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Being cool: how body temperature influences ageing and longevity



Temperature is a basic and essential property of any physical system, including living systems. Even modest variations in temperature can have profound effects on organisms, and it has long been thought that as metabolism increases at higher temperatures so should rates of ageing. Here, we review the literature on how temperature affects longevity, ageing and life history traits. From poikilotherms to homeotherms, there is a clear trend for lower temperature being associated with longer lifespans both in wild populations and in laboratory conditions. Many life-extending manipulations in rodents, such as caloric restriction, also decrease core body temperature. Nonetheless, an inverse relationship between temperature and lifespan can be obscured or reversed, especially when the range of body temperatures is small as in homeotherms. An example is observed in humans: women appear to have a slightly higher body temperature and yet live longer than men. The mechanisms involved in the relationship between temperature and longevity also appear to be less direct than once thought with neuroendocrine processes possibly mediating complex physiological responses to temperature changes. Lastly, we discuss species differences in longevity in mammals and how this relates to body temperature and argue that the low temperature of the long-lived naked mole-rat possibly contributes to its exceptional longevity.
Being cool: how body temperature influences ageing
and longevity
Gerald Keil
Elizabeth Cummings
o Pedro de Magalha
Received: 22 December 2014 / Accepted: 24 March 2015 / Published online: 2 April 2015
Ó The Author(s) 2015. This article is published with open access at
Abstract Temperature is a basic and essential
property of any physical system, including living
systems. Even modest variations in temperature can
have profound effects on organisms, and it has long
been thought that as metabolism increases at higher
temperatures so should rates of ageing. Here, we
review the literature on how temperature affects
longevity, ageing and life history traits. From poik-
ilotherms to homeotherms, there is a clear trend for
lower temperature being associated with longer lifes-
pans both in wild populations and in laboratory
conditions. Many life-extending manipulations in
rodents, such as caloric restriction, also decrease core
body temper ature. Nonetheless, an inverse relation-
ship between temperature and lifespan can be ob-
scured or reversed, especially when the range of body
temperatures is small as in homeotherms. An example
is observed in humans: women appear to have a
slightly higher body temperature and yet live longer
than men. The mechanisms involved in the relation-
ship between temperature and longevity also appear to
be less direct than once thought with neuroendocrine
processes possibly mediating complex physiological
responses to temperature changes. Lastly, we discuss
species differences in longevity in mammals and how
this relates to body temperature and argue that the low
temperature of the long-lived naked mole-rat possibly
contributes to its exceptional longevity.
Keywords Metabolism Neuroendocrine system
Life-extension Rate of living theory
The second law of thermodynamics states that within a
closed thermodynamic system the entropy will in-
crease over time until it reaches thermodynamic
equilibrium. This increase in molecular entropy over
time within living organisms has been proposed, under
the assumption that the secon d law of thermodynamics
applies to open systems, to increase susceptibility to
age-related disorders and thus essentially equate, at a
high level of abstraction, to the ageing process
(Hayflick 2007). Other authors have argued that
ageing is due to an increase in molecular disorder
due to an increase in thermodynamic entropy (Deme-
trius 2013). One of the factors known to affect
thermodynamics is temperature, and ther efore it has
been long speculated that it may influence the ageing
process with organisms ageing faster at higher tem-
peratures due to more molecular damage being
generated (Conti 2008; Liu and Walford 1972; Rikke
and Johnson 2004).
G. Keil E. Cummings J. P. de Magalha
es (&)
Integrative Genomics of Ageing Group, Institute
of Integrative Biology, University of Liverpool,
Liverpool L69 7ZB, UK
Biogerontology (2015) 16:383–397
DOI 10.1007/s10522-015-9571-2
Temperature is an essential property of biological
systems and various studies in many species have
associated temperature with ageing and longevity.
Early studies focused on animals that rely on external
sources of heat (ectotherms) and whose internal
temperature, because it depends on environmental
conditions, can vary considerably (poikilothermy). A
century ago, Loeb and Northrop showed that lifespan
correlates negatively with temperature in fruit flies
Drosophila melanogaster (Loeb and Northrop 1916).
Another early study to observe the effects of tem-
perature on longevity was in the cladoceran crustacean
Daphnia magna (MacArthur and Baillie 1929). Later
studies in other poikilotherms (in particular fishes),
demonstrated that even mild changes in temperature
over long periods of time can influence lifespan
(Walford and Liu 1965). Important contributions to
this field were made by Walford and Liu who pioneered
the use of the South American fish Cynolebias as a
model organism in laboratory temperature and
longevity studies (re viewed in Rikke and Johnson
2004). This was then further explored in species that
can generate their own body heat (endotherms) and
usually maintain a relatively constant body tem-
perature ( T
), also known as homeotherms, like mice
whereby marijuana derivativ es were used to induce
hypothermia. However, this approach was unable to
reduce T
long-term and thus was unable to properly
establish the effect of temperature on mouse longevity
(Rikke and Johnson 2004). Walford instead turned his
attention to the body temperatures of great yoga
masters in India which, despite the low sample size,
showed that a low calorie intake could reduce T
1–2 °C (Walford 1983). This low calorie intake was
then principally used by him to induce low T
homeotherms to investigate the effects of core T
longevity (reviewed in Rikke and Johnson 2004).
Since these early pioneering studies into tem-
perature and longevity, more recent studies have
continued to expand these ideas by using various other
species as models, with further consideration of the
relationship between life-extending interventions such
as caloric restriction (CR) and T
. Here, we review the
literature on how temperature affects ageing and
longevity from poikil otherms to homeotherms, in-
cluding rodent models of life-extension. Possible
mechanisms are discussed as well as the potential role
of a low body temperature on the exceptional
longevity of the naked mole-rat.
Life-extension and temperature
Before exploring thermal effects on ageing and
longevity, a distinction needs to be made between
the different impacts at thermal extremes compared
with T
within the normal range (Fig. 1). In poikilo-
therms, very low body temperatures are associated
with severe enzyme inhibition (Hochachka and
Somero 2002; Portner 2002), leading to a sharp
decline in biological function, preventing organismal
development. At extreme high temperatures, biologi-
cal performance also falls off rapidly: problems
include insufficient capability of respiratory and
circulatory systems to meet increased demand for
oxygen (Portner 2002), prot ein denaturation, and
membrane dysfunction due to increased fluidity
(Hochachka and Somero 2002). Homeotherms suffer
hypo- and hyperthermia when T
deviates too far
below and above the relatively narrow limits of
regulated T
. In both poikilotherms and homeotherms,
it is the effects of temperature on ageing and longevity
across the range of normal T
, rather than under
extreme thermal stress, that is the focus of this review.
Body temperature (T
Fig. 1 A schematic diagram of predicted body temperature
influences on longevity in poikilotherms (top panel) and
homeotherms (bottom panel). Only qualitative differences
between poikilotherms and homeotherms are shown, as axes
are not quantitative. Away from thermal extremes, longevity
predicted by metabolic rate (Gillooly et al. 2001) declines
exponentially with increased body temperature
384 Biogerontology (2015) 16:383–397
Early studies focused on the effects of temperature on
longevity within invertebrates due to their T
determined by their surroundings and thus far easier to
manipulate under laboratory conditions than that of
homeotherms (Table 1). One of these earlier studies
using Drosophila melanogaster showed that they live
about twice as long at 21 °C than at 27 °C (Miquel
et al. 1976). Another invertebrate benchmark study by
Van Voorhies et al. reporte d a 75 % increase in
lifespan of C. elegans from a 5 °C drop in temperature,
consistent between 15–20 and 20–25 °C (Van
Voorhies and Ward 1999). Studies by other labs have
confirmed these results and it is well-established that
temperature has significant effects on the longevity
and ageing rate of Drosophila and C. elegan s (Leiser
et al. 2011).
Many other laboratory studies in insect s have
reported a negative correlation between temperature
and longevity (Gao et al. 2013; Gunay et al. 2010;
Kelly et al. 2013; Liu and Tsai 2000; Matadha et al.
2004; Pakyari et al. 2011; Pandey and Tripathi 2008;
Wang and Tsai 2001; Zhou et al. 2010). For example,
in wasps Trichogramma platneri a5°C drop in
temperature increased median lifespan by 72 %
(McDougall and Mills 1997). A large variation of
effects of temperature on longevity has been observed
in these many studies, though because these species
are poorly studied when compared to traditional model
organisms husbandry conditions may not always be
optimal. Nonetheless, to our knowledge, there is no
invertebrate species in which longevity has been
shown to increase with temperature, with the excep-
tion of pathological effects at very low temperatures.
The thermal sensitivities of survival in laboratory
studies are supported by studies in the wild, even
though these are subj ect to potentially confounding
factors such as the effects of natural enemies on
survival (Angilletta et al. 2004).
