Hypothalamic-Pituitary-Adrenal (HPA) Axis

and Aging
Deepashree Gupta1 and John E. Morley*2

ABSTRACT
Human aging is associated with increasing frailty and morbidity which can result in signifi-
cant disability. Dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to
aging-related diseases like depression, cognitive deficits, and Alzheimer’s disease in some older
individuals. In addition to neuro-cognitive dysfunction, it has also been associated with declin-
ing physical performance possibly due to sarcopenia. This article reviews the pathophysiology
of HPA dysfunction with respect to increased basal adrenocorticotropic hormone (ACTH) and
cortisol secretion, decreased glucocorticoid (GC) negative feedback at the level of the paraven-
tricular nucleus (PVN) of the hypothalamus, hippocampus (HC), and prefrontal cortex (PFC), and
flattening of diurnal pattern of cortisol release. It is possible that the increased cortisol secretion
is secondary to peripheral conversion from cortisone. There is a decline in pregnolone secretion
and C-19 steroids (DHEA) with aging. There is a small decrease in aldosterone with aging, but
a subset of the older population have a genetic predisposition to develop hyperaldosteronism
due to the increased ACTH stimulation. The understanding of the HPA axis and aging remains a
complex area with conflicting studies leading to controversial interpretations.  C 2014 American

Physiological Society. Compr Physiol 4:1495-1510, 2014.

Introduction Human aging is known to be associated with progressive

The release of corticotropin-releasing hormone (CRH),
adrenocorticotropic hormone (ACTH), and cortisol in
response to stress is a vital adaptive response of the body.
Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis
not only provides a quick physical response to stress but also
mediates long-term changes in memory centers in the brain
leading to formation of long-term memories of the experience.
This is an important adaptive mechanism for the body to effec-
tively counteract similar stressors in the future. However, if
this stress reaction is enhanced and/or persistent long term, it
can lead to damage to certain areas of the brain specifically the
prefrontal cortex (PFC), paraventricular neurons (PVN), and
hippocampus (HC) which are important areas for cognition
and memory formation. These areas are also important for
mediating negative cortisol feedback on HPA axis, and dam-
age to these areas perpetuates a vicious cycle of glucocorticoid
excess. Also the absolute number of GC receptors (GR) and
mineralocorticoid or type I receptors (MRs) in these areas
decreases with aging, further blunting the cortisol mediated
negative feedback mechanism. Decrease in numbers of MRs
in the HC are thought to increase basal ACTH and cortisol
concentrations during the quiescent phase-nadir of the circa-
dian rhythm, when circulating cortisol predominantly binds
to MRs. This article discusses these pathologic changes in
detail and the lab abnormalities that accompany them. There
is increased interest in research is this exciting field with
respect to diet (135, 192) and lifestyle changes which can
prevent or reverse morbidity that accompanies aging.
frailty and morbidity. The World Health Organization (WHO)
has estimated that in our lifetime, the number of elderly (ages
65 and up) will triple with a significant reduction in the pro-
portion of children. With increasing human longevity, there
is an increasing focus on research to prevent or delay dis-
abilities associated with aging (67, 125). The HPA hormonal
axis has an important role in maintaining homeostasis and
dysfunction of this axis is one of several plausible pathways
contributing to biological aging (80). Abnormal GC secre-
tion is thought to be involved in many aging-related diseases,
including depression, cognitive deficits, and Alzheimer’s dis-
ease (55, 143, 147, 215). Thus, understanding and modifying
factors underlying abnormal GC signaling may be of consid-
erable importance in the prevention and treatment of aging-
related diseases (163).
ACTH, the principal hormone stimulating adrenal GC
biosynthesis and secretion, is synthesized in the anterior pitu-
itary as part of a much larger precursor molecule called
pro-opiomelanocortin (POMC) (Fig. 1). POMC gets cleaved
into β-lipoprotein and pro-ACTH in the anterior pituitary
* Correspondence to morley@slu.edu
1 Division of Endocrinology, Saint Louis University, St. Louis, Missouri
2 Divisions of Endocrinology and Geriatric Medicine, Saint Louis
University, St. Louis, Missouri
Published online, October 2014 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c130049
Copyright  C American Physiological Society.

