Transcript Document 7633655

AGE-RELATED NEUROENDOCRINE CHANGES AND
THEIR RELEVANCE TO SUCESSFUL OR PATHOLOGICAL
AGING: ETHICAL ISSUES RELATED TO HORMONE
ADMINISTRATION IN THE ELDERLY
E. Ferrari
Dept of Internal Medicine and Medical Therapy, Chair of Gerontology and Geriatrics –
University of Pavia, Italy
714C University Hall – University of California, Berkeley
Thuesday May 3, 2005
GERONT.GERIATR., PAVIA
AGE-RELATED CHANGES
OF THE CNS
• Neuronal loss and compensatory gliosis: particularly
evident at the level of the limbic-hippocampal system
and of the hypothalamus
• Changes of the central neurotransmitter pathways
GERONT. GERIATR., PV
Brain Res 1985 Sep 2; 342 (1): 37-44
The suprachiasmatic nucleus of the human
brain in relation to sex, age and senile
dementia.
Swaab DF, Fliers E, Partiman TS
“... In both sexes a decrease in SCN volume and cell
number was observed in senescence (80-100 years).
The latter change was especially pronounced in patients
with senile dementia of the Alzheimer type (SDAT).”
GERONT. GERIATR., PV
MELATONIN
SECRETION
SCHEMATIC DIAGRAM OF NEURAL STRUCTURES UNDERLYING CIRCADIAN RHYTHM
(REICHLIN S. – The Pineal in “Cecil Textbook of Medicine” pp. 1199-1201
WYNGAARDEN et al (eds.), W.B. Saunders, Philadelphia, 1982)
GERONT. GERIATR., PV
PLASMA MELATONIN CIRCADIAN RHYTHM
pg/ml
70
(x ± SEM)
60
50
40
30
20
10
0
0
Population
mean
2
4
p
12
16
20
22
ACROPHASE Ø
24
L/D
(95% c.l.) §
MESOR M
AMPLITUDE A
(x ± SEM)
(x ± SEM)
(°)
hours
21.12 ± 3.23
17.16 ± 2.91
- 22° 28'
01:30
% Rhythm
cosinor
summary
YOUNG CONTR. 0.0002
(n=15)
8
55.54
(-04° 05' to - 47° 03') (00:16 to 03:08)
GERONT. GERIATR., PV
MELATONIN RHYTHM AS ENDOGENOUS SYNCHRONIZER FOR OTHER RHYTHMS
Pineal gland
12
Light / Dark
0
Temperature
12
12 h
12 h
Melatonin
SCN
12
0
0
12 h
Cortisol
12
0
12 h
Sleep / Wakefulness
Circadian rhythms
GERONT. GERIATR., PV
GERONT. GERIATR., PV
GERONT. GERIATR., PV
PLASMA MELATONIN (• ) AND ORAL TEMPERATURE ( •)
CIRCADIAN RHYTHMS
HEALTHY YOUNGS (n=14)
pg/mL
ELDERLY SUBJECTS (n=14)
°C
37
70
60
pg/mL
°C
40
37
36.8
50
40
36.6
30
36.4
36.8
30
36.6
20
36.4
20
10
36.2
10
0
0
36
0 2 4
8
12
16
Clock time (hours)
36.2
36
0 2
20 22 24
x ± SEM
4
8
12
16
20 22 24
Clock time (hours)
GERONT. GERIATR., PV
PLASMA MELATONIN
CIRCADIAN RHYTHM
DAY / NIGHT aMT6s
URINARY EXCRETION
80
60
70
50
60
% of the total 24 h
70
40
30
20
10
0
Population
mean
0
2
p
4
8
12
16
20
MESOR M
AMPLITUDE A
(x ± SEM)
(x ± SEM)
22
24
ACROPHASE Ø
L/D
50
***
(x ± SEM)
pg/ml
40
30
20
10
0
(95% c.l.) §
day
night
% Rhythm
cosinor
summary
(°)
hours
*** p < .001
YOUNG CONTR. 0.0002
(n=15)
55.54
21.12 ± 3.23
17.16 ± 2.91
- 22° 28'
01:30
(-04° 05' to - 47° 03') (00:16 to 03:08)
GERONT. GERIATR., PV
PLASMA MELATONIN CIRCADIAN RHYTHM
pg/mL
pg/mL
60
mean±SEM
50
mean±SEM
50
40
30
60
40
**
**
30
*
20
***
***
***
***
20
10
10
0
0
0
2
4
8
12
16
hours
*
**
***
P < .05
p < .01
p < .001
20 22
0
2
4
8
12
16
20 22
hours
young subjects
old subjects (65-85 yrs.)
elderly subjects
very old subjects ( > 85 yrs.)
Magri et al, Chronobiol Int, 14: 385; 1997
GERONT. GERIATR., PV
TOTAL aMT6s EXCRETION RATE
g/24h
***
***
18
*
p < .05
16
*** p < .001
14
*
12
10
8
6
4
2
0
Young
Old healthy
Centen
Magri et al, J Pin Res, 36: 256; 2004
GERONT. GERIATR., PV
aMT6s: NIGHT/DAY RATIO
***
5
4,5
4
3,5
3
2,5
2
1,5
1
0,5
0
Young
** p < .01; *** p < .001
**
Old healthy
Centen
Magri et al, J Pin Res, 36: 256; 2004
GERONT. GERIATR., PV
aMT6s EXCRETION RATE DURING
DAY AND NIGHT (% OF 24H)
n.s.
***
80
70
60
50
40
30
20
10
0
***
%
day
night
*** p < .001
Young
Old healthy
Centen
Age vs ur. aMT6S (day) r = -.449, p < .001
Age vs ur. aMT6s (night) r = -.785, p < .001
Magri et al, J Pin Res, 36: 256; 2004
GERONT. GERIATR., PV
CONCLUSIONS
The age-related decrease of melatonin secretion is well evident also
in long living subjects; indeed, the total excretion rate of aMT6s, the
major metabolite of melatonin, clearly declined with age.
However, a certain maintenance of the circadian periodicity of
melatonin secretion was found in centenarians but not in aged
controls.
Since melatonin plays an important role as endogenous synchronizer
and as free radical scavenger, the persistence of the circadian
organization of melatonin secretion could be of great interest in
successful aging.
GERONT. GERIATR., PAVIA
Circadian profile of plasma melatonin in
healthy young and old subjects and in
demented patients (mean ± SEM)
pg/mL
pg/mL
70
35
60
30
50
25
40

