Cold-Induced Thermoregulation and Biological Aging

PHYSIOLOGICAL REVIEWS
Vol. 78, No. 2, April 1998
Printed in U.S.A.
Cold-Induced Thermoregulation and Biological Aging
MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD
Physiology Graduate Group and Department of Nutrition, University of California, Davis, California
I. Introduction 339
A. Definition of aging 340
B. Designs in research on aging 340
II. Overview of the Effects of Aging on Cold-Induced Thermoregulation 341
A. Human investigation 342
B. Animal research 342
C. Cold perception 342
III. Heat Loss 343
A. Vasoconstriction, heat loss, and aging 343
B. Insulative properties of body fat and aging 344
IV. Heat Production 345
A. Skeletal muscle shivering thermogenesis and aging 345
B. Brown adipose tissue nonshivering thermogenesis and aging 347
V. Cold-Induced Thermoregulation and the Rate of Aging 352
VI. Summary and Conclusions 353
A. Summary 353
B. Conclusions 354
Florez-Duquet, Maria, and Roger B. McDonald. Cold-Induced Thermoregulation and Biological Aging. Physiol.
Rev. 78: 339–358, 1998.—Aging is associated with diminished cold-induced thermoregulation (CIT). The mechanisms
accounting for this phenomenon have yet to be clearly elucidated but most likely reflect a combination of increased
heat loss and decreased metabolic heat production. The inability of the aged subject to reduce heat loss during
cold exposure is associated with diminished reactive tone of the cutaneous vasculature and, to a lesser degree,
alterations in the insulative properties of body fat. Cold-induced metabolic heat production via skeletal muscle
shivering thermogenesis and brown adipose tissue nonshivering thermogenesis appears to decline with age. Few
investigations have directly linked diminished skeletal muscle shivering thermogenesis with the age-related reduction
in cold-induced thermoregulatory capacity. Rather, age-related declines in skeletal muscle mass and metabolic
activity are cited as evidence for decreased heat production via shivering. Reduced mass, GDP binding to brown
fat mitochondria, and uncoupling protein (UCP) levels are cited as evidence for attenuated brown adipose tissue
cold-induced nonshivering thermogenic capacity during aging. The age-related reduction in brown fat nonshivering
thermogenic capacity most likely reflects altered cellular signal transduction rather than changes in neural and
hormonal signaling. The discussion in this review focuses on how alterations in CIT during the life span may offer
insight into possible mechanisms of biological aging. Although the preponderance of evidence presented here
demonstrates that CIT declines with chronological time, the mechanism reflecting this attenuated function remains
to be elucidated. The inability to draw definitive conclusions regarding biological aging and CIT reflects the lack
of a clear definition of aging. It is unlikely that the mechanisms accounting for the decline in cold-induced thermoregulation
during aging will be determined until biological aging is more precisely defined.
I. INTRODUCTION bolic heat production. Although the current data strongly
suggest that the decreased cold-induced thermoregulation
An inability to appropriately thermoregulate during reflects a biological age-related phenomenon, clinical hycold
exposure has been established in aged humans and pothermia, a syndrome leading to death, in humans re-
in laboratory animals (22, 73, 79, 94, 107, 148, 162, 166, flects more closely socioeconomic factors; that is, clinical
181). The mechanisms accounting for this phenomenon hypothermia in the elderly is easily preventable by inhave
yet to be clearly elucidated but most likely reflect a creasing the room temperatures and/or increasing insula-
combination of increased heat loss and decreased meta- tion from clothing (i.e., putting on a coat). For this reason,
0031-9333/98 $15.00 Copyright 1998 the American Physiological Society
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MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
we believe that the study of cold-induced thermoregula- If one adheres to a broad definition of aging that includes
tion is better suited as a model to evaluate possible mech- all biological processes throughout the life span, then one
anisms that reflect biological aging. Thus the discussion must consider experimental designs that include the study
in this review focuses on how alterations in cold-induced of early as well as late life experiences (or how early
thermoregulation (CIT) during the life span may offer in- events may affect later outcomes). Those choosing to insight
into possible mechanisms of biological aging. vestigate aging at the point where deterioration of func-
Research on the cold-induced temperature regulation tion is clearly identifiable will focus on the upper end of
during senescence is complicated by the fact that a pre- the life span; that is, the results of any particular investigacise
and generally accepted definition of aging has yet to tion on biological aging will be applicable only as far as
be adopted. Lack of a generally accepted definition of the underlying definition of aging permits.
aging has hampered elucidation of possible mechanisms In our studies on aging, we have taken the position
that reflect decreased CIT during aging; that is, compari- that aging can be defined as the inability of the organism
sons of investigations among laboratories are often com- to maintain homeostatic regulation when given a chalplicated
by difference of age groupings, unknown health lenge. Any alteration in homeostasis must be nonreversi-
status of the population, a diversity of species being used ble, independent of a pathological condition, and contrib-
as models, and lack of valid biomarkers that determine ute significantly to a general loss in function or death.
biological age. These complex ‘‘problems’’ surrounding This definition is similar to that recently presented by
the development of a definition of aging have often re- Masoro (104), who suggests that aging represents ‘‘detrisulted
in misinterpretation of data concerning CIT. It is mental changes with time during postmaturational life
important, therefore, that we begin this review with a that underlie an increasing vulnerability to challenges
brief discussion focusing on definitions of aging and ex- thereby decreasing the ability of the organism to survive.’’
perimental designs for aging research. This section is fol- Vulnerability to challenges implies alterations in homeolowed
by an in-depth analysis of possible mechanism(s) static regulation and, therefore, a decrease of integration
that may account for age-related alterations in CIT. Fi- among several physiological systems. To investigate bionally,
we present experimental evidence suggesting that logical aging from this viewpoint, it is advantageous to
the study of CIT can be used to evaluate mechanisms of use a model system that includes many points of regula-
biological aging at the individual level. tion. We have found that the evaluation of CIT provides
an acceptable system in which to test hypotheses within
A. Definition of Aging
the framework of our broad definition of aging.