Volume 4, October 2014 1495

Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging
MR/GR
− (HC)
PVN
− • Slow/genomic
CRH
− region (hippocampus)
+ • Feedback inhibition at
Anterior pituitary
Posterior pituitary
AVP Stressors
+ IL‐1
POMC IL‐1
+ TNF ‐ α
ACTH
− Figure 2
Adrenal
Glucocorticoids
Figure 1 Normal HPA axis.
and the latter further gets cleaved into ACTH, joining pep-
tide and amino-terminal peptide (58, 228). POMC secretion
is tightly controlled by factors such as CRH, arginine vaso-
pressin (AVP) (138, 186), endogenous circadian rhythm,
stress, and lastly but importantly, feedback inhibition by cor-
tisol. CRH is a 41-amino-acid peptide synthesized in the
PVN of the hypothalamus (4, 238). It is then secreted into the
hypophyseal portal blood and binds to type 1 CRH receptors
on anterior pituitary corticotrophs to stimulate POMC gene
transcription (37). AVP potentiates CRH-mediated POMC
and hence ACTH secretion by acting on V1B receptor (97).
Pro-inflammatory cytokines like interleukin 1 (IL-1), IL-6,
and tumor necrosis factor (TNF)-α and physical stresses can
also augment ACTH secretion, as a direct effect as well as cen-
trally via CRH (11, 38). ACTH binds to G protein-coupled,
melanocortin -2 receptors (MC2R) on adrenocortical cells
(172) to exert both immediate and chronic effects on the
adrenal gland. Acutely adrenal steroidogenesis is increased
via StAR-mediated cholesterol delivery to CYP11A1 enzyme
in the inner mitochondrial membrane (233). Within 24 h of
exposure, ACTH exerts effects at the transcriptional level
to increase synthesis of all steroidogenic CYP enzymes—
CYP11A1, CYP17A1, CYP21A2 as well as CYP11B1 and
hence stimulates GC production (227, 252); it also increases
adrenal weight by inducing both hyperplasia and hypertrophy.
GCs in most mammals is cortisol and corticosterone (CORT)
in rodents; however, CORT can be found in human blood
as well (29). The effect of ACTH on aldosterone secretion
is modest; acutely aldosterone secretion could increase due
to ACTH induced stimulation of early pathways of adrenal
steroidogenesis but this effect is lost with chronic ACTH stim-
ulation. Both GCs and aldosterone exert their genomic effects
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Comprehensive Physiology
Glucocorticoids (GCs) in brain
Mineralocorticoid • Fast/membrane Glucocorticoid
(type I) receptor actions (type II) receptor
actions
• Mainly fou and in limbic • Ubiquitous
distribution in brain
• High affinity for GCs • Low affinity for GCs
nadir of circadian
• Feedback inhibition
after stress response
rhythm • Mediate termination
• Mediate initiation of of stress response
stress response • Promote memory
• Promote appraisal of a consolidation by
novel condition, processing and storing
behavioral flexibility, and experience
selective attention
Glucocorticoid receptors.
via intracellular nuclear receptors termed glucocorticoid or
type II receptor (GR) and mineralocorticoid or type I receptor
(MR), respectively (Fig. 2); they consist of a carboxy-terminal
ligand-binding domain, a central DNA-binding domain and
an N-terminal hypervariable region. The genomic effects of
GCs on MRs and GRs are typically slow in nature; they can
occur in approximately 15 to 30 min after receptor activation
and may last from less than 1 h up to days depending upon
duration of exposure to GCs (59, 118, 170, 171).
There recently has been a discovery of “fast/membrane”
mode of action of MRs and GRs in addition to the
“slow/nuclear” action as described above. This is thought to
be mediated via a nongenomic pathway involving membrane-
located MRs and GRs leading to GC-dependent enhancement
of glutamate in CA1 hippocampal neurons; these membrane
receptors have low ligand affinity compared to nuclear recep-
tors (115, 122, 237). The nongenomic effects occur within
minutes after GC application and have been reported to have
behavioral effects like novelty-induced locomotor activity and
aggressiveness in rats (160, 215).
The human body responds to stressors through differ-
ent physiologic responses. The first response is activation of
sympathetic nervous system and release of adrenaline and
noradrenaline from the adrenal medulla, called the “fight or
flight” response (30, 78). Stressors also activate the HPA axis
by increasing ACTH and GC levels through central actions
of CRH and AVP. Elevation of GCs as a counterregulatory
mechanism to fever, hypoglycemia (69), hypotension, and
exercise (137) is well documented in literature. GCs mobilize
energy by activating proteolysis and lipolysis and inhibiting
glycolysis and immunogenesis in different tissues, to cope
with energy demands triggered by the stressor and to restore
homeostasis (219). When homeostasis has been recovered,
high levels of GCs are tightly regulated by a negative GC
feedback mechanism at the level of the pituitary, PVN, and
HC and this modulates circadian activity of the HPA axis as
well as its stress response (77, 101, 113, 151, 154, 215, 241).
GCs play at least three functions in the brain. The first is,
like in the rest of the body, to regulate energy availability
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Comprehensive Physiology
during the stress response. The second is to promote behav-
ioral adaptation and regulate (either enhance or impair) sev-
eral memory processes (114). The third function of GCs in
the brain is control of the HPA axis activity through GRs.
GCs inhibit POMC gene transcription in the anterior pitu-
itary (138) and CRH and AVP mRNA synthesis and secretion
in the hypothalamus (44, 124). However, GC feedback reg-
ulation of hypothalamic CRH neurons and hippocampal and
PFC pyramidal neurons can become active within seconds
of application of a brief stressor, largely through modulation
of excitatory or inhibitory synaptic inputs to these neurons
(108, 204). MRs are predominantly expressed in the limbic
structures in the brain, mainly the HC and some are also
found in the hypothalamus (75, 105). GR distribution is more
ubiquitous in the brain and highest density is found in the
parvocellular PVN (hypothalamus), in neurons of ascending
aminergic pathways and in limbic neurons controlling PVN
activation trans-synaptically. Coexpression of MR and GR is
most abundant in hippocampal pyramidal cells and amygdale
in almost all species (45, 48, 226).
In the brain, especially in the HC, 11 β-hydroxysteroid
dehydrogenase type 1 (11 β-HSD-1) which regenerates active
glucocorticoids, is widely expressed but the type 2 isoenzyme
of this enzyme, which rapidly inactivates glucocorticoids is
undetectable (47, 76, 113). As a result, MRs bind GCs with a
10-fold higher affinity than GRs and lose their MR selectivity
(47, 203). Binding of GCs to high affinity mineralocorticoid
receptors plays an important role in negative feedback control
and maintenance of basal HPA axis mainly during the nadir
of the circadian rhythm (42, 47) while binding of GCs to low
affinity glucocorticoid receptors plays an important role in
feedback control of HPA axis during stress (180). Chronic
HPA axis inhibition by tonic elevation of plasma GC levels
can regain responsiveness to new acutely applied stressors
by inhibiting noradrenergic neurons via CRH neurons in the
PVN (81).
Specific areas of the brain are activated during the time
of stress-amygdala for emotional response and formation of
emotional memories (153,193), the HC for memory and learn-
ing processes (214), and the frontal cortex for planning and
controlling actions. Together they play an important role in
managing emotions, neuroendocrine responses, and cognitive
learning (199). MRs play an important role in the stress cas-
cade and when activated, amplify the initial stress event (117)
which is followed by MR mediated neuronal stability and
integrity. GR-mediated feedback contains the stress process
and GRs promote memory consolidation by processing and
storing the experience (171, 183, 185, 203, 220). Brain MRs
are also thought to be involved in appraisal of a novel con-
dition, behavioral flexibility (17,184,188), selective attention
and emotions like anxiety (25). Hence MR and GR operate in
balance and mediate initiation (possibly via membrane MR)
(122) and termination of the HPA stress response; termination
is thought to be mediated via negative feedback at intracel-
lular GR, but also MR (93). Compromise of this MR/GR
interaction, particularly in the limbic system neurons during
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Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging
aging is thought to have an adverse impact on mnesic activi-
ties (45). This can lead to an exaggerated or inadequate initial
