Download Negligible senescence in the longest living rodent, the

J Comp Physiol B (2008) 178:439–445
DOI 10.1007/s00360-007-0237-5
R EV IE W
Negligible senescence in the longest living rodent,
the naked mole-rat: insights from a successfully aging species
Rochelle BuVenstein
Received: 11 September 2007 / Revised: 8 November 2007 / Accepted: 5 December 2007 / Published online: 8 January 2008
© Springer-Verlag 2007
Abstract Aging refers to a gradual deterioration in function that, over time, leads to increased mortality risk, and
declining fertility. This pervasive process occurs in almost
all organisms, although some long-lived trees and cold
water inhabitants reportedly show insigniWcant aging. Negligible senescence is characterized by attenuated agerelated change in reproductive and physiological functions,
as well as no observable age-related gradual increase in
mortality rate. It was questioned whether the longest living
rodent, the naked mole-rat, met these three strict criteria.
Naked mole-rats live in captivity for more than 28.3 years,
»9 times longer than similar-sized mice. They maintain
body composition from 2 to 24 years, and show only slight
age-related changes in all physiological and morphological
characteristics studied to date. Surprisingly breeding
females show no decline in fertility even when well into
their third decade of life. Moreover, these animals have
never been observed to develop any spontaneous neoplasm.
As such they do not show the typical age-associated acceleration in mortality risk that characterizes every other
known mammalian species and may therefore be the Wrst
reported mammal showing negligible senescence over the
majority of their long lifespan. Clearly physiological and
biochemical processes in this species have evolved to dramatically extend healthy lifespan. The challenge that lies
ahead is to understand what these mechanisms are.
Communicated by I.D. Hume.
R. BuVenstein (&)
Department of Physiology and The Sam and Ann Barshop Institute
for Longevity and Aging Studies, University of Texas Health
Science Center at San Antonio, 15355 Lambda Dr STCBM 2.2,
San Antonio, TX 78245, USA
e-mail: [email protected]
Keywords Slow aging · Maximum lifespan ·
Oxidative stress · Reproduction · Heterocephalus glaber
Abbreviations
MLSP Maximum lifespan
LQ
Longevity quotient
BMR Basal metabolic rate
ROS
Reactive oxygen species
Introduction
Aging remains one of the most poorly understood biological phenomena. This is partially because it is an inherently
integrative and complex process, further complicated by the
diYculty in separating the eVects of normal aging from
those manifested as a consequence of age-associated diseases. Aging, deWned as a progressive, irreversible, endogenous and deleterious process (Strehler 1962), induces a
decline in physiological and reproductive capacity. Over
time, this turns young healthy adults into older, frail and
less fertile adults who are increasingly susceptible to environmental challenges (such as extreme temperature, or disease-inducing infectious agents) with a concomitant greater
risk of dying (Miller 1999; Martin 2006). The progressive
character of aging suggests that causes are present throughout adult life and rates of aging may be discerned at all
ages, enabling the distinction of the young from old
throughout the animal kingdom. The endogenous nature of
aging implies that mechanisms that determine or limit its
rate are encoded in the genome, and most likely constitute a
suite of genetically determined somatic maintenance mechanisms that may serve as maximum species lifespan
(MLSP) determinants under ideal conditions. The ability
for the genome to evolve these mechanisms that ensure
123
123
30
Naked mo le- rat
20
10
0
0
2
4
6
8
10
12
L n Ma s s ( g )
Fig. 1 Maximum lifespan (MLSP) as a function of body mass of rodents. Please note that the naked mole-rat MLSP lies more than two
standard deviations away from this descriptor
5
Longevity Quotient
longevity, however, can only be expressed when the species is protected from extrinsic factors (e.g., predation and
climatic extremes). While extrinsic factors such as environmental stressors, (e.g., toxic chemicals) may contribute to
the aging process, enhancing or diminishing endogenous
eVects, they, themselves, are not determinants of MLSP.