The fundamental biological mechanisms that underlie
the aging process are unknown. As such, there has
B. Designs in Research on Aging
been little agreement among researchers as to a useful or The development of efficient experimental designs
precise definition of the word aging. Aging, as defined to test hypotheses concerning biological aging presents
generally throughout the biological literature, is the grad- significant challenges that are rarely encountered in other
ual deterioration in function that occurs after maturity. biological research. Methodological issues for design and
This definition is imprecise, however, because biological analysis of aging studies have been reviewed (27, 29, 41,
aging includes all processes, both advantageous and detri- 187) and are discussed only briefly. The primary purpose
mental, occurring within the organism from the beginning of aging research is to determine a biological change oc-
of life (conception/birth?) until death. Some researchers curring as a function of time that is associated with the life
prefer to define biological aging more narrowly by using span of the species. Cross-sectional designs using humans
the word senescence. Senescence is generally accepted and rodents, by far the most common model, are capable
to mean a time-dependent loss in function that leads to of evaluating apparent time-dependent changes but are
disability or death. This definition of aging also lacks pre- limited in their capacity to determine whether these altercision
because it fails to include processes in early life or ations are associated with a basic process of biological
in utero that are recognized as having significant affects aging. This is due, in part, to the fact that cross-sectional
on adult function, disease, and life span (7, 8). In this designs evaluate the biological process between young
review, the words aging and senescence are used inter- and old age groups at a single point in time. There can be
changeably and, unless otherwise noted, refer more no assurance that the measured variable at the given time
closely to the definition of senescence as used above. point will remain constant in the future or will be repre-
Understanding the definition of aging is more im- sentative of the entire population. Without repeated mea-
portant to the study of gerontology than simply a starting
surement over time, it is impossible to determine if the
point for this review. The definition of biological aging is result reflects aging per se or an uncontrolled environmen-
basic to the development of hypotheses-driven research. tal factor or disease. Indeed, several early cross-sectional
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April 1998 COLD-INDUCED THERMOREGULATION AND BIOLOGICAL AGING 341
studies using humans to evaluate CIT included subjects
recruited from a clinical populations. Moreover, crosssectional
designs in humans typically base their criteria
for inclusion of individuals into the oldest grouping on an
arbitrary definition, i.e., those over 65 years, rather than
on more empirically derived data, i.e., survival or mortality
distributions. This often results in the oldest age group
having a wide distribution of ages. Significant biological
differences undoubtedly exist among individuals at 65 vs.
90 yr of age just as they do between a 10 and a 20 yr old.
Cross-sectional studies in humans are better suited for
the development rather than the testing of hypotheses.
Cross-sectional studies of humans are not well suited
for evaluating possible mechanisms of biological aging.
Animal models, including rodents, insects, birds, and fish,
offer the investigator an opportunity to study aging in FIG. 1. Survival curves for male Fischer 344 rats fed ad libitum
a highly controlled environment. Important markers of (group A, solid line) or fed a calorie-restricted diet (group R, dashed
biological aging such as longevity characteristics and late- line). [From Yu et al. (192).]
life disease patterns can be determined easily in a variety
of species. The investigator has significant control of envi-
29 mo (Fig. 1). This distribution of survival illustrates
ronmental factors including diet, husbandry, and genetic
important issues that are rarely controlled for when using
characteristics. Nonetheless, there are several issues in
mean life span as a criterion for senescence. The cause
the design of animal experimentation for the biology of
of death in animals that die at 20 or 29 mo is rarely comaging
that must be considered to appropriately interpret
pared with the animals at the median life span of the
the results. Efficient cross-sectional design of animal exgroup.
It is possible that the cause of biological aging may
perimentation requires a fairly precise determination of
differ significantly among these age cohorts. Differences
the age at which a species becomes senescent and, for
in possible cause of death among aged animals and hureasons
of comparison, the age that the animal reaches
mans also illustrate the most serious problem of using
maturity. Correctly determining the latter has proven to
cross-sectional design: selected mortality; that is, it is posbe
as important to proper design of aging research as the
sible that the results of these investigations on a particular
former. The results from several investigations suggest
older age group more closely reflect phenomena associthat
developmentally immature animals (generally acated
with survival rather than biological aging. Moreover,
cepted as the age at which exponential growth rate is
median life span is based on chronological time. Although
occurring) are not a suitable control group for senescent
chronological time provides an easy marker for senesanimals
(103, 187). Rapidly growing versus weight-stable
cence in a group, it does not consider that the rate of
older animals have significantly different hormonal proaging
is specific to the individual; that is, median life span
files that may affect various physiological systems. Con-
of a species does not reflect biological aging.
clusions based on cross-sectional comparisons between
rapidly growing young and weight-stable old animals more
likely reflect developmental changes rather those associ- II. OVERVIEW OF THE EFFECTS OF AGING ON
ated with senescence.
Determining the age at which a species ‘‘passes’’ into
COLD-INDUCED THERMOREGULATION
senescence is also difficult. The mean life span for a spe- The physiological processes that allow maintenance
cies as determined from survival curve analysis is used of normothermia during cold exposure involve a complex
extensively as a marker of senescence. Mean values, in- series of regulatory steps and are described thoroughly
cluding mean life span, are associated with a distribution elsewhere (55, 65, 77, 142). The high level of regulatory
of the individual data points, thereby resulting in consider- control of CIT has made the study of CIT an attractive
able heterogeneity in the population value; this is particu- and useful system in which to investigate possible mechalarly
true in old animals. Age-related heterogeneity intro- nisms for aging. Briefly, upon exposure to a temperature
duces significant error not often accounted for by stan- below thermoneutrality (28–33C in humans, Ref. 191; 24–
dard error-comparison statistics. For example, the 30C in rats, Refs. 55, 112), thermoreceptors in the skin,
generally accepted mean life span of the Fischer 344 spine, and brain transmit neural signals to the hypothala-
(F344) rat, a species used extensively in aging research, mus. The integration of these neural signals results, in the
is 24–25 mo of age (192). The exponential decline in survi- case of cold exposure, in decreased heat loss and invorship
begins at Ç20 mo of age and may continue until creased heat production. Heat is conserved during cold
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MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
exposure by increasing cutaneous vasoconstriction, and Others have found that although core temperature does
thereby minimizing the heat exchange capacity of the not differ significantly among cold-exposed young and old
skin. Concomitantly, heat production is increased as a individuals, the rate of decline is faster in aged males (73).
