Scand J Med Sci Sports 2010: 20: 4964

doi: 10.1111/j.1600-0838.2009.01084.x

& 2010 John Wiley & Sons A/S

Review

Role of the nervous system in sarcopenia and muscle atrophy with

aging: strength training as a countermeasure
P. Aagaard1, C. Suetta2, P. Caserotti1,4, S. P. Magnusson2,3, M. Kjr2
1

Institute of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark, 2Institute of Sports
Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark, 3Department of Physical Therapy, Centre of Healthy Aging,
Faculty of Health Sciences, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark, 4National Institute of Health,
Bethesda, Washington

Corresponding author: Professor Per Aagaard, PhD, Institute of Sports Science and Clinical Biomechanics, University of
Southern Denmark, Campusvej 55, DK-5230, Odense, Denmark. Tel: 145 6550 3876, Fax: 145 6550 3480, E-mail:
paagaard@health.sdu.dk
Accepted for publication 25 November 2009

Aging is characterized by loss of spinal motor neurons

(MNs) due to apoptosis, reduced insulin-like growth factor
I signaling, elevated amounts of circulating cytokines, and
increased cell oxidative stress. The age-related loss of spinal
MNs is paralleled by a reduction in muscle ber number and
size (sarcopenia), resulting in impaired mechanical muscle
performance that in turn leads to a reduced functional
capacity during everyday tasks. Concurrently, maximum
muscle strength, power, and rate of force development are
decreased with aging, even in highly trained master athletes.
The impairment in muscle mechanical function is accom-

panied and partly caused by an age-related loss in neuromuscular function that comprise changes in maximal MN
ring frequency, agonist muscle activation, antagonist muscle coactivation, force steadiness, and spinal inhibitory
circuitry. Strength training appears to elicit eective countermeasures in elderly individuals even at a very old age
(480 years) by evoking muscle hypertrophy along with
substantial changes in neuromuscular function, respectively.
Notably, the training-induced changes in muscle mass and
nervous system function leads to an improved functional
capacity during activities of daily living.

This article provides a review of the alteration in

neuromuscular organization and function induced by
aging, while addressing its relationship to muscle
atrophy and sarcopenia at old age. In addition, the
article discusses the use of strength training as a
countermeasure for regaining neuromuscular capacity and function in the aging individual. For the
interested reader, several informative review articles
have been published over the last decade that describe the remodeling in neural organization and its
coupling to muscle tissue maintenance with aging in
both human (Grounds 2002; Vandervoort 2002;
Enoka et al., 2003; Grounds et al., 2008) and experimental animal settings (Lu 1998; Tam & Gordon
2003a; Edstrom et al., 2007), respectively.

all, denervated muscle bers are reinnervated

through collateral sprouting of nearby surviving
motor axons or motor end plates, which results in
the formation of very large motor units (MUs)
(discussed in detail below). Consequently, force steadiness and ne motor control are impaired with
aging (Tracy & Enoka 2002), although this change
may relate most directly to age-associated changes in
the variability and common modulation of MU
discharge rate in both agonist and antagonist muscles
(for a detailed review on neural aspects related to
force steadiness and aging, see Enoka et al., 2003).
The age-related loss of spinal MNs leads to a
decline in muscle ber number and size (sarcopenia),
resulting in impaired mechanical muscle performance
(reduced maximal muscle strength, power, and rate
of force development [RFD]) that translates into a
reduced functional capacity during everyday tasks
(level walking, stair walking, rising from a chair).
Specically, muscle atrophy may be considered the
endpoint of dierent conditions such as sarcopenia,
cachexia, and pre-cachexia status. All three conditions are characterized by muscle atrophy (as well as
immobilization) but the underlying mechanisms are
likely, dierent although, aging is often common to

Neuromuscular changes with aging

Aging is characterized by a gradual loss of spinal
motor neurons (MNs) due to apoptosis, reduced
insulin-like growth factor I (IGF-1) signaling, elevated amounts of circulating cytokines [tumor necrosis factor (TNF)-a, TNF-b, interleukin (IL)-6] as
well as increased cell oxidative stress. Some, but not

49

Aagaard et al.
all of them. Aging is accompanied by a substantial
reorganization in the neuromuscular system and the
CNS, which contributes to the loss in motor performance.
As discussed in more detail below, age-related
alterations in neural function can be identied both
at the peripheral level (axons, motor end plates) as
well as at spinal and supraspinal levels. Specically,
experimental evidence of neuromuscular remodeling
at old age include reports of very large MUs based on
macro-electromyography (EMG) recording (Stalberg
& Fawcett 1982; De Koning et al., 1988; Stalberg
et al., 1989; Masakado et al., 1994) and ndings of
ber-type grouping obtained by muscle biopsy sampling (Lexell & Downham 1991; Andersen 2003).
Further, old subjects show compressed rate coding
during graded muscle contraction compared with
young individuals (Barry et al., 2007), while resting
H-reex excitability (Hmax/Mmax) appears to be reduced in elderly individuals (Scaglioni et al., 2002)
indicating elevated presynaptic inhibition of Ia aerents (Morita et al., 1995) and/or reduced MN excitability in the resting condition. Reduced levels of
central activation (CA) (for a review, see Klass et al.,
2007) and elevated levels of antagonist muscle coactivation during MVC (Hakkinen et al., 1998a, 2000;
Izquierdo et al., 1999; Macaluso et al., 2002) and in
postural stability tasks (Earles et al., 2000) can be
observed in some (but not all) elderly individuals. In
addition, aging is accompanied by cortical reorganization (Ward & Frackowiak 2003; Ward et al., 2008)
and ndings of reduced TMS-evoked motor poten-

tials suggest that the excitability of eerent corticospinal pathways is reduced at old age (Eisen et al.,
1991; Sale & Semmler 2005).

