e. ferrari

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).”


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


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


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)


(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


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


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

* *

**

* *


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


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


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


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


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


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


OLD SUBJECTOLD SUBJECT


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











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


% 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


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


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












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.


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


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)


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)

**** ******** ****

°° °°°° °°°°°°


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


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


-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



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)


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



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.


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

************

************

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


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


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

e. ferrari

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