Update in
Preventive/Regenerative Medicine
Inflammation, Hormones, Stem
Cells and Telomeres
Ron Rothenberg MD
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Aging is a disease which can be
prevented or reversed
We are not prisoners of our genetic
destiny
HealthSpan
The HealthSpan Curve
“Conventional Medicine”
Prolongation of Morbidity
Degeneration
HealthSpan
Development
HealthSpan Extension
Development
Degeneration
Goal of Preventive/Regenerative Medicine
HealthSpan Extension, Morbidity
Compression
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Chronic
Inflammation is
a cause and the
effect of the
diseases of
aging
“Unified Theory of Wellness”
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Chronic Inflammation is the cause and the
effect of illness and the diseases of aging
Anti-inflammation through the optimization
of lifestyle, nutraceuticals, hormones,
telomeres and stem cells
Anti-inflammation = Wellness
Anti-inflammation = Peak performance,
health, happiness
Anti-inflammation = optimal stem cell
function
Anti-inflammation = telomere optimization
Regenerative Medicine is:
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Optimal lifestyle
Inflammation reduction
Cutting edge technologies to detect, prevent
and treat aging related disease
Scientific and Evidence Based
Documented in curent Peer reviewed medical
journals.
What do we do in Regenerative medicine?
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Design customized preventive/
regenerative medicine programs
Advanced lab testing
Nutrition - personalized
Exercise
Stress Reduction
Nutraceuticals
Inflammation control
Optimize Bio-identical hormones
Stem cell banking and treatment
Telomere testing and optimization
Lifestyle
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1st treatment in Regenerative
Medicine
Diet, Exercise, Stress Reduction
“Health does not come out of a
pill or an injection.”
Exercise
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Can be 10-20 years younger than biological
age with regular exercise: aerobic, anaerobic,
flexibility
Current data favors sprint type interval training
instead of classic “cardio”
PACE- high intensity, low duration
Exercise promotes longevity and compression
of disability into fewer years (Vita, NEJM 1998
Apr)
Increased production of GH
Increased Sense of Well Being and cognition
Decreases Inflammation, CRP
Prevents telomere loss
Stress Reduction
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Lowers inflammation
Lowers cortisol and protects hippocampus from
damage producing cognitive impairment
Augments anti-cancer, anti-atherosclerosis
hormones-- 2-methoxy Estradiol
Prevents telomere loss
Zacharia LC et al. Catecholamines abrogate antimitogenic
effects of 2-hydroxyestradiol on human aortic vascular
smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001
Nov;21(11):1745-50.
Okereke O. et al. High phobic anxiety is
related to lower leukocyte telomere length
in women. PLoS One. 2012;7(7)
Bio-Identical hormones
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Defined as hormones atom for atom
identical to endogenous hormones
Treat a “deficiency disease”
Improve Quality of Life
Decrease Chronic Inflammation
Do not increase cancer risk
Do not increase heart disease risk
Are a matter of personal choice
Must be given by the correct route
Are a “work in progress”
Balanced hormone optimization
decreases chronic inflammation
Bio-identical hormones to consider
for optimization
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Vitamin D
DHEA, Pregnenolone, Melatonin
Thyroid: T3, T4
Cortisol
Testosterone for men and women
Estrogens: E1, E2, E3
Progesterone for men and women
Growth Hormone
Optimal replacement considers levels
and “How do you feel?”