Spinal MNs and MUs

Electron micrographs obtained in peripheral nerves
of aging experimental animals (old rats) show connective tissue inltration along with decreased myelination and reduced axon density (for a review, see
Edstrom et al., 2007). In human autopsy studies,
aging has been accompanied by a reduced number
and diameter of myelinated MN axons in the ventral
roots, with an accelerated loss of large-diameter
axons (Kawamura et al., 1977a, b; Mittal & Logmani
1987) (Fig. 1). In addition, axonal conduction speed
is reduced with aging, likely due to drop outs of the
largest axonal bers, reduced myelination, and reduced internodal length (Doherty et al., 1993; Metter
et al., 1998; Scaglioni et al., 2002). Findings of
increased H-reex latency in elderly subjects (Scaglioni et al., 2002; Kido et al., 2004) further supports
that peripheral nerve conduction speed is reduced at
old age. The nding that latency of the direct M wave
(5.18 vs 5.19 ms) did not dier between old (68 years)
and young (29 years) subjects despite an elongated
soleus (SOL) H-reex latency (33.24 vs 29.85 ms)
suggests that aging may aect sensory aerent axons
and/or synapses more severely than eerent motor
axons (Scaglioni et al., 2002). However, both sensory
axons and motor axons may demonstrate degenera-

Total number of fibers

5000

Total number of
axonal fibers

4500
4000
3500
3000
2500

young male subject (28 yrs)

20

40
60
Age (years)

80

100

Fig. 1. Total number of axonal bers (top right panel) and number of
large diameter axons (diameter
 12.5 mm, bottom right panel) in
right cervical ventral nerve root bers (C8) of young and old humans
(n 5 10, 2194 years). Inserted pictures show nerve electron micrographs obtained in young (top left)
and old subjects (bottom left) (from
Mittal & Logmani 1987).

50

Fibers 12.5 in diameter

3000
Axonal fibers 12.5 m
diameter

2500
2000
1500
1000
500

Old male subject (83 yrs)

0

20

40
60
Age (years)

80

100

Neural changes with aging and training

subjects (82 years, range 8089) (McNeil et al., 2005)
(Fig. 2, top panel). Notably, maximal isometric
muscle strength did not dier between young and
old individuals but was reduced in very old subjects
(Fig. 2, bottom panel) possibly due to the maintenance of muscle bers (muscle mass) through the
process of collateral reinnervation in the early stages
of MU loss (McNeil et al., 2005). It was suggested
that the progressive loss of MUs with aging might
not lead to functional impairments until a certain
critical threshold is reached. For the TA muscle this
critical threshold appears to be encountered between
70 and 80 years of age where the number of MUs is
about 50% of that found in young, healthy individuals (Fig. 2) (McNeil et al., 2005). The loss in MU
number with aging probably is both muscle specic

Estimated number of MU's

200

150

100

50

Young
(27 yrs)

Old
(66 yrs)

Very Old
(82 yrs)

Young
(27 yrs)

Old
(66 yrs)

Very Old
(82 yrs)

60

50
Dorsiflexor MVC (Nm)

tive changes with aging (Adinol et al., 1991; Lascelles & Thomas 1966).
At the MU level, animal data have demonstrated a
3040% decline in the number of MUs when adult
and old animals were compared (Edstrom & Larsson
1987; Einsiedel & Lu 1992). Likewise, a reduced
number of spinal MNs have been observed in aging
humans, where a 25% average loss in the number of
spinal MNs were seen at lumbospinal segments L1S3 over the age range from 20 to 90 years, with
several subjects of 601 years age demonstrating 50%
fewer MNs compared with 2040-year-old subjects
(Tomlinson & Irving 1977).
Analysis of the composite surface EMG signal
during isometric force ramps of varying contraction
intensity using spike-triggered averaging techniques
or incremental peripheral nerve stimulation have
been used in humans to estimate the number of
functioning MUs across the age span (McNeil
et al., 2005; Dalton et al., 2008). It should be
recognized, however, that the electrophysiological
methods used to estimate the number of functioning
MUs produce results that are highly dependent on
the specic experimental conditions. Thus, motor
unit number estimates (MUNE) varies substantially
when assessed at low vs high contraction intensities,
because high-intensity contractions may preferentially sample large MUs resulting in a smaller
MUNE, whereas low-intensity contraction will
mainly involve smaller MUs to yield a larger
MUNE (Dalton et al., 2008). Consequently, the use
of MUNE techniques to compare MU number in
young and old individuals is only valid if the methodological limitations apply equally to the two age
groups, which may not always be the case.
Early studies have suggested that a marked reduction in the number of excitable (i.e. functioning)
MUs may occur from 60 to 70 years of age (Campbell et al., 1973; Brown et al., 1988; Doherty et al.,
1993). For instance, in 6096-year-old individuals the
estimated number of MUs in selected lower extremity
muscles (extensor digitorum brevis) corresponded to
about 30% of the number observed in younger
individuals (360 years) (Campbell et al., 1973)
(Fig. 3). Similar observations have been reported in
animal models, where the number of spinal MNs in
lower limb muscles decreased at an accelerated rate
during the nal 1/3 of the life span (Kanda et al.,
1996) [cf. Fig. (3b)]. In humans, a reduced number of
MUs were observed also for selected upper extremity
muscles at increasing age (Brown 1972; Sica et al.,
1974; Brown et al., 1988; Doherty & Brown 1993;
Galea 1996). More recently, Rice and colleagues
observed a 39% decrease in the number of MUs in
the TA muscle of old (66 years, range 6169) compared with young individuals (27 years, range 2332)
along with an even greater decline (61%) in very old

40

30

20

10

Fig. 2. Estimated number of functioning motor units (MUs)

in the anterior tibial (TA) muscle (top panel) and maximal
isometric TA muscle strength (MVC; bottom panel) obtained in young (27 years, range 2332), old (66 years, range
6169) and very old subjects (82 years, range 8089) (data
from McNeil et al., 2005).