Low temperature in invertebrates, and ectotherms/
poikilotherms in general, is associa ted with an overall
slower life history, including a slower pace of
development (Gillooly et al. 2002; Trudgill et al.
2005). Antarctic sponges such as Cinachyra antarc-
tica (Epibenthic sponge) and Scolymastra joubini
(Hexactinellid sponge) are known to have slower
growth rates at lower temperatures which may
contribute to their exceptional longevity; these are
possibly the longest-lived animals on earth, estimated
to live up to 1550 and 15,000 years old, respectively
(Gatti 2002). This link between temperature and the
slowing down of development of ectotherms could
possibly support the ‘ra te of living hypothesis’
Table 1 Longevity effects of temperature manipulation on various animal species
Organism Temperatures
studied (in °C)
% increase in t
(from 5 °C
drop unless otherwise specified)
Invertebrates (model organisms only)
D. melanogaster 18–27 86 (Miquel et al. 1976)
C. elegans 15–25 75 (Van Voorhies and Ward 1999)
Poikilothermic vertebrates
Cynolebias adloffi 16 and 22 75 (t
; for 6 °C drop) (Liu and Walford 1966)
Cynolebias bellottii 15 and 20 43 (Liu and Walford 1975)
Nothobranchius furzeri 22 and 25 14 (for 3 °C drop) (Valenzano et al. 2006)
Nothobranchius rachovii 20–30 57 (Hsu and Chiu 2009)
Strain Temperature decrease (in °C) % increase in t
Mammals (mice)
Hcrt-UCP2 (females) 0.34 20 (Conti et al. 2006)
Hcrt-UCP2 (males) 0.3 12
Only laboratory studies specifically manipulating temperature are included. When more than two temperatures were studied, values
were averaged. Extreme temperatures in which pathological effects may play a role (McDougall and Mills 1997; Miquel et al. 1976;
Van Voorhies and Ward 1999) were excluded from the results
is the median lifespan; t
is the age when 45 % of animals have died. See text for details
Biogerontology (2015) 16:383–397 385
whereby lower temperature promotes longevity by
slowing down the rate of reaction of various metabolic
processes which affect development and life history. A
lower temperature may also reduce damage that is the
result of by-products of metabolism such as reactive
oxygen species (ROS).
Vertebrates (ectotherms)
There have been few controlled studies of the effects of
temperature on the longevity of vertebrates. Studies
conducted in wild vertebrate populations have found
evidence that ectotherms tend to live longer at lower
temperatures (Finch 1990;Gosden1996; Munch and
Salinas 2009). This is noticeable in many species of fish
(Beverton 1987; Pauly 1980), and for example in the
Sander vitreus (walleye) and Cottus bairdii (mottled
sculpin) longevity is dependent on temperature; walleye
at lower temperatures in the North USA take longer to
grow and reach maturity and live longer than walleye
fish in the South (Etnier and Starnes 1993;Finch1990;
Gosden 1996). Overall, although it could be related to
extrinsic factors like predation, parasites or infectious
diseases unrelated to ageing, there is a clear trend for
longer lifespans at lower ambient temperatures in wild
species of ectotherms (Munch and Salinas 2009).
In the lab, two classic studies by Walford and
colleagues on the effect of temperature on the
longevity of the short-lived fish Cynolebias showed
that a 5 and 6 °C drop in temperature increased
lifespan by 43 and 75 %, respectively (Liu and
Walford 1966, 1975). Studies on other fishes that
gradually senesce, such as Austrolebias adloffi, have
shown life-extending effects when animals are ex-
posed to lower temperatures (Patnaik et al. 1994).
More recent studies in Nothobranchius furzeri (Valen-
zano et al. 2006) showed that a drop from 25 to 22 °C
resulted in an increase in lifespan of 14 % (Table 1).
In Nothobranchius rachovii, the lifespan effects of
changes in ambient temperature are reportedly greater
with a 50 % increase in lifespan between 30 and 25 °C
and a 64 % lifespan increase between 25 and 20 °C
(Hsu and Chiu 2009). It should be noted, however , that
the survivorship curves in these studies in fish are far
from rectangular (and in particular Nothobranchius
furzeri at 22 °C), which is often an indication that
other pathological processes apart from ageing are
contributing to mortality, perhaps because husbandry
conditions are not as optimized in these animals as in
more widely used biomedical models, and may be a
source of nois e. Lastly, late-onset temperature reduc-
tion has also been shown to extend lifespan in
Nothobranchius guentheri (Wang et al. 2014).
Similar results have been observed in amphibians,
although from field (rather than laboratory) studies.
An intra-species comparison examined the skele-
tochronology from two datasets: one using two
populations (ten urodele and 12 anuran species ) and
the other dataset using multiple populations (two
urodele and nine anuran species), all of which were
from separate geographical locations. The study
concluded that only the altitude and not latitude
gradient correlated with longevity and life history
timing (maturation, mean and maximum age) (Zhang
and Lu 2012 ). A possible explanation why the latitude
did not correlate with longevity is that there was less
variation in temperature along the latitude gradient
during the summer (active season for amphibians) in
comparison to the altitude gradient (Zhang and Lu
2012). Hypoxia is also thought to reduc e the metabolic
rate which could be another reason for animals living
in oxygen poor regions, i.e. higher altitude regions,
living longer (Zhang and Lu 2012).
In Ambystoma macrodactylum (Eastern long toed
salamander), longevity has been shown to be dependent
on temperature with the life history of animals being
considerably longer at lower temperatures (Howard
1997). A similar effect has also been observed in the
northern species of Rana aurora (Californian red-
legged frog) in which development appears to be slower
and animals probably live longer and lay fewer eggs
than its warmer climate counterparts (Davidson 1993).
Likewise, in the long-lived olm (Proteus anguinus),
development is highly temperature-dependent (Bulog
and van der Meijden 1992). The current data suggests
that, like other poikilotherms, at lower ambient tem-
peratures amphibians have greater longevity, although,
because these studies were conducted in the wild,
whether this is due to the actual ambient temperature
and not to other factors in the field, e.g. less predation, is
still open to debate. Nonetheless, these observations
support the ‘rate of living hypothesis’ for temperature
effects on longevity.
In homeotherms most studies have been conducted in
mice. Of note, the Ames dwarf mouse is known to live
386 Biogerontology (2015) 16:383–397
around 1 year longer than wild-type (Brown-Borg
et al. 1996), and it has been speculated that a lower T
could play a role. In one experiment, six female dwarf
mice and six control mice had their T
measured over
24 h across three separate conditions; ad libitum
feeding, food deprivation and cage switching (which
caused stress ). The results showed that the dwarf mice
had a T
lower than their normal counterparts under all
three conditions. For ad libitum feeding the difference
was 1.6 °C, with the same difference being maintained
during food deprivation which reduced the T
in both
mice. The cage switching caused a rise in T
for both
mice, though dwarf mice still maintained a lower T
(Hunter et al. 1999).
It has been speculated that the lower T
of Ames
dwarf mice is due to their deficiency in thyroid
stimulating horm one (TSH) and growth hormone
(GH) with supporting evidence from the Snell dwarf
mouse which also has a deficiency in TSH and GH and
reduced T
(Hunter et al. 1999). Ames and Snell mice
have mutation s in the, respectively, Prop-1 and Pit-1
loci, which lead to a deficiency in TSH, prolactin and
GH and lower levels of insulin (Conti 2008). GH
receptor (GHR) knockout mice and dwarf mice also
have lower levels of insulin and circulating insulin-
like growth factor 1 (IGF1) (Bartke et al. 2001),
similar to CR rodents; as detailed below, CR also
lowers T
. Therefore, the insulin pathway alongside
GH and TSH is a potential mechanism for body
temperature regulation in rodents.
There are many different mutant long-lived mice
(Tacutu et al. 2013). Although T
has only been
carefully studied in a small fraction of these, metabolic
adjustments and a lower T
have been observ ed in
some models (Bartke 2011), including the aforemen-
tioned Ames and Snell dwarf mice and in GHR
knockout mice (Hauck et al. 2001). Interestingly,
Ames dwarf and GHR knockout mice exhibit in-
creased food intake and oxygen consumption per gram
of body weight, although it is unknown whether these
differences may be due to differences in body weight
to surface ratios and/or in body composition (Bartke
2011); that is, increased oxygen consumption could be
a compensatory effect to increased heat loss due to
increased body surface:mass ratio in these small
animals (Bartke and Westbrook 2012). Some mutant
long-lived mice also have a normal T
, such as IGF1
receptor heterozygous animals (Holzenberger et al.
2003). Clearly multiple mechanisms are involved in
extended longevity, and a lower T
and alterations in
energy metabolism may be included (Bartke and
Westbrook 2012), but a lower T
is not a prerequisite
for life-extension.
