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Long term calorie restriction in humans

Long term calorie restriction in humans. John O. Holloszy. MD Division of Geriatrics and Nutritional Sciences. Primary Aging – The inevitable deterioration in structure and function of cells and tissues with advancing age.

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Long term calorie restriction in humans

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  1. Long term calorie restriction in humans John O. Holloszy. MD Division of Geriatrics and Nutritional Sciences

  2. Primary Aging – The inevitable deterioration in structure and function of cells and tissues with advancing age. Secondary Aging – The deterioration in structure and function of cells and tissues caused by diseases, trauma and lifestyle factors and, therefore, at least partially preventable.

  3. Life-expectancy vs. Life Span

  4. Primary aging rate determines life span. Life span and rate of primary aging are determined by genetics but can, to some extent, be modified.

  5. Acute diseases and secondary aging determine life expectancy. Genetic make up plays a major role in determining rate of secondary aging and life expectancy. However, it is possible to powerfully protect against secondary aging and extend life expectancy by means of healthy life-style, changes in environment, and medical interventions.

  6. Aging is the result of: a) failure of maintenance/repair mechanisms to completely protect against damage b) failure of repair mechanisms to completely repair damage leading to accumulation of cell/tissue damage and a progressive decline in structure and function with eventually, failure/death.

  7. The rate of aging is determined by the balance between accumulating damage and maintenance/repair mechanisms. (There are more than 100 genes that regulate detection and repair of damage to DNA.)

  8. Factors involved in mediating cell/tissue damage

  9. Oxidative Stress / Free Radical Damage Inflammation Levels of various growth factors IGF-1 TGF- PDGF VEGFs Insulin Advanced glycation end products Angiotensin Norepinephrine

  10. Body Composition Age mo Carcass Weight, gm Group % Fat % Protein Food-Restricted 9 365 16.5 15.7 Sedentary 30 358 26.9 9.0 367 Runners 9 11.5 16.4 352 19.3 30 9.1 9 29.9 12.4 Freely-Eating 650 Sedentary 30 614 42.7 6.9

  11. Food intake of male wheel runners PF Sedentary Age Period mo FE Sedentary PW Sedentary Runners Food intake, g 9-18 26.7 25.0 17.8 24.0 22.6 19-28 23.7 17.6 22.0 29-32 21.3 17.2 20.6 20.3

  12. 100 Sedentary Runners 80 Food Restricted 60 % survival 40 20 0 500 600 700 800 900 1000 1100 1200 1300 1400 1500 Age, Days

  13. Longevity of the four groups Age of 3 Oldest Rats, days Age at Death, days Group Paired-weight sedentary 1,113 ± 150 1,317 ± 23 Voluntary runners 1,012 ± 138 1,220 ± 11 Pair-fed sedentary 928 ± 186 1,212 ± 18 Freely eating sedentary 923 ± 160 1,209 ± 19

  14. Runners Sedentary FR-runners FR-sedentary

  15. Caloric Restriction Western Diet Age (y) 52.3 ± 10 51.4 ± 12 Male:female 29:4 29:4 Body mass index (kg/m2) 24.8 ± 3.2 19.6 ± 1.6† Total body fat (%) 23.1 ± 1 7 8.4 ± 7† Truncal fat (%) 23.4 ± 9.7 4.6 ± 5.7† Systolic blood pressure (mmHg) 130 ± 13 103 ± 12† Diastolic blood pressure (mmHg) 81 ± 9 63 ± 7†

  16. Caloric Restriction Western Diet Total cholesterol (mg/dl) 202 ± 33 162 ± 34† LDL-cholesterol (mg/dl) 122 ± 30 86 ± 24† HDL-cholesterol (mg/dl) 52 ± 15 64 ± 18* Total chol:HDL-chol Ratio 4.2 ± 1.2 2.5 ± 0.5† Triglycerides (mg/dl) 143 ± 93 58 ± 18†

