Living Longer Presentation 2012
Upcoming SlideShare
Loading in...5
×
 

Like this? Share it with your network

Share

Living Longer Presentation 2012

on

  • 695 views

This presentation explains how and why we age, and how to halt the aging process.

This presentation explains how and why we age, and how to halt the aging process.

Statistics

Views

Total Views
695
Views on SlideShare
563
Embed Views
132

Actions

Likes
0
Downloads
6
Comments
0

3 Embeds 132

http://livelongerfoundation.org 96
http://www.livelongerfoundation.org 34
http://llf.tuckerlong.com 2

Accessibility

Categories

Upload Details

Uploaded via as Microsoft PowerPoint

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment
  • The egg is fertilized as it is released from the ovary and the fimbriae assist the egg into the site of fertilization in the oviduct. It moves up through the ampullary duct as the first cell division occurs and the zona pellucida is shed. Followed by the 2 4 8 cell stage until it reaches the Morula stage where moves into the Uterus. In the uterus it enters the blastula stage and it begins implantation in the upper portoin of the uterine wall. Although fertilization appears to initiate cell division, but is cell proliferation regulated by exogenous or endogenous factors? I would now like to go over some of the histology of the blastocyst.
  • As I run through the pathway, I would like you to only focus on the end points of steroidogenisis. Transition: So how does this relate to our system and more importantly, do we see hormonal changes in the developing embryo?
  • O'Grady, Lois et al, A Practical Approach to Breast Disease, Boston: Little Brown and Company, 1995, 186-187 first two points