HPA stress response, impaired containment, delayed recov-
ery, and compromised adaptation, which in turn can make
the brain susceptible to affective pathologies (47). In mice,
global reduction in GR signaling activates the HPA axis and
impairs cognition (185,206), while deletion of GR in forebrain
only increases corticosterone levels and increases depressive-
like behavior (24, 239). In contrast, forebrain-specific dele-
tion of MR leads to learning and memory impairment (17),
while forebrain overexpression of MR enhances memory and
reduces anxiety (134, 211).
Glucocorticoid Cascade Hypothesis
Stress is an important adaptive response of the body, however
if this response is maintained for more time than necessary
or if chronically activated, harmful effects on the body like
immunosuppression, peripheral muscle dysfunction, and neu-
ronal death can appear; this condition is also referred to as
allostatic load (150). Hence stress has been studied as one
of the factors contributing to unsuccessful aging (152). In
1986, Sapolsky et al. (218), proposed the “Glucocorticoid
cascade hypothesis” which suggests that GCs secreted during
times of stress desensitize the HC to further GC exposure
by downregulating GRs. Initially this effect is self-correcting
and hence reversible, however, long-standing downregulation
of GRs and impairment in the negative GC feedback mecha-
nism in aged rats leads to an enhanced exposure of the brain
to the deleterious effects of GCs which, in turn, would perma-
nently reduce the number of GC-sensitive neurons in the HC
(site of learning and memory) and consequently lead to age-
related cognitive deficits. The damage to HC would further
reduce the expression of GRs and MRs leading to decreased
accuracy of the inhibitory control of GCs, which in turn would
further potentiate damage to the HC, also partly due to gradual
increase in GCs over time (20, 22, 191, 224, 257). The conclu-
sion about neuronal death caused by GCs and stress remains
controversial. In young rodents, while chronic injection of
exogenous stress levels of corticosterone produced neuronal
loss of CA3 comparable to aged rats (217), this effect was
observed only if treatment began when the rats were juvenile
and not if prolonged corticosterone exposure occurred only
during adulthood (230). Recent studies by Sapolsky (216-218)
suggest that excessive glucocorticoid stress response may
actually augment aspects of inflammation during acute brain
injury. Two acute neurological injury rat models—Kainic acid
(KA)-induced excite toxic injury to HC and middle cerebral
artery occlusion (MCAO) model of stroke were studied and
findings supported that GCs can act directly activate myeloid
cells. Myeloid cells migrate to the injury site and in this study
increased nuclear p65 levels and decreased anti-inflammatory
signaling of CX3CL1 after KA administration and produced
more IL-6 in MCAO model; this is contrary to the classi-
cal expectation of GCs suppressing immune cell activation
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Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging
(229). This could partially be explained by differing action of
GCs on different brain areas. The classic anti-inflammatory
effects of GCs are typically seen in subcortical regions like
the substantia nigra (210) and hypothalamus (175), whereas
their immune-activating properties have been primarily seen
in forebrain regions like the hippocampus and frontal cortex
(49, 176). In these forebrain regions, even chronic exposure
to GCs (1-2 weeks) can be immune activating, especially if
it occurs before the injury (175). In addition, GC exposure
before an injury has been shown to augment aspects of the
subsequent inflammatory response to several types of CNS
injury (49,52,72,73,144,175,176). The benefits of exogenous
steroid administration in decreasing vasogenic edema sur-
rounding brain tumors, abscesses, after neurosurgical manip-
ulation and in some inflammatory and auto-immune diseases
like SLE are well known. However, steroids are relatively
ineffective for cytotoxic and vasogenic brain edema during
and after ischemic injury (112) and are contraindicated for
reducing intra cranial pressure in patients with severe Trau-
matic Brain Injury after the multicenter CRASH trial revealed
increased all-cause mortality in patients who received corti-
costeroids vs. the placebo group (207).
Plasma GC gets suppressed by dexamethasone (DEX)
infusions into each brain region of young rats implying that
each region has a role as the feedback site in the brain (164).
DEX is a synthetic GC that inhibits HPA axis via negative
feedback and subsequently decreases release of endogenous
cortisol (71, 234). However, when DEX was infused into
each brain region of aged rats, no suppressive response was
observed, indicating that GC negative feedback ability at the
brain level is markedly decreased in aged rats. Also in aged
rats, the GC negative feedback was enhanced at the systemic
levels but attenuated oppositely at the brain level (163).
In the 1980s and 1990s, several studies showed that lesions
of the HC lead to an enhanced production of GCs under acute
stress conditions (104,114,121,219) thus suggesting that neg-
ative GC feedback at the level of HC plays a major inhibitory
role on HPA axis activity (20, 79, 80). In dogs, it was shown
that hippocampal volume as well as the number of hippocam-
pal mineralocorticoid receptors decrease with age (113). Stud-
ies in rodents suggest that the hypothalamic pituitary adrenal
axis with aging is overactive (Fig. 3). There is a reduction in
both type I (mineralocorticoid) and type II (glucocorticoid)
receptors in the hippocampus resulting in a decreased inhibi-
tion of PVN in the hypothalamus (123, 135, 178). This results
in an attenuation of glucocorticoid feedback resulting in an
increase in portal venous CRH and circulating ACTH, deoxy-
corticosterone, and corticosterone (18, 27, 29, 43, 96, 98). As
GC and ACTH levels increase with aging (156), they sup-
press basal AVP levels by feedback inhibition and hence
basal portal AVP concentrations were found to be signifi-
cantly lower in aged compared to young rats. When aged
rats underwent bilateral adrenalectomy followed by physio-
logic GC replacement, basal portal AVP levels normalized to
that observed in young intact animals (173). Age associated
decrease in hippocampal MRs is hypothesized to increase
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Comprehensive Physiology
Anatomy Hormones and receptors
Paraventricular Glucocorticoid
nucleus receptor
Portal vein CRF Peripheral
organ
response
Pituitary
Cortisol
Blood
ACTH
Adrenal
Figure 3 Effects of aging on the rodent hypothalamic-pituitary-
adrenal axis.
basal ACTH and cortisol concentrations during the quiescent
phase-nadir of the circadian rhythm, when circulating corti-
sol predominantly binds to the MRs. (50, 57, 82, 244). The
MR:GR balance hypothesis states that MR and GR imbal-
ance can lead to neuroendocrine dysregulation and impaired
behavioral adaptation, potentially aggravating aging-related
neurocognitive deterioration (183). Downregulation of hip-
pocampal MRs in aged animals, rodents, dogs as well as
primates, has been a consistent finding (46, 82, 106, 204), and
strategies to enhance MR expression were associated with
enhanced cognitive performance. The gain-of-function muta-
tion in the MR in the Brown Norway rat strain was shown to
confer successful aging (148). Also starting tricyclic antide-
pressants in midlife and continuing them until senescence
ameliorated cognitive impairment in aged rats, thought to
be due to upregulation of MR paralleled by lower corticos-
terone secretion (261). The HC is crucial in memory stor-
age and retrieval and plays an important role in declarative
memory. The effect of GCs on brain functions, in particu-
lar, hippocampus related memory performance is now well
documented. It has been described as showing an inverted
U-shape pattern, with too low or too high levels being associ-
ated with impairment while moderate levels enhance perfor-
mance (61,87,120,139,141,159,182,218,223,233,234,258).
Hypercortisolism has been associated with reduced cell sur-
vival, proliferation, and neurogenesis in the brain especially
at the limbic levels of the hippocampal subfield, CA1, CA3,
and dentate gyrus cells (116). Expression levels and signals
through GRs as well as MRs are likely to decrease in the aged
hippocampus. Aged rats exhibiting impaired spatial mem-
ory show decreases in GR density and GR mRNA in the
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Comprehensive Physiology Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging

