Journal of Gerontology: BIOLOGICAL SCIENCES Copyright 2002 by The Gerontological Society of America

2002, Vol. 57A, No. 3, B115–B125

Dynamics of Stability: The Physiologic Basis of

Functional Health and Frailty
Lewis A. Lipsitz

Hebrew Rehabilitation Center for Aged, Beth Israel Deaconess Medical Center, and Harvard Medical School Division
on Aging, Boston, Massachusetts.

Under basal resting conditions most healthy physiologic systems demonstrate highly irregular,

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complex dynamics that represent interacting regulatory processes operating over multiple time
scales. These processes prime the organism for an adaptive response, making it ready and able
to react to sudden physiologic stresses. When the organism is perturbed or deviates from a given
set of boundary conditions, most physiologic systems evoke closed-loop responses that operate
over relatively short periods of time to restore the organism to equilibrium. This transiently al-
ters the dynamics to a less complex, dominant response mode, which is denoted “reactive tun-
ing.” Aging and disease are associated with a loss of complexity in resting dynamics and
maladaptive responses to perturbations. These alterations in the dynamics of physiologic sys-
tems lead to functional decline and frailty. Nonlinear mathematical techniques that quantify
physiologic dynamics may predict the onset of frailty, and interventions aimed toward restoring
healthy dynamics may prevent functional decline.

N ORMAL physiologic function requires the integration

of complex networks of control systems, feedback
loops, and other regulatory mechanisms to enable an organ-
ism to perform a variety of activities necessary for survival.
The control systems of the human body exist at molecular,
subcellular, cellular, organ, and systemic levels of organiza-
tion. Continuous interplay between the electrical, chemical,
and mechanical components of these systems ensures that
information is constantly exchanged, even as the organism
rests. These dynamic processes give rise to a highly adap-
tive, resilient organism that is primed and ready to respond
to internal and external perturbations.
Recognition of the dynamic nature of regulatory pro-
cesses challenges the prevailing view of homeostasis, which
asserts that all healthy cells, tissues, and organs maintain
static or steady-state conditions in their internal environ-
ment. However, with the development of instruments that
can acquire continuous data from physiologic processes
such as heart rate, blood pressure, balance control (center-
of-pressure displacements), nerve activity, or hormonal se-
cretion, it has become apparent that these systems are in
constant flux, even under so-called steady-state conditions.
Yates introduced the term homeodynamics (1), which con-
veys the notion that the high level of bodily control required
to survive depends on a dynamic interplay of multiple regu-
latory mechanisms rather than constancy in the internal en-
vironment.
Recently, there has been growing interest in the develop-
ment of new measures to describe the dynamics of physio-
logic systems, and use of these measures to distinguish
healthy function from disease, or to predict the onset of ad-
verse health-related events (2). A variety of measures have
been derived from chaos theory and the fields of nonlinear
dynamics and statistical physics. Many of these are based
on the concept of fractals.
The classic definition of a fractal, first described by Man-
delbrot (3), is a geometric object with “self-similarity” over
multiple measurement scales. For example, the ragged, ir-
regular appearance of a coastline or cloud looks similar
whether it is measured in inches, feet, or miles. In fact, the
smaller the measuring device, the larger the length of a frac-
tal object. This is a property known as power-law scaling.
The outputs of dynamic physiologic processes such as heart
rate, which are measured over time rather than space, also
have fractal properties (4). Their oscillations appear self-
similar when observed over seconds, minutes, hours, or
days. Furthermore, they demonstrate power-law scaling in
the sense that the smaller the frequency of oscillation of
these signals, the larger their amplitude (amplitude squared
is power). This power-law relation can also be expressed as
A  1/f , where A is the amplitude, f is the frequency, and 
is the scaling exponent (generally, 0    2).
Taking the log of each side of this equation yields a linear
relationship between amplitude and frequency, the slope of
which is the scaling exponent . Any process with 1/f or
power-law scaling is fractal-like. The scaling exponent (or
slope of the log–log relation) has been used to describe the
complexity of a process; one with long-range correlations
(self-similarity) across many decades in time or space is
considered maximally complex and has a scaling exponent
of 1. White noise or uncorrelated randomness lacks the
long-range correlations characterizing complexity and has
an exponent of 0. Brownian noise (a random walk process),
which has only local, short-term correlations between neigh-

