Update in Preventive/Regenerative Medicine

Inflammation, Hormones, Stem Cells and Telomeres

Ron Rothenberg MD

• Aging is a disease which can be prevented or reversed

• We are not prisoners of our genetic destiny

The HealthSpan Curve

Hea

lthS

pan

“Conventional Medicine”Prolongation of Morbidity

Development

HealthSpanDegeneration

Goal of Preventive/Regenerative MedicineHealthSpan Extension, Morbidity

Compression

Development Deg

ener

atio

nHealthSpan Extension

• Chronic Inflammation is a cause and the effect of the diseases of aging

“Unified Theory of Wellness”

• 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:

• 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?

• 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

• 1st treatment in Regenerative Medicine

• Diet, Exercise, Stress Reduction• “Health does not come out of a

pill or an injection.”

Exercise

• 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• 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)

• 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”

Bio-Identical hormones

Balanced hormone optimization decreases chronic inflammation

• 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 hormones to consider for optimization

Bio-identical hormone optimization• 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

• 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

I n fla m m a to ryc y to k in e s

N F K a p p a B e ta

I n fla m m a to ry E n zym e sC O X , L O X

I n fla m m a to ryC yto k in e s

A ra c h id o n ica c id

B a d E ic o s a n o id sT X A 2 . A S C V D

P G E 2 , L R C 4 - C AP a in P G E 2 , L T B 4

C h ro n ic I lln e s s

A c u te p h a s ep ro te in s

C R P , F ib rin o g e n

EP A

E P A

C o ntr o l i ns ul i n .L e s s o m e g a 6

L e s s D i e tAr ac hado ni c

S tre s sInfe c tio n

D e pre s s io nH ig h G luc o s e a nd I n s u lin

H o rm o ne D e c lineLa c k o f E xe rc is e

A g ingH ig h H o m o c ys te ine

Tra n s Fa ts

E P A

P ro -o x id a n tsV ira l I n fe c tio n s

A n ti-o x id a n tsG lu ta th io n eA n ti -In flam m ator y

C y t o k i n e s

A d h e s io nm o le c u le s

V C A M 1 , IC A M 1 ,M C P 1 , M a dC A M 1

P G I 2 = p ro s ta c yc ling o o d e ic o s a n o id s

C o x ibs blo ckv io x x

W e lln e s sE P A , D H AG o o d

E ic o s a n o id s

D H E A ,T e s to s te ro ne

M e la to nin

H ig hG luc o s e

N u tr i tionGlu c os e an d In s u l in

c on tr ol

ASC VD

A S C V D

ASC VD

H ig hH o m o cy ste in e

B vits

c an c e r

c an c e r

D iabe ticR e t ino pa t hy

A dipo c yte s

G H

G H

I B D

S R IFA n ti- In f la m

D ie t

A S A

a g in g

E 2P 4

R e s v e ratro l

Red inhibits

Yellow activates

Harmonic Theory of Wellness:

Chronic Inflammation Is the Cause and the Effect of the Diseases of Aging

Pain

EPA, DHA from Fish OIL

© Ron Rothenberg 2011

PGE2:PainCancerSkin aging

Angio-tensin II

p53

CRP

ResveratrolEPC’s

Vitamin D

TXA2Athero-sclerosis

I n fla m m a to ryc y to k in e s

N F K a p p a B e ta

I n fla m m a to ry E n zym e sC O X , L O X

I n fla m m a to ryC yto k in e s

A ra c h id o n ica c id

B a d E ic o s a n o id sT X A 2 . A S C V D

P G E 2 , L R C 4 - C AP a in P G E 2 , L T B 4

C h ro n ic I lln e s s

A c u te p h a s ep ro te in s

C R P , F ib rin o g e n

EP A

E P A

C o ntr o l i ns ul i n .L e s s o m e g a 6

L e s s D i e tAr ac hado ni c

S tre s sInfe c tio n

D e pre s s io nH ig h G luc o s e a nd I n s u lin

H o rm o ne D e c lineLa c k o f E xe rc is e

A g ingH ig h H o m o c ys te ine

Tra n s Fa ts

E P A

P ro -o x id a n tsV ira l I n fe c tio n s

A n ti-o x id a n tsG lu ta th io n eA n ti -In flam m ator y

C y t o k i n e s

A d h e s io nm o le c u le s

V C A M 1 , IC A M 1 ,M C P 1 , M a dC A M 1

P G I 2 = p ro s ta c yc ling o o d e ic o s a n o id s

C o x ibs blo ckv io x x

W e lln e s sE P A , D H AG o o d

E ic o s a n o id s

D H E A ,T e s to s te ro ne

M e la to nin

H ig hG luc o s e

N u tr i tionGlu c os e an d In s u l in

c on tr ol

ASC VD

A S C V D

ASC VD

H ig hH o m o cy ste in e

B vits

c an c e r

c an c e r

D iabe ticR e t ino pa t hy

A dipo c yte s

G H

G H

I B D

S R IFA n ti- In f lam

D ie t

A S A

ag in g

E 2P 4

R e s v e ratro l

Red inhibits

Yellow activates

Unified Theory of

Wellness

Chronic Inflammation Is the Cause and the Effect of the Diseases of Aging

Pain

© Ron Rothenberg 2013

PGE2:PainCancerSkin aging

Angiotensin II

p53

CRP

ResveratrolEPC’ s

Vitamin D

TXA2Athero-sclerosis

PTH

Phosphate

Magnesium

RANKL

ImmuneIGF1

If a shark bites you, you need inflammation right now

• 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”

• 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

• EPA inhibits NFkB • EPA decreases TNF alpha and other pro-

inflammatory 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.

Omega 3’s and NFkB

• 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

Resveratrol inhibits NFKB

• 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

Aging causes inflammationYouthful hormones protect

• 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

Vitamin D and inflammation

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

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

• 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

TESTOSTERONE in men

Testosterone Deficiency

• 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

• Diabetes, Metabolic syndrome• Brain• Heart• Frailty syndrome• Bone• Inflammation• Cancer

4 major studies – low T assoc. with increased all cause mortality

• 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• 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

• 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

• Prostate CA 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 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

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

• “There is not now--nor has there ever been a scientific basis for the belief that T causes PC to grow”

• 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

• 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

• 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

• 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 arthritisTRT decreases inflammation

–CRP, IL-6, TNF alpha decreased

T Rx Increases EPC’s

• 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 Bio-identical hormones?

• Wrong Estrogen• 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

Some Problems with WHI

Estradiol

• E1=Estrone• May be more than she needs• Get some anyway through

conversion of E2• E2=Estradiol

• Protective Estrogen via catechol and methoxy metabolites

• E3=Estriol • Cancer protective, weak

Estrogens

Results from the E3N cohort study- Fournier 2007.

• 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

• 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• 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• 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

• 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 - BMJ10 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

• Schierbeck et al Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012;345

Advantages of Estriol (E3)

• 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

• Balance Estrogens, Progesterone and Testosterone

• Every woman needs a unique balance

Bio-Identical Hormone Replacement in Women

Testosterone

Androstenedione

E2

E1

Aromatase

Aromatase

E2S17Beta HSD

Sulfotransferase

Sulfatase

Sulfatase

Estrogen Metabolism - Breast

E2, P4 sulfatase inhibitorsE2 aromatase inhibitor

Testosterone

Androstenedione

E2

E1

Aromatase

Aromatase

E2S17Beta HSD17Beta HSD

Sulfotransferase

Sulfotransferase

Sulfatase

Sulfatase

Estrogen Metabolism - Breast

E2, P4 sulfatase inhibitorsE2,Vit D aromatase inhibitor

Progestin (MPA) sulfatase stim

Vitamin D

Secosteroid hormoneVitamin D3 = Cholecalciferol

“B” Ring is “Broken”

Tryptophan Serotonin

Brzezinski A. Mechanisms of Disease: Melatonin in Humans. The New England Journal of Medicine -- January 16, 1997 -- Vol. 336, No. 3

Folate, B6

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-β-induced 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.

• 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 self-

repair now• We can induce pluripotency in stem cells?

• Acute inflammation activates• Chronic inflammation inhibits

Ectoderm

Stem Cell

Mesoderm

Endoderm

Cardiac

Skeletal

Renal

Muscle

Blood

Etc.

Lung

Gut

Thyroid

Pancreas

Etc.

Skin

Hair

Brain

Nerves

Etc.

Stem Cells and Pluripotency

• Adipose derived Mesenchymal

Stem Cells

• Umbilical Cord Blood Stem Cells

• Bone Marrow Stem Cells

• Adult Peripheral Blood Stem Cells

Non-Controversial Adult Stem Cells

Adult Stem cells • 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 ProtocolsCardiology  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)

• 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

• Werner N et al. Circulating Endothelial Progenitor Cells and Cardiovascular Outcomes. N Engl J Med 353:999, September 8, 2005

Optimize stem cells

• 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

• 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.

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

Resveratrol and stem cells

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 case-control findings from the Shanghai Women's Health Study. Am J Epidemiol. 2013 Apr 1;177(7):617-24

EPCs = Biomarker Aging Increase

• GH/IGF-1• E2 Telomerase• Testosterone• Antioxidants• Exercise• Red Wine, Resveratrol• L-Arginine• Blueberries, Green Tea• Carnosine• Fish Oil • Fucoidan• Melatonin• Gingko Telomerase

Decrease• Inflammation• Inflammatory Cytokines• CRP• ROS

Know your Inflam-aging numbers

• 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

• 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

Unified Theory of Wellness