hippocampus (18, 111). Also, nuclear transport and subse- Disability

quent binding of GRs to the consensus sequence on genes,
that is, GC responsive element, are decreased in the aged Frailty Depression CRF Anorexia
Weight
loss
hippocampus, suggesting the reduced ability of GRs to trans-
duce GC signals (178). The PFC also has an important role Sarcopenia Infections
in maintaining cognitive and memory functions; these are
frequently impaired in elderly subjects. Dysregulation of the Muscle
Immune
function
HPA axis has been shown to be associated with smaller vol- wasting
ume of medial PFC in elderly humans (143). Cortisol Neuronal damage
To some extent, this HPA overactivity is offset by a
decrease in CBG (Cortisol Binding Globulin), resulting in Cognition
Osteopenia
an increase in free corticosterone in older rats (155). The
“glucocorticoid cascade hypothesis” has not been consistently Visceral Insulin Mild
Hip fracture Hypertension cognitive
reproduced in subsequent studies using rats and other models. obesity resistance
impairment
In aged Brown Norway rats, corticosterone levels were very
low but they demonstrated healthy aging (245, 246). Some
Atherosclerosis
of these contradictory findings could be from species-specific Dementia
differences in stress steroid receptor expression (MR and GR
distribution in HC as discussed above). While GRs and MRs Coronary artery
were quite concentrated in the HC of rodent brain (215), disease
non-human primates like Rhesus monkeys express relatively
fewer GRs in the HC but abundant GRs in the hypothalamus Figure 4 Effects of elevated cortisol levels that can accelerate the
aging process.
and pituitary (213). These conflicting findings question the
role of GRs in mediating neuronal death in the HC. Stress
responses in older rats are variable, in some cases showing an stressors, may have dementia or depression, altered sleep pat-
increase and in others no change (103). The ACTH response terns including sleep apnea, obesity or weight loss, alcohol
to hemorrhage in older rats was only 50% of that seen in use and use multiple medications. All of these factors can alter
younger rats (98). Aging Peromyscus californicus showed the HPA axis. In addition, gender differences related to sex
minimal changes in the hypothalamic-pituitary-adrenal axis steroid changes, have not been well studied in older persons.
(94). There is a decrease in portal AVP with aging which For these reasons, the human literature has shown a variety of
as mentioned above, stimulates ACTH production from the contradictory effects.
pituitary in concert with CRH (84). In aged rodents, there is In a prospective study of aging humans, subjects with ris-
a decline in GR number, but not affinity, in peripheral tissues ing cortisol levels during the latest four years demonstrated
(53). This is accompanied by alterations in the glucocorticoid impaired explicit memory with a 14% reduction in hippocam-
inducible tyrosine amino transferase and tryptophan oxyge- pal volume (140). As discussed above, high-affinity MRs are
nase activities in rat liver; these could play a role in changes thought to be responsible for tonic inhibition of HPA activ-
of cell responses to GCs seen with aging (205). Studies in ity during the nadir of the circadian rhythm (15). Conflicting
aged monkeys found an increase in evening cortisol in aged results were elicited when human studies were performed
female rhesus monkeys, an increase in response to CRH and using MR antagonists, like spironolactone to study cortisol
a decrease in cortisol escape after DEX (90).

Table 1 Effects of Aging on the Hypothalamic Pituitary Glucocorti-

Human Studies
Many aging changes are similar to those seen in persons with
hypercortisolemia (Fig. 4). This has led to the concept that
the HPA axis is overactive with aging. However, the data to
support this is limited. The Glucocorticoid Cascade Hypoth-
esis which utilized rats was not reproducible consistently in
human beings and these inconsistencies drew into question the
relevance of Glucocorticoid Cascade Hypothesis for humans
(174). Table 1 summarizes the most likely effects of aging on
the hypothalamic-pituitary-adrenal axis in humans.
Measuring the HPA axis in older persons is fraught with
difficulty. Many older persons live under a variety of illnesses
which alter cytokine levels, have multiple psychological
coid Axis in Humans based on the Best Judgment in Available Literature
r Urinary free cortisol unchanged
r Increased 24 h total and free plasma cortisol
r Increased daily cortisol secretion based on salivary cortisol
r Phase advancement of morning cortisol
r Decreased amplitude of 24 h cortisol secretion
r Increased fragmentation of cortisol secretion
r No change in cortisol binding globulin
r Increased corticosterone production rate
r Small decrease in plasma clearance rate of cortisol
r Increased post dexamethasone cortisol levels
r No change to ACTH response to CRH but a blunted ability of
dexamethasone to suppress the response
r Decreased cortisol response to ACTH
r Older persons had a lower ACTH and cortisol response to a
psychosocial stressor