Living Longer Presentation 2012 Presentation Transcript

  • 1. Aging and Hormone Replacement: The Latest in Disease Prevention From: beautyanalysis.com From: Pilates Reforming NY 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 Hospital Madison, WisconsinLEAD, ‘10
  • 2. The Seven Acts of Life Jacques: All the worlds 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 nurses 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 canons 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;LEAD ‘10
  • 3. 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)LEAD ‘10
  • 4. Function Changes During the Life Cycle Increasing Stable Decreasing function function function Mild Function Moderate Severe0 20 40 60 80 100 Lifespan in YearsLEAD ‘10
  • 5. Function Changes During the Life Cycle: Extending Lifespan Increasing Stable Slow decreasing function function function Cognitive function Increasing Mild Function Vascular function lifespan Immune function Moderate Bone function Reproductive function Severe Athletic performance0 20 40 60 80 100 Lifespan in YearsLEAD ‘10
  • 6. Function Changes During the Life Cycle: Extending Lifespan and Healthspan Increasing Increase stable Delay function function decreasing function Increasing Cognitive function Mild Lifespan and Function Vascular function Healthspan Immune function Moderate Bone function Reproductive function Severe Athletic function0 20 40 60 80 100 Lifespan in YearsLEAD ‘10
  • 7. How and Why Do We Age? • 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. The hormones that regulate reproduction in mammals act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling Provides a credible reason for why and how aging occurs at the evolutionary, physiological and molecular levels How we can halt the aging processLEAD ‘10
  • 8. Reproductive Hormones Regulate Cell Growth, Development and Death fe ta l h C G L H (a d u lt fe m a le ) m ito g e n ic ity in d e x L H (m a le a n d fe m a le ) L H (a d u lt m a le ) Human Chorionic Gonadotropin/ Luteinizing Hormone Mitogenicity Index G e s t a t i o n I n f a n c y C h i l d h o o d P u b e r t y Adult-reproductive Senescence periodLEAD ‘10
  • 9. Hypothalamic-Pitutiary-Gonadal Axis: The Reproductive Axis Receptors for these hormones are expressed in all tissues of the body Feedback mechanisms keep axis in balance during reproductive period LH, FSH, GnRH – mitogenic hormones Sex steroids, activins – differentiative hormonesLEAD ‘10
  • 10. When and Why Do Sex Steroid Levels Change - puberty - menstrual cycle - pregnancy - castration - polycystic ovary syndrome - disease state - menopause/andropause Feedback Regulatory LoopsLEAD ‘10
  • 11. Hypothalamic-Pitutiary-Gonadal Axis: The Reproductive Axis Receptors for these hormones are expressed in all tissues of the body Feedback mechanisms keep axis in balance during reproductive period LH, FSH, GnRH – mitogenic hormones Sex steroids, activins – differentiative hormonesLEAD ‘10
  • 12. Endocrine Dyscrasia in Women and Age- related Diseases Dyotic Signaling: decreased sex steroid signaling, butLEAD ‘10 increased gonadotropin, GnRH and activin signaling
  • 13. Endocrine Dyscrasia in Men and Age- related Diseases Dyotic Signaling: decreased sex steroid signaling, butLEAD ‘10 increased gonadotropin, GnRH and activin signaling
  • 14. The Balance Between Mitogenic and Differentiation Hormones Dictates Cell Fate Mitogenic Signals Differentiation Signals hCG/LH/FSH Cellular Sex steroids GnRH Homeostasis Activins Aberrant Cell Division and Death/Dysfunction Endocrine dyscrasia Equilibrium becomes dysregulated, initiating dyosis which drives senescenceLEAD ‘10
  • 15. Consequences of HPG Dysregulation 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 – SM C/endothelial cells –LEAD ‘10
  • 16. Consequences of HPG Dysregulation: Endocrine Dyscrasia 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 dieLEAD ‘10
  • 17. Leading Causes of Death in the USA Table 1. Leading causes of death in the US Cause of Death All Ages Total 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% → Osteoporosis/low bone mass 55% by 50 years of age → Dementia/cognitive loss 45% by 85 years of ageLEAD ‘10 CDC National Vital Statistics Report, Vol. 57, No. 14, April 17, 2009
  • 18. Evidence that Endocrine Dyscrasia Leads to Aging-related Diseases 1. Epidemiological evidence 2. Clinical evidence 3. Experimental evidence This evidence provides clues as to how to halt the aging process that leads to our age- related diseasesLEAD ‘10
  • 19. Age-related Reproductive Endocrine Dyscrasia Initiates Senescence and Age-related Diseases Epidemiological Evidence (>10 studies)  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 The longer the HPG axis is in balance, the less likelyLEAD ‘10 you are to develop an age-related disease
