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There
are people who reach the age of 85 in a very good physical and mental
condition. There are others who have extensive cognitive difficulties
and physical disorders already by the age of 60. This is why it
is logical to think that a person’s biological age is more
indicative of their health than their chronological age. If an anti-aging
theory or program is developed, it has to be tested whether it works.
In the laboratory, using experimental animals, it is relatively
easy to determine whether a certain anti-aging regime extends the
life span. Not so with humans, because a lifelong study seems at
present far from possible – nobody wants to engage in dedicating
their life to studying something for over 50 years without any knowledge
if the results would be favorable.
This is why there is a need to identify the effects
this certain program has not only in the body’s systems, but
in the general aging process. To determine a person’s biological
age and to assess the effects of different anti-aging techniques
scientist use the so-called biomarkers of aging. It is generally
believed that seven major health areas are affected by aging: cardiovascular
health, glucose regulation, brain function, muscle and skeletal
health, endocrine function, immune system and oxidative stress.
Biomarkers of aging are physical properties in
the human body which indicate that the body is aging. It is indicators
of the normal phenomena of growing old. They are not, however, simply
things which change with age. In order to be called a biomarker,
a factor has to satisfy a number of criteria. The best markers will
be the ones which are not susceptible to influence from the outside
environment. For example, in the US cholesterol levels increase
with age, but this is due to the nature of the American diet and
is not characteristic for other parts of the world. Thus, a true
biomarker would satisfy the following criteria:
A. The marker must predict the rate of aging and be a better predictor
of life span than chronological age.
B. It must be able to be tested on a regular basis
C. It must work both for humans and other species, such as laboratory
animals
D. There is support from human clinical assessment and complementary
research studies.
E. The studies are based on a significant representative sample.
F. The result is a clear association with aging.
G. A relatively narrow standard deviation is present.
So far, around 24 factors have met the criteria
and can be considered biomarkers. They may be indicated especially
for males or for females, and figures may vary between the sexes.
Here is their list:
| 1. 17-ketosteroid/ 17-hydroxycortiosteroid ratio
(male) |
13. Handgrip strength |
| 2. Ascorbic acid |
14. Hemoglobin A1C |
| 3. Basal Metabolic Rate |
15. Lung capacity- FEV1 |
| 4. Blood pressure- pulse |
16. Lung capacity- FVC |
| 5. Blood pressure- systolic |
17. Maximum oxygen update (male) |
| 6. Body Mass Index (female) |
18. Near vision |
| 7. Caries index |
19. Noradrenaline- plasma (male) |
| 8. Creatinine clearance |
20. Peridontal index |
| 9. DHEA-S |
21. PSA total (male) |
| 10. Fibrinogen |
22. Skin elasticity |
| 11. Hair baldness (male) |
23. Testosterone free (male) |
| 12. Hair grayness |
24. Zinc- serum |
In addition,
there are also a number of other factors which may be considered
partially biomarkers of aging. The main problem with these is that
their reliability has not been confirmed through a sufficient amount
of clinical and experimental data. These include body flexibility,
blood urea nitrogen, LDL cholesterol, melatonin levels, static balance,
serotonin levels and many others. They are to a certain degree indicative
of a person’s biological age, but should not be confused with
other general health factors, which do not have a clear association
with age.
Biomarkers of aging could be divided in three
major categories. There are the ones which determine the biological
age, e.g. skin elasticity and visual accommodation. There are markers
which predict the remaining life expectancy; they include DHEA-S,
hand grip strength, etc. Finally, there are factors which determine
disease susceptibility, such as systolic blood pressure and glucose-tolerance
tests. All of the biomarker tests can be classified either as laboratory
tests (e.g. blood and urine tests) or as physical tests undertaken
in a clinic.
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J Steroid Biochem
Mol Biol. 2003 Jun;85(2-5):329-35.
