Living Longer Presentation 2012
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Transcript of Living Longer Presentation 2012
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Aging and Hormone Replacement: The Aging and Hormone Replacement: The Latest in Disease PreventionLatest in Disease Prevention
Craig S. Atwood, Ph.D.
Associate Professor, Section of Geriatrics and Gerontology
University of Wisconsin School of Medicine and Public Health
Geriatrics, Education and Clinical Center, VA HospitalMadison, Wisconsin
From: beautyanalysis.com From: Pilates Reforming NY
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Jacques: All the world's a stage, And all the men and women merely players;
They have their exits and their entrances, And one man in his time plays many parts,
His acts being seven ages. At first, the infant, Mewling and puking in the nurse's arms.
Then the whining schoolboy, with his satchel And shining morning face, creeping like snail
Unwillingly to school. And then the lover, Sighing like furnace, with a woeful ballad
Made to his mistress' eyebrow. Then a soldier, Full of strange oaths and bearded like the pard, Jealous in honour, sudden and quick in quarrel,
Seeking the bubble reputation Even in the canon's mouth. And then the justice,
In fair round belly with good capon lined, With eyes severe and beard of formal cut, Full of wise saws and modern instances;
The Seven Acts of Life
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And so he plays his part. The sixth age shifts Into the lean and slippered pantaloon
With spectacles on nose and pouch on side; His youthful hose, well saved, a world too wide For his shrunk shank, and his big manly voice,
Turning again toward childish treble, pipes And whistles in his sound. Last scene of all,
That ends this strange eventful history, Is second childishness and mere oblivion,
Sans teeth, sans eyes, sans taste, sans everything.
(As You Like It, Act II, Scene VII, lines 139-166)
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Decreasingfunction
Mild
Moderate
Severe
Function Changes During the Life CycleFunction Changes During the Life CycleF
un
ctio
n
Increasingfunction
Stablefunction
0 20 40 8060 100Lifespan in Years
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Slow decreasingfunction
Mild
Moderate
Severe
Function Changes During the Life Cycle: Function Changes During the Life Cycle: Extending LifespanExtending Lifespan
Fu
nct
ion Cognitive function
Vascular functionImmune function
Bone functionReproductive functionAthletic performance
Increasingfunction
Stablefunction
0 20 40 8060 100
Increasinglifespan
Lifespan in Years
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Delaydecreasing
function
Mild
Moderate
Severe
Function Changes During the Life Cycle: Function Changes During the Life Cycle: Extending Lifespan and HealthspanExtending Lifespan and Healthspan
Fu
nct
ion Cognitive function
Vascular functionImmune function
Bone functionReproductive function
Athletic function
Increasingfunction
Increase stablefunction
0 20 40 8060 100
IncreasingLifespan and Healthspan
Lifespan in Years
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• The Reproductive-Cell Cycle Theory of Aging•Bowen, R.L. and Atwood, C.S., 2004, Gerontology, 50, 265-290
•Atwood, C.S. and Bowen, R.L., 2011, Experimental Gerontology,
in press.
How and Why Do We Age? How and Why Do We Age?
The hormones that regulate reproduction in mammals act in an antagonistic pleiotrophic manner to control aging via cell cycle
signaling
How we can halt the aging process
Provides a credible reason for why and how aging occurs at the evolutionary, physiological and molecular levels
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Reproductive Hormones Regulate Cell Growth, Development and Death
fetal hCG
LH (male and female)
LH (adult female)
LH (adult male)
mitogenicity index
Gestation Infancy Childhood Puberty Adult-reproductive period
Senescence
Mito
gen
icity Ind
exH
um
an C
ho
rio
nic
Go
nad
otr
op
in/
Lu
tein
izin
g H
orm
on
e
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Hypothalamic-Pitutiary-Gonadal Axis: Hypothalamic-Pitutiary-Gonadal Axis: The Reproductive AxisThe Reproductive Axis
Feedback mechanisms keep axis in Feedback mechanisms keep axis in balance during reproductive periodbalance during reproductive period
LH, FSH, GnRH – mitogenic hormonesLH, FSH, GnRH – mitogenic hormonesSex steroids, activins – differentiative hormonesSex steroids, activins – differentiative hormones
Receptors for these Receptors for these hormones are hormones are
expressed in all expressed in all tissues of the bodytissues of the body
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Feedback Feedback Regulatory LoopsRegulatory Loops
HYPOTHALAMUS
GnRH
LHFSH
Ovaries
OestrogenProgesterone
Pituitary
Negative feedback
luteal phase
Positive feedbackFollicular
phase
HYPOTHALAMUS
GnRH
LHFSH
Ovaries
OestrogenProgesterone
Pituitary
Negative feedback
luteal phase
Positive feedbackFollicular
phase
- pubertypuberty- menstrual cyclemenstrual cycle- pregnancypregnancy- castrationcastration- polycystic ovary syndromepolycystic ovary syndrome- disease statedisease state- menopause/andropausemenopause/andropause
When and Why Do Sex Steroid Levels When and Why Do Sex Steroid Levels ChangeChange
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Feedback mechanisms keep axis in Feedback mechanisms keep axis in balance during reproductive periodbalance during reproductive period
LH, FSH, GnRH – mitogenic hormonesLH, FSH, GnRH – mitogenic hormonesSex steroids, activins – differentiative hormonesSex steroids, activins – differentiative hormones
