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What Do Hormones Have to Do
with Aging? What Does Aging
Have to Do with Hormones?
S. Mitchell Harman, M.D., Ph.D.
Director and President
Kronos Longevity Research Institute
(KLRI)
Phoenix, Arizona
A Definition of Aging?
• The related deterioration of physiological functions
necessary for :
– Fertility
– Survival
• Progressive loss of:
– Reserve capacity of organ systems
– Ability to compensate for stress or injury
• Process terminating inevitably in death of the
organism
– Increased susceptibility to age-related disease
– Death from disease, not “old age”
Theories of Aging
• Genetic
– Aging is “programmed” into the genes
– Certain genes are “timekeepers” for the aging
process
• Wear and Tear
– Cumulative damage to cells from
• Metabolic processes
• Environmental factors
– Mechanisms to resist and repair damage are
critical
Cellular Damage and Defense
oxygen
glucose
Antioxidants
(GSH, tocopherols, etc.)
N
O2 radicals
DNA damage
Protein damage
Lipid damage
Mitochondria
O•
Cell Membrane
Cytoplasm -proteins
N
Nucleus (DNA)
Energy
OH-
Repair
Processes
SOD
(ATP)
H2O2 Catalase H2O + O2
Defense
Enzymes
GPX
Age-related Changes in Body Composition
and Function
• Body Composition
– Loss of lean body (muscle) mass
• Decreased strength
• Decreased fitness and loss of functional capacity
– Increase in total fat mass (percent body fat)
• Insulin resistance (type 2 diabetes)
• Increased LDL cholesterol, triglycerides, and fatty acids
– Decreased bone density (negative calcium balance)
• Metabolic/Physiologic Function
–
–
–
–
Decreased protein synthesis
Slower healing
Reduced immune system function
Altered hormone balance
Age-related Changes in Body Composition
in Normal Sedentary Men
Muscle Mass (lbs)
Fat (%)
Body Composition
70
60
50
40
30
20
10
20
30
40
50
Age (years)
(Balagopal et al. Endocrine 7:57, 1997)
60
70
80
Isokinetic Force (Nm)
Decreases in Muscle Strength with Age
Men
Women
250
200
150
100
10
20
30
40
50
Age (years)
(Borges, Scand J Rehabil Med 21:45, 1989)
60
70
80
Age-Related Declines in VO2 max in Sedentary
and Physically Active Individuals
VO2 MAX (ml/kg/min)
70
Sedentary
40 yr
50 yr
60 yr
70 yr
60
men
women
Longitudinal
Longitudinal
Longitudinal
Longitudinal
50
40
30
20
10
40
50
60
70
Age (years)
(Wiswell et al., J Gerontol 56:M618, 2001)
80
90
What Are Hormones?
• Natural chemical regulators of cell physiology
• Secreted into the blood by specialized glands
and act at a distance on one or more target
organs
• Mechanisms of Action
– Peptides/Proteins: act at cell membrane receptors
– Steroids: enter nucleus and regulate genes
SUMMARY OF HORMONE PHYSIOLOGY
Higher Centers
Neural activity
(neurotransmitters)
Hypothalamus
Releasing Factors
Thyroid
anterior
Trophic
Hormones
TSH
Adrenal
ACTH
LH
FSH
Pituitary
posterior
-
Testis
Gonads
Ovary
Peripheral
Hormones
-
Liver
GH
Fat
+
+
IGF-I
Cartilage
Bone
Muscle
How Do Hormones Change with Normal Aging?
• Estrogens- decrease to very low levels over a 1-3 year period
at menopause (between ages 45-55)
• Testosterone (T)- Gradual decline from age 30 onward
reaching low (hypogonadal) levels in >50% of men by age 65
• Growth Hormone (GH)- Gradual decrease in secretion (and
circulating IGF-I levels) from age 45-90
• Adrenal Steroids– Active adrenal hormones (cortisol and aldosterone) change little
– DHEA, steady decrease with age to very low levels in both sexes
• Thyroid- not much change in healthy men and women, but
increased prevalence of hypothyroid disease in older persons.
