Avian senescence: underlying mechanisms

Abstract

Candidate mechanisms for physiological aging include free radical production and resulting oxidative damage, progressive erosion
of telomeres and cellular senescence, age-dependent trade-offs in hormone signaling pathways, and immunosenescence, leading
to an increased risk of infection, autoimmune disease, and cancer. These mechanisms are inter-related, not mutually exclusive,
and probably all contribute to the aging phenotype. To date, most studies on mechanisms of aging are based on cell culture
or lab animals, but interest in comparative studies is growing rapidly. Compared to mammals, birds have long life spans for
their body sizes. Birds also appear to have lower rates of free radical production and oxidative damage than mammals, despite
higher levels of oxidative metabolism. High levels of the antioxidant, uric acid, in birds may help protect against oxidative
damage. Cultured bird cells are more resistant to oxidative damage than mammal cells, and membrane phospholipids of birds
are less susceptible to peroxidation than those of mammals of the same size, but show a similar susceptibility as those of
mammals with the same life span. In birds, telomeres shorten with age, and the rate of shortening is proportional to life
span. Telomerase has a higher activity in long-lived than in short-lived species. Within a species, short telomeres correlate
with reduced survival. Birds have higher plasma glucose than mammals, but lower levels of protein glycation, which contributes
to aging damage. Immunosenescence is linked to both oxidative damage and telomere shortening. Patterns of cellular and humoral
immunosenescence differ among species in birds. The rate of decline in cell-mediated immune function is inversely correlated
with life span. Comparative studies on mechanisms underlying senescence in birds will continue to provide us with valuable
information on how aging mechanisms have evolved.

Full text

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REVIEW
Avian senescence: underlying mechanisms
Carol M. Vleck Æ Æ Mark F. Haussmann Æ Æ
David Vleck
Received: 2 January 2007/Revised: 24 June 2007/Accepted: 25 June 2007
? Dt. Ornithologen-Gesellschaft e.V. 2007
Abstract
include free radical production and resulting oxidative
damage, progressive erosion of telomeres and cellular
senescence, age-dependent trade-offs in hormone signaling
pathways, and immunosenescence, leading to an increased
risk of infection, autoimmune disease, and cancer. These
mechanisms are inter-related, not mutually exclusive, and
probably all contribute to the aging phenotype. To date,
most studies on mechanisms of aging are based on cell
culture or lab animals, but interest in comparative studies is
growing rapidly. Compared to mammals, birds have long
life spans for their body sizes. Birds also appear to have
lower rates of free radical production and oxidative damage
than mammals, despite higher levels of oxidative metabo-
lism. High levels of the antioxidant, uric acid, in birds may
help protect against oxidative damage. Cultured bird cells
are more resistant to oxidative damage than mammal cells,
and membrane phospholipids of birds are less susceptible to
peroxidation than those of mammals of the same size, but
show a similar susceptibility as those of mammals with the
same life span. In birds, telomeres shorten with age, and the
rate of shortening is proportional to life span. Telomerase
Candidate mechanisms for physiological aging
has a higher activity in long-lived than in short-lived spe-
cies. Within a species, short telomeres correlate with re-
duced survival. Birds have higher plasma glucose than
mammals, but lower levels of protein glycation, which
contributes to aging damage. Immunosenescence is linked
to both oxidative damage and telomere shortening. Patterns
of cellular and humoral immunosenescence differ among
species in birds. The rate of decline in cell-mediated im-
mune function is inversely correlated with life span. Com-
parative studies on mechanisms underlying senescence in
birds will continue to provide us with valuable information
on how aging mechanisms have evolved.
Keywords
Oxidative damage ? Telomeres
Aging ? Antioxidants ? Immunosenescence ?
Introduction
Senescence refers to the progressive deterioration of
structure and function over time. It manifests as an age-
specific increase in mortality and/or decrease in fertility.
There has been some debate about whether free-living
birds show senescence, and birds have been characterized
as the only large group of organisms having a Type II
survivorship curve in which the probability of adult sur-
vival is more or less independent of age (Campbell and
Reece 2002). That view is changing, however, as long-term
field studies have now documented age-dependent declines
in both the prospects of survival and breeding productivity
in free-living bird populations (Newton and Rothery 1997;
Møller and De Lope 1999; Robertson and Rendell 2001;
Tavecchia et al. 2001; Saino et al. 2002).
Understanding senescence demands both insight into its
evolutionary basis and the identification of its molecular
Communicated by F. Bairlein.
C. M. Vleck (&) ? D. Vleck
Department of Ecology, Evolution and Organismal Biology,
Iowa State University, Ames, IA 50011-1020, USA
e-mail: cvleck@iastate.edu
D. Vleck
e-mail: dvleck@iastate.edu
M. F. Haussmann
Department of Biology, Kenyon College,
Gambier, OH 43022, USA
e-mail: haussmannm@kenyon.edu
123
J Ornithol
DOI 10.1007/s10336-007-0186-5

