1 / 49

E. Ferrari

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.

cira
Télécharger la présentation

E. Ferrari

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. 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

  2. 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

  3. 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

  4. MELATONIN SECRETION

  5. 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

  6. 70 60 50 40 30 20 10 0 L/D 0 2 4 8 12 16 20 22 24 Population mean cosinor summary Ø § AMPLITUDE A ACROPHASE (95% c.l.) MESOR M p % Rhythm (x ± SEM) (x ± SEM) (°) hours 0.0002 YOUNG CONTR. (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) PLASMA MELATONIN CIRCADIAN RHYTHM (x ± SEM) pg/ml GERONT. GERIATR., PV

  7. SCN h 12 0 12 Melatonin h 12 12 0 MELATONIN RHYTHM AS ENDOGENOUS SYNCHRONIZER FOR OTHER RHYTHMS Pineal gland Light / Dark h 12 0 12 Cortisol Temperature h 12 0 12 Sleep / Wakefulness Circadian rhythms GERONT. GERIATR., PV

  8. GERONT. GERIATR., PV

  9. GERONT. GERIATR., PV

  10. °C 40 37 36.8 30 36.6 x ± SEM 20 36.4 10 36.2 0 36 0 0 2 2 4 4 8 8 12 12 16 16 20 20 22 22 24 24 Clock time (hours) PLASMA MELATONIN ( ) AND ORAL TEMPERATURE ( )CIRCADIAN RHYTHMS • • HEALTHY YOUNGS (n=14) ELDERLY SUBJECTS (n=14) pg/mL pg/mL °C 70 37 60 36.8 50 36.6 40 30 36.4 20 36.2 10 0 36 0 0 2 2 4 4 8 8 12 12 16 16 20 20 22 22 24 24 Clock time (hours) GERONT. GERIATR., PV

  11. DAY / NIGHT aMT6s URINARY EXCRETION 80 70 day night 70 60 * * * 60 50 50 40 *** p < .001 % of the total 24 h 40 30 30 20 20 10 10 0 L/D 0 2 4 8 12 16 20 22 24 0 p 0.0002 PLASMA MELATONIN CIRCADIAN RHYTHM (x ± SEM) pg/ml Population mean cosinor summary Ø § AMPLITUDE A ACROPHASE (95% c.l.) MESOR M % Rhythm (x ± SEM) (x ± SEM) (°) hours YOUNG CONTR. (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

  12. PLASMA MELATONIN CIRCADIAN RHYTHM pg/mL pg/mL 60 60 mean±SEM mean±SEM 50 50 40 40 ** ** 30 30 * 20 20 *** *** *** *** 10 10 0 0 0 2 4 8 12 16 20 22 0 2 4 8 12 16 20 22 hours hours young subjects old subjects (65-85 yrs.) elderly subjects very old subjects ( > 85 yrs.) ****** P < .05p < .01p < .001 Magri et al, Chronobiol Int, 14: 385; 1997 GERONT. GERIATR., PV

  13. TOTAL aMT6s EXCRETION RATE *** g/24h *** * p < .05 *** p < .001 18 16 14 * 12 10 8 6 4 2 0 Young Old healthy Centen Magri et al, J Pin Res, 36: 256; 2004 GERONT. GERIATR., PV

  14. aMT6s: NIGHT/DAY RATIO *** ** 5 4,5 4 3,5 3 2,5 2 1,5 1 0,5 0 Young Old healthy Centen ** p < .01; *** p < .001 Magri et al, J Pin Res, 36: 256; 2004 GERONT. GERIATR., PV

  15. % 80 * * * n.s. day night 70 * * * 60 50 40 *** p < .001 30 20 10 0 Centen Young Old healthy aMT6s EXCRETION RATE DURING DAY AND NIGHT (% OF 24H) 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

  16. 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

  17. Circadian profile of plasma melatonin in healthy young and old subjects and in demented patients (mean ± SEM) YOUNG CONTROLS OLD SUBJECTS DEMENTED PATIENTS pg/mL pg/mL 70 35 60 30 50 25 20 40   15  30      10 20      5 10 L/D 0 L/D 0 0 2 4 8 12 16 20 22 24 0 2 4 8 12 16 20 22 24 hours hours OLD SUBJECTS AD 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, Exp Geront, 35: 1239; 2000

  18. HEALTHY OLD OLD DEPRESSED OLD DEMENTED 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 3 0 L/D 0 2 4 8 12 16 20 22 24 2 1 0 MELATONIN INDEX Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004