51

Aagaard et al.
and age-threshold dependent. Thus, estimated MU
number in the SOL muscle did not dier statistically
between old (  75 years) and young (  27years)
males (Dalton et al., 2008). In contrast, the estimated
number of SOL MUs was higher in young-to-middleaged persons (550 years) compared with very old
individuals (90 years) (Vandervoort & McComas
1986). These data suggest that in aging humans the
accelerated decline in MU number may occur at a
slightly older age for the SOL than for the TA muscle
(Dalton et al., 2008). It is possible that this disparity
is related to muscle-specic dierences in muscle
ber-type composition and/or reects long-term
adaptation to a preferential muscle activity pattern
during gait at old age (e.g. greater relative reliance on
ankle plantar exor function), although possibly also
arising as a result of the methodological constraints
discussed above.
Influence of IGF-1 on MNs and axons
The endocrine and paracrine production of IGF-1 is
reduced in elderly individuals, which may bear signicant implications for the prevention as well as the
adaptive compensation for the loss of spinal MNs
with aging. IGF-1 has potent eects on motor axon
myelination, MN apoptosis, stimulation of axonal
sprouting, and repair of damaged axons (for a review, see Grounds 2002). However, it remains to be
determined to which extent local (paracrine) muscle
IGF-1 isoforms produced by myobers and/or ECM
broblasts directly helps to maintain spinal MN
integrity and function in aging human individuals
(Grounds 2002). Elevated levels of inammatory
cytokines TNF-a and TNF-b, which is typically
observed in old individuals, can blunt the IGF1-mediated eects in muscle tissue (Grounds et al.,
2008) and might have similar eects in MNs and
axons. In addition, cytokines such as IL-6 and IL-1
may further accelerate the loss in muscle mass
(sarcopenia) at advancing age.
Animal experiments studying MN disease have
shown that IGF-1 facilitates collateral sprouting of
surviving axons to innervate denervated muscle bers, and reinnervation of muscle bers via axonal
sprouting can compensate for the loss of MNs until
approximately 50% of the MNs have died (Hantai
et al., 1995). Interestingly, these animal data may
explain why maximal muscle strength (MVC) was
similar in young and old humans despite a  40%
reduction in MU number whereas a  60% reduction in MU number in very old subjects was accompanied by substantial impairments in MVC (Fig. 2).
This suggests that a critical threshold of 50% loss in
MU number may exists for a maintained capacity for
reinnervation of abandoned muscle bers by means
of axonal sprouting (McNeil et al., 2005). Conse-

52

quently, when axonal sprouting becomes inadequate

or absent at old age (discussed below), the gradual
loss of MUs results in a substantial loss of muscle
bers that produce marked decreases in muscle mass
and strength, eventually leading to functional disability (McNeil et al., 2005).
Loss of synaptic MN input, axonal degeneration
In rodents the age-related loss in MNs seems to be
small (1015%) even in advanced age. However,
aging MNs show changes (increases or reductions)
in dendritic tree size and decreased synaptic input,
which appears to divide the MN population in one
part that is extensively aected and a subpopulation
of more preserved MNs (for a review of the animal
model, see Edstrom et al., 2007). As suggested by
Edstrom et al. (2007) the loss of synaptic input in
terms of stripping of aerent boutons from spinal
MNs seems to be highly selective and is associated
with signs of neuroaxonal degeneration. An eect of
reactive oxygen species have been implicated as
axons and axon terminals with signs of neurodegeneration and/or neuroaxonal dystrophy have been
observed to contain increased levels of total glutathione indicating redox stress (Ramirez-Leon
et al., 1999). Further, it has been suggested that
axon impairment during aging may start as a distal
process (cf. neuroaxonal dystrophy), causing a partial denervation of myobers within a MU while
intact axon branches strive to reinnervate surrounding denervated bers (Edstrom et al., 2007). At old
age the process of axonal reinnervation appears to be
impaired, which is likely to contribute to the reduced
regenerative capacity of myobers observed in sarcopenic muscle (discussed below).
Animal studies have shown that age-related axon
lesions are more frequent in ventral roots and peripheral nerves of the lumbar spinal cord compared
with the cervical region (Johnson et al., 1995),
suggesting that lower limb muscles may be more
severely aected by age-related deinervation than
upper limb muscles. In support of this notion, a
reduced number of MNs was observed in aged rats
for the hind limb medial gastrocnemius (MG) muscle, whereas the number of MNs innervating the
forelimbs did not dier between middle-aged and
old rats (Hashizume & Kanda 1995) [Fig. 3(a)].
These ndings are in accordance with the observation in humans that aging is accompanied by a
reduced number of muscle bers in the lower limb
(m. quadriceps femoris; Lexell et al., 1988) [Fig. 4b)]
while the estimated number of myobers may remain
largely unaected by aging in selected arm muscles
(m. biceps brachii) (Klein et al., 2003).
Data obtained in animal models suggest that
although skeletal muscles show loss of bers and

Neural changes with aging and training

(a)

(a)

Number of motorneurons
MG

Ulnar

310

140

300

130

290

**
280

120

60-yr old woman

270
110

(b) 1000
Total number of fibres (x1000)

260
250

100

aged

Middle-aged

(b)
Number of motorneurones

80-yr old woman

140
130
120

900
800
700
600
500
400
300
200
100
0

110

10

20

30

40

50

60

70

80

90

Age (years)
100
0

10

15

20

25

30

35

Age (Months)

Fig. 3. (a) Number of spinal medial gastrocnemius (MG)

and ulnar motorneurones (MNs) measured in middle-aged
and old rats. Old rats demonstrated fewer MG MNs whereas
the number of ulnar MNs did not dier between middleaged and old rats (data from Hashizume & Kanda 1995). (b)
Number of MG MNs innervating the lower leg in rats of
varying age. The number of spinal MG MNs was signicantly reduced in animals aged 28 and 30 months compared
with 17-month-old animals (data from Kanda et al., 1996).
Open circles refer to data obtained in previous experiments
from the same research group (see Kanda et al., 1996). Error
bars: group mean SD.

ber atrophy in advanced age (discussed in detail

below), concurrent signs of muscle regeneration
can be observed where some markers of regeneration
are found to change in parallel with the loss in muscle
mass. Notably, sarcopenic muscle may not per se
be in a state of poor adaptive responsiveness, rather
an impaired capacity for axonal reinnervation of
deinnervated myobers may contribute to the net
loss of muscle mass with advancing age (discussed
below).
Reinnervation of muscle fibers by axonal sprouting
Perisynaptic Schwann cells at the neuromuscular
junction extend processes that bridge between denervated and reinnervated endplates, and guide axonal
sprouts to reinnervate the denervated endplates (for a
review, see Tam & Gordon 2003a). Observations in