B115
B116
boring points, has an exponent of 2. When applied to the
frequency spectra of continuous biological signals from
healthy subjects, such as heart rate (4,5), blood pressure (5),
electroencephalographic potentials (6), stride interval (7),
and center-of-pressure displacements (8) (Figure 1), this ap-
proach demonstrates complex fractal-like behavior.
One of the problems complicating the use and interpreta-
tion of dynamic measures is “noise” that is due to external
influences and trends in the data. Furthermore, fractal and
other nonlinear measures require long data sets that span
multiple decades in time, such as 24-hour cardiac record-
ings. During these long periods of data collection, subjects
are necessarily exposed to a number of different activity
states, circadian influences, or external stresses that produce
nonstationarities in the data. To eliminate these nonstation-
arities, a number of filtering techniques and detrending pro-
cedures are generally used. However, these procedures
potentially alter the underlying dynamics, and remove tran-
sients and trends in the data that may have physiologic sig-
nificance. This approach also fails to recognize that dynam-
ics of physiologic systems may change depending on
whether the subject is resting or is responding to a given
perturbation.
Under basal resting conditions, most healthy physiologic
systems demonstrate highly irregular, complex dynamics
that represent multiple interacting influences operating over
multiple time scales. Unlike classic fractal processes in
Figure 1. Center of pressure (COP) displacements (top graphs) and their corresponding log-transformed power specta (bottom graphs) for a
30-year-old healthy woman (left) and a 69-year-old woman with previous falls (right), obtained while the subjects stood on a force plate for 30
seconds. The slope of the regression line through the power spectra represents the scaling exponent , which is greater in the elderly faller than
in the young subject, indicating a loss of complexity.
LIPSITZ
physics in which the same mechanism is engaged over dif-
ferent scales, physiologic processes operate with different
mechanisms interacting over a variety of time scales. This
gives functionality to physiologic systems, enabling them to
respond on any scale necessary to adapt to internal or exter-
nal stresses. When the organism is suddenly perturbed or
deviates from a given set of boundary conditions, many
physiologic systems evoke single closed-loop mechanisms
that operate over relatively short time periods to restore the
organism to a new steady state that is appropriate for the
new set of conditions. The response itself may be periodic
with a single-frequency spectrum, rather than fractal with a
broadband spectrum and power-law scaling. However, when
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a new steady state is achieved, it again demonstrates com-
plex dynamics. The process by which physiologic systems
evoke single-frequency responses to return to a dynamic
steady state (or dynamic equilibrium) can be called reactive
tuning. Therefore, studies attempting to define healthy
physiologic function by the presence of long-range fractal-
like correlations have to distinguish between transient re-
sponse modes and long-term steady-state behavior. Further-
more, the dynamics observed under steady-state conditions
might be used to gauge the capacity of an organism to
mount an appropriate adaptive response when it is per-
turbed.
In this paper I suggest that dynamic, interacting networks
of regulatory systems are the structural and functional scaf-
 DYNAMICS OF HEALTH AND FRAILTY
folds for healthy physiologic function. I will provide evi-
dence for the degradation of these systems with age and dis-
ease and suggest that the loss of adaptive capacity that
ensues may characterize the onset of frailty. Finally, I will
conclude with recent preliminary evidence that age- or dis-
ease-related functional impairments may be reversible with
a number of interventions that restore the underlying dy-
namics.
DYNAMICS OF REST AND RESPONSE
Complexity Begets Functionality
How do we know that a mechanical system is working
properly? One indicator is the stability of its response to a
particular demand, within a given set of boundary condi-
tions. For example, we know the heating system in our home
is working when the internal temperature is stable within 1
or 2 degrees of its preset range. We know our automobile is
functioning properly if it moves steadily at a given speed to-
ward a destination without knocking, pinging, sputtering, or
stalling. Underlying the apparent stability of these common-
place mechanical systems is a complex dynamic; the feed-
back loop between the thermostat, furnace, and radiation
system in the home, or the interacting fuel, electrical, cool-
ing, and power transmission systems in the automobile.
In general, the more complex a system is (i.e., the more
interacting parts it has operating on different scales in time
or space), the greater its functionality (although too complex
a system may freeze up and lose functionality). The home
heating example above is functional only during the winter
months, and it can do nothing more than heat the house.
However, adding an air conditioning unit and appropriate
thermostat control will add year-round functionality. The
greater complexity of the automobile enables it to respond
to multiple road conditions from a parking lot to a highway.
The more complex automobiles of today add functions such
as cruise control, antilock brakes, 4-wheel drive, and trac-
tion control to enable them to adapt more effectively to a
variety of conditions.
Although the mechanical analogy is an oversimplifica-
