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[A1CR]

The paper below and Perspective report appears to describe
how the various models of increased and decreased aging
genetic systems may assist us in understanding the basic
process. CR may be part of the effect for genes that have
shorter or longer lifespan effects, it seems.
In passing, http://en.wikipedia.org/wiki/Centenarians have
been an interest.
It appear counter-intuitive that
http://en.wikipedia.org/wiki/List_of_countries_by_centenarian_populations

reports that Japan has a lower percentage of its population
as centenarians,
compared with the US, UK and France.

Siegfried Hekimi
Perspective
How genetic analysis tests theories of animal aging
Nature Genetics - 38, 985 - 991 (2006)

Each animal species displays a specific life span, rate of
aging and pattern
of development of age-dependent diseases. The genetic bases
of these related
features are being studied experimentally in invertebrate
and vertebrate
model systems as well as in humans through medical records.
Three types of
mutants are being analyzed: (i) short-lived mutants that are
prone to
age-dependent diseases and might be models of accelerated
aging; (ii)
mutants that show overt molecular defects but that do not
live shorter lives
than controls, and can be used to test specific theories
about the molecular
causes of aging and age-dependent diseases; and (iii)
long-lived mutants
that might advance the understanding of the molecular
physiology of
slow-aging animals and aid the discovery of molecular
targets that could be
used to manipulate rates of aging to benefit human health.
Here, I analyze
some of what we know today and discuss what we should try to
find out in the
future to understand the aging phenomenon.

... Figure 1. Examples of life span studies in C. elegans
and mice. (a)
Increased life span of mice under calorie restriction. Mild
calorie
restriction has a smaller effect than more extreme
restriction (data from
ref. 12). (b) Increased life span of worms under calorie
restriction owing
to mutations in the eat-2 gene that slow food intake (data
from ref. 47).
... (e) Life span increase of Igf1r+/- heterozygotes. Igf1r
encodes a
receptor for IGF-1, is similar to DAF-2 and functions in a
similar signaling
pathway (data from ref. 7). ... (g) Absence of life span
shortening of
Sod2+/- mice compared with controls. Sod2+/- mutants have
increased
oxidative stress, yet their life span is not affected, which
is inconsistent
with the oxidative stress theory of aging (data from ref.
42). (h) Absence
of life span shortening of mTR-/- mice after two to three
homozygous mutant
generations. mTR-/- mice lack functional telomerase and have
short and
shortening telomeres. These data suggest that telomere
shortening is not a
universal mechanism that limits animal life spans (data from
ref. 48).

http://en.wikipedia.org/wiki/Maximum_life_span
http://en.wikipedia.org/wiki/Aging Cellular
http://en.wikipedia.org/wiki/Senescence

http://en.wikipedia.org/wiki/Disease . Disease is any
defined physiological
dysfunction of an organism that causes a transient or
permanent increase in
the probability of dying. A disease does not have to
manifest itself in all
circumstances. For example, the deficient thermoregulation
that is observed
in the elderly22 should be considered a disease, even if it
is true that it
decreases the probability of survival only under particular
circumstances
(excessive environmental heat or cold). This is also why one
should view as
diseases some of the manifestations of aging that are not
generally
considered pathological. For example, skin wrinkling does
not immediately
seem to be very dangerous, yet diminished capacity for wound
healing, which
involves the skin's mechanical properties, impairs the
survival of the
elderly23, and in a harsher environment this might become a
problem at a
much younger age.

Age dependency. A phenotype or disease tends to be called
age dependent when
the earliest age of onset is well past the beginning of
adulthood or when
its incidence increases exponentially with chronological
age. Many
age-dependent diseases tend to be degenerative diseases that
cannot be cured
spontaneously once initiated but instead tend to worsen with
time.