• Insulin- loss of sensitivity to insulin action with aging and
obesity
Free T Index (nMol/nMol)
Total Testosterone (nMol/L)
Linear Segment Plots by Decade; Longitudinal Effects
of Aging on Date-adjusted T and Free T Index
0.6
(177)
(177)
0.5
(144)
(151)
(158)
0.4
(109)
(43)
(144)
(151)
(158)
0.3
0.2
(Harman et al. J Clin Endocrinol Metab 86:724, 2001)
(109)
(43)
Percentage of Healthy BLSA Men by Decade
Hypogonadal by Total T and Free T Criteria
94
100
Percentage
80
251
Testosterone
Free T Index
60
350
40
20
18
0
20-29
201
30-39
279
40-49
332
50-59
60-69
70-79
Age Decade
(Harman, et al. J Clin Endocrinol Metab 86:724, 2001)
80+
Effects of Aging on Growth Hormone
Secretion in Men
Growth Hormone (ng/ml)
15
10
Young
5
0
15
Old
10
5
0
8:00 am
12:00 pm
4:00 pm
8:00 pm
12:00 am
Time
(Corpas, et al., J Clin Endocrinol Metab 75:530, 1992)
4:00 am
8:00 am
Serum IGF-I Levels vs. Age in
Healthy Women and Men in the BLSA
(n=131)
Women
IGF-I (ng/ml)
500
(n=258)
Men
400
r = 0.546 p < 0.0001
r = 0.639 p < 0.001
300
200
100
0
20
40
60
80
100 20
40
Age (years)
(O’Connor, et al. J Gerontol 53:M176, 1998)
60
80
100
Similarities of Changes in Body Composition,
Muscle Strength, Aerobic Capacity and Metabolic Variables
with Aging and in Hormone Deficiency/Excess States
Aging
Lean Body Mass
Muscle Strength
Aerobic Capacity
Percent Body Fat
Total and LDL
Cholesterol
Insulin sensitivity
Glucose tolerance
Low GH
Low T
High
Cortisol
Low E2
Relationship of Aging Process to
Hormone Regulation?
Underlying Aging Processes
Oxidative Stress?
Glycosylation/Crosslinking?
Other?
Damage to
DNA, Lipids, Proteins
Altered Cellular
Function
?
?
Aging Changes:
Body Composition
Function
Altered Hormone
(1) Secretion
(2) Action
Strategies for Intervention
• Replace hormones
Study Design - Subjects and Interventions
Subjects: 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
(women had had no exogenous estrogens for at least 3 months; men had total T levels
≤16.3 nM/L [470 ng/dL] ).
Study Design: Double-masked, placebo-controlled, randomized, non cross-over, 2x2
factorial
Women
GH + HRT Placebo
GH Placebo + HRT
GH + HRT
GH Placebo + HRT Placebo
Men
GH + T Placebo
GH Placebo + T
GH + T
GH Placebo + T Placebo
GH = rhGH 20 µg/kg s.c. 3x/wk in the p.m.
HRT = 100 µg/day E2 patch + 2.5 mg/day MPA p.o.
T = 100 mg Testosterone enanthate i.m. every 2 wk
(Blackman et al., JAMA 288:2282, 2003)
Hormone Levels in Men Before and During Treatment
IGF-I (ng/ml)
350
GH + T
GH
T
Placebo
Men
250
150
50
-4
0
4
8
12
Testosterone (ng/dl)
1000
GH + T
GH
Week
16
20
T
24
28
Placebo
800
Men
600
400
200
-4
0
4
8
12
Week
(Blackman et al., JAMA 288:2282, 2003)
16
20
24
28
Effects of Hormone Administration on Lean Body
Mass and Body Fat (DEXA) in Healthy Elderly Men
Percent Change
12
10
5
LBM
0
-5
8
0.0001
6
0.0001
4
2
0
0.12
-15
T
0.0001
Fat Mass
-20
0.059
Placebo
0.0001
-10
GH
GH+T
-25
Placebo
GROUP
(Blackman et al., JAMA 288:2282, 2003)
T
GH
GH+T
Effects of Hormones on Strength and
VO2max (ml O2/min/kg BW) in Healthy Elderly Men
Percent Change
10
8
15
10
6
0.053
4
0.28
2
0.0001
5
0.49
0.49
0.86
0
0
0.11
0.11
-5
-2
-4
Aerobic Capacity
Strength
Placebo
T
GH
GH+T
-10
Placebo
GROUP
(Blackman et al., JAMA 288:2282, 2003)
T
GH
GH+T
Potential Risks of Hormone Treatments
• Growth Hormone
–
–
–
–
–
–
–
Arthritis
Carpal tunnel syndrome
Fluid retention
Hypertension
Diabetes
Cancers (?)