Maximum species lifespan is considered an important
species characteristic of the aging process. Reported MLSP
varies more than 40,000-fold across the animal kingdom
and even within mammals MLSP varies by two orders of
magnitude. Generally MLSP lengthens in a predictable
manner as species increase in size, such that for every doubling of body mass, there is, on average, a 13% increase in
MLSP for non-volant, non-aquatic mammals (de Magalhaes et al. 2007). Even in that tightly controlled study where
only veriWed lifespan data from the newly formed “Anage
web site” were used, and aquatic cetaceans and volant bats
omitted from regression analyses, a large proportion of the
variation (>50%) is not explained by body mass. Rather
MLSP appears to be taxon speciWc such that within mammals cetaceans, primates and bats have higher longevity
quotients (LQs—i.e. the ratio of observed lifespan to that
predicted by size for non-volant mammals), while marsupials are shorter-lived (de Magalhaes et al. 2007).
Longevity may also be dependent upon ecological variables that inXuence extrinsic mortality (Ricklefs 1998):
subterranean animals, protected from both climatic
extremes and predation, tend to live longer than the aboveground dwelling similar-sized species (BuVenstein 2005)
and similarly, Xying mammals that rest in inaccessible
localities (e.g. caves) and avoid land predators by Xying are
also extremely long-lived (Austad and Fischer 1991).
Extended longevity is also correlated with group or social
living, such that bats that live in large roosts, social primates, colony dwelling mole-rats, and the eusocial insects
(honey bees, wasps, and ants) all show extended longevity
(Carey and Judge 2001; BuVenstein 2005; Keller and Jemielty 2006). Enhanced Wtness and prolonged longevity in
these species may reXect intergenerational transfer of information, communal care of young and shared foraging
endeavors (BuVenstein 2005).
Within some taxa certain species conspicuously stand
out as being exceptionally long-lived. One such species is
the naked mole-rat, the longest-living rodent known
(Fig. 1); with a LQ that far exceeds any other rodent species
(Fig. 2). Naked mole-rats (Rodentia: Bathyergidae; Heterocephalus glaber) are mouse-sized (»35 g) hystricognath
rodents, that in captivity live more than 28.3 years (BuVenstein and Jarvis 2002). Not only can we glean considerable
insight into the various evolutionary theories of aging
(alluded to above), but this species may also provide information about the timing of age-related declines, and mechanisms employed during the ubiquitous aging process.
J Comp Physiol B (2008) 178:439–445
Maximum lifespan (y)
440
N a k e d m o l e - r at
4
3
2
1
LQ=1
0
0
2
4
6
8
10
12
L n M as s ( g )
Fig. 2 Longevity quotients of rodents. These values are determined
using the observed MLSP and the lifespan values predicted from the
relationship between maximum lifespan and body mass (as determined
from de Magalhaes et al. (2007) equation (MLSP = 3.34 M0.193 (g) for
all mammals excluding cetaceans and bats). A longevity quotient of 1
means that observed MLSP is similar to that predicted by body size.
The naked mole-rat is an extreme outlier from the general trend, living
Wve times longer than expected by mass
It was speciWcally questioned whether this exceptionally
long-lived rodent, like marine inhabitants from cold aquatic
environments (Finch and Austad 2001) showed signs of
negligible senescence at both physiological and biochemical levels. Negligible senescence was a term coined by
Caleb Finch (1990), to describe the very slow aging
reported in coldwater Wsh, bivalves, turtles and whales.
Many of these organisms, aged by growth zone analyses of
the otolith, ear bone or shell, are thought to live for more
than 100 years. Caleb Finch proposed three speciWc criteria
to test the occurrence of negligible senescence, namely no
observable: (1) age-related increase in mortality rate, (2)
decrease in reproduction rate after maturity, and (3) no agerelated decline in physiological capacity. This paper
reviews the data attained to date which leads us to ask if the
naked mole-rat may be the Wrst known mammal to show
signs of negligible senescence over the major proportion of
its long lifespan. If so how is this species able to exhibit
retarded rates of aging.