Bio-identical hormone optimization
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Is a clinical specialty
Optimal range not reference range
When lab and clinical do not agree clinical wins
Evolutionary Biology
Hormone decline does not serve
any positive biological function
Evolution is blind to events after
reproductive age
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Eicosanoid hormones
• Regulated by Lifestyle, Diet, Insulin,
Omega 3’s, Endocrine Hormones,
Mind-Body connection, Vitamins and
Nutraceuticals
Autocrine
Paracrine
Endocrine
Lifestyle impacts hormone levels and
actions
Lifestyle decreases inflammation
©Ron
Ron Rothenberg
©
Rothenberg2011
2013
Vitamin D
D
Vitamin
Stress
Stress
Infection
Adipocytes
GH
Infection
Adipocytes
GH
Depression
Depression
High Glucose and Insulin
High Glucose and Insulin
Hormone Decline
Hormone Decline
Lack of Exercise
Inflammatory
Lack of Exercise
Inflammatory
Aging
cytokines
Anti-Inflam
Aging
cytokines
High Homocysteine Anti-Inflam
Diet
High Homocysteine
Diet
Trans Fats
Trans Fats
CRP
CRP
Nutrition
Nutrition
Glucose
and Insulin
Glucose and
Insulin
control
control
Yellow activates
activates
Yellow
P4
Angiotensin II
GH
GH
Anti-oxidants
Anti-oxidants
Glutathione
Glutathione
P4
Inflammatory
Inflammatory
Cytokines
Cytokines
EPA
EPA
NF Kappa Beta
NF Kappa Beta
cancer
cancer
Adhesion
Adhesion
Inflammatory Enzymes
molecules Inflammatory
Enzymes
molecules
VCAM1,
ICAM1,
COX, LOX
VCAM1,
ICAM1,
COX,
LOX
MCP1, MadCAM1
Resveratrol
Resveratrol
DHEA,
DHEA,
Testosterone
Testosterone
Melatonin
Melatonin
IGF1
EPA
EPA
Angiotensin II
Phosphate
PTH
Cytokine s
High
High
Glucose
Glucose
Red inhibits
inhibits
Red
SRIF
SRIF
E2
E2
Anti-Inflammatory
Anti-Inflammatory
Cytokine s
p53
p53
Pro-oxidants
Pro-oxidants
Viral Infections
Viral Infections
EPA,
DHA
RANKL
from Fish
OIL
Immune
MCP1, MadCAM1
Resveratrol
Resveratrol
EPC’s
EPC’s
ASA
ASA
High
High
Homocysteine
Homocysteine
Harmonic
Theory
Unified
Theory
of
of Wellness:
Wellness
Chronic
Chronic
Inflammation Is
Inflammation
Is
the Cause and
the
and
the Cause
Effect of
the
the
Effect of
Diseases
of the
Diseases
of
Aging
Aging
Control insulin.
Control
Lessinsulin.
omega 6
Less omega
6
Less Diet
Less
Diet
Arachadonic
Arachadonic
Arachidonic
Arachidonic
acid
acid
aging
EPA
EPA
Bad Eicosanoids
BadTXA2.
Eicosanoids
ASCVD
TXA2.
ASCVD
PGE2, LRC4 - CA
PGE2,
CA
Pain LRC4
PGE2,-LTB4
Pain PGE2, LTB4
aging
B vits
B vits
Acute phase
Acute
phase
proteins
proteins
CRP, Fibrinogen
CRP, Fibrinogen
Coxibs block
Coxibs vioxx
block
vioxx
Diabetic
Retinopathy
Diabetic
ASCVD
ASCVD
Retinopathy
ASCVD
ASCVD
PGI2=prostacyclin
PGI2=prostacyclin
good eicosanoids
good eicosanoids
EPA, DHA
EPA, DHA
IBD
IBD
Good
Good
Eicosanoids
Eicosanoids
cancer
cancer
Magnesium
Pain
Pain
PGE2:
Pain
Cancer
Skin aging
ASCVD
ASCVD
Chronic Illness
Chronic Illness
Wellness
Wellness
TXA2
Atherosclerosis
If a shark bites you, you need
inflammation right now
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Blood vessels constrict to stop bleeding
Fibrinogen and clotting factors increase
to stop bleeding
White blood cells fight infection
Pain reminds you “Don’t
swim with sharks”
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Acute inflammation
keeps us alive
Chronic inflammation
kills us slowly
Why do we have all this
inflammation anyway?
Antagonistic Evolutionary Benefit
What helped our Paleolithic ancestors make it
to reproductive age…is killing us now
• Insulin Resistance – helped store fat and
survive famine
• Anti-inflammation resistance – helped survive
acute infectious disease and trauma
• Thyroid resistance
– reverse T3 increased in
times of famine or stress
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Omega 3’s and NFkB
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EPA inhibits NFkB
EPA decreases TNF alpha and other proinflammatory cytokines
Zhao Y et al. Eicosapentaenoic acid
prevents LPS-induced TNF-alpha
expression by preventing NF-kappaB
activation. J Am Coll Nutr. 2004
Feb;23(1):71-8.
