What Do Hormones Have to Do with Aging? What Does Aging Have to Do with Hormones?

What Do Hormones Have to Do with Aging? What Does Aging Have to Do with Hormones?

What Do Hormones Have to Do with Aging? What Does Aging Have to Do with Hormones?

Director and PresidentDirector and PresidentKronos Longevity Research InstituteKronos Longevity Research Institute

(KLRI)(KLRI)Phoenix, ArizonaPhoenix, Arizona

S. Mitchell Harman, M.D., Ph.D.S. Mitchell Harman, M.D., Ph.D.

A Definition of Aging?A Definition of Aging?

• The related deterioration of physiological functions The related deterioration of physiological functions necessary for :necessary for :– FertilityFertility– SurvivalSurvival

• Progressive loss of:Progressive loss of:– Reserve capacity of organ systems Reserve capacity of organ systems – Ability to compensate for stress or injuryAbility to compensate for stress or injury

• Process terminating inevitably in death of the Process terminating inevitably in death of the organismorganism– Increased susceptibility to age-related diseaseIncreased susceptibility to age-related disease– Death from disease, not “old age”Death from disease, not “old age”

Theories of AgingTheories of Aging

• GeneticGenetic– Aging is “programmed” into the genesAging is “programmed” into the genes– Certain genes are “timekeepers” for the aging Certain genes are “timekeepers” for the aging

processprocess

• Wear and TearWear and Tear– Cumulative damage to cells fromCumulative damage to cells from

• Metabolic processesMetabolic processes• Environmental factorsEnvironmental factors

– Mechanisms to resist and repair damage are Mechanisms to resist and repair damage are criticalcritical

NN

NN

oxygenoxygen glucoseglucose

SODSOD

CatalaseCatalaseGPXGPX

HH22OO22 HH22O + OO + O22

DefenseDefenseEnzymesEnzymes

Cellular Damage and DefenseCellular Damage and Defense

OO22 radicalsradicals

O•O•

OHOH-

DNA damageDNA damageProtein damageProtein damageLipid damageLipid damage

Antioxidants (GSH, tocopherols, etc.)

RepairRepairProcessesProcesses

EnergyEnergy(ATP)(ATP)

MitochondriaMitochondria

Nucleus (DNA)Nucleus (DNA)

Cell MembraneCell Membrane

Cytoplasm -proteinsCytoplasm -proteins

Age-related Changes in Body Composition Age-related Changes in Body Composition and Functionand Function

• Body CompositionBody Composition– Loss of lean body (muscle) massLoss of lean body (muscle) mass

• Decreased strengthDecreased strength• Decreased fitness and loss of functional capacityDecreased fitness and loss of functional capacity

– Increase in total fat mass (percent body fat)Increase in total fat mass (percent body fat)• Insulin resistance (type 2 diabetes)Insulin resistance (type 2 diabetes)• Increased LDL cholesterol, triglycerides, and fatty acidsIncreased LDL cholesterol, triglycerides, and fatty acids

– Decreased bone density (negative calcium balance) Decreased bone density (negative calcium balance)

• Metabolic/Physiologic FunctionMetabolic/Physiologic Function– Decreased protein synthesis Decreased protein synthesis – Slower healingSlower healing– Reduced immune system functionReduced immune system function– Altered hormone balanceAltered hormone balance

Age-related Changes in Body Composition Age-related Changes in Body Composition in Normal Sedentary Menin Normal Sedentary Men

Bod

y C

omp

osit

ion

Bod

y C

omp

osit

ion

Age (years)Age (years)(Balagopal et al. Endocrine 7:57, 1997)(Balagopal et al. Endocrine 7:57, 1997)

2020 3030 4040 5050 6060 7070 80801010

2020

3030

4040

5050

6060

7070Muscle Mass (lbs) Muscle Mass (lbs) Fat (%) Fat (%)

Decreases in Muscle Strength with AgeDecreases in Muscle Strength with Age

(Borges, (Borges, Scand J Rehabil Med 21:45, 1989) 1989)(Borges, (Borges, Scand J Rehabil Med 21:45, 1989) 1989)Age (years)Age (years)