result of shivering in skeletal muscle and nonshivering These data are supported by the findings of Sugarek (162),
thermogenesis in a variety of peripheral tissues, but most who reported that median times for a return to baseline
notably in brown adipose tissue (BAT). In the event that oral temperature after ingestion of iced water was 30%
the heat produced is insufficient and/or heat is not appro- slower in aged (ú60 yr) humans as compared with individ-
priately conserved during cold exposure, hypothermia enuals between the ages of 40 and 59 yr. The age-related
sues. Extreme hypothermia may lead to stroke or myocar- decrease in cold-exposed rectal temperature may be de-
dial fibrillation and, eventually, death.
pendent on gender. Rectal temperatures of younger (20–
30 yr) and older women (51–72 yr) exposed to temperatures
ranging for 10 to 20C for2hdonotdiffer signifi-
A. Human Investigation cantly. Rectal temperatures of older men are significantly
less than those of older and younger women and younger
Initial reports of altered CIT in human elderly are men (181). Although the current experimental evidence
based largely on observations in clinical settings. These supports a suggestion of blunted CIT during aging, sig-
descriptions suggest that hypothermia in the cold-exposed
elderly reflects a loss of metabolically active tissue,
nificant conflicting data preclude a definitive conclusion.
poor circulation, and a slow adjustment to changing temperature,
although no measurements of these variables
B. Animal Research
were conducted (22–24, 88, 186). Concluding that CIT is
reduced during aging based on investigations using elderly
hypothermia victims may be inappropriate because the
health status of these patients before cold exposure is
rarely known; that is, disease rather than biological aging
may influence greatly the observed hypothermia. Nonetheless,
the susceptibility of the elderly to hypothermia is
consistent with the finding that Ç9% of elderly in the
United Kingdom have morning core temperatures within
one-half a degree of the clinical definition of hypothermia,
35C (49). The contribution of biological aging to the low
core temperature observed in these individuals is unknown
because inadequate home heating and socioeco-
nomic factors accounted for a significant portion of the
variance. Moreover, elderly individuals, aged 69–90 yr,
living in conditions of adequate home heating did not ex-
perience significant declines in core temperature or inci-
dences of hypothermia (23). Although some clinical and
epidemiological evidence may support the suggestion that
CIT declines with aging, the influence of biological aging
on the ability to maintain normal body temperature during
cold exposure is difficult to precisely determine from
Research using animal models to investigate the ef-
fect of aging on CIT is limited to rodent models (6, 28,
40, 44, 51, 67, 79, 94, 107, 109–115, 149, 150, 152, 154, 155,
165, 167–170, 185). These investigations are, in general,
consistent with observations in humans that CIT declines
with advancing age (Table 2). With the exception of one
investigation (44), reports before 1980 do not provide suf-
ficient data on animal husbandry or life-span characteristics
necessary to rule out the influence of disease. Thus
caution should be used when interpreting the results of
these investigations. Virtually every investigation performed
after life span and housing conditions were standardized
reports that aged mice and rats have significantly
lower cold-exposed core temperatures than do young ani-
mals; that is, the preponderance of evidence in studies
using laboratory rodents suggests that CIT declines with
advancing age. In addition, the observation in humans that
older females tend to maintain core temperature in the
cold better than do males is supported by the animal work
(51, 107, 109, 113).
these types of investigations.
To more accurately determine the effects that biologi-
C. Cold Perception
cal aging may have on CIT, investigations in humans Appropriate perception of ambient temperature is
should include subjects in which health status is clearly critical to initiating the physiological response to cold
defined and the time of exposure and the ambient temper- exposure. Age-related functional decrements in other sen-
atures are controlled within narrow limits. Healthy older sory systems such as vision, hearing, and taste (116) imply
individuals exposed to cold (0–17C) for periods ranging that the ability to perceive cold may also be attenuated
from 30 min to 2hdonottolerate the exposure to the in the elderly (186). Elderly human subjects exposed to
same degree as do younger subjects (Table 1; Refs. 42, gradually declining temperatures below thermoneutrality
72, 73, 105, 181, 182). Rectal temperature of men aged 46– and allowed to adjust the ambient temperature to a self-
67 yr exposed to 17C for 30 min is significantly lower selected comfortable point tend to make the initial adjust-
than that observed in boys between the ages of 10 and 16 ment more slowly than do younger individuals (124). The
yr, but not compared with males 19–29 yr of age (182). slower adjustment occurs despite the fact that body tem-
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April 1998 COLD-INDUCED THERMOREGULATION AND BIOLOGICAL AGING 343
TABLE 1. Effect of age on cold-exposed core temperature in humans
Exposure Conditions
Age, yr Body Core Temperature, C
Weight, Temperature, Time, Reference
Gender n Mean Range kg C min Precold Cold Change No.