One landmark study used transgenic mice (Hcrt-
UCP2: over-expressed uncoupling protein 2 in
hypocretin neurons) to lower the core T
by 0.3 °C
(males) and 0.34 °C (females), resulting in an increase
in median lifespan of, respectively, 12 and 20 %
(Table 1) (Conti et al. 2006). It should be noted,
however, that the mortality curve of control females in
Conti et al. (2006) was far from rectangular and they
are considerably shorter-lived than males, suggesting
potential problems in the experimental conditions.
Nonetheless, this study provided causal evidence that
a lower T
increases longevity in mammals. By
contrast, one study did not find a correlation between
and longevity in individual mice by measuring T
female MF1 outbred mice between the ages of 6 and
13 months. Instead, the results suggested that
metabolic intensity positively correlated with longevi-
ty (Speakman et al. 2004). However, the variance in
temperature in this study was not reported and might
not have been sufficient for an effect on lifespan to be
observed. Although not a model of life-extension, it is
also interesting to note that in rats a two-fold and 40 %
increase of thyroxin and blood serum triiodothyronine
levels, respectively, resulted in a 2 °C increase in T
well as a shortening of their lifespan (Bozhkov and
Nikitchenko 2014).
In C57B1/6 mice, arguably the most commonly
used strain in biogerontology, males tend to live
longer than females and several hypotheses have been
proposed for this gender longevity difference, such as
the unequal inheritance of sex chromosomes, envi-
ronmental factors and physiology (Sanchez-Alavez
et al. 2011 ). It has also been speculated that T
play a role in this gender difference. In C57B1/6 mice,
it was shown that young (6 months old) females have a
0.2–0.5 °C higher than their male counterpart s. For
older (24 months old) mice both genders maintained a
similar circadian profile, however at rest the females
had a T
0.6 °C higher than males. The results also
show evidence that the decline of T
with age may be
mediated via reduced locomotor activity. Further-
more, it has been hypothesized that the sex hormones
act preferentially on the preoptic area of the hypotha-
lamus which may influence T
(Sanchez-Alavez et al.
2011). Therefore, gender differences in T
Biogerontology (2015) 16:383–397 387
influenced by the gonads and are thus perhaps
responsible for the differing lifespan between the
sexes in C57B1/6 mice (Sanchez-Alavez et al. 2011 ).
In humans, women appear to have a slightly higher
body temperature than men (36.4 ± 0.67 °C (standard
error) vs. 36.2 ± 0.61 °C) and mean temperature
decreases 0.17 °C between ages 20–30 and ages
70–80 (Waalen and Buxbaum 2011). Another human
ageing study, the Baltimore Longitudinal Study of
Aging, compared the survival between healthy males
in ages ranging from 16 to 95. After age correction,
results showed three biomarkers for ageing: tem-
perature, insulin and dehydroepiandrosterone sulphate
(DHEAS); lower temperature, insulin and higher
DHEAS levels correlated with highe r survival rates
with no evidence suggesting that any of the individuals
underwent CR (Roth et al. 2002). Since T
with age in rodents and in humans, it is also tempting
to speculate that this could have, at least indirectly,
anti-ageing effects.
Caloric restriction and temperature
Caloric restriction, limiting calorie intake without
causing malnutrition, has been shown to extend
lifespan in multiple model systems (de Magalhaes
et al. 2012; Masoro 2005; Spindler 2010). When
comparing mortality curve trajectories under CR or
reduced T
, however, some studies have observed a
difference between the two. Evidence of this comes
from Drosophila whereby CR initially delays age-
related mortality in the short-term, which results in an
increase in the overall lifespan, although in the long-
term the rate of the mortality trajectory is the same as
that of non-CR flies (Fig. 2) (Mair et al. 2003).
However, a lowered T
has a different effect whereby
it extends lifespan as well as reducing the slope of the
mortality trajectory (Fig. 2) (Miquel et al. 1976),
suggesting that in Drosophila lowered T
and CR
utilize alternative pathways to reduce mortality.
Whether this is the case in homeotherms is unknown.
CR has long been associated with a reduction in T
with a 1–1.5 °C drop as a general rule in rodents
(Duffy et al. 1989; Spindler 2010; Walford and
Spindler 1997). Further evidence for CR reducing T
comes from the LSXSS series of 22 recombinant
mouse strains plus six classical inbred strains: under
CR, strains such as 12956 and C57BL/6 showed a drop
of 1–2 °CinT
whilst others such as BALB/c and A
had a T
drop of 3–5 °C (Rikke and Johnson 2004).
Some other rodent studies have failed to observe a fall
in T
in CR but this may be due to the use of a rectal
probe to measure T
which requires som e form of
restraint resulting in physiological stress to the rodent
which thus may prevent a fall in T
(Lane et al. 1996).
[A more reliable way to measure T
in rodents by
avoiding stress is by using an infrared high perfor-
mance non-contact thermometer which has been
calibrated through implantable micro-chips with tem-
perature transponders (Warn et al. 2003)]. CR in
mammals can reduce the metabolic rate and it is
believed that it is this reduction which lowers heat
production and thus believed to cause a fall in T
thought that this is a mechanism which has evolved to
allow animals to cope in times of limited food
Fig. 2 A schematic diagram of the age-specific mortality rates
of male D. melanogaster which had undergone CR or been fed
ad libitum (top panel) and at either 27 or 18 °C ambient
temperatures (bottom panel). Adapted from (Mair et al. 2003)
388 Biogerontology (2015) 16:383–397
(Carrillo and Flouris 2011). It should be mentioned,
however, that there is some debate concerning the
impact of CR on mammalian metabolic rate (Green-
berg and Boozer 2000; McCarter and Palmer 1992),
and some studies in rodents suggest that CR can
extend lifespan without reducing metabolic rate (Ma-
soro 2005).
B6 (lymphoma prone) mice kept at a higher room
temperature (30 °C) did not reduce T
when under CR
and this caused a reduction in daily hypothermia and
reduced the life-extending effects of CR and in
particular its anti-lymphoma action (Koizumi et al.
1996). Likewise, CR is known to reduce cell prolif-
eration and at higher room temperatures this effect
weakens. It has therefore been suggested that CR’s
induction of hypothermia could cause this anti-lym-
phoma action which promotes longevity. However, in
MRL (autoimmune prone) mice the high room tem-
perature (30 °C) had no effect in reducing the CR-
mediated delay of autoimmune diseases (Koizumi
et al. 1996).
One emerging important consideration is that CR
has strain-specific effects. Surprisingly, when looking
across 31 strains with varying CR lifespan effects,
reduction in T
was a negative predictor of life-
extension. In other words, strains with a greater T
reduction were more likely to have shorter lifespans
under CR and vice versa. This effect depended on the
correlation between temperature and body fat re-
sponses, since mouse strains with a lower reduction in
under CR also had a lower reduction in body fat,
suggesting CR life-extending responses are associated
with minimal loss of temperature and least reduction
in body fat (Liao et al. 2011). These findings also
contradict the aforementioned results on Hcrt-UCP2
mice that suggested that a modest reduction in T
marked effects on longevity by itself, which is clearly
not observed in theses strains. That said, these studies
may not be directly comparable since one previous
study on the same strains found that differences in T
were associated with variation in the rate of heat loss,
not heat production (Rikke and Johnson 2007). All in
all, it does not appear that the longevity effects of CR
in mice are per se a result of a drop in T
Studies are also emerging concerning the effects of
CR on rhesus monkeys, suggesting health benefits but
more modest (if any) lifespan effects than observed in
rodents (Colman et al. 2009; Mattison et al. 2012). In
rhesus monkeys placed under CR for 6 years it was
shown that a fall in 30 % of calorie intake reduced the
by 0.5 °C compared to ad libitum feeding after
matching for age. In 2.5 year-old monkeys on a short-
term (1 month) CR of 30 %, the T
drop was 1.0 °C.
For short-term CR the energy expenditure had fallen
by 24 % over 24 h. The association between a fall in
and energy expenditure suggests that CR acts to
conserve energy by reducing the T
. In the long-term
study, however, temperature was only measured in the
mid-morning when it may have been more reliable to
record it throughout the day (Lane et al. 1996 ).
Another study in rhesus monkeys also showed that CR
caused roughly a 0.7 °C drop in T
as well as
reductions in insulin and higher serum DHEAS (Roth
et al. 2002).