30
20


10



20

15
 

10

0
L/D
0
2
4
8

5
12 16 20 22 24
hours

L/D
0
0
2
4
8
12 16 20 22 24
hours
YOUNG CONTROLS
OLD SUBJECTS
OLD SUBJECTS
AD PATIENTS
DEMENTED PATIENTS
VD PATIENTS
Old subjects vs young controls
 = p<.05;  = p<.01;  = p<.001
AD patients vs VD patients  = p<.05;  = p<.001;  = p<.001
Demented patients vs young controls  = p<.05;  = p<.01;  = p<.001
Demented patients vs old subjects
 = p<.05;  = p<.001;  = p<.001
Ferrari et al, Exp Geront, 35: 1239; 2000
PLASMA MELATONIN
CIRCADIAN RHYTHM
pg/ml
32
pg/ml
24
35
16
30
8
25
0
NOCTURAL PEAK
20
15
10
pg/ml
4
5
0
0
2
4
8
12
16
20
22
24
L/D
3
2
HEALTHY OLD
1
OLD DEPRESSED
0
OLD DEMENTED
MELATONIN INDEX
Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004
RELATIONSHIP BETWEEN MELATONIN SECRETION AND AGING
C Melatonin declines with aging
C Pineal calcification increases with aging
C Melatonin administration (or pineal extracts) prolong life span in
mice
C Grafting og young pineal to old mices increases survival
C Melatonin is a potent free radical scavenger
C Melatonin (via AVT) increases slow wave sleep
C Pinealectomy facilitates the onset of abnormal involontar
movements
C Pinealectomy reduces hypothalamic opioid concentrations
C Pinealectomy disrupts opioid peptides rhythms
C Pinealectomy produces dishinibition of the HPA axis
Therapeutic perspectives of
melatonin in aging
MELATONIN: POSSIBLE ANTI-AGING EFFECTS
Endogenous synchronizer of several biological circadian
rhythms with involvement in the maintenance of the
circadian structure of the organism
Immune-enhancing acticity
General regenerative capacity
Anti-oxidant activity:
• Direct : free radical scavenger
• Indirect : enhancement of the cerebral glutatione peroxidase
activity
GERONT.GERIATR., PV
MELATONIN: POSSIBLE USE IN INSOMNIA
Rationale:
Lower urinary melatonin excretion in elderly subjects with sleep
disturbances
Haimov et al, Br Med J 309: 167; 1994
Evidence:
Melatonin administration (1-2 mg) at bedtime improves the
begining and the maintenance of sleep.
Haimov et al, Sleep 18: 598; 1995
HPA AXIS
THE ROLE OF THE HIPPOCAMPUS IN HYPOTHALAMICPITUITARY ADRENAL AXIS CONTROL
-
-
(from SECKL JR et al., modified J Endocr145; 201-211: 1995)
GERONT. GERIATR., PV
Frontal/Cortex
Hippocampus
GRs
–
–
–
Hypothalamus
+
–
Corticotropin Releasing
Factor (CRF)
Pituitary
+
Adrenocorticotropin
Adrenal Cortex
Corticosteroids
(From LUPIEN et al., Behavioural Brain Research, 127, 137-158, 2001)
MRs
GRs
FRONTAL CORTEX
GRs
HIPPOCAMPUS
MRs
GRs
High cortisol levels
Low cortisol levels
Stress-induced cortisol levels
Basal cortisol levels
Morning cortisol levels
Evening and night cortisol levels
GERONT. GERIATR., PV
EVIDENCES FOR A STRESS – HIPPOCAMPUS LINK
Presence of glucocorticoid receptors in the animal and
human hippocampus
High levels of stress hormones are associated with