  19. RELATIONSHIP BETWEEN MELATONIN SECRETION AND AGING • Melatonin declines with aging • Pineal calcification increases with aging • Melatonin administration (or pineal extracts) prolong life span in mice • Grafting og young pineal to old mices increases survival • Melatonin is a potent free radical scavenger • Melatonin (via AVT) increases slow wave sleep • Pinealectomy facilitates the onset of abnormal involontar movements • Pinealectomy reduces hypothalamic opioid concentrations • Pinealectomy disrupts opioid peptides rhythms • Pinealectomy produces dishinibition of the HPA axis

  20. Therapeutic perspectives of melatonin in aging

  21. 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

  22. 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

  23. HPA AXIS

  24. 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

  25. Frontal/Cortex Hippocampus GRs MRs GRs – – Hypothalamus – Corticotropin Releasing Factor (CRF) + Pituitary – Adrenocorticotropin + Adrenal Cortex Corticosteroids (From LUPIEN et al., Behavioural Brain Research, 127, 137-158, 2001)

  26. FRONTAL CORTEX HIPPOCAMPUS GRs MRs GRs • High cortisol levels • Stress-induced cortisol levels • Morning cortisol levels • Low cortisol levels • Basal cortisol levels • Evening and night cortisol levels GERONT. GERIATR., PV

  27. 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

  28. CLOSED-LOOP SYSTEM OF MODULATORY ACTIONS Cognitive processing Cognitive function Mood and behaviour Stress hormones GERONT. GERIATR., PV

  29. ADRENOCORTICAL AGE-RELATED 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

  30. 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 Circadian profile of plasma ACTH in healthy young and old subjects (mean ± SEM)            Old subjects vs young controls  = p<.05;  = p<.01;  = p<.001 Ferrari et al, Neuroendocrinology 61: 464; 1995

  31. YOUNG CONTROLS OLD SUBJECTS DEMENTED PATIENTS 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 10            5 5 L/D L/D 0 0 0 2 4 8 12 16 20 22 24 0 2 4 8 12 16 20 22 24 hours hours OLD SUBJECTS AD 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

  32. p< .05 AGE vs NADIR r= .2970 p< .05 AGE vs AMPLITUDE r= -.2603 OLD SUBJECTS YOUNG CONTROLS SERUM CORTISOL CIRCADIAN RHYTHM 25 µg/dL µg/dL mean±SEM 30 20 25 15 20 15 10 * *** 10 *** 5 ** 5 *** *** *** *** 0 0 NADIR ZENITH 0 2 4 8 12 16 20 22 24 Clock time (hours) 250 % mesor mean±SEM *** p< .001 AGE vs 8-24 200 r= -.3891 150 *** Student's t test 100 *** *** *** * * p< .05 50 ** p< .01 *** p< .001 0 0 2 4 8 12 16 20 22 24 Clock time (hours) Ferrari et al, Eur J Endocrinol, 144: 319; 2001

  33. SERUM DHEA-S CIRCADIAN RHYTHM µmol/L mean±SEM µmol/L *** 10 10 8 *** 8 6 6 * * * ** * * * * * 4 4 2 2 0 0 NADIR ZENITH 0 2 4 8 12 16 20 22 24 Clock time (hours) Student's t test p< .001 r= -.5510 AGE vs NADIR * p< .05 OLD SUBJECTS p< .001 r= -.6605 AGE vs ZENITH ** p< .01 YOUNG CONTROLS p< .001 AGE vs MESOR r= -.6453 *** p< .001 p< .001 r= -.5752 AGE vs AMPLITUDE Ferrari et al, Eur J Endocrinol, 144: 319; 2001

  34. YOUNG CONTROLS OLD SUBJECTS DEMENTED PATIENTS Circadian profile of serum cortisol in healthy young and old subjects and in demented patients (mean ± SEM) mg/dL mg/dL 25 30        25  20        20 15  15  10   10        5    5    L/D L/D 0 0 0 2 4 8 12 16 20 22 24 0 2 4 8 12 16 20 22 24 hours hours OLD SUBJECTS AD 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

  35. 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 * p < 0.016 L/D 0 0 2 4 8 12 16 20 22 24 clock time (hours) Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004

  36.          *** *** *** *** *** *** *** *** ***                           0 24  p<.05;  p<.01;  p<.001* p<.05; ** p<.01; *** p<.001 p<.05;   p<.01;    p<.001 Old subjects vs young controlsOld demented vs young controlsOld demented vs old subjects DEXAMETHASONE TEST (1 mg at 23:00) SERUM CORTISOL CIRCADIAN RHYTHM *** *** µg/dl 20 µg/dl (x ± SEM) * 20 *** 15 *** * 10 15 5 10 0 MESOR pre-DXM MESOR post-DXM 5 *** L/D * 0 % 60 2 4 8 12 16 20 22 *** 50 hours 40 30 20 AGE vs DELTA %AGE vs CORTISOL MESOR POST DXM r = .44 p < .001r = .62 p < .001 10 0 MESOR DELTA % OLD SUBJECTS OLD DEMENTED YOUNG CONTROLS Magri et al, Chronobiol Int, 14: 385; 1997