INSERM U588, Institut F. Magendie, 1
rue Camille Saint-Saens, 33077 Bordeaux Cedex, France.
Intensive studies in animals established
that neuroactive steroids display neuronal actions and influence
behavioral functions. We describe here investigations on
the role of neuroactive steroids in learning and memory
processes during aging and suggest their role as biomarkers
of cognitive aging. Our work demonstrated the role of the
steroid pregnenolone (PREG) sulfate as a factor underlying
an individual's age-related cognitive decline in animals.
As new perspectives of research we argue that knowing whether
neuroactive steroids exist as endogenous neuromodulators
and modulate physiologically behavioral functions is essential.
To this end, a new approach using the sensitive, specific,
and accurate quantitative determination of neuroactive steroids
by mass spectrometry seems to have potential for examining
the role of each steroid in discrete brain areas in learning
and memory alterations, as observed during aging.
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Laboratory of Applied Physiology, Graduate
School of Human and Environmental Studies, Kyoto University.
The purposes of this study were (1)
to estimate biological age score (BAS) in Japanese healthy
women based on the 4-7 years longitudinal data for physiological,
hematological and biochemical examinations and (2) to examine
the rate of aging changes in adult women based on the estimated
BAS. The samples consisted of cross-sectional (n=981) and
longitudinal (n=110) groups. Out of 31 variables examined,
five variables (forced expiratory volume in 1.0 s, systolic
blood pressure, mean corpuscular hemoglobin, glucose, albumin/globulin
ratio) that met the following criteria: 1) significant cross-sectional
correlation with age; 2) significant longitudinal change
in the same direction as the cross-sectional correlation;
and (3) assessment of redundancy, were selected as candidate
biomarkers of aging. This variable set was then submitted
into a principal component analysis, and the first principal
component obtained from this analysis was used as an equation
for assessing one's BAS. Individual BAS showed a high longitudinal
stability of age-related changes, suggesting high predictive
validity of our newly developed aging measurement equation.
However, changes in the aging rate based on the estimated
BAS were not constant. The mean slopes of the regression
lines of BAS for the three age groups (age<45, 45</=age<65
yrs, 65</=age) were 0.095, 0.065, 0.138, respectively.
One-way analysis of variance detected a significant difference
(F=5.14, p<0.01) among the three age groups. These results
suggest that the rate of aging in adult women is relatively
slower until 65 years of age, but after 65, the rate of
aging shows a rapid increase. We concluded that the longitudinal
method used for selection of variables to compute the BAS
was useful and theoretically valid compared to those obtained
from cross-sectional data analysis.
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Gerontologic Research Department--INRCA,
Center of Biochemistry, Via Birarelli 8, I-60123, Ancona,
Italy.
An ever increasing number of people
have been engaging in aging research using various interventions
aimed to modify aging processes, and/or life span, of experimental
animals. Since this type of studies needs outcome parameters
for assessing the efficacy of such interventions, research
on biomarkers of aging (ABs) has received new stimuli. In
the present paper, the problem of the occurrence of a vicious
circle any time we study ABs and determinants of aging is
addressed. In fact, while ABs would represent the standard
reference to be used in the study of the main causes of
processes of aging, these very determinants should already
be known in order to get reliable ABs. A feasible way to
overcome this impasse is proposed, using mathematical models
of survivorship or mortality based on biological hypotheses
and accounting for inter-individual heterogeneity, a necessary
ingredient for a correct interpretation of survival results.
Specific kinetics of experimental parameters that are candidates
as ABs can be compared to the kinetics hypothesized for
general biological functions entering the model. We have
built a model of this type that can also be used to perform
a reliable overall gross estimate of the rate of aging,
R(a), in the population, a parameter useful when judging
the success of interventions aimed to act on determinants
of aging. The perspective that theory of complex systems
can be of help in the search for ABs is also discussed.
