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GERONT.GERIATR., PAVIA
AGE-RELATED NEUROENDOCRINE CHANGES AND AGE-RELATED NEUROENDOCRINE CHANGES AND THEIR RELEVANCE TO SUCESSFUL OR PATHOLOGICAL THEIR RELEVANCE TO SUCESSFUL OR PATHOLOGICAL
AGING: ETHICAL ISSUES RELATED TO HORMONE AGING: ETHICAL ISSUES RELATED TO HORMONE ADMINISTRATION IN THE ELDERLYADMINISTRATION IN THE ELDERLY
E. FerrariE. 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
AGE-RELATED CHANGES AGE-RELATED CHANGES OF THE CNSOF THE CNS
• Neuronal loss and compensatory gliosis: particularly Neuronal loss and compensatory gliosis: particularly
evident at the level of the limbic-hippocampal system evident at the level of the limbic-hippocampal system
and of the hypothalamusand of the hypothalamus
• Changes of the central neurotransmitter pathwaysChanges of the central neurotransmitter pathways
GERONT. GERIATR., PV
Brain Res 1985 Sep 2; 342 (1): 37-44Brain Res 1985 Sep 2; 342 (1): 37-44
The suprachiasmatic nucleus of the human The suprachiasmatic nucleus of the human brain in relation to sex, age and senile brain in relation to sex, age and senile dementia.dementia.
Swaab DF, Fliers E, Partiman TSSwaab DF, Fliers E, Partiman TS
““... In both sexes a decrease in SCN volume and cell ... In both sexes a decrease in SCN volume and cell number was observed in senescence (80-100 years). number was observed in senescence (80-100 years). The latter change was especially pronounced in patients The latter change was especially pronounced in patients with senile dementia of the Alzheimer type (SDAT).”with senile dementia of the Alzheimer type (SDAT).”
GERONT. GERIATR., PV
MELATONIN MELATONIN SECRETIONSECRETION
SCHEMATIC DIAGRAM OF NEURAL STRUCTURES UNDERLYING CIRCADIAN RHYTHM
(REICHLIN S. – The Pineal in “Cecil Textbook of Medicine” pp. 1199-1201WYNGAARDEN et al (eds.), W.B. Saunders, Philadelphia, 1982) GERONT. GERIATR., PV
(x ± SEM)(x ± SEM)pg/mlpg/ml
22 44 88 1212 1616 2020 222200
1010
2020
3030
4040
5050
6060
7070
00 2424 L/DL/D
PLASMA MELATONIN CIRCADIAN RHYTHM PLASMA MELATONIN CIRCADIAN RHYTHM
% Rhythm% RhythmMESOR MMESOR M
(x ± SEM)(x ± SEM) (x ± SEM)(x ± SEM)
AMPLITUDE AAMPLITUDE A ACROPHASEACROPHASE
(°)(°)
(95% c.l.)(95% c.l.)
hourshours
YOUNG CONTR.YOUNG CONTR. (n=15)(n=15)
pp
0.00020.0002 55.5455.54 21.12 ± 3.2321.12 ± 3.23 17.16 ± 2.9117.16 ± 2.91 - 22° 28'- 22° 28'
(-04° 05' to - 47° 03')(-04° 05' to - 47° 03')
01:3001:30
(00:16 to 03:08)(00:16 to 03:08)
ØØ §§Population Population meanmean
cosinor cosinor summarysummary
GERONT. GERIATR., PV
Pineal glandPineal gland
CortisolCortisol1212 00 1212 hh
1212 00 1212 hh
Sleep / WakefulnessSleep / Wakefulness
1212 00 1212 hh
TemperatureTemperature
MelatoninMelatonin1212 00 1212 hhLight / DarkLight / Dark
SCNSCN
Circadian rhythmsCircadian rhythms
MELATONIN RHYTHM AS ENDOGENOUS SYNCHRONIZER FOR OTHER RHYTHMSMELATONIN RHYTHM AS ENDOGENOUS SYNCHRONIZER FOR OTHER RHYTHMS
GERONT. GERIATR., PV
GERONT. GERIATR., PV