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and physiological mechanisms. Here we focus on the latter
and review current knowledge of the physiology and bio-
chemistry of aging in birds. Questions of interest include,
which systems, cells, and molecules within an organism
show the marks of senescence, how variation in these
characters affects fitness-related variables like survival and
reproduction both within and between species, and what
mechanisms account for differences in life span. Most of
our understanding of biochemical and physiological
mechanisms that result in or defend against aging is based
on cell culture or studies of laboratory model organisms.
Such studies have identified an array of genes that affect
life span and aging (Guarente and Kenyon 2000; Nystro ¨m
and Osiewacz 2004). As yet, however, we know little about
the relevance of many of these laboratory results to vari-
ations in life span in nature (Miller et al. 2002). Selection
for rapid growth and early reproduction under laboratory
conditions is likely to have been accompanied by the
accumulation of genes causing early aging that are easily
identified in laboratory screens but of little importance in
natural populations. Similarly, the interpretation of cell
culture data can be difficult to relate to in vivo conditions
(Patil et al. 2005). To understand the mechanisms respon-
sible for the evolution of aging, insights from these labo-
ratory models must be evaluated in free-living populations.
Birds constitute an attractive system for comparative
studies because they are relatively long-lived (Holmes and
Austad 1995) and because a large amount of demographic
and population data are available for free-living birds that
differ greatly in life span.
Among (but not within) species, life span varies with
body mass; larger organisms generally live longer than
smaller organisms. Metabolic rate also scales with body
size, such that mass-specific metabolic rates and cellular
rates of O2 consumption increase with decreasing size
(Calder 1984). This observation has led to the ‘‘rate of
living’’ hypothesis, which suggests that smaller animals
‘‘live fast and die young’’ (Pearl 1928; Sohal and Weind-
ruch 1996; Speakman et al. 2002). This pattern, which was
developed from comparative biology studies, is also con-
sistent with the idea that a principal mechanism of senes-
cence is the accumulation of oxidative damage. Within
many species, manipulations to increase daily energy
expenditure generally decrease survival and vice versa
(reviewed in Speakman et al. 2002). For example, birds
that delay reproduction produce fewer offspring, but live
longer (Alonso-Alvarez et al. 2006). This rate of living
hypothesis is, however, clearly incomplete. Birds have
higher metabolic rates than mammals of comparable size,
yet they also live longer (Speakman 2005b). Relative to
their maximum life span, the basal metabolic rates of birds
are more than threefold higher than those of mammals
(Fig. 1). Analysis of how birds manage to achieve low
rates of senescence and long life spans compared to
mammals with the same ‘‘rate of living’’ may direct our
attention to effective targets for intervention to slow
senescence.
Candidate mechanisms for physiological aging with
broad experimental support include oxidative damage to
macromolecules, progressive erosion of telomeres and
cellular replicative senescence, age-dependent trade-offs in
signaling pathways involving insulin and insulin-like
growth factors, and immunosenescence with increasing
risk of infection, autoimmune disease, and cancer. These
mechanisms areinter-related—not
sive—and probably all contribute to the aging phenotype.
We will examine each of these, drawing selectively from
work on birds and other taxa to identify current insight and
future opportunities to advance our understanding of aging
using birds as a model system.
mutually exclu-
Mechanisms of aging: oxidative damage
Harman’s (1956) hypothesis that cumulative oxidative
damage leads to the progressive loss of physiological
function over time is the leading candidate mechanism for
aging (Beckman and Ames 1998; Grune and Davies 2001).
The production of reactive oxygen species (ROS) is a
routine consequence of cellular metabolism; consequently,
oxidative damage can account for the ubiquity of aging.
ROS molecules are produced primarily at the membranes
of the mitochondria in association with the electron trans-
port chain of cellular respiration and include the superoxide
radical, hydroxyl radical, and hydrogen peroxide. The latter
is often a focus of study because it is relatively stable and
Fig. 1 Basal metabolic rate and life span in birds (dashed line) and
mammals (solid line) calculated from equations relating metabolic
rates (McKechnie and Wolf 2004; White and Seymour 2005) and life
spans (Speakman 2005b) to body mass. For birds, we converted rates
of oxygen consumption to power, assuming 19.64 J/ml O2
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can diffuse out of the cell. These molecules are all highly
reactive and can generate substantial damage to macro-
molecules. The production of ROS is also associated with
the immune system, where they play a role in defense
against toxins and invading microorganisms, and in cellular
apoptosis; thus, a certain level of ROS production is nec-
essary for homeostasis (Finkel and Holbrook 2000). The
production of ROS is tempered by a variety of antioxidant
molecules that scavenge ROS, including enzymatic an-
tioxidants (e.g., superoxide dismutase, catalase, and glu-
tathioneperoxidases),endogenous
antioxidants (e.g., glutathione, ascorbate, uric acid) and
diet-derived molecules such as vitamin E and carotenoids.
The balance between ROS production and activity of the
antioxidant systems determines the level of ROS in the
cells and the rate of damage to macromolecules, including
DNA, proteins, carbohydrates, and lipids. The extent of
damage at any point in time is also a function of the sus-
ceptibility of different macromolecules to damage based on
their chemistry and on a battery of repair processes, par-
ticularly excision repair of damaged DNA (Lombard et al.
2005). A review of methods for analyzing oxidative stress
can be found in Han et al. (2000).
non-enzymatic
ROS production
Mitochondria are thought to be the most important source
of ROS in animal cells, although much remains to be
learned about the mechanisms and control of ROS gener-
ation (Balaban et al. 2005). In limited comparative studies,
animal species with longer life spans appear to have lower
rates of ROS production (Sohal et al. 1989; Sohal et al.
1990; Barja et al. 1994; Perez-Campo et al. 1998; Barja and
Herrero 2000). In mammals, metabolic rate and rate of
mitochondrial ROS production in the heart, kidney, and
liver are inversely related to maximum life span (Sohal and
Weindruch 1996). Such observations suggest a biochemi-
cal link between the concept of rate of living and oxidative
stress, although as Speakman (2005a) has pointed out, such
correlations may reflect covariation of both traits with body
mass rather than any functional relationship. Differences in
rates of ROS production have been proposed to account for
the comparatively long life spans of birds compared to
mammals. The estimated production of hydrogen peroxide
per unit of oxygen consumed in pigeons (Columba livia) is
lower than that in similar-sized rats (Rattus norvegicus)
(Ku and Sohal 1993; Barja et al. 1994). Relatively low
mitochondrial ROS production was subsequently con-
firmed in several pigeon tissues and in canaries (Serinus
canarius)andbudgerigars
(Herrero and Barja 1997; Barja 1998). The differences
between species in terms of mitochondrial ROS production
are, however, generally smaller than the differences in life
(Melopsittacusundulates)
span (Barja 2004c), and St-Pierre et al. (2002) suggested
that technique artifacts may have exaggerated the magni-
tude of reported differences between birds and mammals. If
birds do have lower rates of ROS production than mam-
mals, uncoupling proteins, which are molecules than can
prevent ROS accumulation in mitochondria (Criscuolo
et al. 2005a), are one candidate mechanism. Uncoupling
proteins are present in birds and can modulate ROS pro-
duction (Criscuolo et al. 2005b).
Understanding the role of ROS production in aging is
challenging as much of this research must be carried out
with cell cultures, isolated mitochondria, or cell constructs
such as yeast expressing avian proteins (see Criscuolo et al.
2005b), which makes the interpretation of its importance to
aging in free-living birds difficult at best. It seems likely
that birds have relatively lower ROS production per unit of
oxygen consumed than mammals, but the magnitude of that
reduction, its root cause, and its overall contribution to
determining rates of senescence are still active areas of
research. Birds remain an attractive model for under-
standing the role of ROS production in senescence because
life spans (and presumably rates of senescence) vary tre-
mendously among species, providing the raw material for
critical comparative studies.
Antioxidants
Elevated antioxidant levels have been correlated with in-
creases in life span both within and among species (Cutler
1991; Arking 1995; Packer 1995; Sohal et al. 2002; Serra
et al. 2003), although the evidence is not always compel-
ling (Finkel and Holbrook 2000; Sohal et al. 2002; Barja
2004b) and there are clear exceptions (Lopez-Torres et al.
1993; Andziak et al. 2005). Antioxidant supplements usu-
ally do not increase longevity, and are even harmful in
some cases, but they may protect against some pathologies
and early death (Barja 2004a). Ku and Sohal (1993) com-
pared superoxide dismutase and glutathione peroxidase
activity between similarly sized pigeons and rats and found
higher levels of these enzymatic antioxidants in pigeons for
most tissues. In a larger comparative study (Perez-Campo
et al. 1998), levels of glutathione peroxidase and reductase
were lower in long-lived pigeons and canaries than in
shorter-lived guinea pigs, rats, trout, and frogs, which is
contrary to the expected result if enzymatic antioxidants
are a major contributor to the regulation of life span.
In humans, total antioxidant capacity and superoxide
dismutase decline with age (Mecocci et al. 2000; Rao et al.
2003). We recently measured total antioxidant capacity in
zebra finch (Taeniopygia guttata) plasma using a modified
oxygen radical absorbing capacity procedure (Huang et al.
2002; Prior et al. 2003). We found no change in plasma
antioxidant capacity in birds ranging in age from 0 to
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7 years (F = 0.74, n = 32, p = 0.40) (Conrad and Vleck,
unpublished data). Such maintenance of antioxidant
capacity, if characteristic of birds in general, could reduce
oxidative damage and decrease rates of senescence. Red
blood cell resistance to oxidative stress, however, did de-
cline in zebra finches between 200 and 400 days of age
(Alonso-Alvarez et al. 2006).
The ubiquity of senescence suggests that mechanisms
that reduce the accrual of age-related damage and increase
life span are expensive, so we expect to see trade-offs
between the investment in such self-maintenance and the
investment in current reproduction. In zebra finches whose
reproductive effort was increased by brood manipulation,
the effective levels of superoxide dismutase and glutathi-
one peroxidase decreased, either because enzyme activity
decreased (males) or because estimated daily energy
expenditure and presumably ROS production increased
(females) (Wiersma et al. 2004). In male zebra finches (but
not females), resistance of the red blood cells to free radical
attack and short-term survival declined with increased
reproductive effort, although individual life span was not
correlated with resistance (Alonso-Alvarez et al. 2006).
Reduced protection against oxidative damage when
reproductive effort increases and compromised survival
when oxidative protection is reduced suggest that in birds,
oxidative protection may be an important variable in the
evolution of life span and reproductive schedules.
Carotenoids are antioxidants that have been the focus of
considerable research because their dietary origin (for
vertebrate animals) facilitates manipulation and because
they serve multiple functions. In many bird species, car-
otenoids are important for plumage, beak color, and other
sexual ornaments (von Schantz et al. 1999; Blount et al.
2003a; McGraw et al. 2004). Carotenoids in egg yolk affect
embryonic physiology (Royle et al. 2001) and in adults,
they affect immunocompetence (McGraw and Ardia 2003).
Nutritional state early in life has long-term affects on
carotenoid levels (Blount et al. 2003b; Alonso-Alvarez
et al. 2004), so there are multiple reasons to suspect that
trade-offs in carotenoid allocation could affect survival.
However, carotenoid supplementation does not increase
resistance to oxidative stress in nestling kestrels (Falco
tinnunculus) (Costantini et al. 2007) or in greenfinches
(Carduelis chloris) (Horak et al. 2006). Barja (2004a)
suggested that dietary compounds are unlikely to be
determinants of endogenous aging and species-specific life
spans, but this suggestion may not hold for dietary factors
involved in life-history tradeoffs, such as carotenoids.
In most birds, the major nitrogen excretory product is
uric acid (Braun and Dantzler 1984), and plasma uric acid
levels are routinely in the 0.2–0.5 mM range (see Vleck
and Vleck 2002). In humans, chronic levels of uric acid
greater than about 0.4 mM cause gout (Pittman and Bross
1999), and values in most mammals (<0.01 mM) are much
lower than in birds (Johnson and Rideout 2004). Uric acid
is a potent scavenger of oxidants, and it has been proposed
that uricotelism in birds could contribute to low ROS levels
(Klandorf et al. 1999). Diet manipulation studies in
chickens have shown that plasma uric acid concentration is
inversely correlated with cellular oxidation activity (Si-
moyi et al. 2002), leading the authors to suggest that uric
acid could have an important anti-aging role in birds.
Similarly, the approximately threefold higher level of uric
acid in humans compared to other primates may account
for their longer life span (Short et al. 1997). The role of
uric acid as an antioxidant system accounting for greater
life spans in birds compared to mammals deserves further
investigation.
Cumulative damage to macromolecules
Oxidative damage to lipids and proteins increases with age
in many animals (Stadtman 1992; Cini and Moretti 1995;
Dubey et al. 1996; Yan et al. 1997; Pamplona et al. 1999;
Tahara et al. 2001), although we are aware of no published
data for birds. Oxidative damage to DNA as a function of