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Laboratory of Neurosciences, Gerontology
Research Center, National Institute on Aging, National Institutes
of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
If effective anti-aging interventions
are to be identified for human application, then the development
of reliable and valid biomarkers of aging are essential
for this progress. Despite the apparent demand for such
gerotechnology, biomarker research has become a controversial
pursuit. Much of the controversy has emerged from a lack
of consensus on terminology and standards for evaluating
the reliability and validity of candidate biomarkers. The
initiation of longitudinal studies of aging in long-lived
non-human primates has provided an opportunity for establishing
the reliability and validity of biomarkers of aging potentially
suitable for human studies. From the primate study initiated
in 1987 at the National Institute on Aging (NIA), the following
criteria for defining a biomarker of aging have been offered:
(1) significant cross-sectional correlation with age; (2)
significant longitudinal change in the same direction as
the cross-sectional correlation; (3) significant stability
of individual differences over time. These criteria relate
to both reliability and validity. However, the process of
validating a candidate biomarker requires a greater standard
of proof. Ideally, the rate of change in a biomarker of
aging should be predictive of lifespan. In short-lived species,
such as rodents, populations differing in lifespan can be
identified, such as different strains of rodents or groups
on different diets, such as those subjected to calorie restriction
(CR), which live markedly longer. However, in the NIA primate
study, the objective is to demonstrate that CR retards the
rate of aging and increases lifespan. In the absence of
lifespan data associated with CR in primates, validation
of biomarkers of aging must rely on other strategies of
proof. With this challenge, we have offered the following
strategy: If a candidate biomarker is a valid measure of
the rate of aging, then the rate of age-related change in
the biomarker should be proportional to differences in lifespan
among related species. Thus, for example, the rate of change
in a candidate biomarker of aging in chimpanzees should
be twice that of humans (60 vs 120 years maximum lifespan);
in rhesus monkeys three times that of humans (40 vs 120
years maximum lifespan). The realization of this strategy
will be aided by developing a primate aging database, a
project that was recently launched in cooperation with the
NIA, the National Center for Research Resources, and the
University of Wisconsin Regional Primate Research Center.
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Department of Pathology and Geriatrics
Center, University of Michigan School of Medicine, Ann Arbor
48109-0940, USA.
Seven T-cell subset values were measured
in each of 559 mice at 8 months of age, and then again in
the 494 animals that reached 18 months of age. The group
included virgin males, virgin females, and mated females,
and it was produced by using a four-way cross-breeding system
that generates genetic heterogeneity equivalent to a very
large sibship. An analysis of covariance showed that four
T-cell subsets-CD4, CD4 memory, CD4 naive, and CD4 cells
expressing P:-glycoprotein-were significant predictors (p
<.003) of longevity when measured at 18 months of age
after adjustment for the possible effects of gender and
mating. The subset marked by CD4 and P:-glycoprotein expression
showed a significant interaction effect: this subset predicted
longevity only in males. Among subsets measured when the
mice were 8 months of age, only the levels of CD8 memory
cells predicted longevity (p =.016); the prognostic value
of this subset was largely limited to mated females. A cluster
analysis that separated mice into two groups based upon
similarity of T-cell subset patterns measured at 18 months
showed that these two groups differed in life expectancy.
Specifically, mice characterized by relatively low levels
of CD4 and CD8 memory cells, high levels of CD4 naive cells,
and low levels of CD4 cells with P:-glycoprotein (64% of
the total) lived significantly longer (50 days = 6%; p <.0007)
than mice in the other cluster. The results are consistent
with the hypothesis that patterns of T-cell subsets vary
among mice in a manner than can predict longevity in middle
age, and they suggest that these subsets may prove to be
useful for further studies of the genetics of aging and
age-sensitive traits.
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Department of Psychology, Johns Hopkins
University, Baltimore, MD 21218, USA.