Resveratrol inhibits
NFKB
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Bhardwaj A et al. Resveratrol inhibits
proliferation, induces apoptosis, and
overcomes chemo resistance through
down-regulation of STAT3 and nuclear
factor-kappaB-regulated antiapoptotic
and cell survival gene products in human
multiple myeloma cells. Blood. 2007 Mar
15;109(6):2293-302.
Turns on Sirtuin genes
Aging causes inflammation
Youthful hormones protect
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IL-6 proinflammatory cytokine
Stays low in youth except for trauma, infection,
stress
Testosterone and Estrogens down regulate IL-6
gene expression
Ershler, WB et al. Age-associated Increased
Interleukin-6 Gene Expression, Late-Life
Diseases and Frailty. Annu. Rev. Med. 2000.
51:245–270
Vitamin D and inflammation
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Inversely associated with CRP and frailty
Inhibits NFKB
Boxer RS et al. The Association Between
Vitamin D and Inflammation with the 6-Minute
Walk and Frailty in Patients with Heart Failure. J
Am Geriatr Soc. 2008 Jan 5
Szeto, FL et al. Involvement of the vitamin D
receptor in the regulation of NF-kappaB activity
in fibroblasts. J Steroid Biochem Mol Biol. 2007,
March
Basics still apply
Hormone optimization is the finishing touch
on lifestyle: Nutrition, Exercise, Stress
Reduction, Anti-oxidants and Nutraceuticals
• Use hormones when necessary to treat a
deficiency disease
• Bio-identical
• Titrate to youthful levels and clinical
response - control metabolites when
needed
• Advanced treatments are backed up by
current medical literature
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New Thyroid Concepts
• Lab tests lack sensitivity
• TSH not most sensitive test
• “Normal” TSH getting lower all the time
• Free T3 best clue
• Clinical correlation required!
• When all else fails, look at the patient.
• The wide range of “euthyroid” is not
“optimal thyroid”
• Patients feel better and lose weight on a
T3/T4 combination
• Patients feel best on Porcine Desiccated
Thyroid Extract
• Ask your patient if she thinks her thyroid
replacement is optimal?
• Potential side effects of bone loss and atrial
fib can be monitored and avoided with
thyroid optimization
• Cardiovascular benefits of optimal T3
DTE = Desiccated Thyroid Extract =
Porcine thyroid vs. Levothyroxine (T4)
Double blind crossover study
• Conclusion:
• DTE caused more weight loss
• 50% felt better on DTE
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Hoang TD et al. Desiccated thyroid extract compared
with levothyroxine in the treatment of
hypothyroidism: a randomized, double-blind,
crossover study. J Clin Endocrinol Metab. 2013
May;98(5):1982-90.
Cardiovascular benefits of optimal T3
Lowers CRP - Christ-Crain, 2003
Lowers Homocysteine – Nedrebo, 1998
Dilates coronary arteries – Yoneda, 1998
Anti-arrhythmic:
V Tach associated with low T3 low ratio of T3/T4
and high reverse T3 – Shimoyama, 1993
• Low fT3 predicts post op AF p=.001 – Cerillo,
2003
• RT3 strongest predictor of mortality in first year
post Acute MI - Friberg, 2001
• Higher free T3, greater survival post MI – Pavlou
2003
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TESTOSTERONE in men
Testosterone Deficiency
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Half of healthy men between the
ages of 50–70 yr will have a
Bioavailable Testosterone level
below the lowest level seen in
healthy men who are 20–40 yr of
age
Korenman SG, Morley JE, Mooradian AD,
et al. 1990 Secondary hypogonadism in
older men: its relationship to impotence.
J Clin Endocrinol Metab. 71:963–969.
Testosterone Deficiency is a
lethal disease
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Diabetes, Metabolic syndrome
Brain
Heart
Frailty syndrome
Bone
Inflammation
Cancer
4 major studies – low T assoc. with
increased all cause mortality
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Shores MM, Moceri VM, Gruenewald DA, et al. Low testosterone is
associated with decreased function and increased mortality risk: a
preliminary study of men ina geriatric rehabilitation unit. J Am
Geriatr Soc 2004;52:2077e81.
