology
Slowed aging

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Stress resistance versus resilience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
3. Why physiology is important for understanding stress resistance and resilience with aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
4. Using early warning signs to prevent a tipping point in stress resistance and resilience . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

1. Introduction
for in investigations of stress adaptation. We make the argument
that targeting adaptation to stress for future treatments aimed at
The Geroscience Interest Group identified seven pillars of aging
“slowing aging” also requires application of physiological princi-
research that distinguish the key processes to understanding and
ples, which might be lost by using only a reductionist approach.
treating biological aging (Kennedy et al., 2014). One of the seven
To help inform our Viewpoint, we will distinguish the differences
pillars is “adaptation to stress” for which the authors identified
between stress resistance and resilience, argue that physiological
the important goals of bridging the continuum from psycholog-
concepts help in understanding complex problems, and provide
ical to molecular studies, differentiating positive low dose stress
one recommendation on how to move such studies forward.
(hormesis) from toxic stress, and aligning animal and human stud-
ies. We agree that these are important goals toward which our
laboratories are currently working. The purpose of this Viewpoint 2. Stress resistance versus resilience
is to highlight the importance of integrative physiology, including
physiological redundancy, and how such factors must be accounted Under the umbrella of adaptation to stress are two distinct
concepts, stress resistance and resilience. While conceptually dis-
tinct, stress resistance and resilience are likely accomplished by
∗ Corresponding author. both independent and overlapping mechanisms. The distinctness
E-mail addresses: Benjamin.f.miller@colostate.edu (B.F. Miller), of these concepts is well recognized in some scientific fields, but
seals@colorado.edu (D.R. Seals), Karyn.hamilton@colostate.edu (K.L. Hamilton). perhaps less so in the basic biology of aging. As an example, The

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National Institute on Aging recently released an RFA titled, “Short-
term measurements of improved physical and molecular resilience in
pre-clinical models” (https://grants.nih.gov/grants/guide/rfa-files/
RFA-AG-17-014.html). The definition of resilience provided by the
RFA is, “. . .to maintain or recover appropriate function in response
to a physical stressor” (underline is our emphasis). As described
next, this definition encompasses aspects of both stress resis-
tance and resilience, even though the RFA was titled for resilience
only.
To clearly define stress resistance versus resilience, we rely on
descriptions from other areas of study. A symposium entitled “The
neurobiology of the stress-resistant brain” defined stress resistance
as the mechanisms involved in preventing a “tipping point” from
adaptive to maladaptive responses. This definition was contrasted
with resilience, which is mediated by mechanisms that facilitate
recovery after crossing the “tipping point” (Fleshner et al., 2011).
In ecology, stress resistance is defined as change in a system aris-
ing from a disturbance, whereas resilience is defined as change in
a system following the relaxation of a disturbance (Nimmo et al.,
2015). The distinction between the ability to prevent something
from imposing damage, versus the ability to recover after a dam-
aging event is important. Because stress resistance and resilience
are not always equal, the mechanisms that underpin each can
be distinct. Further, efforts to increase either stress resistance or
resilience may not also improve the other, and conceivably could
hinder the other if energetic resources are allocated to one versus
the other. As an example, steel is designed to resist bending to an
outside force (highly stress resistant), but it does not return to shape
after relaxation of the force (low resilience). Rubber on the other
hand may bend quite easily to an outside force (low stress resis-
tance), but returns to its original shape after removal of the force
(high resilience). Both of these strategies are effective for minimiz-
ing damage, but clearly having qualities of one does not guarantee
the other and often comes at the cost of the other.
While stress resistance and resilience are distinct in con-
cept, experimental or practical distinction can be difficult and
is often overlooked. Use of primary fibroblasts in culture is
a well-established model for determining cellular stress resis-
tance/resilience in aging. For example, in studies using fibroblasts
derived from animals selected to have varying lifespans, it is com-
mon practice to apply a range of concentrations of a stress to
determine a lethal dose (LD50) of that stressor, or to apply a sub-
lethal dose to determine the response to that dose (Harper et al.,
2007; Pickering et al., 2015; Salmon et al., 2005). Although these
experimental approaches are lumped under the category of stress
resistance, the two approaches may be testing stress resistance and
resilience. In the case of determining the LD50 with viability the
primary outcome, stress resistance, the ability to avoid a tipping
point (i.e. cell death), is tested. When using a sub-lethal dose, if the
application of the stress is not damaging, the outcome is a mea-
sure of stress resistance. However if some form of damage occurs
(e.g. oxidative damage), the transcriptional or post-transcription
events put in motion to recover from the stress are more indicative
of resilience. Even the distinction in this example is not entirely
clear-cut and emphasizes the experimental challenge of measur-
ing stress resistance and resilience, which are likely accomplished
via both distinct and overlapping mechanisms.