Receptors for these Receptors for these hormones are hormones are
expressed in all expressed in all tissues of the bodytissues of the body
Hypothalamic-Pitutiary-Gonadal Axis: Hypothalamic-Pitutiary-Gonadal Axis: The Reproductive AxisThe Reproductive Axis
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Endocrine Dyscrasia in Women and Endocrine Dyscrasia in Women and Age-Age-related Diseasesrelated Diseases
Dyotic Signaling: decreased sex steroid signaling, but increased gonadotropin, GnRH and activin signaling
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Dyotic Signaling: decreased sex steroid signaling, but increased gonadotropin, GnRH and activin signaling
Endocrine Dyscrasia in Men and Endocrine Dyscrasia in Men and Age-Age-related Diseasesrelated Diseases
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The Balance Between Mitogenic and The Balance Between Mitogenic and Differentiation Hormones Dictates Cell FateDifferentiation Hormones Dictates Cell Fate
Mitogenic SignalshCG/LH/FSH
GnRH
Differentiation SignalsSex steroids
ActivinsCellular
Homeostasis
Aberrant Cell Division and Death/Dysfunction
Equilibrium becomes dysregulated, initiating dyosis which drives senescence
Endocrine dyscrasia
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Aberrant re-entry of cells into the cell cycle
Tissues with differentiated cell types
• Brain – neurons – Alzheimer’s disease
• Heart – endothelial cells/cardiomyocytes – CHD
Tissues with totipotent stem cell types
• Lung, liver, colon, reproductive tissues – cancer
• Vasculature – SMC/endothelial cells – stroke
• Bone – osteoclasts/osteoblast – osteoporosis
• Metabolism – diabetes mellitus
Consequences of HPG DysregulationConsequences of HPG Dysregulation
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Global and pervasive deterioration in bodily function – explains why we develop our age-related diseases
Rate at which degenerative changes occurs depends on how
dysregulated the HPG axis becomes
Organs involved is dependent upon the influence of both
environmental and genetic factors
These factors determine who will age faster and who will age slower
But, we all eventually die
Consequences of HPG Dysregulation: Consequences of HPG Dysregulation: Endocrine DyscrasiaEndocrine Dyscrasia
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Leading Causes of Death in the USALeading Causes of Death in the USA
Table 1. Leading causes of death in the USCause of Death All AgesTotal Number of Deaths 2,426,264 100%Diseases of the heart 631,636 26.0%Malignant Neoplasms (Cancer) 559,888 23.1%Cerebrovascular diseases 137,119 5.7%Chronic Lower Respiratory Disease 124,583 5.1%Accidents (unintentional injuries) 121,599 5.0%Diabetes Mellitus 72,449 3.0%Alzheimer’s disease 72,432 3.0%Influenza and Pneumonia 56,326 2.3%
Table 1. Leading causes of death in the USCause of Death All AgesTotal Number of Deaths 2,426,264 100%Diseases of the heart 631,636 26.0%Malignant Neoplasms (Cancer) 559,888 23.1%Cerebrovascular diseases 137,119 5.7%Chronic Lower Respiratory Disease 124,583 5.1%Accidents (unintentional injuries) 121,599 5.0%Diabetes Mellitus 72,449 3.0%Alzheimer’s disease 72,432 3.0%Influenza and Pneumonia 56,326 2.3%
CDC National Vital Statistics Report, Vol. 57, No. 14, April 17, 2009
Osteoporosis/low bone massOsteoporosis/low bone mass 55% by 50 years of age55% by 50 years of age
45% by 85 years of age45% by 85 years of ageDementia/cognitive lossDementia/cognitive loss
→→→
→
→→
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1. Epidemiological evidence
2. Clinical evidence
3. Experimental evidence
Evidence that Endocrine Dyscrasia Evidence that Endocrine Dyscrasia Leads to Aging-related DiseasesLeads to Aging-related Diseases
This evidence provides clues as to how to halt the aging process that leads to our age-
related diseases
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Age-related Reproductive Endocrine Age-related Reproductive Endocrine DyscrasiaDyscrasia Initiates Senescence and Age-related Diseases Initiates Senescence and Age-related Diseases
Epidemiological Evidence (>10 studies)
The longer the HPG axis is in balance, the less likely The longer the HPG axis is in balance, the less likely you are to develop an age-related diseaseyou are to develop an age-related disease
Disease risk in women with later menopause:
↓ cardiovascular disease
↓ calcifications in the aorta
↓ atherosclerosis
↓ dementia/cognitive decline
↓ osteoporosis/bone fractures
↓ colorectal and breast cancer
↑ uterine and ovarian cancer
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Age-related Reproductive Endocrine Age-related Reproductive Endocrine DyscrasiaDyscrasia Initiates Senescence and Age-related Diseases Initiates Senescence and Age-related Diseases
Epidemiological Evidence (>16 studies) Disease risk in women with early reproductive endocrine dyscrasia (oophorectomy or natural):
↑ cardiovascular disease (fatal and non-fatal)
↑ stroke
↑ dementia/cognitive decline/Parkinsonism
↑ osteoporosis/bone fractures
↑ lung cancer
↑ depression and anxiety
↓ breast and ovarian cancer
Earlier endocrine dysrasia is associated with earlier onset Earlier endocrine dysrasia is associated with earlier onset of age-related diseaseof age-related disease
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Age-related Reproductive Endocrine Age-related Reproductive Endocrine DyscrasiaDyscrasia Initiates Senescence and Age-related Diseases Initiates Senescence and Age-related Diseases
Experimental Evidence