Male 9 NR 10–13 34.8 17 30 37.6 37.5 00.1 182
Male 7 NR 14–16 50.9 17 30 37.4 37.2 00.2 182
Male 10 NR 19–26 76.7 17 30 37.3 36.8* 00.5† 182
Male 7 NR 46–67 81.4 17 30 37.2 36.6* 00.6† 182
Female 10 24 20–30 59.3 10 120 36.6 36.5 0.1 181
Male 10 22 20–30 70.8 10 120 36.9 36.6 00.3 181
Female 7 61 51–72 64.3 10 120 36.7 36.8 /0.1 181
Male 10 64 51–72 73.7 10 120 36.6 36.3 00.3‡ 181
Male NR NR 46–50 63.1 10 120 36.2 35.3* 00.9 105
Male NR NR 61–70 54.7 10 60 36.9 35.5* 01.4 105
Male 9 21.7 20–25 64.5 12–17 60 37.2 37.1 00.1 73
Male 10 63.7 60–71 53.7 12–17 60 37.3 37.1 00.21 73
Male 8 26.5 21–29 78.6 5 30 37.2 37.0 00.2 42
Male 11 63.5 55–66 79.8 5 30 37.0 36.8 00.2 42
Investigations listed here include only those in which cold exposure conditions were controlled. NR, data not reported. *Value is significantly
different from precold value. †Significantly different from 10–13 and 14–16 age group. ‡Significantly different from females of similar age.
perature of the older group declines to a greater degree rectly as the difference between core and skin tempera-
than that of the younger individuals. The elderly also apture (181, 182) or changes in peripheral blood flow (68,
pear to be less able to discriminate between a close range 84, 140). Direct evaluation of age-related vasoconstriction
of ambient temperatures; that is, younger individuals can during whole body cold exposure has not been reported.
distinguish ambient temperatures of Ç1C, whereas some Rather, much of the current understanding regarding this
older subjects are unable to detect differences of up to relationship is suggestive. Enlargement in the vessel diam-
4C (25). Aging rats given access to a variety of ambient eter and wall thickness is associated with an age-related
temperatures prefer a temperature at which they experi- increase of arterial wall stiffness (89). Increase in the arteence
a significantly larger decline in body temperature rial wall stiffness decreases the distensibility of the vessel
relative to younger animals (128).
wall that, in turn, results in resistance to constriction and
the likelihood of increased heat loss. Although the mecha-
III. HEAT LOSS
nisms reflecting the increase in arterial wall stiffness are
unknown, decreases in elastin and increases in the con-
The thermoregulatory regions of the hypothalamus
initiate the decline in heat loss from the body via vasocon-
striction of the cutaneous vasculature upon exposure to
a cold environment (65). Peripheral blood flow is shunted
away from the skin toward deep body tissue, and conductive
and convective heat loss from the skin’s surface is
reduced. The ability to reduce heat loss during cold expo-
sure is dependent, to a large degree, on the reactive tone
of the cutaneous vasculature but may also include the
insulative properties of body fat. Age-related changes in
the amount of body fat and the response of the cutaneous
vasculature could result in increased heat loss and lead
to diminished core temperature during cold exposure.
centration of collagen cross-links of the peripheral vasculature
are suggestive of age-related alterations in the vasoconstriction
(118, 138). These investigations have been
generally carried out using large vessels, e.g., aorta, iso-
lated from rodents or in tissues from type II diabetic hu-
mans. It is not clear if the small vessels within the skin,
those involved primarily in vasoconstriction response of
the healthy elderly, show a similar distribution of collagen
cross-links with aging.
Investigations evaluating cutaneous fingertip blood
flow as an index of vascular constriction during cold expo-
sure suggest an equal magnitude in the vasoconstriction
response of young and old subjects (84, 140). However,
the vasoconstrictor response occurs more slowly in the
elderly and takes twice as long to attain the same level
A. Vasoconstriction, Heat Loss, and Aging
of vasoconstriction as observed in the younger subjects.
Richardson et al. (140) found that although the cold-in-
Heat conservation during periods of cold exposure duced vasoconstriction occurs within the first minute in
is linked directly to efficient vasoconstriction. Observa- both young and old subjects, the response to the cold is
tions in humans suggest that inefficient vasoconstriction not maintained in the elderly, and blood flow returns to
response of the aged during cold exposure is related to precold levels.
increased heat loss. Vasoconstriction is estimated indi- Diminished response of smooth muscle to neural and
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MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
TABLE 2. Effect of age on cold-exposed core temperature in rodents
Exposure Conditions
Age, Temperature, Time,
Core
Temperature, O2 Reference
Species Strain Gender mo n C h CConsumption No.
Mice C57B1/6J Male 10 7 10 3 36 NR 44
Male 30 7 10 3 28† NR 44
Mice NMRI Female 4–6 NR 0 2 37.5 F 40
Female 12 NR 0 2 35† F* 40
Rats SD Male 3 24 18 1.5 37 NS 6
Male 6 24 18 1.5 37 F 6
Male 9 12 18 1.5 37 NS 6
Male 13 9 18 1.5 36 F 6
Male 24 9 18 1.5 36 F 6
Mice C57B1/6J Male 6–7 16 15 3 34.2 NR 67
Male 13–14 16 15 3 32.5† NR 67
Male 19–20 20 15 3 32† NR 67
Rats SD Male 6–9 8 010 2 33.5 F 94
Male 23–26 8 010 2 29.5† F* 94
Rats SD Male 5 10 6 6 38.5 F 114
Male 26 8 6 6 36.1† F* 114
Rats F344 Male 12 10 6 6 35 F 112
Male 24 9 6 6 32† F* 112
Rats F344 Male 6 5–6 6 1.5 35.7 NR 109
Female 6 5–6 6 1.5 36.3 NR 109
Male 12 5–6 6 1.5 35.9† NR 109
Female 12 5–6 6 1.5 36.1 NR 109
Male 26 5–6 6 1.5 34.8 NR 109
Female 26 5–6 6 1.5 35.3 NR 109
Rats SD Male 3–6 8 010 2 31.4 F 185
Male 26–30 8 010 2 28.9† F* 185
Rats F344 Male 6 6 6 4 36.8 F 51
Female 6 10 6 4 36.9 F 51
Male 12 7 6 4 36.4 F 51
Female 12 7 6 4 36.8 F 51
Male 26 5 6 4 35.7‡ F 51
Female 26 7 6 4 36.2 F 51
Mice C57BL/6J Male 12 13 6 3 35.8 NS 154
Male 24 10 6 3 33.4† NS 154
Core temperature is mean value reported after cold exposure. Symbols used in O2 consumption column indicate a significant increase (F),
decrease (f), or no difference (NS) relative to precold conditions. NR, data not reported. *Rate of increase in cold-exposed O2 consumption value
is significantly less than in younger animals. †Significantly different from younger group value. ‡Significantly different from all other values in this
investigation.