age has attracted more attention because of its central role
in determining the structure of other macromolecules.
DNA damage can be estimated by measuring the oxidation
product, 8-oxo-deoxyguanosine (8-oxo-dG) (Fraga et al.
1990; Hamilton et al. 2001a, b). Such oxidative damage to
both nuclear and mitochondrial DNA increases with age in
several mammals (Sohal and Weindruch 1996; Stedtman
and Levine 2000; Hamilton et al. 2001b). Oxidative dam-
age to heart and brain is inversely related to maximum life
span in six species of mammals (Barja and Herrero 2000),
although this relation disappears when the effects of body
mass on life span are included in the analysis (Speakman
2005a). Herrero and Barja (1999) reported that 8-oxo-dG
levels are generally lower in the mitochondrial DNA of the
heart and brain of birds than in those of mammals, but in
these studies they did not account for age-related changes.
We recently found that the level of 8-oxo-dG increases
significantly with age in zebra finch skeletal muscle
(p = 0.002) and brain (p = 0.01), but not in the liver
(p = 0.54), which includes actively dividing cells (Liu
2004). These tissue differences presumably reflect the
failure of cells with damaged DNA to replicate and the
accumulation of damage in post-mitotic tissues such as
muscle and brain. Surprisingly, in free-living birds of three
other species, we did not find an increase in oxidative
damage to muscle tissue with age (Liu 2004). In tree
swallows (Tachycineta bicolor), common terns (Sterna
hirundo), and Leach’s storm-petrels (Oceanodroma leu-
corhoa), which were sampled at about 60% of their max-
imum life span, the levels of 8-oxo-dG were the same or
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even lower than those in nestlings, although the sample
sizes were small. The difference between captive (zebra
finch) and free-living (swallows, terns, and storm-petrels)
populations could indicate that in the wild, only those
individuals with the lowest exposure to damage or greatest
capacity to resist oxidative stress live to old age. Testing
this hypothesis would require a longitudinal study—not a
cross-sectional study of age-related changes—because the
pattern of change in age-dependent traits can differ within-
and between-individuals (van de Pol and Verhulst 2006).
Susceptibility to damage
Birds have been reported to have superior defenses against
cellular damage by ROS. Cultures of avian kidney cells
and embryonic fibroblasts of birds survive exposure to
ROS and hyperoxic conditions better than mammalian cells
(Ogburn et al. 1998; Ogburn et al. 2001). Within birds,
budgerigars with a maximum life span of about 20 years
show greater cellular resistance to oxidative damage than
Japanese quail (coturnix coturnix japonica) with a maxi-
mum life span of only about 5 years (Ogburn et al. 2001).
The resistance of fibroblasts to a variety of stressors is
positively correlated with maximum life span in eight
species of mammals (Kapahi et al. 1999).
One trait that affects susceptibility to oxidative damage
is the level of saturation of membrane phospholipids.
Susceptibility to lipid peroxidation (the peroxidizability
index) (Holman 1954) increases with the polyunsaturation
of membrane phospholipids and is associated with elevated
oxidative damage to lipids, proteins, and DNA (Pamplona
et al. 2004). Animals with high cellular metabolism tend to
have polyunsaturated phospholipid membranes; function-
ally, this accelerates many processes catalyzed by mem-
brane proteins because of the greater fluidity of such
membranes (Hulbert 2005). The degree of unsaturation
tends to be greater in small species than in large species in
both birds and mammals, although the unsaturation is
generally lower in birds than in mammals of the same body
mass (Hulbert et al. 2002). Oxidation of membrane phos-
pholipids is particularly insidious because lipid peroxida-
tion is an autocatalytic chain reaction, causing further
oxidative damage. Thus, adjustments in membrane lipid
chemistry could mediate the rates of oxidative damage and
contribute to variations in life span. Pamplona et al. (1999)
reported that the peroxidizability index was lower in pi-
geons than in rats, as were the products of lipid peroxida-
tion. The peroxidizability index is negatively correlated
with life span in mammals and birds (Pamplona et al. 1998,
2000; Hulbert et al. 2002). Remarkably, the relationship
between peroxidizability index and life span appears to be
identical for both mammals and birds (Hulbert 2003,
2005), even though the metabolic rate for a given life span
is much higher in birds than in mammals (see Fig. 1). The
identical scaling of the peroxidizability index and life span
in birds and mammals suggests that we may be able to
account for much of the variation in maximum life span
among taxa based on membrane lipid composition.
Repair mechanisms
Numerous mechanisms to repair nuclear DNA have
evolved, reflecting the selective importance of the accurate
maintenance of DNA to cell and organismal function. The
efficiency of DNA repair mechanisms within an individual
may decline over time and contribute to a progressive in-
crease in oxidative damage (see review in Lombard et al.
2005), although this has not been examined in birds. As
yet, comparative data on DNA repair capability are not
available, but data from mouse mutants (Nijnik et al. 2007)
demonstrate that variation in repair affects the decline in
hematopoietic stem cells and, thus, one symptom of aging
and immunosenescence.
Genome size and structure may also affect senescence
because it affects mechanisms for the repair of double
strand-breaks in DNA. Non-homologous DNA end-joining
is an efficient—but error-prone—repair mechanism that
should be favored if genome size (and thus the frequency of
double-stranded breaks) is large or if DNA contains a sub-
stantial fraction of repetitive DNA. Homologous recombi-
nation is a less efficient—but a more precise—mechanism
for repair. The avian genome is, on average, two- to three-
foldsmallerthanothermulticellulareukaryotesbecauseofa
low fraction of repetitive DNA (Burt 2002). If bird cells
favor homologous recombination over non-homologous
DNA end-joining to repair double-stranded DNA breaks
(seeTakataetal.1998),thenthiscouldcontributetoreduced
damage to chromosomes after oxidative challenge and also
to birds’ relatively long life spans (Lieber and Karanjawala
2004). Interestingly, despite the generally small genome
sizes in birds, there appears to be an inverse relationship
between life span and genome size within avian fami-
lies (Monaghan and Metcalfe 2000; but see Ricklefs and
Scheuerlein 2001).
Caloric restriction
Within a species, it is well known that caloric restriction
can increase longevity (Masoro 2003). Restricting caloric
intake by 20–40% while maintaining essential nutrients
appears to slow the intrinsic rate of aging and onset of age-
associated diseases by attenuating oxidative damage and/or
altering the insulin/insulin-like growth factor systems (see
below) (Masoro 2005). In domestic poultry, caloric
restriction is routinely used to delay maturation and extend
the reproductive life span, and similar results can be
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produced in Japanese quail (Ottinger et al. 2005). Such a
response, however, is probably best viewed as an adaptive
mechanism to prolong life in short-term stressful situations
by diverting energy from reproduction to self-maintenance
(Kirkwood 2002). Caloric restriction per se is unlikely to
underlie mechanisms accounting for differences in the rates
of senescence among species since reduction in reproduc-
tive value of an individual would inherently be selected
against.
Mechanisms of aging: telomeres and cellular senescence
Telomeres are protective structures at the ends of eukary-
otic chromosomes, whose sequence (TTAGGG)nis highly
conserved among vertebrates (Meyne et al. 1989). Telo-
meres function during cell replication and in maintaining
genomic stability and normal physiology (McClintock
1941; Watson 1972; Prowse and Greider 1995). They
shorten when cells divide, in part because DNA polymer-
ase is unable to completely replicate the 3¢ end of linear
DNA, leaving a single-stranded overhang (Sedivy 1998).
Thus, aging is normally accompanied by telomere short-
ening (reviewed in Haussmann et al. 2003). Oxidative
stress, which preferentially causes breaks in the G-rich,
single-strand overhang, also contributes to telomere
shortening (von Zglinicki 2000; von Zglinicki et al. 2000).
In cell culture, when telomeres shorten to a critical length,
cells enter a terminal non-dividing state known as repli-
cative senescence (Hornsby 2003). Whether or not repli-
cative senescence is a causal agent of aging in vivo is
controversial, because cells in culture often suffer abnor-
mal stress, and most cells in vivo probably do not divide
often enough to erode telomeres significantly (Rubin 2002;
Wright and Shay 2002; Campisi 2003; Patil et al. 2005).
Although telomeres are not strict ‘‘aging’’ clocks (Harley
1991), substantial evidence suggests that telomeres are
important to the aging phenotype (Campisi 2003; Patil
et al. 2005). Senescent cells in vivo secrete degradative
enzymes and inflammatory cytokines that disrupt nearby
cells, contributing to aging and the threat of cancer
(Campisi 2005). Telomere erosion in some cells (perhaps
most importantly in the immune system) is thought to
eventually limit their replicative capacity (Weng et al.
1995; Akbar et al. 2004; Reed et al. 2004). Furthermore,
telomere erosion, which occurs more rapidly in the face of
various types of stressors (Epel et al. 2004; Valdes et al.
2005), is associated with several age-related diseases,
including cancer and cardiovascular disease (Klapper et al.
2001; Wong et al. 2003; Wu et al. 2003; Serrano and
Andres 2004; Campisi 2005).
The enzyme telomerase, a ribonucleoprotein capable of
elongating telomeres (Greider 1995), can maintain telomere
length in some cells, most notably the germ cells. Telo-
merase activity in most cell lines is, however, too low to
maintain constant telomere length (Engelhardt et al. 1997;
Lansdorp 2005), and thus telomeres in tissues like blood
cells shorten with age. Telomerase activity is repressed in
most normal adult somatic tissues, probably as a mecha-
nism to prevent tumor growth (Taylor and Delany 2000;
Grupp and Parwaresch 2002). Blood cell telomeres shorten
with age in most bird species (Vleck et al. 2003; Monaghan
and Haussmann 2006), and we have shown that the rate of
this shortening is inversely related to maximum life span in
both birds and mammals—shorter-lived species show
greater telomere loss per year than longer-lived species
(Haussmann et al. 2003). This result remains when the
comparative method (Felsenstein 1985) is used to account
for phylogenetic relatedness between the species sampled
(Haussmann 2005). Interestingly, in three long-lived sea-
birds, two procellariids—Leach’s storm petrel and wan-
dering albatross (Diomedia exulans)—and the European
shag (Phalacrocorax aristotelis), telomeres do not appear
to shorten with age in adults and may even lengthen
(Haussmann et al. 2003; Hall et al. 2004). The rate of
shortening is not constant over the lifetime of an individual;
greater shortening occurs early in life when growth and cell
turnover would be the highest (Bru ¨mmendorf et al. 2002;
Pauliny et al. 2006). In shags, the telomere shortening rate is
greater for chicks heavy for their size or in those produced
late in the season, both of which may be associated with
increased levels of oxidative stress that could increase
telomere shortening (Hall et al. 2004).
Patterns of telomerase activity are consistent with pat-
terns in rates of change in telomere length among bird
species (Haussmann et al. 2004). Telomerase profiles in
bone marrow (stem cells for red blood cells) are high in
hatchlings and down-regulated in adults in relatively short-
lived zebra finches and tree swallows, but remain high
throughout life in two long-lived seabirds, common terns
and Leach’s storm-petrel (Haussmann et al. 2007). Given
the prevailing view that down-regulation of telomerase
after embryonic development is important as a deterrent
against tumor formation, how these long-lived bird species
avoid the tendency of telomerase to promote the formation
of tumors is of special interest.
Emerging evidence suggests that telomere length is
correlated with fitness in a variety of species. In humans,
short telomere length at a given age is associated with
increased risk of mortality (Cawthon et al. 2003), and long
telomeres confer a survival advantage in the face of stress
in the roundworm, C. elegans (Joeng et al. 2004). Within
birds, 1-year-old tree swallows with long telomeres are
more likely to survive and return to the breeding colony
than individuals of the same age but with shorter telomeres
(Haussmann et al. 2005b). Indeed, the predicted life span
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based on survival data is nearly threefold greater for
swallows in the top quartile for telomere length than for
birds in the bottom quartile. Consequently, cross-sectional
comparisons may actually underestimate the rate of telo-
mere shortening within individuals. Pauliny et al. (2006)
also reported evidence that birds with longer than expected
telomeres were of higher quality, which these researchers
defined as greater longevity (sand martins, Riparia riparia)
or higher reproductive success (male, but not female,
dunlin, Calidris alpina).
Aviv et al. (2003) and Monaghan and Haussmann
(2006) have suggested that telomere length may provide a
measure of biological life expectancy rather than chrono-
logical age because it indexes individual history, such as
early growth conditions or the pace of deterioration. We
know that various types of stressors can accelerate telo-
mere shortening (Zeichner et al. 1999; Epel et al. 2004;
Hall et al. 2004; Valdes et al. 2005), and telomere short-
ening could simply be a covariate of other changes, such as
oxidative damage (von Zglinicki 2002), that may directly
affect function and fitness. Simultaneous analysis of fitness
components, oxidative stress, and telomere dynamics are
required to determine whether or not in vivo cellular
senescence can contribute directly to organismal level
senescence and decreased survival.
Mechanisms of aging: hormonal signaling
Endocrine regulation plays a central role in metabolism,
reproduction, and behavior and probably has an integral
role in affecting life span (Wise 2000). Signaling pathways
involving insulin and insulin-like growth factor-1 (IGF-1)
have received considerable attention because they are
implicated in the regulation of life span in organisms
