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

1
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

2
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

3
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

4
Cellular Damage and Defense
N
5
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

6
Age-related Changes in Body Composition in
Normal Sedentary Men
Muscle Mass (lbs)
70
Fat ()
60
50
Body Composition
40
30
20
10
20
30
40
50
60
70
80
Age (years)
(Balagopal et al. Endocrine 757, 1997)
7
Decreases in Muscle Strength with Age
Men
250
Women
200
Isokinetic Force (Nm)
150
100
10
20
30
40
50
60
70
80
Age (years)
(Borges, Scand J Rehabil Med 2145, 1989)
8
Age-Related Declines in VO2 max in Sedentary and
Physically Active Individuals
70
men
Sedentary
women
40 yr Longitudinal
60
50 yr Longitudinal
60 yr Longitudinal
70 yr Longitudinal
50
VO2 MAX (ml/kg/min)
40
30
20
10
40
50
60
70
80
90
Age (years)
(Wiswell et al., J Gerontol 56M618, 2001)
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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

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SUMMARY OF HORMONE PHYSIOLOGY
Higher Centers
Neural activity (neurotransmitters)
-


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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 gt50
  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

12
Linear Segment Plots by Decade Longitudinal
Effects of Aging on Date-adjusted T and Free T
Index
0.6
20
(177)
(177)
0.5
18
(144)
Total Testosterone (nMol/L)
(151)
0.4
16
(144)
Free T Index (nMol/nMol)
(151)
(158)
14
(109)
0.3
(158)
(109)
(43)
12
(43)
0.2
10
30
50
40
60
70
80
90
50
30
40
60
70
80
90
Age (years)
Age (years)
(Harman et al. J Clin Endocrinol Metab 86724,
2001)
13
Percentage of Healthy BLSA Men by
DecadeHypogonadal by Total T and Free T Criteria
94
100
80
251
Testosterone
Free T Index
60
Percentage
350
40
20
332
279
18
201
0
20-29
30-39
40-49
50-59
60-69
70-79
80
Age Decade
(Harman, et al. J Clin Endocrinol Metab 86724,
2001)
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Effects of Aging on Growth Hormone Secretion in
Men
15
Young
10
5
0
Growth Hormone (ng/ml)
800 am
1200 pm
400 pm
800 pm
1200 am
400 am
800 am
Time
(Corpas, et al., J Clin Endocrinol Metab 75530,
1992)
15
Serum IGF-I Levels vs. Age in Healthy Women and
Men in the BLSA
500
(n131)
(n258)
Women
Men
400
r 0.546 p lt 0.0001
r 0.639 p lt 0.001
300
IGF-I (ng/ml)
200
100
0
20
40
60
80
100
20
40
60
80
100
Age (years)
(OConnor, et al. J Gerontol 53M176, 1998)
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Similarities of Changes in Body Composition,
Muscle Strength, Aerobic Capacity and Metabolic
Variables with Aging and in Hormone
Deficiency/Excess States
High Cortisol
Low T
Low GH
Low E2
Aging
Lean Body Mass Muscle Strength
Aerobic Capacity
Percent Body Fat
Total and LDL Cholesterol
Insulin sensitivity Glucose tolerance
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Relationship of Aging Process to Hormone
Regulation?
Underlying Aging Processes Oxidative Stress?
Glycosylation/Crosslinking? Other?
?
Altered Hormone (1) Secretion (2) Action
Damage to DNA, Lipids, Proteins Altered
Cellular Function
?
Aging Changes Body Composition Function
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Strategies for Intervention