impairment in declarative memory
Chronic exposure to high levels of stress hormones is
associated to hippocampal atrophy
Stress hormones can impair neurogenesis in the
hippocampus
GERONT. GERIATR., PV
CLOSED-LOOP SYSTEM OF MODULATORY ACTIONS
Cognitive processing
Cognitive function
Mood and behaviour
Stress hormones
GERONT. GERIATR., PV
ADRENOCORTICAL AGERELATED CHANGES
• Frequent adrenal nodular hyperplasia, as a consequence of silent, multiple
hemorragic events
• Age-related decrease of zona reticularis width, and consequent increase of the
ratio between the fascicolata/reticularis width
• Selective impairment of the 17-20 lyase activity (opposite phenomenon to
adrenarche)
• Relative maintenance of cortisol secretion even if with a trend towards the
increase at night-time
• Progressive age-related reduction of DHEA and DHEAS secretion
GERONT. GERIATR., PV
Circadian profile of plasma ACTH in healthy
young and old subjects (mean ± SEM)
pg/mL
35
30
25
20


15
10









5
L/D
0
0
2
4
8
12 16 20 22 24
hours
YOUNG CONTROLS
OLD SUBJECT
Old subjects vs young controls
 = p<.05;  = p<.01;  = p<.001
Ferrari et al, Neuroendocrinology 61: 464; 1995
Circadian profile of plasma ACTH in healthy
young and old subjects and in demented
patients (mean ± SEM)
pg/mL
pg/mL
35
35
30
30
25
25
20
20
15
15
10
5

 



 




10


5
L/D
0
0
2
4
8
12 16 20 22 24
hours
L/D
0
0
2
4
8
12 16 20 22 24
hours
YOUNG CONTROLS
OLD SUBJECTS
OLD SUBJECTS
AD PATIENTS
DEMENTED PATIENTS
VD PATIENTS
Old subjects vs young controls
 = p<.05;  = p<.01;  = p<.001
Demented patients vs young controls  = p<.05;  = p<.01;  = p<.001
Demented patients vs old subjects
 = p<.05;  = p<.001;  = p<.001
AD patients vs VD patients  = p<.05;  = p<.001;  = p<.001
Ferrari et al, Neuroendocrinology 61: 464; 1995
SERUM CORTISOL CIRCADIAN RHYTHM
µg/dL 25
mean±SEM
20
µg/dL
30
25
15
20
10
15
*
10
***
5
**
*** ***
5
*** ***
0
0 2 4
mean±SEM
***
NADIR
***
***
*
***
***
50
0
0 2 4
8
12
16
20 22 24
Clock time (hours)
ZENITH
AGE vs NADIR
r= .2970
p< .05
AGE vs
r= -.3891
p< .001
r= -.2603
p< .05
8-24
AGE vs AMPLITUDE
150
100
0
8
12
16
20 22 24
Clock time (hours)
% mesor 250
200
***
Student's t test
* p< .05
** p< .01
*** p< .001
OLD SUBJECTS
YOUNG CONTROLS
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
SERUM DHEA-S CIRCADIAN RHYTHM
µmol/L
mean±SEM
µmol/L
10
***
10
8
8
6
4 *
*
**
*
*
*
*
6
*
*
4
2
2
0
0
0 2 4
8
12
16
***
20 22 24
NADIR
ZENITH
Clock time (hours)
Student's t test
AGE vs NADIR
r= -.5510
p< .001
AGE vs ZENITH
AGE vs MESOR
r= -.6605
p< .001
OLD SUBJECTS
r= -.6453
p< .001
YOUNG CONTROLS
AGE vs AMPLITUDE
r= -.5752
p< .001
* p< .05
** p< .01
*** p< .001
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
Circadian profile of serum cortisol in healthy
young and old subjects and in demented
patients (mean ± SEM)
g/dL
25
20
g/dL

