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.

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.

Life-expectancy

vs.

Life Span

Primary aging rate determines life span.

Life span and rate of primary aging are determined by genetics but can,

to some extent, be modified.

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.

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.

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.)

Factors involved in mediating cell/tissue damage

Oxidative Stress / Free Radical DamageInflammation

Levels of various growth factorsIGF-1TGF-PDGFVEGFsInsulin

Advanced glycation end productsAngiotensin

Norepinephrine

Body Composition

GroupAgemo

CarcassWeight, gm

% Fat % Protein

Food-Restricted

Sedentary

Runners

Freely-Eating

Sedentary

9

30

9

30

9

30

365

358

16.5

26.9

15.7

9.0

367

352

11.5

19.3

16.4

9.1

650

614

29.9

42.7

12.4

6.9

Food intake of male wheel runners

Age Periodmo

FESedentary

Runners PWSedentary

PFSedentary

Food intake, g

19-28

9-18

29-32

26.7 25.0 17.8 24.0

23.7 22.6 17.6 22.0

20.6 21.3 17.2 20.3

500

% s

urvi

val

100

20

60

Age, Days

80

40

600 700 800 900 1000 1100 1200 1300 1400 15000

Sedentary

Runners

Food Restricted

Longevity of the four groups

GroupAge

at Death,days

Age of3 Oldest

Rats,days

Paired-weight sedentary

Voluntary runners

Pair-fed sedentary

Freely eating sedentary

1,113 ± 150

1,012 ± 138

928 ± 186

923 ± 160

1,317 ± 23

1,220 ± 11

1,212 ± 18

1,209 ± 19

RunnersSedentaryFR-runners

FR-sedentary

Diastolic blood pressure (mmHg)

Systolic blood pressure (mmHg)

Truncal fat (%)

Total body fat (%)

Body mass index (kg/m2)

Male:female

63 ± 7†81 ± 9

103 ± 12†130 ± 13

4.6 ± 5.7†23.4 ± 9.7

8.4 ± 7†23.1 ± 1 7

19.6 ± 1.6†24.8 ± 3.2

29:429:4

51.4 ± 1252.3 ± 10Age (y)

Caloric RestrictionWestern Diet

58 ± 18†143 ± 93Triglycerides (mg/dl)

2.5 ± 0.5†4.2 ± 1.2

64 ± 18*52 ± 15HDL-cholesterol (mg/dl)

86 ± 24†122 ± 30LDL-cholesterol (mg/dl)

162 ± 34†202 ± 33Total cholesterol (mg/dl)

Total chol:HDL-chol Ratio

Caloric RestrictionWestern Diet

74 ± 22†91 ± 13Triiodothyronine (ng/dl)

14.9 ± 3.1†22.1 ± 6.6TGFβ1 (ng/ml)

0.2 ± 0.3†1.1 ± 1.2C-reactive protein (mg/L)

0.7 ± 0.5*1.5 ± 0.9TNFα (pg/ml)

1.5 ± 0.9†7.4 ± 6Insulin (µU/ml)

84 ± 8†95 ± 9Glucose (mg/dl)

Caloric RestrictionWestern Diet

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

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

Common Carotid Intima-Media Thickness

CR Exercise U.S.

CCAIMT, mm 0.54 ± 0.08 0.66 ± 0.12 0.80 ± 0.13

2.5 ± 0.52.9 ± 0.64.5 ± 1.1Total chol:HDL-chol

64 ± 2159 ± 1347 ± 8HDL-cholesterol (mg/dl)

89 ± 3094 ± 21124 ± 37LDL-cholesterol (mg/dl)

159 ± 36165 ± 33211 ± 36Total cholesterol (mg/dl)

19.6±1.620.3 ± 2.023.7 ± 2.6Body mass index (kg/m2)

7 ± 4.8 yr1.0 ± 0.3 yrBefore CR

Atherosclerosis risk factors in CR Society members before and after starting CR

Caloric Restriction

49 ± 1468 ± 22134 ± 81Triglycerides (mg/dl)

61 ± 771 ± 782 ± 9Diastolic blood pressure (mmHg)

101 ± 9112 ± 12131 ± 15Systolic blood pressure (mmHg)

7 ± 4.8 yr1.0 ± 0.3 yrBefore CR

Atherosclerosis risk factors in CR Society members before and after starting CR

Caloric Restriction

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

Measurements Used to Evaluate Rate of Aging

Pulmonary function tests, including FVC, FEV1 and MVV

Treadmill exercise test for determination of maximal heart rate and VO2max

• Aortic Pulse Wave Velocity

Augmentation Index

Echocardiographic – Doppler evaluation of left ventricular diastolic function

24 hr ECG recording for measurement of heart rate variability

CR: y = -0.20x + 51.9

R2 = 0.15

Sed: y = -0.40x + 54.2

R2 = 0.77

Trained: y = -0.46x + 77.2

R2 = 0.69

10

20

30

40

50

60

70

80

30 40 50 60 70 80Age (years)

VO

2max

(m

L/k

g/m

in)

Sedentary

Trained

0

1

2

3

4

5

6

10 30 50 70 90Age (years)

VO

2max

(L

/min

)