doi: 10.1161/hh1001.091963
© 2001 American Heart Association, Inc.
Editorial |
Heart Aging
A Fly in the Ointment?
From the Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute of Aging, National Institute of Health, Baltimore, Md.
Correspondence to Edward G. Lakatta, MD, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute of Aging, National Institute of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224. E-mail lakattae{at}grc.nia.nih.gov
Key Words: heart rate • aging heart • Drosophila
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Introduction |
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 Top Introduction References |
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Epidemiological studies have determined that age, per se, is the major risk for coronary artery disease, hypertension, and resultant chronic heart failure, which are the major diseases that affect our society. One interpretation of the marked effect of advancing age on the occurrence of these diseases is that aging is synonymous with these disease processes; another is that other defined risk factors for these diseases, eg, hypertension or diabetes, vary in number or severity with increasing age. Still another viewpoint posits that increasing age is the equivalent of an increased time at risk. A contrasting view is that cardiovascular structure and function change with time because of an aging process that alters the substrate on which pathophysiologic mechanisms interact.1 According to this view, age-associated changes become partners with these disease mechanisms to determine the threshold for clinical signs and symptoms, severity, and prognosis of cardiovascular diseases in older persons. In this regard, the enhanced risk for older persons is attributable to an interaction between age and time-of-disease presence. Researchers of heart disease mechanisms must "fess up" to the recognition of the reality of these age-disease interactions. In reality, interactions are more complex and involve age, disease, lifestyle (including environment), and the genetic components of each of these. We have begun to understand some aspects of the former three, but the latter likely involves complex genetic traits that by and large presently remain elusive.
Quantitative information on
cardiovascular structure and function in health to
define specific phenotypic characteristics or biomarkers of
cardiovascular aging is necessary for an in-depth
analysis of genetic contributions to aging and disease. During
the last three decades, a sustained effort has been applied to
characterize the effects of aging on multiple aspects of
cardiovascular structure and function in study
populations, such as the Baltimore Longitudinal Study on Aging (BLSA).
In this study, community-dwelling volunteers are rigorously screened to
detect both clinical and occult cardiovascular disease
and are characterized with respect to lifestyle (eg, diet and exercise
habits) in an attempt to clarify the interactions of these factors and
those changes that result from aging per
se.2 Perspectives
gleaned from these and other studies in humans and from studies in
animal models indicate that one of the most prominent characteristics
of cardiovascular aging in the absence of detectable
disease is a reduction in the cardiac reserve, attributable in large
measure to a reduction in the maximum heart rate that can be achieved
during stress
(Figure
).
This impaired cardioacceleration during stress is shared by humans and
rodents. In humans, the age-associated heart deficit during treadmill
running can be roughly estimated by the algorithm: 220 minus age in
years.
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Whereas impaired cardioacceleration during stress is a
candidate biomarker of aging in mammals, its genetic basis and that of
other notable age-associated changes in cardiovascular
structure and function3 have
essentially not been addressed. This is attributable, in part, to the
complex interactions of age, disease, lifestyle, and genetics, noted
above. One escape route from the dilemma of these interactions is a
search for genetic markers for heart rate reserve impairment in less
complex organisms than humans and rodents. However, a delineation of
the cardiovascular aging phenotype in less
complex organisms is paramount to unraveling potential genetic
mechanisms involved. In this issue of
Circulation Research,
Paternostro et al4 have
developed methods to study cardiac function in vivo in
Drosophila melanogaster, the
fruit fly, of different adult ages. Using two different approaches to
stress the heart (elevated ambient temperature and external electrical
pacing), these authors found that the maximal heart rate that can be
achieved in these flies is substantially reduced with adult aging. The
maximal heart rate decline with aging in flies over the adult range is
linear, analogous to the age-associated decline in humans
(Figure
).
Other aspects of cardiac aging in
Drosophila, including an
age-associated increase in heart rhythm disturbances, are also
described.