GERONT. GERIATR., PV
pg/mLpg/mL
00 22 44 88 1212 1616 2020 2222 24243636
36.236.2
36.436.4
36.636.6
36.836.8
3737
Clock time (hours)Clock time (hours)00 22 44 88 1212 1616 2020 2222 2424
00
1010
2020
3030
4040
5050
6060
7070°C°C
x ± SEMx ± SEM
pg/mLpg/mL
00 22 44 88 1212 1616 2020 2222 24243636
36.236.2
36.436.4
36.636.6
36.836.8
3737
Clock time (hours)Clock time (hours)00 22 44 88 1212 1616 2020 2222 2424
00
1010
2020
3030
4040°C°C
PLASMA MELATONIN ( ) AND ORAL TEMPERATURE ( )PLASMA MELATONIN ( ) AND ORAL TEMPERATURE ( )CIRCADIAN RHYTHMSCIRCADIAN RHYTHMS
••
HEALTHY YOUNGS (n=14) ELDERLY SUBJECTS (n=14)
GERONT. GERIATR., PV
(x ± SEM)(x ± SEM)pg/mlpg/ml
22 44 88 1212 1616 2020 222200
1010
2020
3030
4040
5050
6060
7070
00 2424 L/DL/D
PLASMA MELATONIN PLASMA MELATONIN CIRCADIAN RHYTHM CIRCADIAN RHYTHM
dayday nightnight
*** p < .001*** p < .001
% o
f th
e to
tal 2
4 h
% o
f th
e to
tal 2
4 h
0010102020
3030
40405050
6060
7070
8080
* *
**
* *
DAY / NIGHT aMT6s DAY / NIGHT aMT6s URINARY EXCRETION URINARY EXCRETION
% Rhythm% RhythmMESOR MMESOR M
(x ± SEM)(x ± SEM) (x ± SEM)(x ± SEM)
AMPLITUDE AAMPLITUDE A ACROPHASEACROPHASE
(°)(°)
(95% c.l.)(95% c.l.)
hourshours
YOUNG CONTR.YOUNG CONTR. (n=15)(n=15)
pp
0.00020.0002 55.5455.54 21.12 ± 3.2321.12 ± 3.23 17.16 ± 2.9117.16 ± 2.91 - 22° 28'- 22° 28'
(-04° 05' to - 47° 03')(-04° 05' to - 47° 03')
01:3001:30
(00:16 to 03:08)(00:16 to 03:08)
ØØ §§Population Population meanmean
cosinor cosinor summarysummary
GERONT. GERIATR., PV
pg/mLpg/mL
00 22 44 88 1212 1616 2020 222200
1010
2020
3030
4040
5050
6060
hourshours
mean±SEMmean±SEM
********
******** ******************
pg/mLpg/mL
00 22 44 88 1212 1616 2020 222200
1010
2020
3030
4040
5050
6060
hourshours
mean±SEMmean±SEM
young subjectsyoung subjects old subjects (65-85 yrs.)old subjects (65-85 yrs.)elderly subjectselderly subjects very old subjects ( > 85 yrs.)very old subjects ( > 85 yrs.)
PLASMA MELATONIN CIRCADIAN RHYTHMPLASMA MELATONIN CIRCADIAN RHYTHM
******
******
P < .05P < .05p < .01p < .01p < .001p < .001
GERONT. GERIATR., PVMagri et al, Chronobiol Int, 14: 385; 1997
0022446688
10101212141416161818
************
**
g/24hg/24h
TOTAL aMT6s EXCRETION RATETOTAL aMT6s EXCRETION RATE
* p < .05* p < .05
*** p < .001*** p < .001
YoungYoung CentenCentenOld healthyOld healthy
GERONT. GERIATR., PVMagri et al, J Pin Res, 36: 256; 2004
aMT6s: NIGHT/DAY RATIOaMT6s: NIGHT/DAY RATIO
000,50,5
111,51,5
222,52,5
333,53,5
444,54,5
55 ****** ****
** p < .01; *** p < .001** p < .01; *** p < .001
YoungYoung CentenCentenOld healthyOld healthy
GERONT. GERIATR., PVMagri et al, J Pin Res, 36: 256; 2004
aMT6s EXCRETION RATE DURING aMT6s EXCRETION RATE DURING DAY AND NIGHT (% OF 24H)DAY AND NIGHT (% OF 24H)
Age vs ur. aMT6S (day) r = -.449, p < .001Age vs ur. aMT6S (day) r = -.449, p < .001Age vs ur. aMT6s (night) r = -.785, p < .001Age vs ur. aMT6s (night) r = -.785, p < .001
Old healthyOld healthy00
10102020303040405050606070708080%%
n.s.n.s.