Khaw KT, Dowsett M, Folkerd E, et al. Endogenous testosterone
and mortality due to all causes, cardiovascular disease, and cancer
in men: European prospective investigation into cancer in Norfolk
(EPIC-Norfolk) Prospective Population Study. Circulation
2007;116:2694e701.
Shores MM, Matsumoto AM, Sloan KL, et al. Low serum
testosterone and mortality in male veterans. Arch Intern Med
2006;166:1660e5.
Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum
testosterone and mortality in older men. J Clin Endocrinol Metab
2008;93:68e75
High T = Low Mortality
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10 year prospective study
11,606 men – 40-79 years old
High Endogenous T = low mortality from
CV disease and cancer
Low T predicts CV disease
High T = no increase in Prostate Cancer
“Paradoxically” fear of Prostate Ca has
keep men from T treatment
Khaw KT. et al. Endogenous testosterone and
mortality due to all causes, cardiovascular disease,
and cancer in men. Circulation. 2007;116:2694-2701
Testosterone Treatment and Mortality
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1000 male veterans , > 40 years old, 4 yrs Rx
Total test < 250
400 treated with testosterone
Mortality treated 10% vs. 20% controls p < .00001
Decreased risk of death
Hazard ratio 0.61
95% confidence interval 0.42–0.88, p = .008
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Prostate CA
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treated 1.6%
untreated 2.0
Shores MM et al. Testosterone Treatment and Mortality in Men with
Low Testosterone Levels. J Clin Endocrinol Metab. 2012 Apr
History of “T causes PC” myth
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1941: Huggins and Hodges - marked
reductions in T by castration or estrogen
treatment caused metastatic PC to regress
Administration of exogenous T caused PC to
grow. This was based on only one patient
Based on increased alkaline phosphatase
Multiple subsequent reports revealed no PC
progression with T administration
Some men even experienced subjective
improvement, such as resolution of bone pain
Morgantaler A. Testosterone and Prostate
Cancer: An Historical Perspective on a Modern
Myth. Eur Urol. 2006 Jul 26
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Recent data have shown no apparent
increase in PC rates in clinical trials of T
supplementation in normal men or men
at increased risk for PC
No relationship of PC risk with serum T
levels in multiple longitudinal studies
No reduced risk of PC with low T.
The paradox in which castration causes
PC to regress yet higher T fails to cause
PC to grow
Resolved by a saturation model, in which
maximal stimulation of PC is reached at
relatively low levels of T
Morgentaler conclusion
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“There is not now--nor has there
ever been a scientific basis for the
belief that T causes PC to grow”
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Morgentaler A. Testosterone and
Prostate Cancer: An Historical
Perspective on a Modern Myth. Eur
Urol. 2006 Jul 26
Treating with T after Radical
Prostatectomy for PCa
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Organ confined PC
Radical Prostatectomy
PSA <0.1 after 1 year
Treated with T
No recurrences or increase in PSA
• Agarwal PK et al. Testosterone
replacement therapy after primary
treatment for prostate cancer. J Urol.
2005 Feb;173(2):533-6.
Less PCa recurrence with
Testosterone treatment
• S/P Radical prostatectomy
• Hypogonadal treated vs. not hypogonadal or
treated > 36 months
• Biochemical recurrence
– 3.8% treatment with testosterone group
– 16% in no testosterone group
– P = .02
• Pastuszak AW. Testosterone replacement
therapy in patients with prostate cancer after
radical prostatectomy. J Urol. 2013
Aug;190(2):639-44
TRT. Prostate Ca, Brachytherapy
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TRT 0.5 – 8.5 years after brachytherapy
Follow up 1.5- 9 years
1 patient with transient rise of PSA <1.0
No patient stopped TRT due to cancer
recurrence or disease progression
Sarosdy MF. Testosterone replacement for
hypogonadism after treatment of early prostate
cancer with brachytherapy. Cancer. 2007 Feb
1;109(3):536-41.
