THEMED ARTICLE I Hypertension Review

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Aging and hypertension

Expert Rev. Cardiovasc. Ther. 8(11), 15311539 (2010)

Motoki Fukutomi1
andKazuomi Kario2
1
Department of Cardiology, Yamaguchi
Grand Medical Center, 77 Osaki, Hofu,
Yamaguchi 747-8511, Japan
2
Division of Cardiovascular Medicine,
Department of Medicine, Jichi Medical
University School of Medicine, 3311-1,
Yakushiji, Shimotsuke,
Tochigi329-0498, Japan
Aging is known to be a dominant risk factor in the progression of hypertension. Thus,
accompanied by an increasing mean age of the population in developed countries, prevention
and management of hypertension in the elderly is a task of pressing urgency. Age-associated
blood pressure elevation is a result of the aging process in organ systems, which play a key role
in the regulation of blood pressure. In addition, advanced aging of the cardiovascular system
contributes to the presence of a varied phenotype in elderly hypertension, such as nocturnal
hypertension and morning hypertension. Therefore, in order to detect and treat age-associated
hypertension appropriately, it is important to assess ambulatory blood pressure monitoring
throughout the 24-h period.

Author for correspondence:

Tel.: +81 285 587 344
Keywords : aging arterial structure circadian rhythm hypertension morning hypertension
Fax: +81 285 442 132
kkario@jichi.ac.jp
The population in developed countries is rapidly
aging. The worldwide population aged 65years
or older was projected to increase between 2000
and 2003 from 420 to 973million [1] . In Japan,
which is known as the country with the longest
living people, the number of elderly people is
expected to reach 30% of the population within
the next 20years. With the increasing age of
the population, it seems that the incidence of
cardiovascular disease is rising.
Hypertension, the chronic disease commonly
observed in older individuals that has a close
association with aging, largely contributes to
an increase of cardiovascular risk among this
age group (65 years of age). It is also well
known that aging itself is a powerful risk fac-
tor for the development of hypertension, and
blood pressure (BP) progressively elevates with
aging, beginning in childhood and continu-
ing into adulthood [2] . Therefore, manage-
ment of age-associated hypertension may be a
key issue in the prevention of cardiovascular
events among an aging population. However,
the relationship between chronological age and
the development of hypertension varies among
different individuals. For example, one per-
son may develop hypertension during mid-life,
while another will not not display BP elevation
throughout their lifetime. Familial history of
hypertension and genetics are considered to be
unmodifiable factors that have great influence
on such personal variety. In addition to these
factors, the concept of biological age could
also explain the multiplicity of relationship
between aging and hypertension. Biological
age reflects the age-associated functional dec-
rement of body more accurately than chrono-
logical age. With advanced biological age,
there is marked changes in pathophysiological
factors such as arterial structure and func-
tion, renal function, sympathetic nerve system
activity and reninangiotensinaldosterone
system (RAAS) activity. These age-associated
systemic changes strongly contribute to BP
elevation. Furthermore, aged cardiovascular
systems contribute to the presence of abnormal
BP variability. Thus, in order to improve the
cardiovascular prognosis in elderly subjects,
it is necessary to understand the influence of
aging on the various changes in BP.
In this article, we will summarize the aging
process of organs and endocrine systems lead-
ing to BP elevation, and note the representative
clinical features of age-associated hypertension
with the several types of abnormal BP variability.
Mechanism of age-associated
hypertension
Age-associated change of arterial
structure & function
The structure and function of systemic arter-
ies change throughout the lifetime of humans.
It has been reported that intimal wall thick-
ening and dilatation are dominant structural
changes that occur within large elastic arteries
during the human aging process [3] . Thickened

www.expert-reviews.com 10.1586/ERC.10.78 2010 Expert Reviews Ltd ISSN 1477-9072 1531