YoungYoung
* *
**
* * dayday nightnight
*** p < .001*** p < .001
CentenCenten
* *
**
* *
GERONT. GERIATR., PVMagri et al, J Pin Res, 36: 256; 2004
CONCLUSIONS CONCLUSIONS
The age-related decrease of melatonin secretion is well evident also The age-related decrease of melatonin secretion is well evident also
in long living subjects; indeed, the total excretion rate of aMT6s, the in long living subjects; indeed, the total excretion rate of aMT6s, the
major metabolite of melatonin, clearly declined with age. major metabolite of melatonin, clearly declined with age.
However, a certain maintenance of the circadian periodicity of However, a certain maintenance of the circadian periodicity of
melatonin secretion was found in centenarians but not in aged melatonin secretion was found in centenarians but not in aged
controls. controls.
Since melatonin plays an important role as endogenous synchronizer Since melatonin plays an important role as endogenous synchronizer
and as free radical scavenger, the persistence of the circadian and as free radical scavenger, the persistence of the circadian
organization of melatonin secretion could be of great interest in organization of melatonin secretion could be of great interest in
successful aging.successful aging.
GERONT. GERIATR., PAVIAGERONT. GERIATR., PAVIA
Circadian profile of plasma melatonin in Circadian profile of plasma melatonin in healthy young and old subjects and in healthy young and old subjects and in
demented patients (mean ± SEM)demented patients (mean ± SEM)
001010202030304040505060607070
00 22 44 88 1212 1616 2020 2222 24240055
101015152020252530303535
00 22 44 88 1212 1616 2020 2222 2424L/DL/D
hourshours
pg/mLpg/mL
L/DL/D
hourshours
pg/mLpg/mL
YOUNG CONTROLSYOUNG CONTROLS
OLD SUBJECTSOLD SUBJECTS
DEMENTED PATIENTSDEMENTED PATIENTS
OLD SUBJECTSOLD SUBJECTS
AD PATIENTSAD PATIENTS
VD PATIENTSVD PATIENTS
Old subjects vs young controls Old subjects vs young controls = p<.05; = p<.05; = p<.01; = p<.01; = p<.001 = p<.001
Demented patients vs young controls Demented patients vs young controls = p<.05; = p<.05; = p<.01; = p<.01; = p<.001 = p<.001
Demented patients vs old subjects Demented patients vs old subjects = p<.05; = p<.05; = p<.001; = p<.001; = p<.001 = p<.001
AD patients vs VD patients AD patients vs VD patients = p<.05; = p<.05; = p<.001; = p<.001; = p<.001 = p<.001
Ferrari et al, Exp Geront, 35: 1239; 2000
PLASMA MELATONIN PLASMA MELATONIN CIRCADIAN RHYTHMCIRCADIAN RHYTHM
00
55
1010
1515
2020
2525
3030
3535
00 22 44 88 1212 1616 2020 2222 2424
pg/mlpg/ml
L/DL/D
00
11
22
33
44
MELATONIN INDEXMELATONIN INDEX
pg/mlpg/ml
00
88
1616
2424
3232
NOCTURAL PEAKNOCTURAL PEAK
pg/mlpg/ml
HEALTHY OLDHEALTHY OLD
OLD DEMENTEDOLD DEMENTEDOLD DEPRESSEDOLD DEPRESSED
Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004Ferrari 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
GERONT.GERIATR., PV GERONT.GERIATR., PV
MELATONIN: POSSIBLE ANTI-AGING EFFECTSMELATONIN: POSSIBLE ANTI-AGING EFFECTS
Endogenous synchronizer of several biological circadian Endogenous synchronizer of several biological circadian rhythms with involvement in the maintenance of the rhythms with involvement in the maintenance of the circadian structure of the organismcircadian structure of the organism
Immune-enhancing acticityImmune-enhancing acticity
General regenerative capacityGeneral regenerative capacity
Anti-oxidant activity:Anti-oxidant activity:Direct :Direct : free radical scavenger free radical scavengerIndirect : Indirect : enhancement of the cerebral glutatione peroxidase enhancement of the cerebral glutatione peroxidase activityactivity
••••
MELATONIN: POSSIBLE USE IN INSOMNIAMELATONIN: 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 AXISHPA AXIS