A CR study in humans (Soare et al. 2011) used three
groups each consisting of 24 individuals; one group on
a CR diet for 6 years, another consisting of endurance
runners (EX) and the final group of healthy individuals
with a sedentary lifestyle (less than 1 h of exercise per
week) who ate a western diet (WD). For the CR group,
their energy intake was 23 and 37 % lower than the
WD and EX groups , respectively. All groups were
matched according to age and sex, with the EX group
being matched on body fat percentage to the CR
group. Each individual then had their T
every minute over a 24-h period using an ingested
telemetric capsule. The results showed that T
lowest amongst the CR group with a mean 24-h
temperature of 36.64 °C ± 0.16 (SD) in comparison
to 36.86 °C ± 0.2 for EX and 36.83 °C for WD. It was
discovered that the percentage of body fat is also
linked to 24-h T
, although body fat is not likely to
play a role in T
reduction as both the EX and CR
groups had a similar low percent age of body fat,
however the mean 24-h, day-time and night-time T
the CR group was roughly 0.2 °C lower than that of
the EX group. Therefore, T
was thought to be
controlled primarily through CR (Soare et al. 2011).
CR responses can be thought of as an energy
conservation mechanism which, over the long-term in
monkeys, humans and rodents, can cause a fall in
circulating triiodothyronine levels which regulate
body temperature and thus causes the T
to drop
(Soare et al. 2011). Short-term CR also reduces T
overweight individuals attempting to lose weight ,
however in overweight, weight stable individual s this
was not shown to be the case. In normal and obese
individuals with stable weight, T
remains the same in
Biogerontology (2015) 16:383–397 389
both; obese individuals are thought to achieve this via
heat dissipation in their more peripheral regions. CR
individuals also have lower levels of insulin, leptin
and total testosterone which may also contribute to
heat reduction (Soare et al. 2011). Another study
conducted using human volunteers who underwent CR
(25 % CR of the baseline energy require ment) for
6 months exhibited lower levels of fasting serum
insulin, a significant fall in both the total 24-h and
sleeping energy expenditure, which correlated with a
drop in thyroid hormone concentration, as well as a
0.2 °C decrease in T
. Similar results were also shown
in their CREX group (12 % CR and 12 % increase in
energy expenditure) including a drop of 0.3 °CinT
Both the CR, CREX and the very low calorie diet
group (890 kcal/d) had lower levels of DNA damage
suggesting a possible mechanism for promoting
longevity, however whether this is maintained long-
term has yet to be verified (Heilbronn et al. 2006).
Mechanisms of temperature life-extending effects
Thermodynamic explanations to agei ng have been
long proposed, in which ageing is the result of an
increase in molecular disorder and a decrease in
metabolic stability (Demetrius 2013). The intuitive
interpretation for how low body temperature extends
longevity is that it affects metabolic rates and this
decreases the rate of biochemical reactions and retards
whatever process(es) cause(s) ageing. Since metabolic
rate increases exponentially with temperature (Gil-
looly et al. 2001), it is reasonable to postulate that
temperature acts exponentially on 1/lifespan and
hence that lower temperature acts exponentially to
extend lifespan (Fig. 1), especially over a small
temperature range, and indeed this has been shown
in some studies in poikilotherms (McDougall and
Mills 1997; Munch and Salinas 2009). One study in
the housefly (Musca domestica) supported this idea by
showing that animals at 15 °C lived longer but were
much less active than at 23 °C, and that lower physical
activity by itself was associated with a longer lifespan
(Ragland and Sohal 1975). Inducing mild heat stress
can also incr ease the lifespan in both D. melanogaster
and C. elegans by stimulating pathwa ys associated
with genome stability in an effect known as hormesis.
A recent study which heat shocked (34 °C for 2 h)
younger male D. melanogaster three times showed an
up-regulation of genes involved in the cellular
response to heat 10–51 days after heat shocking,
suggesting that the heat shock HSP70 pathway may be
involved in fly longevity (Sarup et al. 2014). Although
the specific mechanisms for the long lifespan of mice
with a lower core T
remain unknown, an increase in
energy efficiency was observed that appears to be
related to the reduced metabolic requirements to
maintain a lower T
(Conti et al. 2006). This in turn
could impact on various forms of molecular damage,
including oxidative stress and DNA damage (Farmer
and Sohal 1987; Lindahl and Nyberg 1972).
The fact that CR does not always extend lifespan,
and in diverse mouse strains its longevity effect is
actually associated with smaller decreases in tem-
perature, suggests that other factors may obscure or
reverse expected effects of T
on ageing. That women
have higher temperatures than men and yet live longer,
while female C57B1 /6 mice have higher temperatures
than males and live less, supports this. Similarly, it has
long been argued that a drop in T
reduces the
production of ROS which then prolongs lifespan
(Conti 2008). A reduction in oxidative damage and
enhanced antioxidant systems in ectothermic animals
kept at lower temperatures (and thus longer-lived) has
been observed, for example in fish (Hsu and Chiu
2009; Wang et al. 2014). More recently, however, the
free radical theory of ageing has come under fire due to
a plethora of studies with disc ouraging results, raising
questions about the role of ROS in ageing (reviewed in
de Magalhaes and Church 2006; Lapointe and Hekimi
2010). Therefore, it appea rs that the view that a drop in
by itself increases lifespan is overly simplistic.
More recent results suggesting that specific
mechanisms retard ageing in response to lower
temperature challenge thermodynamic explanations.
In C. elegans it has been discovered that its cold
sensing TRP channel TRPA-1 can promote longevity
when there is a drop in temperature by inducing a
calcium influx into the cell, activating PKC which via
SGK-1 activates the DAF-16/FOXO transcription
factor (Xiao et al. 2013). Caenorhabditis elegans
thermosensory neurons can also play a role in the
effect temperature has on longevity at warmer tem-
peratures (25 °C). Mutations in thermosensory neu-
rons have been shown to shorten lifespan even further
in warmer temperatures by causing a fall in the
expression levels of daf-9. DAF-9 regulates the
nuclear hormone receptor DAF-12 and so daf-12 null
mutations can inhibit this process (Lee and Kenyon
390 Biogerontology (2015) 16:383–397
2009). Overall, these results demonstrate that the
temperature effect on C. elegans longevity is not a
passive process and further challenges the ‘rate of
living theory’ (Xiao et al. 2013). Similarly, in fruit
flies, changing back and forth the ambient temperature
from hot to cold, animals have a similar longevity of
flies kept in cold conditions (Liu and Walford 1972;
Rikke and Johnson 2004), which suggest that it is not
the exposure time to cold but rather physiological
adaptations to it that are important.
It has been proposed that CR reduces T
which in
turn affects the hormonal axis that may have down-
stream targets that increase lifespan (Mobbs et al.
2001). An endocrine role thus seems plausible. Tem-
perature in ectotherms can act on hormones associated
with growth and development to induce heterochrony
(McKinney and McNamara 1991). Indeed, there is
evidence from various studies suggesting that the GH/
IGF system mediates the effects of temperature on the
growth and development of fish (reviewed in Gab illard
et al. 2005). Intere stingly, one study of exercise in
young men showed a strong relations hip between T
increase during exercise and GH levels, although this
was not dependent on ambient temperature; this
suggests that body temperature could in some way be
a stim ulus for GH secretion (Bridge et al. 2003).
Recall, however, that we previously mentioned that
GH/insulin is also a possible mechanism for T
regulation, and thus the causality of these events
remains to be fully elucidated.
Another hypothesis is that a lower T
longevity through utilizing various metabolic path-
ways which suppr ess autoimmunity in old age (Rikke
and Johnson 2004). A lower T
also increases resis-
tance to environmental factors, which has been shown
in hypothermic rodents to have a greater resistance to
irradiation. This is further highlighted in hypothermic
rabbits which had a 109 greater resistance to bacterial
endotoxins than normal rabbits (Liu and Walford 1972;
Rikke and Johnson 2004). A lower developmental
temperature in D. melanogaster also results in en-
hanced stress resistance (Kim et al. 2010), at least to
some types of stress.
In terms of responses to lower temperat ure in
homeotherms, brown adipose tissue (BAT), which
contains large amounts of mitochondria, is used to
generate heat in cold environments via uncoupling
proteins, in particular UCP1 within the mitochon-
drial membrane. Mice deficient in UCP1 have been
shown to have an increased susceptibility to obesity
during ageing when exposed to a high fibre diet and
kept at a constant room temperature of 23 °C
(Kontani et al. 2005). In humans, the A-3826G
polymorphism in the UCP1 gene promot er region
reduces UCP1 expression and could be more
susceptible to a higher body mass including greater
levels of subcutaneous fat (Sramkova et al. 2007).
Another role which has been established for UCP is
in the reduction of ROS production when up-
regulated and it has been proposed that this is one
of the factors which might contribute to the link
between lower T
and longevity (Carrillo and
Flouris 2011). In rats exposed to the cold or treated
with triiodothyronine, UCP3 was up-regulated in
BAT, suggesting that UCP3 has a role in the
regulation of T
and energy expenditure (Larkin
et al. 1997). Research using 6 month-old 344
Fischer rats showed a 4-fold increase of UCP1, a
2-fold increase of interscapular BAT mass and a
26-fold increas e in cell proliferation after cold
exposure, whereas rats at 26 months showed no
such increase. This further shows that the response
to temperature varies depending on age (Florez-
Duquet et al. 1998). Age-related thermogenic im-
pairment possibly contributes to diabetes and obesity
in ageing, and recent results from mice sugges t it
may be mediated by ghrelin signalling (Lin et al.