varying from yeast (Fabrizio et al. 2001) to mice (Bartke
et al. 2001) although, clearly, it is the processes which
these signaling molecules regulate that may affect life
span, not simply their levels. Chronically elevated insulin
may negatively affect survival and life span in vertebrates
via its effects on mitochondrial ROS production (Lambert
and Merry 2004), but normal levels of insulin are necessary
for the regulation of glucose metabolism. In vertebrates,
growth hormone elevates IGF-1 production, which works
through a signaling pathway that overlaps that of insulin to
affect growth, development, and metabolism. Silencing the
IGF-1 pathway lengthens life span in a variety of labora-
tory model organisms, possibly by increasing resistance to
oxidative stress (Migliaccio et al. 1999; Walker and Lith-
gow 2003) and/or reducing cancer risk (Pollak et al. 2004).
Effects of reduced IGF-1 usually also include reduced
metabolic rate (and body temperature in homeotherms),
hypoglycemia, small body size, hypogonadism, and
reduced fertility (but see Holzenberger et al. 2003), all of
which should be strongly selected against in nature (Harley
1991; Carter et al. 2002). Consequently, it remains unclear
whether or not the modulation of IGF-1 signaling con-
tributes to variations in life span between species.
There should be balancing selection on insulin and IGF-
1 levels within a species to optimize growth, metabolism,
and reproduction (facilitated by elevated levels) while
limiting damage from elevated levels. Altered insulin lev-
els have profound pathological effects in mammals. In
particular, chronically elevated plasma glucose and insulin
is associated with an increased risk of type II diabetes in
humans, but insulin levels have not yet been linked directly
to life span (Rincon et al. 2005). In birds, insulin is more
potent than mammalian insulin, and both insulin and glu-
cagon are consistently found at higher concentrations in
birds than in mammals (Hazelwood 2000). To date, the
contribution of insulin and IGF-1 and their signaling
pathways to variations in life span among free-living ani-
mals is unknown, although there are a few hints based on
rodent work (Miller et al. 2002; Harper et al. 2003). If these
signaling pathways play a role in governing functional
decline with aging, contrasting birds and mammals should
provide a powerful tool for identifying that role.
Birds have extremely high concentrations of blood
glucose relative to those found in mammals. Plasma glu-
cose concentrations in hummingbirds feeding on high
carbohydrate solutions can reach 41 mM (vs. a typical level
of about 5 mM in humans) (Beuchat and Chong 1998), yet
hummingbirds can live as long as 12 years (Calder 1990).
Plasma glucose in fasting penguins averages over 16 mM
(Vleck and Vleck 2002). Hyperglycemia is thought to
contribute to aging in part due to the non-enzymatic gly-
cation of proteins, yet levels of glycated hemoglobin in
birds are lower than those in many mammals (reviewed in
Beuchat and Chong 1998). Glycated proteins can react
further to form advanced glycosylation end products
(AGEs), which then cause cross-linking in long-lived
protein such as collagen and lens crystallins (Holmes et al.
2001). Pentosidine is one such AGE that increases with age
in the collagen of skin. Pentosidine in skin and foot web-
bing in a variety of bird species has been shown to increase
linearly with age, leading to the suggestion that its level in
skin could be used as a measure of age in wild birds
(Chaney et al. 2003). To date, we do not know if rates of
AGE accumulation are related to life span in birds.
Mechanisms of aging: immunosenescence
Immunosenescence refers to the deterioration of immune
function with age. It is thought to increase susceptibility to
infection, autoimmune disease, and cancer (Miller 1996).
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Immunological deterioration has been linked to both oxi-
dative damage (de la Fuente 2002) and telomere shortening
(Mariani et al. 2003), so it is probably not so much a cause
of aging as a symptom. The rate of immunosenescence is
correlated with individual longevity in humans as well as
with differences in life expectancy among species (Pawelec
et al. 1999).
Immune function in vertebrates includes both innate (or
natural) immunity and acquired (or adaptive) immunity.
Both types can be subdivided into humoral and cell-med-
iated immunity, although there is much interaction among
these systems. Immunosenescence in mammals is charac-
terized by decreases in both cellular (T-cell mediated) and
humoral (B-cell mediated) responses, with the most
prominent changes involving a decline in T-cell-mediated
immunity (Miller 1996). B-cell function may not change
with age (Son et al. 2003), or observed changes may be
largely the result of age-related changes in helper T-cells
(Pawelec et al. 1999). Acquired immunity is guided by
T-cells that must undergo extensive clonal proliferation on
contact with an antigen; hence, unlike most tissues, these
lymphocytes are under enormous replicative stress, leading
to the potential for critical telomere shortening (Akbar
et al. 2004). Consequently, replicative senescence of lym-
phocytes and the consequent reduction of their diversity are
likely candidates for causing immunosenescence (Roma-
nyukha and Yashin 2003; Effros 2004). Essentially, both
lymphocyte specificity and replicative capacity decrease
with age. In elderly humans, T-cell distribution changes in
favor of memory cells, with the lower production of new
naı ¨ve cells (Akbar et al. 2004), a condition which in mice
leads to relatively short life spans (Miller 2001). Unlike
adaptive immunity, components of innate defense may
actually increase in old age (Ortega et al. 2000), which may
not be completely desirable because it increases the po-
tential for autoimmune disease.
Immune function has received considerable attention in
behavioral ecology of birds because the cost of mounting
an immune response affects life-history traits such as
breeding effort and reproductive success (see Norris and
Evans 2000; Martin et al. 2001; Kilpimaa et al. 2003; Ardia
2005). In birds, the strength of cell-mediated immunity
increases with maximum life span (Tella et al. 2001),
suggesting that long-lived species invest more in immune
function than shorter-lived species. This is consistent with
evolutionary theory that predicts a greater investment in
self-maintenance should be associated with longer life span
(Kirkwood and Holliday 1979).
Information on how immune function changes as birds
age is just beginning to emerge. Lozano and Lank (2002)
found that cell-mediated immunity was lower in older birds
than younger ones in a captive breeding flock of ruffs
(Philomachus pugnax). Humoral immunity decreases with
age in barn swallows (Hirundo rustica) (Saino et al. 2003)
and in collared flycatchers (Ficedula albicollis) (Cichon
et al. 2003). We found that cell-mediated immunity de-
creases with age in zebra finches, tree swallows, and
Leach’s storm-petrels and that the rate of decrease is in-
versely correlated with life span (Haussmann et al. 2005a).
About 50% of the response is gone after about 80% of the
maximum life span, but in zebra finches this occurs over
about 4 years, whereas in the long-lived storm-petrel it
occurs over about 30 years. Most recently, we have shown
that acquired T-cell mediated immunity declines with age
in tree swallows but that acquired and innate humoral
immunity do not change (Palacios et al. 2007); thus, in this
species, immunosenescence is not a feature of all aspects of
the immune system. Since humoral immunity does show
age-related decline in barn swallow and collared flycatch-
ers, there is clearly variation in the pattern of immunose-
nescence among species. Whether this variation is
adaptive, perhaps responding to prevalence of parasites or
risk of infection, or allows for trade-offs among the dif-
ferent branches of the immune system is not yet known.
Likewise, how a compromise of the immune system affects
survival in nature is not straightforward (Adamo 2004),
although this information is critical to our understanding of
the role that immunosenescence may play in the evolution
of differences in life span between species.
Conclusions and future research
The complexity of aging makes it highly unlikely that it
can be attributed to a single cause (Weinert and Timiras
2003). It has been suggested that somewhere between 25
and 33% of the determination of life span is heritable
(Kirkwood 2002), and life span is undoubtedly a complex
polygenic trait. Recent insight that homologous genes, such
as those associated with the insulin and IGF-1 signaling
pathways, contribute to life span in diverse organisms
(Longo and Finch 2003) suggests that such genes may be
important in all animals, although this line of investigation
would profit from working with animals in their natural
environment to avoid the biases that result from using
laboratory lines selected for rapid population growth in a
favorable environment. Now that the chicken genome has
been sequenced (Wallis 2004) and work is proceeding on
several other avian species (e.g., zebra finches), it is only a
matter of time until the genomics of aging will be extended
to include birds.
Identifying the evolutionary importance of different
mechanisms as causes of agingrequires comparative studies
and statistical approaches that can evaluate the direct and
indirect effects of multiple interacting factors. Figure 2
indicates how the various factors we have discussed here
J Ornithol
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could interact to affect survival and reproductive success,
the critical components of fitness. Physiological studies that
aim to identify mechanisms must always be mindful of the
pitfalls of assigning cause and effect based on correlation,
or of attributing function to a particular process that may
only be correlated with yet a third variable. For example,
because life span scales with body mass, any claim that a
particular process governs life span must take body mass
into account (Speakman 2005a).
Longitudinal studies of aging in free-living birds are
rare, but need to increase because longitudinal studies have
greater power to identify age-related changes than do
cross-sectional studies (Aviv et al. 2006). In addition,
longitudinal studies allow us to distinguish between dif-
ferences that result from intrinsic processes in all individ-
uals within a population and differences (or similarities)
between age groups that result from selection that prefer-
entially removes some phenotypes earlier in life than others
(van de Pol and Verhulst 2006). That is, they may allow us
to identify traits of current selective importance in the
evolution of life span that could otherwise be overlooked.
Comparative studies have a special power for identify-
ing which of the candidate mechanisms of aging have been
of evolutionary importance in vertebrate animals because
they can take advantage of the long-term natural experi-
ments that have produced an array of species that differ in
life span. However, conclusions based on comparative data
require special methods of comparative analysis. Such
analyses (Speakman et al. 2002; Haussmann 2005;
Lorenzini et al. 2005; Speakman 2005a) are surprisingly
rare in the literature on aging. Different species may share
traits because of shared ancestry, or they may exhibit
differences that are not, in fact, related to differences in
their biology of aging. A comparison of two species (e.g.
pigeons vs. rats) provides little basis for generalizations
about adaptation (Garland and Adolph 1994), but they are
common in the literature on aging.
Birds are diverse and taxonomically well known and
show considerable variation in their maximum life span; in
addition, many populations are well studied both physio-
logically and demographically. Some well-studied popu-
lations provide access to large numbers of known-aged
individuals. It is relatively easy to observe functionally
and selectively important traits such as growth rate, for-
aging behavior, reproductive effort, and reproductive
success in birds. To date, the study of birds has provided a
wealth of information about life history evolution and the
trade-off between survival and reproductive effort. Birds
hold considerable promise as candidate organisms en-
abling critical tests of the mechanisms underlying senes-
cence, in part because measurements can be made across
the life spans of individuals to track cellular and molecular
changes with age, to determine which factors affect rate of
change, and to assess how these changes correlate with
individual survival schedules. Continued study of birds
will substantially strengthen our understanding of the
evolution of the mechanisms involved in fundamental life
history trade-offs.
Acknowledgements
Ornithological Congress for helping to organize the IOC symposium
on Avian Senescence. David Winkler has helped to shape our
thinking about aging in birds. The research described here was sup-
ported by the National Institute on Aging under Grant No RO3
AGO22207 and the National Science Foundation under Grant No.
0408008. All experiments comply with the current laws of the United
States and the Iowa State University Committee on Animal Care
approved protocols.
We thank Pat Monaghan and the International
References
Adamo SA (2004) How should behavioural ecologists interpret
measurements of immunity? Anim Behav 68:1443–1449
Akbar AN, Beverley PCL, Salmon M (2004) Will telomere erosion
lead to a loss of T-cell memory? Natl Rev Immunol 4:737–743
Alonso-Alvarez C, Bertrand S, Devevey GL, Proust J, Faivre B, Sorci
G (2004) Increased susceptibility to oxidative stress as a
proximate cost of reproduction. Ecol Lett 7:363–368
Alonso-Alvarez C, Bertrand S, Devevey GL, Proust J, Faivre B,
Chastel O, Sorci G (2006) An experimental manipulation of life-
history trajectories and resistance to oxidative stress. Evolution
60:1913–1324
Andziak B, O’Connor TP, Buffenstein R (2005) Antioxidants do not
explain the disparate longevity between mice and the longest-
living rodent, the naked mole-rat. Mech Ageing Dev 126:1206–
1212
Ardia DR (2005) Tree swallows trade off immune function and
reproductive effort differently across their range. Ecology
86:2040–2046
Fig. 2 Diagram of hypothesized causes of aging and their interac-
tions in birds. Effects are either positive (green, +), negative (red, –),
or change with age (brown,+/–). Interactions among these factors
determine reproductive success and fitness differences among
individuals within a species (shaded portion) and are hypothesized
to be the underlying mechanism for the evolution of different life
spans among species (unshaded portion)
J Ornithol
123