  • 20. Age-related Reproductive Endocrine Dyscrasia 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 of age-related diseaseLEAD ‘10
  • 21. Age-related Reproductive Endocrine Dyscrasia Initiates Senescence and Age-related Diseases Experimental Evidence Positive relationships between age-related diseases and decreased circulating sex steroids and increased gonadotropins in both men and women  Coronary heart disease  Stroke (except women)  Alzheimer’s disease/dementia/cognitive loss  Osteoporosis/bone fractures  Cancer  Obesity, metabolic syndrome/diabetes mellitis II  Frailty (men) The more dysregulated your HPG axis, the more likely youLEAD ‘10 are to develop age-related diseases
  • 22. Sex Hormones and Age-related Disease Risk Males 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 strengthLEAD ‘10 • increased body fat
  • 23. Hypothalamic-Pitutiary-Gonadal Axis: The Reproductive Axis All hormones of the axis have important physiological functionsLEAD ‘10
  • 24. Reproductive Hormones are Required for Growth and Development, and Maintenance of Tissues During Adulthood Embryonic and fetal growth and development: hCG – proliferative functions Progesterone – promotes neurogenesis and differentiation Adult tissue maintenance: LH – induces neurogenesis in the adult brain Estradiol – promotes neuritogenesis - neurite extension, dendritic spine formation, synaptogenesis Progesterone – promotes angiogenesis, mammary gland development Sex hormones are required for normal adult tissue maintenanceLEAD ‘10
  • 25. Sex Steroid Hormones Are Synthesized by the Gonads and the Brain: Feedback Regulatory Loops 1 5 1 2 3 3 4 2 5 4 Sex steroids are made by the brain, for the brainLEAD ‘10
  • 26. Life Extension Strategies Through Hormone Supplementation or Suppression 1. Modulating Reproductive Parameters  later menopause  later puberty  pregnancy and lactational amenorrhea  stress: caloric restriction or cold  ~5-20 yearsLEAD ‘10
  • 27. Suppressing the HPG Axis as a Means to Extend Longevity Life-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 agonistsLEAD ‘10 halves the risk of death from Alzheimer’s disease
  • 28. Life Extension Strategies Through Hormone Supplementation or Suppression 2. Pharmacological solutions Hormone replacement therapies (physiological hormones)  Sex steroids – 17β -estradiol, progesterone and testosterone  Currently we cannot replace all hormones lost  Partial replacement Hormone suppression therapies  GnRH agonists and antagonists  Comes with some negative issues – osteoporosis, heart disease but appears positive for Alzheimer’s disease  5-20 years  These above strategies are the best we can do currently  Focus on sex steroid replacement otherwise known as hormoneLEAD ‘10 replacement therapy
  • 29. Hormone 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 analogsLEAD ‘10
  • 30. Reversing Endocrine Dyscrasia as a Means to Extend LongevityLEAD ‘10
  • 31. Reversing Endocrine Dyscrasia: Restoring Some Balance to the HPG Axis It’s not perfect, but it’s the best we can do for nowLEAD ‘10
  • 32. What are Sex Steroids Cholesterol Progesterone Sex steroid synthesis begins in the embryo and continues throughout life Decreases in sex steroid synthesis with menopause and andropauseLEAD ‘10
  • 33. What are Sex Steroids Human sex steroids are made by: - ovaries and testes - adrenal glands - brain - adipose tissueLEAD ‘10
  • 34. What are Sex Steroids Human sex steroids are made by: - ovaries or testes - adrenal glands - brain - adipose tissue Classes of sex steroids - androgens (testosterone) - estrogens (17β-estradiol) - progestagens (progesterone) All hormones are found in males and femalesLEAD ‘10
  • 35. Cholesterol Steroid Biosynthesis StAR followed by P450 side chain cleavage Pregnenolone 17αOH Pregnenolone DHEA 17αHSD 17,20 3βHSD 3βHSD lyase 3βHSD Progesterone 17αOH Progesterone Androstenedione 21 & 11β 17βHSD 17βHSD hydroxylase + Testosterone Corticosterone Cortisol aromatase 18 hydroxylase 5α & 18 HSD reductase 17β-Estradiol Aldosterone Physiologically DHT important steroidsLEAD ‘10
  • 36. Age-related Reproductive Endocrine Dyscrasia and Age-related Diseases Clinical and Epidemiological Evidence 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  Alzheimer’s disease/dementia/cognitive loss  Coronary heart disease*  Stroke (except women)*  Osteoporosis/bone fractures  Obesity, metabolic syndrome/diabetes mellitis II*  Cancer*LEAD ‘10
