DESIDERATA OF BIOMARKERS

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BIOMARKERS PROGRAMDESIGN CHARACTERISTICS

• Most studies were cross-sectional
• About 60 of the studies utilized rats
• Most studies utilized a single genotype
• (88 in rats 70 in mice)
• Most information was generated for C57BL/6 mice
  and F344 rats

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BIOMARKERS PROGRAMDESIGN CHARACTERISTICS

• More than ¾ of the studies in both species
  employed a single sex (70 of mouse studies used
  males 80 of rat studies used males)
• Age ranges emphasized period prior to median
  survival age of ad lib animals of the most
  investigated genotypes

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FEMALE AD LIB
MALE AD LIB
FEMALE CR
MALE CR
MEDIAN LIFESPANS (WEEKS) OF RAT GROUPS
MEDIAN LIFESPANS (WEEKS) OF MOUSE GROUPS
C57BL/6
DBA/2
B6D2F1
B6C3F1
5
10
15
25
20
30
35
45 50
0
AGE (MONTHS)
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Approximate ages evaluated in studies on rats.
5
10
15
25
20
30
35
45
0
AGE (MONTHS)
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Approximate ages evaluated in studies on mice
AGE (MONTHS)
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BIOMARKERS PUBLICATIONSSOME KEY WORDS

• Dystrophic neurons Pathologic lesions
  Sensorimotor coordination Avoidance learning
  Oxidative damage Cognitive functioning
  Learning Memory I compounds Lymphocyte
  proliferation Spermatozoa production
  Epithelial cell proliferation Reactive oxygen
  radicals Weight gain Amyloidosis CD4
  T cells Bone marrow stromal cells Tail
  tendon break time Glaucoma DNA polymerase
  Excision repair Ecotropic retroviruses
  Cellular replication Growth hormone receptor
  Wound repair Nonenzymatic glycation of
  collagen Retinal aging Ribonuclease
  formation T-kininogen
• Norepinephrine uptake/release
  Somatostatin mRNA Phosphoinositide metabolism
  Plasma glucose Hippocampal fiber sprouting
  Fundus contraction Serotonin release
  Microalbuminuria

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BIOMARKERS PROGRAMSYNOPSIS OF RESULTS

• Most biomarkers displayed differences across the
  age groups
• Most biomarker domains showed effects of caloric
  restriction
• Many specificities were found in respect to
  sensitivity to caloric restriction
• -some markers are sensitive to CR at some ages
  but not others
• -some markers show sensitivity in some strains
  but not in others
• -some markers show sensitivity only in one sex

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BIOMARKERS PROGRAMSOME GENERAL CONCLUSIONS

• The finding of widespread influence of caloric
  restriction on biological variables suggests that
  CR is operating at a fundamental level
• This widespread influence makes differential
  selection of biomarkers to constitute a standard
  panel difficult

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A DEPLETION MODEL
A COMPARTMENT MODEL
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A HIERARCHICAL MULTI-COMPARTMENT MODEL OF AGING
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BIOMARKERS PROGRAMSOME GENERAL CONCLUSIONS (cont)

• Results from the Biomarker Program extend the
  data base to inform new research to identify
  minimally overlapping markers to sample broadly
  the complex systems of aging
• Until such research results are available, panel
  construction can be based on practical and
  logistical considerations, and should sample
  biological processes broadly
• Animal subjects employed in assessment procedures
  should include a variety of genotypes and both
  sexes

