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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

Long term calorie restriction in humans

John O. Holloszy. MD

Division of Geriatrics and Nutritional Sciences

slide2

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.

slide3

Life-expectancy

vs.

Life Span

slide4

Primary aging rate determines life span.

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

slide5

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.

slide6

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.

slide7

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.)

slide9

Oxidative Stress / Free Radical Damage

Inflammation

Levels of various growth factors

IGF-1

TGF-

PDGF

VEGFs

Insulin

Advanced glycation end products

Angiotensin

Norepinephrine

slide10

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

slide11

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

slide12

100

Sedentary

Runners

80

Food Restricted

60

% survival

40

20

0

500

600

700

800

900

1000

1100

1200

1300

1400

1500

Age, Days

slide13

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

slide14

Runners

Sedentary

FR-runners

FR-sedentary

slide15

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†

slide16

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†

slide17

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†

slide18

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

slide19

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

slide20

Common Carotid Intima-Media Thickness

CR

Exercise

U.S.

CCAIMT, mm

0.54 ± 0.08

0.66 ± 0.12

0.80 ± 0.13

slide21

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

slide22

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

slide23

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

slide24

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

slide25

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)

slide26

6

5

Trained

4

3

VO2max (L/min)

Sedentary

2

1

0

10

30

50

70

90

Age (years)