Page 10

Arking R (1995) Antioxidant genes and other mechanisms involved in
the extended longevity of Drosophila. In: Cutler RG, Packer L,
Bertram J, Mori A (eds) Oxidative stress and aging. Birkhauser
Verlag, Basel, pp 123–139
Aviv A, Levy D, Mangel M (2003) Growth, telomere dynamics and
successful and unsuccessful human aging. Mech Ageing Dev
124:829–837
Aviv A, Valdes AM, Spector TD (2006) Human telomere biology:
pitfalls of moving from the laboratory to epidemiology. Int J
Epidemiol 35:1424–1429
Balaban RS, Nemoto S, Finkel T (2005) Mitochondria, oxidants, and
aging. Cell 120:483–495
Barja G (1998) Mitochondrial free radical production and aging in
mammals and birds. Ann NY Acad Sci 854:224–238
Barja G (2004a) Aging in vertebrates, and the effect of caloric
restriction: a mitochondrial free radical production—DNA
damage mechanism? Biol Rev 79:235–251
Barja G (2004b) Mammalian and bird aging, oxygen radicals, and
restricted feeding. In: Nystro ¨m T, Osiewacz HD (eds) Model
systems in aging. Springer, Heidelberg
Barja G (2004c) Free radicals and aging. Trends Neurosci 27:595–
600
Barja G, Herrero A (2000) Oxidative damage to mitochondrial DNA
is inversely related to maximum life span in the heart and brain
of mammals. FASEB J 14:312–318
Barja G, Cadenas S, Rojas C, Pe ´rez-Campo R, Lo ´pez-Torres M
(1994) Low mitochondrial free radical production per unit O2
consumption can explain the simultaneous presence of high
longevity and high aerobic metabolic rate in birds. Free Radic
Biol Med 21:317–328
Bartke A, Coschigano K, Kopchick J, Chandrashekar V, Mattison J,
Kinney B, Hauck S (2001) Genes that prolong life: relationships
of growth hormone and growth to aging and life span. J Gerontol
56A:B340–349
Beckman KB, Ames BN (1998) The free radical theory of aging
matures. Physiol Rev 78:547–581
Beuchat CA, Chong CR (1998) Hyperglycemia in hummingbirds and
its consequences for hemoglobin glycation. Comp Biochem
Physiol A 120:409–416
Blount JD, Metcalfe NB, Arnold KE, Surai PF, Devevey GL,
Monaghan P (2003a) Neonatal nutrition, adult antioxidant
defenses and sexual attractiveness in the zebra finch. Proc R
Soc Lond B 270:1691–1696
Blount JD, Metcalfe NB, Birkhead TR, Surai PF (2003b) Carotenoid
modulation of immune function and sexual attractiveness in
zebra finches. Science 300:125–127
Braun E, Dantzler W (1984) Endocrine regulation of avian renal
function. J Exp Zool 232:715–723
Bru ¨mmendorf TH, Mak J, Sabo KM, Baerlacher GM, Dietz K,
Abkowitz JL, Lansdorp PM (2002) Longitudinal studies of
telomere length in feline blood cells: implications for hemato-
poietic stem cell turnover in vivo. Exp Hematol 30:1147–1152
Burt DW (2002) Origin and evolution of avian microchromosomes.
Cytogenet Genet Res 96:97–112
Calder WA (1990) Avian longevity and aging. In: Harrison DE (ed)
Genetic effects on aging II. Telford, Caldwell, pp 185–204
Calder WAI (1984) Size, Function, and Life History. Harvard
University Press, Cambridge
Campbell NA, Reece JB (2002) Biology. Benjamin Cummings, San
Francisco
Campisi J (2003) Cancer and ageing: rival demons? Nature 3:339–349
Campisi J (2005) Senescent cells, tumor suppression, and organismal
aging: good citizens, bad neighbors. Cell 120:513–522
Carter SC, Ramsey MM, Sonntag WE (2002) A critical analysis of
the role of growth hormone and IGF-1 in aging and lifespan.
Trends Genet 18:295–301
Cawthon RM, Smith KR, O’Brien E, Sivatchenki A, Kerber RA
(2003) Association between telomere length in blood and
mortality in people aged 60 years or older. Lancet 361:393–395
Chaney RCJ, Blemings KP, Bonner J, Klandorf H (2003) Pentosidine
as a measure of chronological age in wild birds. Auk 120:394–
399
Cichon M, Sendecka J, Gustafsson L (2003) Age-related decline in
humoral immune function in collared flycatchers. J Evol Biol
6:1205–1210
Cini M, Moretti A (1995) Studies on lipid peroxidation and protein
oxidation in the aging brain. Neurobiol Aging 16:53–57
Costantini D, Fanfani A, Dell’Omo G (2007) Carotenoid availability
does not limit the capability of nestling kestrels (Falco
tinnunculus) to cope with oxidative stress. J Exp Biol
210:1238–1244
Criscuolo F, Gonzalez-Barroso MDM, Bouillaud F, Ricquier D,
Miroux B, Sorci G (2005a) Mitochondrial uncoupling proteins:
new perspectives for evolutionary ecologists. Am Nat 166:686–
699
Criscuolo F, Gonzalez-Barroso MDM, Le Maho Y, Ricquier D,
Bouillaud F (2005b) Avian uncoupling protein expressed in
yeast mitochondria prevents endogenous free radical damage.
Proc R Soc Lond B 272:803–810
Cutler RG (1991) Antioxidants and aging. Am J Clin Nutr 53:373S–
379S
de la Fuente M (2002) Effects of antioxidants on immune system
ageing. Eur J Clin Nutr 56
Dubey A, Forster MJ, Lal H, Sohal R (1996) Effect of age and caloric
intake on protein oxidation in different brain regions and on
behavioral functions of the mouse. Arch Biochem Biophys
333:189–197
Effros RB (2004) Impact of the Hayflick Limit on T cell responses to
infection: lessons from aging and HIV disease. Mech Ageing
Dev 125:103–106
Engelhardt M, Kumar R, Albanell J, Pettengell R, Han W, Moore M
(1997) Telomerase regulation, cell cycle, and telomere stability
in primitive hematopoietic cells. Blood 90:182–193
Epel E, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD,
Cawthon RM (2004) Accelerated telomere shortening in response
to life stress. Proc Natl Acad Sci USA 101:17312–17315
Fabrizio P, Pozza F, Pletcher SD, Gendron CM, Longo VD (2001)
Regulation of longevity and stress resistance by Sch9 in yeast.
Science 292:288–290
Felsenstein J (1985) Phylogenies and the comparative method. Am
Nat 125:1–15
Finkel T, Holbrook NJ (2000) Oxidants, oxidative stress and the
biology of aging. Nature 408:239–247
Fraga CG, Shigenaga MK, Park J, Degan P, Ames BN (1990)
Oxidative damage to DNA during aging: 8-hydroxy-2¢-deoxy-
guanosine in rat organ DNA and urine. Proc Natl Acad Sci USA
87:4533–4537
Garland TJ, Adolph SC (1994) Why not to do two-species compar-
ative studies: limitations on inferring adaptation. Physiol Zool
67:797–828
Greider C (1995) Telomerase biochemistry and regulation. In:
Blackburn E, Greider C (eds) Telomeres. Cold Spring Harbor
Laboratory Press, Cold Spring Harbor, pp 35–68
Grune T, Davies KJA (2001) Oxidative processes in aging. In:
Masoro EJ, Austad SN (eds) Handbook of the biology of aging.
Academic, San Diego, pp 25–58
Grupp G, Parwaresch R (2002) Telomerases, telomeres and cancer.
Kluwer, New York
Guarente G, Kenyon C (2000) Genetic pathways that regulate ageing
in model organisms. Nature 408:255–262
Hall ME, Nasir L, Daunt F, Gault EA, Croxall JP, Wanless S,
Monaghan P (2004) Telomere loss in relation to age and early
J Ornithol
123