Active Prostate CA and
Testosterone Therapy
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13 testosterone deficient men with untreated
prostate CA
Testosterone increased 238 to 664, PSA,
prostate volume – unchanged
After 2.5 years - No cancer found in 54% of
prostate biopsies.
No local progression or metastases
Morgantaler et al.Testosterone Therapy in Men
with untreated Prostate CA. J Urol 2011 Apr,
(185:4) 1256-60
 TRT
benefits from head to toe
–Improved mood, cognitive, function,
Alzheimer's prevention
–Improved Body composition, more
muscle, less fat, reversal of
osteoporosis
–Improved libido and erectile function
–Reverses Insulin Resistance and type
2 diabetes
–Less inflammation, pain, osteo and
rheumatoid arthritis
 TRT
decreases inflammation
–CRP, IL-6, TNF alpha decreased
T Rx Increases EPC’s
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Hypogonadism – low EPC
T gel 50 mg/day x 6 months
• Normalized EPC’s
• Androgen receptor expressed on EPC’s
May be mechanism of T benefit in CV
disease
Foresta C et al. Reduced Number of
Circulating Endothelial Progenitor Cells in
Hypogonadal Men. Journal of Clinical
Endocrinology & Metabolism
91(11):4599–4602
BHRT
• Have you patients asked for “Bio-identical
“hormones?
• Is there an increased risk of breast cancer
or cardiovascular disease or CVA or VTE
with BHRT?
• Does a woman s/p hysterectomy need
progesterone as well as estrogen?
• Is there any advantage to custom
compounded hormones?
• Do the findings of the WHI apply to Bioidentical hormones?
Some Problems with WHI
• Wrong Estrogen
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CEE is not a human hormone
Mostly Equillin
Low Estradiol (E2)
No Estriol
(E3)
• Wrong “Progesterone”
• MPA blocks progesterone receptors and is not
a human hormone
• Wrong route
• Oral Estrogens increase inflammation
• Wrong women
• Older with established CV disease
• Rossouw JE wt al. Risks and benefi ts of estrogen plus progestin in
healthy postmenopausal women: principal results from the Women’s
Health Initiative randomized controlled trial. JAMA 2002;288
Estradiol
Estrogens
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E1=Estrone
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May be more than she needs
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Get some anyway through
conversion of E2
E2=Estradiol
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Protective Estrogen via catechol
and methoxy metabolites
E3=Estriol
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Cancer protective, weak
Results from the E3N cohort studyFournier 2007.
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80,377 postmenopausal women
No increase or decrease in breast cancer in
women on E2 and Progesterone.
E2 plus MPA had RR of 1.69 or 69% increase
in risk of breast cancer.
Fournier A . Unequal risks for breast cancer associated
with different hormone replacement therapies: results
from the E3N cohort study. Breast Cancer Res Treat.
2007 Feb 27
Mortality from Estrogen
Avoidance
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Hysterectomized women 50-59
No Estrogen replacement
10 year period starting 2002
18,000-91,000 died prematurely - calculated
Excess mortality from AMI, Breast cancer
Sarrel P el al. The Mortality Toll of Estrogen
Avoidance: An Analysis of Excess Deaths Among
Hysterectomized Women Aged 50 to 59 Years. Am J
Public Health July 18, 2013: e1-e6.
BHRT Cardioprotective
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Transdermal E2 does not increase risk
of VTE like oral E2
Cardioprotective, decreased risk of AMI
Decreased risk of T2DM
Micronized P4 reduces risk of T2DM,
does not increase risk of VTE, reduces
BP
Mueck AO. Et al. Postmenopausal hormone
replacement therapy and cardiovascular
disease: the value of transdermal estradiol and
micronized progesterone. Climacteric. 2012
Apr;15 Suppl 1:11-7
BHRT safer
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HRT in young post-menopausal women safe and
effective tool for
• Counteract climacteric symptoms
• Prevent long-term degenerative diseases
• Osteoporotic fractures
• Cardiovascular disease
• Diabetes mellitus
• Cognitive impairment
Non oral estrogens: No VTE and better BP
Natural Progesterone - positive cognitive effects and
no increase in breast cancer
TD Estrogen and Natural Progesterone significant
advantages
L'hermite M et al. Could transdermal estradiol +
progesterone be a safer postmenopausal HRT? A
review. Maturitas. 2008 Jul-Aug;60(3-4):185-201.