THE ROLE OF THE HIPPOCAMPUS IN HYPOTHALAMIC-PITUITARY ADRENAL AXIS CONTROL
-
-
-
(from SECKL JR et al., modified J Endocr145; 201-211: 1995) GERONT. GERIATR., PV
Frontal/CortexFrontal/Cortex HippocampusHippocampus
HypothalamusHypothalamus
PituitaryPituitary
Adrenal CortexAdrenal Cortex
GRsGRs MRsMRsGRsGRs––––
++
++
––
––
Corticotropin ReleasingCorticotropin ReleasingFactor (CRF)Factor (CRF)
AdrenocorticotropinAdrenocorticotropin
CorticosteroidsCorticosteroids
(From LUPIEN et al., Behavioural Brain Research, 127, 137-158, 2001)(From LUPIEN et al., Behavioural Brain Research, 127, 137-158, 2001)
FRONTAL CORTEXFRONTAL CORTEX HIPPOCAMPUSHIPPOCAMPUS
GRsGRs
GRsGRs
MRsMRs
Low cortisol levelsLow cortisol levels
Basal cortisol levelsBasal cortisol levels
Evening and night cortisol levelsEvening and night cortisol levels
High cortisol levelsHigh cortisol levels
Stress-induced cortisol levelsStress-induced cortisol levels
Morning cortisol levelsMorning cortisol levels
GERONT. GERIATR., PV
EVIDENCES FOR A STRESS – HIPPOCAMPUS LINKEVIDENCES FOR A STRESS – HIPPOCAMPUS LINK
Presence of glucocorticoid receptors in the animal and Presence of glucocorticoid receptors in the animal and human hippocampushuman hippocampus
High levels of stress hormones are associated with High levels of stress hormones are associated with impairment in declarative memoryimpairment in declarative memory
Chronic exposure to high levels of stress hormones is Chronic exposure to high levels of stress hormones is associated to hippocampal atrophyassociated to hippocampal atrophy
Stress hormones can impair neurogenesis in the Stress hormones can impair neurogenesis in the hippocampushippocampus
GERONT. GERIATR., PV
Stress hormonesStress hormones
Cognitive functionCognitive function
Mood and behaviourMood and behaviour
Cognitive processingCognitive processing
CLOSED-LOOP SYSTEM OF MODULATORY ACTIONSCLOSED-LOOP SYSTEM OF MODULATORY ACTIONS
GERONT. GERIATR., PV
ADRENOCORTICAL AGE-ADRENOCORTICAL AGE-RELATED CHANGES RELATED CHANGES
• Frequent adrenal nodular hyperplasia, as a consequence of silent, multiple Frequent adrenal nodular hyperplasia, as a consequence of silent, multiple
hemorragic eventshemorragic events
• Age-related decrease of zona reticularis width, and consequent increase of the Age-related decrease of zona reticularis width, and consequent increase of the
ratio between the fascicolata/reticularis widthratio between the fascicolata/reticularis width
• Selective impairment of the 17-20 lyase activity (opposite phenomenon to Selective impairment of the 17-20 lyase activity (opposite phenomenon to
adrenarche)adrenarche)
• Relative maintenance of cortisol secretion even if with a trend towards the Relative maintenance of cortisol secretion even if with a trend towards the
increase at night-timeincrease at night-time
• Progressive age-related reduction of DHEA and DHEAS secretionProgressive age-related reduction of DHEA and DHEAS secretion
GERONT. GERIATR., PV
Circadian profile of plasma ACTH in healthy Circadian profile of plasma ACTH in healthy young and old subjects (mean ± SEM)young and old subjects (mean ± SEM)
hourshours
0055
101015152020252530303535
00 22 44 88 1212 1616 2020 2222 2424L/DL/D
pg/mLpg/mL
YOUNG CONTROLSYOUNG CONTROLS
OLD SUBJECTOLD SUBJECT
Old subjects vs young controls Old subjects vs young controls = p<.05; = p<.05; = p<.01; = p<.01; = p<.001 = p<.001
Ferrari et al, Neuroendocrinology 61: 464; 1995
Circadian profile of plasma ACTH in healthy Circadian profile of plasma ACTH in healthy young and old subjects and in demented young and old subjects and in demented
patients (mean ± SEM)patients (mean ± SEM)
0055
101015152020252530303535
00 22 44 88 1212 1616 2020 2222 2424hourshours
L/DL/D
hourshours