• Replace hormones

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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 (lt230 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 Men GH HRT Placebo GH T
Placebo GH Placebo HRT GH Placebo
T GH HRT GH T GH Placebo HRT
Placebo 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 2882282, 2003)
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Hormone Levels in Men Before and During Treatment
IGF-I (ng/ml)
(Blackman et al., JAMA 2882282, 2003)
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Effects of Hormone Administration on Lean Body
Mass and Body Fat (DEXA) in Healthy Elderly Men
5
0
0.12
-5
Percent Change
0.0001
-10
-15
0.0001
Fat Mass
-20
-25
Placebo
T
GH
GHT
GROUP
(Blackman et al., JAMA 2882282, 2003)
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Effects of Hormones on Strength and VO2max (ml
O2/min/kg BW) in Healthy Elderly Men
15
Aerobic Capacity
10
0.0001
5
Percent Change
0.49
0.49
0
0.11
0.11
-5
-10
Placebo
T
GH
GHT
GROUP
(Blackman et al., JAMA 2882282, 2003)
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Potential Risks of Hormone Treatments

• Testosterone
• Prostate
• Hyperplasia (BPH)
• Cancer
• Coronary Heart Disease
• Decreased HDL
• Increased LDL
• Polycythemia
• Minor
• Acne
• Sleep apnea

• Growth Hormone
• Arthritis
• Carpal tunnel syndrome
• Fluid retention
• Hypertension
• Diabetes
• Cancers (?)
• Accelerated Aging (?)
• Female HRT
• Mastodynia
• Vaginal Bleeding
• Thrombosis
• Cholelithiasis
• Breast Cancer

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Frequency of Adverse Effects During Hormone
Administration in Healthy Elderly Men
Edema
Carpal Tunnel
Placebo
Adverse Effect
T
Arthralgias
GH
GHT
Gynecomastia
Headaches
Men
0
10
20
30
40
50
60
Percent of Group
(Blackman et al., JAMA 2882282, 2003)
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Strategies for Intervention

• Replace Hormones
• Replace Cells

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Selective Destruction and Regrowth of Leydig
Cells in Young and Old Rats
Young Leydig Cells
New Generation of Leydig Cells
?
Aged Leydig Cells
Adapted from Zirkin, B. et al.
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Testosterone Secretion by Perfused Testis Before
and After EDS Treatment
ND
ND
Adapted from Zirkin, B. et al.
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Strategies for Intervention

• Replace Hormones
• Replace Cells
• Prevent Damage to Cells

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Strategies for Intervention

• Replace Hormones
• Replace Cells
• Prevent Damage to Cells
• Repair Damage to Cells

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How Do Hormones Work?
Hormone
Hormone Receptor
Outer
Cell Membrane
Inner
Inactive Enzyme Protein
ATP
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How Do Hormones Work?
Binding
Outer
Cell Membrane
Inner
32
How Do Hormones Work?
Change in Receptor Configuration
Outer
Cell Membrane
Receptor Activation
Inner
33
How Do Hormones Work?
Outer
Cell Membrane
Inner
Lysis of ATP
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How Do Hormones Work?
Outer
Cell Membrane
Inner
ADP
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How Do Hormones Work?
Outer
Cell Membrane
Inner
Phosphorylation
36
How Do Hormones Work?
Outer
Cell Membrane
Inner
Enzyme Activation
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Why is Hormone Regulation and Action Altered in
the Elderly?
Hormone
Hormone Receptor
Outer
Old Cell Membrane
Inner
Inactive Enzyme Protein
ATP
38
Why is Hormone Regulation and Action Altered in
the Elderly?
Binding
Outer
Old Cell Membrane
Inner
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Why is Hormone Regulation and Action Altered in
the Elderly?
No Change in Receptor Configuration
Outer
Old Cell Membrane
No Receptor Activation
Inner
Enzyme Protein Remains Inactive
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Effects of Saturated vs. Polyunsaturated Fat on
Stimulated Cylase Activity in Hepatocytes and
Adipocytes of Old Rats
10 Corn Oil
1000
10 Coconut Oil
8.5 Coco/2.5 corn
800
Adenyl Cyclase Activity (pmol/mg/10 min)
300
600
200
400
100
200
Hepatocytes
Adipocytes
0
4
5
6
7
4
5
6
7
8
9
-log Glucagon M
-log Isoproteronol M
From Dax et al. Endocrinology, 1990, 1272236
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KLRI Omega-3 Hormone Pilot Study

• Six men and six women gt 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 ?-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)

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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!