tion, physiology can be similarly understood. Underlying
the relatively uniform homeostatic responses of living or-
ganisms to a variety of stimuli lies a complex dynamic that
creates functionality. Unlike mechanical systems that tend
to fail when they become too complex (e.g., computers
when too much software is installed), physiologic systems
are built in such a way that larger-scale components (e.g.,
skeletal, nervous, and circulatory systems) protect the finer-
scale parts (e.g., cells and organelles). In physiology, the
greater the complexity, the greater the range of adaptive re-
sponses. In support of this notion, I will briefly review the
origin of complex dynamics during resting steady-state con-
ditions in a variety of physiologic processes, and the differ-
ence between resting dynamics and the response to a pertur-
bation (reactive tuning).
Origin of Complex Dynamics in Physiology
Because of the ready availability of electrocardiographic
and blood pressure monitoring devices in medical practice,
cardiovascular dynamics are probably the most intensively
B117
studied in humans. The sympathetic and parasympathetic
limbs of the autonomic nervous system probably account
for most of the short-term (second-to-second) beat-to-beat
variability in heart rate and blood pressure. On longer time
scales of minutes to hours, hormonal and temperature influ-
ences may dominate, whereas over 24-hour periods, cir-
cadian rhythms exert their control. The importance of the
autonomic nervous system in beat-to-beat cardiovascular
variability is evident from pharmacologic blocking studies.
During blockade of the parasympathetic and sympathetic
nervous systems with atropine and propanolol, respectively,
beat-to-beat heart rate fluctuations disappear. Yamamoto
and colleagues have shown that vagal blockade with atro-
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pine decreases the fractal nature of heart rate variability (9),
whereas beta-adrenergic blockade with propanolol does not
(10). However, these authors comment that during beta
blockade, activity of the parasympathetic nervous system
alone is not sufficient to produce fractal-like 1/f scaling of
heart rate variability (9).
The maturation of sympathetic innervation to the heart
during the first month of life in neonatal swine provides an-
other example of the influence of the autonomic nervous
system on heart rate variability, and it supports the contribu-
tion of sympathetic innervation to heart rate complexity
(11). As sympathetic neurons from the right stellate gan-
glion sprout connections to the heart during this time period,
baby pigs develop increasing complexity in their heart rate
time series. When the stellate ganglion is denervated at
birth, the animals fail to develop the heart rate irregularity
that is characteristic of mature animals.
Similarly, the transplanted human heart has been shown
by Kresh and Izrailtyan to develop increasing complexity of
heart rate variability (measured by pointwise-correlation di-
mension analysis) following implantation (12). At implanta-
tion the donor heart manifests a metronome-like heart rate
that evolves in a nonmonotonic fashion, increasing by 100
days, decreasing transiently by 20–30 months, and then ris-
ing to its peak by 7–10 years after implantation. This “dy-
namic reorganization in the allograft rhythm-generating
system” probably represents the emergence of local intra-
cardiac control mechanisms, followed by systemic hor-
monal and neural inputs that evolve over the course of graft–
host adaptation.
The resting output of the brain’s motor control system is
an irregular, low-amplitude physiologic tremor. This proba-
bly arises from the rich interconnected network of neurons
arising from the motor cortex, basal ganglia, cerebellum,
and other structures. Using a network model of dopaminer-
gic innervation in the nigrostriatal pathway of the brain to
produce a time series characteristic of the normal aperiodic
physiologic tremor, Edwards and colleagues have shown
that parameter changes representing weakened synaptic
connections result in the emergence of a periodic tremor re-
sembling that of Parkinson’s disease (13). This loss of com-
plexity through “dynamic simplification,” as they call it, not
only suggests potential mechanisms underlying the complex
output of the motor control system but also demonstrates
how the loss of complex dynamics may be associated with
the development of disease.
Mathematical models based on nonlinear dynamics and
B118
chaos theory can be used to illustrate how different levels of
system inputs and different engagements of system compo-
nents can generate a variety of dynamic behaviors. As shown
in Figure 2, the logistic equation will generate different dy-
namic behaviors, progressing from periodic to chaotic, de-
pending on the initial value for parameter a. In similar fash-
ion, the behavior of a given biologic system might differ,
depending on the value of a particular input. For example,
Figure 2. Plots of the iteration of the logistic equation, xi  1  axi(1  xi), with different values for the coefficient a. Note how the dynamics
change depending on the value of a.
LIPSITZ
the output of the dopaminergic nigrostriatal system in the
brain that controls movement differs according to the rela-
tive concentration of dopamine. Normal concentrations of
dopamine produce smooth movements and an irregular, low-
amplitude physiologic resting tremor, whereas low concen-
trations produce stiff movements with a periodic, high-
amplitude Parkinsonian tremor. Excessive concentrations of
dopamine produce dystonic and dyskinetic motor activity.
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 DYNAMICS OF HEALTH AND FRAILTY B119