Fig. 4. The eect of aging on anatomical muscle size and

muscle ber number. Aging is characterized by a decrease in
anatomical muscle cross-sectional area (CSA) and inltration of non-contractile tissue such as collagen and fat (a)
(Caserotti et al., 2008a, b). In addition, the number of muscle
bers is reduced with aging as indicated by autopsy studies
(b) (m. quadriceps femoris; data from Lexell et al., 1988).

aged animal muscle suggest that the capacity for

axonal and endplate sprouting is relatively limited
(see Lu 1998). Thus, motor endplate sprouting was
reduced in the EDL muscle of aged rats in response
to partial denervation, suggesting that in highly aged
animals nerve terminals and axons may approach
their maximal capacity for sprouting (Rosenheimer
1990). Interestingly, in extensively denervated rat
muscle the production of perisynaptic Schwann cell
processes was inhibited and axonal sprouting was
impaired or fully abolished in situations of high
neuromuscular activity such as extensive running
exercise (Tam & Gordon 2003b). In a rat model of
partial TA denervation, high levels of daily neuromuscular activity (running exercise 8 h daily) was
shown to inhibit the outgrowth of sprouts by preventing Schwann cell bridging (Tam & Gordon
2003b). It was therefore suggested that with very
high daily neuromuscular activity, the large levels of
acetylcholine released from intact endplate terminals
could suppress glial brillary acidic protein synthesis
in perisynaptic Schwann cells leading to impaired
axonal growth between innervated and denervated
terminals (Tam & Gordon 2003b). Similarly to aging,
neuromuscular inactivity also seems to produce in-

53

Aagaard et al.
hibition of axonal sprouting in partially denervated
muscle, likely due to failure of perisynaptic Schwann
cell processes to bridge and guide axonal sprouts to
reinnervate denervated endplates, and/or caused by a
reduced calcium inux into nerve terminals to support sprout growth (see Tam & Gordon 2003a).
Thus, it is possible that both chronic inactivity and
neuromuscular hyperactivity (i.e. excessive endurance training) may decrease muscle ber reinnervation in elderly individuals. These ndings coupled
with the acute rise in myobrillar protein synthesis
rate with electrical stimulation mimicking strength
training but not endurance training suggest that
resistance rather than endurance exercise (Atherton
et al., 2005) may be the preferred training modality
for sarcopenic elderly individuals.
In summary, normal aging appears to be characterized by a temporal progression of MU loss
accompanied by adaptive axonal sprouting, which
is gradually replaced by maladaptive peripheral
sprouting. In turn, the gradual impairment in axonal
sprouting capacity at old age results in a progressive
loss of motor endplate terminals, which initiates an
accelerated loss of muscle bers.
Spinal circuitry function
In humans the eect of aging on spinal circuitry
function has been examined by recording of evoked
spinal responses (H-reex) at rest and in various
contraction tasks. Old subjects demonstrate reduced
H-reex responses compared with younger individuals when recorded at rest (Morita et al., 1995;
Scaglioni et al., 2002), during quiet standing (Koceja
et al., 1995; Earles et al., 2000; Koceja & Mynark
2000; Kido et al., 2004), in walking (Kido et al., 2004)
as well as during more complex postural tasks (Earles

54

Effects of physical activity on the age-related loss of MNs

A relevant question is whether the age-related reduction in the number of spinal MNs and peripheral
motor axons is preventable by training or regular
physical exercise? As discussed below, the answer
seems to be a strict no. On the other hand, certain
types of exercise (i.e. strength training) can evoke
adaptive changes in muscle and CNS function that to
a large extent can compensate for the age-induced
loss of MNs (discussed below).
In animal models increased muscle loading activity
have not prevented the loss in spinal MN number
with aging, at least when increased muscle loading
was achieved by synergist muscle ablation (Kanda
et al., 1996) [Fig. 3(b)]. Likewise, soma size of both

(b)

15
H
M

Hmax / Mmax (mV)

(a)
Hmax or Mmax (mV)

Fig. 5. Changes in H-reex excitability with aging. (a) Soleus Hmax

and Mmax amplitudes measured
during quiet standing with a soleus
electromyography level of 15%
MVC. Note the decline in Hmax
and Mmax with increasing age
(Mmax
r 5  0.62,
Hmax
r 5  0.76; Po0.05). (b) Hmax/
Mmax ratio showing a signicant
decrease with aging (r 5  0.79;
Po0.01) (graphs from Kido et al.,
2004).

et al., 2000), collectively suggesting that aging may be

accompanied by reduced spinal MN excitability and/
or increased presynaptic and/or postsynaptic spinal
inhibition (Fig. 5). Alternatively, the observed
changes in H-reex amplitude with aging could arise
from systematic changes in the MH recruitment
curve hence potentially reecting changes in the
recruitment of Ia aerents with this experimental
technique. Therefore, ndings of age-related alterations in the ability to modulate the H-reex response
during specic motor tasks (isometric contraction,
walking) relative to a reference condition (i.e. sitting
rest) may provide a more reliable picture of the
change in spinal circuitry function with aging. Using
this analytical approach, reduced spinal reciprocal
inhibition was observed in old individuals during
quiet standing and walking (Kido et al., 2004)
(Fig. 6), which indicates that human aging involves
a remodeling in spinal circuitry function, at least for
MNs innervating muscles of the lower limb.