  37. SYNACTHEN TEST(2500 ng i.v. at 20:30) µg/dl (mean ± SEM) 60 ** *** ** * 40 50 40 30 30 20 20    10  10       ° ° *** *** *** *** *** 0 0 DELTA (µg) A.U.C. (µg/dl/h) 0 15 30 60 90 + + + + minutes OLD SUBJECTS OLD DEMENTED YOUNG CONTROLS Old subjects vs young controlsOld demented vs young controlsOld demented vs old subjects p<.05; p<.01; p<.001* p<.05; ** p<.01; *** p<.001np<.05;nnp<.01;nnnp<.001 ° °° °°° Ferrari et al, Eur J Endocrinol, 144: 319; 2001

  38. 8 6 4 2 * 0 24 0 2 4 8 12 16 20 22 24 SERUM DHEA-S CIRCADIAN RHYTHM µmol/L µmol/L 10 10 8 6 4 * 2 * ** * * * * * L/D L/D 0 0 2 4 8 12 16 20 22 young controls AD old healthy subjects old demented MID old healthy sub. vs young controls p< .001 MID vs AD p< .05 old demented vs young controls p< .001 old healthy sub. vs old demented * p< .05; ** p< .01 Ferrari et al, Eur J Endocrinol, 144: 319; 2001

  39. Cortisol/DHEAS molar ratio 0,6 0,5 * * * * * * n n n n n n n n 0,4 * * * * * * * * * * * * n n * * * n * * * n n n 0,3 * * * n n (Mean ± SEM) 0,2             0,1                0 L/D -0,1 0 2 4 8 12 16 20 22 24 OLD SUBJECTS OLD DEMENTED YOUNG CONTROLS Old subjects vs young controlsOld demented vs young controlsOld demented vs old subjects  p<.05;  p<.01;  p<.001* p<.05; ** p<.01; *** p<.001np<.05;n np<.01;n n n p<.001 Ferrari et al, Eur J Endocrinol, 144: 319; 2001

  40. RELATIONSHIP BETWEEN CORTISOL AND DHEA-S SECRETION Ratio between the circadian mesors of cortisol and DHEA-S 1.42 ± 0.65 YOUNG CONTROLS *** 6.81 ± 1.10 OLD HEALTHY SUBJECTS *** ** 11.6 ± 1.35 OLD DEMENTED SPEARMAN RANK ORDER CORRELATIONS r = 0.4566 p < 0.001 Mesor Cortisol / Mesor DHEA-S vs Age r = - 0.3974 p < 0.01 Mesor Cortisol / Mesor DHEA-S vs MMSE Ferrari et al, Eur J Endocrinol, 144: 319; 2001

  41. SERUM DHEA-S CIRCADIAN RHYTHM 3.5 µg/dL mean±SEM 3 2.5 2 HEALTHY ELD. 1.5 MAJOR DEPR. SENILE DEM. 1 0.5 0 0 2 4 8 12 16 20 22 24 clock time (hours) Ferrari et al, Arch Gerontol Geriatr, S9: 171; 2004

  42. 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

  43. 3 cm CEREBRAL MORPHOMETRIC ANALYSIS HIPPOCAMPUS RIGHT *** *** *** *** 5 vs agevs cortisol noct. increasevs DHEAs mesor r = -.88 p<.001r = .40 p<.05r = .63 p<.01 4 3 LEFT 2 vs agevs cortisol noct. increasevs DHEAs mesor r = -.82 p<.001r = .45 p<.05r = .64 p<.01 1 0 RIGHT LEFT YOUNG CONTROLS OLD HEALTHY SUB. OLD DEMENTED *** p<.001 Magri et al, Dem Ger Cogn Dis, 11: 90; 2000

  44. 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

  45. PHYSIOLOGICAL FUNCTIONS OF DHEA(S) antiautoimmune antidiabetic antiosteoporotic DHEA (S) antiobesity antiatherosclerotic antidementia anticancer GERONT. GERIATR., PV

  46. 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

  47. AT TODAY, IN OLDER SUBJECTS, ADMINISTRATION OF DEHYDROEPIANDROSTERONE HAS NO WELL-DEFINED BENEFITS GERONT. GERIATR., PV

  48. 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

More Related