To complement the use of in vitro models and survival assays dis-
cussed above, measuring in vivo physiological responses to stress
can provide valuable indicators of resistance and resilience. For
example, in vivo functional responses to stressors such as acute
ambient heat exposure have been used for decades in both pre-
clinical models and human subjects (Haak et al., 2009). In human
subjects, impaired stress resistance with aging during acute heat
exposure is shown by attenuated cutaneous active vasodilation and
sweating (Holowatz et al., 2003), an insufficient increase in cardiac
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output (Minson et al., 1998), and impaired redistribution of blood
flow from the renal and splanchnic organs to the skin for cooling
(Minson et al., 1998), and a resultant increase in rate of rise in body
core temperature in older adults (Larose et al., 2013). In contrast,
examples of reduced physiological resilience with aging include
slower wound healing (Sgonc and Gruber, 2013) and recovery from
surgery in older animals and people (Bautmans et al., 2014). For
example, recovery from a total knee replacement, a common ortho-
pedic intervention in older individuals, requires recovery of bone
integrity, regrowth or possibly regeneration of muscle, reestablish-
ment of blood flow, and reintegration of movement patterns to
return to the mobility present prior to surgery. A failure of any of
these processes may compromise the resilience of the new joints
and the recipients.
Although some recent publications use only the term resilience,
not distinguishing between stress resistance and resilience (Hadley
et al., 2017; Kirkland et al., 2016; LeBrasseur, 2017), the distinction
can be important in the context of aging. The popular contemporary
term “healthspan” {Kirkland:2009 p886}, serves as a useful exam-
ple for illustrating this point in aging research. Healthspan is the
period spent free of chronic disease, while lifespan is the period
spent alive. Healthspan incorporates absence (in this case of dis-
ease) as does stress resistance (in this case of damage), whereas
resilience does not. The absence of damage from a stress (stress
resistance) may obviate the need for mechanisms to recover from a
stress (resilience). It is conceivable that stress resistance is impor-
tant earlier in life to prevent the onset of damage accumulation,
whereas resilience is more important later in life when cellular
compromises have already occurred. Even if stress resistance and
resilience share some cellular mechanisms, there is heuristic value
in considering them distinct.
3. Why physiology is important for understanding stress
resistance and resilience with aging
In The Way of the Investigator, the eminent physiologist Wal-
ter B. Cannon recalled his initial formulation of the flight or fight
response: “These changes—the more rapid pulse, the deeper breath-
ing, the increase of sugar in the blood, the secretion from the adrenal
glands—were very diverse and seemed unrelated. Then, one wakeful
night, after a considerable collection of these changes had been dis-
closed, the idea flashed through my mind that they could be nicely
integrated if conceived as bodily preparations for supreme effort in
flight or in fighting.” We use this example because it illustrates how a
physiological phenomenon could only be understood when diverse
and seemingly unrelated responses were considered as a whole.
More recently, Joyner and Dempsey discussed the importance of
understanding physiological redundancy to understand the posi-
tive effects of exercise, a notable physiological stress (Joyner and
Dempsey, 2017). If we insert the broad term “stress” in place of
“exercise” in the framework that Joyner and Dempsey provide, we
need to appreciate that: 1) stress is integrated and acted on at the
cellular, organ, system and organismal levels, 2) multiple redun-
dant mechanisms contribute to a stress response, and 3) responses
are often remote to the direct site of stress.
As stated in the opening of this Viewpoint, members of the
Geroscience Interest Group singled out “adaptation to stress” as
one of the seven pillars of aging research (Kennedy et al., 2014).
The word “adaptation” has differing meanings when considered in
a biological compared to a physiological context. In biology, the
word “adaptation” refers to a trait that evolves by natural selec-
tion, which is beyond the scope of this perspective. On the other
hand, physiological adaptation refers to the stereotypic series of
events in which a stress or disturbance to a system is detected by a
sensor, a response is initiated to minimize disturbance to homeo-
 B.F. Miller et al. / Ageing Research Reviews 38 (2017) 1–5
stasis, and further feedback occurs to maintain the appropriateness
of the initial response. In sum, the success of this feedback loop is
determined by maintained or even improved function.