10

0
20

40
60
Age (years)

80

1.0
0.8
0.6
0.4
0.2
0
20

40
60
Age (years)

80

Neural changes with aging and training

Soleus

(a)

Tibialis anterior

CP Nerve stimulation (1.5 x MT)

(b)

1.0
standing
walking

0.6
r = 0.57
0.4
0.2

0.8
Inhibition

Inhibition

0.8

0
20

Tibial Nerve stimulation (1.5 x MT)

1.0

0.6

r = 0.75

0.4
r = 0.47

0.2
r = 0.61
40
60
Age (years)

80

0
20

40
60
Age (years)

80

Fig. 6. Reciprocal inhibition of ongoing electromyography (EMG) activity elicited by antagonist muscle nerve stimulation (1.5
times motor threshold). (a) Reciprocal inhibition of soleus EMG activity during standing and walking. Inhibition calculated as
the dierence between the mean rectied EMG of a selected 10-ms window and background EMG, normalized by the
background EMG and averaged for a background EMG level of 2060% MVC. Reciprocal inhibition of the SOL muscle
declined with aging (standing: r 5  0.57, walking: r 5  0.61; Po0.05). (b) Reciprocal inhibition of TA EMG activity,
normalized and averaged for the background EMG level of 1050% MVC. Reciprocal inhibition of the TA muscle declined
with aging (standing: r 5  0.47, walking: r 5  0.75; Po0.05) (graphs from Kido et al., 2004).

a-MNs and g-MNs remained unaected by increased

muscle loading, suggesting that the benecial eects
of elevated loading activity might be canceled by
concurrent detrimental eects (Kanda et al., 1996).
Data exist to suggest that neuronal survival may, at
least partly, depend on the supply of trophic substance from the CNS (i.e. nerve growth factor) and/or
target organ (Kromer 1987). Uptake and transport of
trophic substance might depend on neuronal activity
(Heuser & Reese 1973), and it is possible that
increased muscle activity augments the supply of
trophic substances that are transported retrogradely
either from distal axon sites or the target motor
endplate and/or orthogradely through presynaptic
neurons (Kanda et al., 1996). Thus, elevated neuromuscular activity (i.e. exercise) may lengthen the life
span of neurons, while in contrast the increase in
cellular metabolism may increase the formation of
free radicals, which may damage various cell functions and eventually cause cell death (Kanda et al.,
1996). This tentative hypothesis is supported by the
nding that reinnervation of denervated muscle bers
by means of collateral axonal sprouting was impaired
not only in conditions of chronic inactivity but also
with neuromuscular hyperactivity as discussed above.
Changes in muscle mass with aging (sarcopenia)
Aging is associated with a loss in muscle mass that
results from a reduced number of muscle bers [Fig.
(4b)] and atrophy of remaining muscle bers that is
accompanied by an increased inltration of noncontractile tissue (collagen, fat) [Fig. 4(a)]. For
some muscles the reduction in muscle ber number
may start at a relatively early age (rectus abdominis

muscle) (Inokuchi et al., 1975) whereas for other

muscles the decline seems to accelerate from the sixth
decade (Lexell et al., 1983, 1988) [Fig. 4(b)]. Single
muscle ber atrophy is observed at old age, where the
type II muscle bers are more aected than type I
bers (2560% vs 025% reduced single ber CSA)
(Larsson et al., 1978; Klitgaard et al., 1990; Fiatarone Singh et al., 1999; Andersen 2003; Kosek et al.,
2006) although reports of similar decrements in types
I and II area also exist (Essen-Gustavsson & Borges
1986). At least, in part, the muscle ber atrophy is
caused by a reduced rate of myobrillar muscle
protein synthesis at old age (Balagopal et al., 1997;
Welle & Thornton 1997).
Although not a universal nding (Hikida et al.,
1998; Roth et al., 2000; Carlson et al., 2009), old
individuals may show reduced amounts of myogenic
satellite cells (Kadi et al., 2004; Sajko et al., 2004)
that could contribute to the age-related loss in muscle
ber size. Regardless, load-mediated satellite cell
activation has been reported to be reduced in aged
compared with young rats (Gallegly et al., 2004).
Similar results recently were obtained in aging individuals who showed impaired myogenic satellite
cell activation due to diminished Notch signaling in
response to short-term (14-day) lower limb immobilization followed by a period of strength training
(Carlson et al., 2009).
In animal models (rat) the muscle atrophy observed during aging may not involve upregulation of
enzymes involved in cellular protein degradation via
the ubiquitin proteasome pathway (Edstrom et al.,
2007). The same authors also showed that MuRFbx
and Atrogin-1, which drive ubiquitin proteasomemediated myobrillar proteolysis, are downregulated

55

Aagaard et al.
in aged sarcopenic muscle, suggesting that the agerelated sarcopenia may dier from the muscle atrophy occurring in disease or disuse (Edstrom et al.,
2006). In contrast, elevated MuRF-1 and Atrogin-1
mRNA levels were observed in very old animals
(Clavel et al., 2006). MuRF-1 but not Atrogin-1
were elevated in very old humans (85 years) (Raue
et al., 2007) and did not dier between less old (72
years) and young individuals (Whitman et al., 2005).
Collectively, these data suggest that the age-related
sarcopenia may dier from the muscle atrophy
associated with disease or disuse, at least below a
certain age (in humans  80 years).

Changes in muscle mechanical function with aging

The impairment in neuromuscular function and the
loss of skeletal muscle mass associated with aging
have signicant consequences for mechanical muscle
function. Thus, marked decreases in maximum muscle strength, power, and RFD (measured as the rate
of force rise: DF/Dt) are observed with aging (Skelton
et al., 1994; Izquierdo et al., 1999; McNeil et al.,
2007; Caserotti et al., 2008b), even when chronically
strength-trained elderly individuals are compared
across the age range (Pearson et al., 2002). The loss
in muscle mass [i.e. Fig. 4(a)] and the resulting
reduction in mechanical muscle output leads to a
loss in function (Janssen et al., 2002; Buchman et al.,
2007) during typical activities of daily living such as
rising from a chair, stair walking, and in postural
balance control (Tinetti et al., 1988; Bassey et al.,
1992; Skelton et al., 1994; Izquierdo et al., 1999;
Foldvari et al., 2000). In further support of a close
linkage between mechanical muscle function and
functional capacity in the elderly, parallel and interrelated gains in functional performance and maximal
muscle strength/power/RFD have been observed
following strength training in old individuals (Fiatarone et al., 1994; Chandler et al., 1998; Suetta et al.,
2004a; Caserotti et al., 2008a, b).
The capacity for rapid muscle force production
can be evaluated by analysis of the contractile RFD
(Aagaard et al., 2002, 2007). RFD is markedly
reduced with aging, both when expressed in absolute
terms or when normalized to body mass, respectively
(Izquierdo et al., 1999; Barry et al., 2005; Klass et al.,
2008). Notably, relative RFD (absolute RFD normalized to maximal isometric or dynamic strength
capacity) also appears to be reduced with increased
age (Izquierdo et al., 1999; Klass et al., 2008),
suggesting that aging involves qualitative changes
in skeletal muscles and/or in the neuronal system.
Similar to muscle power, maximal RFD appears to
decline with age even in highly sprint-/strengthtrained individuals (Korhonen et al., 2006). Despite

56

this decline, however, aged sprinters demonstrated

markedly higher RFD than age-matched untrained
elderly individuals.