The choice by Paternostro et al4 to target Drosophila melanogaster for characterization of the phenotype of heart aging was undoubtedly dictated by the fact that it is the first organism possessing a circulatory system to have its genome completely sequenced.5 Additionally, the Drosophila genome is relevant to cardiac disease and development in mammals. A recent, large-scale survey of 287 human disease genes within the Drosophila genome showed that 62% have conserved homologues.6 In other studies, Drosophila mutations in the potassium channel gene HERG (human ether-a-go-go–related gene), which causes long-QT syndrome in humans,7 were identified by the homology of HERG to the Drosophila potassium channel gene ether-a-go-golP.8 An important gene that regulates cardiac development in Drosophila that has also been shown to be relevant to cardiac development in higher organisms is the cardiac transcription factor (Nkx2-5/Csx)9 10 in mouse, a homologue of the Drosophila gene tinman.11 There is also evidence that myocyte enhancer binding factor-2 transcription factors and transforming growth factor-ß signaling are involved in cardiogenesis in both flies and mammals.11 These discoveries about cardiac development in Drosophila complement those made in the zebrafish vertebrate model.12
The fruit fly, because of its small number of genes (13 600) and short lifespan,13 has already been commonly used as a model organism for studying the genetics of aging that pertain to longevity. However, studies of this sort in Drosophila, like others of promising models used in research on aging in yeast, worms, and bacteria,14 15 16 17 have focused mainly on the replicative senescence of actively dividing cells. Paternostro et al4 logically propose that genetic screens in flies, on the basis of deviations from the differences in heart rates under stress, could be exploited to identify conserved genes across species that are linked to the rate at which the heart beats and that these genes may be the same as those that are linked to age-associated decline in heart rate and to other aspects of other altered cardiac function declines that accompany aging in Drosophila.
To date there have been no studies describing pacemaker-like cells in Drosophila. But there is a great deal of information on mechanisms that regulate the heart rate in mammals that may provide some clues that are relevant to the search for changes in specific gene expression that may underlie the observed age-associated impairment in cardioacceleration during stress. Impaired cardioacceleration during stress could involve regulatory factors that control the intrinsic pacemaker function of specialized sinoatrial pacemaker cells or modulation of these factors by stretch or autonomic receptor stimulation.
The intrinsic heart rate in humans, ie, that measured in the presence of sympathetic and vagal blockade, decreases between early adulthood and middle age.18 Classic electrophysiological studies have identified several ionic currents involved in regulating the intrinsic heart rate19 that are prime candidates as mechanisms for alterations in heart rate control with aging. Recent studies in isolated mammalian sinoatrial nodal cells have discovered a prominent role of intracellular Ca2+ in the heart rate modulation.20 21 22 23 24 25 More specifically, localized Ca2+ release via ryanodine receptors beneath the sinoatrial nodal cell-surface membrane occurring during the interbeat interval activates the Na+-Ca2+ exchanger, producing an inward current; this augments the slope of the membrane depolarization before the subsequent action potential, leading to its earlier occurrence and, thus, to an increase in heart rate.26 Accordingly, in embryonic stem cells that develop along the cardiac lineage in vitro, the presence of a ryanodine receptor (RyR2) is required for the progressive increase in heart rate with time27 ; in the absence of an Na+-Ca2+ exchange, mice die in utero,28 29 their hearts beatless, although the response to external pacing remains intact.28 (So! Now we have wingless, flightless, and beatless phenotypes.)