Physiological redundancy, mediated by fundamental feedfor-
ward and feedback control mechanisms, influences assessment
and interpretation of stress resistance and resilience. For exam-
ple, acute glucose ingestion is a stress that is handled easily at
younger ages when the pancreas produces sufficient insulin and
multiple insulin-sensitive organs respond with increased glucose
uptake and decreased glucose production. As humans age, tissues
become resistant to insulin, representing a metabolic stress. How-
ever, for a period of time beyond the onset of this stress, glucose
regulation can be maintained by compensatory increases in insulin
secretion. At some point the increased resistance outpaces the
ability to increase insulin release, and overall glucose tolerance
decreases. Because of physiological redundancy, glucoregulation
can be maintained despite earlier failure of specific mechanisms
of stress resistance.
A recent article nicely summarizes the redundant factors that
determine the stress resistance/resilience of a cell (Smirnova et al.,
2015). When one considers the redundant systems within a cell, the
multiple cell types in a tissue, the many tissue types in an organ-
ism, and the regulatory systems that orchestrate the coordinated
responses of different tissues, understanding these redundancies
become exceedingly complex and daunting. To make sense of the
complexity reductionist approaches are often used. The reduction-
ist approach is invaluable for identifying mechanisms of adaptation
to stress in the cell (Alper et al., 2015; Pickering et al., 2015), and
much of what we know about cellular stress adaptation and aging
has come from the study of fibroblasts in vitro (see (Alper et al.,
2015) for a good summary). However, there are instances when
cellular stress resistance is not apparent in fibroblasts derived from
long-lived species (Harper et al., 2006; Page et al., 2014). What these
and other aging studies (e.g. (Chakkalakal et al., 2012)) illustrate is
that extracellular events can determine cellular fate and therefore
the complexity of redundant regulatory systems found in vivo need
to be considered.
As an example of in vivo complexity, consider the example of
oxidative stress. Studies of fibroblasts have used oxidative stress
induced by either direct H2 O2 application or through ROS gener-
ating treatments such as paraquat (e.g. (Harper et al., 2007; 2006;
Pickering et al., 2014; 2012)). In cultured fibroblasts it is possible to
determine the stress resistance to a lethal dose of ROS, and/or the
transcriptional program put in motion after a ROS stress. In vivo, the
situation is much more complicated as the stress originating from
the cell can have effects at the cellular, organ, system and organ-
ismal levels, and can also result in physiological compensation at
each level (Fig. 1). For example, a prolonged increase in oxidative
stress in a skeletal muscle may lead to a decrease in mitochondrial
function in the myofiber (cell), decreased muscle function/force
(organ), decreased vasodilatory capacity of the local vasculature
(system), and/or decreased ambulatory ability (whole organism).
In turn, these decrements can result in compensation or correction
by increased mitochondrial biogenesis (cell), increased endogenous
antioxidants (cell and organ), an increase in oxygen delivery (sys-
tem), and/or an increase in motor unit recruitment to maintain
muscle function (whole organism). It is very important to under-
stand the factors that determine resistance/resilience to cellular
ROS, but ultimately, it is the integrated systemic response and the
failure of the integrated systemic responses that determines resis-
tance/resilience to ROS in vivo. Therefore, although the reductionist
approach is and will continue to be a critical piece of the puzzle,
to make measurable progress toward designing strategies to slow
aging requires the addition of an integrative physiological view of
the basic biology (Joyner, 2015).
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3
4. Using early warning signs to prevent a tipping point in
stress resistance and resilience
In the article “Anticipating Critical Transitions” (Scheffer et al.,
2012), the authors make the argument that “tipping points” (note
the same terminology in the definition of stress resistance in Sec-
tion I) are critical points of unwanted collapse that are usually
unanticipated. The inability to forecast this collapse is usually due
to the difficulty in predicting complex systems. The authors provide
diverse examples from ecosystems, financial markets and climate.
Smirnova et al. recognize how the framework of Scheffer et al.
helps to understand cellular resilience (Smirnova et al., 2015). We
also recognize how the anticipating critical transitions may inform
future clinical studies that seek to slow aging through targeting
stress resistance or resilience. The question becomes how do we
anticipate tipping points in order to preserve human health?