hormonal stimuli may contribute to blunted or delayed striction responsiveness during cold exposure in the el-
vasoconstriction response of the elderly and can significantly
affect the amount of heat loss during cold exposure
(19, 34, 45, 99, 139, 172). The increase in peripheral blood
derly reflects primarily increased arterial wall stiffness.
flow in beagles (61) and humans (68) is generally less
during a-adrenergic stimulation in older versus younger
B. Insulative Properties of Body Fat and Aging
subjects. This does not necessarily indicate that de- The amount of body fat may also contribute significreased
vasoconstriction in the aging subject reflects al- cantly to an effective defense against excessive heat loss
tered adrenergic response. The difference in blood flow in older individuals (30). The epidemiological and experidoes
not appear to reflect an alteration in a-adrenergic mental evidence suggest that the amount and percentage
sensitivity (60). Hogikyan and Supiano (68) report that of body fat increase with age (37). Some suggest that the
decreased responsiveness of the smooth muscle a-adren- greater amount of body fat in older versus younger subergic
receptor is compensated for by increased sympa- jects improves thermoinsulation and decreases heat loss
thetic nervous system activity. The net outcome is no during cold exposure (73, 181). This improvement in thersignificant
alteration in a-adrenergic-mediated vasocon- moinsulation is related to a reduction in the skin-to-ambistriction
response during aging. Although further evalua- ent temperature thermal gradient; that is, older, fatter
tion of possible age-related changes to arterial smooth males exposed to temperatures between 10 and 20C have
muscle is warranted, it appears that diminished vasocon- significantly lower skin temperatures than do younger,
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April 1998 COLD-INDUCED THERMOREGULATION AND BIOLOGICAL AGING 345
leaner individuals (181). The reduction in the thermogra- A. Skeletal Muscle Shivering Thermogenesis
dient did not, however, prevent a greater decrease in coldexposed
rectal temperatures of the older versus younger
and Aging
males. Although the older females had the highest percent
of body fat and had no change in rectal temperature during
cold exposure, Wagner and Horvath (181) concluded
that the amount of body fat does not fully reflect differences
in cold-exposed rectal temperatures. They observed
that younger women had 12% more body fat than agematched
males, yet the rectal temperature of these
women was significantly lower. These investigators suggest
that age-related differences other than percent body
fat must account for the difference between older males
and females. The differing results between males and females
may reflect the greater variability associated with
the measurement of body fat observed previously in elderly
versus younger adults (131). This suggestion is supported
by the observation that significant correlation between
body fat and rectal temperature exists even when
weak and nonsignificant differences are found in the per-
Heat produced via shivering thermogenesis in skele-
tal muscle is important for maintaining homeothermy and
is estimated to provide up to one-third of the total heat
production during cold exposure (48). Shivering thermo-
genesis may also become more important during aging as
the contribution of nonshivering heat production appears
to decline (see sect. IIIB). Therefore, changes in skeletal
muscle could potentially play a role in the decline of cold-
exposed thermoregulation during aging. However, similar
to the results of heat loss during cold exposure, few inves-
tigations have directly linked diminished skeletal muscle
shivering thermogenesis to the age-related reduction in
cold-induced thermoregulatory capacity. Rather, age-re-
lated declines in skeletal muscle mass and metabolic ac-
tivity are cited as evidence for decreased heat production
via shivering (82).
cent body fat among older and younger men (12). When
the body fat variable is removed from regression analysis,
1. Skeletal muscle mass
older men have higher skin temperature, greater heat loss, A decrease in skeletal muscle mass as a function of
and lower tissue insulation than do younger individuals; biological aging has been generally accepted for several
that is, these investigators suggest that greater body fat years (59). The direct relationship among skeletal muscle
in older men represents only a correlational rather than mass, aging, and cold-exposed thermoregulation is un-
causal relationship to reduced heat conservation. More- clear. Part of the problem of evaluating the impact of
over, older rats that have similar or greater body fat than human muscle atrophy during aging on CIT lies in the
younger animals consistently show lower cold-induced variability associated with estimates of lean body mass
core temperatures (115). Although some evidence indi- (131). In addition, although the methods used to estimate
cates that the amount of body fat may impact the conser- lean body mass are entirely appropriate for use in a
vation of heat during cold exposure, it appears that inade- healthy adult population, several of these methods may
quate cutaneous vasoconstriction is more likely the cause contain inherent assumptions that have yet to be validated
of age-related increases in heat loss.
in the elderly (81, 144). Longitudinal investigations using
creatinine clearance as an index for estimates of metabolically
active tissue suggest that lean body mass declines
IV. HEAT PRODUCTION 3–5% per decade after the age of 30 (175). This particular
longitudinal study did not, however, effectively control
The effect of aging on metabolic heat production dur- for differences in physical activity and nutritional habits
ing cold exposure is controversial. Investigations evaluat- among the participants. Longitudinal data describing the
ing metabolic heat production in humans and in rodents influence of physical activity on lean body mass are lim-
have found a decrease (72, 112, 155, 170, 171, 184) or no ited, but several cross-sectional investigations of elderly
difference (51, 112, 182) in cold-exposed oxygen con- populations have shown that exercise maintains or imsumption
rates between young and old subjects. The ap- proves lean body mass (18, 141, 160); that is, if the atrophy
parent discrepancy among the results most likely reflects of muscle mass contributes to the decline in cold-exposed
differences in study design that include degree and dura- thermoregulation of the elderly, it is not clear whether
tion of cold exposure as well as the age and gender of the this effect is due to biological aging or to a sedentary life-
elderly subjects. Although experimental conditions can be style.
controlled to a greater extent in studies using laboratory Because physical activity is known to increase or
rodents as compared with humans, inconsistency of re- maintain lean body mass in the elderly, it is possible that
sults concerning the effect of aging on cold-induced meta- the fitness level of an aging individual may prevent attenubolic
heat production persists. In the following section, ation of cold-exposed thermoregulation. A comparison
the discussion focuses on the affect of aging on the indi- among older and younger sedentary men and older trained
vidual components that contribute to overall increases in men indicates that rectal temperatures after 30 min at 5C
metabolic heat production during cold exposure. of the two older groups do not differ significantly but are
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MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
35, 178, 176, 179). An impaired glucose uptake into the
muscle observed in older individuals could reduce the
amount of heat produced through shivering thermogenesis.