  • 37. 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.LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 38. 1996LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 39. 1996LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 40. 1996LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 41. 1997LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 42. 1997LEAD, ‘10©2006 Galerie Beckel-Odille-Boicos
  • 43. 1998LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 44. 1999LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 45. 2000LEAD, ‘10 ©2006 Galerie Beckel-Odille-Boicos
  • 46. 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 19961997 1997 1998 1999 2000LEAD, ‘10
  • 47. Macroscopic Differences Between AD and Control Brains Aged Control Brain Alzheimer’s Disease • narrowing of gyri (blue arrow) • widening of sulci (yellow arrow (Adapted from Kisilevsky, 1994) • Neurodegenerative disorder of the elderly • Memory loss and impairments of behavioral, language and visuo-spatial skillsLEAD ‘10
  • 48. The Brain and Alzheimer DiseaseAlzheimer’s disease attacks nerve cells in several regionsof the brain. Overt Neuropathology: • Neurons loss/dysfunction • Synapse loss/dysfunction • Neurofibillary tangles – P-tau • Amyloid plaques – amyloid-β • Microgliosis 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 Alzheimers are found in the nearby entorhinal cortex (notLEAD ‘10 shown).
  • 49. The Biochemical and Pathological Changes Associated with AD Cell Cycle Related Events • Cell cycle proteins • Chromosome replication • Elevated mtDNA/Cox-1 levels • Oxidative stress • APP processing • Tau phosphorylation • Mitotic signal transduction pathwaysLEAD, ‘10
  • 50. Why is the Cell Cycle Reactivated in Alzheimer’s Disease?Certain HPG hormones are mitogenic(cell proliferation) - LH, FSH, GnRH - increase amyloid-β deposition, tau phosphorylationCertain HPG hormones are differentiative(specify cell function) - sex steroids, activins - reduce amyloid-β deposition, tau phosphorylation Loss of balance in the reproductive hormonal axis leads to aberrant reactivation of the cell cycle leading to neuron deathLEAD, ‘10
  • 51. Epidemiological and Clinical Evidence for Sex Hormones as the Cause of AD • female predominance (general population) • 2:1 ratio of women to men • abrupt earlier loss of gonadal function in women • increased risk of dementia in women who had oophorectomy (ovaries removed) • positive relationships between AD and decreased sex steroids and increased LH/FSH levels after menopause/andropause • hormones regulate biochemical and neuropathological changes associated with AD • physiological hormone replacement therapies delay onset and decrease incidenceLEAD ‘10
  • 52. Clinical Trials Demonstrate Importance of Physiological Sex Steroids for Cognition  Intervention (treatment) trials – 17β -estradiol improves cognitive performance in women with AD (3 controlled studies and 5 uncontrolled studies) – testosterone improves cognitive performance in men with AD (1 controlled study)  Prospective cohort studies – 17β -estradiol reduces the incidence (1 study) and delays the onset (4 studies) of AD in older women – 17β -estradiol improves cognitive performance in cognitively healthy post-menopausal women (12 of 15 studies; 3 studies showed no benefit)  26 different studies indicate physiological forms of estrogens and testosterone are beneficial for cognitive healthLEAD ‘10
  • 53. Estradiol Halts Cognitive Decline and Enhances Cognition  Estradiol study, elderly women, 5 years  No estradiol - 16% developed AD  Estradiol - 1.7% developed AD  Other studies  Women who suffered only moderate memory problems from Alzheimers disease improved their memory while on HRTLEAD ‘10
  • 54. Compelling Evidence that Sex Steroids are Important for Brain Health  Why are we not all taking human estradiol and progesterone post-menopause to supplement for the loss of these hormones with aging?  And testosterone during andropause in men to supplement for the loss of these hormones with aging?LEAD ‘10
  • 55. Unphysiological Sex Steroids and Disease Risk 1. Women Health Initiative Studies  Human versus non-human sex hormones  Non-human sex hormones developed initially for treatment of menopausal symptoms (profit from patented sex steroids)  Analogs/non-human forms developed for human use  Long-term use led to health issues 2. Risk of cancer, stroke and heart diseaseLEAD ‘10
  • 56. 1. Women’s Health Initiative Studies Horse-derived and synthetic analogs: PREMARIN – conjugated equine estrogens (estrone sulfate) PREMPRO – CEE plus medroxyprogesterone acetate Let’s compare estradiol with CEE…..LEAD ‘10