The goal of the current project is
to develop a multivariate statistical strategy for the formation
of behavioral indices of performance and, further, to apply
this strategy to establish the relationship between age
and important characteristics of performance. The strategy
was to begin with a large set of measures that span a broad
range of behaviors. The behavioral effects of the following
variables were examined: Age (4, 12, 24, and 30 months),
genotype [Fischer 344 and a hybrid (F1) of Fischer 344 and
Brown Norway (F344xBN)], gender (Fischer 344 males and Fischer
344 females), long-term diet (ad lib diet or dietary restriction
beginning at 4 months of age), and short-term diet (ad lib
diet or dietary restriction during testing). The behavioral
measures were grouped into conceptually related indicators.
The indicators within a set were submitted to a principal
component analysis to help identify the summary indices
of performance, which were formed with the assumption that
these component scores would offer more reliable and valid
measures of relevant aspects of behavioral performance than
would individual measures taken alone. In summary, this
approach has made a number of important contributions. It
has provided sensitive and selective measures of performance
that indicated contributions of all variables: psychological
process, age, genotype, gender, long-term and short-term
diet and has increased the sensitivity of behavioral measures
to age-related behavioral impairment. It has also improved
task-manageability by decreasing the number of meaningful
variables without losing important information, consequently
providing a simplification of the pattern of changes.
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Division of Biometry and Risk Assessment,
National Center for Toxicological Research, Food and Drug
Administration, Jefferson, Arkansas 72079-9502, USA.
The collaborative Interagency Agreement
between the National Center for Toxicological Research (NCTR)
and the National Institute on Aging (NIA) was aimed at identifying
and validating a panel of biomarkers of aging in rodents
in order to rapidly test the efficacy and safety of interventions
designed to slow aging. Another aim was to provide a basis
for developing biomarkers of aging in humans, using the
assumption that biomarkers that were useful across different
genotypes and species were sensitive to fundamental processes
that would extrapolate to humans. Caloric restriction (CR),
the only intervention that consistently extends both mean
and maximal life span in a variety of species, was used
to provide a model with extended life span. C57BI/6NNia,
DBA/2JNia, B6D2F1, and B6C3F1 mice and Brown Norway (BN/RijNia),
Fischer (F344/NNia) and Fischer x Brown Norway hybrid (F344
x BN F1) rats were bred and maintained on study. NCTR generated
data from over 60,000 individually housed animals of the
seven different genotypes and both sexes, approximately
half ad libitum (AL) fed, the remainder CR. Approximately
half the animals were shipped to offsite NIA investigators
internationally, with the majority of the remainder maintained
at NCTR until they died. The collaboration supplied a choice
of healthy, long-lived rodent models to investigators, while
allowing for the development of some of the most definitive
information on life span, food consumption, and growth characteristics
in these genotypes under diverse feeding paradigms.
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Jean Mayer USDA Human Nutrition Research
Center on Aging at Tufts University, Boston, Massachusetts
02111, USA.
This study of B6C3F1 hybrid mice
was designed to determine the effects of caloric restriction
(CR) on age-related pathologic changes. These changes accompany
and may, in part, account for the apparent effect of CR
in slowing the rate of aging. The study also explored whether
lesions observed in groups of animals killed at 6 month
intervals can serve as biomarkers of aging. Approximately
30 mice of each sex and each of two diet groups--CR and
ad libitum fed (AL)--and each of six age groups--6, 12,
18, 24, 30, and 36 months of age--from the Biomarkers of
Aging Program of the National Institute on Aging were killed
and all tissues from each were examined for the histological
presence or absence of lesions. A total of 209 distinct
lesions were observed, of which 51 occurred in at least
10% of the AL or CR mice. The average number of lesions
per mouse increased linearly with age in all diet-sex groups
except in male CR mice. This increase was significantly
smaller in CR than in AL mice of both sexes. The number
of distinct lesions also increased with age in both diet
groups but much less rapidly in CR mice. Nearly all lesions,
including neoplastic, and nonneoplastic proliferative and
degenerative ones, occurred significantly less often in
CR than in AL mice at all ages. Foci of leukocytes in the
liver, however, occurred more frequently in CR mice. Lung
adenomas in old female mice occurred with equal frequency
in both diet groups. A parsimonious classification tree
analysis showed that diet groups could have been distinguished
at each age by an evaluation of relatively few lesions and
tissues. Altogether, this study suggests strongly that the
prevalence of many individual lesions, the total lesion
burden, and the total types of lesions are good biomarkers
of aging because they increase with age and reflect the
effect of CR in slowing the aging process. The study also
shows that lesions occur stochastically, randomly, and independently
in genetically homogeneous mice raised in a nonvariable
environment.