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Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging
secretion during the circadian rhythm; this could partially
be attributed to the different doses and experimental mod-
els used for these studies. Some studies showed increased
cortisol secretion during both peak and trough of the cir-
cadian rhythm (51, 262), while others showed no discern-
able effect of spironolactone on basal HPA activity or HPA
response to CRH stimulation (14, 53, 160). In normal young
subjects, administration of a more selective MR antago-
nist, canreonate, either as a short infusion or as prolonged
treatment in different doses, induced significant increase in
HPA activity during the nadir phase of the circadian rhythm
(5,16,19,56,82,89,146). High doses of MR antagonists were
shown to enhance HPA response to both CRH and AVP stim-
ulations suggesting increased CRH and AVP levels mediate
the stimulatory effect of MR blockade (5, 16, 106). Blocking
of CNS MRs after pretreatment with canreonate was capa-
ble of enhancing the ACTH and cortisol responses to CRH
during sleep, but not during wakefulness (21). Another study
showed that subchronic treatment with canreonate amplified
cortisol secretion during physical activity and this remained
elevated during subsequent rest (255). In elderly humans,
acute administration of canreonate showed increased HPA
axis activity during the nadir of the circadian rhythm; this
response, however, was less marked than younger subjects,
possibly due to age-related MR function impairment (82).
Subchronic treatment of aging individuals with spironolac-
tone not only increased HPA axis activity during nadir of
circadian rhythm, but also increased circadian peak cortisol
and salivary cortisol concentrations (106).
Studies with MR agonists like fludrocortisone (FC) also
provided interesting data on HPA axis activity. In young
healthy human subjects, high pharmacologic doses of FC can
significantly inhibit cortisol levels during nadir of circadian
rhythm and reduce stimulatory effect of metyrapone on ACTH
and 11-deoxycorticosterone (28,187,189). On the other hand,
acute administration of FC showed only a minor reduction of
HPA activity in elderly subjects (187). Hence based on cur-
rent evidence, there is an increased age associated liability
of human HPA axis particularly with respect to impairment
in central MRs; this seems to be similar to the results from
animal studies.
Interestingly, recent studies have shown that GRs in
humans are susceptible to epigenetic changes related to GR
promoters in response to early-life experiences (35, 157, 181,
222). Phenotypes with MR: GR imbalance due to genetic fac-
tors and early-life experiences might be vulnerable to late-life
stressors (183). Also Glucocorticoid Vulnerability Hypothesis
in contrast to the Glucocorticoid Cascade Hypothesis suggests
that a history of chronic stress leaves an “imprint” on the HC,
making it vulnerable even when GCs are not elevated at the
time of metabolic challenge; hence, chronic stress and GCs
might play a critical role in priming HC to be more suscepti-
ble to subsequent insults (41). More studies are needed in the
future to validate this hypothesis.
In young persons, cortisol has an early morning peak fol-
lowed by a decline throughout the day reaching minimal
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Comprehensive Physiology
levels around midnight. In older persons, this circadian
rhythm is flattened (65, 249). In persons over 70 years of age,
cortisol tends to increase in the evening, though not in all stud-
ies (128, 161, 243, 244). The time of the cortisol nadir tends
to be shorter. These changes are associated with a decrease
in rapid eye movement sleep. The maximum levels of early
morning cortisol tend to occur earlier, that is, exhibiting phase
advancement (161,244). These changes lead to smaller ampli-
tude in the circadian amplitude of cortisol secretion (243).
There is an increase in 24 h plasma free and total cortisol
levels in older men and women (198). This increase is corre-
lated with an increase in corticosteroid production rate. They
also found an increase in lunch-time food associated corti-
sol with aging. There was no change in CBG. The data for
plasma clearance rate (PCR) for cortisol and aging is less
clear. Older data suggested an increase in half-life with aging
and a decrease in PCR (225, 240, 256). However, each of
these studies included using a very high dose of tracer and
assumed a single-pool model. Barton et al. (9, 10) used mod-
ern methodology and found small, nonsignificant, decrease in
PCR in older men and women. Values in women tended to be
lower.
Conventional assessment of only total cortisol may under-
estimate the actual extent of hypercortisolism in the elderly.
Kudielka et al. (127) showed that there was an age-related
reduction in CBG in older men, though this was not seen
by others (191). Salivary cortisol is considered a reasonable
proxy for free cortisol. Salivary cortisol levels showed a ten-
dency to increase with age even when measured at different
times of the day suggestive of age-dependent increases in
basal HPA activity (40, 179). Dmitrieva et al. (54) found that
older males, especially, if they used medications, were more
likely to have slightly higher salivary cortisol levels with a flat-
tened diurnal pattern. When an appropriate protocol to include
only healthy older persons was used, there was no difference
in urinary free cortisol (UFC) in older persons (34). UFC was
slightly lower in older women than men and this has been
confirmed in other studies (85, 236). There is a decline in
urinary aldosterone (236). Higher UFC levels are present in
older persons who have fragmented sleep; interestingly the
association between elevated 24-h UFC and impaired sleep
and earlier awakening was seen in older women not receiving
estrogen replacement therapy (196,197). Elevated interleukin
1-β also correlates with higher UFC levels (197). Levels of
UFC are found to be elevated in persons with dementia (145)
and memory decline (223).
When dynamic testing of the HPA axis with 1 mg
overnight DEX suppression (1 mg orally administered at
2300) was performed, no significant difference in cortisol
levels between young and healthy old subjects was seen;
however post DEX cortisol levels were higher in dementia
patients compared to age-matched controls (143, 177). Some
studies have reported a high percentage of “non-responders”
in healthy old subjects (about 30%) and in dementia patients
(50%) (66, 67). Hence, it is thought that when aging is
associated with dementia, the adreno-cortical response to
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Comprehensive Physiology Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging

stressful events might be greater and more prolonged 67). Aging change Aging change
in males in females
It is well known that depression by itself can be associated
Cholesterol
with a pseudo-Cushingoid state. Intuitively, depressed elderly
(a common comorbidity) may demonstrate decreased ability
of DEX to suppress plasma cortisol and increased basal as Decreased Pregnenolone Decreased
well as stress-related cortisol secretion (32).
Pavlov et al. (191) examined the effects of an evening Decreased
Pregnenolone
sulfate Decreased
ovine CRH injection on stimulated cortisol, ACTH and DHEA
17 OH pregnenolone
levels in 49 healthy men, aged 21 to 86 years. Older men
had higher basal cortisol levels (P < 0.05) but there was
17,20-lyase(desmolase)
no difference in amplitude of either the ACTH or cortisol
response to ovine CRH. They, however, found that peak cor- Decreased Dehydroepiandrosterone Decreased
tisol responses occurred significantly earlier in older men.
DEX is less successful at blunting the CRH effect in older DHEA sulfate Decreased
Decreased
compared to younger persons (95). Conflicting results were
Androstenedione Decreased
seen when a psychosocial stress test elicited a higher ACTH Decreased
response in younger than older adults (127). More studies are Decreased Testosterone Decreased
needed to determine which of these studies is providing the Unchanged Estradiol Decreased
true pattern.
Unchanged 17 OH progesterone