2014). Moreover, BAT activity and mass decline
with age, even if this is much more pronounced in
men than in women (Pfannenberg et al. 2010).
Lastly, when exposed to cold temperature, mice tend
to have lower levels of body fat than mice in
surroundings with normal temperature levels, this
reduction in body fat by a fall in temperature has
been thought to be the reason for a fall in tumour
incidences (Carrillo and Flouris 2011), in part icular
given the known links between obesity and cancer,
including in an age-related fashion (de Magalhaes
Although it is possible that a low temperature
decreases accumulation of molecular damage, this
appears to be an oversimplistic interpretation, in
particular in mammals in which various physiological
processes, such as in adipose tissue and neuroendocrine
changes, are associated with temperature and ageing.
More integrative studies of the relationships between
temperature, ageing mechanisms and longevity are
Biogerontology (2015) 16:383–397 391
Species correlations between temperature
and longevity
In homeotherms undergoing torpor or hibernation, T
falls and endothermy is temporarily replaced with
ectothermy. Hibernation can also increase the survival
rate by five times between similar-sized hibernating
and non-hibernating mamm als (Turbill et al. 2011).
Indeed, a study usin g a super tree (50 % of longevity
records from wild population studies where mortality
is not controlled) of Chiroptera showed that bats’
lifespan correlates strongly with the length of hiber-
nation, body mass and occasional cave use (Wilkinson
and South 2002). Another study found that smaller
mammals which hibernate tend to have longer
maximum lifespans (50 % greater for 50 g of species),
lower reproductive rates and longe r generation times
than similar-sized non-hibernating species (Turbill
et al. 2011).
Hibernation protects against predation by reducing
the chance of detection via lowering levels of
metabolism, having a cold and motionless body and
lower emissions of body odours. As such, it is thought
that predator avoidance is the main reason behind
hibernation in small mammals rather than the conser-
vation of energy, as hibernation can occur during times
of the year when sufficient food is available (Turbill
et al. 2011). It has been proposed that insulin can cause
hypothermia during hibernation, although this remains
unproven, but it can act independently of lower T
shown in studies u sing poikilotherms (Andrews 2007).
Moreover, hibernation could be used in times of
limited food supply and hence have a similar role as
CR. In bats, hibernation reduces T
by 85 % (from 40 to
6 °C) which is then maintained over a course of several
weeks at a time. This reduces the metabolic rate to 5 %
of the room temperature resting rate which reduces the
amount of energy used by the animal; thus it might
reduce the oxidative damage cause d by internal
metabolic pathways and increas e lifespan (Wilkinson
and South 2002), although as discussed above this
simplistic interpretation has been attacked.
Comparisons across species have largely disproved
the rate of living theory in homeotherms (de Magal-
haes et al. 2007; Speakman 2005). A low T
is by no
means a prerequisite for the evolution of longevity or
always associated with it. For exampl e, birds tend to
have a higher T
and live longer than similar-sized
mammals; likewise, marsupials have a low T
compared to placental mammals and generally have
shorter lifespans (de Magalhaes et al. 2007). A large
comparative study of temperature, metabolic rate,
body size and longevity in mammals revealed a strong
positive correlation betwee n T
and basal metabolic
rate (BMR), yet no correlation between BMR and
longevity. However, a negative correlation was ob-
served between T
and time to maturity and a weak,
borderline significant negative correlation was also
observed between T
and longevity (de Magalhaes
et al. 2007). Although other factors, like ecological
constraints (Demetrius and Gundlach 2014), are
involved in the evolution of life histories and mam-
mals have a very narrow range of body temperatures,
these results suggest that T
might affect the timing of
life history events in ways unrelated to metabolic rate.
Influence of temperature on the long lifespan
of the naked mole-rat
Capable of living over 30 years (Tacutu et al. 2013),
the naked mole- rat (Heterocephalus glaber) is the
longest-lived rodent and is exceptionally resistant to
cancer (Buffenstein 2008). This has led to a growing
number of studies in this species (Gorbunova et al.
2014), including large-scale genome sequencing ef-
forts (Keane et al. 2014). Naked mole-rats are also
unique among mammals in that they are poikilotherms
and have a low metabolic rate and body temperature
when compared to other mammals (Buffenstein and
Yahav 1991; McNab 1980). Therefore, and given the
aforementioned impact of temperature on longevity,
one major open question is whether the exceptional
longevity of the naked mole-rat could at least partly be
due to its comparatively low T
. We attempted to
explore this by extrapolating from other studies.
Wild-derived mice, as these are more likely to be
representative of the Mus musculus species than
laboratory strains, have a T
of 36.9 °C (Tacutu
et al. 2013). Because naked mole-rats are incapable of
maintaining their body temper ature, their average T
during their lifespan is not known for sure; the AnAge
database of ageing and longevity in animals lists
32.1 °C, taken from (White and Seymour 2003), and
one study reported a mean T
of 30.6 °C (McNab
1980). However, pregnant females have a higher T
*1.5 °C (Buffenstein et al. 1996), and yet there is no
evidence that queens have a shorter lifesp an (Buffen-
stein 2008). Because a female can become a breeding
392 Biogerontology (2015) 16:383–397
queen early in life, and can essentially be pregnant
most of the time, T
of breeding females can be
estimated based on the T
increase during the various
stages of pregnancy (Buffenstein et al. 1996), and
assuming that a female can be pregnant continuously
with only a one-week interval between pregnancies,
since gestation in naked mole-rats is *10 weeks with
as little as 1 week post-partum estrus (Buffenstein
et al. 1996). Mean estimated T
is thus (1 week 9
30 °C ? 3 9 33.4 ? 4 9 34.6 ? 3 9 34. 8)/11 =
34.2 °C. As this assumes continuous pregnancies
throughout adult lifespan, 34.2 °C marks an upper
limit for T
, with the lower value of 32.1 °C a realistic
range of mean T
values; the data from White and
Seymour (2003) is also based on multiple studies and
thus preferred to McNab (1980).
Given that the results from various animals show
that a lower T
increases longevity, it seems plausible
that the low T
of naked mole-rats contributes to their
longevity. Although non-contentious and clearly im-
portant, this issue has not been addressed before.
Therefore, we attempted to est imate quantitatively the
effect of T
on the longevity of the naked mole-rat
based on studies conducted on other organisms.
Specifically, we employed those organisms on
Table 1, with the exception of transgenic mice given
that the magnitude of changes observed are inconsis-
tent with the abovementioned resu lts from other
mouse strains and with the thermal sensitivity of
longevity from species comparisons (Table 2).
To extrapolate T
effects on longevity from studies
in various species, a linear regression of ln-trans-
formed lifespan against temperature produced a slope
from which the longevity of mice with the T
of naked
mole-rats was predicted. The use of semi-log plots of
lifespan against temperature is based on the afore-
mentioned assumption that temperature acts exponen-
tially on 1/lifespan, in line with previous studies
(McDougall and Mills 1997; Munch and Salinas
2009). Given the effects of temperature on the
longevity of various species, the longevity of mice at
the T
of naked mole-rats (32.1–34.2 °C) can be
estimated as 4.5–7.3 years. The lowest predicted
effect of temperature on longevity is the result from
Nothobranchius furzeri (Table 1), for which we feel
further studies are necessary given the aforementioned
concerns regarding the survival curve at the lower
temperature. Excluding Nothobranchius furzeri, and
averaging the othe r species, we estimate that hypo-
thetically mice with the body temperature of the naked
mole-rat may live 30–65 % longer or 5.3–6.6 years. It
is also tempting to hypothesize that, assuming these
calculations can be extrapolated to them, naked mole-
rats with a T
of 37 °C might not live more than
20–25 years. Our approach, of course, assumes that
intra-species effects can be extrapolated across species
Table 2 Longevity and
body temperature of mole-
rats and selected related
Species with questionable
longevity records that may
be significantly
Only rodents for which
data on body temperature
) and maximum lifespan
) is available in the
AnAge database (Tacutu
et al. 2013) were included
Species Family t
(years) Body weight (g) T
Cryptomys anselli Bathyergidae 20.6 90
Cryptomys damarensis Bathyergidae 15.5 180 35.2
Cryptomys hottentotus Bathyergidae 11
132.5 34.4
Cryptomys mechowi Bathyergidae 16
250 34
Georychus capensis Bathyergidae 11.2
181 36.4
Heliophobius argenteocinereus Bathyergidae 160 35.1
Heterocephalus glaber Bathyergidae 31 35 32.1
Nannospalax ehrenbergi Muridae 20.2 160 35.5
Other rodents
Cavia porcellus Caviidae 12 728 39
Mus musculus Muridae 4 20.5 36.9
Rattus norvegicus Muridae 3.8 300 37.1
Sciurus carolinensis Sciuridae 23.6 533 38.7
Average for rodents
9.2 1175 36.8
Biogerontology (2015) 16:383–397 393
and is thus only a first approximation of the contribu-
tion of T
to the longevity of naked mole-rats.