L'hermite M et al. Could transdermal estradiol +
progesterone be a safer postmenopausal HRT? A
review. Maturitas. 2008 Jul-Aug;60(3-4):185-201
BHRT – Climacteric 2012
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TD E2 – no increased risk of VTE or
CVA
P4 unlike progestins – no increased
risk of VTE or Breast Cancer
Simon JA. What's new in hormone replacement
therapy: focus on transdermal estradiol and
micronized progesterone. Climacteric. 2012 Apr;15
Suppl 1:3-10
HRT 2012 - BMJ
10 years of randomized treatment
• Oral HRT (estradiol, norithindrone) early after
menopause
• Significantly reduced
Risk of mortality
Heart failure
Myocardial infarction
• Without any apparent increase in risk of
Cancer
Venous thromboembolism
Stroke
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Schierbeck et al Effect of hormone replacement therapy
on cardiovascular events in recently postmenopausal
women: randomised trial. BMJ 2012;345
Advantages of Estriol (E3)
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E3 can bind preferentially to ER beta and
inhibits ER alpha
ER beta is protective of brain and
cardiovascular function
Low E3 levels associated with increased
BC
Schmidt JW et al. Hormone replacement therapy in
menopausal women: Past problems and future
possibilities. Gynecol Endocrinol. 2006 Oct;22
(10):564-77
Bio-Identical Hormone
Replacement in Women
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Balance Estrogens, Progesterone and
Testosterone
Every woman needs a unique balance
Estrogen Metabolism - Breast
Testosterone
Testosterone
Sulfotransferase
E2
E2 Sulfatase
Sulfotransferase
Aromatase
Aromatase
Vitamin D
17Beta
HSD
17Beta
HSD
Androstenedione
Androstenedione
Aromatase
Aromatase
Sulfatase
E2S
E2S
Sulfotransferase
E1
E1
Sulfatase
Sulfatase
E2, P4 sulfatase inhibitors
E2, P4
sulfatase inhibitors
E2,Vit
D aromatase
inhibitor
E2 aromatase
inhibitor stim
Progestin
(MPA) sulfatase
Secosteroid hormone
Vitamin D3 = Cholecalciferol
“B” Ring is “Broken”
Tryptophan
Serotonin
Folate, B6
Brzezinski A. Mechanisms
of Disease: Melatonin in
Humans. The New England
Journal of Medicine -January 16, 1997 -- Vol.
336, No. 3
Melatonin increase EPC’s
• Melatonin has immunomodulatory effects
• Melatonin stimulates production of
EPC’s, natural killer cells and CD4 cells
and inhibits CD 8 cells
• Cardinale, D et al. Melatonin and the Immune
System in aging. NeuroImmuno Modulation
2008;15:272-278.
Melatonin
• Expressed by all life forms bacteria to
mammals
• Declines with aging
• Sleep/wake cycle, Jet lag
• Buffers Immune system
• Prolongs lifespan/HealthSpan of animals
• Neuro protective
• Cardio-protective
• Anti-cancer
• Anti-inflammation
• Protects against ionizing radiation
• Reiter RJ et al. Pharmacological utility of melatonin in
reducing oxidative cellular and molecular damage. Pol J
Pharmacol. 2004 Mar-Apr;56(2):159-70.
• Carrillo-Vico A et al. Melatonin: buffering the immune
system. Int J Mol Sci. 2013 Apr 22;14(4):8638-83.
• Pierpaoli W, Regelson W. Pineal control of aging: effect
of melatonin and pineal grafting on aging mice. Proc
Natl Acad Sci U S A 1994;91:787-91.
• Carretero, M et al. Long-term melatonin administration
protects brain mitochondria from aging. Journal of
Pineal Research. 47(2):192-200, September 2009.
