Invited Review: Aging and the cardiovascular system

Alberto U. Ferrari, Alberto Radaelli and Marco Centola

J Appl Physiol 95:2591-2597, 2003. ;
doi: 10.1152/japplphysiol.00601.2003
You might find this additional info useful...
This article cites 43 articles, 28 of which you can access for free at:
http://jap.physiology.org/content/95/6/2591.full#ref-list-1
This article has been cited by 36 other HighWire-hosted articles:
http://jap.physiology.org/content/95/6/2591#cited-by
Updated information and services including high resolution figures, can be found at:
http://jap.physiology.org/content/95/6/2591.full
Additional material and information about Journal of Applied Physiology can be found at:
http://www.the-aps.org/publications/jappl

Journal of Applied Physiology publishes original papers that deal with diverse area of research in applied
physiology, especially those papers emphasizing adaptive and integrative mechanisms. It is published 12 times a
year (monthly) by the American Physiological Society, 9650 Rockville Pike, Bethesda MD 20814-3991. Copyright
2003 the American Physiological Society. ISSN: 8750-7587, ESSN: 1522-1601. Visit our website at
http://www.the-aps.org/.

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

This information is current as of June 20, 2013.

J Appl Physiol 95: 25912597, 2003;

10.1152/japplphysiol.00601.2003.

highlighted topics

Physiology of Aging
Invited Review: Aging and the cardiovascular system
Alberto U. Ferrari, Alberto Radaelli, and Marco Centola
Dipartimento di Medicina, Prevenzione e Biotecnologie Sanitarie, Centro di Fisiologia
Clinica e Ipertensione, Universita` di Milano-Bicocca, 20122 Milano; Divisione di
Cardioriabilitazione, Ospedale di Seregno, Azienda Ospedaliera Vimercate (MI), 20059 Vimercate, Italy

heart; blood vessels; atherosclerosis; baroreceptor reflexes; autonomic

nervous system

Senectus ipsast morbu [senescence is a disease in itself].

Terentius Afer, Phormio, 575

Concepts and suggestions from Latin wisdom are often

confirmed by modern knowledge, and the one mentioned
above undoubtedly carries some truth: advanced age may
induce a decline in bodily functions and overall cardiovascular performance even in the absence of overt
disease. On the other hand, two major arguments
stand against Terentius statement. 1) Although quite
a few cardiovascular features of the elderly most likely
depend on aging per se, in many instances impaired
performance is not only the consequence of advanced
age but also results from various combinations of more
or less apparent cardiovascular or noncardiovascular
illnesses: thyroid dysfunction, diabetes, heart failure,
borderline hypertension, and others may be good examples of such situations, in which it is thus difficult to
discriminate between disease-related and age-related
alterations. 2) The issue is further complicated by the
fact that age-related changes by no means consist of
a uniform and generalized structural degeneration
Address for reprint requests and other correspondence: A. U.
Ferrari, Centro Fisiologia Clinica e Ipertensione, Via F. Sforza, 35,
20122 Milano (E-mail: alberto.ferrari@unimib.it).
http://www.jap.org

and/or functional decline; rather, different components

of the cardiovascular system may be affected quite
heterogeneously, which means that in aging at least
some functions not only fail to show an impairment but
may indeed be paradoxically enhanced. This also has
the obvious methodological implication that age-related changes have to be systematically analyzed and
their various elements and underlying mechanisms
carefully dissected before any safe conclusions can be
reached, which makes this area of research a particularly demanding one.
On the basis of the above premises, the present
discussion will address the effects of aging on the
heart, the blood vessels, and the reflex control of the
cardiovascular system. Whenever relevant information
is available, attention will be given to the mechanisms
responsible for the age-related modifications as well as
to their homeostatic and clinical implications. Conventionally, a cutoff point for advanced age in humans
may be set at 65 yr, and this is adopted in the present
article as well as in most quoted references dealing
with human studies. A corresponding cutoff point for
rats may be set at age above 18 mo. A summary of the
major age-related effects in the cardiovascular system
is provided in Table 1.

8750-7587/03 $5.00 Copyright 2003 the American Physiological Society

2591

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

Ferrari, Alberto U., Alberto Radaelli, and Marco Centola. Invited Review: Aging and the cardiovascular system. J Appl Physiol 95:
25912597, 2003; 10.1152/japplphysiol.00601.2003.Aging is associated with complex and diversified changes of cardiovascular structure
and function. The heart becomes slightly hypertrophic and hyporesponsive to sympathetic (but not parasympathetic) stimuli, so that the exercise-induced increases in heart rate and myocardial contractility are
blunted in older hearts. The aorta and major elastic arteries become
elongated and stiffer, with increased pulse wave velocity, evidence of
endothelial dysfunction, and biochemical patterns resembling early atherosclerosis. The arterial baroreflex is sizably altered in aging, but
different components are differentially affected: there is a definite impairment of arterial baroreceptor control of the heart but much better
preserved baroreceptor control of peripheral vascular resistance. Alterations at the afferent, central neural, efferent, and effector organ portions of the reflex arch have been claimed to account for age-related
baroreflex changes, but no conclusive evidence is available on this mechanistic aspect. Reflexes arising from cardiopulmonary vagal afferents are
also blunted in aged individuals. The cardiovascular and reflex changes
brought about by aging may have significant implications for circulatory
homeostasis in health and disease.