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Department of Chemistry and Biochemistry,
University of South Carolina, Columbia 29208, USA.
Oxidative stress is apparent in pathology
associated with aging and many age-related, chronic diseases,
including atherosclerosis, diabetes mellitus, rheumatoid
arthritis, and neurodegenerative diseases. Although it cannot
be measured directly in biological systems, several biomarkers
have been identified that provide a measure of oxidative
damage to biomolecules. These include amino acid oxidation
products (methionine sulfoxide, ortho-tyrosine (o-tyr) and
dityrosine, chlorotyrosine and nitrotyrosine), as well as
chemical modifications of protein following carbohydrate
or lipid oxidation, such as N epsilon-(carboxymethyl)lysine
and N epsilon-(carboxyethyl)lysine, and malondialdehyde
and 4-hydroxynonenal adducts to amino acids. Other biomarkers
include the amino acid cross-link pentosidine, the imidazolone
adducts formed by reaction of 3-deoxyglucosone or methylglyoxal
with arginine, and the imidazolium cross-links formed by
the reaction of glyoxal and methylglyoxal with lysine residues
in protein. These compounds have been measured in short-lived
intracellular proteins, plasma proteins, long-lived extracellular
proteins, and in urine, making them valuable tools for monitoring
tissue-specific and systemic chemical and oxidative damage
to proteins in biological systems. They are normally measured
by sensitive high-performance liquid chromatography or gas
chromatography-mass spectrometry methods, requiring both
complex analytical instrumentation and derivatization procedures.
However, sensitive immunohistochemical and ELISA assays
are now available for many of these biomarkers. Immunochemical
assays should facilitate studies on the role of oxidative
stress in aging and chronic disease and simplify the evaluation
of therapeutic approaches for limiting oxidative damage
in tissues and treating pathologies associated with aging
and disease. In this article we summarize recent data and
conclusions based on immunohistochemical and ELISA assays,
emphasizing the strengths and limitations of the techniques.
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Division of Natural Environmental Sciences,
Faculty of Integrated Human Studies, Kyoto University, Japan.
We examined a dataset derived from
a battery of hematology and blood chemistry tests to identify
candidate biomarkers of aging in a sample of 33 male rhesus
monkeys (Macaca mulatta) ranging in age from 4-27 years.
About half this sample comprised an experimental group subjected
to 30% calorie restriction for six to seven years compared
to the control group fed the same nutritionally fortified
diet to approximate ad lib levels. Variables that met the
following criteria were selected: (1) longitudinal change
within the cohorts of control monkeys; (2) cross-sectional
correlation with age across the adult lifespan in the control
group; (3) stability of individual differences within all
groups; and (4) no obvious redundancy with other selected
variables. Five variables emerged from this step-wise selection,
including the percentage lymphocytes, and serum levels of
alkaline phosphatase, albumin, creatinine, and calcium.
These variables were then submitted to a principal component
analysis, which yielded a single component accounting for
about 58% of the total variance. Based on this marked degree
of covariance, these candidate biomarkers of aging could
be combined into a biological age score (BAS) for the control
and experimental groups. When chronological age was regressed
onto BAS, the slopes of the control and experimental groups
could be compared. Although a trend toward a slower aging
rate in calorie-restricted monkeys was apparent, this analysis
did not detect a statistically significant difference in
the rate of aging between these groups estimated by this
index. Despite this result, a logical strategy was confirmed
for expanding the search for candidate biomarkers of aging
to apply to this and to other studies assessing interventions
that purport to affect the rate of aging in long-lived species.