11 Deoxycortisol

Basal Levels of Adrenal Steroid ? Unchanged Cortisol ? Unchanged

Hormones Unchanged Progesterone ? Unchanged

Four studies have examined the effects of aging on circulat- 11 Deoxycorticosterone

ing steroid hormones (13, 99, 131, 167). A composite of their
findings is shown in Figure 5. With aging there is a marked
decline in C-19 steroids [dehydroepiandrosterone (DHEA)
and DHEA-sulfate]. This leads to a decline in sex steroids. It
is important to recognize these adrenal precursor steroids are
converted in active androgens and/or estrogens in peripheral
tissues (132). Thus, in males nearly half of the androgens
are derived in peripheral tissues from metabolizing enzymes
(133). In females approximately 100% of active estrogens
come from adrenal precursor steroids, and nearly three quar-
ters prior to menopause (130). The decline in C-19 steroids
occurs predominantly between 20 to 30 years old and 50 to
60 years old. Changes beyond 60 years are less dramatic.
Studies have shown a small decline in pregnenolone lev-
els with age in men as well as women (13, 99, 131, 167). In
addition, there is a marked decline in pregnenolone sulfate
after 60 years of age (99, 150, 167). The relatively intact lev-
els of 17α OH progesterone, cortisol and progesterone with
aging suggest that the 17, 20 lyase (desmolase) enzyme is age
sensitive.
Response of Aging Adrenals to ACTH
Old rats have a decline in ACTH-stimulated production of cor-
ticosterone from adrenocortical cells (3). This is associated
with an increase in the size of both the zona fasciculata and
reticularis due to an increase in number and volume of cells
(130). Intracellularly, there is an increase in mitochondrial
volume and proliferation of the smooth endoplasmic reticu-
lum. These findings have been interpreted as an attempt by
Corticosterone
Unchanged Aldosterone
Figure 5 The effect of aging on basal adrenal steroid hormones.
increased ACTH secretion to overcome the decline in adrenal
corticosterone production. With aging there is an increase in
cholesterol ester stores in adrenal cells. This suggests that
there is impairment in cholesterol to undergo intramitochon-
drial transformation to pregnenolone.
Human studies with respect to adrenal responsiveness
to ACTH have shown conflicting results. Maki (146) com-
pared the effects of cosyntropin administration in young and
older males who had received DEX suppression. The 3 h
response of all adrenal hormones measured was lower in
older males, despite an increase in the apparent half-life
of cosyntropin. At 24 h, there was an increase in 17-OH-
pregnenolone, providing further evidence for a decrease in
C17, 20 lyase function. While decreased C17, 20 lyase func-
tion was reported in two other studies (190, 250), these two
studies showed unchanged or increased ACTH-stimulatability
of cortisol, aldosterone, and other delta 4 steroids (androstene-
dione, 17-hydroxyprogesterone, and progesterone) with age
than that in young subjects. The adrenal response of delta 5-
steroids (dehydroepiandrosterone, 17-hydroxypregnenolone,
and pregnenolone) to ACTH was found to be significantly
decreased with aging. We postulate that the above mentioned