pg/mLpg/mL
0055
101015152020252530303535
00 22 44 88 1212 1616 2020 2222 2424L/DL/D
pg/mLpg/mL
YOUNG CONTROLSYOUNG CONTROLS
OLD SUBJECTSOLD SUBJECTS
DEMENTED PATIENTSDEMENTED PATIENTS
OLD SUBJECTSOLD SUBJECTS
AD PATIENTSAD PATIENTS
VD PATIENTSVD PATIENTS
Old subjects vs young controls Old subjects vs young controls = p<.05; = p<.05; = p<.01; = p<.01; = p<.001 = p<.001
Demented patients vs young controls Demented patients vs young controls = p<.05; = p<.05; = p<.01; = p<.01; = p<.001 = p<.001
Demented patients vs old subjects Demented patients vs old subjects = p<.05; = p<.05; = p<.001; = p<.001; = p<.001 = p<.001
AD patients vs VD patients AD patients vs VD patients = p<.05; = p<.05; = p<.001; = p<.001; = p<.001 = p<.001
Ferrari et al, Neuroendocrinology 61: 464; 1995
NADIRNADIR ZENITHZENITH00
55
1010
1515
2020
2525
3030
SERUM CORTISOL CIRCADIAN RHYTHMSERUM CORTISOL CIRCADIAN RHYTHM
Clock time (hours)Clock time (hours)
µg/dLµg/dL
00 22 44 88 1212 1616 2020 2222 242400
55
1010
1515
2020
2525
Clock time (hours)Clock time (hours)
% mesor% mesor
00 22 44 88 1212 1616 2020 2222 242400
5050
100100
150150
200200
250250
*** ****** ***
***
*
**
******
*** ***
***
*
mean±SEMmean±SEM
mean±SEMmean±SEM
µg/dLµg/dL
OLD SUBJECTSOLD SUBJECTSYOUNG CONTROLSYOUNG CONTROLS
*** p< .001*** p< .001** p< .01** p< .01* p< .05* p< .05
***
AGE vs NADIRAGE vs NADIR r= .2970r= .2970 p< .05p< .05
AGE vs 8-24AGE vs 8-24 p< .001p< .001r= -.3891r= -.3891
AGE vs AMPLITUDEAGE vs AMPLITUDE p< .05p< .05r= -.2603r= -.2603
Student's t testStudent's t test
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
SERUM DHEA-S CIRCADIAN RHYTHMSERUM DHEA-S CIRCADIAN RHYTHM
OLD SUBJECTSOLD SUBJECTSYOUNG CONTROLSYOUNG CONTROLS *** p< .001*** p< .001
** p< .01** p< .01* p< .05* p< .05
AGE vs NADIRAGE vs NADIR r= -.5510r= -.5510 p< .001p< .001AGE vs ZENITHAGE vs ZENITH r= -.6605r= -.6605 p< .001p< .001AGE vs MESORAGE vs MESOR r= -.6453r= -.6453 p< .001p< .001AGE vs AMPLITUDEAGE vs AMPLITUDE p< .001p< .001r= -.5752r= -.5752
Clock time (hours)Clock time (hours)
µmol/Lµmol/L µmol/Lµmol/L
00 22 44 88 1212 1616 2020 2222 242400
22
44
66
88
1010
NADIRNADIR ZENITHZENITH00
22
44
66
88
1010
mean±SEMmean±SEM
** * *
* * * ***
***
***
Student's t testStudent's t test
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
Circadian profile of serum cortisol in healthy Circadian profile of serum cortisol in healthy young and old subjects and in demented young and old subjects and in demented
patients (mean ± SEM)patients (mean ± SEM)
00
55
1010
1515
2020
2525
00 22 44 88 1212 1616 2020 2222 24240055
10101515
2020
2525
3030
00 22 44 88 1212 1616 2020 2222 2424
L/DL/D
hourshours
L/DL/D
hourshours
g/dLg/dL g/dLg/dL
YOUNG CONTROLSYOUNG CONTROLS
OLD SUBJECTSOLD SUBJECTS
DEMENTED PATIENTSDEMENTED PATIENTS
OLD SUBJECTSOLD SUBJECTS
AD PATIENTSAD PATIENTS
VD PATIENTSVD PATIENTS
Old subjects vs young controls Old subjects vs young controls = p<.05; = p<.05; = p<.01; = p<.01; = p<.001 = p<.001
Demented patients vs young controls Demented patients vs young controls = p<.05; = p<.05; = p<.01; = p<.01; = p<.001 = p<.001
Demented patients vs old subjects Demented patients vs old subjects = p<.05; = p<.05; = p<.001; = p<.001; = p<.001 = p<.001
AD patients vs VD patients AD patients vs VD patients = p<.05; = p<.05; = p<.001; = p<.001; = p<.001 = p<.001
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
clock time (hours)clock time (hours)00 22 44 88 1212 1616 2020 2222 2424
00
55
1010
1515
2020
** **
µg/dLµg/dL
SERUM CORTISOL CIRCADIAN RHYTHMSERUM CORTISOL CIRCADIAN RHYTHM
Cortisol level at 24Cortisol level at 240000 Kruskal-Wallis Test: Kruskal-Wallis Test:
H(2, N=56)=8.26H(2, N=56)=8.26
* * p < 0.016p < 0.016
mean ± SEMmean ± SEM
L/D
HEALTHY ELD.HEALTHY ELD.