Coronary heart disease Stroke (except women) Alzheimer’s disease/dementia/cognitive loss Osteoporosis/bone fractures Cancer Obesity, metabolic syndrome/diabetes mellitis II Frailty (men)
Positive relationships between age-related diseases and decreased circulating sex steroids and
increased gonadotropins in both men and women
The more dysregulated your HPG axis, the more likely you are to develop age-related diseases
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Sex Hormones and Age-related Disease RiskSex Hormones and Age-related Disease Risk
Low T but elevated LH is associated with-Specific symptoms:
• frailty• increased prostate cancer• decreased sexual desire, shrinkage of testes• low sperm count• height loss• hot flushes, sweats
Other less specific symptoms:• decreased energy• poor concentration and memory• sleep disturbances• reduced muscle bulk and strength• increased body fat
MalesMales
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Hypothalamic-Pitutiary-Gonadal Axis: Hypothalamic-Pitutiary-Gonadal Axis: The Reproductive AxisThe Reproductive Axis
All hormones of the axis have All hormones of the axis have important physiological functionsimportant physiological functions
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Reproductive Hormones are Required for Growth Reproductive Hormones are Required for Growth and Development, and Maintenance of Tissues and Development, and Maintenance of Tissues
During AdulthoodDuring Adulthood
Embryonic and fetal growth and development:Embryonic and fetal growth and development:hCG – proliferative functionshCG – proliferative functionsProgesterone – promotes neurogenesis and differentiationProgesterone – promotes neurogenesis and differentiation
Adult tissue maintenance:Adult tissue maintenance:LH –LH – induces neurogenesis in the adult braininduces neurogenesis in the adult brainEstradiol – promotes neuritogenesis - neurite extension, Estradiol – promotes neuritogenesis - neurite extension,
dendritic spine formation, synaptogenesisdendritic spine formation, synaptogenesisProgesterone – promotes angiogenesis, mammary gland Progesterone – promotes angiogenesis, mammary gland
developmentdevelopmentSex hormones are required for normal adult tissue Sex hormones are required for normal adult tissue
maintenancemaintenance
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Sex Steroid Hormones Are Synthesized by the Sex Steroid Hormones Are Synthesized by the Gonads and the Brain: Feedback Regulatory Gonads and the Brain: Feedback Regulatory
LoopsLoops
11
2233
1122334455
44
55
Sex steroids are made by the brain, for the brain
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1. Modulating Reproductive Parameters1. Modulating Reproductive Parameters later menopauselater menopause later pubertylater puberty pregnancy and lactational amenorrheapregnancy and lactational amenorrhea stress: caloric restriction or coldstress: caloric restriction or cold
~5-20 years~5-20 years
Life Extension Strategies Through Hormone Life Extension Strategies Through Hormone Supplementation or SuppressionSupplementation or Suppression
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Suppressing the HPG Axis as a Means to Suppressing the HPG Axis as a Means to Extend LongevityExtend LongevityLife-extending modalities
• caloric restriction (fasting, inadequate or inconsistent food supply)
• cold• stress
- all modalities suppress HPG axis hormones
- decrease fertility
- sparing of ovarian and testicular reserves
- offset the reproductive clock to a later time when the environment might be better for reproducing and raising offspring
- suppressing gonadotropins with GnRH agonists halves the risk of death from Alzheimer’s disease
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2. Pharmacological solutions2. Pharmacological solutions
Hormone replacement therapies (physiological hormones)Hormone replacement therapies (physiological hormones) Sex steroids – 1Sex steroids – 1-estradiol, progesterone and testosterone-estradiol, progesterone and testosterone Currently we cannot replace all hormones lostCurrently we cannot replace all hormones lost Partial replacementPartial replacement
Hormone suppression therapiesHormone suppression therapies GnRH agonists and antagonistsGnRH agonists and antagonists Comes with some negative issues – osteoporosis, heart disease Comes with some negative issues – osteoporosis, heart disease
but appears positive for Alzheimer’s diseasebut appears positive for Alzheimer’s disease
5-20 years5-20 years These above strategies are the best we can do currentlyThese above strategies are the best we can do currently Focus on sex steroid replacement otherwise known as hormone Focus on sex steroid replacement otherwise known as hormone
replacement therapyreplacement therapy
Life Extension Strategies Through Hormone Life Extension Strategies Through Hormone Supplementation or SuppressionSupplementation or Suppression
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Hormone Replacement TherapyHormone Replacement Therapy
Compelling evidence for endocrine dyscrasia as promoting age-related diseases comes from HRT studies
Sex steroids used to supplement those sex steroids no longer produced by the gonads
Women: estrogen, progesterone, or both given to women after menopause to replace the hormones no longer produced by the ovaries (~50 years of age)
Men: testosterone given to men with hypogonadism to replace testosterone no longer produced by testes
Sources vary: Physiologically (bio)identical human hormones Unphysiological hormones - hormones extracted from horse