Accelerated Aging (?)
• Female HRT
–
–
–
–
–
Mastodynia
Vaginal Bleeding
Thrombosis
Cholelithiasis
Breast Cancer
• Testosterone
– Prostate
• Hyperplasia (BPH)
• Cancer
– Coronary Heart Disease
• Decreased HDL
• Increased LDL
– Polycythemia
– Minor
• Acne
• Sleep apnea
Adverse Effect
Frequency of Adverse Effects During Hormone
Administration in Healthy Elderly Men
Edema
Carpal Tunnel
Placebo
T
Arthralgias
GH
GH+T
Gynecomastia
Headaches
Men
0
10
20
30
40
Percent of Group
(Blackman et al., JAMA 288:2282, 2003)
50
60
Strategies for Intervention
• Replace Hormones
• Replace Cells
Selective Destruction and Regrowth of
Leydig Cells in Young and Old Rats
EDS
Young Leydig Cells
New Generation of
Leydig Cells
EDS
Aged Leydig Cells
Adapted from Zirkin, B. et al.
?
Testosterone Secretion by Perfused Testis
Before and After EDS Treatment
Testosterone Production
(ng/testis/hour)
5000
Young
4000
Old
3000
2000
1000
ND ND
0
Control
Adapted from Zirkin, B. et al.
1 week
5 weeks
Time
10 weeks
Strategies for Intervention
• Replace Hormones
• Replace Cells
• Prevent Damage to Cells
Strategies for Intervention
•
•
•
•
Replace Hormones
Replace Cells
Prevent Damage to Cells
Repair Damage to Cells
How Do Hormones Work?
Hormone
Hormone Receptor
Outer
Cell
Membrane
Inner
ATP
Inactive
Enzyme Protein
How Do Hormones Work?
Binding
Outer
Cell
Membrane
Inner
How Do Hormones Work?
Outer
Change in Receptor
Configuration
Cell
Membrane
Inner
Receptor Activation
How Do Hormones Work?
Outer
Cell
Membrane
Inner
Lysis of ATP
How Do Hormones Work?
Outer
Cell
Membrane
Inner
ADP
How Do Hormones Work?
Outer
Cell
Membrane
Inner
Phosphorylation
How Do Hormones Work?
Outer
Cell
Membrane
Inner
Enzyme
Activation
Why is Hormone Regulation and
Action Altered in the Elderly?
Hormone
Hormone Receptor
Outer
Old Cell
Membrane
Inner
ATP
Inactive
Enzyme Protein
Why is Hormone Regulation and
Action Altered in the Elderly?
Binding
Outer
Old Cell
Membrane
Inner
Why is Hormone Regulation and
Action Altered in the Elderly?
Outer
No Change in
Receptor Configuration
Old Cell
Membrane
Inner
No Receptor Activation
Enzyme Protein
Remains Inactive
Effects of Saturated vs. Polyunsaturated Fat on Stimulated
Cylase Activity in Hepatocytes and Adipocytes of Old Rats
10% Corn Oil
10% Coconut Oil
8.5% Coco/2.5% corn
Adenyl Cyclase Activity
(pmol/mg/10 min)
1000
800
600
300
400
200
200
100
Hepatocytes
Adipocytes
0
9
8
7
6
5
4
-log [Glucagon] M
From: Dax et al. Endocrinology, 1990, 127:2236
7
6
5
-log [Isoproteronol] M
4
KLRI Omega-3 Hormone Pilot Study
• Six men and six women > 60 years of age
• Dietary Intervention
– 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)
• Provocative Testing of Multiple Hormone Axes
–
–
–
–
–
–
Pituitary: GnRH and GHRH tests
Adrenal: ACTH test
Testis: hCG stimulation (men only)
Liver: glucagon stimulation test
Fat cells (catecholaminergic): graded isuprel test
Insulin sensitivity: statin-insulin suppression test
• Results?? (study complete, assays pending)
Summary
• Biological aging in humans produces changes in
– Hormone secretion and action
– Body composition and function
• Some (but not all) aging changes in body
composition and function are attributable to
hormonal alterations
• Potential sites of intervention include
–
–
–
–
Hormone replacement
Cellular processes of oxidation and glycosylation
Cell membrane signal transduction
Stem cells
• More research is needed!