Attempting reasonable questions without suggesting answers
Is what we call 'aging' a mechanism or concept? One can
describe at least
two views of the meaning of the term 'the aging process'24,
25, 26, 27 (Fig.
2). In one view, aging is a biochemical mechanism that does
not induce
disease in itself, but whose progression is an
ever-increasing risk factor
for both the onset and the severity of age-dependent
diseases and leads to a
lesser ability to resist, survive and recover from
physiological
disturbances. In the other view, the aging process is but the
conceptualization of the collection of all age-dependent
diseases. In a
given species, such as humans, age-dependent diseases,
whether immediately
life-threatening or less severe at first, arise in a pattern
that is
relatively stereotyped within a population and is easily
recognized as the
consequence of increasing age, both by visible signs
(graying, wrinkles,
increased body fat, changes in posture) and by patterns of
disease
prevalence (such as atherosclerosis, cancer and, later in life,
neurodegenerative diseases). Interestingly, the view that
the molecular
mechanism that underlies aging is the accumulation of
unrepaired damage28
seems to be consistent with both views of aging. Indeed, in
the first view,
the effect of the accumulated damage is diffuse: it creates
a decrease in
the strength of homeostasis that leads to an increase in the
risk of
developing disease, but it does not initiate disease. In the
other view, the
damage directly produces disease, with different types of
damage producing
different diseases.

... Three types of aging mutants, three types of information
... At the
other extreme, only a mutant that produces a phenotype that
fully
recapitulates aging over a short life span would be
considered a true aging
gene. However, no mutant whose phenotype fully looks like
aging has yet been
identified. ... individuals with Werner syndrome, who
recapitulate several
features of aging and are short-lived, are also of short
stature32. Yet in
mice, dogs and humans, small size is linked to long, not
short, life span33,
34, 35, 36. Another problem is that we do not yet know
whether the molecular
mechanisms that induce pathologies in these mutants are the
same as those
that act during aging ... a manipulation that increases the
rate of aging is
expected to be accompanied by increased oxidative damage
accumulation. ... I
propose the term 'even-lived' for mutants that display a
well-characterized
molecular, physiological or anatomical phenotype that does
not affect life
span. The information provided by even-lived mutants might
be unjustifiably
undervalued. Although a lack of effect on aging could be due
to the mutant
having too little of an effect, it is also possible that
these mutants can
uncover processes that are not causal to aging. Here are two
examples ...
Rudolph et al. definitively demonstrated that progressive
telomere
shortening could not be the cause of aging in mice48 (Fig.
1h). Indeed, the
telomeres in these animals become shorter at each
generation49, yet it took
over three generations and considerable telomere shortening
before any
effect on life span and health became evident. In humans,
telomeres are
shorter than in mice, and there is considerable evidence
that telomere
shortening participates in the pathologies that arise in old
individuals50.
These observations indicate that telomeres might be an
important target of
the cause or causes of aging but not itself a cause.
...Another striking
recent example ... mice with mutations in Sod2, the gene
that encodes the
mitochondrial matrix Mn2+ superoxide dismutase51. Homozygous
Sod2-/-
knockout mice die within a few weeks, but heterozygous
Sod2+/- mice live as
long as wild-type controls42 (Fig. 1g) in spite of the fact
that their
superoxide dismutase activity is decreased in the one place
in which one
would expect decreased oxidative defenses to impinge on
aging: the
mitochondria. In fact, these heterozygous animals display
moderately
increased oxidative stress throughout their life span42, 52. ...

... Figure 3. The relationship between life span and
age-dependent diseases.
(a) Schematic illustration ... If one could prevent all
age-dependent
diseases that have an early time of onset, life expectancy
would increase
substantially and would be limited only by late-onset
diseases like
Alzheimer disease. If one could prevent all the currently
known late-onset
diseases as well, it is likely that life span would become
limited by some
very late-onset diseases that have not yet been observed
because of the
limits on maximum life span resulting from the early-onset
diseases. (b)
Results from a study79 exemplifying that a very long life
span, as seen in
human centenarians, is accompanied by a dramatic delay in
the onset of the
set of age-dependent diseases responsible for the deaths of
most individuals
with average life spans (diseases considered were
hypertension, heart
disease, diabetes, stroke, non-skin cancer, skin cancer,
osteoporosis,
thyroid condition, Parkinson disease and chronic obstructive
pulmonary
disease). 'Escapers' never developed any of the diseases,
'delayers'
developed the diseases close to the end of their lives and
'survivors'
developed some of the diseases but survived nonetheless to
become
centenarians.