J Comp Physiol B (2008) 178:439–445
441
Mortality rates of naked mole-rats are highest in their Wrst
2 months of life, and death in this age cohort is generally
attributed to inadequate maternal care, cannibalism by siblings and poor inoculation of gastrointestinal Xora and fauna.
Thereafter, age-speciWc rates of mortality are not evident,
with random distribution of deaths by natural causes in all
age groups. It is extremely diYcult to plot mortality curves
for our colonies, as the animals were routinely used in experiments or individuals were removed from colonies to found
new colonies and many of our earlier cohorts were given to
other researchers and zoos, while colonies may continue to
expand through successful reproductive endeavors. Therefore, data from wild-caught animals and animals born in the
Wrst year in captivity are presented in Fig. 3. Of these 86 animals, 43% were still alive 24 years later, when a building
malfunction resulted in the animal facility overheating
thereby accidentally killing all the animals housed in that
room. Looking at this Wgure it is evident that there is no speciWc increase in age-related mortality over a 24-year period.
Mortality reports collated over a single year (to assess the
impact thereof on the proportion of the age cohort of the
population that was still alive) revealed a similar percentage
of still living animals at 7% (n = 87), 35% (n = 89), 53%
(n = 19) and 85% (n = 27) of maximum lifespan (Fig. 4),
despite the smaller number of total animals in the older age
cohorts. Sherman and Jarvis (2002) also reported that 87%
of the animals that they had identiWed as more than 15 years
of age (ranging from 15 to >26 years) were still alive 2 years
after their initial analyses. Deaths occur with equal low frequency in all age-cohorts and do not follow the expected
actuarial aging pattern of increasing mortality as animals
exceed 50% of their maximum lifespan (Fig. 4).
Although we do not house naked mole-rats in a barrier
facility, we seldom Wnd sick animals and to date, have not
100
% Alive
80
60
40
20
Proportion of age cohort (%)
Age-related changes in mortality rate
% alive
% dead
100.0
80.0
60.0
40.0
20.0
0.0
7
35
53
85
Proportion of MLSP (%)
Fig. 4 Percentage of animals out of the total population age cohort
that were alive (grey bars) or died (black bars) of natural causes over
a 12-month-period. Age cohort data are expressed as a percentage of
MLSP. Relative annual death rates at 7% of MLPS (2 years of age,
n = 87), 35% (10 years, n = 89), 53% (15 years, n = 19) and 85%
(24 years, n = 27) were similar
observed a single incidence of cancer in our large colony
(n = 800 animals). Naked mole-rats do not show the typical
age-associated acceleration in mortality risk that characterizes nearly every other mammalian species for which
detailed survival data are available. Our unusual mortality
pattern may reXect the low susceptibility of these animals
to cancer and disease and may also indicate that naked
mole-rats may live longer than our current MLSP record.
It appears that naked mole-rats show few signs of agerelated mortality until very late in life, and may show a sudden increase in death near the MLSP. Although this has not
been previously reported for mammals, this pattern has
been observed for a number of insects (e.g. mayXies) that
reproduce only once, shortly before they die (Carey 2002).
Death in these semelparous organisms, however, appears to
be primarily determined by reproductive activities rather
than aging per se. Although, it is possible that iteroparous
organisms may also show this sudden death at late age, to
date there are no published lifespan data that show this type
of pattern and all the published data for mammals show
gradual age-related increases in mortality rate. The oldest
cohort in my naked mole-rat colony (>27.5 years) is now
beginning to show pronounced signs of aging and are less
active and appear frail. It is therefore most likely that these
captive caught individuals are near the end of their lifetime
and that they possibly will show a sudden increase in death
very near their MLSP, rather than the typical gradual agerelated increase in mortality.