Our view is that body temperature likely explains
a small part of the exceptional longevity of the naked
mole-rat. We also think that consideration should be
given to body temperat ure in comparative studies of
ageing. Mole-rats in general have a low T
in species
comparisons (Table 2), possibly because they live in
stable, protected environments, and it is tempting to
speculate that this has contributed to the evolution of
longevity in mole-rats of different taxa. Not surpris-
ingly, the naked mole-rat has the longest lifespan and
the lowest T
of studied mole-rats (Table 2). In this
context, other small, long-lived rodents like the
Eastern gray squirrel (Sciurus carolinensis), which
can live up to 23.6 years and actually has a higher T
(38.7 ° C) than the rodent average (Table 2), may be
equally informative to biogerontology. On the other
hand, the bowhead whale (Balaena mysticetus) is the
longest-lived mammal (estimated maximum lifespan
of 211 years), which has led to its genom e being
recently sequenced (Keane et al. 2015). Its average
has been estimated to be 33.8 °C (SD = 0.83,
N = 28) which is lower than other non-hibernating
eutherian mammals, and its metabolic resting rate
also appears to be lower than that of other cetaceans
(George 2009). While additional studies are warrant-
ed, a relatively low T
might have contributed, even
if to a small degree, to the bowhead’s exceptional
longevity. We hope these considerations, although
speculative, will stimulate further work on the
important topic of temperature effects on species
Concluding remarks
It is clear that temperature affects longevity from
invertebrates to mammals both within species and
possibly across species. This was initially thought to
be due to thermodynamic effects and the direct effects
of low metabolism (e.g., reduced oxidative and/or
DNA dam age), but now a picture is emerging that, as
often happens in biology, the mechanisms are not as
simple as once thought. The interplay of processes
involved suggests a role of neuroendocrine mechan-
isms in responses to low temper ature that in turn
impact on ageing and longevity.
Acknowledgments We are grateful to David Atkinson for
suggestions on previous drafts of this manuscript. Further thanks
to other members of the Integrative Genomics of Ageing Group
for useful discussions on this topic and to Louise Crompton for
assistance in compiling the relevant literature. Current work in
the JPM lab is supported by Grants from the UK Biotechnology
and Biological Sciences Resource Council (BB/K016741/1) and
the Wellcome Trust (WT094386MA).
Open Access This article is distributed under the terms of the
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... While an increase in temperature accelerates the rates of biological reactions, a decrease in temperature has the opposite effect [277]. The inverse relationship between rates of metabolism and longevity is why lower body temperatures are associated with longer lifespans, whereas higher body temperatures are more common in short-lived individuals [278][279][280]. In homeotherms, interventions that influence rates of aging and lifespan, for instance caloric restriction, also tend to alter body temperature in a manner that is consistent between the aforementioned relationship between temperature and longevity [278,281]. ...
... The inverse relationship between rates of metabolism and longevity is why lower body temperatures are associated with longer lifespans, whereas higher body temperatures are more common in short-lived individuals [278][279][280]. In homeotherms, interventions that influence rates of aging and lifespan, for instance caloric restriction, also tend to alter body temperature in a manner that is consistent between the aforementioned relationship between temperature and longevity [278,281]. Cold temperatures in homeotherms lead to the generation of heat in brown adipose tissue via UCP1 [101][102][103][104][105]. Given the involvement of UCP proteins in regulation of longevity (as discussed above), cold-induced uncoupling could constitute another mechanism by which low temperatures promote longevity. In agreement, overexpression of Ucp2 in the hypocretin neurons of mouse hypothalamus extended the animals' longevity by lowering their core body temperature [125]. ...
... In poikilotherms such as C. elegans and Drosophila, a decrease in ambient temperature promotes stress resistance and counteracts inflammatory signaling [282]. While it is tempting to speculate that the relationship between temperature and age-related pathology stems from the propensity of temperature to increase thermodynamic entropy [278,283], it is likely that additional levels of complexity bear upon this relationship. Indeed, flies cycled between hot and cold ambient temperatures live for as long as those that are reared at steady low ambient temperature [278,279,284]. ...
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Despite significant advances in our understanding of the mechanisms that underlie age-related physiological decline, our ability to translate these insights into actionable strategies to extend human healthspan has been limited. One of the major reasons for the existence of this barrier is that with a few important exceptions, many of the proteins that mediate aging have proven to be undruggable. The argument put forth here is that the amenability of ion channels and transporters to pharmacological manipulation could be leveraged to develop novel therapeutic strategies to combat aging. This review delves into the established roles for ion channels and transporters in the regulation of aging and longevity via their influence on membrane excitability, Ca2+ homeostasis, mitochondrial and endolysosomal function, and the transduction of sensory stimuli. The goal is to provide the reader with an understanding of emergent themes, and prompt further investigation into how the activities of ion channels and transporters sculpt the trajectories of cellular and organismal aging.
... Notable that although low body temperature is usually attributed to the reduction of calorie intake there are studies demonstrating that reduction in core body temperature could influence longevity independently of CR both in poikilotherms and homeotherms 6,13 . The negative correlation between temperature and longevity has been discovered in the nematodes, rotifers, fruit flies, and in several killifish species [14][15][16] . Moreover, several long-lived mutant mice have shown a decrease in core body temperature, which supports the idea of maintaining the positive effect in mammals 13,17 . ...
... The significant lifespan-extending effects of low-temperature conditions are also consistent with the many studies conducted on invertebrate and vertebrate models [13][14][15][16][17] . Previously published studies have shown that the longest maximum lifespan of D. melanogaster (wild-type Oregon-R males) at 18°C varies within the range of 163-180 days 35,36 . ...
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Aging is one of the global challenges of our time. The search for new anti-aging interventions is also an issue of great actuality. We report on the success of Drosophila melanogaster lifespan extension under the combined influence of dietary restriction, co-administration of berberine, fucoxanthin, and rapamycin, photodeprivation, and low-temperature conditions up to 185 days in w 1118 strain and up to 213 days in long-lived E(z)/w mutants. The trade-off was found between longevity and locomotion. The transcriptome analysis showed an impact of epigenetic alterations, lipid metabolism, cellular respiration, nutrient sensing, immune response, and autophagy in the registered effect.
... Layered on top of metabolic mode, environmental temperature itself is expected to be a strong driver of mortality in ectotherms, affecting both the evolution and the plasticity of aging through metabolic mechanisms [ (10,31,32), but see (33)]. Within many endothermic species, individuals with lower body temperatures live longer and age slower than those with higher body temperatures (29,34), but across species, this pattern is less clear (35). Similarly, ectotherms in cooler climates may also exhibit longer lifespans compared with those in warmer climates [(10, 11); referred to as the temperature hypothesis hereafter]. ...
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Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging.
... temperature-dependent sex determination Temperature influences the fitness of organisms by influencing vital variables such as developmental rate (Arrighi et al. 2013), metabolic rate (Neubauer and Andersen 2019), growth rate (Boltaña et al. 2017), body size (Atkinson 1994), and length of life span (Keil et al. 2015). However, these variables may influence the fitness of males and females differently, and for some species and populations, it may be more favorable to develop into males at some temperatures, and females at others. ...
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Environmental factors influencing parents or offspring during embryogenesis can have knock-on effects at later life stages of the offspring. These effects may prepare the progeny for conditions that they may encounter as larvae, juveniles and/or adults. Here, we give examples on how knock-on effects of temperature and predator cues can affect phenotypes of fish, amphibians and reptiles. Such effects are best described in reptiles, but are generally widespread among ectotherms. Most of the species are oviparous with egg incubation outside the mother’s body. The eggs can be exposed to highly different and variable environmental conditions, and developmental plasticity may help offspring to cope with influences they may encounter at a later stage, e.g. whether the habitat will be warmer or colder, safer or riskier than what they a priori are adapted for. Knock-on effects can be considered a subset of phenotypically plastic responses. They can be instantaneous or delayed, have a physiological foundation, and can be manifested as temperature dependent sex determination and changes in morphological, physiological, life history and behavioural characters. They are often, but not exclusively, assumed evolutionarily favourable, particularly beneficial for invasive species and during periods of rapidly changing environments. However, although several studies suggest that plasticity in some cases increases survival and reproductive success, the fitness gain is still virtually untested. It is assumed that epigenetic mechanisms, such as DNA methylation and histone modifications, could ultimately be important components of molecular mechanisms that allow early perceived cues to be expressed at a later stage in life. Although some empirical cases support this, evidence is still mostly circumstantial. Future research should investigate mechanisms and fitness effects of early environmental stimuli. These effects are important for the ecology of species and should be taken into account in experiments on ecological effects of environmental variables. This is of particular interest today because of climate change and increasing anthropogenic habitat alterations.