2592

INVITED REVIEW

Table 1. Effects of aging on major structural and functional characteristics of the cardiovascular system
Cardiac Changes

Vascular Changes

Heart weight
Cardiomyocyte dimensions
Cardiomyocyte number
Collagen in cross-linking
Ejection fraction
Stroke volume
Cardiac output
Early diastolic filling
End-diastolic filling
Chronotropic responsiveness to -adrenergic stimuli/catecholamines
Inotropic responsiveness to -adrenergic stimuli/catecholamines
Inotropic response to digitalis glycosides
Peak cardiac output to maximal effort
Lusitropic function
Release of natriuretic peptides

1
1
2
1

2
1
2
2
2
2
2
1

Arterial wall thickness (intima-media)

Subendothelial collagen
Elastin
Elastin fragmentation
Proteoglycans
MMP activity
Intimal migration/proliferation of VSMC
Arterial distensibility
Pulse wave velocity
Total peripheral resistance
Endothelial permeability
Endothelial nitric oxide release
Inflammatory markers/mediators
SOD activity
-Adrenergic-mediated vasodilation

1
1
2
1
1
1
1
2
1
1
1
2
1
2
2

2, diminished; 1, augmented; , unchanged; VSMC, vascular smooth muscle cells; SOD, superoxide dismutase; MMP, matrix metalloproteinases.

Structural changes. Even in subjects apparently free

of hypertension or other causes of increased afterload,
aging is associated with a mild increase in heart
weight, reflecting some degree of left ventricular hypertrophy (16). In some studies (17), an age-dependent
change in cardiac shape has been described, with a
rightward shift in the ascending aorta and a proximal
bulge in the interventricular septum, which entail a
narrowing of the left ventricular outflow tract. Cardiomyocyte dimensions are somewhat increased,
whereas their numbers are decreased; collagen may
become more prominent because of both quantitative
and qualitative changes, with focal deposits and diffuse
increases in the cross-linking between adjacent fibers.
Because of the concomitant cardiomyocyte enlargement, however, no increase in the collagen-to-myocyte
ratio is observed. Such changes are believed to be of
functional importance, especially for diastolic events
(see below). An additional change described in the
aging heart is a partial degeneration of cardiac sympathetic nerve supply (33).
Functional changes. In the resting aging heart, there
are largely no alterations of systolic function, with preserved ejection fraction and stroke volume; because resting heart rate is unchanged or only minimally reduced
with aging, cardiac output is also preserved (38).
Instead, diastolic function does undergo significant
age-related changes, with a reduction in early diastolic
filling compensated for by increased end-diastolic filling and a consequent progressive reduction of the echocardiographic early wave/atrial wave (E/A) velocity ratio (34).
Aging also alters cardiac responsiveness to -adrenergic stimuli, be they pharmacologically or physiologically determined. Both the catecholamine- or exerciseinduced increases in heart rate and myocardial contractility are definitely blunted in elderly subjects (15).
Thus, for cardiac output to be increased in proportion
to the bodys metabolic needs despite inadequate contractile and chronotropic reserves, the aging left venJ Appl Physiol VOL

tricle mainly engages the Frank-Starling mechanism,

i.e., it undergoes marked increases in volume, both
end-diastolic and end-systolic. Via such hemodynamic
a pattern, the aging heart can significantly increase its
maximum output and allows elderly subjects to perform vigorous exercise, although not up to the same
intensity as a younger individual can sustain. Overall,
the peak cardiac output attained in response to maximal effort is blunted by some 2030% in elderly compared with young healthy subjects, the blunting being
largely attributable to a lesser degree of effort tachycardia rather than to altered stroke volume (15). To
draw an overall picture of modified cardiac exercise
physiology in aging, it was suggested that the heart of
the elderly behaves like a younger heart subjected to
-blocker treatment (23).
Further age-related cardiac alterations relate to lusitropic function, with delayed relaxation as a consequence of enhanced duration of contraction. The latter
results from prolonged action potential and active state
rather than from changes in passive mechanical properties or myocardial catecholamine content (25). The
above-mentioned alterations may be of considerable
clinical importance as a possible functional substrate
of the notorious propensity of elderly individuals to
develop diastolic heart failure.
The aged heart also shows a reduction in the inotropic
responses to digitalis (but not to calcium ions, indicating
that the defect involves the signaling processes rather
than the contractile machinery itself) (28).
AGING AND THE VASCULATURE