• Lissoni P. Biochemotherapy with standard
chemotherapies plus the pineal hormone melatonin in
the treatment of advanced solid neoplasms. Pathol Biol
(Paris). 2007 Apr-May;55(3-4):201-4
• Flynn-Evans EE et al. Total visual blindness is
protective against breast cancer. Cancer Causes
Control. 2009 Aug 1.
• Mills Edward et al. Melatonin in the treatment of
cancer: a systematic review of randomized controlled
trials and meta-analysis Journal of Pineal Research.
39(4):360-366, November 2005.
• Dominguez-Rodriguez A et al. Clinical aspects of
melatonin in the acute coronary syndrome. Curr Vasc
Pharmacol. 2009 Jul;7(3):367-73.
• Liu XJ et al. Melatonin protects against amyloid-βinduced impairments of hippocampal LTP and spatial
learning in rats. Synapse. 2013 Apr 26.
• Moriya, T. et al. Melatonin influences the proliferative
and differentiative activity of neural stem cells. J.
Pineal Res. 2007, 42, 411-418.
• Reiter R et al. The disaster in Japan: utility of
melatonin in providing protection against ionizing
radiation. J Pineal Res. 2011 May;50(4):357-8.
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Stem cells are the tools of regenerative medicine
We can use adult autologous stem cells for
regenerative medicine now
We can stimulate endogenous stem cells for selfrepair now
We can induce pluripotency
in stem cells?
Acute inflammation activates
Chronic inflammation inhibits
Stem Cells and Pluripotency
Skin
Hair
Ectoderm
Brain
Nerves
Etc.
Cardiac
Skeletal
Mesoderm
Renal
Muscle
Blood
Etc.
Stem Cell
Lung
Gut
Endoderm
Thyroid
Pancreas
Etc.
Non-Controversial
Adult Stem Cells
• Adipose derived Mesenchymal
Stem Cells
• Umbilical Cord Blood Stem Cells
• Bone Marrow Stem Cells
• Adult Peripheral Blood Stem Cells
Adult Stem cells
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The stem cells that you have in your own bone
marrow, fat and other organs
Some can transform into any tissue
Can be collected through fat retrieval
The next step in Preventive/Regenerative
Medicine
Lifestyle, Nutraceuticals and hormone
optimization improve quantity and quality
No ethical controversy
MSCs from Adipose
Kleinhenz May 2011
Available Protocols
Cardiology and
Vascular
Acute MI, Ischemic Chronic Heart Failure, Non
Ischemic Heart Failure, Critical Limb Ischemia
Pulmonology
Emphysema, Chronic Bronchitis, Pulmonary
Fibrosis, Pulmonary Hypertension
Ophthalmology
Retinitis Pigmentosa, Macular Degeneration,
Diabetic Retinopathy, Glaucoma
Endocrinology
Type II Diabetes
Immunology
Lupus, Rheumatoid Arthritis,
Fibromyalgia, Asthma, Crohn's Disease
Neurology
Multiple Sclerosis, Parkinson’s, ALS, Alzheimer’s,
Stroke, Cerebral Palsy
Nephrology
Renal Failure
Anti-Aging
Human Frailty Syndrome
Other
Osteoarthritis, Erectile Dysfunction
Endothelial Progenitor cells
(EPCs)
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Stem cells that reside in the adult bone
marrow and adipose tissue or circulate in
the blood
Differentiate and mature into endothelial
cells.
Responsible for postnatal vasculogenesis
and tissue repair
Identified by stem-cell markers (CD34+,
CD133+)
EPCs decrease with age and are a
measurement of vascular senescence and
a biomarker of aging
EPC’s and CV Outcomes
• Higher EPC’s – 70 % less death
from CV causes
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Werner N et al. Circulating
Endothelial Progenitor Cells and
Cardiovascular Outcomes. N Engl J
Med 353:999, September 8, 2005
Optimize stem cells
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Optimized hormones and nutraceuticals
increase quality and quantity of
endogenous adult stem cells
Combinations of nutrients produce a
synergistic effect to promote proliferation
of human hematopoietic progenitors.
Nutrients can act to promote healing via
an interaction with stem cell populations.
Stem cells optimization through
nutraceuticals
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Blueberry
Green tea
Vitamin D3
Carnosine
Bickford PC et al. Nutraceuticals synergistically
promote proliferation of human stem cells.