0
0
5
10
15
20
25
30
Min Age (y)
Fig. 3 Using data from our original Weld caught population and those
born the Wrst year in captivity, the frequency of death by natural causes
in each age cohort is plotted. Please note that at the end of this monitored period 39 individuals older than 20 years of age were still alive
Reproductive function and age
A trade-oV between fecundity and life expectancy is an
integral component of most evolutionary theories of aging
(Ricklefs 1998). The antagonistic pleiotropy theory of
123
442
J Comp Physiol B (2008) 178:439–445
aging posits that natural selection has favored genes conferring short-term beneWts to the organism at the cost of deterioration in later life. This forms the basis of the disposable
soma theory of aging as outlined by Kirkwood (1977) that
suggests that animals either partition more energy to
somatic maintenance, or partition more energy into reproductive processes. They therefore have greater reproductive
output over a shorter period and because their tissues are
not adequately maintained, die young. On the other hand,
those animals that do not reproduce immediately but rather
maintain, and repair their soma, lived longer. The vast
majority of individuals in a naked mole-rat colony never
reproduce (Jarvis 1981). Those that do become dominant
breeding females, however, show no diVerence in captive
lifespan to those that never breed (Table 1; Sherman and
Jarvis 2002; BuVenstein 2005) and generally continue to
breed until they die. Once they become established breeding females and have completed their reproductive growth
surge of lumber vertebrae (O’Riain et al. 2000), reproductive output increases with age as a result of larger litter
sizes in well-established breeders (Table 2). Indeed our
most successful captive born breeding female reproduced
for the last 11 years of her life, and reared more than 900
babies in her 23.66 years life time (BuVenstein and Jarvis
2002). An age-related decline in reproductive fertility was
not evident since she produced 21 pups in her last litter.
Indeed most of the established breeding females over
20 years of age produce very large litters (Table 2), indicative of sustained fertility in later life. While elderly breeding females tend to have very large litters, many of the pups
born to elderly females die before weaning. This may be
due to inadequate maternal milk production or greater disturbance in larger colonies where the older well-established
breeders tend to be found.
Demographic studies in the wild concur. Breeding
females maintain their dominance for at least 17 years (Braude personal communication) and live at least four times
longer than non-breeding (»4 years) individuals (Table 1).
Higher mortality rates in non-breeding castes than breeders
in the wild are to be expected, given the greater likelihood
of extrinsic causes of mortality by either predation or accidental death.
Similar lifespan between breeders and non-breeders in
captivity is all the more surprising when the energetic
Table 1 Lack of diVerent MLSP among breeders and non-breeding
naked mole-rats
Breeder
Non-breeder
MLSP captivity (years)
>28.3
>27
MLSP wild Braude, personal
communication (years)
>17
»4
45
35
Mass of old NMR >24 years (g)
123
Table 2 DiVerential reproductive success of young and old breeding
females
Young breeder
Old breeder
Mass (g)
37
45
Mean mass increase (%)
33
84
Max mass increase (%)
57
110
Mean litter size
9
16
Max litter size
12
29
Pup mass (g)
1.0–2.2
1.0–2.4
demands associated with pregnancy are taken into account
(Urison and BuVenstein 1995). Breeding females may
breed continuously (approximately every 3 months) from
the time they become breeders until they die. Body mass
may double by the end of gestation and this is associated
with a >1.5-fold increase in metabolic rate (Urison and
BuVenstein 1995), even higher energetic demand during
lactation, and concomitant oxidative stress. Clearly breeding females partition a considerable proportion of their
energy resources into reproduction, yet nevertheless adequately maintain their soma and reproductive tissues far
longer than do most small mammals.
Naked mole-rat reproductive data therefore does not
support the disposable soma theory of aging. Fertility
clearly does not become impaired with age, as commonly
occurs in most mammals and as such naked mole-rat reproductive information concurs with one of the key criteria
used in the deWnition of negligible senescence.
Age-related changes in behavior, physiology
and morphology
Older naked mole-rats, like those of most other species,
tend to be less active. Sleep patterns in both young and old
naked mole-rats are random and do not follow a speciWc
circadian rhythm, as commonly occurs in other small mammals (Davis-Walton and Sherman 1994; Riccio and Goldman 2000), but more closely resemble those of longer
living species, be they aquatic or large mammals (Siegel
2005).