Isok

inet

ic F

orce

(N

m)

Isok

inet

ic F

orce

(N

m)

10 20 30 40 50 60 70 80

100

150

200

250Men Women

Age-Related Declines in VOAge-Related Declines in VO22 maxmax in Sedentary in Sedentary

and Physically Active Individualsand Physically Active Individuals

Age (years)Age (years)

VO

VO

22 MA

X (

ml/

kg/

min

) M

AX

(m

l/k

g/m

in)

40 50 60 70 80 9010

50

60

70 Sedentary

40 yr Longitudinal50 yr Longitudinal60 yr Longitudinal70 yr Longitudinal

20

30

40

menwomen

(Wiswell et al., J Gerontol 56:M618, 2001)(Wiswell et al., J Gerontol 56:M618, 2001)

What Are Hormones?What Are Hormones?

• Natural chemical regulators of cell physiologyNatural chemical regulators of cell physiology

• Secreted into the blood by specialized glands Secreted into the blood by specialized glands and act at a distance on one or more target and act at a distance on one or more target organsorgans

• Mechanisms of ActionMechanisms of Action– Peptides/Proteins: act at cell membrane receptorsPeptides/Proteins: act at cell membrane receptors

– Steroids: enter nucleus and regulate genesSteroids: enter nucleus and regulate genes

Higher CentersHigher CentersNeural activity

(neurotransmitters)Neural activity

(neurotransmitters)

HypothalamusHypothalamus

ThyroidThyroid

AdrenalAdrenal

TestisTestis

OvaryOvaryGonadsGonads

PituitaryPituitaryposteriorposterioranterioranterior

Trophic HormonesTrophic Hormones

LHFSHLHFSHACTHACTH

TSHTSHGHGH

IGF-IIGF-I

PeripheralHormonesPeripheralHormones

Releasing FactorsReleasing Factors

SUMMARY OF HORMONE PHYSIOLOGYSUMMARY OF HORMONE PHYSIOLOGY

LiverLiver

Fat

BoneBone

CartilageCartilage

MuscleMuscle

-

+

+

-

-

How Do Hormones Change with Normal Aging?How Do Hormones Change with Normal Aging?

• EstrogensEstrogens- decrease to very low levels over a 1-3 year period - decrease to very low levels over a 1-3 year period at menopause (between ages 45-55)at menopause (between ages 45-55)

• Testosterone (T)Testosterone (T)- Gradual decline from age 30 onward - Gradual decline from age 30 onward reaching low (hypogonadal) levels in >50% of men by age 65reaching low (hypogonadal) levels in >50% of men by age 65

• Growth Hormone (GH)Growth Hormone (GH)- Gradual decrease in secretion (and - Gradual decrease in secretion (and circulating IGF-I levels) from age 45-90circulating IGF-I levels) from age 45-90

• Adrenal SteroidsAdrenal Steroids--– Active adrenal hormones (cortisol and aldosterone) change littleActive adrenal hormones (cortisol and aldosterone) change little

– DHEA, steady decrease with age to very low levels in both sexesDHEA, steady decrease with age to very low levels in both sexes

• ThyroidThyroid- not much change in healthy men and women, but - not much change in healthy men and women, but increased prevalence of hypothyroid disease in older persons.increased prevalence of hypothyroid disease in older persons.

• InsulinInsulin- loss of sensitivity to insulin action with aging and - loss of sensitivity to insulin action with aging and obesityobesity

Linear Segment Plots by Decade; Longitudinal Effects Linear Segment Plots by Decade; Longitudinal Effects

of Aging on Date-adjusted T and Free T Indexof Aging on Date-adjusted T and Free T Index

30 40 50 60 70 80 9010

12

14

16

18

20

Tot

al T

esto

ster

one

(nM

ol/L

)T

otal

Tes

tost

eron

e (n

Mol

/L)

(144) (151)

(158)(109)

(43)

(177)