... discovery of the identity of DAF-2 as an insulin
receptor-like molecule
has prompted investigation of similar pathways in other
organisms57, 62, 63,
64 and has demonstrated their conserved importance for
aging, as Igf1r+/-
heterozygous female mice are long-lived7 (Fig. 1e). ...
Sir2-like proteins,
which affect gene expression, are being studied in organisms
such as
yeast69, 70, worms71, flies72 and mammals73, 74, 75. A
demonstration of
their promise in increasing mammalian life span is eagerly
awaited.

One question that has tried gerontologists is whether the
long life of
centenarians is based on genetic differences with
non-centenarians, which
would make them a type of long-lived mutant, or whether the
environment is
responsible for their longevity. Twin studies have shown
that there is some,
but not very high, heritability to life spans centered
around the general
population's average76. It indicates, unsurprisingly, that
our genotype
makes a least some difference to our health. In contrast,
studies on
centenarians have suggested that there is a very high
heritability of the
ability to live much longer than most of the population9,
11, 77. This
suggests that centenarians are not just lucky beneficiaries
of being at the
extreme of a continuum of small additive genetic and
environmental effects
but rather that they carry advantageous alleles in one or a
few genes that
have a global effect on life span. ...

Analysis of the health histories of centenarians has shown
that these
individuals tend not to develop, or develop only very late
in life, all of
the usual life-threatening degenerative diseases79 (Fig.
3b). This
observation suggests that the classic set of diseases to
which most people
succumb (for example, atherosclerosis, diabetes, stroke,
cancer and
neurodegenerative diseases) might have in common something
from which a
simple change in genetic make-up can protect surprisingly well.
Retrospectively, this great insight seems almost
tautological. Indeed, how
could one live a very long time if burdened with
life-threatening diseases?
However, the fact that many centenarians do not seem to
develop these
diseases but nonetheless develop many other signs of aging
and ultimately
die implies that when humans, or other organisms, are
capable of escaping
one type of degenerative disease, some other disease with
later onset will
have the opportunity to develop (Fig. 3a). ... view of the
aging process as
independent of the disease it promotes (Fig. 2), as the
physiology of very
old individuals has been interpreted as frailty but not as
disease81.
However, I believe this is not a legitimate distinction, as
the same
'frailty' would certainly be interpreted as disease in a
chronologically
young individual. ...

... trade-offs: what is lost for the price of a long life?
... many severe
alterations in development and reproduction ... pituitary
long-lived dwarf
mice need special care even under laboratory conditions33.
In contrast, the
long-lived indy flies84 and the insulin-signaling pathway
age-1 worms85 show
relatively subtle deficits in nutrient storage and
developmental choice,
respectively. ...

Evolutionary conservation of mechanisms of aging
There are a number of reasons to believe that the most
fundamental
mechanisms of aging might be conserved among animals: (i)
the scaling of
life span with body size across several orders of
magnitude86; (ii) the
almost universal association of chronological age with an
increase in
oxidative stress and oxidative damage (regardless of whether
oxidative
damage has an important causal role in aging, the
association between the
two must be explained); (iii) the widespread effect of
caloric restriction
in prolonging animal life span12, 26 (Fig. 1a,b) and (iv)
that evolutionary
pressures for increased reproduction that are believed to
make aging
inevitable should act similarly on the physiology of most
sexually
reproducing animals species. ... striking commonalities
between the life
span effects of the insulin-signaling pathway in worms,
flies and mice33, 61
... aging is accompanied by the gradual accumulation of
damage at all levels
(molecular, cellular and organismal) ... longevity-promoting
effects of ...
insulin signaling, indicates that there are also molecular
mechanisms that
are shared across species. What is the meaning of a lack of
evolutionary
conservation? For example, knockout of the mouse ortholog of
the gene
responsible for human Werner's syndrome (WRN) does not lead
to a similar
syndrome in mice87. This, however, does not disqualify WRN
as a human aging
gene if the correct view is that aging has many causes and
is just the name
given to the pattern of independently caused diseases
observed in a given
species (Fig. 2).

... although mice are not humans, it is not surprising that
efforts are
underway to target pharmacologically the products of the
gene whose
alterations affect the rate of aging. ... their availability
will allow for
further tests of the generality of the findings in
invertebrates and in mice
by allowing intervention on the same genes and processes in
animal species
that are not genetically tractable, which is the case of
most long-lived
species, including humans.