MAJOR DEPR.MAJOR DEPR.
SENILE DEM.SENILE DEM.
Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004
DEXAMETHASONE TEST (1 mg at 23:00)DEXAMETHASONE TEST (1 mg at 23:00) SERUM CORTISOL CIRCADIAN RHYTHM SERUM CORTISOL CIRCADIAN RHYTHM
µg/dlµg/dl (x ± SEM)(x ± SEM)
hourshours
MESOR DELTA %MESOR DELTA %00
1010
2020
3030
4040
5050
6060******
********%%
MESOR pre-DXMMESOR pre-DXM MESOR post-DXMMESOR post-DXM00
55
1010
1515
2020
******
**
******
******
********
µg/dlµg/dl
OLD SUBJECTSOLD SUBJECTS OLD DEMENTEDOLD DEMENTED YOUNG CONTROLSYOUNG CONTROLS
Old subjects vs young controlsOld subjects vs young controlsOld demented vs young controlsOld demented vs young controlsOld demented vs old subjectsOld demented vs old subjects
p<.05; p<.05; p<.01; p<.01; p<.001 p<.001** p<.05; p<.05; **** p<.01; p<.01; ****** p<.001 p<.001 p<.05; p<.05; p<.01; p<.01; p<.001 p<.001
AGE vs DELTA %AGE vs DELTA %AGE vs CORTISOL MESOR POST DXM AGE vs CORTISOL MESOR POST DXM
r = .44 p < .001r = .44 p < .001r = .62 p < .001r = .62 p < .001
22 44 88 1212 1616 2020 222200
55
1010
1515
2020
00
******
******
******
******
******
******
******
******
L/DL/D
2424
******
Magri et al, Chronobiol Int, 14: 385; 1997
Old subjects vs young controlsOld subjects vs young controlsOld demented vs young controlsOld demented vs young controlsOld demented vs old subjectsOld demented vs old subjects
p<.05; p<.01; p<.001p<.05; p<.01; p<.001* * p<.05;p<.05; ** ** p<.01;p<.01; *** *** p<.001p<.001 p<.05;p<.05; p<.01;p<.01; p<.001p<.001
SYNACTHEN TESTSYNACTHEN TEST(2500 ng i.v. at 20:30)(2500 ng i.v. at 20:30)
OLD SUBJECTSOLD SUBJECTS OLD DEMENTEDOLD DEMENTED YOUNG CONTROLSYOUNG CONTROLS
00 1515 3030 6060 909000
1010
2020
3030
4040
5050
6060 µg/dlµg/dl
A.U.C. (µg/dl/h)A.U.C. (µg/dl/h) DELTA (µg)DELTA (µg)00
1010
2020
3030
4040
minutesminutes
****** ****** ****** ****** ******
°° °°
++ ++ ++ ++
(mean ± SEM)(mean ± SEM)
**** ******** ****
°° °°°° °°°°°°
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
ADADMIDMID
µmol/Lµmol/L µmol/Lµmol/L1010
old demented vs young controls p< .001old demented vs young controls p< .001
old healthy sub. vs young controls p< .001old healthy sub. vs young controls p< .001
old healthy sub. vs old demented * p< .05; ** p< .01old healthy sub. vs old demented * p< .05; ** p< .01
SERUM DHEA-S CIRCADIAN RHYTHMSERUM DHEA-S CIRCADIAN RHYTHM
young controlsyoung controls
old demented old demented old healthy subjectsold healthy subjects
MID vs AD p< .05MID vs AD p< .05
L/DL/D
00 22 44 88 1212 1616 2020 222200
22
44
66
88
1010
** ** ** **** ** **** **
2424
**
22 44 88 1212 1616 2020 222200
22
44
66
88
00 2424L/DL/D
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