Structural changes. Aging large arteries are elongated and tortuous and have an enlarged lumen and a
thickened wall, the thickening mainly affecting the
intima and the media (44). In the former, arteries from
healthy elderly subjects show no endothelial lesions or
discontinuities; endothelial cells may, however, be irregular in shape and have increased height; there may
be migration and/or proliferation of vascular smooth
muscle cells, with infiltration in the subendothelial

95 DECEMBER 2003

www.jap.org

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

AGING AND THE HEART

2593

INVITED REVIEW

J Appl Physiol VOL

pulse pressure. In turn, elevated pressure is a stimulus

for further development of vessel wall hypertrophy and
stiffness, so that adverse phenomena beget each other
and a more or less rapidly progressing vicious circle is
established.
AGING AND BARORECEPTOR REFLEXES

Arterial baroreflexes. An age-related decline in the

ability of arterial baroreceptors to modulate cardiac
chronotropic activity was repeatedly documented in
experimental animals and in humans by different technical approaches: when baroreceptors are stimulated
via a transient phenylephrine-induced elevation in
blood pressure, the reflex slowing of the heart is less in
aged compared with younger individuals (12, 19). The
same is true for the cardioacceleration after baroreceptor deactivation via intravenous bolus administration
of a peripheral vasodilator. Even using more sophisticated, nonpharmacological approaches such as the
computer-based cross-spectral evaluation of the R-R
interval to systolic blood pressure power ratio or the
sequence technique (2), the derived indexes of so-called
dynamic baroreflex sensitivity invariably were smaller
in aged compared with younger individuals (36).
The wealth of data documenting age-related depression of the baroreceptor-heart rate reflex tended to be
generalized and gave rise to the notion of age-related
depression of the baroreflex at large; however, this
represents just one more example of unsafe extrapolation and was indeed not confirmed when the effects of
aging on baroreflex components other (and physiologically more important) than control of the sinus node
were directly examined. Microneurographic evaluation
of the baroreceptor control of efferent muscle sympathetic nerve activity (8, 18), studies employing the neck
chamber technique to manipulate carotid baroreceptor
activity in humans (see below), as well as various
approaches employed in animals to elicit arterial
baroreceptor-mediated reflex responses (12, 32), did on
the one hand confirm that in advanced age the baroreceptor-heart rate reflex is impaired but on the other
hand revealed much better preserved control of blood
pressure and sympathetic activity. Animal models,
particularly the aging rat, may be valuable in this area
because in this species there is virtually no age-related
increase in blood pressure nor development of atherosclerotic disease. To take advantage of these features,
we compared in 3- to 6-mo-old and 24-mo-old rats the
pressor responses to bilateral carotid artery occlusion
obtained in the unanesthetized animal via chronically
implanted pericarotid balloon occluders. A representative example of the observed responses is shown in Fig.
1. It is notable that the magnitude of the pressor
response to baroreceptor deactivation is largely similar
in the adult and senescent animal; it is also apparent,
however, that in the latter the time course of the
response is definitely prolonged (12). Interestingly, this
pattern is qualitatively similar to that observed in a
fairly large population of human subjects with a wide
age range in whom the baroreceptor control of blood

95 DECEMBER 2003

www.jap.org

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

space, exaggerated deposition of collagen, elastin, and

proteoglycans, along with abnormal abundance of leukocytes and macrophages. Numerous substances involved in inflammatory and/or atherosclerotic processes such as adhesion molecules, matrix metalloproteinases, transforming growth factor-, and others,
such as proinflammatory cytokines, are also more
abundant in aging arterial intimae (3, 30).
Functional changes. The fundamental age-related
change in arterial function is impairment of distensibility (37) and thus of the cushioning function of the
aorta and its major branches, associated with an enhancement in pulse wave velocity; such changes have
been suggested to be nonuniform throughout the arterial tree with more marked alterations in elastic-type
vs. muscle-type arteries (43). Increased stiffness is not
solely dependent on structural alterations but also is
majorly affected by humoral and endothelial regulation of vascular smooth muscle tone: aged vessels show
an increased endothelial permeability and a reduced
nitric oxide-dependent vasodilator response to acetylcholine (41); this was consistently observed in different
regional beds of both animals and humans including
the coronary bed (10). Also the vasodilator responses to
2-adrenoceptor agonists are clearly attenuated because of reduced number and affinity of specific receptors; albeit to a probably lesser extent, vasoconstrictor
responses to -receptor stimulation are also diminished in aged arteries (11).
Although the above-mentioned age-related functional alterations have been observed in atherosclerosis-free normotensive individuals, most of them are
also present in atherosclerotic vessels, which are also
known to be stiffer than normal but in which, unlike in
aging, focal lesions, vessel stenosis, and plaque rupture
eventually develop. Thus, because aging and atherosclerosis run along very similar biochemical pathways
and determine many similar vascular alterations, vessel aging may be viewed as representing the prodromal
stage of atherosclerotic disease or, conversely, atherosclerosis may be viewed as a form of accelerated arterial aging (probably favored by coexisting noxious stimuli such as e.g., dyslipidemia, smoking, or hypertension).
One may on the other hand maintain that the two
processes are distinct in origin because in many senescent subjects the age-related alterations are clearly
present but apparently fail to ever progress to overt
focal disease. This conceptual alternative may be to
some extent academic, however. The real challenge, in
the genomic era, will rather be to identify (and ultimately to control) the genetic and/or molecular mechanisms governing the transition from largely benign
age-related changes to pathological atherosclerotic degeneration. For further details on this highly complex
and rapidly expanding issue, the reader is referred to a
recent and comprehensive review series (24, 26, 27).
The systemic hemodynamic consequences of age-related vascular hypertrophy and stiffness include a
moderate increase in total peripheral resistance and
the well-known tendency to increased systolic and