Observations of increased skeletal muscle insulin resistance
(133, 134) and decreased glucose tolerance (31,
32, 36, 76) imply a disruption in the contribution from
glucose to the overall metabolic heat production of skeletal
muscle. However, more recent data suggest that factors
other than aging per se have a significant impact on
glucose uptake into skeletal muscle. Several investigations
have reported that obesity and physical inactivity
FIG. 2. Total body mass-independent oxygen consumption (Vg O2; increase insulin resistance (9, 26, 135, 184). Insulin resismean
{ SE) of 12- and 24-mo-old sedentary and exercise-trained male tance in elderly, obese subjects is significantly reduced
Fischer 344 rats during 6hofcold exposure (6C). * Significant differ-
ence from other 3 groups (P õ 0.05). [From McDonald et al. (112).]
after weight reduction (184). In addition, physical activity
in previously untrained older insulin-resistant individuals
has been shown to increase glucose uptake into muscle
significantly less than those of the younger individuals through an increase in the muscle glucose transporter
(42). Moreover, cold-exposed oxygen consumption does GLUT-4 (83). It is now well recognized that obesity and
not differ between the groups, whereas thermoconduction inactivity are the most important factors contributing to
is significantly higher in the older versus younger groups the development of glucose intolerance in most of the
regardless of exercise training. These data suggest that older population (135).
the lower cold-exposed rectal temperatures in the older Although direct evaluation of the relationship bemen
more likely reflect an elevated heat loss, via blunted tween the cold-induced skeletal muscle glucose disposal
cutaneous vasoconstriction, rather than an attenuated
rate and aging is limited, the findings from at least one
level of heat production. Although body fat was signifiinvestigation
suggest that serum glucose does not contribcantly
less in the older trained versus sedentary men, the
ute significantly to skeletal muscle thermogenesis during
relationship to skeletal muscle mass was not determined.
cold exposure; that is, glucose utilization in skeletal mus-
The results from investigations evaluating the influcle,
estimated from in vivo cellular incorporation of 2ence
of age-related muscle atrophy on cold-exposure in
[ 14 C]deoxyglucose, does not increase significantly during
aging rodents suggest that exercise training increases heat
cold exposure in younger or older, male or female, F344
production (112, 154, 155). Oxygen consumption during
rats (113). Moreover, serum insulin levels decline significold
exposure of aging male F344 rats trained for 6 mo
cantly during cold exposure (51, 156, 161). It is unlikely
on a treadmill is significantly greater than the levels obthat
glucose uptake into skeletal muscle would increase
served in sedentary animals (112; Fig. 2). The cold-exsignificantly
during a period of decreasing insulin secreposed
rectal temperatures of older exercise-trained rats
tion.
are significantly greater than that of their sedentary coun-
Investigations evaluating the impact of glucose upterparts.
Exercise training in the younger animals has no
take on cold-induced thermogenesis suggest that serum
significant effect on oxygen consumption or rectal temglucose
does not play a significant role in a possible reperature
during cold exposure. The greater oxygen conduction
of cold-exposed skeletal muscle thermogenesis
sumption of the older exercise-trained rats is correlated
during aging. It is more likely that alterations to coldwith
a reduction in fat weight and an increase in fat-free
exposed skeletal muscle metabolism reflect changes in
weight. However, increased skeletal muscle mass in the
the amount of glycogen stored and/or the rate of glycogenexercise-trained
rats cannot entirely account for the imolysis.
Skeletal muscle glycogen is an important metabolic
proved cold-exposed rectal temperatures. Older sedentary
substrate during cold-induced thermogenesis, and its utilirats
have similar rates of cold-exposed oxygen consumpzation
has been shown to increase during cold exposure
tion and greater fat-free weight than do the younger seden-
(86, 91, 100). However, hindlimb glycogen concentrations
tary animals, yet the rectal temperature is significantly
are not altered with aging (15, 91).
less in the older sedentary group. These data suggest that
Glycogen utilization depends not only on the amount
enhanced thermogenesis following exercise training is not
of skeletal muscle glycogen but also on the muscle’s cadue
simply to more fat-free weight, but is more likely due
pacity for glycogen breakdown. An age-related decline
to alterations in the metabolic characteristics of the lean
tissue.
in glycogenolysis may lead to a decline in intramuscular
glucose available for cold-exposed shivering thermogene-
2. Carbohydrate metabolism sis. Studies have demonstrated that both catecholamine-
Glucose uptake into muscle and its metabolism is and exercise-induced glycogenolysis in the lower limb are
important to cold-induced shivering thermogenesis (13, unaffected by age. Larkin et al. (90) assessed both recep-
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April 1998 COLD-INDUCED THERMOREGULATION AND BIOLOGICAL AGING 347
tor and postreceptor stimulation of glycogenolysis in the pact the capacity for cold-induced shivering thermogenehindlimb
muscle isolated from young and old F344 rats. sis. Several investigations have demonstrated an age-re-
Their results show that both of these steps in glycogenoly- lated decrease in the activity of skeletal muscle enzymes
sis are unaffected by age. Using in situ phosphorylase involved in aerobic metabolism, such as succinate dehy-
activity, an index of glycogen breakdown, Campbell et al. drogenase, malate dehydrogenase, and citrate synthase
(15) also observed no overall decline in glycogen utiliza- (20, 38, 39, 78). Others have reported modest or no sigtion
in the hindlimb of young versus old F344 rats. It is nificant change in oxidative enzymes with aging (2, 3, 10,
unlikely that carbohydrate availability, via glucose uptake 21, 51, 92, 132). Although these studies may appear to
and/or glycogen utilization, is reduced as a result of bio- be contradictory, aging affects differentially the level of
logical aging.