urine plus synthetic analogs
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Reversing Endocrine Dyscrasia as a Reversing Endocrine Dyscrasia as a Means to Extend LongevityMeans to Extend Longevity
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Reversing Endocrine Dyscrasia: Reversing Endocrine Dyscrasia: Restoring Some Balance to the HPG AxisRestoring Some Balance to the HPG Axis
It’s not perfect, but it’s the best we can do for now
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What are Sex SteroidsWhat are Sex Steroids
Sex steroid synthesis begins in the embryo and continues throughout life
Decreases in sex steroid synthesis with menopause and andropause
ProgesteroneCholesterol
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What are Sex SteroidsWhat are Sex Steroids
Human sex steroids are made by:- ovaries and testes - adrenal glands- brain- adipose tissue
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What are Sex SteroidsWhat are Sex Steroids
Human sex steroids are made by:- ovaries or testes - adrenal glands- brain- adipose tissue
Classes of sex steroids- androgens (testosterone)- estrogens (17-estradiol)- progestagens (progesterone)
All hormones are found in males and females
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Steroid Biosynthesis Cholesterol
StAR followed by P450 side chain cleavage
Pregnenolone 17αOH Pregnenolone DHEA
Androstenedione
17αHSD 17,20 lyase3βHSD 3βHSD3βHSD
Progesterone 17αOH Progesterone
Testosterone
17βHSD
17-Estradiol
17βHSD
+
aromatase
DHT
5α reductase
21 & 11β hydroxylase
Corticosterone Cortisol18 hydroxylase & 18 HSD
Aldosterone Physiologically important steroids
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Age-related Reproductive Endocrine Age-related Reproductive Endocrine Dyscrasia and Age-related Diseases Dyscrasia and Age-related Diseases
Clinical and Epidemiological Evidence
Alzheimer’s disease/dementia/cognitive loss Coronary heart disease* Stroke (except women)* Osteoporosis/bone fractures Obesity, metabolic syndrome/diabetes mellitis II* Cancer*
Supplementation with physiological sex steroid post-menopause and during andropause delays the onset, decreases the incidence and often improves
the course of age-related diseases
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William Utermohlen’s self-portraits reveal his
descent into dememtia over the span of nearly
four decades. Left, a self-portrait from 1967.
When he learned in 1995 that he had Alzheimer’s
disease, William Utermohlen, an American
artist in London, responded in
characteristic fashion.
©2006 Galerie Beckel-Odille-Boicos
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1996
©2006 Galerie Beckel-Odille-Boicos
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1996
©2006 Galerie Beckel-Odille-Boicos
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1996©2006 Galerie Beckel-Odille-Boicos
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©2006 Galerie Beckel-Odille-Boicos
1997
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©2006 Galerie Beckel-Odille-Boicos
1997
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©2006 Galerie Beckel-Odille-Boicos
1998
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©2006 Galerie Beckel-Odille-Boicos
1999
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©2006 Galerie Beckel-Odille-Boicos
2000
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William Utermohlen’s self-portraits reveal his descent into dememtia over the span of nearly four decades.
First picture, a self-portrait from 1967.
1996 1996 1996 1996 1996 1996 1996 1996
1997 1997 1997 1997 1998 1998 1999 1999 2000 2000
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Macroscopic Differences Between AD Macroscopic Differences Between AD and Control Brainsand Control Brains
• narrowing of gyri (blue arrow)
• widening of sulci (yellow arrow)
(Adapted from Kisilevsky, 1994)
Alzheimer’s DiseaseAged Control Brain
• Neurodegenerative disorder of the elderlyNeurodegenerative disorder of the elderly• Memory loss and impairments of behavioral, language and visuo-spatial skillsMemory loss and impairments of behavioral, language and visuo-spatial skills
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Alzheimer’s disease attacks nerve cells in several regions of the brain.
A. Cerebral Cortex: Involved in conscious thought and language.B. Basal forebrain: Has large numbers of
neurons containing acetylcholine, a
chemical important in memory and learning.
C. Hippocampus: Essential to memory storage.
The earliest signs of Alzheimer's are found in the nearby entorhinal cortex (not shown).
The Brain and Alzheimer DiseaseThe Brain and Alzheimer Disease
• Neurons loss/dysfunction• Synapse loss/dysfunction• Neurofibillary tangles – P-tau• Amyloid plaques – amyloid-• Microgliosis
Overt Neuropathology:
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The Biochemical and Pathological Changes The Biochemical and Pathological Changes Associated with ADAssociated with AD
Cell Cycle Related EventsCell Cycle Related Events
• Cell cycle proteinsCell cycle proteins
• Chromosome replication Chromosome replication
• Elevated mtDNA/Cox-1 levelsElevated mtDNA/Cox-1 levels
• Oxidative stress Oxidative stress
• APP processingAPP processing
• Tau phosphorylation Tau phosphorylation
• Mitotic signal transduction pathwaysMitotic signal transduction pathways
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Why is the Cell Cycle Reactivated in Why is the Cell Cycle Reactivated in Alzheimer’s Disease?Alzheimer’s Disease?