Volume 4, October 2014 1501

Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging
Decreased
glucocorticoid
receptor
Mild
cortisol
ACTH 11 Hydroxysteroid
Cortisone
Cholesterol Cortisone and
esters poorly cortisol levels
converted to normal
pregnenolone
Increased numbers
and size of
glucocorticoid-
producing cells
Triglycerides
absorbed
postmeal
Figure 6 Hypothesis: Cortisol increase in older persons is due to
conversion of cortisone to cortisol in adipose tissue.
contradictory findings between the Maki and subsequent stud-
ies could be due to DEX pretreatment in the Maki study. In
another study, the adrenal androgen responsiveness to three
doses of ACTH was examined (83). All three doses resulted
in lower responses of DHEA to ACTH in older compared
to younger persons. The cortisol response to ACTH was
similar in older men compared to younger men at the two
higher doses. At the lowest dose there was a significantly
decreased cortisol response in the older group. To surmise,
aging adrenals probably show decreased ACTH stimulation
of adrenal androgens but data with respect to ACTH effects
on other adrenal hormones is conflicting.
We postulate another reason for the small increases in
circulating cortisol and the increased cortisol production rate
seen in older persons. Just as androgenic steroids are produced
in peripheral tissues, so is cortisol from liver and adipose tis-
sue by 11β hydroxysteroid dehydrogenase. It seems likely
that the increase in circulating cortisol in aging is due to an
increase in adipose tissue associated with aging. This would
be compatible with the meal associated increase in cortisol
that has been seen in older persons, related to the increase in
cortisol associated production in fat associated with increas-
ing triglyceride deposition into fat (Fig. 6).
Aldosterone
Aldosterone is produced by the zona glomerulosa of the
adrenal cortex. ACTH stimulates the secretion of aldos-
terone through the stimulation of deoxycorticosterone. Cir-
culating potassium levels also regulate aldosterone secretion.
The major regulator of aldosterone is the renin-angiotensin-
aldosterone system (RAAS).
1502
Comprehensive Physiology
The RAAS is one of the main systems involved in
the regulation of blood pressure and sodium homeostasis.
Aging is associated with a decline in urinary excretion of
18-hydroxycortisol and aldosterone (235). In animal experi-
ments and in humans, decreased plasma renin activity with a
parallel lowering of aldosterone levels was observed with
aging. Young (20-30 year old) subjects were compared with
elderly (62-70 year old) healthy subjects (254). The age-
Cortisol related differences in plasma renin activity and aldosterone
were found to be more pronounced in stimulated conditions
(sitting in an upright position, salt restriction, and plasma
volume depletion) than under basal conditions (14, 102).
Age-related alterations of the kidney (glomerulosclerosis,
Adipose decreased number of functional nephrons) might account for
tissue
increased the age-related differences in the active to inactive plasma
with aging renin ratio. A diminished synthesis of angiotensinogen by the
liver could contribute to the decreased activity of RAAS in
aging. This is partially compensated by increased density of
angiotensin II receptors reported in elderly patients. The intra
renal system showed downregulation of renin mRNA and
angiotensin-converting enzyme levels with aging, whereas
angiotensinogen levels remained stable. The decrease in
renin mRNA appeared to precede the fall in plasma renin
concentration in the aging process. Additional studies in
15-month-old rats confirmed that both basal and stimulated
renal renin release rates were impaired in older rats. Thus, both
decreased renin synthesis and impaired renin release underlie
the fall in plasma renin with normal aging (119). Further-
more, aging is associated with a reduced adrenal responsive-
ness to angiotensin II, contributing to lower production of
aldosterone and alterations of sodium homeostasis. Adrenal
glomerulosa cells from old cows showed lower basal and
angiotensin stimulated aldosterone synthesis (195). Estradiol
and progesterone also stimulate the secretion of renin and
reduced levels of these hormones at menopause could lead to
reduced plasma renin activity.
Aging also has direct effects on adrenal cortical function.
There is 40% reduction of aldosterone in vivo in older rats
given corticotropin-releasing hormone (27). A similar decline
was seen in old rats after ACTH injection (3). In rats, isolated
adrenal capsules containing predominantly the zona glomeru-
losa, showed decreased basal secretion of aldosterone (200).
These perfused capsules also demonstrated both a decreased
sensitivity and magnitude of response to ACTH and potas-
sium. This supports the fact that there is an age-related impair-
ment in adrenal release of aldosterone. Older humans showed
a decrease in plasma response of 19 hydroxyandrost-4-ere-
3, 17 dione, and a lesser decrease in aldosterone to ACTH
stimulation (83, 107). Parker et al. (190) failed to show a
decrease in aldosterone production to ACTH in older humans.
Morimoto et al. (165) reported a reduced aldosterone response
to ACTH in sodium restricted older individuals. Overall, these
studies support a small decrease in aldosterone secretion in
response to ACTH with aging.
Hyperaldosteronism is the most common cause of sec-
ondary hypertension. It occurs in between 5% and 15% of
Volume 4, October 2014
Comprehensive Physiology
middle aged or older males. Hyperaldosteronism is the most
common cause of resistant hypertension (194). These per-
sons tend to be older, have greater vascular stiffness and pro-
nounced left ventricular hypertrophy. Many of these persons
have bilateral adrenal hyperplasia, most probably secondary
to the age-associated increase in ACTH secretion. Recently,
a subset of these individuals has been identified with gain of
function mutations in KLNJ5 (6). These patients have small
aldosterone producing adenomas, often less than 1 cm, that
are missed with computed tomography. Again, expression of
these mutations may be secondary to the age-related increase
in ACTH secretion, particularly as these cells anatomically
resemble cortisol secreting cells of the zona fasciculate.
Adrenomedullary Hormones
and Aging
Central administration of CRH causes increases in
epinephrine and norepinephrine, making it the coordinator
of the peripheral responses to stress (26). In rats, there is a
decrease in CRH mRNA levels in the paraventricular nucleus
with aging and this is related to a decline in catecholamine
response to stress (39).
With aging, sympathetic activation was evident in the
heart, gut and the liver at rest as well as in response to imme-
diate as well as prolonged stressors. Sympathetic nerve activ-
ity at rest, also known as sympathetic tone, is found to be
increased in many parts of the body during aging (63, 248).
The mechanism is thought to be increased turnover of sym-
patho excitatory noradrenaline (or norepinephrine) accompa-
nied by activation of sympathetic outflows to the heart and
hepatomesenteric circulation but not to the kidneys (64, 86).
Conversely, adrenal medullary release of epinephrine is sub-
normal in the elderly, at rest and during stress (62). It was
found that adrenaline (or epinephrine) secretion from the
adrenal medulla was 40% lower in older compared with young
healthy men (248). However, this difference was not reflected
in corresponding plasma adrenaline (or epinephrine) concen-
tration, which is not significantly different based on age,
as plasma clearance was 20% lower in older men. Finally,
adrenaline might be released from the heart at rest in older
individuals. The postulated mechanisms for decreased adrenal
adrenaline production are reductions in preganglionic nerve
activity to the adrenal medulla and reduction in adrenaline
synthesis and storage in the adrenal medulla. Thus, the age-
related changes in sympathetic nerve activity appear to vary
depending on the particular organ system (212, 221). Data
indicate the changes at the effector level; for example, vaso-
constriction and tachycardia in response to standing are the
result of changes in catecholamine receptor function on end-
organ tissues and impairments in end-organ function occur