Page 11

environment in long-lived birds. Proc R Soc Lond B 271:1571–
1576
Hamilton ML, Guo ZM, Fuller CD (2001a) A reliable assessment of
8-oxo-2-deoxyguanosine levels in nuclear and mitochondrial
DNA using the sodium iodide method to isolate DNA. Nucleic
Acids Res 29:2117–2126
Hamilton ML, Remmen HV, Drake JA, Yang H, Guo ZM, Kewitt K,
WalterCA,RichardsonA(2001b)DoesoxidativedamagetoDNA
increase with age? Proc Natl Acad Sci USA 98:10469–10474
Han D, Loukianoff S, McLaughlin L (2000) Oxidative stress indices:
analytical aspects and significance. In: Sen CK, Packer L,
Ha ¨nninen O (eds) Handbook of oxidants and antioxidants in
exercise. Elsevier Science, Amsterdam, pp 433–483
Harley CB (1991) Telomere loss: mitotic clock or genetic time bomb?
Mutat Res 256:271–282
Harman D (1956) Aging: a theory based on free radical and radiation
chemistry. J Gerontol 11:298–300
Harper JM, Wolf N, Galecki AT, Pinkosky SL, Miller RA (2003)
Hormone levels and cataract scores as sex-specific, mid-life
predictors of longevity in genetically heterogeneous mice. Mech
Ageing Dev 124:801–810
Haussmann MF (2005) The evolution of avian lifespan: an exami-
nation of telomere dynamics and immunosenescence. PhD
thesis. Iowa State University, Ames
Haussmann MF, Winkler DW, O’Reilly KM, Huntington CE, Nisbet
ICT, Vleck CM (2003) Telomeres shorten more slowly in long-
lived birds and mammals than in short-lived ones. Proc R Soc
Lond B 270:1387–1392
Haussmann MF, Winkler DW, Huntington CE, Nisbet ICT, Vleck
CM (2004) Telomerase expression is differentially regulated in
birds of differing life span. Ann NY Acad Sci 1019:186–190
Haussmann MF, Winkler DW, Huntington CE, Vleck D, Sanneman
CE, Hanley D, Vleck CM (2005a) Cell-mediated immunosenes-
cence in birds. Oecologia 145:270–275
Haussmann MF, Winkler DW, Vleck CM (2005b) Longer telomeres
associated with higher survival in birds. Biol Lett 1:212–214
Haussmann MF, Winkler DW, Nisbet ICT, Huntington CE, Vleck
CM (2007) Telomerase activity is maintained throughout the
lifespan of long-lived birds. Exp Gerontol 42:610–618
Hazelwood RL (2000) Pancreas. In: Whitow GC (ed) Sturkie’s avian
physiology, 5th edn. Academic, San Diego, pp 539–555
Herrero A, Barja G (1997) Sites and mechanisms responsible for the
low rate of free radical production of heart mitochondria in the
long-lived pigeon. Mech Ageing Dev 98:95–111
Herrero A, Barja G (1999) 8-oxo-deoxyguanosine levels in heart and
brain mitochondrial and nuclear DNA of two mammals and three
birds in relation to their different rates of aging. Aging Clin Exp
Res 11:294–300
Holman RT (1954) Autoxidation of fats and related substances. In:
Holman RT, Lundberg WO, Malkin T (eds) Progress in
chemistry of fats and other lipids, vol 2. Pergamon, London,
pp 51–98
Holmes DJ, Austad SN (1995) Birds as animal models for the
comparative biology of aging: a prospectus. J Gerontol Biol Sci
50A:B59–B66
Holmes DJ, Flu ¨ckiger R, Austad SN (2001) Comparative biology of
aging in birds: an update. Exp Gerontol 36:869–883
Holzenberger M, Dupont J, Ducos B, Leneuve P, Ge ´loen A, Even PC,
Cervera P, Le Bouc Y (2003) IGF-1 receptor regulates lifespan
and resistance to oxidative stress in mice. Nature 421:182–187
Horak P, Zilmer M, Saks L, Ots I, Karu U, Zilmer K (2006)
Antioxidant protection, carotenoids and the cost of immune
challenge in greenfinches. J Exp Biol 209:4329–4338
Hornsby PJ (2003) Replicative senescence of human and mouse cells
in culture: significance for aging research. Mech Ageing Dev
124:853–855
Huang D, Ou B, Hampsch-Woodill M, Flanagan JA, Prior RL (2002)
High-throughput assay of oxygen radical absorbance capacity
(ORAC) using a multichannel liquid handling system coupled
with a microplate fluorescence reader in 96-well format. J Agric
Food Chem 50:4437–4444
Hulbert AJ, Faulks SC, Buttemer WA, Else PL (2002) Acyl
composition of muscle membranes varies with body size in
birds. J Exp Biol 205:3561–3569
Hulbert AJ (2003) Life, death and membrane bilayers. J Exp Biol
206:2303–2311
Hulbert AJ (2005) On the importance of fatty acid composition of
membranes for aging. J Theor Biol 234:277–288
Joeng KS, Song EJ, Lee J-J, Lee J (2004) Long lifespan in worms
with long telomeric DNA. Nat Genet 36:607–611
Johnson RJ, Rideout BA (2004) Uric acid and diet—insights into the
epidemic of cardiovascular disease. N Eng J Med 350:1071–
1073
Kapahi P, Boulton ME, Kirkwood TBL (1999) Positive correlation
between mammalian life span and cellular resistance to stress.
Free Radic Biol Med 26:495–500
Kilpimaa J, Alatalo RV, Siitari H (2003) Trade-offs between sexual
advertisement and immune function in the pied flycatcher
(Ficedula hypoleuca). Proc R Soc Lond 271:245–250
Kirkwood TBL (2002) Evolution of ageing. Mech Ageing Dev
123:737–745
Kirkwood TBL, Holliday R (1979) The evolution of ageing and
longevity. Proc R Soc Lond 205:531–546
Klandorf H, Probert IL, Iqbal M (1999) In the defense against
hyperglycemia: an avian strategy. Worlds Poul Sci J 55:251–268
KlapperW,ParwareschR,KruppG(2001)Telomerebiologyinhuman
aging and aging syndromes. Mech Ageing Dev 122:695–712
Ku HH, Sohal RS (1993) Comparison of mitochondrial pro-oxidant
generation and anti-oxidant defenses between rat and pigeon:
possible basis of variation in longevity and metabolic potential.
Mech Ageing Dev 72:67–76
Lambert AJ, Merry BJ (2004) Effect of caloric restriction on
mitochondrial reactive oxygen species production and bioener-
getics: reversal by insulin. Am J Physiol Regul Integr Comp
Physiol 286:R71–R79
Lansdorp PM (2005) Role of telomerase in hematopoietic stem cells.
Ann NY Acad Sci 1044:220–227
Lieber MR, Karanjawala ZE (2004) Ageing, repetitive genomes and
DNA damage. Natl Rev Mol Cell Biol 5:69–75
Liu W (2004) DNA oxidation damage of birds: measuring, analyzing
and comparing. MSc thesis. Iowa State University, Ames
Lombard DB, Chua KF, Mostoslavsky R, Franco S, Gostissa M, Alt
FW (2005) DNA repair, genome stability, and aging. Cell
120:497–512
Longo VD, Finch CE (2003) Evolutionary medicine: from dwarf
model systems to healthy centenarians? Science 299:1342–1346
Lopez-Torres M, Perez-Campo R, Rojas C, Cadenas S, Barja G
(1993) Maximum life span in vertebrates: relationship with liver
antioxidant enzymes, glutathione system, ascorbate, urate,
sensitivity to peroxidation, true malondialdehyde, in vivo
H2O2, and basal and maximum aerobic capacity. Mech Ageing
Dev 70:177–199
Lorenzini A, Tresini M, Austad SN, Cristofalo VJ (2005) Cellular
replicative capacity correlates primarily with species body mass
not longevity. Mech Ageing Dev 126:1130–1133
Lozano GA, Lank DB (2002) Seasonal trade-offs in cell-mediated
immunosenescence in ruffs (Philomachus pugnax). Proc R Soc
Lond B 270:1203–1208
Mariani E, Meneghetti A, Formentini I, Neri S, Cattini L, Ravaglia G,
Forti P, Facchini A (2003) Telomere length and telomerase
activity: effect of ageing on human NK cells. Mech Ageing Dev
124:403–408
J Ornithol
123