enzymes depending on the fiber composition and function
3. Lipid metabolism
of the muscle. For example, weight-bearing muscles in
rats, such as soleus, do not undergo fiber atrophy and a
Cold-induced thermoregulation is associated with an decreases in mitochondrial enzymes during aging. Nonincrease
in lipid metabolism (177, 176). Using indirect weight-bearing muscles, such as the epitrochlearis and
calorimetry and respiratory exchange techniques in cold- flexor digitorum longus, appear to be signficantly affected
exposed humans, Vallerand and Jacobs (176) observed by age (17, 69, 183). In studies where age-related declines
that the cold-induced increase in heat production was in oxidative enzymes have been noted, exercise has re-
associated with increased levels in both carbohydrate and versed these effects, emphasizing the physiological imlipid
oxidation, 588 and 63%, respectively. The source of pact of a sedentary life-style, rather than an effect of bio-
free fatty acids utilized in lipid metabolism during cold logical aging (21, 78, 86, 117).
exposure is thought to be intramuscular triglyceride Most investigations designed to determine the contri-
stores (56, 102). Direct evidence linking the availability of bution of skeletal muscle shivering thermogenesis to the
intramuscular triglycerides to blunted thermogenesis in maintenance of body temperature suggest only minor al-
the elderly is limited. Metabolic heat production is main- terations with age. Nonetheless, Lee and Wang (94) sug-
tained in the cold despite a reduction in lipid metabolism, gest that cold-induced heat production through shivering
induced by administration of nicotinic acid (102, 101). The thermogenesis can be pharmacologically enhanced. In
maintenance of thermogenesis under these conditions their investigations, 23- to 26-mo-old Sprague-Dawley rats
was attributed to a compensatory increase in carbohy- were given either an intraperitoneal injection of norepi-
drate metabolism. The data suggest that both carbohynephrine, aminophylline (a phosphodiesterase inhibitor),
drate and lipid metabolism are important in maintaining or norepinephrine plus aminophylline. Older rats given
homeothermy in the cold in adult subjects. However, the aminophylline increased heat production above control
contribution of carbohydrate and lipid metabolism to re- animals. No further increases in heat production were
duced cold-induced thermogenesis in the elderly awaits observed when norepinephrine was given in combination
further investigation. Because of the extensive lipid de- with aminophylline, nor was heat production increased
posits in the body, it is unlikely that lipid is a limiting above basal levels when only norepinephrine was in-
energy source contributing to the blunted cold-induced jected. The increase in heat production in the aminophyl-
thermogenesis observed in the elderly.
line-injected older rats was not sufficient to prevent a
Although a decrease in carbohydrate and lipid metab- significant decrease in cold-induced body temperature
olism is unlikely, it is conceivable that substrate delivery compared with the younger animals. Because the thermo-
to shivering skeletal muscle declines during aging. Mc- genic action of norepinephrine is primarily directed to-
Donald et al. (110) used radioactively labeled microward BAT nonshivering thermogenesis and the effect of
spheres to evaluate the effect of age on regional blood aminophylline is limited to skeletal muscle, these data
flow, one determinant of substrate delivery, during cold would suggest that the location of insufficient cold-in-
exposure. Their data demonstrate that the cold-induced duced heat production of the older rat, i.e., heat produc-
increase in skeletal muscle blood flow is maintained in tion sufficient to maintain core temperature, is brown fat
aging rats displaying significant decreases in core temperature.
This also demonstrates that the mechanisms re-
rather than shivering thermogenesis.
sponsible for the cold-induced elevation in skeletal muscle
blood flow function appropriately during aging and
are not likely to lead to a decline in substrate delivery
during cold exposure.
B. Brown Adipose Tissue Nonshivering
Thermogenesis and Aging
4. Cellular metabolic capacity
Brown adipose tissue is the principal anatomic location
of nonshivering thermogenesis (63). The mechanisms
Age-related alterations in the variables involved in that induce thermogenesis in this tissue have been identiskeletal
muscle oxidative metabolism may negatively im- fied and are discussed at length elsewhere (4, 64). Briefly,
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MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
FIG. 3. Schematic describing influence of norepinephrine
(NE) on uncoupling of oxidative phosphorylation
leading to brown fat nonshivering thermogenesis.
b 3, b-adrenergic receptor; cAMP, adenosine 3,5-cyclic
monophosphate; HSL, hormone-sensitive lipase; UCP,
uncoupling protein. [From Trayhurn (173).]
the release of norepinephine from the terminal endings ity, increased to the perirenal BAT depot in response to
of sympathetic neurons initiates the events leading to the norepinephrine, the physiological stimulus for nonshiv-
onset of nonshivering thermogenesis. Norepinephrine ering heat production (5). These data suggest that the
binds primarily to b-adrenergic receptors, including the response of human BAT to its principal agonist, norepi-
novel adrenoceptor subtype b 3 (4), and the transduction nephrine, is intact. Moreover, mitchondrial uncoupling
of this signal is mediated through a second messenger protein, the identifying characteristic of BAT, has been
pathway involving adenylyl cyclase. In turn, fatty acids immunohistochemically identified in humans (87). Al-
are mobilized from intracellular stores of triacylglycerides though the role of BAT nonshivering thermogenesis in
and oxidized in the mitochondria. The oxidation of fatty humans has yet to be fully elucidated, it is conceivable
acids is ‘‘uncoupled’’ from the electron transfer system that a reduction in this tissue’s capacity to produce heat
via a novel uncoupling protein within the mitochondria could contribute to the blunted cold-exposed thermoregu-
so that heat, rather than ATP, is the metabolic end product
(Fig. 3; Refs. 54, 173, 174). Although BAT constitutes only
latory response of the elderly.