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GENERATION OF ANIMAL MODELS FOR BIOGERONTOLOGY BY
GENETIC PROCEDURES
INBREEDING HETEROGENEOUS STOCKS MOLECULAR
CONSTRUCTS SELECTIVE BREEDING PHENOTYPIC GENOTY
PIC (MARKER BASED)
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GENERATION OF ANIMAL MODELS FOR BIOGERONTOLOGY BY
GENETIC PROCEDURES
GENERATION OF CONTRASTING INTEGRATED SYSTEMS
PHENOTYPIC SELECTIVE BREEDING
IGF-1
OXIDATIVE DAMAGE
METABOLIC RATE
OBESITY
POLY-QTL GENOTYPIC SELECTIVE BREEDING
QTLs FOR LONGEVITY
QTLs FOR OXIDATIVE DAMAGE
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SELECTIVE BREEDING HYPNOTIC DOSE SENSITIVITY
10000
8000
6000
SLEEP TIME (SECONDS)
4000
2000
0
0
2
4
6
8
10
14
16
18
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GENERATION
McClearn Kakihana, 1981
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GENERATION OF ANIMAL MODELS FOR BIOGERONTOLOGY BY
GENETIC PROCEDURES
ISOLATION OF SUBSYSTEMS OF COMPLEX SYSTEMS
MONO-QTL SELECTION
CONFIRMATION OF QTL NOMINATIONS
CHARACTERIZATION OF MECHANISM OF SINGLE LOCUS
ANTAGONISTIC SELECTION
HIGH LOW IGF-1 EQUAL BODY WEIGHTS
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Comparison of genotypically selected lines for
chromosome 2 QTLTarantino, 1998
Alcohol Preference Ratio
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GENERATION OF ANIMAL MODELS FOR BIOGERONTOLOGY BY
GENETIC PROCEDURES
AMPLIFICATION OF COMPENSATORY PATHWAYS
SELECT TO MINIMIZE OR ELIMINATE SYMPTOMS OF
SINGLE LOCUS ob-ob Prop1df db/db
dw/dw SELECT TO MINIMIZE OR
ELIMINATE RESPONSE TO RISK FACTOR
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Genetic Background and Expression of Diabetes
Mutant
.
80
70
60
MALE Db/-
50
MALE db/db
Body Weight (gms.)
40
FEMALE Db/-
30
FEMALE db/db
20
10
0
C57BL/KsJ
Strain
Leiter, Coleman, Hummel 1981. Diabetes,
121029-1034
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Genetic Background and Expression of Diabetes
Mutant
80
70
60
MALE Db/-
50
MALE db/db
Body Weight (gms.)
40
FEMALE Db/-
30
FEMALE db/db
20
10
0
129/J
C57BL/KsJ
Strain
Leiter, Coleman, Hummel 1981. Diabetes,
121029-1034.
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Genetic Background and Expression of Diabetes
Mutant
80
70
60
MALE Db/-
50
MALE db/db
Body Weight (gms.)
40
FEMALE Db/-
30
FEMALE db/db
20
10
0
C57BL/KsJ
CBA/Lt
Strain
Leiter, Coleman, Hummel 1981. Diabetes,
121029-1034.
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GENERATION OF ANIMAL MODELS FOR BIOGERONTOLOGY BY
GENETIC PROCEDURES
SERIATIM ASSEMBLY OF COMPLEX SYSTEMS
TANDEM SELECTION OF LINES HOMOZYGOUS FOR
INCREASING OR FOR DECREASING LONGEVITY QTLs
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GENERATION OF ANIMAL MODELS FOR BIOGERONTOLOGY BY
GENETIC PROCEDURES
GENERATION OF SYSTEMS WITH CONTRASTING
SENSITIVITY TO ENVIRONMENTAL INFLUENCES
PHENOTYPIC SELECTION FOR HIGH AND LOW RESPONSE
TO CALORIC RESTRICTION
PHENOTYPIC SELECTION FOR HIGH AND LOW RESPONSE
TO EXERCISE REGIMEN
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GENERATION OF ANIMAL MODELS FOR BIOGERONTOLOGY BY
GENETIC PROCEDURES
MANIPULATION OF POLYGENIC CONTROL OF GENE
EXPRESSION
PARTICULAR RNA OR PROTEIN PRODUCTION
CHIP EXPRESSION PATTERN