Certain HPG hormones are mitogenicCertain HPG hormones are mitogenic(cell proliferation)(cell proliferation)
- LH, FSH, GnRH- LH, FSH, GnRH- increase amyloid-- increase amyloid- deposition, tau phosphorylation deposition, tau phosphorylation
Certain HPG hormones are differentiativeCertain HPG hormones are differentiative(specify cell function)(specify cell function)
- sex steroids, activins- sex steroids, activins- reduce amyloid-- reduce amyloid- deposition, tau phosphorylation deposition, tau phosphorylation
Loss of balance in the reproductive hormonal axis leads to Loss of balance in the reproductive hormonal axis leads to aberrant reactivation of the cell cycle leading to aberrant reactivation of the cell cycle leading to
neuron deathneuron death
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Epidemiological and Clinical Evidence for Epidemiological and Clinical Evidence for Sex Hormones as the Cause of ADSex Hormones as the Cause of AD
• female predominance (general population)female predominance (general population)• 2:1 ratio of women to men2:1 ratio of women to men• abrupt earlier loss of gonadal function in womenabrupt earlier loss of gonadal function in women
• increased risk of dementia in women who had increased risk of dementia in women who had oophorectomy (ovaries removed)oophorectomy (ovaries removed)
• positive relationships between AD and decreased positive relationships between AD and decreased sex steroids and increased LH/FSH levels after sex steroids and increased LH/FSH levels after menopause/andropausemenopause/andropause
• hormones regulate biochemical and hormones regulate biochemical and neuropathological changes associated with ADneuropathological changes associated with AD• physiological hormone replacement therapies delay physiological hormone replacement therapies delay onset and decrease incidenceonset and decrease incidence
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Clinical Trials Demonstrate Importance of Clinical Trials Demonstrate Importance of Physiological Sex Steroids for CognitionPhysiological Sex Steroids for Cognition
Intervention (treatment) trialsIntervention (treatment) trials– 1717-estradiol -estradiol improvesimproves cognitive performance in women with cognitive performance in women with
AD (3 controlled studies and 5 uncontrolled studies)AD (3 controlled studies and 5 uncontrolled studies)– testosterone testosterone improvesimproves cognitive performance in men with AD cognitive performance in men with AD
(1 controlled study)(1 controlled study)
Prospective cohort studiesProspective cohort studies– 1717-estradiol -estradiol reducesreduces the incidence (1 study) and the incidence (1 study) and delaysdelays the the
onset (4 studies) of AD in older women onset (4 studies) of AD in older women – 1717-estradiol -estradiol improvesimproves cognitive performance in cognitively cognitive performance in cognitively
healthy post-menopausal women (12 of 15 studies; 3 studies healthy post-menopausal women (12 of 15 studies; 3 studies showed no benefit)showed no benefit)
2626 different studies indicate physiological forms of different studies indicate physiological forms of estrogens and testosterone are beneficial for estrogens and testosterone are beneficial for cognitive healthcognitive health
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Estradiol Halts Cognitive Decline and Estradiol Halts Cognitive Decline and Enhances CognitionEnhances Cognition
Estradiol study, elderly women, 5 yearsEstradiol study, elderly women, 5 years No estradiol - 16% developed ADNo estradiol - 16% developed AD Estradiol - 1.7% developed AD Estradiol - 1.7% developed AD
Other studiesOther studies Women who suffered only moderate memory Women who suffered only moderate memory
problems from Alzheimer's disease improved problems from Alzheimer's disease improved their memory while on HRTtheir memory while on HRT
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Compelling Evidence that Sex Steroids Compelling Evidence that Sex Steroids are Important for Brain Healthare Important for Brain Health
Why are we not all taking human estradiol and Why are we not all taking human estradiol and progesterone post-menopause to supplement for the progesterone post-menopause to supplement for the loss of these hormones with aging?loss of these hormones with aging?
And testosterone during andropause in men to And testosterone during andropause in men to supplement for the loss of these hormones with supplement for the loss of these hormones with aging? aging?
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Unphysiological Sex Steroids and Unphysiological Sex Steroids and Disease RiskDisease Risk
1. Women Health Initiative Studies 1. Women Health Initiative Studies Human versus non-human sex hormonesHuman versus non-human sex hormones Non-human sex hormones developed initially for Non-human sex hormones developed initially for
treatment of menopausal symptoms (profit from treatment of menopausal symptoms (profit from patented sex steroids)patented sex steroids)
Analogs/non-human forms developed for human Analogs/non-human forms developed for human useuse
Long-term use led to health issuesLong-term use led to health issues
2. Risk of cancer, stroke and heart disease2. Risk of cancer, stroke and heart disease
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1. Women’s Health Initiative Studies1. Women’s Health Initiative Studies
PREMARIN – conjugated PREMARIN – conjugated equine estrogens (estrone equine estrogens (estrone sulfate)sulfate)
PREMPRO – CEE plus PREMPRO – CEE plus medroxyprogesterone acetatemedroxyprogesterone acetate
Horse-derived and synthetic analogs:Horse-derived and synthetic analogs:
Let’s compare estradiol Let’s compare estradiol with CEE…..with CEE…..