Long-living mole-rats show only slight changes in morphology and maintain physiological function and activity
well into their third decade of life. Basal metabolic rate
(BMR) is unchanged and gastrointestinal absorption and
enzymatic activities show only slight deterioration with age
(O’Connor et al. 2002; BuVenstein 2005; Yang and BuVenstein 2002). Similarly, sustained vascular youthfulness, in
keeping with attenuated rates of aging, is evident (Fig.5;
Csiszar et al. 2007).
Regardless of whether BMR is expressed per fat free
mass or as mass-speciWc metabolic rate it remains
J Comp Physiol B (2008) 178:439–445
443
120
100
80
Ma x im a l l v a s cu la r r el a x at io n
to acetyl choline (%)
60
40
Rat
Naked mole-rat
20
0
0
2
6
4
120
8
10
12
14
10
12
14
Age (years)
100
80
60
40
20
0
0
2
6
4
8
% of maximal lifespan
Fig. 5 Unchanged age-related vascular relaxation properties in response to acetylcholine of naked mole-rat vessels, compared to those
from Fisher 344 rat. Figure modiWed from Csiszar et al. (2006)
unchanged at least till 20 years of age (Table 3; O’Connor
et al. 2002). BMR of naked mole-rats is 30% lower than
predicted by body mass (O’Connor et al. 2002), but this
reduction in oxygen consumption with its inevitable byproduct, oxidative damage, is not suYcient to fully account
for the Wvefold diVerence in extended longevity (compared
to that predicted from body size). Given their exceptional
longevity it is not surprising that naked mole-rats have the
highest mass-speciWc lifetime energy expenditure (LEE) of
any known mammal (O’Connor et al. 2002). LEE does not
take into account the diVerences in metabolic expenditure
when not at rest nor the amount of time spent active.
Unchanged vascular function is also evident, with blood
vessels maintaining elasticity over a prolonged period of
time (Csiszar et al. 2006). Unlike the substantial decline in
NO-mediated dilations in rat arteries (Hamilton et al. 2001;
Table 3 Unchanged physiological, morphological and biochemical variables with age in
naked mole-rats
Csiszar et al. 2002, 2005), sensitivity of the naked mole-rat
smooth muscle cells to NO does not change over a 10-year
period or over a similar proportionate change in total
lifespan (Fig. 5). Indeed NO is known to exert vasculoprotective and anti-atherogenic eVects and atherosclerotic vascular disease is often thought to be due decreased
bioavailability of NO with aging (reviewed in reference
Csiszar et al. (2005)) and data on naked mole-rat support
this premise.
Bone integrity of naked mole-rats is also maintained
from 2 to more than 24 years of age, with considerable evidence of highly eYcient bone remodeling processes (large
number of secondary osteons, well maintained cortical
bone and remodeling through growth plate) so that bone
mineral content remains unchanged (Kramer, Jepsen, Terranova and BuVenstein, unpublished data).
Many animals as they age become insulin-insensitive
and glucose-intolerant. Not surprisingly given the attenuated age-related physiological and morphological changes,
no change in glucose handling is evident over a large age
range (BuVenstein et al. 2007) and similarly glycated
hemoglobin levels remain constant (Yang and BuVenstein
2004).
Although the particular sets of genes responsible for
senescence and the associated physiological end-points are
likely to vary among species, attenuated changes in a wide
variety of physiological, morphological, biochemical and
molecular variables with age collectively suggest that physiological and biochemical functions of naked mole-rats are
not compromised. As such, the naked mole-rat appears to
meet the third criteria of negligible senescence.
Age-related changes in biochemical markers
One would expect that long-lived animals would accrue
less oxidative damage (Harman 1956). However, recent
studies revealed that this is not the case in naked mole-rats.