  • 57. Clinical and Observational Studies of Natural and Unnatural Sex Steroids on Cognitive Outcome  17β -estradiol:  100% of studies show improvement in cognition in AD subjects  80% of studies show improvement in cognitive performance in healthy older women  Conjugated equine estrogens:  ~50% of studies show a delay in onset and halting of the progression of AD  ~50% of studies show an improvement in cognitive performance in healthy older women  One study, the Women’s Health Initiative – Memory Study (WHIMS) showed that women taking CEE (Premarin) or CEE with medroxyprogesterone (Prempro) were more likely to show cognitive decline  Different forms of estrogen vary in their effects, and side effects, on the brain and other tissuesLEAD ‘10
  • 58. Undoing the ‘Scientific’ Damage Natural Forms of Sex SteroidsLEAD ‘10
  • 59. Undoing the ‘Scientific’ Damage Natural Forms of Sex SteroidsLEAD ‘10
  • 60. Undoing the ‘Scientific’ Damage Natural Forms of Sex Steroids Progesterone TestosteroneLEAD ‘10
  • 61. Undoing the ‘Scientific’ Damage Natural Forms of Sex Steroids Progesterone Testosterone Major differences in biological actionLEAD ‘10
  • 62. Undoing the ‘Scientific’ Damage Natural Forms of Sex Steroids Progesterone Testosterone Synthetic/Animal Forms of Medroxyprogesteron Sex Steroids e (MPA) Biologically – we might expect major differences, and we doLEAD ‘10
  • 63. Undoing the ‘Scientific’ Damage Natural Forms of Sex Steroids Progesterone Testosterone Unlike progesterone, medroxyprogesterone:  DOES NOT protect against glutamate-induced Medroxyprogesteron neuronal toxicity (Nilsen et al., 2006, Gynecol e (MPA) 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 andLEAD ‘10 Brinton, 2003, PNAS; Brinton, 2009)
  • 64. Undoing the ‘Scientific’ Damage Natural Forms of Sex Steroids Progesterone Testosterone 17β-estradiol Synthetic/Animal Forms of Medroxyprogesteron Sex Steroids e (MPA)LEAD ‘10
  • 65. Undoing the ‘Scientific’ Damage Natural Forms of Sex Steroids Progesterone Testosterone 17β-estradiol Synthetic/Animal Forms of Medroxyprogesteron Sex Steroids e (MPA) Estrone sulfate Major estrogen from horse urine found in PremarinLEAD ‘10 Biologically – major differences in
  • 66. Undoing the ‘Scientific’ Damage Natural Forms of Sex Steroids Progesterone Testosterone 17β-estradiol CEE – different signaling pathways? Estrone sulfate  major CEE = estrone sulfate  contain ~ 15 different estrogens Major estrogen  excretory products from horse urine  decreased ER binding found in  conjugation - hormonal inactivation to limit Premarin signaling (sulfation or glucuronidation)LEAD ‘10 Biologically – major differences in
  • 67. Undoing the ‘Scientific’ Damage The Bottom Line We need to be supplementing our body with sex steroids that are physiologically relevant! For Women: 17β-estradiol and progesterone For Men: testosterone and progesterone No study has ever shown a negative cognitive outcome from the use of human sex steroids.LEAD ‘10 Predominantly a US problem
  • 68. Small Changes Can Lead to Big 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 diseasesLEAD ‘10
  • 69. 2. Cancer Risk for Hormone Replacement Therapies (HRT)  There is an indisputable increase in the risk of breast, uterine and ovarian cancer with CEE and estradiol supplementation CEE Estradiol Cancer Usage Incidence Cancer Usage Incidence (years) (/1000) (years) (/1000) Breast >10 3-6 Breast >10 1-13 Ovarian >10 3-11 Ovarian >10 1-3 Uterine >10 7-15 Uterine >10 1-5 Total ~23/1000 Total ~12/1000 ~1-2 women per 100 will develop a reproductive cancerLEAD ‘10
  • 70. Cancer Risk for Hormone Replacement Therapies (HRT)  But estradiol replacement therapy decreases the risk of other diseases: heart disease, AD, stroke, osteoporosis, diabetes mellitus II, etc  Does the risk of cancer or other diseases from HRT outweigh the risk from developing other diseases of aging?LEAD ‘10
  • 71. 2. Cancer Risk for Hormone Replacement Therapies (HRT)  But HRT decreases the risk of nearly every other disease: heart disease, AD, stroke, osteoporosis, diabetes mellitus II, etc  Does the risk of cancer or other diseases from HRT outweigh the risk from developing other diseases of aging? NOLEAD ‘10
  • 72. Humans: Estrogen Replacement Therapy Decreases Mortality Consistently show a 20-50% decrease in mortality among estrogen (CEE) usersLEAD ‘10 Paganini-Hill et al., 2006
  • 73. Higher Age at Menopause Increases Female Post-Reproductive Lifespan9 studies demonstrate advanced age at menopause - ↑ longevity Ossewaarde et al., (2005) Age at menopause (years) Advanced age at last reproduction is associated with improved longevity~ 2.4% reduced mortality per year increase in age at menarcheLEAD ‘10