2594

INVITED REVIEW

pressure was examined by the neck chamber technique: when carotid baroreceptor deactivation was produced by applying positive neck pressure for 2-min
periods, the late, steady-state reflex blood pressure rise
was largely similar in the different age groups,
whereas the early response was significantly attenuated in the older compared with the younger subjects
(14). Although based on different techniques, the parallel findings on age-related effects obtained in humans
and rats do support the notion that, with aging, baroreceptor control of blood pressure is quantitatively preserved but has a significantly slowed time course.
More recently, a novel approach to quantitate the
blood pressure-buffering ability of arterial baroreflexes
was used to compare this function in older vs. younger
humans (22): transient blood pressure elevations were
produced by intravenous administration of phenylephrine in the control condition and during ganglionic
blockade by trimetaphan, the potentiation of the response under the latter condition being taken as a
measure of the reflex blood pressure buffering capability. Older subjects clearly showed attenuated potentiation of the pressor responses during trimetaphan
blockade, and the authors concluded that aging is associated with impaired baroreflex buffering; this conclusion may not be definitive, however, because this
albeit ingenious approach is not devoid of limitations,
as discussed by the authors themselves, insofar as
phenylephrine is not selectively acting on resistance
arterioles. Even more importantly, trimetaphan drastically lowered systemic blood pressure and did so to a
quite different extent in the two age groups (much
more markedly and indeed almost to shock-like levels
in aged subjects), which may complicate the interpretation of the results. Thus the issue of the age-related
J Appl Physiol VOL

95 DECEMBER 2003

www.jap.org

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

Fig. 1. Typical recordings showing the blood pressure response to

bilateral common carotid artery occlusion in unanesthetized, freemoving rats chronically instrumented with an intra-arterial catheter
and bilateral pericarotid balloon occluders. Examples from an adult
(A) and an old (B) animal are depicted. Note the slower time course
but the maintained magnitude of the blood pressure rise in the old
rat. (Reprinted from Ref. 12.) ABP, arterial blood pressure; MAP,
mean arterial pressure; HR, heart rate; b/min, beats per minute.

baroreflex modifications remains in need of further

assessment, especially as far as the baroreflex control
of the peripheral circulation is concerned, to reconcile
the sizeable discrepancies existing between the results
and interpretations of different studies.
Lack of consensus on the merely descriptive aspects
of age-related baroreflex modifications makes it even
harder to address their underlying mechanisms. The
issue is intrinsically difficult because of the multiplicity of the factors potentially involved; indeed, reduced
distensibility of the arterial walls hosting the baroreceptors, blunted transduction of the stretch signal by
the mechanosensitive elements, altered central neural
processing of the afferent input, abnormal prevailing
levels of efferent neural sympathetic or parasympathetic outflows, changes in end-organ (cardiac and vascular) responsiveness to neural stimuli, i.e., changes at
virtually every portion of the reflex arch, have all been
claimed to characterize aged compared with younger
individuals.
As to the possible alterations at the afferent limb of
the reflex, recent findings based on beat-to-beat assessment of carotid artery diameter supported reduced
strain in vessels from aged individuals, compatible
with reduced stimulus to baroreceptors and reduced
afferent signal (20). It is to be noted, however, that the
above-mentioned study suggested that arterial stiffening alone could not entirely account for the baroreflex
blunting and that neural age-related alterations also
gave a significant contribution. Even more intriguing,
classical studies performed some 20 years ago on an
isolated rat aortic arch-aortic nerve preparation had
also reported reduced strain of the aged aortas, but this
was accompanied by unchanged rather than depressed
baroreceptor activity (1). Obviously, applicability of
such in vitro evidence to in vivo functioning is to be
considered with caution, and we have thus to admit
that the all issue is far from being settled.
Disparate findings have also been reported as to the
age-related changes in effector organ responsiveness.
We mentioned above that adrenergically mediated cardiac responses are attenuated with aging, and this
notion can be viewed as being experimentally well
supported. Concerning the parasympathetic autonomic
limb, cardiac vagal modulation was extensively explored by use of many different approaches (Valsalva
maneuver, cough, baroreflex stimulation, heart rate
variability, etc.), and age-related blunting of this function was invariably observed; all such studies, however, could not address the issue of whether the agerelated defect depends on neural vagal discharge to the
sinus node or on the ability of the cardiac pacemaker
itself to respond. Indeed, studies directly testing cardiac responsiveness to parasympathetic stimuli in aging have been limited. We therefore addressed this
issue by using adult and senescent rats in which the
bradycardic responses to electrical stimulation of the
peripheral end of the cut right vagal trunk were evaluated. Although on the basis of the available evidence
the expectation was that that blunted responses would
have been observed in the aged animals, the results