 Review Fukutomi & Kario
intimal wall with aging is composed of increased matrix pro-
teins including collagen, fibronectin, proteoglycans and vas-
cular smooth muscle cells (VSMCs) [4] . Such age-associated
structural changes in the central artery are accompanied by a
reduction in compliance of elastic arteries and increased vascular
stiffness. Pulse wave velocity (PWV), a noninvasive index of
arterial stiffness, has been established as increasing with age[5] .
Furthermore, advancing age is associated with endothelial dys-
function [6,7] , which is caused by a progressive impairment of
the nitric oxide (NO) pathway and increased oxidative stress.
These age-dependent subclinical changes in vascular structure
and function strongly contribute to the development of hyper-
tension. Recently, this pathophysiology has been recognized as
the early vascular aging (EVA) concept, which was proposed
by Nilsson etal. [8] .
In young individuals who have distensible aorta with pre-
served windkessel function, the arterial pressure wave travels
at a slow speed and returns from the peripheral reflection site in
diastole of the cardiac cycle. On the other hand, in the stiffened
large artery of older people, the arterial pressure wave travels
down faster and returns earlier to the heart in late systole and
augments aortic systolic peak pressure with a decrease of dia-
stolic pressure. These changes in the arterial wave form are the
pathophysiological mechanism of isolated systolic hyperten-
sion, which is commonly seen in elderly hypertensives (Figure1) .
Arterial stiffness
Collagen
Elastin
Endothelial dysfunction
Microvascular remodeling Arterial system
in elderly subject
Expert Rev. Cardiovasc. Ther. Future Science Group (2010)
Figure1. Age-associated change of arterial system and wave-form in elderly subject.
VSMC: Vascular smooth muscle cell.
1532
Recent studies documented that increase of PWV precedes the
development of hypertension [5,9] , suggesting that stiffening of
a large artery may play an important role in the initiation of
age-associated BP elevation. In addition, it was reported that
capillary BP in peripheral sites increases throughout human
aging [10] . Such increased peripheral resistance accompanied by
endothelial dysfunction contributes to enhance the magnitude
of the reflection wave and further augments the systolic BP.
Age-associated change of renal function
Elevation in perfusion pressure in the renal artery results in
an increase in sodium and water excretion by the kidneys, and
this pressure-natriuresis mechanism maintains the appropriate
level of body fluid volume. More than 40years ago, Guyton
and colleagues suggested that the kidneys play a central role
in BP control, and the shift in the pressurenatriuresis curve
at a higher set point is the dominant mechanism of persistent
hypertension[11] . Such a kidney hypothesis is supported by the
transplant study that demonstrated that a kidney from a nor-
motensive donor cured hypertension in subjects with end-stage
renal disease [12] . With advancing age, the weight and size of a
kidney progressively declines after the 40s decade of life, and
renal regression phenomenon involves a change of histological
features in the kidney; for example, glomeruli decrease, glo-
merulosclerosis, tubular atrophy and arterial intimal fibrosis[13] .
Arterial thickness
VSMCs
Matrix proteins
Isolated systolic hypertension
Arterial wave-form in elderly subject
Arterial wave-form in young subject
Ejected wave
Reflected wave
Expert Rev. Cardiovasc. Ther. 8(11), (2010)