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Center for Developmental and Health Genetics,
Pennsylvania State University, University Park 16802, USA.
The escalating interest in research
on interventions that may affect aging processes has necessarily
focussed attention on the outcome measures. The desirable
characteristics of these "biomarker variables"
have been widely discussed. This article offers some reflections
on validity, reliability, and generalizability of biomarkers.
It is argued that our comprehension of aging will evolve
iteratively from application of a diversity of biomarker
variables. Each of these will have strengths and shortcomings
from methodological and measurement points of view. The
siren song that a "gold standard" index of aging
can be found should be ignored.
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Department of Pathology, University of
Michigan School of Medicine, Ann Arbor, USA.
A longitudinal experiment was designed
to test the hypothesis that individual mice differ in their
aging rate and to validate candidate biomarkers proposed
to measure the rate of aging. Mice were bred as the genetically
heterogeneous progeny of a cross between CB6F1 mothers and
C3D2F1 fathers. Half of the mice were fed ad libitum (AL
group), and the other half were subjected to 60% calorie
restriction (CR group). Each mouse was tested at about 9
months of age using age-sensitive tests of immune status,
and then again at about 12 months of age using age-sensitive
tests of muscle function. The data were then analyzed using
the method of partial least squares to determine the combinations
of test weights that maximize the covariance of the weighted
sum of immune measures with the weighted sum of muscle function
measures. Both AL and CR mice exhibited a statistically
significant relation between the immune status tests and
the muscle function tests. Maximal covariance was obtained
with a set of weighting coefficients consistent with our
working hypothesis: mice with high levels of CD4 memory
T cells (which increase with age) also had relatively low
levels of muscle strength and endurance. Low strength was
associated with low CD8 cells in the AL mice, with high
numbers of CD8 memory cells in the CR mice and with low
CD3 cells in both diet groups. The partial least squares
method generates composite indices of immune status and
muscle function that can be evaluated as biomarkers of aging
rate in these mice. Further work will be needed to assess
whether these tests predict either longevity or the trajectory
of change in other age-sensitive molecular and physiological
traits.
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Institut National de la Sante et de la
Recherche Medicale U 224, Centre National de la Recherche
Scientifique, Faculte Xavier Bichat, Paris, France.
This study was designed to characterize
the rat serum proteins as biomarkers of the normal aging
process. Crossed immunoelectrophoresis or electroimmunodiffusion
quantitation of proteins was performed in rats aged 6, 12,
24, and 30 mo. Selection of healthy animals was based on
confrontation of crossed immunoelectrophoresis patterns
with those of experimentally inflamed young adults and with
individual anatomopathological data. Convergence of inflammatory
patterns and severe histological lesions was the exclusion
criterion. Senescence-induced decrease was demonstrated
for eight proteins [negative senescence reactants (SRs-)]
and increase for six proteins [positive SRs (SRs+)]. Most
SRs belonged to the class of proteins responsive to acute
inflammation [acute phase reactants (APRs)]. One SR+, the
thyroxine-binding globulin, a high-affinity thyroid hormone
binder, emerged as a particularly reliable senescence biomarker,
showing the highest aging-related variation (8-fold increase
from 6 to 30 mo) and not belonging to the APR class. Chronic
treatment with perindopril, an angiotensin I-converting
enzyme inhibitor used in heart and renal disease therapy,
significantly enhanced thyroxine-binding capacity, possibly
by preventing age-related alterations of serum lipids. Serum
protein patterns prove valuable both as indexes for selecting
aging animals free from superimposed pathologies and as
parameters of senescence-induced changes in protein biosynthesis.