2595

INVITED REVIEW

indicated that the exact opposite is the case: as shown

in Fig. 2, aged rats displayed much larger bradycardic
responses than did the adult ones. In additional experiments in which, rather than by an electrophysiological
approach, cardiac muscarinic receptors were pharmacologically activated by graded intravenous bolus injections of acetylcholine, the results went in the same
direction, with much larger acetylcholine-induced bradycardic responses in old compared with adult rats
(13). To account for these somewhat surprising findings, one may hypothesize that chronically attenuated
cardiac parasympathetic drive in advanced age brings
about sinus nodal muscarinic receptor upregulation
and thus cardiac hyperresponsiveness to their activation; obviously, this albeit plausible explanation is admittedly speculative and indeed hardly amenable to be
experimentally verified, at least in the rat species.
Identifying and mechanistically characterizing agerelated modifications in the central neural mechanisms controlling the cardiovascular system at large
and the baroreflex in particular is a tremendously
difficult and as yet largely unmet goal. A few points are
nonetheless fairly well documented: The age-related
increase in circulating levels of norepinephrine (46) as
well as the direct evidence of a clear-cut age-related
increase in efferent sympathetic nerve activity obtained via microneurographic recordings from the peroneal nerves (45) support the notion of a physiological
sympathetic overactivity in advanced age. Sympathetic overactivity (qualitatively similar to that chronically occurring in hypertension or acutely arising during the defense reaction) might per se account for
reduced vagal efferent drive and partly suppressed
baroreflex control of the heart, whereas less prominent
(if any) interference with baroreflex control of the peripheral vessels would be implied (9). It may also
represent a further factor contributing to age-related
arterial stiffening if one considers that sympathetic
J Appl Physiol VOL

HOMEOSTATIC AND CLINICAL IMPLICATIONS OF

AGE-RELATED CARDIOVASCULAR MODIFICATIONS

In the following, final section, the way age-related

changes may affect cardiovascular homeostasis and be
more or less directly relevant to geriatric medicine will
be briefly discussed. This has obviously no ambition to
be exhaustive and rather intends to provide some significant examples.
First, there should be little question that a physiological age-related alteration in left ventricular diastolic function is a predisposing factor to the development of diastolic heart failure, which is indeed highly
prevalent in elderly patients, accounting for up to 50%
of all heart failure patients in this age range according
to some reports.
Second, combined occurrence of enhanced pulse
wave velocity and prolonged ejection time critically
facilitates summation of antegrade and retrograde arterial waves, which may contribute to elevation of
systolic blood pressure and pulse pressure in aged
subjects. This has obvious implications as a powerful
mechanism favoring onset and/or progression of vascular damage and increased risk of adverse physiological
or clinical outcomes, including excessive cardiac workload and oxygen demand, left ventricular hypertrophy,
further arterial stiffening itself, (cerebro)vascular
events, and decline of renal function.
Third, altered endothelial function in aging coronary
vessels is a further element that causes advanced age
to be listed among coronary risk factors. Likewise,
there is now convincing evidence that increased carotid

95 DECEMBER 2003

www.jap.org

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

Fig. 2. Effects of aging on cardiac parasympathetic responsiveness.

The peripheral end of the right vagus was electrically stimulated at
progressively increasing frequencies in adult and old anesthetized
rats, and stimulus-response relationships from the two groups were
obtained. Note the markedly increased bradycardic responses in the
old animals. In the latter, results from the strongest, 16-Hz stimulus
are missing because this stimulus induced cardiac arrest in most
experiments and had to be immediately withdrawn. (Reprinted from
Ref. 13.) HR, change in heart rate.

activity tonically restrains arterial distensibility (31).