Effects of strength training in the elderly

Physical exercise contains many dierent components that can be used to stimulate aerobic tness,
muscle strength and power, muscle mass, ne motor
control, etc. Exercise may be characterized as endurance (aerobic), or resistance (strength) training, or a
mix thereof. Endurance training consists of repeated
low-force contractions with low-frequency muscle
ber activation patterns performed for a prolonged
period (420 min). In contrast, strength training exercise involves relatively few high-force contractions
with high-frequency muscle ber activation pattern
applied intermittently (o24 min of total work per
muscle group). Although the relative importance of
these exercise components has not been examined in
depth, strength training appears to oer some benets over endurance training for improving neuromuscular function and increase muscle mass.

Adaptive changes in maximal muscle strength, power,

and RFD
Although maximal muscle strength, power, and
RFD decline with aging even in chronically
(strength-) trained individuals (Pearson et al., 2002;
Korhonen et al., 2006), signicant benecial eects
of physical exercise may still be achieved. Thus, the
capacity for rapid muscle force production (RFD)
observed in elderly strength-trained individuals
(Korhonen et al., 2006) is substantially greater
(  fourfold) than that reported in sedentary agematched subjects (Izquierdo et al., 1999). Moreover,
80-year-old strength-trained lifters demonstrated similar maximal muscle power as that produced by 60year-old untrained elderly individuals, suggesting
that within this age range chronic strength training
can eectively compensate for about 20 years of
sarcopenic decline in muscle power (Pearson et al.,
2002; their g. 3). A substantial decit (43%) in rapid
force capacity (RFD) was observed between 80- and
60-year-old untrained women that was abolished in
response to 12 weeks of explosive-type heavy-resistance strength training (Caserotti et al., 2008b)
further indicating that a marked juvenilization in
terms of mechanical muscle function (  20 years)
may be achieved when old individuals are engaged in
strength training.
Maximal muscle power is found to increase after
strength training in the elderly (De Vos et al., 2005;
Caserotti et al., 2008a), including very old individuals
(80 years) (Fielding et al., 2002; Caserotti et al.,

Neural changes with aging and training

force (Del Balso & Cafarelli 2007, Klass et al., 2008),
suggesting that RFD is highly inuenced by the
magnitude of neuromuscular activity irrespective of
age.

2008b). Notably, greater gains in maximal muscle

strength and muscular endurance were observed after
strength training using heavy loads (80% 1RM)
compared with less heavy loads (50% 1RM) (De
Vos et al., 2005). Similarly, a large number of studies
have demonstrated marked gains in maximal muscle
strength of elderly individuals following heavy-resistance training (i.e. Hakkinen et al., 1998a, b, 2001;
Hortobagyi et al., 2001; Suetta et al., 2004a; Barry
et al., 2005; Caserotti et al., 2008b).
The capacity for rapid force
R production (RFD)
and the contractile impulse ( Fdt) is also increased
after strength training in elderly individuals (Hakkinen et al., 1998a, 2001; Hortobagyi et al., 2001;
Suetta et al., 2004a; Barry et al., 2005; Caserotti
et al., 2008b), along with signs of elevated eerent
neuromuscular activity as reected by increased surface EMG amplitude (Hakkinen et al., 1998a 2001;
Suetta et al., 2004a; Barry et al., 2005) (Fig. 7).
Recent studies have demonstrated moderate to
strong relationships both in young and old individuals between the integrated EMG amplitude and
contractile RFD in the early phase of rising muscle

Strength training appears to elicit signicant changes

in neuromuscular function in elderly individuals. For
example, aging individuals demonstrate elevated
muscle EMG amplitudes during MVC contraction
following a period of strength training, suggesting an
increase in the magnitude of eerent neuromuscular
activity (Hakkinen et al., 1998a, b, 2001; Suetta et al.,
2004a; Barry et al., 2005).
Maximum RFD is inuenced by maximal MN
ring frequency (Baldissera et al., 1987; Garland &
Grin 1999; Van Cutsem & Duchateau 2005), and
by the presence of MN discharge doublets (  5 ms
interspike interval) (Van Cutsem & Duchateau 2005).
Notably, maximum MN ring frequency during
isometric or dynamic ballistic MVC is reduced in
old compared with young subjects (Connelly et al.,

(a)

Older

RFD (Nm/s)

800

Adaptive changes in neuromuscular function

Young

600

*
*

400

*
*

30
50
milliseconds

100

200
0
peak

EMG root mean sqaure (mV)

(b)

30
50
milliseconds

0.70

100

peak

Young

Older

0.60

0.50
0.40
0.30

brachioradialis
brachialis
biceps short head
biceps long head

*
*

0.20
0.10

0
50 ms

100 ms
milliseconds

50 ms

100 ms
milliseconds

Fig. 7. Explosive force capacity

(rate of force development: RFD)
in young (2135 years, n 5 8)
and old (6079 years, n 5 8) individuals before (open bars) and after
(hatched bars) 4 weeks of strength
training using combined isometric
elbow exion and supination
MVC. Training led to increased
RFD in both young and old individuals (middle panels; *Po0.05),
which was accompanied by increases in elbow exor electromyography amplitude (bottom panels;
*Po0.05) (data from Barry et al.,
2005).

