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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!