These structural changes have a close association with functional
decline in the kidney, suggesting that age-associated renal dys-
function may be one of the most important determinants in BP
elevation with aging.
In addition, it has been reported that dysregulation of effec-
tive sodium excretion by the kidney is largely related to the
circadian BP abnormality. In healthy subjects, ambulatory BP
displays a normal dipping pattern during the night by 1020%
compared with daytime, and this normal type is called dipper.
However, some patients with renal dysfunction tend to show a
diminished fall of BP during the night (<10%), which is called
nondipper[14,15] . This nondipping pattern in patients with renal
dysfunction is a compensatory phenomenon, which enhances
pressure natriuresis during the night for diminished natriuresis of
the daytime [16] . Thus, it has been suggested that elderly hyper-
tensives with advanced renal aging tend to show nocturnal BP
elevation as well as daytime hypertension.
Age-associated changes of the sympathetic
nervoussystem
Earlier studies have documented the increase of sympathetic ner-
vous activity in the spontaneously hypertensive rat (SHR)[17,18]
and hypertensive patients [19] . Based upon this evidence, it has
been suggested that overactivity of the sympathetic nervous
system largely contributes to the development of essential hyper-
tension. It is also well known that this sympathetic nerve acti-
vation gradually progresses with human aging [2022] . In addi-
tion, there is a positive correlation between sympathetic nervous
activity and BP level in older female subjects [23] . These find-
ings indicate the possibility that enhancement of sympathetic
nerve activation with increasing age plays an important role in
the pathogenesis of age-associated hypertension, particularly
in women.
Furthermore, previous studies demonstrated that sympathetic
nerve activation affects not only BP level, but also the 24h BP
profile including day/night BP rhythm. It was documented that
extreme dippers, who have a marked nocturnal BP reduction
(>20%), demonstrated an increase of plasma norepinephrine[24] .
In addition, it was reported that greater levels of sympathetic
activity were linked to increased daytime BP variability and
greater BP fall at night in a study of young normotensive sub-
jects [25,26] . On the other hand, Grassi and colleagues reported
that the riser pattern of circadian BP rhythm, which has higher
nocturnal BP than that of the daytime, was associated with a
greater sympathetic activation compared with dippers, nondip-
pers and extreme dippers [27] . These findings suggest that sym-
pathetic nervous activation may be linked to the two extremes of
circadian BP abnormality, extreme dippers and risers.
Age-associated change of RAAS
Normal aging is characterized by changes in the activity or
responsiveness of hormonal systems, including the RAAS. In
general, the systemic, circulating RAAS is inappropriately nor-
mal or elevated in patients with obesity, despite increased sodium
intake, sodium/water retention and central blood volume,
www.expert-reviews.com
Aging & hypertension Review
suggesting that systemic RAAS activation is a key determinant
in the development of obesity-related hypertension [28] . However,
it is unclear whether this systemic RAAS activation is associated
with the progression of age-associated hypertension, because it is
known that systemic RAAS is gradually suppressed throughout
the aging process [29,30] .
According to previous findings, angiotensinII (ATII) is known
to be not only generated in the circulation, but also produced
in systemic organs, including the kidney vessels, heart, adrenal
gland, eye, testis and brain [31] . It was also reported that such
local RAAS tend to increase with advancing age, indicating that
this age-associated activation of the local hormonal system may
partly affect BP dysregulation with aging. In a rat model study,
it was reported that ATII administered into this rostral ventro-
lateral medulla (RVLM), which is known to be in the brainstem
region regulating the sympathetic tone and baroreceptor reflex,
caused a greater increase in sympathetic nerve activity and BP.
In addition, another study revealed that transgenic rats that have
a deficiency in brain angiotensin did not show age-associated BP
elevation [32] .
It has also been documented that diffuse intimal media thick-
ening of aged central arteries exhibits increased ATII immuno
staining and an increase of ATII downstream proinflammatory
signaling molecules, including TGFb1, matrix metalloprotein-
ases (MMPs) and monocyte chemoattractant protein-1 (MCP1)
in rodents [33] , primates [34] and humans [35] . This age-associated
proinflammatory state promoted by exaggerated local ATII sig-
naling may have a key role in progression of arterial remodeling
and hypertension.
Furthermore, in the Trial of Preventing Hypertension
(TROPHY) study, early pharmacological treatment with ARBs
of subjects with highnormal BP prevented or delayed the
development of clinical hypertension [36] . These findings sug-
gest that RAAS activation at the tissue level contributes to
cardiovascular aging, and that inhibition of this system may
induce a significant protective effect on the development of
age-associatedhypertension.
Environmental factors
It has been well established that there is a positive relationship
between sodium intake and BP, as habitual high sodium intake
accelerates the development of hypertension. However, accord-
ing to a previous report, Yanomamo Indians in the Brazilian
Amazon jungle, who did not use salt in their diet, showed no
BP elevation with aging [37] . This finding suggests that daily
sodium intake is an important factor in the progression of
age-associatedhypertension.
Furthermore, a previous longitudinal study demonstrated
that nuns, who live in environments with little psychosocial
stress, maintained a normal level of BP during 30 years of
follow-up study [38] . In addition, a recent report demonstrated
that chronic but not acute psychosocial stress may be a cause
of BP elevation [39] . These findings suggest that psychosocial
stress is also an important factor for BP elevation throughout
human life.
1533
 Review Fukutomi & Kario
Phenotype of age-associated hypertension
Isolated systolic hypertension
Systolic BP increases throughout a lifetime, while diastolic BP does
not change or decrease particularly over the ages of 5060years.
