Dietary Restriction and Aging in Rhesus Monkeys: The University of Wisconsin Study

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Dietary Restriction and Aging in Rhesus
MonkeysThe University of Wisconsin Study
Richard Weindruch, Ph.D. University of Wisconsin
Department of Medicine, Section of Geriatrics VA
Geriatric Research, Education, and Clinical
Center rhweindr_at_wisc.edu
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Topics

• Comments on DR/CR and the Biomarker Challenge
• Studies in Primates Can DR slow aging?
• -The UW-Madison Study
• -Human DR an emerging area
• Conclusions

• .

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Acknowledgements
Tsuyoshi Kayo Roger Klopp Tom Prolla Tom
Pugh Dhanu Shanmuganayagam
Roz Anderson Jamie Barger Jenny
Christensen Ricki Colman Kazu Higami
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Active Areas of DR Study

• Mechanisms by which DR retards aging in rodents
  and model organisms
• Development of DR mimetics
• Efficacy of DR in primates

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Diseases/Disorders Opposed by CR in Rodents

• Cancers (e.g., breast, lymphoma, GI, brain,
  prostate)
• Obesity
• Diabetes
• Hypertension
• Heart Failure
• Kidney Disease
• Autoimmune Diseases (lupus, anemia, etc.)
• Muscle Wasting

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Relationship Between Caloric Intake and Maximum
Life Span in Mice
60
?
?
50
?
40
Life Span (months)
?
30
20
10
0
60
40
80
140
120
100
Caloric Intake per Week
Weindruch et al., J. Nutr. 116641-54, 1986.
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Gene Expression Profiling

• DNA
• 25,000
• total genes

mRNA
Proteins

• enzymes
• structural
• transport
• signaling, etc.

Affymetrix GeneChip? microarray allows the
analysis of gt36,000 mouse genes and ESTs
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Gene Expression Profile of Aging and CR
C-K Lee, J. Barger, T. Kayo, Y Higami, DB
Allison, T Prolla, R Weindruch et al. Mouse
gastrocnemius Science 2851390-3, 1999 Mouse
neocortex cerebellum Nature Genet. 25 294-7,
2000 Monkey (rhesus) vastus lateralis PNAS
985093-8, 2001 Mouse heart PNAS 9914988-93,
2002 Mixture model approach Comp. Stat. Data
Anal. 391-20, 2002 Mouse adipose tissue FASEB J
18415-7, 2004 J. Nutr. 136343-52, 2006
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Our Use of Gene Expression Profiling

• Determine the biological age of a tissue at the
  molecular level
• Uncover mechanisms of aging
• Discover mechanisms of aging retardation by CR
• Quantify the efficacy of a candidate CR mimetic
  at the molecular level

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Two Types of Transcriptional Effects Associated
with Caloric Restriction
1. Prevention of age-associated changes total
or partial 2. Transcriptional reprogramming
shifting the expression levels of genes which do
not show age-associated transcriptional changes
(biomarkers of CR)
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Adipose Tissue

• 15 years ago was viewed as a metabolically inert
  tissue now seen as a metabolically active tissue
• Also a source of hormones and inflammatory
  factors released into the blood
• DR in mice markedly affects gene expression
  profiles
• -Higami et al., FASEB J 2004 ?nuclear-encoded
  mitochondrial ETS transcripts
• -Higami et al., J. Nutr 2006 ?
  proinflammatory transcripts

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DR and Aging in Rhesus Monkeys The University of
Wisconsin Study
Overall Hypothesis DR will retard aging in a
primate species as reflected by attenuated rates
of change of most biological indicators of aging,
increased health span and increased longevity.

• Overall Specific Aims
• To help develop the rhesus monkey as a model for
  the study of aging.
• To determine DRs influence on the rate of aging
  in a primate species by evaluating indicators of
  biological age, health span, disease patterns
  and longevity.