Page 12

Martin TE, Møller AP, Merino S, Clobert J (2001) Does clutch size
evolve in response to parasites and immunocompetence? Proc
Natl Acad Sci USA 98:2071–2076
Masoro EJ (2003) Subfield history: caloric restriction, slowing aging,
and extending life. Sci Aging Knowledge Environ 26(8):re2. doi:
10.1126/sageke.2003.8.re2
Masoro EJ (2005) Overview of caloric restriction and ageing. Mech
Ageing Dev 126:913–922
McClintock B (1941) The stability of broken ends of chromosomes in
Zea mays. Genetics 41:234–282
McGraw KJ, Ardia DR (2003) Carotenoids, immunocompetence, and
the information content of sexual colors: an experimental test.
Am Nat 162:704–712
McGraw KJ, Hill GE, Navara KJ, Parker RS (2004) Differential
accumulation and pigmenting ability of dietary carotenoids in
colorful finches. Physiol Biochem Zool 77:484–491
McKechnie AE, Wolf BO (2004) The allometry of avian basal
metabolic rate: good predictions need good data. Physiol
Biochem Zool 77:502–521
Mecocci P, Polidori MC, Trojano L, Cherubini A, Cecchetti R, Pini
G, Straatman M, Monti D, Stahl W, Sies H, Franceschi C, Senin
U (2000) Plasma antioxidants and longevity: a study on healthy
centenarians. Free Radic Biol Med 28:1243–1248
Meyne J, Ratliff RL, Moyzis RK (1989) Conservation of the human
telomere sequence (TTAGGG)-n among vertebrates. Proc Natl
Acad Sci USA 86:7049–7053
Migliaccio E, Giorgio M, Mele S, Pelicci G, Reboldi P, Pandolfi PP,
Lanfrancone L, Pelicci PG (1999) The p66shcadaptor protein
controls oxidative stress response and life span in mammals.
Nature 402:309–313
Miller RA (1996) The aging immune system: primer and prospectus.
Science 273:70–74
Miller RA (2001) Biomarkers of aging: prediction of longevity by
using age-sensitive T-cell subset determinations in a middle-
aged, genetically heterogeneous mouse population. J Gerontol A
Biol Sci Med Sci 56A:B180–B186
Miller RA, Harper JM, Dysko RC, Durkee SJ, Austad SN (2002)
Longer life spans and delayed maturation in wild-derived mice.
Exp Biol Med 227:500–508
Monaghan P, Haussmann MF (2006) Do telomere dynamics link
lifestyle and lifespan? Trends Ecol Evol 21:47–53
Monaghan P, Metcalfe NB (2000) Genome size and longevity. Trends
Genet 16:331–332
Møller AP, De Lope F (1999) Senescence in a short-lived migratory
bird: age-dependent morphology, migration, reproduction and
parasitism. J Anim Ecol 68:163–171
Newton I, Rothery P (1997) Senescence and reproductive value in
sparrowhawks. Ecology 78:100–1008
Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C,
Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T,
Bell JI, Slijepcevic P, Goodnow CG, Jeggo P, Cornall RJ (2007)
DNA repair is limiting for haematopoietic stem cells during
ageing. Nature 447
Norris K, Evans MR (2000) Ecological immunology: life history
trade-offs and immune defense in birds. Behav Ecol 11:19–26
Nystro ¨m T, Osiewacz HD (2004) Model systems in aging. Springer,
Heidelberg
Ogburn C, Austad S, Holmes D, Kiklevich V, Gollahon K,
Rabinovitch P, Martin G (1998) Cultured renal epithelial cells
from birds and mice: enhanced resistance of avian cells to
oxidative stress and DNA damage. J Gerontol Biol Sci Med Sci
53A:B287–B292
Ogburn CE, Carlberg K, Ottinger MA, Holmes DJ, Martin GM,
Austad SN (2001) Exceptional cellular resistance to oxidative
damage in long-lived birds requires active gene expression. J
Gerontol 56A:B468–B474
Ortega E, Garcia JJ, De la Fuente M (2000) Aging modulates some
aspects of the non-specific immune response of murine macro-
phages and lymphocytes. Exp Physiol 85:519–525
Ottinger MA, Mobarak M, Abdelnabi M, Roth G, Proudman J,
Ingram DK (2005) Effects of caloric restriction on reproductive
and adrenal systems in Japanese quail: are responses similar to
mammals, particularly primates? Mech Ageing Dev 126:967–
975
Packer L (1995) Oxidative stress, antioxidants, aging and disease. In:
Cutler RG, Packer L, Bertram J, Mori A (eds) Oxidative stress
and aging. Birkhauser Verlag, Basel, pp 1–14
Palacios MG, Cunnick JE, Winkler DW, Vleck CM (2007) Immu-
nosenescence in some but not all immune components in a free-
living vertebrate, the tree swallow. Proc R Soc Lond B 274:951–
957
Pamplona R, Portero-Ortin M, Riba D, Ruiz C, Prat J, Bellmunt MJ,
Barja G (1998) Mitochondrial membrane peroxidizability index
is inversely related to maximum life span in mammals. J Lipid
Res 39:1989–1994
Pamplona R, Portero-Otin M, Requena JR, Thorpe SR, Herrero A,
Barja G (1999) A low degree of fatty acid unsaturation leads to
lower lipid peroxidation and lipoxidation-derived protein mod-
ification in heart mitochondria of the longevous pigeon than in
the short-lived rat. Mech Ageing Dev 106:283–296
Pamplona R, Portero-Ortin M, Riba D, Requena JR, Thorpe SR,
Lopez-Torres M, Barja G (2000) Low fatty acid unsaturation: a
mechanism for lowered lipoperoxidative modification of tissue
proteins in mammalian species with long life spans. J Gerontol A
Biol Sci Med Sci 55:B286–B291
Pamplona R, Portero-Otin M, Sanz A, Requena JR, Barja G (2004)
Modification of the longevity-related degree of fatty acid
unsaturation modulates oxidative damage to proteins and
mitochondrial DNA in liver and brain. Exp Gerontol 39:725–733
Patil CK, Mian IS, Campisi J (2005) The thorny path linking cellular
senescence to organismal aging. Mech Ageing Dev 126:1040–
1045
Pauliny A, Wagner RH, Augustiin J, Szeip T, Blomqvist D (2006)
Age-independent telomere length predicts fitness in two bird
species. Mol Ecol 15:1681–1687
Pawelec G, Effros RB, Caruso C, Remarque E, Barnett Y, Solana R
(1999) T cells and aging. Front Biosci 4:D216–269
Pearl R (1928) The rate of living. Knopf, New York
Perez-Campo R, Lopez-Torres M, Cadenas S, Rojas C, Barja G
(1998) The rate of free radical production as a determinant of the
rate of aging: evidence from the comparative approach. J Comp
Physiol B 168:149–158
Pittman JR, Bross MH (1999) Diagnosis and management of gout.
Am Fam Physician 59:1799
Pollak MN, Schernhammer ES, Hankinson SE (2004) Insulin-like
growth factors and neoplasia. Nat Rev Cancer 4:505–517
Prior RL, Hoang H, Gu L, Wu X, Bacchiocca M, Howard L,
Hampsch-Woodill M, Huang D, Ou B, Jacob R (2003) Assays
for hydrophilic and lipophilic antioxidant capacity (oxygen
radical absorbance capacity (ORACFL)) of plasma and other
biological and food samples. J Agric Food Chem 52:3273–3279
Prowse KR, Greider CW (1995) Developmental and tissue-specific
regulation of mouse telomerase and telomere length. Proc Natl
Acad Sci USA 92:4818–4822
Rao DV, Boyle GM, Parsons PG, Watson K, Jones GL (2003)
Influence of aging, heat shock treatment and in vivo total
antioxidant status on gene-expression profile and protein
synthesis in human peripheral lymphocytes. Mech Ageing Dev
124:55–69
Reed JR, Vukmanovic-Stejic M, Fletcher JM, Soares MVK, Cook JE,
Orteu CH, Jackson SE, Birch KE, Foster GR, Salmon M,
Beverley PCL, M.H.A R, Akbar AN (2004) Telomere erosion in
J Ornithol
123