The mechanisms responsible for increased sympathetic activity and central suppression of the baroreflex
in advanced age are unknown and may operate at
many possible sites in the brain (4, 42).
Cardiopulmonary reflexes. These reflexes have generally been given lesser attention than the arterial
baroreflexes: their physiological role may, however, be
quite relevant in the setting of aging if one considers
their ability to control plasma renin activity and renal
function alongside with the limited ability of elderly
individuals to cope with fluid and electrolyte balance
challenges. Indeed, although only few studies systematically addressed the issue of cardiopulmonary reflexes in aging, the evidence is largely in favor of a
blunting in the hemodynamic and even more so in the
humoral component of the cardiopulmonary reflex in
aged compared with younger human subjects (5, 21).
The question remains open, however, whether the impairment depends on defective cardiopulmonary receptor modulation of sympathetic activity or on reduced
forearm vascular responsiveness to neural stimuli (7).
In addition, there have been studies that came to
conclusions at variance with the above and reported
preserved rather than attenuated cardiopulmonary reflex control of forearm vascular resistance in elderly
compared with young healthy subjects (40).

2596

INVITED REVIEW

J Appl Physiol VOL

ently healthy elderly humans. Such epidemiological,

experimental, and clinical knowledge will form the
basis for growing numbers of elderly subjects to be
allowed to perpetuate their independence and wellbeing as late as possible in life (so-called successful
aging; Ref. 26) and for modern societies and health
professionals to become increasingly effective in providing prevention, diagnosis, and treatment of the cardiovascular disease epidemic worldwide.
REFERENCES
1. Andresen MC. Short- and long-term determinants of baroreceptor function in aged normotensive and spontaneously hypertensive rats. Circ Res 54: 750759, 1984.
2. Bertinieri G, Di Rienzo M, Cavallazzi A, Ferrari AU, Pedotti A, and Mancia G. Evaluation of baroreceptor reflex by
blood pressure monitoring in unanesthetized cats. Am J Physiol
Heart Circ Physiol 254: H377H383, 1988.
3. Challah M, Nadaud S, Philippe M, Battle T, Soubrier F,
Corman B, and Michel JB. Circulating and cellular markers of
endothelial dysfunction with aging in rats. Am J Physiol Heart
Circ Physiol 273: H1941H1948, 1997.
4. Chapleau MW, Cunningham JT, Sullivan MJ, Wachtel RE,
and Abboud FM. Structural versus functional modulation of
the arterial baroreflex. Hypertension 26: 341347, 1995.
5. Cleroux J, Giannattasio C, Bolla G, Cuspidi C, Grassi G,
Mazzola C, Sampieri L, Seravalle G, Valsecchi M, and
Mancia G. Decreased cardiopulmonary reflexes with aging in
normotensive humans. Am J Physiol Heart Circ Physiol 257:
H961H968, 1989.
7. Davy KP, Seals DR, and Tanaka H. Augmented cardiopulmonary and integrative sympathetic baroreflexes but attenuated
peripheral vasoconstriction with age. Hypertension 32: 298304,
1998.
8. Davy KP, Tanaka H, Andros EA, Gerber JG, and Seals DR.
Influence of age on arterial baroreflex inhibition of sympathetic
nerve activity in healthy adult humans. Am J Physiol Heart Circ
Physiol 275: H1768H1772, 1998.
9. Djojosugito AM, Folkow B, Kylstra PH, Lisander B, and
Tuttle RS. Differentiated interaction between the hypothalamic
defence reaction and baroreceptor reflexes. I. Effects on heart
rate and regional flow resistance. Acta Physiol Scand 78: 376
385, 1970.
10. Egashira K, Inou T, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Kuga T, Urabe Y, and Takeshita A. Effects of age on
endothelium-dependent vasodilation of resistance coronary artery by acetylcholine in humans. Circulation 88: 7781, 1993.
11. Elliott HL, Sumner DJ, McLean K, and Reid JL. Effect of
age on the responsiveness of vascular alpha-adrenoceptors in
man. J Cardiovasc Pharmacol 4: 388392, 1982.
12. Ferrari AU, Daffonchio A, Albergati F, and Mancia G.
Differential effects of aging on the heart rate and blood pressure
influences of arterial baroreceptors in awake rats. J Hypertens 9:
615621, 1991.
13. Ferrari AU, Daffonchio A, Gerosa S, and Mancia G. Alterations in cardiac parasympathetic function in aged rats. Am J
Physiol Heart Circ Physiol 260: H647H649, 1991.
14. Ferrari AU, Grassi G, and Mancia G. Alterations in reflex
control of the circulation associated with aging. In: Handbook of
Hypertension: Hypertension in the Elderly, edited by Amery A
and Staessen J. Amsterdam: Elsevier Science, vol. 12, p. 3950,
1989.
15. Fleg JL, OConnor FC, Gerstenblith G, Becker LC, Clulow
J, Schulman SP, and Lakatta EG. Impact of age on the
cardiovascular response to dynamic upright exercise in healthy
men and women. J Appl Physiol 78: 890900, 1995.
16. Gerstenblith G, Fredriksen J, Yin FCP, Fortuin NJ,
Lakatta EG, and Weisfeldt ML. Echocardiographic assessment of a normal adult aging population. Circulation 56: 273
278, 1977.