  • 74. Cancer Risk for Hormone Replacement Therapies (HRT)  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 unimportant in the face of memory loss.LEAD ‘10
  • 75. Cancer Risk for Hormone Replacement Therapies (HRT)  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 unimportant in the face of memory loss.  Example 2: I am 65 years of age and have cognitive decline. May consider risk of cancer unimportant in the face of memory loss.LEAD ‘10
  • 76. Cancer Risk for Hormone Replacement Therapies (HRT)  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 unimportant in the face of memory loss.  Example 2: I am 65 years of age and have cognitive decline. May consider risk of cancer unimportant in the face of memory loss.  Example 3: I am 70 years of age without cognitive loss, but a family history of cancer. May consider risk of cancer outweighs risks of memory loss.LEAD ‘10
  • 77. Cancer Risk for Hormone Replacement Therapies (HRT)  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 unimportant in the face of memory loss.  Example 2: I am 65 years of age and have cognitive decline. May consider risk of cancer unimportant in the face of memory loss.  Example 3: I am 70 years of age without cognitive loss, but a family history of cancer. May consider risk of cancer outweighs risks of memory loss.  Example 4: I am 70 years of age and have cognitive decline. I also have a family history of cancer.LEAD ‘10
  • 78. Summary: Sex Hormones and Age- related Disease Risk Maintaining sex steroid levels reduces the risk of: Alzheimer’s disease Stroke* Coronary heart disease* Osteoporosis Obesity, metabolic syndrome/diabetes mellitis II* Depression and anxiety Menopausal symptoms Maintaining sex steroid levels increase the risk of: Cancer Quality of life Partial hormone replacement therapyLEAD ‘10 Living longer!
  • 79. Female Hormone Replacement Therapy: What Should I Take? • Women – 17β -estradiol (USP) - patch (Climara or Vivelle) – progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – first pass changes in liver • Dose – 17β -estradiol (USP) - 0.025 mg/day – progesterone (USP) - 30 mg/day • Route? – Varies for hormone • Opposed or unopposed? – 17β -estradiol + progesterone – decreased uterine cancer • Timing, duration and cyclicity? – during menopause – for relief of menopausal symptom – post-menopause: window – 5 years versus forever – continuous progesterone to avoid breakthrough bleedingLEAD ‘10
  • 80. Male Hormone Replacement Therapy: What Should I Take? • Men – testosterone (USP) - gel or underarm topical – progesterone (USP) - Pro Gest (cream) – preferable; Prometrium (pill) – first pass changes in liver • Dose – testosterone (USP) – 10 mg/day – progesterone (USP) - 30 mg/day • Route? – Transdermal to avoid oral first pass effects through liver • Opposed or unopposed – testosterone + progesterone? • Timing, duration and cyclicity – Starting at andropause (30-50 years) – Starting when hypogonadal (i.e. low serum T) and phenotypic changes menopause – for relief of menopausal symptom – Continuous?LEAD ‘10
  • 81. Life Extension Strategies Through Hormone Supplementation or Suppression 3. Replacing gonadal cells  Ovarian and testicular implants?  Would provide complete hormone replacement  Would eliminate the negative consequences resulting from partial hormone replacement???  Ovary replacement shown to increase longevity  Human embryonic stem cell technologies  Not currently a possibility for humans  20-40 yearsLEAD ‘10
  • 82. Healthy Lifespan Extension Following Ovary Transplantation 40% increase in life expectancy Rebalancing the HPG Axis Increases LongevityLEAD ‘10 Cargill et al., (2003)
  • 83. Restoration of the HPG Axis Extends Lifespan and Healthspan Increasing Increase stable Delay function function decreasing function Increasing Cognitive function Mild Lifespan and Function Vascular function Healthspan Immune function Moderate Bone function Reproductive function Severe Athletic function0 50 100 150 Lifespan in YearsLEAD ‘10
  • 84. Laboratory of Endocrinology, Aging and Disease (LEAD) Post-doctoral Students • Giuseppe Verdile, Ph.D. Research Staff • Glenda M. Bishop, Ph.D. • Hong Zeng, M.S. • Sivan Vadakkadath Meethal, Ph.D. • Zvezdana Kubats, M.S., • Prashob Porayette, M.B.B.S., M.S. • Patrick F. Lyon, M.S. • John Wung, B.S. Graduate Students • Sandra L. Siedlak, M.S. • Tianbing Liu, M.Sc. • Ryan Haasl, M.Sc. • Hsien Chan, B.Sc. • Jon Sweeney, B.S. • Andrea C. Wilson, B.S. • Derek Simon • Miguel Gallego, B.S. • Jacob Basson, B.S. • Kentaro Hayashi, M.Sc. Duke University, Raleigh, NC Richard L. Bowen, M.D.LEAD ‘10
  • 85. Life and Death is About Balance: Hormonal Balance! Live Longer Foundation, Inc. www.livelongerfoundation.orgLEAD ‘10