... • Survival: We expected heat treatments to increase survival under heat stress and cold treatments to increase survival under cold stress (Cossins & Bowler, 1987). • Size, longevity and development time: Previous studies have shown that size, longevity and development time are usually reduced in warmer temperatures (Keil et al., 2015;Ohlberger, 2013), and we, therefore, expected to find the same pattern in our analysis. The direction of clinal patterns assessed under common garden conditions can be used to indirectly infer adaptive patterns in colder versus warmer environments, with repeated genetic clines implying convergent evolutionary responses to common patterns of spatially varying phenotypic selection (Endler, 1977). ...
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Populations must adapt to environmental changes to remain viable. Both evolution and phenotypic plasticity contribute to adaptation, with plasticity possibly being more important for coping with rapid change. Adaptation is complex in species with separate sexes, as the sexes can differ in the strength or direction of natural selection, the genetic basis of trait variation, and phenotypic plasticity. Many species show sex differences in plasticity, yet how these differences influence extinction susceptibility remains unclear. We first extend theoretical models of population persistence in changing environments and show that persistence is affected by sexual dimorphism for phenotypic plasticity, trait genetic architecture, and sex‐specific selection. Our models predict that female‐biased adaptive plasticity—particularly in traits with modest‐to‐low cross‐sex genetic correlations—typically promotes persistence, though we also identify conditions where sexually monomorphic or male‐biased plasticity promotes persistence. We then perform a meta‐analysis of sex‐specific plasticity under manipulated thermal conditions. Although examples of sexually dimorphic plasticity are widely observed, systematic sex differences are rare. An exception—cold resistance—is systematically female‐biased and represents a trait wherein sexually dimorphic plasticity might elevate population viability in changing environments. We discuss our results in light of debates about the roles of evolution and plasticity in extinction susceptibility.
... Some of the physiological stresses experienced by individuals during hibernation are similar to those observed with ageing, and therefore the molecular and physiological responses required for an individual to successfully hibernate may prevent aging 36,46 . Additionally, hibernation combines conditions known to promote longevity 36,46,79 , such as food deprivation (calorie restriction [80][81][82] ), low body temperature 79,83-85 and reduced metabolic rates 46 . Conceivably, these factors may also be associated with the slower marmot ageing observed in the beginning and end of their active season (Fig. 2b). ...
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Species that hibernate generally live longer than would be expected based solely on their body size. Hibernation is characterized by long periods of metabolic suppression (torpor) interspersed by short periods of increased metabolism (arousal). The torpor–arousal cycles occur multiple times during hibernation, and it has been suggested that processes controlling the transition between torpor and arousal states cause ageing suppression. Metabolic rate is also a known correlate of longevity; we thus proposed the ‘hibernation–ageing hypothesis’ whereby ageing is suspended during hibernation. We tested this hypothesis in a well-studied population of yellow-bellied marmots ( Marmota flaviventer ), which spend 7–8 months per year hibernating. We used two approaches to estimate epigenetic age: the epigenetic clock and the epigenetic pacemaker. Variation in epigenetic age of 149 samples collected throughout the life of 73 females was modelled using generalized additive mixed models (GAMM), where season (cyclic cubic spline) and chronological age (cubic spline) were fixed effects. As expected, the GAMM using epigenetic ages calculated from the epigenetic pacemaker was better able to detect nonlinear patterns in epigenetic ageing over time. We observed a logarithmic curve of epigenetic age with time, where the epigenetic age increased at a higher rate until females reached sexual maturity (two years old). With respect to circannual patterns, the epigenetic age increased during the active season and essentially stalled during the hibernation period. Taken together, our results are consistent with the hibernation–ageing hypothesis and may explain the enhanced longevity in hibernators.
... It has long been debated whether senescence in birds is analogous to that in mammals [18] because birds do not show clear external signs of ageing. However, both taxa evolved endothermy, and higher body temperatures appear to foster cellular senescence [19][20][21]. Seabirds are among the birds with the longest longevity [22]; for example, the bluefooted booby (Sula nebouxii) can live up to 22 years [23,24], and the magnificent frigatebird (Fregata magnificens) up to 30 years [25]. Adult populations of the blue-footed booby are slightly male-biased and those of F. magnificens are strongly male-biased (male/female ratios of greater than 1 and greater than 2, respectively; electronic supplementary material, figure S1) [26][27][28]. ...
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Females and males often exhibit different survival in nature, and it has been hypothesized that sex chromosomes may play a role in driving differential survival rates. For instance, the Y chromosome in mammals and the W chromosome in birds are often degenerated, with reduced numbers of genes, and loss of the Y chromosome in old men is associated with shorter life expectancy. However, mosaic loss of sex chromosomes has not been investigated in any non-human species. Here, we tested whether mosaic loss of the W chromosome (LOW) occurs with ageing in wild birds as a natural consequence of cellular senescence. Using loci-specific PCR and a target sequencing approach we estimated LOW in both young and adult individuals of two long-lived bird species and showed that the copy number of W chromosomes remains constant across age groups. Our results suggest that LOW is not a consequence of cellular ageing in birds. We concluded that the inheritance of the W chromosome in birds, unlike the Y chromosome in mammals, is more stable.
... Growth in crustaceans is known to slow considerably at lower temperatures within the thermal tolerance range of a species (Lagerspetz and Vainio, 2006;Stoner et al., 2010). Additionally, lower temperatures in invertebrates are typically associated with an overall slower life-history and longer lifespan (Keil et al., 2015) which is consistent with model simulations (Fig. 4). Simulated growth trajectories expressed as length and dry-weight fitted observed data, however, the time when specific life stages were reached were slightly different to those values reported by other authors (Hosie, 1982). ...
The krill Nyctiphanes australis is the most abundant and ecologically important euphausiid in southern Australia and New Zealand coastal and shelf waters. The species lives in coastal environments, which are currently susceptible to shifts in temperature and productivity. Due to its abundance, it sustains many inshore fisheries and, for this reason, determining the potential outcome of future changes in sea temperature and productivity for Nyctiphanes is important. The temperature- and food-dependence of growth and reproduction of Nyctiphanes species can be made through Dynamic Energy Budget models (DEB), developed here to quantify how temperature and food availability affects growth, fecundity, egg size, and the energetic content of the eggs throughout the krill life-span. The DEB model predictions are in good agreement with measured life-history traits for the species and show that krill grows slower during winter while females do not always reach sexual maturity when temperature are below 8 °C and food levels are low. We found that higher temperatures and low food levels decrease the energetic content and diameter of the eggs by ∼20%, affecting the length and age at which N. australis commence reproduction. Under current scenarios of future ocean warming, these results indicate that populations of N. australis are likely to decline, with potential knock-on effects on coastal marine ecosystems and inshore fisheries.
Higher temperatures expected in a future warmer climate could adversely affect the growth and development of mosquitoes. This study investigated the effects of elevated temperatures on longevity, gonotrophic cycle length, biting rate, fecundity, and body size of Anopheles gambiae (s.l.) (Diptera: Culicidae) mosquitoes. Anopheles gambiae (s.l.) eggs obtained from laboratory established colonies were reared under eight temperature regimes (25, 28, 30, 32, 34, 36, 38, and 40°C), and 80 ± 10% RH. All adults were allowed to feed on a 10% sugar solution soaked in cotton wool; however, some mosquitoes were provided blood meal using guinea pig. Longevity was estimated for both blood-fed and non-blood-fed mosquitoes and analyzed using the Kaplan–Meier survival analysis. One-way ANOVA was used to test the effect of temperature on gonotrophic cycle length, biting rate, and fecundity. Adult measurement data were log-transformed and analyzed using ordinary least square regression with robust standard errors. Increasing temperature significantly decreased the longevity of both blood-fed (Log-rank test; X2(4) = 904.15, P < 0.001) and non-blood-fed (Log-rank test; X2(4) = 1163.60, P < 0.001) mosquitoes. In addition, the fecundity of mosquitoes decreased significantly (ANOVA; F(2,57) = 3.46, P = 0.038) with an increase in temperature. Body size (β = 0.14, 95% CI, 0.16, 0.12, P < 0.001) and proboscis length (β = 0.13, 95% CI, 0.17, 0.09, P < 0.001) significantly decreased with increasing temperature from 25 to 34°C. Increased temperatures expected in a future warmer climate could cause some unexpected effects on mosquitoes by directly influencing population dynamics and malaria transmission.
