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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)
(Blackman et al., JAMA 288:2282, 2003)(Blackman et al., JAMA 288:2282, 2003)
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
(Blackman et al., JAMA 288:2282, 2003)(Blackman et al., JAMA 288:2282, 2003)
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
(Blackman et al., JAMA 288:2282, 2003)(Blackman et al., JAMA 288:2282, 2003)
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
(Blackman et al., JAMA 288:2282, 2003)(Blackman et al., JAMA 288:2282, 2003)
Strategies for InterventionStrategies for Intervention
• 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.
Strategies for InterventionStrategies for Intervention
• Replace HormonesReplace Hormones
• Replace CellsReplace Cells
• Prevent Damage to CellsPrevent Damage to Cells
Strategies for InterventionStrategies for Intervention
• Replace HormonesReplace Hormones
• Replace CellsReplace 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
How Do Hormones Work? How Do Hormones Work?
CellMembrane
Inner
Outer
Binding
How Do Hormones Work? How Do Hormones Work?
CellMembrane
Inner
Outer
Receptor Activation
Change in Receptor Configuration
How Do Hormones Work? How Do Hormones Work?
CellMembrane
Inner
Outer
Lysis of ATP
How Do Hormones Work? How Do Hormones Work?
CellMembrane
Inner
Outer
ADP
How Do Hormones Work? How Do Hormones Work?
CellMembrane
Inner
Outer
Phosphorylation
How Do Hormones Work? How Do Hormones Work?
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
Why is Hormone Regulation and Why is Hormone Regulation and Action Altered in the Elderly?Action Altered in the Elderly?
Old CellMembrane
Inner
Outer
Binding
Why is Hormone Regulation and Why is Hormone Regulation and Action Altered in the Elderly?Action Altered in the Elderly?
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!