 




30

 

 


15
25
20

15

10







5
5
L/D
0
0
2
4
8

10
12 16 20 22 24
hours






L/D
0
0
2
4
8
12 16 20 22 24
hours
YOUNG CONTROLS
OLD SUBJECTS
OLD SUBJECTS
AD PATIENTS
DEMENTED PATIENTS
VD PATIENTS
Old subjects vs young controls
 = p<.05;  = p<.01;  = p<.001
Demented patients vs young controls  = p<.05;  = p<.01;  = p<.001
Demented patients vs old subjects

 = p<.05;  = p<.001;  = p<.001
AD patients vs VD patients  = p<.05;  = p<.001;  = p<.001
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
SERUM CORTISOL CIRCADIAN RHYTHM
µg/dL
20
mean ± SEM
HEALTHY ELD.
MAJOR DEPR.
SENILE DEM.
15
*
*
10
Cortisol level at 2400
Kruskal-Wallis Test:
5
H(2, N=56)=8.26
L/D
* p < 0.016
0
0
2
4
8
12
16
clock time (hours)
20 22 24
Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004
DEXAMETHASONE TEST (1 mg at 23:00)
SERUM CORTISOL CIRCADIAN RHYTHM
***
***
µg/dl
µg/dl
(x ± SEM)
20
*
***
***
15
*
10
15
10
20
***
5
***
***
***
***
***
***
***
0
***
MESOR pre-DXM
MESOR post-DXM
5
***
L/D
0
0
2
4
8
12
16
20
22
24
p<.05; p<.01;
p<.001
Old subjects vs young controls
Old demented vs young controls * p<.05; ** p<.01; *** p<.001
Old demented vs old subjects
p<.05; p<.01;
p<.001
OLD SUBJECTS
OLD DEMENTED
60
50
hours
AGE vs DELTA %
AGE vs CORTISOL MESOR POST DXM
%
r = .44 p < .001
r = .62 p < .001
*
***
40
30
20
10
0
MESOR DELTA %
YOUNG CONTROLS
Magri et al, Chronobiol Int, 14: 385; 1997
SYNACTHEN TEST
(2500 ng i.v. at 20:30)
µg/dl
(mean ± SEM)
60
50
40
40
30
***
**
**
*
A.U.C. (µg/dl/h)
DELTA (µg)
30
20
20