95 DECEMBER 2003

www.jap.org

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

intima or media thickness (by ultrasound) predicts

occurrence of cardiovascular events (35).
Fourth, the observation of slowed arterial baroreceptor-mediated blood pressure responses in advanced age
may impair moment-to-moment adjustments of sympathetic nerve activity and peripheral vascular resistance, with increased propensity of elderly subjects to
postural or postprandial hypotension as well as to
inordinate blood pressure peaks. Even in lack of such
clinically significant phenomena, the age-related
changes in neural cardiovascular control are likely to
be responsible for the increased spontaneous blood
pressure variability (with concomitant reduction of
heart rate variability) typical of aged subjects.
Fifth, it is tempting to extrapolate from studies linking reduced baroreceptor control of heart rate to the
risk of life-threatening arrhythmias in cardiac patients
and envisage that the adverse potential of this alteration may also extend to the aging condition. In this
regard, it is interesting to recall that habitual exercise
is well known to exert an antiarrhythmic effect and
that in elderly populations it was shown to oppose
many age-related alterations (38), including impairment of the arterial baroreflex (20). Ongoing studies in
our human laboratory suggest that similar benefits
may be obtained by training elderly individuals to slow
breathing.
Sixth, impaired effectiveness of the cardiopulmonary
reflex in aging may contribute to altered electrolyte
and fluid homeostasis and facilitated dehydration:
these changes may also be among the factors that
dictate caution in prescribing and dosing diuretic therapy in elderly patients.
In conclusion, cardiovascular aging encompasses
such a wide and complex range of phenomena at the
structural, functional, and molecular levels that its
study has come to be viewed as a distinct branch of
physiology, whose advances will be crucial to understand the functioning of an increasingly larger section
of the population and will help to succeed in the difficult task of defining the border between normality and
disease. More specifically, future research efforts
should in the authors opinion pursue the following
objectives: 1) to extend and refine risk factor characterization, i.e., to qualitatively and quantitatively define those clinical-functional features of elderly individuals that are most tightly associated with development of cardiovascular disease; 2) to identify (in this
case, with no restriction to elderly populations) genetic
polymorphisms able to predict development of most
marked and/or early structural or functional alterations typical of aging, such as left ventricular diastolic
dysfunction, sympathetic overactivity, vascular stiffness, defective endothelial function, arterial wall thickening, and so forth; and 3) to verify whether lifestyle or
pharmacological interventions (exercise, sodium restriction, interference with lipid metabolism or the
renin-angiotensin system) shown to have favorable effects on arterial structure and function in humans or
experimental animals (29, 39) may also prevent or
delay cardiovascular events and mortality in appar-

2597

INVITED REVIEW

J Appl Physiol VOL

33.
34.
35.

36.

37.
38.

39.

40.
41.

42.
43.

44.

45.
46.

is attenuated in the elderly. J Auton Nerv Syst 73: 182185,

1998.
McLean MR, Goldberg PB, and Roberts J. An ultrastructural study of the effects of aging on sympathetic innervation
and atrial tissue in the rat. J Mol Cell Cardiol 15: 7592, 1983.
Miller TR, Grossman SJ, Schechtman KB, Biello DR, Ludbrook PA, and Ehsani AA. Left ventricular diastolic filling and
its association with age. Am J Cardiol 58: 531535, 1986.
OLeary DH, Polak JF, Kronmal RA, Manolio TA, Burke
GL, and Wolfson SK Jr. Carotid-artery intima and media
thickness as a risk factor for myocardial infarction and stroke in
older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 340: 1422, 1999.
Parati G, Frattola A, Di Rienzo M, Castiglioni P, Pedotti A,
and Mancia G. Effects of aging on 24-h dynamic baroreceptor
control of heart rate in ambulant subjects. Am J Physiol Heart
Circ Physiol 268: H1606H1612, 1995.
Roach MR and Burton AC. The effect of age on the elasticity
of human iliac arteries. Can J Biochem Physiol 37: 557570,
1959.
Rodeheffer RJ, Gerstenblith G, Becker LC, Fleg JL, Weisfeldt ML, and Lakatta EG. Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac
dilatation and increased stroke volume compensate for diminished heart rate. Circulation 69: 203213, 1984.
Rywik TM, Blackman R, Yataco AR, Yataco AR, Vaitkevicius PV, Zink RC, Cottrell EH, Wright JG, Katzel LI, and
Fleg JL. Enhanced endothelial vasoreactivity in endurance
trained older men. J Appl Physiol 87: 21362142, 1999.
Shi X, Gallagher KM, Welch-OConnor RM, and Foresman
BH. Arterial and cardiopulmonary baroreflexes in 60- to 69- vs.
18- to 36-yr old humans. J Appl Physiol 80: 19031910, 1996.
Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A,
Fasolo CB, Sudano I, and Salvetti A. Aging and endothelial
function in normotensive subjects and patients with essential
hypertension. Circulation 91: 19811987, 1995.
Tanabe S and Bunag RD. Aging escalates baroreceptor reflex
suppression by the posterior hypothalamus in rats. Hypertension
17: 8090, 1991.
Van der Heijden-Spek, Staessen JA, Fagard RH, Hoeks
AP, Boudier HA, and van Bortel LM. Effect of age on brachial
artery wall properties differs from the aorta and is gender
dependent: a population study. Hypertension 35: 637642, 2000.
Virmani R, Avolio AP, Mergner WJ, Robinowitz M, Herderick EE, Cornhill JF, Guo SY, Liu TH, Ou DY, and
ORourke M. Effect of aging on aortic morphology in populations with high and low prevalence of hypertension and atherosclerosis: comparison between occidental and Chinese communities. Am J Pathol 139: 11191129, 1991.
Wallin BG and Sundlof G. A quantitative study of muscle
nerve sympathetic activity in resting normotensive and hypertensive subjects. Hypertension 1: 6777, 1979.
Ziegler MG, Lake CR, and Kopin IJ. Plasma noradrenaline
increases with age. Nature 261: 333335, 1976.