Age (years)Age (years) Age (years)Age (years)F

ree

T I

ndex

(n

Mol

/nM

ol)

Fre

e T

Ind

ex (

nM

ol/n

Mol

)

(144)

(151)

(158)

(109)

(43)

(177)

30 40 50 60 70 80 90

0.6

0.5

0.4

0.3

0.2

(Harman et al. J Clin Endocrinol Metab 86:724, 2001)(Harman et al. J Clin Endocrinol Metab 86:724, 2001)

Percentage of Healthy BLSA Men by DecadePercentage of Healthy BLSA Men by DecadeHypogonadal by Total T and Free T CriteriaHypogonadal by Total T and Free T Criteria

18 201279

332

350

251

94

0

20

40

60

80

100

Per

cen

tage

Per

cen

tage

20-29 30-39 40-49 50-59 60-69 70-79 80+

Age DecadeAge Decade

Free T Index

Testosterone

(Harman, et al. J Clin Endocrinol Metab 86:724, 2001)(Harman, et al. J Clin Endocrinol Metab 86:724, 2001)

Effects of Aging on Growth Hormone Effects of Aging on Growth Hormone Secretion in MenSecretion in Men

8:00 am 12:00 pm 4:00 pm 8:00 pm 12:00 am 4:00 am 8:00 am

Time

0

5

10

15

Gro

wth

Hor

mon

e (n

g/m

l) Young

0

5

10

15

Old

(Corpas, et al., J Clin Endocrinol Metab 75:530, 1992)(Corpas, et al., J Clin Endocrinol Metab 75:530, 1992)

Serum IGF-I Levels vs. Age in Serum IGF-I Levels vs. Age in Healthy Women and Men in the BLSAHealthy Women and Men in the BLSA

0

100

200

300

400

500

IGF

-I (

ng/m

l)

20 40 60 80 100

r = 0.639 p < 0.001

Women

20 40 60 80 100

r = 0.546 p < 0.0001

Men

Age (years)

(n=131) (n=258)

(O’Connor, et al. J Gerontol 53:M176, 1998)(O’Connor, et al. J Gerontol 53:M176, 1998)

Similarities of Changes in Body Composition, Similarities of Changes in Body Composition, Muscle Strength, Aerobic Capacity and Metabolic Variables Muscle Strength, Aerobic Capacity and Metabolic Variables

with Aging and in Hormone Deficiency/Excess Stateswith Aging and in Hormone Deficiency/Excess States

AgingAging Low GHLow GH Low TLow T Low E2Low E2

Lean Body MassLean Body MassMuscle StrengthMuscle Strength

Aerobic CapacityAerobic Capacity

Percent Body FatPercent Body Fat

Total and LDLTotal and LDL CholesterolCholesterol

Insulin sensitivityInsulin sensitivityGlucose toleranceGlucose tolerance

HighHighCortisolCortisol

Relationship of Aging Process to Relationship of Aging Process to Hormone Regulation?Hormone Regulation?

Underlying Aging Processes Oxidative Stress? Glycosylation/Crosslinking? Other?

Altered Hormone (1) Secretion (2) Action

Aging Changes: Body Composition Function

Damage to DNA, Lipids, Proteins

Altered CellularFunction

?

?

Strategies for InterventionStrategies for Intervention

• Replace hormonesReplace hormones

Study Design - Subjects and InterventionsStudy Design - Subjects and Interventions

SubjectsSubjects: Healthy women and men, ages 65-88 y (mean, 72 y) with baseline age-related : Healthy women and men, ages 65-88 y (mean, 72 y) with baseline age-related reductions in serum IGF-I (<230 µg/L) and low to low normal gonadal steroid levels reductions in serum IGF-I (<230 µg/L) and low to low normal gonadal steroid levels (women had had no exogenous estrogens for at least 3 months; men had total T levels (women had had no exogenous estrogens for at least 3 months; men had total T levels ≤16.3 nM/L [470 ng/dL]≤16.3 nM/L [470 ng/dL] ).).