-0,1-0,1
00
0,10,1
0,20,2
0,30,3
0,40,4
0,50,5
0,60,6
00 22 44 88 1212 1616 2020 2222 2424
Cortisol/DHEAS molar ratioCortisol/DHEAS molar ratio
OLD SUBJECTSOLD SUBJECTS OLD DEMENTEDOLD DEMENTED YOUNG CONTROLSYOUNG CONTROLS
Old subjects vs young controlsOld subjects vs young controlsOld demented vs young controlsOld demented vs young controlsOld demented vs old subjectsOld demented vs old subjects
p<.05; p<.05; p<.01; p<.01; p<.001 p<.001 * * p<.05;p<.05; ** ** p<.01; p<.01; *** *** p<.001 p<.001 p<.05;p<.05; p<.01;p<.01; p<.001 p<.001
******
******
****** **
****
******
****** **
****
******
******
L/DL/D
(Mean ± SEM)(Mean ± SEM)
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
SPEARMAN RANK ORDER CORRELATIONSSPEARMAN RANK ORDER CORRELATIONS
RELATIONSHIP BETWEEN CORTISOLRELATIONSHIP BETWEEN CORTISOL AND DHEA-S SECRETION AND DHEA-S SECRETION
YOUNG CONTROLSYOUNG CONTROLS 1.42 ± 0.651.42 ± 0.65
6.81 ± 1.106.81 ± 1.10
11.6 ± 1.3511.6 ± 1.35******
******
****
Ratio between the circadian Ratio between the circadian mesors of cortisol and DHEA-Smesors of cortisol and DHEA-S
OLD HEALTHY SUBJECTSOLD HEALTHY SUBJECTS
OLD DEMENTEDOLD DEMENTED
Mesor Cortisol / Mesor DHEA-S vs AgeMesor Cortisol / Mesor DHEA-S vs Age r = 0.4566r = 0.4566 p < 0.001p < 0.001r = - 0.3974r = - 0.3974 p < 0.01p < 0.01Mesor Cortisol / Mesor DHEA-S vs MMSEMesor Cortisol / Mesor DHEA-S vs MMSE
Ferrari et al, Eur J Endocrinol, 144: 319; 2001
SERUM DHEA-S CIRCADIAN RHYTHMSERUM DHEA-S CIRCADIAN RHYTHM
clock time (hours)clock time (hours)
µg/dLµg/dL
00 22 44 88 1212 1616 2020 2222 2424
00
0.50.5
11
1.51.5
22
2.52.5
33
3.53.5mean±SEMmean±SEM
HEALTHY ELD.HEALTHY ELD.
MAJOR DEPR.MAJOR DEPR.
SENILE DEM.SENILE DEM.
Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004
The simultaneous evaluation of cortisol and DHEAS secretion The simultaneous evaluation of cortisol and DHEAS secretion allows us to identify hormonal secretory changes reflecting the allows us to identify hormonal secretory changes reflecting the brain steroidal milieu, already present in physiological aging and brain steroidal milieu, already present in physiological aging and more evident in pathological conditions.more evident in pathological conditions.
The adrenal biosynthetic imbalance between cortisol and The adrenal biosynthetic imbalance between cortisol and androgens, may play a pathogenetic role in the occurrence of androgens, may play a pathogenetic role in the occurrence of degenerative changes in selective brain areas, particularly involved degenerative changes in selective brain areas, particularly involved in cognitive and affective performances.in cognitive and affective performances.