Reactive Tuning sympathetic activation and vasoconstriction, and prevents

An important premise underlying this paper is that the
complexity of physiologic control systems serves an impor-
tant purpose; that is, it enables the organism to mount a fo-
cused response on a number of different time scales in order to
return to a new steady state. In the field of nonequilibrium
statistical mechanics, the relationship between the correla-
tion properties of the fluctuations of a system and its relax-
ation to equilibrium can be described by the fluctuation–dis-
sipation theorem (14). Herein, I refer to the relation between
underlying complex fluctuations and the focused (less com-
plex) response to a perturbation as reactive tuning. In biol-
ogy and medicine, this concept is evident in a number of
blood pressure overshoots through sympathetic withdrawal
and vasodilation. This feedback mechanism keeps blood
pressure in the range necessary to ensure adequate organ per-
fusion. Many elderly subjects (Figure 3) have less complexity
of heart rate and blood pressure dynamics in the supine and
tilted positions (5). Moreover, they may fail to tune in on a
dominant frequency when tilted (15). In Figure 3, the hyper-
tensive elderly subject does not develop low-frequency
(baroreflex-mediated) systolic blood pressure oscillations
when tilted, and the subject also experiences orthostatic hy-
potension. Thus, an age- or disease-related loss of complexity
in resting dynamics may hinder reactive tuning and thereby

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disparate systems discussed in the paragraphs that follow.
As shown in Figure 3, the complex blood pressure dy-
namics of the supine resting state, represented by a broad
power spectrum, give rise to low-frequency “Mayer waves”
with a dominant frequency at approximately 0.1 Hz when a
healthy young subject is tilted upright to mimic standing.
This low-frequency blood pressure oscillation is thought to
result from baroreflex-mediated vasomotor activity that
counters the reduction in venous return to the heart through
lead to maladaptive responses to physiologic stresses. Further
research is needed to determine whether the absence of reac-
tive tuning predisposes to blood pressure destabilization or
other functional alterations in physiologic systems.
Notably, too great a low-frequency heart rate (16) or
blood pressure (17) response may also be destabilizing, re-
sulting in the development of vasovagal syncope during tilt.
This is consistent with the notion that the maximal response
is maladaptive if it is unable to restore the system to a dy-

Figure 3. Systolic blood pressure (SBP) power spectra and their corresponding time series (inserts) in the supine (top) and tilted (bottom) po-
sitions for a 34-year-old male subject (left) and a 64-year-old male subject (right). Note the marked increase in power at 0.1 Hz during tilt in the
young subject, and the absence of this response in the elderly subject. The elderly subject also has supine systolic hypertension and orthostatic
hypotension at the onset of tilt.
B120 LIPSITZ

namic steady state. In physical systems this type of response
may produce resonances or ringing phenomena that ulti-
mately cause the system to fail. For example, the collapse of
the Tacoma Narrows Bridge in 1940 presumably occurred
because wind blowing over its surface at the same fre-
quency as the natural frequency of the bridge generated
large-wave oscillations that grew until the structure failed.
In support of the preceding concepts, Butler and col-
leagues (18) found that orthostatic challenges (lower body
negative pressure and head-up tilt) increased the  coeffi-
cient (decreased the fractal dimension or complexity) of the
1/f heart rate spectrum in healthy young subjects. Those sub-
jects who experienced presyncope during orthostatic stress
trol systems to be altered during a given perturbation in or-
der to restore the system to a new steady state. In this case,
the response may not be predicable from the resting dynam-
ics of the system. The process of cerebral autoregulation
provides a good example of a physiologic process in which
the resting relationship between blood pressure and cerebral
blood flow is altered during acute hypotension, so that
abrupt changes in blood pressure do not threaten cerebral
blood flow. Using the transfer function between blood pres-
sure and cerebral blood flow velocity oscillations while sub-
jects rested in a sitting position, we were unable to predict
changes in cerebral blood flow from changes in blood pres-
sure that occurred when subjects suddenly stood up (19).