One key to anticipating tipping points is to understand early
warning signs that predict future collapse so that adjustments can
be made to avoid that collapse. As Scheffer et al., explain, early
warning signs are often characterized by a slower rate of recov-
ery from a disturbance or by an increased variance in the response
to a repeated stimulus (Scheffer et al., 2012). Further, Smirnova
et al., provide a helpful framework from which we paraphrase
three important points for understanding a complex system: 1) a
dynamic system cannot be understood from a single observation,
2) there needs to be repeated measurements under different con-
ditions to provide a robust view of the system, and 3) the better
we understand normal states and earlier perturbations, the bet-
ter we know how to further monitor changes that predict failure
(Smirnova et al., 2015).
To provide an example, we discuss glycemic control. The fail-
ure of glycemic control leads to diabetes, and there are now
well-established clinical indicators of pre-diabetes. However, the
use of metformin in those without diabetes has been touted as
a potential treatment to slow the aging process (Barzilai et al.,
2016). Two potential scenarios could account for the positive
effects of metformin on the aging process, even in the absence of
diabetes – improvements to glucoregulation or previously unrecog-
nized pleiotropic effects that are independent of glycemic control.
Using newer technology like continuous glucose monitoring (CGM)
makes it possible to test whether improvements in glucoregulation,
which may not register as abnormal by established clinical test-
ing, contributes to the aging process by the framework proposed
by Smirnova et al. CGM can make measurements of blood glu-
cose at 5 min intervals for up to 10 days. This technology, therefore,
allows multiple observations, measurements under many condi-
tions (e.g. capturing fasted, fed, post-activity, nighttime, etc.), and
by monitoring prior to disease may provide insight into early warn-
ing signs. For example, Wijsman et al. used CGM to demonstrate
that in otherwise healthy older individuals, there is a greater vari-
ability in glucose concentration throughout the day as compared
to younger individuals, and that 24-h glucose concentrations are
lower in older individuals with a propensity for longevity compared
to age-matched controls with lesser longevity (Wijsman et al.,
2013). It is, therefore, possible that CGM could be used to monitor
the sluggishness or variability of glucose responsiveness to identify
if metformin is really having more subtle effects on glycemic control
then previously appreciated. Information from this approach could
then in turn be used to identify critical points of intervention for
slowed aging treatments. Further, since these measurements inte-
grate multiple levels of physiological control they provide insight
into early periods were redundant mechanisms begin to fail.
Better maintenance of integrative physiological homeostasis
during acute whole-body stress, as indicated, for example, by a
slower rate of rise in internal body temperature in response to
heating, likely represents another useful model of stress resistance
4 B.F. Miller et al. / Ageing Research Reviews 38 (2017) 1–5

Fig. 1. A given stress can alter function at many physiological levels (indicated with arrows). For example, in skeletal muscle prolonged ROS generation in excess of antioxidant
capacity can result in protein damage that decreases mitochondrial function. The resultant decrease in mitochondrial function may not be detectable because of multi-level
compensatory mechanisms (examples indicated in red text). It is only when multiple compensatory mechanisms fail that there is an apparent decrease in stress resistance
and/or resilience in skeletal muscle resulting from increased oxidative stress.

in humans. Finally, assessing the physiological responses to stren- References

uous large-muscle dynamic exercise will continue to serve as a
robust model for determining in vivo stress resistance using an
integrative physiological approach. Indeed, simple assessments of
maximal exercise capacity are strong predictors of risk of morbid-
ity, frailty, disability and mortality in middle-aged and older adults
(Joyner and Dempsey, 2017), and may therefore represent an easily
determined biomarker of resistance to stress. Although challeng-
ing, further studies should focus on the physiological adjustments
that maintain a set point during a physiological stress versus those
that facilitate recovery after failure to reestablish a set point.
5. Conclusion
Understanding stress resistance and resilience are likely to pro-
vide insight into slowing the aging process to increase healthspan.
We first emphasized that stress resistance and resilience are not
one in the same and that targeting one may not benefit the other.
We then recommended that in addition to the well-established and
insightful approaches at the cellular level, physiological approaches
should be used to increase applicability to humans given their
multiple integrated systems and biological redundancy. Although
designing studies to understand stress resistance and resilience
that consider multiple systems is daunting, we provided an exam-
ple of a framework that is used in unrelated fields for understanding
complex systems. One key aspect of this framework is to under-
stand early warning signs that are predictive of later failure to
intervene prior to reaching a tipping point. Fully understanding
these warning signs is likely only possible when considering in vivo
physiology because multiple and, often, remote systems can act
redundantly to resist change.
Acknowledgements
We thank Vienna Brunt for her assistance with manuscript
preparation.
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