  17. Caloric Restriction Western Diet Glucose (mg/dl) 95 ± 9 84 ± 8† Insulin (µU/ml) 7.4 ± 6 1.5 ± 0.9† TNFα (pg/ml) 1.5 ± 0.9 0.7 ± 0.5* C-reactive protein (mg/L) 1.1 ± 1.2 0.2 ± 0.3† TGFβ1 (ng/ml) 22.1 ± 6.6 14.9 ± 3.1† Triiodothyronine (ng/dl) 91 ± 13 74 ± 22†

  18. Growth Factors (serum) CR EX U.S. Diet ng/ml IGF-1 180 ± 50 171 ± 45 218 ± 46 PDGF-AB 12.2 ± 4.9 14.8 ± 4.9 17.5 ± 5.5 TGF--1 14.9 ± 3.1 19.0 ± 3.7 22.1 ± 6.6

  19. Adipokines CR EX U.S. Diet Leptin, ng/ml 1.9 ± 1.4 2.4 ± 1.3 8.3 ± 4.8 Adiponectin, ng/ml 16.6 ± 8.3 11.4 ± 6.3 9.0 ± 4.1

  20. Common Carotid Intima-Media Thickness CR Exercise U.S. CCAIMT, mm 0.54 ± 0.08 0.66 ± 0.12 0.80 ± 0.13

  21. Atherosclerosis risk factors in CR Society members before and after starting CR Caloric Restriction Before CR 1.0 ± 0.3 yr 7 ± 4.8 yr Body mass index (kg/m2) 23.7 ± 2.6 20.3 ± 2.0 19.6±1.6 Total cholesterol (mg/dl) 211 ± 36 165 ± 33 159 ± 36 LDL-cholesterol (mg/dl) 124 ± 37 94 ± 21 89 ± 30 HDL-cholesterol (mg/dl) 47 ± 8 59 ± 13 64 ± 21 2.5 ± 0.5 Total chol:HDL-chol 4.5 ± 1.1 2.9 ± 0.6 Triglycerides (mg/dl) 134 ± 81 68 ± 22 49 ± 14

  22. Atherosclerosis risk factors in CR Society members before and after starting CR Caloric Restriction Before CR 1.0 ± 0.3 yr 7 ± 4.8 yr Systolic blood pressure (mmHg) 131 ± 15 112 ± 12 101 ± 9 Diastolic blood pressure (mmHg) 82 ± 9 71 ± 7 61 ± 7

  23. Diet vs. CR-Growth Factors and Hormones CR Raw Food Vegans IGF-1 (ng/ml) 177±53 139±34 IGFBP-3 (ng/ml) 3991±893 4210±512 IGF-1/IGFBP-3 0.044±0.010 0.033±0.011 PDGF-AB (ng/ml) 12.5±4.8 15.2±5.3 Cortisol (mcg/dl) 15.2±4.9 12.3±5.2 Leptin (ng/ml) 1.8±1.2 3.7±3.5 Adiponectin (ng/ml) 15.7±8.1 9.6±4.4 T3 (ng/dl) 73±21 89±15 Testosterone (nmol/L) 12.3±6.7 12.4±8.8 Free Androgen (nmol/L) 5.2±3.4 5.1±4.2 Values are means ± SD

  24. Aortic Pulse Wave Velocity • Augmentation Index • Echocardiographic – Doppler evaluation of left ventricular diastolic function • 24 hr ECG recording for measurement of heart rate variability • Treadmill exercise test for determination of maximal heart rate and VO2max • Pulmonary function tests, including FVC, FEV1 and MVV Measurements Used to Evaluate Rate of Aging

  25. Trained: y = -0.46x + 77.2 2 = 0.69 R 80 70 60 max (mL/kg/min) 50 40 2 30 VO Sed: y = -0.40x + 54.2 CR: y = -0.20x + 51.9 20 2 R = 0.77 2 R = 0.15 10 30 40 50 60 70 80 Age (years)

  26. 6 5 Trained 4 3 VO2max (L/min) Sedentary 2 1 0 10 30 50 70 90 Age (years)

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