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had a significantly greater increase in  at the highest levels
of lower body negative pressure, indicating a greater loss of
complexity in heart rate variability. These data suggest that
the healthy heart rate response to tilt is associated with re-
duced complexity (i.e., reactive tuning), but in some individ-
uals with maximal responses the cardiovascular system is
unable to achieve a new steady state and syncope results.
If reactive tuning is operative, one would expect the rest-
ing, equilibrium relationship between two interacting con-
This is probably due to autoregulatory vasodilation of the
peripheral cerebral vasculature, which restores blood flow
in response to reduced perfusion pressure. The activation of
a focused adaptive mechanism to preserve cerebral blood
flow (cerebral autoregulation) in a healthy young subject is
evident in the dynamics of the blood flow velocity time se-
ries shown in Figure 4. Note how the dynamic response is
greatly damped in the elderly subjects with and without hy-
pertension.

Figure 4. Continuous blood pressure (top panels) and cerebral blood flow velocity waveforms during sitting, then after active standing (ar-
row) for a healthy young subject, normotensive elderly subject, and hypertensive elderly subject. Note the differences in cerebral blood flow dy-
namics in response to the blood pressure decline between young and elderly subjects. (Reprinted with permission from Ref. 51.)
 DYNAMICS OF HEALTH AND FRAILTY
The postural control system provides another example of
reactive tuning. Using a random walk model to analyze the
moment-to-moment changes in center-of-pressure (COP)
trajectories when healthy young subjects stood quietly on a
balance platform, Collins and De Luca (20) showed two
types of dynamic behavior: first, short-term open-loop ac-
tivity, in which short, rapid COP displacements (sway) have
a tendency to drift away from an equilibrium point, and
second, longer-term closed-loop activity, in which larger,
slower COP displacements that trend away from an equilib-
rium point tend to be followed by movements back toward
equilibrium. Thus, unbounded movements over short inter-
vals in distance or time give way to negatively (anti-) corre-
lated corrective movements once a given stimulus threshold
is exceeded.
The adaptive advantage of complex behavior is also evi-
dent in recent work on social networks. Several studies have
shown strong relationships between social integration and
mortality following myocardial infarction, functional recov-
ery from stroke, and the development of dementia (21,22).
These data lend further support to the notion that the under-
lying complexity of a system—in this case, an individual’s
social integration and connectedness—improves one’s abil-
ity to overcome severe illness.
Thus, complex network-like infrastructures that permit
dynamic interactions between individual components dur-
ing steady-state conditions appear to be associated with a
focused adaptive response at times of stress. This concept of
reactive tuning may explain a wide range of behaviors, such
as when a chaotic stock market makes a unidirectional cor-
rection in response to a change in interest rate or when birds
on differing flight paths flock together to migrate over long
distances (23). These observations highlight the importance
of distinguishing the complex nonlinear dynamics of the
basal state from the less complex, linear dynamics that arise
in response to a given stimulus. Furthermore, they suggest
the need for further research to determine whether complex
fractal-like structures and processes have evolved in bio-
logic systems to permit an efficient adaptive response that
can rapidly restore the organism to equilibrium during the
exigencies of everyday life.
ALTERATIONS IN AGING AND DISEASE: THE PATHWAY
TO FRAILTY
In a previous paper, Lipsitz and Goldberger (24) sug-
gested that normal human aging is associated with a loss of
complexity in a variety of fractal-like anatomic structures
and physiologic processes. This loss of complexity is mani-
fest in many ways. It can be quantified by a change in frac-
tal dimension (e.g., breakdown in bone trabecular architec-
ture or loss of 1/f scaling of cardiac interval time series),
narrowing of a frequency response (e.g., presbycusis), loss
of long-range correlations in time series data (e.g., cardiac
interval, blood pressure, or stride-length time series), in-
creased randomness or stochastic activity (e.g., cardiac in-
tervals or COP displacements), or greater periodicity (e.g.,
electroencephalogram slow waves).
For this discussion, it is important to recognize the differ-
ence between variability and complexity. As shown in Fig-
ure 5, a highly variable signal, such as a high-amplitude sine
B121
wave, is minimally complex and can be described mathe-
matically by a simple periodic function. In contrast, a highly
complex signal may have marked irregularity, but less vari-
ability (lower amplitude), requiring an aperiodic, nonlinear
function to describe it. Therefore, loss of amplitude (vari-
ability) of a periodic process such as melatonin (25) or thy-
roid-stimulating hormone secretion (26) that occurs with
aging should not be confused with a loss of complexity.
Furthermore, aging can be associated with a decrease in
complexity, but greater variability in physiologic systems.
The concept of reactive tuning suggests that a loss of com-
plexity during resting conditions impedes an individual’s
ability to mount a focused response during stress. This
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would result in greater variability of the response. In addi-
tion, complexity loss within elderly individuals could result
in increased variability of a given response between individ-
uals. Thus, compared with healthy young individuals,
healthy elderly people may look more alike under steady-
state conditions, but less alike when challenged by internal
or external perturbations.
Not only aging, but also disease results in a loss of com-
plexity (Table 1). The tremor of Parkinson’s disease,
Cheyne-Stokes respiration of heart failure, periodic breath-
ing of high-altitude sickness, electroencephalographic spike
waves of epilepsy, emotional cycling of manic-depressive