95 DECEMBER 2003

www.jap.org

Downloaded from http://jap.physiology.org/ by guest on June 20, 2013

17. Goor D, Lillehei CW, and Edwards JE. The sigmoid septum: variation in the contour of the left ventricular outlet. Am J
Roentgenol Radium Ther Nucl Med 107: 366376, 1969.
18. Grassi G, Seravalle G, Bertinieri G, Turri C, DellOro R,
Stella ML, and Mancia G. Sympathetic and reflex alterations
in systo-diastolic and systolic hypertension of the elderly. J Hypertens 18: 587593, 2000.
19. Gribbin B, Pickering TG, Sleight P, and Peto R. Effect of
age and high blood pressure on baroreflex sensitivity in man.
Circ Res 29: 424431, 1971.
20. Hunt BE, Farquar WB, and Taylor JA. Does reduced vascular stiffening fully explain preserved cardiovagal baroreflex
function in older, physically active men? Circulation 103: 2424
2427, 2001.
21. Jingu S, Takeshita A, Imaizumi T, Sakal K, and Nakamura
M. Age-related decreases in cardiac receptor control of forearm
vascular resistance in humans. Clin Exp Hypertens A11: 211
216, 1989.
22. Jones PP, Christou DD, Jordan J, and Seals DR. Baroreflex
buffering is reduced with age in healthy men. Circulation 107:
17701774, 2003.
23. Julius S, Antoon A, Witlock LS, and Conway J. Influence of
age on the hemodynamic response to exercise. Circulation 36:
222230, 1976.
24. Lakatta EG. Arterial and cardiac aging: major shareholders in
cardiovascular disease enterprises. Part III. Cellular and molecular clues to heart and arterial aging. Circulation 107: 490497,
2003.
25. Lakatta EG, Gerstenblith G, Angell CS, Shock NW, and
Weisfeldt ML. Prolonged contraction duration in aged myocardium. J Clin Invest 55: 6168, 1975.
26. Lakatta EG and Levy D. Arterial and cardiac aging: major
shareholders in cardiovascular disease enterprises. Part I. Aging
arteries: a set up for vascular disease. Circulation 107: 139
146, 2003.
27. Lakatta EG and Levy D. Arterial and cardiac aging: major
shareholders in cardiovascular disease enterprises. Part II: The
aging heart in health: links to heart disease. Circulation 107:
346354, 2003.
28. Lakatta EG and Yin FC. Myocardial aging: functional alterations and related cellular mechanisms. Am J Physiol Heart Circ
Physiol 242: H927H941, 1982.
29. Levy BI, Michel JB, Salzmann JL, Devissaguet M, and
Safar ME. Remodeling of heart and arteries by chronic converting enzyme inhibition in spontaneously hypertensive rats. Am J
Hypertens 4: 240S245S, 1991.
30. Li Z, Fro lich J, Galis ZS, and Lakatta EG. Increased expression of matrix metalloproteinase-2 in the thickened intima of
aged rats. Hypertension 33: 116123, 1999.
31. Mangoni AA, Mircoli L, Giannattasio C, Mancia G, and
Ferrari AU. Effect of sympathectomy on mechanical properties
of common carotid and femoral arteries. Hypertension 30: 1085
1088, 1997.
32. Matsukawa T, Sugiyama Y, Watanabe T, Kobayashi F, and
Mano T. Baroreflex control of muscle sympathetic nerve activity