57

Aagaard et al.
1999; Kamen & Knight 2004; Klass et al., 2008).
Likewise, the incidence of MN doublet ring seems
reduced in the elderly, during both rapid dynamic
muscle contraction (Klass et al., 2008) and graded
isometric ramp contractions (Christie & Kamen
2006). Importantly, strength training can increase
maximum MN ring frequency in the elderly and
fully eliminate the age-related dierence in maximum
MN ring frequency observed in the untrained state
(Kamen & Knight 2004). Thus, MN ring frequency
recorded in the VL muscle during maximal isometric
quadriceps contraction increased in elderly (mean
age 77 years, range 6781 years) and young subjects
(21 years, range 1829 years) from 17.5 to 26 Hz and
from 24 to 28 Hz, respectively, with no dierence
observed between the two age groups after the period
of training (Kamen & Knight 2004). A vefold
elevated incidence of doublet discharge ring was
reported after ballistic strength training in young
subjects, which was suggested to be of importance
for the concurrent gain in rapid muscle strength
(RFD) (Van Cutsem et al., 1998). Future studies
should clarify if similar eects can be achieved with
strength training in aged individuals.
Elderly individuals may show reduced central
muscle activation (CA) as assessed by electrical
muscle stimulation superimposed onto MVC, albeit
not a universal nding (for a review, see Klass et al.,
2007). CA may increase with strength training in the
elderly (Scaglioni et al., 2002; Morse et al., 2007;
Suetta et al., 2007, 2009), and strong positive

relationships (r 5 0.860.92) between individual

changes in CA assessed by single-stimuli-interpolated twitch analysis in the quadriceps muscle and
maximal isometric knee extensor strength (MVC)
have been reported following strength training in
very old individuals (801 years) (Harridge et al.,
1999) (Fig. 8). Unilateral long-term limb disuse in
elderly subjects (  70 years) due to hip arthrosis
was accompanied by a marked reduction in CA for
the aected limb (57.6%, 100% 5 full activation) vs
the non-aected limb (CA: 70.7%) (Suetta et al.,
2007). CA was reduced from 88.6% to 80.2%
following short-term (2 weeks) limb immobilization
in physically active elderly subjects (67.3 years,
range 6174 years) but remained unchanged
(91.6% vs 90.6%) in young subjects (24.4 years,
range 2127 years) using interpolated twitch-doublet stimulation in the quadriceps muscle, indicating
that the neuromotoric system of lower-limb muscles
in old individuals may be more aected by shortterm unloading than in young subjects (Suetta et al.,
2009). Subsequent re-training by means of strength
training (4 weeks) fully restored CA in old subjects
(from 80.2% to 90.6%) whereas CA increased above
pre-training levels in young subjects (from 90.6% to
95.2%), suggesting that the range of neuromuscular
plasticity to retraining following immobilization
may dier between old and young individuals
(Suetta et al., 2009).
The amount of antagonist muscle coactivation
varies across contraction tasks. However, elderly

Post training

Pre training

25N

58

2s

(a) 140

(b) 80

120

r = 0.92

60
d MVC/CSA (%)

100
d MVC (%)

Fig. 8. Central activation (CA)

and maximal isometric knee extensor strength in very old individuals
(851 years, range 8597, n 5 11)
before and after a period of
heavy-resistance strength training.
CA was assessed using superimposed twitch interpolation (top panels) where superimposed twitches
were greatly reduced after training
along with marked increases in
MVC strength (top panel showing
illustrative individual). Relative
gains in CA with training were
strongly associated with the gain
in MVC (bottom panels), also
when MVC was normalized to
knee extensor muscle CSA (right
bottom panel) (data from Harridge
et al., 1999).

25N

2s

80
60
40
20
0

40
r = 0.86
20
0
20

20
20 10

10

20

d Activation (%)

30

40

20 10

10

20

30

d Activation (%)

40

50

Neural changes with aging and training

individuals may show elevated antagonist muscle
coactivation during leg extensor and arm exor
MVCs (Hakkinen et al., 1998a, 2001; Klein et al.,
2001; Macaluso et al., 2002), although not a consistent nding (Hakkinen et al., 2000; Barry et al.,
2005; Simoneau et al., 2005; Morse et al., 2007;
Klass et al., 2008). If elevated before training,
antagonist coactivation typically decreases in elderly individuals following strength training (Hakkinen et al., 1998a, 2001), although increased
antagonist coactivation may also occur (De Boer
et al., 2007). Thus, in old individuals where antagonist coactivation is elevated above normal levels
(42025% maximum agonist activity) it is a typical
nding that coactivation is decreased in response to
strength training. Nevertheless, elderly individuals
typically show elevated muscle coactivation during
daily movement tasks such as during stair climbing
and in single-step descent (Larsen et al., 2008;
Hortobagyi & Devita 2000), which seems to be
unaected by strength training (Larsen et al., data
in publication).
Fine motor control (force steadiness and force
accuracy) appear to be impaired in the elderly, as
indicated by an elevated variability (increased SD)
and reduced matching accuracy in the muscle force
(moment) produced during isometric and dynamic
force tracking tasks (Hortobagyi et al., 2001; Tracy
& Enoka 2002). Notably, ne motor control can be
improved by strength training in the elderly, as
evidenced by improvements in both force steadiness
and force accuracy (Hortobagyi et al., 2001; Tracy
et al., 2004; Tracy & Enoka 2006).
Adaptive changes in muscle size and architecture
Strength training using heavy loads (470% 1RM,
1014 weeks) leads to gains (512%) in muscle CSA
and volume in elderly individuals, as evaluated by
MRI or CT scanning (Frontera et al., 1988; Hakkinen et al., 1998a, b; Esmarck et al., 2001; Ferri et al.,
2003; Reeves et al., 2004a; Suetta et al., 2004a).
Notably, old and young individuals may demonstrate similar adaptive plasticity to strength training
of moderate duration (35 months). Thus, reviewing
a number of studies the relative gain in anatomical
muscle size was not dierent between old and young
individuals, respectively (0.070.12%/day vs 0.04
0.11%/day) (Narici et al., 2004, their Table 1).
Training-induced increases (2040%) in single
muscle ber area have been observed when assessed
in elderly individuals by muscle biopsy sampling
techniques (Frontera et al., 1988; Hakkinen et al.,
1998b, 2001; Hikida et al., 2000; Esmarck et al.,
2001; Kosek et al., 2006; Suetta et al., 2008) including
very old individuals (801 years) (Kryger & Andersen
2007). However, the response may be blunted in the