Study DesignStudy Design: Double-masked, placebo-controlled, randomized, non cross-over, 2x2 : Double-masked, placebo-controlled, randomized, non cross-over, 2x2 factorialfactorial

Women MenGH + HRT Placebo GH + T Placebo GH Placebo + HRT GH Placebo + TGH + HRT GH + TGH Placebo + HRT Placebo GH Placebo + T Placebo

GH = rhGH 20 µg/kg s.c. 3x/wk in the p.m.GH = rhGH 20 µg/kg s.c. 3x/wk in the p.m.HRT = 100 µg/day EHRT = 100 µg/day E22 patch + 2.5 mg/day MPA p.o. patch + 2.5 mg/day MPA p.o.

T = 100 mg Testosterone enanthate i.m. every 2 wkT = 100 mg Testosterone enanthate i.m. every 2 wk

(Blackman et al., JAMA 288:2282, 2003)(Blackman et al., JAMA 288:2282, 2003)

50

150

250

350

-4 0 4 8 12 16 20 24 28Week

Men

PlaceboTGHGH + T

Hormone Levels in Men Before and During TreatmentHormone Levels in Men Before and During TreatmentIG

F-I

(n

g/m

l)


Effects of Hormone Administration on Lean Body Effects of Hormone Administration on Lean Body Mass and Body Fat (DEXA) in Healthy Elderly MenMass and Body Fat (DEXA) in Healthy Elderly Men

GROUP

Per

cen

t C

han

ge

0.059

0.0001

0.0001

0

2

4

6

8

10

12

Placebo T GH GH+T

LBM0.12

0.0001

0.0001

-25

-20

-15

-10

-5

0

5

Placebo T GH GH+T

Fat Mass


Effects of Hormones on Strength and Effects of Hormones on Strength and VOVO22max (ml Omax (ml O22/min/kg BW) in Healthy Elderly Men/min/kg BW) in Healthy Elderly Men

GROUP

0.49

0.11

0.0001

-10

-5

0

5

10

15

Placebo T GH GH+T

Aerobic Capacity

Per

cen

t C

han

ge

0.49

0.110.86

0.28

0.053

-4

-2

0

2

4

6

8

10

Placebo T GH GH+T

Strength


Potential Risks of Hormone TreatmentsPotential Risks of Hormone Treatments

• TestosteroneTestosterone– ProstateProstate

• Hyperplasia (BPH)Hyperplasia (BPH)

• CancerCancer

– Coronary Heart DiseaseCoronary Heart Disease

• Decreased HDLDecreased HDL

• Increased LDLIncreased LDL

– PolycythemiaPolycythemia

– MinorMinor

• AcneAcne

• Sleep apneaSleep apnea

• Growth HormoneGrowth Hormone– ArthritisArthritis– Carpal tunnel syndromeCarpal tunnel syndrome– Fluid retentionFluid retention– HypertensionHypertension– DiabetesDiabetes– Cancers (?)Cancers (?)– Accelerated Aging (?)Accelerated Aging (?)

• Female HRTFemale HRT– Mastodynia Mastodynia – Vaginal BleedingVaginal Bleeding– ThrombosisThrombosis– CholelithiasisCholelithiasis– Breast CancerBreast Cancer

Frequency of Adverse Effects During Hormone Frequency of Adverse Effects During Hormone Administration in Healthy Elderly MenAdministration in Healthy Elderly Men

0 10 20 30 40 50 60

Percent of Group

Headaches

Gynecomastia

Arthralgias

Carpal Tunnel

Edema

Ad

vers

e E

ffec

t

Men

GH+T

GH

T

Placebo



• Replace HormonesReplace Hormones

• Replace CellsReplace Cells

Selective Destruction and Regrowth of Selective Destruction and Regrowth of Leydig Cells in Young and Old RatsLeydig Cells in Young and Old Rats

Young Leydig CellsYoung Leydig CellsNew Generation of Leydig CellsNew Generation of Leydig Cells

EDSEDS

EDSEDS

Aged Leydig CellsAged Leydig Cells

??

Adapted from Zirkin, B. et al.Adapted from Zirkin, B. et al.