These rodents produce similar amounts of, or marginally
Naked mole-rat
Mice and rats
Source
Basal metabolic rate
Unchanged
Declines
O’Connor et al. (2002)
Vascular relaxation
Unchanged
Declines
Csiszar et al. (2006)
Bone cortical area
Unchanged
Declines
Kramer, unpublished data
Bone mineral density
Unchanged
Declines
O’Connor et al. (2002)
Articular cartilage
Unchanged
Declines
Pinto, unpublished data
ROS production
Unchanged
Increases
Csiszar et al. (2006)
Antioxidant activity
Unchanged
Increases
Andziak et al. (2005)
Oxidative damage
Unchanged
Increases
Andziak and BuVenstein (2006)
Glucose tolerance
Unchanged
Declines
BuVenstein et al. (2007)
Glycated hemoglobin
Unchanged
Declines
Yang and BuVenstein (2002)
123
444
less, ROS than shorter-lived species (Labinskyy et al. 2006;
Lambert et al. 2007) and possess an antioxidant defense
suite that is not superior to shorter living rodents with similar levels of catalase activity, low levels of glutathione and
glutathione peroxidase and with no evidence of compensation by the upregulation of other antioxidants (Andziak
et al. 2005, 2006). Even from young age naked mole-rats
exhibit high levels of oxidative damage to DNA lipids and
proteins without any impact upon physiological function
(Andziak et al. 2006), yet they continue to thrive for an
additional 26 years while young mice have less than 3 years
of life left (Andziak et al. 2006). Despite these very high
steady state oxidative damage levels, naked mole-rats
exhibit markedly attenuated age-related changes in mitochondrial mass and eYciency as well ROS production
(Cziszar et al. 2007), antioxidant activity (Andziak and
BuVenstein 2006), membrane composition (Hulbert et al.
2006) and lipid peroxidation (Andziak and BuVenstein
2006). Moreover, although protein oxidation is high, it too
does not alter with age and appears to have no impact on
enzymatic activity, unfolding resistance or ubiquitination
(Pierce et al. 2006). These data collectively suggest that
even at the cellular level functional integrity is maintained
during their long lives and repair and removal of damaged
macromolecules closely match that accrued. Membrane
composition and tight regulation of cellular metabolism and
the functional organelles involved in these processes, may
explain the remarkable resistance of naked mole-rat tissues
to a wide range of oxidative insults (Labinskyy et al. 2006;
Hulbert et al. 2007).
It is not known why naked mole-rats exhibit such high
levels of oxidative damage, especially at young age with no
impairment of function. While it could be because oxidative damage has nothing to do with aging, it could also be
due in part to early life stresses prior to the development of
an adequate antioxidant defense, and these may be associated with being housed in captivity under the comparatively
hyperoxic above ground atmosphere relative to that
encountered in deep underground burrows teeming with
colony members and other oxygen-sapping organisms
(BuVenstein 2000). Alternately, high oxidative stress may
reXect the lack of a circadian sleep rhythm and short naps
rather than prolonged sleep especially in young precocial
pups (Bennett and Faulks 2000). Both rodents and Xies that
are sleep-deprived have high levels of oxidative stress and
evidence of membrane disruption and sleep deprivation can
cause death more quickly than food deprivation (Siegel
2005).
High levels of oxidative stress with no impact upon longevity and physiological function and furthermore not
resulting in age-related damage accrual challenge the
revered oxidative stress theory of aging (Harman 1956) and
thus demand further investigation.
123
J Comp Physiol B (2008) 178:439–445
Conclusion
Despite some gaps in our current knowledge concerning
comprehensive demographic statistics and the proximate
mechanisms employed to retard aging, naked mole-rats
appear to concur with all three criteria for negligible senescence proWles. Despite living nine-times longer than similar
sized mice, these rodents show attenuated age-associated
acceleration in mortality risk, continue to reproduce well
into their third decade and show no typical signs of agerelated deteriorations in physiological or biochemical function, until possibly very near their MLSP. No doubt, these
unusual rodents will provide novel insights into the mechanisms involved in aging, be they public or private (Martin
2006), thereby facilitating their extraordinary longevity.
They thus may prove to be an invaluable useful non-traditional model for aging research and for testing the ubiquity
of both ultimate and proximate theories of aging.