illness, periodic oscillations of leukocyte counts in leuke-
mia, and regular rhythm of ventricular tachycardia are com-
mon examples (4). Figure 1 shows the breakdown of fractal-
like 1/f scaling in the dynamics of COP displacements in an
elderly man with a history of falling. A loss of fractal orga-
nization has been shown to be a predictor of adverse out-
comes in a variety of physiologic systems, including cardiac
interval or stride-length time series (Table 2). Hormones
such as melatonin or insulin will not function normally un-
less secreted in a pulsatile fashion (25,27). Thus, normal
physiologic function appears to depend on complex under-
lying dynamics.
The unfortunate final common pathway of aging or mul-
tisystems disease is the loss of adaptive capacity and ulti-
mate decline in functional independence that characterizes
frailty. Figure 6 illustrates how a loss of complexity may
lead to frailty. In health, a rich, fractal-like network of mul-
tiple interacting biologic inputs results in a complex output,
characteristic of an organism with high functionality that
can readily adapt to the stresses of everyday life. As age or
disease reduce the number and connectedness of these in-
puts, the output signal is simplified, becoming less complex
and more periodic or random. Consequently, functional ca-
pacity is reduced. As system complexity falls further, func-
tional capacity ultimately crosses a frailty threshold, result-
ing in marked vulnerability to injury, disease, and finally
death. For this reason, frail elderly individuals are particu-
larly vulnerable to falls, confusion, incontinence, and func-
tional dependency when exposed to common environmen-
tal, pharmacologic, or emotional stresses.
Fortunately, there is considerable redundancy in many bi-
ologic systems in a healthy organism; for example, humans
have far more muscle mass, neuronal circuitry, renal neph-
rons, and hormonal stores than are needed to survive. This
physiologic reserve allows most individuals to compensate
B122
Figure 5. The difference between complexity and variability.
effectively for age- and disease-related changes. Because
the network structure of physiologic systems also enables
alternate pathways to be used to achieve the same functions,
physiologic changes that result from aging alone usually do
not have much impact on everyday life. Accordingly, other-
wise healthy individuals who suffer from a single organ in-
jury such as a stroke may regain functional capacity if other
neural components and their connections can compensate.
This forms the rationale for the restoration of health through
a variety of interventions that promote the development of
new network connections.
RESTORING HEALTHY DYNAMICS
There are at least three types of interventions that could
potentially restore healthy dynamics in biologic systems,
and thus improve functional health or prevent the onset of
frailty. These include the following: first, single interven-
tions such as exercise, medications, or hormones that have
multisystem effects; second, multifactorial interventions
that identify and treat different system-specific contributors
to disease and disability; and third, external control devices
and procedures that have direct effects on system dynamics.
Over the past decade, a number of studies have examined
the effects of a variety of these interventions on the dynam-
ics of different diseases and conditions.
Single Interventions
One of the most widely studied single interventions to
improve functional ability is exercise. Aerobic exercise
training for 6–9 months has been shown to restore heart rate
variability in older adults (38–40), while a 6-month home-
based program of strength and balance training reduced the
fluctuations in stride time dynamics associated with gait in-
stability (41). These studies reported measures of variabil-
ity, rather than complexity, leaving some uncertainty as to
whether exercise interventions indeed restore the complex
fractal-like dynamics that characterize healthy physiologic
functions. During acute treadmill exercise, the short-term
LIPSITZ
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correlation properties of heart rate dynamics are increased
(42), indicating they become less complex, as would be ex-
pected if reactive tuning were operative. It is not yet known
whether chronic exercise training has an effect on resting
heart rate dynamics.
Using the slope of the log-transformed cardiac interval
power spectrum (1/f slope) as well as a technique called de-
trended fluctuation analysis (32) that quantifies the short-
term (4–11 beats) correlation properties of the cardiac inter-
beat interval data, Lin and colleagues (43) showed that the
Table 1. Decreased Complexity in Disease
Disease (Ref.) Measure
Alzheimer’s (28) EEG correlation dimension is reduced
Emphysema (29) Reduced 1/f slope of size distribution of terminal
airspace clusters
Fibrillation
Ventricular (30) Reduced HR fractal scaling (1/f slope) and
long-range correlations (DFA)
Atrial (31) Increased RR regularity (ApEn) and decreased
long-range correlations (DFA)
CHF & CAD (32 & 33) Reduced HR fractal scaling (1/f ) and long-range
correlations (DFA)
Aging & Huntington’s (7) Loss of stride interval long-range correlations
(DFA)
Breast cancer (34) Fractal dimension of mammographic mass
Notes: CHF  congestive heart failure; CAD  coronary artery disease; 1/f 
the slope of the log-transformed power spectrum (see text); DFA  detrended
fluctuation analysis, a technique that quantifies the fractal-like correlation prop-
erties of time series data (32) by measuring the root-mean-square fluctuations of
the integrated and detrended data in observation windows of different sizes and
then plotting them against the size of the window on a log–log scale—the slope
of the regression line that relates log-fluctuation to log-window size quantifies
the complexity of the data (1  fractal, 0.5  random, 1.5  random walk);
ApEn  approximate entropy, a measure of regularity in time series data (50);
ApEn quantifies the (logarithmic) likelihood that a series of data points that are
a certain distance apart for a given number of observations remain within the
same distance on next incremental comparisons. EEG  electroencephalogram;
HR  heart rate; RR  cardiac interbeat interval.
 DYNAMICS OF HEALTH AND FRAILTY B123