Thus, isolated systolic hypertension, defined as systolic BP of
140mmHg or higher and diastolic BP below 90mmHg, is known
to be the most frequent type of hypertension among elderly sub-
jects. The National Health and Nutrition Examination Suevey
(NHANES)III study found that 87% of elderly hypertensive
patients showed isolated systolic hypertension [40] . Such character-
istic change in older people, accompanied by a large pulse pressure
(i.e., the difference between systolic and diastolic BP), can mainly
be explained by the age-dependent change of arterial structure and
function, as previously described. Previous studies have confirmed
the association between isolated systolic hypertension and the risk
of morbidity and mortality [41,42] . Furthermore, in patients with
isolated systolic hypertension, several large trials have documented
the improvement of cardiovascular outcome by a reduction in
systolic BP using antihypertensive drugs based on diuretics [43] ,
calcium channel blockers [41,44] and ARBs [45] . Therefore, for
elderly patients with systolic h
ypertension, the control of systolic
BP seems to be significantlybeneficial.
White coat hypertension
White coat hypertension, also called isolated office hypertension,
refers to a persistent BP elevation in the office with a normal
BP outside of the office. Furthermore, the difference between
office BP and daytime BP is usually called the white coat effect
(WCE). Patients with white coat hypertension are known to be
older than normotensives, and advancing age is the strong deter-
minant of WCE [46,47] . Our groups study found that approxi-
mately 3040% of elderly hypertensive subjects were white coat
hypertensive [48,49] . Thus, it is possible that white coat hyperten-
sion with exaggerated WCE is one of the clinical phenotypes
of age-associated hypertension. The mechanisms of the pressor
response of white coat hypertension are not well understood.
However, anxiety and other psychological factors seem to be
related to this phenomenon in the clinical condition. Thus far,
white coat hypertension has been recognized as a low-risk condi-
tion. However, in recent longitudinal studies, white coat hyper-
tension was found to be a risk factor for sustained hypertension
[50,51] and incidence of cardiovascular events [52,53] , indicating
that careful observation is needed for this type of hypertensive
patient over a long period. Furthermore, several studies showed
that a large WCE was associated with increased arterial stiffness
[54] , arterial compliance [55] and carotid intimamedia thickness
[56] compared with normotensives. While these findings suggest
that a large WCE may adversely affect arterial vasculature, it is
possible that arterial aging may be a cause of exaggerated blood
pressure response in the specific environment.
Nocturnal hypertension
As described previously, nondippers have been proposed as one
subgroup with abnormal diurnal BP variation with diminished
nocturnal BP reduction. In older hypertensive patients, the
1534
proportion of nondippers tends to increase compared with in
younger subjects [57] , suggesting that loss of nocturnal BP dip is
one of the feature of age-associated BP abnormality. One study
found that 43% of elderly hypertensive patients demonstrated
nocturnal BP elevation [58] . Previous studies identified several
physiological and psychological factors that appear to underly
this interaction between aging and nocturnal BP rhythm.
Impairment of nocturnal sleep quality, which is the cause and
consequence of restorative physical condition during the night in
elderly people, has a large influence on the abnormal night-time
BP rhythm [59] . In addition, nondipping has also been reported
to be associated with a depressive mood [60] and cognitive impair-
ment [61] , which is observed in a relatively large number of elderly
subjects. Furthermore, in older persons, it is known that reduced
renal capacity of sodium filtration enhances sodium sensitivity
and diminishes the nocturnal BP fall [62] . Thus, with advanced
renal aging, the presence of a nondipping BP profile may reflect
another side of sodium-sensitive hypertension. Many investiga-
tors have reported that nondippers were exposed to a greater
risk of advanced target organ damage, such as left ventricular
hypertrophy [63] , cerebrovascular disease[64] and microalbumin-
uria [65] , than dippers. Therefore, for elderly hypertensives, it is
important to control 24h BP without overlooking nocturnal
BP elevation.
Morning hypertension
It is well known that cardiovascular events occur more frequently
in the morning than at other times of the day. Recent clinical
studies have demonstrated that an exaggerated morning BP surge
is a risk for cardiovascular events [49,66] . From the viewpoint of
circadian BP pattern, there are two types of morning hyperten-
sion (Figure2) . One is the nondipper/riser (nocturnal hyperten-
sion) type, which is accompanied by persistent BP elevation from
night-time to morning. In this type of morning hypertension, it
is possible that a large part of the cardiovascular risk could be
explained by the nocturnal BP elevation.
On the other hand, another type of morning hypertension is
so-called morning BP surge type, which involves extreme BP
elevation at the time of waking. This type of morning hyper-
tension accounts for 20% of elderly hypertensive patients [49] .
The increased morning BP surge seems to be a response to
aadrenergic vasoconstriction with an increase in heart rate,
vascular tone and blood viscosity [67] . Elderly subjects tend to
show the enhanced morning BP surge, suggesting that this type
of hypertension may be partly related to age-associated physi-
cal changes [68] . In addition, in our previous study of elderly
hypertensive patients, silent cerebral infarcts assessed by MRI
and the intimamedia thickness of the internal carotid artery
were significantly associated with exaggerated morning BP surge,
indicating that morning BP surge may have an important role
in the progression of vascular damage [67,69] . Furthermore, in
another recent study, small artery remodeling, which was directly
assessed by the median thickness to lumen diameter ratio of the
subcutaneous small artery, is significantly correlated with a morn-
ing BP surge [70] . Previous studies have reported that small artery
Expert Rev. Cardiovasc. Ther. 8(11), (2010)
 Aging & hypertension Review