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Highlights: • Metabolic rate is inversely related to time-flow perception • Overeating at overweight impairs digestion, increases metabolic rate, accelerates aging, and limits lifespan • The ‘Obesity paradox’ is driven by individual bodyweight and individual limit of weight gain mode • Weight loss delays aging, prolong lifespan, creates ‘weight gain potential energy’.
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Studies in invertebrates have led to the identification of a number of genes that regulate lifespan, some of which encode components of the insulin or insulin-like signalling pathways. Examples include the related tyrosine kinase receptors InR (Drosophila melanogaster) and DAF-2 (Caenorhabditis elegans) that are homologues of the mammalian insulin-like growth factor type 1 receptor (IGF-1R). To investigate whether IGF-1R also controls longevity in mammals, we inactivated the IGF-1R gene in mice (Igf1r). Here, using heterozygous knockout mice because null mutants are not viable, we report that Igf1r(+/-) mice live on average 26% longer than their wild-type littermates (P < 0.02). Female Igf1r(+/-) mice live 33% longer than wild-type females (P < 0.001), whereas the equivalent male mice show an increase in lifespan of 16%, which is not statistically significant. Long-lived Igf1r(+/-) mice do not develop dwarfism, their energy metabolism is normal, and their nutrient uptake, physical activity, fertility and reproduction are unaffected. The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing. These results indicate that the IGF-1 receptor may be a central regulator of mammalian lifespan.
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Darwinian fitness describes the capacity of an organism to appropriate resources from the environment and to convert these resources into net-offspring production. Studies of competition between related types indicate that fitness is analytically described by evolutionary entropy, a statistical measure which is positively correlated with population stability, and describes the number of accessible pathways of energy flow between the individuals in the population. Directionality theory is a mathematical model of the evolutionary process based on the concept evolutionary entropy as the measure of fitness. The theory predicts that the changes which occur as a population evolves from one non-equilibrium steady state to another are described by the following directionality principle-the fundamental theorem of evolution: (a) an increase in evolutionary entropy when resource composition is diverse, and resource abundance constant; (b) a decrease in evolutionary entropy when resource composition is singular, and resource abundance variable. Evolutionary entropy characterizes the dynamics of energy flow between the individual elements in various classes of biological networks: (a) demographic, where the units are individuals parameterized by age, and their age-specific fecundity and mortality; (b) metabolic, where the units are metabolites, and the transitions are the biochemical reactions that convert substrates to products; (c) social, where the units are social groups, and the forces are the cooperative and competitive interactions between the individual groups. This article reviews the analytical basis of the evolutionary entropic principle, and describes applications of directionality theory to the study of evolutionary dynamics in two biological systems; (i) social networks-the evolution of cooperation; (ii) metabolic networks-the evolution of body size. Statistical thermodynamics is a mathematical model of macroscopic behavior in inanimate matter based on thermodynamic entropy, a statistical measure which describes the number of ways the molecules that compose the a material aggregate can be arranged to attain the same total energy. This theory predicts an increase in thermodynamic entropy as the system evolves towards its equilibrium state. We will delineate the relation between directionality theory and statistical thermodynamics, and review the claim that the entropic principle for thermodynamic systems is the limit, as the resource production rate tends to zero, and population size tends to infinity, of the entropic principle for evolutionary systems.
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Graphical Abstract Highlights d Genome and two transcriptomes of the bowhead whale, the longest-lived mammal d Bowhead-specific mutations in genes associated with cancer and aging (e.g., ERCC1) d Duplications in genes associated with DNA repair, cell cycle, and aging (e.g., PCNA) d Changes in genes related to thermoregulation (UCP1) and other bowhead traits Correspondence In Brief The bowhead whale is the longest-lived mammal, possibly living over 200 years. Keane et al. sequence the bowhead genome and transcriptome and perform a comparative analysis with other cetaceans and mammals. Changes in bowhead genes related to cell cycle, DNA repair, cancer, and aging suggest alterations that may be biologically relevant.
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Aging is associated with severe thermogenic impairment, which contributes to obesity and diabetes in aging. We previously reported that ablation of the ghrelin receptor, growth hormone secretagogue receptor (GHS-R), attenuates age-associated obesity and insulin resistance. Ghrelin and obestatin are derived from the same preproghrelin gene. Here we showed that in brown adipocytes, ghrelin decreases the expression of thermogenic regulator but obestatin increases it, thus showing the opposite effects. We also found that during aging, plasma ghrelin and GHS-R expression in brown adipose tissue (BAT) are increased, but plasma obestatin is unchanged. Increased plasma ghrelin and unchanged obestatin during aging may lead to an imbalance of thermogenic regulation, which may in turn exacerbate thermogenic impairment in aging. Moreover, we found that GHS-R ablation activates thermogenic signaling, enhances insulin activation, increases mitochondrial biogenesis, and improves mitochondrial dynamics of BAT. In addition, we detected increased norepinephrine in the circulation, and observed that GHS-R knockdown in brown adipocytes directly stimulates thermogenic activity, suggesting that GHS-R regulates thermogenesis via both central and peripheral mechanisms. Collectively, our studies demonstrate that ghrelin signaling is an important thermogenic regulator in aging. Antagonists of GHS-R may serve as unique anti-obesity agents, combating obesity by activating thermogenesis.
Thermal conductance is a measure of the ease with which heat is exchanged between a body and the environment. It may include or exclude evaporative heat loss. If evaporative heat loss is included, conductance in endotherms should be used only at temperatures below thermoneutrality because evaporation is of little importance only at these temperatures. The slope of the curve of metabolism on air temperature equals conductance if and only if the curve extrapolates to body temperature when the rate of metabolism is zero. Slopes fitted by the method of least squares () usually are less than the mean minimal conductance () calculated from individual measurements of metabolism below thermoneutrality, because most endotherms mix physical and chemical thermoregulation at temperatures below thermoneutrality. The extent to which an extrapolation of the fitted curve overestimates body temperature (δT) is related to the error by which fitted slopes estimate mean minimal conductance: . This relation can be used to correct fitted slopes in the literature to mean minimal conductances, as long as the mean air temperature at which minimal conductance is being estimated falls between 12 and 20 C and mean body temperature falls between 32 and 38 C.
Hochachka P.W., Somero G.N. (2002) Biochemical adaptation: mechanism and process in physiological evolution. New York: Oxford University Press. 466 p.
Development of experimental models of life span regulation is an important goal of modern gerontology. We proposed a thyroxin model of accelerated aging. Male Wistar rats at the age of 17months received thyroxin in drinking water at a concentration of 6mg/L for 2months as a model of induced hyperthyroidism (IH). Administration of thyroxin resulted in a decrease in life span and a 2°C increase in body temperature that was accompanied by a 2 fold increase in thyroxin level and a 40% increase in triiodothyronine in blood serum. Induced hyperthyroidism can be used as a model of accelerated aging. We also found that thyroxin administration acts as uncoupler of oxidative phosphorylation as treatment was accompanied by an increase in the generation of superoxide radicals by 50%. Antioxidant enzyme activity remained unchanged (glutathione peroxidase, glutathione reductase mitochondrial) or was reduced (glutathione-S-transferase by 1.7 times) as compared with the control. The activity of glucose-6-transferase was increased by 2.8 times as compared with control, and malate dehydrogenase activity in liver increased by 6.8 times. Induced hyperthyroidism in rats resulted in distinct epigenotype which was accompanied by a decrease in life span. Copyright © 2014. Published by Elsevier Inc.
Two different mechanisms are considered to be related with aging. Cumulative molecular damage caused by reactive oxygen species (ROS), the by-products of oxidative phosphorylation, is one of these mechanisms (ROS concept). Deregulated nutrient sensing by insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) pathway is the second mechanism (IIS concept). Temperature reduction (TR) is known to modulate aging and prolong lifespan in a variety of organisms, but the mechanisms remain poorly defined. Here we first demonstrate that late onset TR from 26oC to 22oC extends mean lifespan and maximum lifespan by approximately 5.2 and 3 weeks, respectively, in the annual fish Nothobranchius guentheri. We then show that TR is able to decrease the accumulation of histological aging markers senescence-associated β-galactosidase (SA-β-Gal) in the epithelium and lipofuscin (LF) in the liver, and to reduce the protein oxidation and lipid peroxidation levels in the muscle. We also show that TR can enhance the activities of catalase, glutathione peroxidase and superoxide dismutase, and stimulate the synthesis of SirT1 and FOXO, both of which are the downstream regulator of IIS pathway. Taken together, our findings suggest that late onset TR, a simple non-intrusion intervention, can retard aging process in aged fish, resulting in their lifespan extension, via a synergistic action of antioxidant system and IIS pathway. This also suggests that combined assessment of ROS concept and IIS concept will contribute to providing more comprehensive view of anti-aging process.