10
0
***
0
°
***
+ 15
°
***
+ 30


***
***
+ 60
+ 90
10
0
minutes
OLD SUBJECTS
OLD DEMENTED
YOUNG CONTROLS
Old subjects vs young controls
° p<.05; °° p<.01; °°° p<.001
Old demented vs young controls
* p<.05; ** p<.01; *** p<.001
Old demented vs old subjects
n
p<.05; nn p<.01; nnn p<.001
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
SERUM DHEA-S CIRCADIAN RHYTHM
µmol/L
µmol/L
10
10
8
8
6
6
4
4
2
*
*
*
**
*
*
*
*
2
*
L/D
0
0
2
4
8
12
16
20 22 24
L/D
0
0
2
4
young controls
old healthy subjects
old demented
old healthy sub. vs young controls
old demented vs young controls
old healthy sub. vs old demented
8
12
16
20 22 24
AD
MID
p< .001
MID vs AD
p< .05
p< .001
* p< .05; ** p< .01
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
Cortisol/DHEAS molar ratio
0,6
0,5
0,4
n
n
n
*
*
*
n
*
*
*
n
n
*
*
*
n
n
0,3
*
*
*
*
*
*
n
*
*
*
n
n
n
n
n
*
*
*
n
n
*
*
*
*
*
*
0,2
(Mean ± SEM)
0,1
0
L/D
-0,1
0
2
4
OLD SUBJECTS
8
12
OLD DEMENTED
Old subjects vs young controls
p<.05; p<.01;
p<.001
Old demented vs young controls * p<.05; ** p<.01; *** p<.001
Old demented vs old subjects
n p<.05; n n p<.01; n n n p<.001
16
20 22 24
YOUNG CONTROLS
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
RELATIONSHIP BETWEEN CORTISOL
AND DHEA-S SECRETION
Ratio between the circadian
mesors of cortisol and DHEA-S
YOUNG CONTROLS
1.42 ± 0.65
OLD HEALTHY SUBJECTS
***6.81 ± 1.10
OLD DEMENTED
** 11.6 ± 1.35
***
SPEARMAN RANK ORDER CORRELATIONS
Mesor Cortisol / Mesor DHEA-S vs Age
r = 0.4566
p < 0.001
Mesor Cortisol / Mesor DHEA-S vs MMSE
r = - 0.3974
p < 0.01
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
SERUM DHEA-S CIRCADIAN RHYTHM
µg/dL 3.5
mean±SEM
3
2.5
2
HEALTHY ELD.
1.5
MAJOR DEPR.
SENILE DEM.
1
0.5
0
0
2
4
8
12
16
clock time (hours)
20 22 24
Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004
The simultaneous evaluation of cortisol and DHEAS secretion
allows us to identify hormonal secretory changes reflecting the
brain steroidal milieu, already present in physiological aging and
more evident in pathological conditions.
The
adrenal
biosynthetic
imbalance
between
cortisol
and
androgens, may play a pathogenetic role in the occurrence of
degenerative changes in selective brain areas, particularly involved
in cognitive and affective performances.
Chronic exposure to stress and the related neuroendocrine
changes especially in aged people could foster the occurrence and
progression of alterations leading to frailty and disease
CEREBRAL MORPHOMETRIC ANALYSIS
HIPPOCAMPUS
cm
3
***
***
5
***
***
4
RIGHT
vs age
vs cortisol noct. increase
vs DHEAs mesor
r = -.88 p<.001
r = .40 p<.05
r = .63 p<.01
LEFT
vs age
vs cortisol noct. increase
vs DHEAs mesor
r = -.82 p<.001
r = .45 p<.05
r = .64 p<.01
3
2
1
0
RIGHT
YOUNG CONTROLS
LEFT
OLD HEALTHY SUB.
OLD DEMENTED
*** p<.001
Magri et al, Dem Ger Cogn Dis, 11: 90; 2000
CONCLUSIONS
The relationships between the hippocampal volume and the
parameters of the cortisol and DHEA-s secretions suggest the
existence of a link between the adrenocortical secretory
dissociation and the degenerative changes of some CNS areas.
Within the limits of our morphometric approach to the study of
brain aging, our results suggest that the changes of the limbic-
hippocampal area may be related more to the subjects’ age, while
the modifications of the hormonal circadian profiles should be
linked to both aging and cerebral pathology.
GERONT. GERIATR., PV
PHYSIOLOGICAL FUNCTIONS OF DHEA(S)
antiautoimmune
antidiabetic
antiosteoporotic
DHEA (S)
antiatherosclerotic
antiobesity
antidementia
anticancer
GERONT. GERIATR., PV
TRIALS OF DHEA REPLACEMENT THERAPY
► DEPRESSION (Wolkowitz, 1997
► ANTIAGING (Yen, 1995)
► DIABETES TYPE 2 (Casson, 1995)
► FATIGUE (Scott, 1999)
► LUPUS (Van Vollenhoven)
Oral dosage range: 5-50 mg/day; doses of 100 mg/day are
sometimes used in elderly individulas
AT TODAY, IN OLDER SUBJECTS, ADMINISTRATION OF
DEHYDROEPIANDROSTERONE HAS NO WELL-DEFINED
BENEFITS
GERONT. GERIATR., PV
Pre-treatment with TGF-β1 protects hippocampal
neurones from induced apoptotic injury
Increased TGF-β1 expression in oldest rats
PROTECTION AGAINST PROGRESSION OF THE CELL
DEATH CASCADE WITH DECREASE IN INDUCED
APOPTOSIS
POSSIBLE MANIPULATION OF ENDOGENOUS
NEUROTROPHIC FACTORS
Henrich-Noack et al, Stroke 1996, Mattson and Furukawa, Rest Neurol Neurosci, 1996,
Bye et al, Neuroscience, 2001