Chronic exposure to stress and the related neuroendocrine Chronic exposure to stress and the related neuroendocrine changes especially in aged people could foster the occurrence and changes especially in aged people could foster the occurrence and progression of alterations leading to frailty and diseaseprogression of alterations leading to frailty and disease
OLD HEALTHY SUB.OLD HEALTHY SUB.YOUNG CONTROLSYOUNG CONTROLS OLD DEMENTEDOLD DEMENTED
CEREBRAL MORPHOMETRIC ANALYSISCEREBRAL MORPHOMETRIC ANALYSIS
HIPPOCAMPUSHIPPOCAMPUS
RIGHTRIGHTvs agevs agevs cortisol noct. increasevs cortisol noct. increasevs DHEAs mesor vs DHEAs mesor
r = -.88 p<.001r = -.88 p<.001r = .40 p<.05r = .40 p<.05r = .63 p<.01r = .63 p<.01
LEFTLEFT
r = -.82 p<.001r = -.82 p<.001r = .45 p<.05r = .45 p<.05r = .64 p<.01r = .64 p<.01
vs agevs agevs cortisol noct. increasevs cortisol noct. increasevs DHEAs mesor vs DHEAs mesor
LEFTLEFT00
11
22
33
44
55
RIGHTRIGHT
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cmcm 33
*** p<.001 *** p<.001 Magri et al, Dem Ger Cogn Dis, 11: 90; 2000
CONCLUSIONSCONCLUSIONSThe relationships between the hippocampal volume and the The relationships between the hippocampal volume and the
parameters of the cortisol and DHEA-s secretions suggest the parameters of the cortisol and DHEA-s secretions suggest the
existence of a link between the adrenocortical secretory existence of a link between the adrenocortical secretory
dissociation and the degenerative changes of some CNS areas.dissociation and the degenerative changes of some CNS areas.
Within the limits of our morphometric approach to the study of Within the limits of our morphometric approach to the study of
brain aging, our results suggest that the changes of the limbic-brain aging, our results suggest that the changes of the limbic-
hippocampal area may be related more to the subjects’ age, while hippocampal area may be related more to the subjects’ age, while
the modifications of the hormonal circadian profiles should be the modifications of the hormonal circadian profiles should be
linked to both aging and cerebral pathology.linked to both aging and cerebral pathology.GERONT. GERIATR., PV
PHYSIOLOGICAL FUNCTIONS OF DHEA(S)
DHEA (S)
antidiabeticantiautoimmune
antiosteoporotic
antiobesity
antidementia
anticancer
antiatherosclerotic
GERONT. GERIATR., PV
TRIALS OF DHEA REPLACEMENT THERAPY
► DEPRESSION (Wolkowitz, 1997DEPRESSION (Wolkowitz, 1997
► ANTIAGING (Yen, 1995)ANTIAGING (Yen, 1995)
► DIABETES TYPE 2 (Casson, 1995)DIABETES TYPE 2 (Casson, 1995)
► FATIGUE (Scott, 1999)FATIGUE (Scott, 1999)
► LUPUS (Van Vollenhoven)LUPUS (Van Vollenhoven)
Oral dosage range: 5-50 mg/day; doses of 100 mg/day are Oral dosage range: 5-50 mg/day; doses of 100 mg/day are sometimes used in elderly individulassometimes used in elderly individulas
AT TODAY, IN OLDER SUBJECTS, ADMINISTRATION OF AT TODAY, IN OLDER SUBJECTS, ADMINISTRATION OF
DEHYDROEPIANDROSTERONE HAS NO WELL-DEFINED DEHYDROEPIANDROSTERONE HAS NO WELL-DEFINED
BENEFITSBENEFITS
GERONT. GERIATR., PV
Pre-treatment with TGF-Pre-treatment with TGF-ββ1 protects hippocampal 1 protects hippocampal neurones from induced apoptotic injuryneurones from induced apoptotic injury
Increased Increased TGF-TGF-ββ1 expression in oldest rats1 expression in oldest rats
PROTECTION AGAINST PROGRESSION OF THE CELL PROTECTION AGAINST PROGRESSION OF THE CELL DEATH CASCADE WITH DECREASE IN INDUCED DEATH CASCADE WITH DECREASE IN INDUCED
APOPTOSISAPOPTOSIS
POSSIBLE MANIPULATION OF ENDOGENOUS POSSIBLE MANIPULATION OF ENDOGENOUS NEUROTROPHIC FACTORSNEUROTROPHIC FACTORS
Henrich-Noack et al, Stroke 1996, Mattson and Furukawa, Rest Neurol Neurosci, 1996, Henrich-Noack et al, Stroke 1996, Mattson and Furukawa, Rest Neurol Neurosci, 1996, Bye et al, Neuroscience, 2001Bye et al, Neuroscience, 2001