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Department of Pharmacology, Baylor College
of Medicine, Houston, TX 77030.
I-compounds are species-, tissue-,
genotype-, gender-, and diet-dependent bulky DNA modifications
whose levels increase with animal age. While a few of these
DNA modifications represent oxidation products, the majority
of I-compounds appear to be derived from as yet unidentified
endogenous DNA-reactive intermediates other than reactive
oxygen species. Circadian rhythms of certain I-compounds
in rodent liver imply that levels of these DNA modifications
are precisely regulated. Caloric restriction (CR), the currently
most effective method available to retard aging and carcinogenesis,
has been previously shown to elicit significant elevations
of I-compound levels in tissue DNA from Brown-Norway (BN)
and F-344 rats as compared to age-matched ad libitum fed
(AL) animals. The present investigation has extended this
work by examining liver and kidney DNA I-compound levels
in three genotypes of rats (F-344, BN, and F-344 x BN) and
two genotypes of mice (C57BL/6N and B6D2F1) under identical
experimental conditions in order to determine whether correlations
exist between I-compound levels, measured in middle-aged
animals, and median lifespan. Levels of a number of liver
and kidney I-compounds were found to display genotype- and
diet-dependent, statistically significant positive linear
correlations with median lifespan in both species. In particular,
the longer-lived hybrid F-344 x BN rats and B6D2F1 mice
tended to exhibit higher I-compound levels than the parent
strains. CR enhanced I-compound levels substantially in
both rats and mice. Thus, I-compounds, measured at middle
age, reflected the functional capability ('health') of the
organism at old age, suggesting their predictive value as
biomarkers of aging. The positive linear correlations between
levels of certain I-compounds (designated as type I) and
lifespan suggest that these modifications may be functionally
important and thus not represent endogenous DNA lesions
(type II), whose levels would be expected to correlate inversely
with lifespan.
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Center for Developmental and Health Genetics,
College of Health and Human Development, Pennsylvania State
University, University Park 16802-6501.
Different types of stability of a
biomarker are important properties, influencing the degree
of predictability across age (ordinal stability) and the
interpretation of quantitative and qualitative change with
age (structural stability). These properties may be expected
to differ from biomarker to biomarker and may change with
age. Any age-related process with individual differences
in time of onset of change or in rate of change will necessarily
display reduced ordinal stability. Another source of reduced
correlation across occasions is the short-term fluctuance
of individuals due to cyclic processes and to responsiveness
to environmental displacements of biomarker values and recovery
therefrom. Structural stability of composite variates may
be quite high across relatively short intervals but sufficiently
low across longer intervals as to suggest the inappropriateness
of simple description of mean changes or differences across
these longer time spans. The outcome with multivariate composites
raises the issue that single biomarkers may have quite different
meanings at different parts of the life span.
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Department of Internal Medicine, St.
Louis University School of Medicine.
The rate of aging is not uniform
among all individuals. Thus, determination of the biological
age of an individual and possibly the biological age of
his or her organ systems poses a special challenge to the
gerontologist. This could be accomplished if specific biomarkers
of aging were available, which would allow standardization
of studies, help us understand the various determinants
of aging, monitor the impact of various interventions on
the rate of aging, and possible allow estimates of life
expectancy and predictions of future morbidity. Specific
criteria need to be developed for accepting a parameter
as a biomarker of aging, since an age-related alteration
in a biological parameter does not necessarily qualify.
Potential biomarkers of human aging include in vitro proliferative
capacity of fibroblasts, glycation of collagen, and DNA
unwinding rate.
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Department of Pharmacology, Texas College
of Osteopathic Medicine, Fort Worth 76107.