despite well-maintained or even increased sympathetic nerve
activity. This decline of catecholamine receptor sensitivity
during aging might be a result of receptor desensitization;
Volume 4, October 2014
Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging
alternatively, changes in receptor sensitivity might be the early
event that leads to a compensatory increase in sympathetic
nerve activity (110).
Frailty and Corticosteroids
Frailty is defined as an older person who is functioning nor-
mally, but when exposed to stressful conditions (either phys-
ical or psychological) has a decreased ability to maintain
his/her activities of daily living (166, 169). Frailty is a pre-
disability state and as such needs to be distinguished from
disability.
In 2001, Fried and her colleagues (74) created a physi-
cal frailty phenotype. This consisted of weight loss (10 lbs.
in 1 year), exhaustion (by self-report), grip strength (in the
lowest 20%), walking speed (in the lowest 20%), and low
physical activity (kcals/week in the lowest 20%). This phys-
ical phenotype has been shown to be highly predictive of the
development of disability and mortality (8,23). Epidemiolog-
ical studies have suggested a number of endocrine changes
with aging including vitamin D deficiency and low testos-
terone (in males) are related to frailty (31, 60, 259).
The International Association of Nutrition and Aging has
developed an extremely simple screen for frailty—the FRAIL
(1, 2). This has been shown to have similar predictive failure
to other frailty screening tests (168, 260). The components of
the FRAIL are given in Table 2.
Frail persons are particularly vulnerable to stress and
so it has been postulated that increased activity of the
hypothalamic-pituitary-adrenal axis may accelerate their
decline. Previously, it has been shown that psychosocial stres-
sors, for example, the period after earthquakes or the decision
of Britain to return Hong Kong to China, can increase mor-
tality in old-old persons (36,70). In an attempt to confirm this
hypothesis, a number of studies on the hypothalamic-pituitary
adrenal axis have been undertaken in frail older persons.
Utilizing community dwelling subjects in the Women’s
Health and Aging Study, it was found that both evening corti-
sol and 24 h salivary cortisol were positively correlated with
frailty burden (247). Frailty burden was defined by using the
Fried physical frailty phenotype. Frailty burden was also asso-
ciated with a smaller circadian variation in cortisol. Holanda
et al. (109) also reported increased salivary cortisol in frail
persons. Another study in nursing home residents found that
frail individuals were suppressed to a lesser degree by DEX
than were more successful agers (33). In the Hertfordshire
Table 2 Components of a Simple Screening Test for Frailty—the
FRAIL
Fatigue
Resistance (climb 1 flight of stairs)
Aerobic (walk one block)
Illness (more than 5)
Loss of weight (>5% in 6 months)
1503
Hypothalamic-Pituitary-Adrenal (HPA) Axis and Aging
Aging Study, a high cortisol: DHEA sulfate ratio was associ-
ated with increased frailty (12).
In addition to these findings, Rao et al. (201) found that
only 25% of frail patients responded to 1 mcg ACTH stim-
ulation compared to 80% of nonfrail controls. This relative
hypoadrenalism in frail compared to other older persons needs
to be studied further but there is no current evidence to estab-
lish a causal relationship between hypoadrenalism and frailty.
The effect on cortisol changes with aging has also been
studied on physical performance tests. In the Whitehall II
and Caterphilly Prospective Cohort slower walking speed
was associated with a reduction in diurnal cortisol variabil-
ity (79, 129). In the Longitudinal Aging Study Amsterdam
(LASA), women with higher cortisol levels showed worse per-
formance on a standing balance test; while men had a slower
walking speed and were slower to do chair rises (192). Lower
diurnal salivary cortisol levels were associated with poorer
performance on the Berg Balance Scale and a decrease in
handgrip performance (100). In this study, older participants
had a significantly higher cortisol area under the curve (AUC),
lower overall DHEA levels, lower DHEA AUC, a decreased
diurnal slope of decline and increased cortisol: DHEA ratio.
Sarcopenia is defined as the loss of muscle mass asso-
ciated with limited mobility (68, 208). Miller et al. (162)
examined younger patients with computed tomography deter-
mined loss of psoas muscle area and fat infiltration. They
compared them to age matched controls without muscle loss.
They found that both muscle loss and fat infiltration was asso-
ciated with increased 24 urine cortisol secretion. Waters et al.
(253) reported elevated cortisol and leptin levels in sarcopenic
older subjects relative to their low body fat mass. Overnight
higher UFC levels were an independent predictor of future
fracture at any site (88).
DHEA and its sulfate have been touted as antiaging
hormones. Again, literature shows conflicting data. DHEA-
S has been shown epidemiologically to predict frailty
(68, 136, 208, 251). Valenti et al. (242) found that in males
aged 60 to 79 years of age, DHEA-S was correlated with
muscle strength and calf muscle area. In young menopausal
women DHEA-S was related to loss of appendicular muscle
mass but not muscle strength (209). Lower DHEA-S levels
were associated with a higher degree of physical disability in
women (92). However, in middle aged males DHEA-S failed
to correlate with either muscle mass or grip and lower limb
muscle strength (91). Replacement studies of DHEA on mus-
cle mass and strength have had minimal effects, questioning
DHEA as a likely antiaging hormone (7, 126).
Conclusion
There is reasonable evidence to conclude that with aging there
is an increase in cortisol at the circadian trough and possi-
bly in total throughout the day. There is a clear blunting in
the diurnal rhythm of cortisol production as well as inade-
quate cortisol suppression with DEX suppression. One of the
1504
Comprehensive Physiology
mechanisms behind cortisol elevation could be dysfunction
of MRs in HC with aging. As mentioned above, these high-
affinity receptors bind cortisol at low levels in the HC and
hence control feedback inhibition on HPA-axis at the nadir
of the circadian rhythm. Salivary cortisol studies seemed to
support these results. The reason for the failure to find an
increase in 24 h urine cortisol is uncertain, but could be due
to renal dysfunction for aging. While the glucocorticoid cas-
case hypothesis proposed chronically elevated GC levels in
aged mice leading to neuronal cell loss in the HC resulting in
memory loss, these findings could not be replicated in other
animal models and humans making us question the validity
of this hypothesis. High GCs in aging humans could prime
the aging brain to future metabolic stressors as suggested in
the glucocorticoid vulnerability hypothesis, but more studies
are needed in this area before making any conclusions.
While ACTH levels in aging are also increased, there
could be decreased adrenal responsiveness to ACTH; studies
show conflicting data with respect to cortisol but there seems
to be decreased adrenal androgen production in response to
ACTH. Decreased C 17, 20 lyase levels have been reported.
It is possible that much of the increase in cortisol with aging
is due to conversion of cortisone to cortisol in adipose tissue,
which is increased with aging; however, this is our hypothesis
and there is no literature to support this.
The steroid precursor, pregnenolone, is decreased with
aging due to problems with lipid uptake into mitochon-
dria. The C19 steroids (DHEA and DHEA-S) are markedly
decreased with aging; however the clinical significance of
this is questionable. Aldosterone shows a small decrease and
adrenal medullary epinephrine secretion declines with aging.
Overall, conflicting studies and the problem of reconciling
in vivo and in vitro studies and the decline in glucocorticoid
receptor activity with aging makes it difficult to draw firm
conclusions concerning the physiological outcomes of alter-
ations in the HPA axis with aging. The role, if any, of the HPA
axis in aging, frailty, sarcopenia and Alzheimer’s is uncertain
at this time.
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