Going to bed Waking

Sleep

Morning hypertension
BP (mmHg)

Nondipper/riser (nocturnal hypertension) type

135/85
Morning BP surge
120/75

Surge type

Time

Figure2. Two types of morning hypertension.

BP: Blood pressure.
remodeling is initiated from the earliest stage of hypertension and
is a predictor of incident hypertension in the future [71,72] ; the
presence of exaggerated morning BP surge may indicate a state
of prehypertension [73] .
Orthostatic hypertension
In older people, orthostatic hypotension is a common type of
BP dysregulation leading to dizziness, syncope and fall. On the
other hand, orthostatic hypertension, the clinical condition

p = 0.003
Urinary albumin excretion rate (mg/g Cr)

p = 0.003
Brain natriuretic peptide (pg/ml)

p < 0.02

75.7
250 80
209.1
200 60

150
33.4
40
100 23.6
39.7 20
50 34.1

0 0
OHYPO ONT OHT OHYPO ONT OHT

Figure3. Relationship betweeen orthostatic blood pressure change and the measurement of target organ damage.
OHT: Orthostatic hypertension; OHYPO: Orthostatic hypotension; ONT: Orthostatic normotension.
Reproduced with permission from [75] .

www.expert-reviews.com 1535
 Review Fukutomi & Kario

Aging
relatively younger people may be a sign
Sodium intake
Psychosocial stress of increased cardiovascular risk with
Local RAAS advanced physical aging.

Sympathetic nervous activity Expert commentary

& five-year view
Arterial stiffness Age-associated BP elevation is closely
Microvascular remodeling Renal dysfunction
dependent on the degeneration of function
Endothelial dysfunction
and structure in the cardiovascular system.
Coexistence of different degrees of organ
aging in a person contribute to a variety
Isolated systolic hypertension of clinical hypertension with abnormal
BP variability (Figure4) . This suggests that
Morning hypertension Nocturnal hypertension ambulatory BP measurement is useful for
White coat hypertension Orthostatic hypertension
not only evaluating BP abnormality, but
also the presence of subclinical physical
Figure4. Aging and blood pressure variation. aging. Therefore, a clinical approach using
RAAS: Reninangiotensinaldosterone system. this device would make it possible to pro-
vide an early intervention in age-dependent
with BP elevation upon standing, is also known to be an age- cardiovascular changes leading to the development of hyperten-
associated BP abnormality [74] . In our study of elderly hyperten- sion. In general, among patients with hypertension, it is neces-
sive patients, 10% of patients showed orthostatic hypertension sary to control their BP level strictly in order to improve their
detected by self-measured home BP [75] . While the mecha- cardiovascular prognosis. And when we treat elderly hypertension
nism of orthostatic hypertension is unclear, we have reported with disrupted diurnal blood pressure variation, we should pay
that the increase of a-sympathetic nerve activity upon stand- attention to controlling blood pressure throughout the night and
ing may play an important role in the pathological process of into the early morning. In addition, further studies are required
orthostatic hypertension[24] . This orthostatic hypertension has to research whether normalization of abnormal BP variability
been revealed as a new cardiovascular risk factor in our groups could improve future cardiovascularprognosis.
studies of elderly hypertensives (Figur e 3) [24,75,76] . Clinically,
awaking movement in the morning is accompanied by rapid Financial & competing interests disclosure
postural changes, suggesting that the risk of orthostatic hyper- The authors have no relevant affiliations or financial involvement with any
tension may overlap with surge-type morning hypertension. organization or entity with a financial interest in or financial conflict with
In the Coronary Artery Risk Development in Young Adults the subject matter or materials discussed in the manuscript. This includes
(CARDIA) study, young adults with BP elevation upon stand- employment, consultancies, honoraria, stock ownership or options, expert
ing have a high risk of developing hypertension in the future[77] . testimony, grants or patents received or pending, or royalties.
These findings suggest that orthostatic hypertension among No writing assistance was utilized in the production of this manuscript.

Key issues
Aging is a dominant risk factor of hypertension.
Advanced aging of the arteries, kidneys and the sympathetic nerve system, and local reninangiotensinaldosterone system activation,
contribute to the development of hypertension.
There are several types of age-associated hypertension with abnormal blood pressure variability.
Ambulatory blood pressure monitoring is useful for the detection and management of age-associated hypertension.

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