Table 2. Long-Term Consequences of Complexity Loss

Authors (Ref.) Subjects Complex System Complex Measure Adverse Outcome

Ho and colleagues (35) 52 CHF pts  52 matched controls RR interval (2 ECG) DFA Mortality 1.9 y
Huikuri and colleagues (36) 347 random elders 65 y Heart rate (24 ECG) 1/f slope Mortality 10 y
Makikallio and colleagues (30) Case-control, post-MI
VF RR interval (24 ECG) DFA 1/f slope VF
Huikuri and colleagues (33) 446 MI pts w/decreased LV fxn RR interval (24 ECG) DFA Mortality 1.9 y
Makikallio and colleagues (37) 499 CHF pts w/EF 35% RR interval (24 ECG) DFA Mortality 1.8 y
Colantonio and colleagues (21) 87 elderly stroke survivors Psychosocial fxn Social network index Fxn loss, NH adm
Fratiglioni and colleagues (22) Pop. of 1203 elders 75 y Psychosocial fxn Social network Dementia

Notes: CHF  congestive heart failure; MI  myocardial infarction; VF  ventricular fibrillation; LV  left ventricular; EF  cardiac ejection fraction; pts 
patients; fxn  function; RR  cardiac interbeat interval; ECG  electrocardiogram; DFA  detrended fluctuation analysis; 1/f slope  slope of the log-transformed
power spectrum.

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beta-adrenergic blocker atenolol increased fractal-like heart
rate complexity in 10 patients with advanced congestive
heart failure over a 1- and 3-month treatment period. Unfor-
tunately, the study was not placebo controlled. Additional
research is needed to confirm this result and determine
whether an increase in complexity is associated with physi-
ologic and functional improvements in such patients.
Estrogen replacement therapy is another single interven-
tion with wide-ranging effects on urogenital health, bone
turnover, cardiovascular physiology, and neurocognitive
function. In addition to its well-known effects on improving
the structural integrity of osteoporotic bone, and thus reduc-
ing fractures, we have recently shown it to improve inte-
grated baroreflex regulation of vascular sympathetic out-
flow when given to postmenopausal women for 6 months
(44). The functional implications of this result are not yet
known.
Multifactorial Interventions
The traditional approach to human biology and medicine
is reductionistic, organizing bodies of knowledge into indi-
vidual organ systems (e.g., cardiology, nephrology, pul-
monology, etc.) and explaining health and disease as the ab-
sence or presence of specific abnormalities in these organs.
However, because the human body is a complex system, its
function in health and disease cannot be fully explained by
an understanding of its component parts. In recent years it
has become evident that most pathologic conditions are sys-