Acknowledgments Peter Hornsby, Pedro de Magalhaes and an
anonymous reviewer are sincerely thanked for their constructive comments on this manuscript. Author gratefully acknowledges the contributions by his CCNY students (Yael Edrey, Yael Grun Kramer, Mario
Pinto and Ting Yang) and collaborators (Dianna Casper, Asish Chaudhuri Anthony Hulbert, Jenny Jarvis, Karl Jepsen, Justine Salton, Carl
Terranova). The animal care staV at the University of Cape Town,
Medical School of the University of the Witwatersrand, and City College of New York is sincerely thanked for their dedicated and prolonged care of these unusual colonies. Funding from the NIH/NIA is
gratefully acknowledged (AG-022891).
References
Andziak B, BuVenstein R (2006) Disparate patterns of age-related
changes in lipid peroxidation in long-lived naked mole-rats and
shorter-lived mice. Aging Cell 5:525–532
Andziak B, O’Connor TP, BuVenstein 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
Andziak B, O’Connor TP, Qi W, De Waal EM, Pierce A, Chaudhuri
AR, Van Remmen H, BuVenstein R (2006) High oxidative damage levels in the longest-living rodent, the naked mole-rat. Aging
Cell 5:463–471
Austad SN (2001) An experimental paradigm for the study of slowly
aging organisms. Exp Gerontol 36:599–605
Austad SN, Fischer KE (1991) Mammalian aging, metabolism, and ecology: evidence from bats and marsupials. J Gerontol 46:B47–B53
Bennett NC, Faulks CG (2000) African mole-rats: ecology and eusociality. Cambridge University Press, Cambridge
BuVenstein R (2000) Ecophysiological responses to an underground
habitat. In: Lacey E, Patton J, Cameron G (eds) The biology of subterranean rodents. Chicago University Press, Chicago, pp 62–110
BuVenstein R (2005) The naked mole-rat: a new long-living model for
human aging research? J Gerontol 60:1369–1377
BuVenstein R, Jarvis JUM (2002) The naked mole rat—a new record
for the oldest rodent. Science’s SAGE KE. http://sageke.sciencemag.org/cgi/content/full/sageke;2002/21/pe7
BuVenstein R, Kang HJ, Biney A (2007) Glucose tolerance and insulin
sensitivity in an extremely long-living rodent, the naked mole-rat.
FASEB J 21:A1423–A1423
J Comp Physiol B (2008) 178:439–445
Carey JR (2002) Longevity minimalists: life table studies of two species of northern Michigan adult mayXies. Exp Gerontol 37:567–
570
Carey JR, Judge DS (2001) Life span extension in humans is self-reinforcing: a general theory of longevity. Popul Dev Rev 27:411–
436
Csiszar A, Ungvari Z, Edwards JG, Kaminski PM, Wolin MS, Koller
A, Kaley G (2002) Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res 90:1159–
1166
Csiszar A, Pacher P, Kaley G, Ungvari Z (2005) Role of oxidative and
nitrosative stress, longevity genes and poly(ADP-ribose) polymerase in cardiovascular dysfunction associated with aging. Curr
Vasc Pharmacol 3:285–291
Csiszar A, Ahmad M, Smith KE, Labinskyy N, Gao Q, Kaley G, Edwards JG, Wolin MS, Ungvari Z (2006) Bone morphogenetic protein-2 induces proinXammatory endothelial phenotype. Am J
Pathol 168:629–638
Csiszar A, Labinskyy N, Orosz Z, Xiangmin Z, BuVenstein R, Ungvari
Z (2007) Vascular aging in the longest-living rodent, the naked
mole rat. Am J Physiol Heart Circ Physiol 293:H919–H927
Davis-Walton J, Sherman PW (1994) Sleep arrhythmia in the eusocial
naked mole-rat. Naturwissenschaften 81:272–275
de Magalhaes JP, Costa J, Church GM (2007) An analysis of the relationship between metabolism, developmental schedules, and longevity using phylogenetic independent contrasts. J Gerontol A