Because of the importance of central
nervous system (CNS) functions to productive capacity and
quality of life, biomarkers of these functions will play
a key role in evaluating the success of interventions targeting
aging processes. The CNS biomarkers may also be useful for
predicting aging in other systems and in the organism as
a whole. Age-related behavioral changes, the products of
CNS aging, have content and predictive validity with respect
to human functional capacities and may, therefore, represent
important "neurobehavioral" markers of functional
aging. This article presents a discussion of some behavioral
paradigms which are currently being considered as neurobehavioral
biomarkers of aging in mice and the experimental approaches
being employed in the assessment of their validity. Studies
conducted in the authors' laboratory using dietary restriction
and genetic comparisons to evaluate the validity of neurobehavioral
biomarkers have revealed several methodological concerns,
and hypothetical and empirical examples of these pitfalls
are described and discussed. In spite of those concerns,
it is concluded that approaches to validity using genetic
comparisons and dietary restriction can be successfully
implemented and should ultimately lead to identification
of valid and useful neurobehavioral biomarkers of aging.
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Division of Restorative Medicine, University
of Arizona College of Medicine.
The identification of specific biomarkers
of aging would be an important milestone in gerontologic
research. In this communication, the goals of identifying
biomarkers of aging are summarized and some criteria for
defining biomarkers are suggested. An age-related alteration
in a biological parameter is not necessarily a biomarker
of aging. None of the previously observed age-related changes
satisfies all the criteria. Potential biomarkers that are
applicable to human aging include in vitro proliferative
capacity of fibroblasts, glycation of collagen, and DNA
unwinding rate. Future research should focus on identifying
age-related changes that are not merely expressions of aging,
but also have some causal link to aging.
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Jackson Laboratory, Bar Harbor, Maine
04609.
Objective tests that allow early
detection of deleterious changes with age are necessary
to develop treatments enhancing the health span--the length
of healthy life. Here we report tests of eight biological
systems that can be performed in mice with no harm to the
subjects. Male and female B6, CBA and F1 mice were used.
While most test results correlated with chronological age
in most genotypes, none predicted subsequent longevities
in more than two genotypes. Surprisingly, the open field
activity test that most consistently predicted longevities,
did not correlate with chronological age. Six tests predicted
beneficial effects of food restriction in F1 males, but
only one correctly predicted the deleterious effects of
the same food restriction regimen in B6 males. These results
suggest that different biological systems age at different
rates, that rates are affected by genotype and that an anti-aging
treatment beneficial in one genotype may be harmful in another.
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Wistar Institute, Philadelphia,
Pennsylvania 19104.
Normal human fibroblast-like cells
show a declining proliferative capacity with age. Eventually
the cultures become senescent and incapable of replicating.
Loss of proliferative capacity is characterized by a declining
fraction of cells which synthesize DNA in a defined time
period, a gradually increasing cell cycle time, and a declining
saturation density. For 36 sublines of WI-38 cells and 17
sublines of IMR-90 cells, we have characterized the fraction
of cells synthesizing DNA and the saturation density throughout
their life spans. These parameters were both related in
a regular and consistent way with the percent life span
completed and determined retrospectively by cell counts
at each subcultivation until phase-out. Thus, these two
determinations serve as independent biomarkers for cell
culture aging as they relate to one functional parameter--proliferative
capacity. As such, they can be used to assess functional
age independently of chronological age.
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Molecular Physiology and Genetics
Section, National Institute on Aging, Baltimore, Maryland
21224.
A series of questions is presented
regarding a logical strategy for developing biomarkers of
aging. The questions pertain to the conceptualization process
in determining how to define aging and what extraneous and
possibly confounding variables must be controlled in measuring
this epiphenomenon. In addition, the investigator must consider
the degree of generalization that is intended to apply to
a candidate biomarker of aging. Empirical questions are
also to be considered. Specifically, how will reliability
and validity of the candidate biomarker be quantified and
assessed? What statistical methods will be applied in this
process? The need for biomarkers of aging as research tools
in gerontology is argued, but the greater need for agreement
on how to direct the conceptualization of this effort is
also emphasized.
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