Figure 6. The physiologic basis of frailty. Multiple interacting physiologic inputs (top) produce highly irregular, complex dynamics (middle),
which impart a high level of functionality (bottom) on an organism. As the inputs and their connections degrade with age, the output signal be-
comes more regular and less complex, resulting in functional decline. Ultimately, with continued loss of physiologic complexity, function may
fall to the critical level below which an organism can no longer adapt to stress (the frailty threshold).
B124 LIPSITZ
temic illnesses, affecting a multitude of organ systems and
functional processes. Treatments that have an impact on
multiple components of an illness have been found to be
more effective than standard unidimensional approaches.
For example, multifactorial interventions have been shown
to be effective treatments for common geriatric syndromes
such as falls (45) or delirium (46), which are often due to in-
teracting abnormalities in multiple organ systems. The rec-
ognition that congestive heart failure is a systemic disease
characterized not only by a reduction in cardiac inotropy but
also by increased sympathetic nervous system activity, acti-
vation of the renin–angiotensin system, and skeletal muscle
dysfunction has led to more effective treatments with com-
binations of beta-blockers, angiotensin-converting enzyme
inhibitors, and exercise training. Similarly, refractory de-
pression is now being managed with combinations of anti-
depressants that affect multiple neurotransmitters, and dia-
betes is being effectively treated with pharmacologic agents
to improve insulin action as well as its release. Although to
my knowledge the effect of multifactorial interventions on
the dynamics of specific physiologic systems has yet to be
studied, these interventions apparently have favorable ef-
fects on the overall integrity and integration of multiple or-
gans and processes that are necessary for healthy physical
or cognitive function. As is characteristic of nonlinear sys-
tems, the whole is greater than the sum of its parts.
It is clear that future genomic therapies for disease and
disability will also require nonreductionistic, multifactorial
approaches. Although the correction of a single genetic de-
fect will be effective for certain conditions, the majority of
chronic diseases will require polygenic interventions that
correct not only individual gene products but also the spatial
and temporal characteristics that enable these products to
promote effective function of an entire organism.
External Dynamic Control Techniques
Insight into the role of nonlinear dynamics in healthy
physiology is leading to a variety of new approaches for the
treatment of disease that directly influence system dynamics.
Examples include the following: ameliorating decondition-
ing and muscle weakness by administering hormones in pul-
satile fashion, improving insulin action and glucose utiliza-
tion through oscillating insulin infusions (27), and increasing
blood oxygenation during artificial ventilation by varying
end-expiratory pressure with the addition of noise (47).
One area in which dynamic control processes are likely to
make important therapeutic contributions is in the preven-
tion and termination of cardiac arrhythmias. Garfinkel and
colleagues used nonlinear dynamics to stabilize drug-induced
irregular cardiac activity in a section of tissue from the in-
terventricular septum of the rabbit heart (48). By plotting
one interbeat interval versus the previous interbeat interval
of the normal cardiac rhythm, one can create a “first-return
map” that displays recurrent patterns of points representing
an underlying periodic fixed point. Using pacing procedures
to alter the interbeat intervals, or pharmacologic approaches
to change atrioventricular nodal conduction, one can perturb
the aperiodic activity of a cardiac arrhythmia and force it
into a stable rhythm (49). In the future, algorithms could be
built into external pacing devices to terminate arrhythmias
by exploiting their underlying nonlinear dynamics.
Acknowledgments
This work was supported by the Hebrew Rehabilitation Center for Aged
and Grants AG04390, AG08812, and AG05134 from the National Institute
on Aging. Dr. Lipsitz holds the Irving and Edyth S. Usen and Family Chair in
Geriatric Medicine at the Hebrew Rehabilitation Center for Aged. The author
is grateful to Dr. Yaneer Bar-Yam for his helpful comments and suggestions.
Address correspondence to Lewis A. Lipsitz, MD, Hebrew Rehabilita-
tion Center for Aged, 1200 Centre Street, Boston, MA 02131. E-mail:
Lipsitz@mail.hrca.harvard.edu
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Received October 1, 2001
Accepted November 12, 2001
Decision Editor: John A. Faulkner, PhD