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Clinical and Observational Studies of Natural and Clinical and Observational Studies of Natural and Unnatural Sex Steroids on Cognitive OutcomeUnnatural Sex Steroids on Cognitive Outcome
1717-estradiol:-estradiol: 100% of studies show improvement in cognition in AD subjects100% of studies show improvement in cognition in AD subjects 80% of studies show improvement in cognitive performance in 80% of studies show improvement in cognitive performance in
healthy older womenhealthy older women
Conjugated equine estrogens: Conjugated equine estrogens: ~50% of studies show a delay in onset and halting of the ~50% of studies show a delay in onset and halting of the
progression of ADprogression of AD ~50% of studies show an improvement in cognitive ~50% of studies show an improvement in cognitive
performance in healthy older womenperformance in healthy older women One study, the Women’s Health Initiative – Memory Study One study, the Women’s Health Initiative – Memory Study
(WHIMS) showed that women taking CEE (Premarin) or CEE (WHIMS) showed that women taking CEE (Premarin) or CEE with medroxyprogesterone (Prempro) were more likely to show with medroxyprogesterone (Prempro) were more likely to show cognitive cognitive declinedecline
Different forms of estrogen vary in their effects, and side effects, Different forms of estrogen vary in their effects, and side effects, on the brain and other tissueson the brain and other tissues
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ DamageNatural Forms of Sex Steroids
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ DamageNatural Forms of Sex Steroids
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage
Progesterone Testosterone
Natural Forms of Sex Steroids
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage
Progesterone Testosterone
Natural Forms of Sex Steroids
Major differences in biological action
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage
Progesterone Testosterone
Medroxyprogesterone (MPA)
Natural Forms of Sex Steroids
Synthetic/Animal Forms of Sex Steroids
Biologically – we might expect major differences, and we do
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage
Progesterone Testosterone
Medroxyprogesterone (MPA)
Natural Forms of Sex Steroids
Unlike progesterone, medroxyprogesterone:
DOES NOT protect against glutamate-induced neuronal toxicity (Nilsen et al., 2006, Gynecol Endocrinol.; Jodhka et al., 2009, Endocrinology)
DOES NOT protect against the neuro-degeneration induced by traumatic brain injury (Wright et al., 2008; Brain)
DOES prevents neurogenesis (Nilsen and Brinton, 2003, PNAS; Brinton, 2009)
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage
Progesterone Testosterone
Medroxyprogesterone (MPA)
17-estradiol
Natural Forms of Sex Steroids
Synthetic/Animal Forms of Sex Steroids
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage
Progesterone Testosterone
Medroxyprogesterone (MPA)
17-estradiol
Estrone sulfate
Natural Forms of Sex Steroids
Synthetic/Animal Forms of Sex Steroids
Biologically – major differences in function
Major estrogen from horse urine
found in Premarin
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Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ Damage
Progesterone Testosterone 17-estradiol
Estrone sulfate
Natural Forms of Sex Steroids
Biologically – major differences in action
CEE – different signaling pathways? major CEE = estrone sulfate contain ~ 15 different estrogens excretory products decreased ER binding conjugation - hormonal inactivation to limit signaling (sulfation or glucuronidation)
Major estrogen from horse urine
found in Premarin
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We need to be supplementing our body with sex steroids that are physiologically relevant!
For Women: 17-estradiol and progesterone
For Men: testosterone and progesterone
Undoing the ‘Scientific’ DamageUndoing the ‘Scientific’ DamageThe Bottom Line
No study has ever shown a No study has ever shown a negative cognitive outcome from negative cognitive outcome from the use of human sex steroids.the use of human sex steroids.
Predominantly a US problemPredominantly a US problem
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Small Changes Can Lead to Big Small Changes Can Lead to Big Differences!Differences!
Synthetic sex steroids- anabolic steroids – androgenic (T and DHT)
- synthetic estrogens and progestagens used in hormone replacement therapies, oral contraceptives and other reproductive conditions or diseases
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2. Cancer Risk for Hormone Replacement 2. Cancer Risk for Hormone Replacement Therapies (HRT)Therapies (HRT)
There is an indisputable increase in the risk of breast, uterine There is an indisputable increase in the risk of breast, uterine and ovarian cancer with CEE and estradiol supplementationand ovarian cancer with CEE and estradiol supplementation
CancerCancer UsageUsage
(years)(years)Incidence Incidence (/1000)(/1000)
BreastBreast >10>10 3-63-6
OvarianOvarian >10>10 3-113-11
UterineUterine >10>10 7-157-15
TotalTotal ~23/1000~23/1000
CEECEE EstradiolEstradiol
CancerCancer UsageUsage
(years)(years)Incidence Incidence (/1000)(/1000)
BreastBreast >10>10 1-131-13
OvarianOvarian >10>10 1-31-3
UterineUterine >10>10 1-51-5
TotalTotal ~12/1000~12/1000
~1-2 women per 100 will develop a reproductive cancer~1-2 women per 100 will develop a reproductive cancer
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Cancer Risk for Hormone Replacement Cancer Risk for Hormone Replacement Therapies (HRT)Therapies (HRT)
But estradiol replacement therapy decreases But estradiol replacement therapy decreases the risk of other diseases: heart disease, AD, the risk of other diseases: heart disease, AD, stroke, osteoporosis, diabetes mellitus II, etcstroke, osteoporosis, diabetes mellitus II, etc
Does the risk of cancer or other diseases Does the risk of cancer or other diseases from HRT outweigh the risk from developing from HRT outweigh the risk from developing other diseases of aging?other diseases of aging?