Biol Sci Med Sci 62:149–160
Finch CE (1990) Longevity, senescence and the genome. University of
Chicago Press, Chicago
Finch CE, Austad SN (2001) History and prospects: symposium on
organisms with slow aging. Exp Gerontol 36:593–597
Hamilton CA, Brosnan MJ, McIntyre M, Graham D, Dominiczak AF
(2001) Superoxide excess in hypertension and aging: a common
cause of endothelial dysfunction. Hypertension 37:529–534
Harman D (1956) Aging: a theory based on free radical and radiation
chemistry. J Gerontol 11:298–300
Hulbert AJ, Faulks SC, BuVenstein R (2006) Oxidation-resistant membrane phospholipids can explain longevity diVerences among the
longest-living rodents and similarly-sized mice. J Gerontol A Biol
Sci Med Sci 61:1009–1018
Hulbert AJ, Pamplona R, BuVenstein R, Buttemer WA (2007) Life and
death: metabolic rate, membrane composition and lifespan of animals. Physiol Rev 87:1175–1213
Jarvis JUM (1981) Eusociality in a mammal: cooperative breeding in
naked mole-rat colonies. Science 212:571–573
445
Keller L, Jemielty S (2006) Social insects as a model to study the
molecular basis of ageing. Exp Gerontol 41:553–556
Kirkwood TB (1977) Evolution of ageing. Nature 24:301–304
Labinskyy N, Csiszar A, Orosz Z, Rivera A, Smith K, BuVenstein R,
Ungvari Z (2006) Comparison of endothelial function, O2.- and
H2O2 production and vascular oxidative stress resistance between the longest-living rodent, the naked mole-rat and mice. Am
J Physiol 291:H2698–H2704
Lambert AJ, Boysen HM, Buckingham JA, Yang T, Podlutsky A, Austad SN, Kunz TH, BuVenstein R, Brand MD (2007) Low rates of
hydrogen peroxide production by isolated heart mitochondria
associate with long maximum lifespan in vertebrate homeotherms. Aging Cell 6:607–618
Martin GM (2006) Keynote lecture: an update on the what, why and
how questions of ageing. Exp Gerontol 41:460–463
Miller RA (1999) Kleemeier award lecture: are there genes for aging?
J Gerontol Biol Sci 54A:B297–B307
O’Connor TP, Lee A, Jarvis JUM, BuVenstein R (2002) Prolonged longevity in naked mole-rats: age-related changes in metabolism,
body composition and gastrointestinal function. Comp Biochem
Physiol 133:835–842
O’Riain MJ, Jarvis JUM, Alexander R, BuVenstein R, Peeters C (2000)
Morphological castes in a vertebrate. Proc Natl Acad Sci USA
97:13194–13197
Pierce AP, De Waal E, BuVenstein R, Chaudhuri A (2006) Elevated
carbonylations on speciWc proteins in the longest living rodent,
the naked mole rat. Free Radic Biol Med 41:S139
Riccio AP, Goldman BD (2000) Circadian rhythms of body temperature
and metabolic rate in naked mole-rats. Physiol Behav 71:15–22
Ricklefs RE (1998) Evolutionary theories of aging; conWrmation of a
fundamental prediction, with implications for the genetic basis
and evolution of life span. Am Nat 152:24–44
Siegel JM (2005) Clues to the functions of mammalian sleep. Nature
437:1264–1271
Sherman PW, Jarvis JUM (2002) Extraordinary life spans of naked
mole-rats (Heterocephalus glaber). J Zool (Lond) 258:307–311
Strehler BL (1962) Time, cells and aging. Academic Press, New York
Urison NT, BuVenstein R (1995) Metabolic and body temperature
changes during pregnancy and lactation in the naked mole-rat
(Heterocephalus glaber). Physiol Zool 68:402–420
Yang T, BuVenstein R (2002) Disparate age eVects on gastrointestinal
enzymes in naked mole-rats. Integr Comp Biol 42:1340–1341
Yang T, BuVenstein R (2004) EVect of aging on glycated hemoglobin
and blood glucose concentration in naked mole-rats. FASEB J
18:A1301–A1302
123