Page 13

memory T cells induced by telomerase inhibition at the site of
antigenic challenge in vivo. J Exp Med 199:1433–1443
Ricklefs RE, Scheuerlein A (2001) Comparison of aging-related
mortality among birds and mammals. Exp Gerontol 36:845–857
Rincon M, Rudin E, Barzilai N (2005) The insulin-IGF-1 signaling in
mammals and its relevance to human longevity. Exp Gerontol
40:873–877
Robertson R, Rendell WB (2001) A long-term study of reproductive
performance in tree swallows: the influence of age and
senescence on output. J Anim Ecol 70:1014–1031
Romanyukha AA, Yashin AI (2003) Age related changes in
population of peripheral T cells: towards a model of immunose-
nescence. Mech Ageing Dev 124:433–443
Royle NJ, Surai PF, Hartley IR (2001) Maternally derived androgens
and antioxidants in bird eggs: complementary but opposing
effects? Behav Ecol 12:381–385
Rubin H (2002) The disparity between human cell senescence in vitro
and lifelong replication in vivo. Nat Biotechnol 20:675–681
Saino N, Ambrosini R, Martinelli R, Møller AP (2002) Mate fidelity,
senescence in breeding performance and reproductive trade-offs
in the barn swallow. J Anim Ecol 71:309–319
Saino N, Ferrari RP, Romano M, Rubolini D, Møller AP (2003)
Humoral immune response in relation to senescence, sex and
sexual ornamentation in the barn swallow (Hirundo rustica). J
Evol Biol 16:1127–1134
Sedivy JM (1998) Can ends justify the means? Telomeres and the
mechanisms of replicative senescence and immortalization in
mammalian cells. Proc Natl Acad Sci USA 95:9078–9081
Serra V, von Zglinicki T, Lorenz M, Saretzki G (2003) Extracellular
superoxide dismutase is a major antioxidant in human fibroblasts
and slows telomere shortening. J Biol Chem 278:6824–6830
Serrano AL, Andres V (2004) Telomeres and cardiovascular disease.
Does size matter? Circ Res 94:575–584
ShortR, Williams DD, BowdenDM (1997)Circulating antioxidants as
determinants of the rate of biological aging in pigtailed macaques
(Macaca nemestrina). J Gerontol Biol Sci 52A:B26–B38
Simoyi MF, Van Dyke K, Klandorf H (2002) Manipulation of plasma
uric acid in broiler chicks and its effect on leukocyte oxidative
activity. Am J Physiol Regul Integr Comp Physiol 282:R791–
R796
Sohal RS, Weindruch R (1996) Oxidative stress, caloric restriction
and aging. Science 273:59–63
Sohal RS, Svensson I, Sohal BH, Brunk UT (1989) Superoxide anion
radical production in different species. Mech Ageing Dev
49:129–135
Sohal RS, Svensson I, Brunk UT (1990) Hydrogen peroxide
production by liver mitochondria in different species. Mech
Ageing Dev 53:209–215
Sohal RS, Mockett RJ, Orr WC (2002) Mechanisms of aging: an
appraisal of the oxidative stress hypothesis. Free Radic Biol Med
33:575–586
Son NH, Joyce B, Hieatt A, Chrest FJ, Yanovski J, Weng N-P (2003)
Stable telomere length and telomerase expression from naive to
memory B-lymphocyte differentiation. Mech Ageing Dev
124:427–432
Speakman JR (2005a) Correlations between physiology and life-
span—two widely ignored problems with comparative studies.
Aging Cell 4:167–175
Speakman JR (2005b) Body size, energy metabolism and lifespan. J
Exp Biol 208:1717–1730
Speakman JR, Selman C, McLaren JS, Harper JE (2002) Living fast,
dying when? The links between energetics and aging. J Nutr
132:1583–1597
St-Pierre J, Buckingham JA, Roebuck SJ, Brand MD (2002)
Topology of superoxide production from different sites in the
mitochondrial electron transport chain. J Biol Chem 277
Stadtman ER (1992) Protein oxidation and aging. Science 257:1220–
1224
Stedtman ER, Levine RL (2000) Protein oxidation. Ann NY Acad Sci
899:191–208
Tahara S, Matsuo M, Kaneko T (2001) Age-related changes in
oxidative damage to lipids and DNA in rat skin. Mech Ageing
Dev 122:415–426
Takata M, Sasaki MS, Sonoda E, Morrison C, Hashimoto M, Utsumi
H, Yamaguchi-Iwai Y, Shinohara A, Takeda S (1998) Homol-
ogous recombination and non-homologous end-joining pathways
of DNA double-strand break repair have overlapping roles in the
maintenance of chromosomal integrity in vertebrate cells.
EMBO J 17:5497–5508
Tavecchia G, Pradel R, Boy V, Johnson AR, Cezilly F (2001) Sex-
and age-related variation in survival and cost of first reproduc-
tion in greater flamingos. Ecology 82:165–174
Taylor HA, Delany ME (2000) Ontogeny of telomerase in chicken:
impact of downregulation on pre- and postnatal telomere length
in vivo. Dev Growth Differ 42:613–621
Tella JL, Scheuerlein A, Ricklefs RE (2001) Is cell-mediated
immunity related to the evolution of life-history strategies in
birds? Proc R Soc Lond 269:1059–1066
Valdes AM, Andrew T, Gardner JP, Kimura M, Oelsner E, Cherkas
LF, Aviv A, Spector TD (2005) Obesity, cigarette smoking, and
telomere length in women. Lancet 366:662–664
van de Pol M, Verhulst S (2006) Age-dependent traits: a new
statistical model to separate within- and between-individual
effects. Am Nat 167:766–773
Vleck CM, Vleck D (2002) Physiological condition and reproduc-
tive consequences in Ade ´lie penguins. Integr Comp Biol
42:76–83
Vleck CM, Haussmann MF, Vleck D (2003) The natural history of
telomeres: tools for aging animals and exploring the aging
process. Exp Gerontol 38:791–795
von Schantz T, Bensch S, Grahn M, Hasselquist D, Wittzell H (1999)
Good genes, oxidative stress and condition-dependent sexual
signals. Proc R Soc Lond B 266:1–12
von Zglinicki T (2000) Role of oxidative stress in telomere length
regulation and replicative senescence. Ann NY Acad Sci
908:99–110
von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends
Biochem Sci 27:339–344
von Zglinicki T, Pilger R, Sitte N (2000) Accumulation of single-
strand breaks is the major cause of telomere shortening in human
fibroblasts. Free Radic Biol Med 28:64–74
Walker GA, Lithgow GJ (2003) Lifespan extension in C. elegans by a
molecular chaperone dependent upon insulin-like signals. Aging
Cell 2:131–139
Wallis JW (2004) A physical map of the chicken genome. Nature
432:761–764
Watson JD (1972) Origin of concatameric T4 DNA. Nat New Biol
239:197–201
Weinert BT, Timiras PS (2003) Physiology of aging. Invited review:
theories of aging. J Appl Physiol 95:1706–1716
Weng N, Levine BL, June CH, Hodes RJ (1995) Human naive and
memory T lymphocytes differ in telomeric length and replicative
potential. Proc Natl Acad Sci 92:11091–11094
White CR, Seymour RS (2005) Allometric scaling of mammalian
metabolism. J Exp Biol 208:1611–1619
Wiersma P, Selman C, Speakman JR, Verhulst S (2004) Birds
sacrifice oxidative protection for reproduction. Proc R Soc Lond
B 271[Suppl]:S360–S363
Wise PM (2000) Neuroendocrine correlates of aging. Neuroendocri-
nol Physiol Med 371–387
Wong K-K, Maser RS, Bachoo RM, Menon J, Carrasco DR, Gu Y,
Alt FW, DePinho RA (2003) Telomere dysfunction and Atm
J Ornithol
123

Page 14

deficiency compromises organ homeostasis and accelerates
ageing. Nature 421:643–648
Wright WE, Shay JW (2002) Historical claims and current interpre-
tations of replicative aging. Nat Biotechnol 20:682–688
Wu X, Amos CI, Zhu Y, Zhao H, Grossman BH, Shay JW, Luo S,
Hong WK, Spitz MR (2003) Telomere dysfunction: a potential
cancer predisposition factor. J Natl Cancer Inst 95:1211–1218
Yan LJ, Levine RL, Sohal RS (1997) Oxidative damage during aging
targets mitochondrial aconitase. Proc Natl Acad Sci USA
94:11168–11172
Zeichner SL, Palumbo P, Feng Y, Xiao X, Gee D, Sleasman J,
Goodenow M, Riggar R, Dimitrov D (1999) Rapid telomere
shortening in children. Blood 93:2824–2830
J Ornithol
123