Stem Cells Dev. 2006 Feb;15(1):118-23.
Resveratrol and stem
cells
J.G. et al. Effects of resveratrol on
endothelial progenitor cells and their
contributions to reendothelialization in
intima-injured rats. J Cardiovasc
Pharmacol. 2006 May;47(5):711-21
Telomeres at both ends of each
chromosome
Repetitive DNA sequences
(six-nucleotide TTAGGG)
• Biomarkers of Aging
• A Major Cause of
Cellular Aging
Telomere Function
• Serve as chromosome end caps to protect
genomic integrity
• Prevent fusion
• Prevent genomic instability
• Necessary for cellular replication
• Protection from cellular senescence
• Protection from DNA mutations that can
lead to cancer
• Sahin E, Depinho RA. Linking functional decline of
telomeres, mitochondria and stem cells during ageing.
Nature. 2010 Mar 25;464(7288):520-8.
Telomere Length vs. Cellular Age
What Can Be Done To Keep
Telomeres Long?
• Slow Telomere loss
– Lifestyle
• Nutrition, Exercise, stress reduction
– Neutraceuticals
• Omega 3’s, resveratrol
– Limit inflammation
– Limit free radial damage
– Youthful hormone levels
• Activate Telomerase.
Telomerase
• An enzyme that stabilizes telomere
length by adding DNA repeats (TTAGGG)
onto the telomeric ends of the
chromosomes, compensating for the
erosion of telomeres when cells divide.
• Jaskelioff M. Telomerase reactivation reverses tissue
degeneration in aged telomerase-deficient mice
Nature. 2011 Jan 6;469(7328):102-6.
Telomerase Activation:
• Was used to reverse some aspects of
aging in old mice
• Brain, spleen and reproductive organs
were rejuvenated
• Resulting in increased neurons and new
viable sperm cells.
• Sense of smell returned.
• None of the mice developed cancer..
• Jaskelioff M et al. Telomerase reactivation reverses tissue
degeneration in aged telomerase-deficient mice. Nature. 2011 Jan
6;469(7328):102-6.
Telomere and Exercise
• VO2 max associated with telomere length
• Exercise (3 x a week) associated with
greater telomere length. P < .01
• Harley CB A natural product telomerase activator as
part of a health maintenance program. Rejuvenation
Res. 2011 Feb;14(1):45-56.
• Østhus IB et al. Telomere length and long-term
endurance exercise: does exercise training affect
biological age? A pilot study. PLoS One. 2012;7(12)
• Kim JH et al. Habitual physical exercise has beneficial
effects on telomere length in postmenopausal women.
Menopause. 2012 Oct;19(10):1109-15.
Telomere Length and
Breast Cancer Risk
• Telomere shortening is associated
with increased risk of breast
cancer
• Qu S et al Association of leukocyte telomere
length with breast cancer risk: nested casecontrol findings from the Shanghai Women's
Health Study. Am J Epidemiol. 2013 Apr
1;177(7):617-24
EPCs = Biomarker Aging
Increase
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GH/IGF-1
E2
Telomerase
Testosterone
Antioxidants
Exercise
Red Wine, Resveratrol
L-Arginine
Blueberries, Green Tea
Carnosine
Fish Oil
Fucoidan
Melatonin
Gingko
Telomerase
Decrease
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Inflammation
Inflammatory Cytokines
CRP
ROS
Know your Inflam-aging numbers
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CRP
<1
Fasting Insulin
<7
Homocysteine
<7
AA/EPA Ratio
<1.5
25-OH-D
65 -100
Telomere length
< 15 % short
Stem cell function-CD 34+ >2,400,000
Cytokines
• IL-6
<12 pg/l
• TNF alpha
<8 pg/l
• IL-1 beta
<15 pg/l
Unified Theory of Wellness
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Control Inflam-Aging
Optimize hormones
Optimize stem cells
Optimize telomeres
Increased quality of life
We all have to die sometime
What will the journey be like?
Rectangularize
And if we delay, intervene and reverse
the diseases of aging….
Increased quantity of life as well