In both humans and rodents, impaired signaling via cardiac G protein–coupled receptors is a characteristic feature of cardiac aging that has been linked to impaired heart rate control.3 Specifically, a reduction in spontaneous heart rate variability and in the maximum heart rate achieved during stress in older mammals has been linked to impaired autonomic modulation of the heart rate; a reduced ß-adrenergic component is particularly remarkable in this regard.1 3 Hence, infusions of catecholamines at rest increase heart rate to a lesser extent in older versus younger mammals.3 Although a primitive autonomic nervous system in insects has been reported,30 specific details are lacking. A link between ß-adrenergic stimulation of heart rate and Ca2+ release via ryanodine receptor in mammalian cells has been recently uncovered.31 32 More specifically, ß-adrenergic receptor stimulation exerts its action via recruitment of ryanodine receptors to participate in the preaction potential Ca2+ release, and this amplifies the resultant involvement and slope of the pacemaker potential via the Na+-Ca2+ exchange mechanism noted above.33
Thus, initial genome screens for common genetic bases
for the prominent age-associated decline in heart rate control in
Drosophila
(Figure)
will surely focus on genes that code for proteins for specific ion
channels and Ca2+ regulation and for G
protein–signaling components. Still other mechanisms involved in
altered heart rate control with aging need to be addressed. The number
of sinoatrial nodal cells has been reported to decrease dramatically
with age.3 Factors that
govern impulse generation and conduction among cells, which are
required for an impulse to exit the sinus node, also need to be
addressed. Heart rate control is like a symphony in that many
mechanisms act together to determine heart rate. It is likely that
changes in the expression of multiple genes could be
involved.
In addition to the similarities between the age-associated changes in heart rate control in Drosophila versus human and rodents,4 there are also apparent notable differences. In mammals, the basal or resting heart rate is unchanged or changes minimally with adult age.1 3 In Drosophila, an age-associated decline in the prestress heart rate with aging, which was marked as the age-associated maximum heart rate decline during stress in some experiments, was observed.4 It might be argued that the prestress heart rate in flies studied by Paternostro et al4 is not basal or that, in fact, the decline in the maximum stressed heart rate in flies may be linked to the same mechanism that underlies the prominent decline observed in prestress heart rate. If this were the case, it might complicate the extrapolation of insights from the fly genome to humans. Additionally, the maximum heart rate achievable by external pacing does not decline with age in mammals34 as it does in flies.4 Another apparent difference between humans and flies is that heart rate variability invariably has been found to decline with advancing age in humans3 whereas in flies, Paternostro et al4 have observed an increase in its variability with age.4
Paternostro et
al4 propose a temperature
increase or external pacing to increase heart rate as stressors that
could be used in conjunction with genetic screening. However, are these
stressors appropriate? Might temperature or external pacing act to
change heart rate via some other mechanism than those that underlie the
loss of heart rate control with aging in mammals, eg, adrenergic
receptor stimulation, stretch, or a change in the number of pacemaker
cells and the communication among or between these cells and
surrounding, nonspecialized cells with respect to pacemaker function?
Aerobic stress, such as exercise, is a common stress used in studies of
heart rate reserve in humans and rodents and would be of interest to
use in flies. Previous studies, in fact, have observed an
age-associated reduction in work capacity in
Drosophila as a function of
age.35 In this study, the
ability of flies kept in a vial to climb up the side of the vial after
mechanical stimulation reduced with age over the same age range as the
heart rate declined in the
Figure.
As noted, the heart rate deficit with aging in humans and rodents or
Drosophila is a prominent
component of diminished cardiac reserve and is thus a major factor
underlying the age-associated reduction in aerobic work
capacity.
In summary, the fly seems not an unwelcome addition to the proverbial ointment of cardiac aging but rather may prove to be a valuable new model in the study of cardiac aging, particularly with respect to interactions between age, lifestyle, disease, and genetics involved in the determination of cardiovascular structure and function during the later part of a human’s existence. The extent of the relevance of this type of information gleaned from studies in flies to mice and humans remains to be demonstrated. Although the study by Paternostro et al4 has taken the first big step, it is clear that progress in the genetics of cardiac aging in flies requires additional discoveries to be made in defining the Drosophila cardiac phenotype that evolves during aging. Fly physiologists, take heed!
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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