Highest Priority The assessment of health span,
functionality, disease patterns and longevity.
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DR and Aging in Rhesus Monkeys University of
Wisconsin Study Design
C, n5
R, n8
All animals were 6-14 years old at onset X
indicates a death. Funding NIA - P01 AG11915
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P01 Dietary Restriction and Aging in Rhesus
Monkeys R. Weindruch, PI
CORE A Administrative Biostatistical
Support R. Weindruch, CL
PROJECT 3 Quantitative Analysis of Immunity to
Viral Immunogens
PROJECT 1 Oxidative Stress Sarcopenia
Biostatistics sub to UAB D. Allison
Project discontinued. Portions now in Core B
Longevity Disease
R. Weindruch, PL
Immunologic
Energy Metabolism
CORE B
CORE B
P. 2,4
Body Composition
Cardiovascular
INDICATORS OF BIOLOGICAL AGE OR CALORIC
RESTRICTION
P. 1,2,4, CORE B
P. 2, CORE B
Oxidative Stress
Gene Expression Patterns
P. 1, CORE B
P. 1, 2, CORE A
Neurologic
Endocrine
Clinical Health
PROJECT 4 Brain Structure Function
PROJECT 2 Energy Balance and Metabolism
P. 4, CORE B
P. 2, CORE B
CORE B
S. Johnson, PL
D. Schoeller, PL
CORE B Animal Health Sample Procurement R.
Colman, CL
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P01 Dietary Restriction and Aging in Rhesus
Monkeys R. Weindruch, PI
CORE A Administrative Biostatistical
Support R. Weindruch, CL
PROJECT 1 Oxidative Stress Sarcopenia
Biostatistics sub to UAB D. Allison
Longevity Disease
R. Weindruch, PL
Immunologic
Energy Metabolism
CORE B
CORE B
P. 2,4
Body Composition
Cardiovascular
INDICATORS OF BIOLOGICAL AGE OR CALORIC
RESTRICTION
P. 1,2,4, CORE B
P. 2, CORE B
Oxidative Stress
Gene Expression Patterns
P. 1, CORE B
P. 1, 2, CORE A
Neurologic
Endocrine
Clinical Health
PROJECT 4 Brain Structure Function
PROJECT 2 Energy Balance and Metabolism
P. 4, CORE B
P. 2, CORE B
CORE B
S. Johnson, PL
D. Schoeller, PL
CORE B Animal Health Sample Procurement R.
Colman, CL
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Longitudinal Body Weight
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Does DR in monkeys extend lifespan?
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Signs of Improved Health in Monkeys on DR

• ? fat mass (70)
• ? insulin sensitivity
• Complete protection from Type 2 diabetes
• ? rate of loss of muscle with aging (sarcopenia)
• Favorable changes in circulating lipids
  ?C-reactive protein
• ? oxidative damage in muscle
• ? lumbar spine osteoarthritis
• Emerging increase in survival

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Adipocytokines CR
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Levels of C-reactive Protein in Group 1 Monkeys
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Caloric Restriction Slows Age-Associated Muscle
Loss in Monkeys
Panel A Scale-measured body weight. Panel B
Estimated skeletal muscle mass adjusted for
current weight and weight at the start of
experiment
Colman et al., in preparation
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Caloric Restriction and Human Health

• Okinawans reportedly eat 40 fewer kcal as
  others in Japan and have the highest
  centenarians
• Higher kcal intakes are linked to an increased
  risk of developing of prostate, breast, GI and
  brain cancers as well as Alzheimers and
  Parkinsons disease
• People on CR show an improved risk factor profile
  for CV disease in (PNAS 2004) and less
  age-related decline in diastolic function (J Am
  Coll Cardiol 2006)
• In the NIAs CALERIE trial, Ravussins group
  reported (JAMA 2006) that overwt. people on CR
  for 6 mo showed decreased insulin levels and body
  temperatures compared to controls.

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Data from People on CR
Fontana et al. (2004) PNAS 101 6659-63

• 18 persons from the Caloric Restriction Optimal
  Nutrition Society
• Body fat Controls 22 CR 7

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Intima - Media Thickness of Common Carotid
Arteries

TE Meyer et al., J. Amer. Coll. Cardiol. 2006
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Summary

• Omic approaches provide a global view of the
  biological state of a tissue/organism and have
  the potential to contribute importantly to the
  biomarker challenge in multiple fields.
• Our studies in rhesus monkeys support the
  possibility that CR may be able to retard the
  aging process in primates however, definitive
  data are about a decade away.
• Emerging data from studies of people on long-term
  CR suggest an increased resistance to develop CV
  disease.