very old (  80 years) compared with that seen in less

old (o65 years) and young individuals (Fiatarone
Singh et al., 1999; Martel et al., 2006; Slivka et al.,
2008; Raue et al., 2009) suggesting that a limited
adaptive plasticity in skeletal muscle growth may
exist for the very old.
Training and maintained physical activity may not
per se prevent the loss in type II ber size with aging
(discussed above). Thus, a trend for a decline in type
II muscle ber area was reported in elderly chronically trained sprinters compared with young sprinters, although ber size was substantially greater in
elderly sprinters than in untrained individuals of
similar age (Korhonen et al., 2006). Similarly, old
track and eld athletes (sprint, jumping, throwers;
73.9 years, range 6878) exposed to lifelong strength
training showed 1827% elevated type II muscle ber
area (with no dierence in type I and type II ber
area) when compared with non-trained age-matched
individuals, where muscle ber area diered in the
order IIXoIIAoI (Aagaard et al., 2007). Collectively, these data suggest that the age-related loss in
muscle ber size to some extent can be compensated
by long-term (life-long) training involving strength
conditioning exercise.
Similar to that seen in young individuals (Aagaard
et al., 2001), adaptive changes in muscle architecture
can be observed in elderly subjects in response to
heavy-resistance strength training. Thus, following
1252 weeks of training muscle ber pennation angle
increased in the resting VL muscle from 7.2 to 8.61 in
frail elderly hip replacement patients (Suetta et al.,
2008), from 11.3 to 14.51 in physically active elderly
individuals (Reeves et al., 2004b), and from 15.41 to
17.31 in the lateral gastrocnemius, the latter measured during isometric MVC (Morse et al., 2007). A
blunted adaptive change in muscle pennation angle
was observed in previously physically active elderly
compared with young subjects when 14 days of limb
immobilization was followed by short-term strength
training (4 weeks) (old: 9.0 ! 8.4 ! 8.61; young:
10.4 ! 9.4 ! 10.51), suggesting that traininginduced changes in muscle architecture may take
longer time to occur in older than younger individuals (Suetta et al., 2009). Importantly, the traininginduced increase in ber pennation angle allows for
greater relative changes in single muscle ber CSA
than anatomical CSA (Aagaard et al., 2001; Suetta
et al., 2008 vs 2004a), hence resulting in a qualitative
improvement of the aging skeletal muscle that per se
contributes to the gain in maximal muscle strength,
RFD, and power.
Consequences for functional capacity
The improvement in mechanical muscle function
induced by strength training in aging individuals

59

Aagaard et al.
frequently results in an improved functional capacity
during tasks of daily living, especially in frail elderly
or very old individuals (Fiatarone et al., 1994; Suetta
et al., 2004a,b; Beyer et al., 2007; Caserotti et al.,
2008b). Thus, in a classical study Fiatarone et al.
(1994) demonstrated that strength training in very
old (87.1 years) frail nursing home residents led to a
28% increased stair walking speed along with a 12%
gain in maximal horizontal walking speed. Similar
ndings were reported in elderly post-operative hip
replacement patients, where maximal horizontal
walking speed, time for ve repeated sit-to-stand
movements, and maximal stair climbing speed were
2830% improved following 12 weeks strength training (Suetta et al., 2004b). The increase in maximal
gait speed was associated (r 5 0.79) with the improvement in rapid force capacity (RFD) (Suetta
et al., 2004a), indicating that training-induced gains
in mechanical muscle function can be a highly
eective way to increase functional capacity in frail
elderly individuals. In comparison, traditional rehabilitation training led to statistically non-signicant
changes of 019% (Suetta et al., 2004b).
Somewhat smaller, albeit statistically signicant,
improvement were observed following 36-week multicomponent training including strength exercises
combined with balance, aerobic, exibility, and coordination components in elderly males (75 years),
which resulted in a 916% improved performance in
chair rise test, 10 and 30 m maximal walking speed
(Caserotti et al., 2008a). Similar ndings have been
observed in elderly women (78 years, range 7090)
who had experienced previous falls: 6 months of
multicomponent strength training resulted in 10
21% improvement in sit-to-stand test performance
and speed of maximal horizontal walking, and in
stair climbing, respectively (Beyer et al., 2007). Importantly, the improvement in functional capacity
remained present at follow-up testing 6 months after
cessation of training (Beyer et al., 2007).
Methodological constraints
In the rst half of this review article a large number
of cross-sectional studies were reported. Obviously,
the cross-sectional nature of these data inherently
restraints the conclusions that can be made about the

longitudinal physiological adaptation to aging. On

the other hand, while very dicult to perform over a
more extended age range (3050 years) long-term
longitudinal aging studies also to some extent are
biased by selection (survival) of certain genetic subpopulations and/or lifestyle preferences, respectively.
Consequently, valuable information can be obtained
from cross-sectional studies, which subsequently may
be scrutinized and explored in longitudinal intervention studies as described in detail in the latter half of
the present review.
Conclusions
In conclusion, aging is characterized by loss of spinal
MNs due to apoptosis, reduced IGF-1 signaling,
elevated amounts of circulating cytokines, and increased cell oxidative stress. The age-related loss of
spinal MNs is paralleled by a reduction in muscle
ber number and size (sarcopenia), consequently
leading to an impaired mechanical muscle performance and a reduced functional capacity during
everyday tasks. It is suggested that sarcopenic muscle
may not per se be in a state of poor adaptive
responsiveness, rather an impaired capacity for axonal reinnervation of deinnervated myobers may be
responsible for the net loss of muscle mass with
advancing age. Concurrent decreases in maximum
muscle strength, power, and rate of force development are observed with aging, even in highly trained
master athletes. The impairment in muscle mechanical function is accompanied and partly caused by an
age-related loss in neuromuscular function that comprise changes in maximal MN ring frequency,
agonist muscle activation, antagonist muscle coactivation, force steadiness, and spinal inhibitory circuitry. However, elderly individuals demonstrate
substantial adaptive plasticity in both skeletal muscles and the neuromuscular system in response to
strength training (resistance exercise), which to a
large extent can compensate for the age-related
declines in muscle size and neuronal function, respectively, and lead to improved functional capacity
even at very old age.
Key words: motor neurons, CNS, muscle power,
RFD, strength training.

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