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2. Cancer Risk for Hormone Replacement 2. Cancer Risk for Hormone Replacement Therapies (HRT)Therapies (HRT)
But HRT decreases the risk of nearly every But HRT decreases the risk of nearly every other disease: heart disease, AD, stroke, other disease: heart disease, AD, stroke, osteoporosis, diabetes mellitus II, etcosteoporosis, diabetes mellitus II, etc
Does the risk of cancer or other diseases Does the risk of cancer or other diseases from HRT outweigh the risk from developing from HRT outweigh the risk from developing other diseases of aging?other diseases of aging?
NONO
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Humans: Estrogen Replacement Humans: Estrogen Replacement Therapy Decreases MortalityTherapy Decreases Mortality
Consistently show a 20-50% decrease in mortality among estrogen (CEE) users
Paganini-Hill et al., 2006
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Higher Age at Menopause Increases Female Higher Age at Menopause Increases Female Post-Reproductive Post-Reproductive LifespanLifespan
Advanced age at last reproduction is associated with improved longevity
~ 2.4% reduced mortality per year increase in age at menarche
Age at menopause (years)
9 studies demonstrate advanced age at menopause - ↑ longevity
Ossewaarde et al., (2005)
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Cancer Risk for Hormone Cancer Risk for Hormone Replacement Therapies (HRT)Replacement Therapies (HRT)
Example 1: I am 80 years of age and have no family history of Example 1: I am 80 years of age and have no family history of cancer, but my cognition is declining. May consider risk of cancer, but my cognition is declining. May consider risk of cancer unimportant in the face of memory loss.cancer unimportant in the face of memory loss.
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Cancer Risk for Hormone Cancer Risk for Hormone Replacement Therapies (HRT)Replacement Therapies (HRT)
Example 1: I am 80 years of age and have no family history of Example 1: I am 80 years of age and have no family history of cancer, but my cognition is declining. May consider risk of cancer, but my cognition is declining. May consider risk of cancer unimportant in the face of memory loss.cancer unimportant in the face of memory loss.
Example 2: I am 65 years of age and have cognitive decline. Example 2: I am 65 years of age and have cognitive decline. May consider risk of cancer unimportant in the face of memory May consider risk of cancer unimportant in the face of memory loss.loss.
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Cancer Risk for Hormone Cancer Risk for Hormone Replacement Therapies (HRT)Replacement Therapies (HRT)
Example 1: I am 80 years of age and have no family history of Example 1: I am 80 years of age and have no family history of cancer, but my cognition is declining. May consider risk of cancer, but my cognition is declining. May consider risk of cancer unimportant in the face of memory loss.cancer unimportant in the face of memory loss.
Example 2: I am 65 years of age and have cognitive decline. Example 2: I am 65 years of age and have cognitive decline. May consider risk of cancer unimportant in the face of memory May consider risk of cancer unimportant in the face of memory loss.loss.
Example 3: I am 70 years of age without cognitive loss, but a Example 3: I am 70 years of age without cognitive loss, but a family history of cancer. May consider risk of cancer family history of cancer. May consider risk of cancer outweighs risks of memory loss.outweighs risks of memory loss.
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Cancer Risk for Hormone Cancer Risk for Hormone Replacement Therapies (HRT)Replacement Therapies (HRT)
Example 1: I am 80 years of age and have no family history of Example 1: I am 80 years of age and have no family history of cancer, but my cognition is declining. May consider risk of cancer, but my cognition is declining. May consider risk of cancer unimportant in the face of memory loss.cancer unimportant in the face of memory loss.
Example 2: I am 65 years of age and have cognitive decline. Example 2: I am 65 years of age and have cognitive decline. May consider risk of cancer unimportant in the face of memory May consider risk of cancer unimportant in the face of memory loss.loss.
Example 3: I am 70 years of age without cognitive loss, but a Example 3: I am 70 years of age without cognitive loss, but a family history of cancer. May consider risk of cancer family history of cancer. May consider risk of cancer outweighs risks of memory loss.outweighs risks of memory loss.
Example 4: I am 70 years of age and have cognitive decline. Example 4: I am 70 years of age and have cognitive decline. I also have a family history of cancer. I also have a family history of cancer.
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Summary: Sex Hormones and Age-Summary: Sex Hormones and Age-related Disease Riskrelated Disease Risk
Maintaining sex steroid levels reduces the risk of:Maintaining sex steroid levels reduces the risk of:
Alzheimer’s diseaseAlzheimer’s disease
Stroke*Stroke*
Coronary heart disease*Coronary heart disease*
OsteoporosisOsteoporosis
Obesity, metabolic syndrome/diabetes mellitis II*Obesity, metabolic syndrome/diabetes mellitis II*
Depression and anxietyDepression and anxiety
Menopausal symptomsMenopausal symptoms
Maintaining sex steroid levels increase the risk of:Maintaining sex steroid levels increase the risk of:
CancerCancer
Quality of lifeQuality of life
Living longer!Living longer!