Testosterone Secretion by Perfused Testosterone Secretion by Perfused Testis Before and After EDS TreatmentTestis Before and After EDS Treatment

ND ND

Adapted from Zirkin, B. et al.Adapted from Zirkin, B. et al.




• Prevent Damage to CellsPrevent Damage to Cells




• Prevent Damage to CellsPrevent Damage to Cells

• Repair Damage to CellsRepair Damage to Cells

How Do Hormones Work? How Do Hormones Work?

CellMembrane

Inner

Outer

Hormone

Hormone Receptor

ATPInactive

Enzyme Protein


CellMembrane

Inner

Outer

Binding


CellMembrane

Inner

Outer

Receptor Activation

Change in Receptor Configuration


CellMembrane

Inner

Outer

Lysis of ATP


CellMembrane

Inner

Outer

ADP


CellMembrane

Inner

Outer

Phosphorylation


CellMembrane

Inner

Outer

EnzymeActivation

Why is Hormone Regulation and Why is Hormone Regulation and Action Altered in the Elderly?Action Altered in the Elderly?

Old CellMembrane

Inner

Outer

Hormone

Hormone Receptor

ATPInactive

Enzyme Protein


Old CellMembrane

Inner

Outer

Binding


Old CellMembrane

Inner

Outer

No Change in Receptor

Configuration

No Receptor Activation

Enzyme ProteinRemains Inactive

Effects of Saturated vs. Polyunsaturated Fat on Stimulated Effects of Saturated vs. Polyunsaturated Fat on Stimulated Cylase Activity in Hepatocytes and Adipocytes of Old RatsCylase Activity in Hepatocytes and Adipocytes of Old Rats

0

200

400

600

800

1000

Ad

enyl

Cyc

lase

Act

ivit

y (

pmol

/mg/

10 m

in)

456789

-log [Glucagon] M

8.5% Coco/2.5% corn10% Coconut Oil10% Corn Oil

4567

-log [Isoproteronol] M

300

200

100

Hepatocytes Adipocytes

From: Dax et al. Endocrinology, 1990, 127:2236

KLRI Omega-3 Hormone Pilot StudyKLRI Omega-3 Hormone Pilot Study• Six men and six women > 60 years of ageSix men and six women > 60 years of age• Dietary InterventionDietary Intervention

– Non oily fish x 6/week plus 15 ml/day olive/corn oil (50/50)Non oily fish x 6/week plus 15 ml/day olive/corn oil (50/50)– Oily fish x 8/week plus 15 ml/day fish oil (4 g of Ω-3)Oily fish x 8/week plus 15 ml/day fish oil (4 g of Ω-3)

• Provocative Testing of Multiple Hormone AxesProvocative Testing of Multiple Hormone Axes– Pituitary: GnRH and GHRH testsPituitary: GnRH and GHRH tests– Adrenal: ACTH testAdrenal: ACTH test– Testis: hCG stimulation (men only)Testis: hCG stimulation (men only)– Liver: glucagon stimulation testLiver: glucagon stimulation test– Fat cells (catecholaminergic): graded isuprel testFat cells (catecholaminergic): graded isuprel test– Insulin sensitivity: statin-insulin suppression testInsulin sensitivity: statin-insulin suppression test

• Results?? (study complete, assays pending)Results?? (study complete, assays pending)

SummarySummary

• Biological aging in humans produces changes inBiological aging in humans produces changes in– Hormone secretion and action Hormone secretion and action – Body composition and functionBody composition and function

• Some (but not all) aging changes in body Some (but not all) aging changes in body composition and function are attributable to composition and function are attributable to hormonal alterationshormonal alterations

• Potential sites of intervention includePotential sites of intervention include– Hormone replacementHormone replacement– Cellular processes of oxidation and glycosylationCellular processes of oxidation and glycosylation– Cell membrane signal transductionCell membrane signal transduction– Stem cellsStem cells

• More research is needed!More research is needed!

Documents

What Do Hormones Have to Do with Aging? What Does Aging Have to Do with Hormones?