Partial hormone Partial hormone replacement therapyreplacement therapy
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Female Hormone Replacement Therapy:Female Hormone Replacement Therapy:
What Should I Take?What Should I Take?• WomenWomen
– 1717-estradiol (USP) - patch (Climara or Vivelle)-estradiol (USP) - patch (Climara or Vivelle)
– progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – first pass changes in liverfirst pass changes in liver
• DoseDose
– 1717-estradiol (USP) - 0.025 mg/day-estradiol (USP) - 0.025 mg/day
– progesterone (USP) - 30 mg/dayprogesterone (USP) - 30 mg/day
• Route?Route?
– Varies for hormoneVaries for hormone
• Opposed or unopposed?Opposed or unopposed?
– 1717-estradiol + progesterone-estradiol + progesterone
– decreased uterine cancerdecreased uterine cancer
• Timing, duration and cyclicity?Timing, duration and cyclicity?
– during menopause – for relief of menopausal symptomduring menopause – for relief of menopausal symptom
– post-menopause: window – 5 years versus foreverpost-menopause: window – 5 years versus forever
– continuous progesterone to avoid breakthrough bleedingcontinuous progesterone to avoid breakthrough bleeding
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Male Hormone Replacement Therapy:Male Hormone Replacement Therapy:
What Should I Take?What Should I Take?• MenMen
– testosterone (USP) - gel or underarm topicaltestosterone (USP) - gel or underarm topical
– progesterone (USP) - Pro Gest (cream) – preferable; Prometrium progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – first pass changes in liver(pill) – first pass changes in liver
• DoseDose
– testosterone (USP) – 10 mg/day testosterone (USP) – 10 mg/day
– progesterone (USP) - 30 mg/dayprogesterone (USP) - 30 mg/day
• Route?Route?
– Transdermal to avoid oral first pass effects through liverTransdermal to avoid oral first pass effects through liver
• Opposed or unopposedOpposed or unopposed
– testosterone + progesterone?testosterone + progesterone?
• Timing, duration and cyclicityTiming, duration and cyclicity
– Starting at andropause (30-50 years)Starting at andropause (30-50 years)
– Starting when hypogonadal (i.e. low serum T) and phenotypic Starting when hypogonadal (i.e. low serum T) and phenotypic changes menopause – for relief of menopausal symptomchanges menopause – for relief of menopausal symptom
– Continuous? Continuous?
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3. Replacing gonadal cells3. Replacing gonadal cells Ovarian and testicular implants?Ovarian and testicular implants? Would provide Would provide completecomplete hormone replacement hormone replacement Would eliminate the negative consequences resulting from partial Would eliminate the negative consequences resulting from partial
hormone replacement???hormone replacement???
Ovary replacement shown to increase longevityOvary replacement shown to increase longevity Human embryonic stem cell technologiesHuman embryonic stem cell technologies Not currently a possibility for humansNot currently a possibility for humans
20-40 years20-40 years
Life Extension Strategies Through Hormone Life Extension Strategies Through Hormone Supplementation or SuppressionSupplementation or Suppression
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Healthy Lifespan Extension Following Healthy Lifespan Extension Following Ovary TransplantationOvary Transplantation
Cargill et al., (2003)
40% increase in life expectancy
Rebalancing the HPG Axis Increases Longevity
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Delaydecreasing
function
Mild
Moderate
Severe
Restoration of the HPG Axis Extends Restoration of the HPG Axis Extends Lifespan and HealthspanLifespan and Healthspan
Fu
nct
ion Cognitive function
Vascular functionImmune function
Bone functionReproductive function
Athletic function
Increasingfunction
Increase stablefunction
0 50 100 150
IncreasingLifespan and Healthspan
Lifespan in Years
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Laboratory of Endocrinology, Laboratory of Endocrinology, Aging and Disease (LEAD)Aging and Disease (LEAD)
Post-doctoral Students• Giuseppe Verdile, Ph.D. • Glenda M. Bishop, Ph.D.• Sivan Vadakkadath Meethal, Ph.D.• Prashob Porayette, M.B.B.S., M.S.
Graduate Students• Tianbing Liu, M.Sc.• Hsien Chan, B.Sc.• Andrea C. Wilson, B.S.• Miguel Gallego, B.S.• Kentaro Hayashi, M.Sc.
Duke University, Raleigh, NCRichard L. Bowen, M.D.
Research Staff• Hong Zeng, M.S.• Zvezdana Kubats, M.S., • Patrick F. Lyon, M.S. • John Wung, B.S.• Sandra L. Siedlak, M.S.• Ryan Haasl, M.Sc.• Jon Sweeney, B.S.• Derek Simon • Jacob Basson, B.S.
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Life and Death is About Balance:Life and Death is About Balance:Hormonal Balance!Hormonal Balance!
Live Longer Foundation, Inc.Live Longer Foundation, Inc.
www.livelongerfoundation.org