Ç1% of the total body mass in the adult rodent, this tissue
contributes as much as one-third to total cold-exposed
1. Brown adipose tissue mass
oxygen consumption (48). Nonshivering thermogenesis in The heat-producing potential of BAT is typically ex-
BAT can be an important component in the maintenance pressed as a function of the uncoupling protein (UCP)
of homeothermy during cold exposure. concentration in the tissue. The greater the UCP concen-
The role of BAT in human CIT is less clear. Several tration, the greater the capacity to uncouple mitochoninvestigations
have identified significant amounts of BAT drial oxidative phosphorylation so that heat is produced.
in prenatal and newborn humans (1, 75). Because skeletal The total amount of brown fat mass may be linked directly
muscle function is not fully developed in the newborn, to the concentration of UCP and the nonshivering thermononshivering
thermogenesis is the principal mechanism genic potential of the tissue. Rodents with large interscapfor
heat production in the postnatal infant. As the human ular brown adipose depots per gram of body mass tend to
matures, however, significant atrophy of BAT occurs. It have a greater resistance to declining core temperatures
remains to be elucidated if atrophy of BAT in humans during cold exposure. Brown adipose tissue mass and
reflects a normal biological aging process or the capacity UCP concentration increase significantly in rodents exof
the human to adjust environmental factors as a means posed to 10C for 5–10 days (14, 43, 52). Conversely, if
to protect against the cold (i.e., turn up the heat, put on nonshivering thermogenesis is blocked by BAT denervaa
jacket). Nonetheless, autopsy investigations evaluating tion or administration of adrenergic antagonists, the coldthe
content of BAT in adults have found depots of this induced BAT hypertrophy and elevated levels of UCP are
tissue in similar anatomic locations as those observed in reduced significantly (57, 58, 129).
rodents (1, 74). To our knowledge, only one investigation Brown adipose tissue mass of rodents declines with
has shown that blood flow, one index of metabolic capac- age and is concomitant with diminished total protein and
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FIG. 4. Interscapular brown adipose tissue
(IBAT) mass (A), IBAT uncoupling protein
(UCP) concentration (B), brown adipocyte cell
size (C), and IBAT cell proliferation (D) in male
Fischer 344 rats exposed to cold (10C) or noncold
(25C) for 5 days. Non-cold-exposed means
sharing a common lowercase letter do not differ
significantly (P õ 0.05). Cold-exposed means
sharing a common uppercase letter do not differ
significantly (P õ 0.05). * Within an age group,
cold-exposed value is significantly different
from non-cold-exposed mean. [From Florez-Duquet
et al. (47).]
UCP concentrations (71, 107, 109, 112, 150, 189). The age- BAT cell proliferative capacity have yet to be elucidated.
related reduction in BAT mass has been associated with Norepinephrine infusion and BAT denervation of sympa-
the inability of old rats to maintain core temperature dur- thetic neurons in young rats demonstrate that norepineph-
ing cold exposure, although a mechanism for this atrophy rine is essential for the proliferative response of brown
has not been elucidated. Recent observations suggest that fat during cold exposure (129). Norepinephrine has also
BAT in aging animals may be less responsive to trophic been shown to stimulate proliferation of brown adipoinfluences.
Cold exposure of 10C for 5 days results in a cytes in culture (125, 126). It is reasonable to suggest that
significant increase in interscapular BAT mass of young alterations in sympathetic signaling to brown fat in aged
but not old (46; Fig. 4A). Furthermore, only the young rats may affect cell proliferation in this tissue. However,
animals respond to chronic cold exposure with an in- plasma norepinephrine is increased, not decreased, in
crease in BAT UCP concentrations (Fig. 4B). aged versus younger laboratory rodents exposed to cold
The greater BAT mass of young versus old rats fol- for a period from 4 h to 6 days (51). These observations
lowing chronic cold exposure could be because of differ- are consistent with several previous investigations de-
ences in the degree of hyperplasia, hypertrophy, or a comscribing elevated serum concentrations of norepinephrine
bination of both. In our study, chronic cold exposure re- in aging animals and humans (79, 80, 96, 106, 164, 180,
sults in a similar degree of brown adipocyte hypertrophy 193). The enhanced sympathetic tone, as indicated by in-
in both the young adult and old animals (Fig. 4C). Con- creased serum norepinephrine levels, would imply that
versely, cell proliferation, as measured by 5-bromo-2- the neural signal is intact and does not account for dedeoxyuridine
incorporation, is nearly 20 times greater in creased cell proliferation of BAT.
the younger versus older rats after chronic cold exposure The attenuated in vivo brown preadipocyte prolifera-
(Fig. 4D); that is, it appears that BAT in older rats has a tion previously observed in 26- versus 6-mo male F344 rats
reduced capacity for cell proliferation. The suggestion of could reflect reduced numbers of brown preadipocytes,
diminished cell proliferative capacity of brown fat ob- diminished proliferative responsiveness of brown preadi-
served in these aging animals is consistent with the generpocytes to trophic stimuli, and/or altered availability of
ally held concept of attenuated cell proliferation during trophic stimuli. We evaluated these possibilities in brown
aging (29).
preadipocytes isolated from BAT and maintained in fetal
Mechanisms affecting the age-related diminution of bovine serum-supplemented culture media. Although
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MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
TABLE 3. Investigations reporting reduced GDP binding form of the UCP. Shortly thereafter, several investigators
in brown fat of aging rodents established immunochemical tests to quantify this brown
fat-specific mitochondrial protein (16, 33, 93). The identi-
Rat Strain Sex Age, mo Stimulus
Reference
No. fication and isolation of the UCP allows a more direct
measurement of brown fat thermogenesis. Uncoupling
BN/BiRij
Wistar
Fischer 344
Fischer 344
Female
Male
Male
Male
3 vs. 36
3 vs. 24
6 vs. 24
7 vs. 24
Resting
Resting
b-Adrenergic agonist
Cold exposure
71
189
150
112
protein expression, as indicated by UCP mRNA, has also
been used as an index of nonshivering thermogenesis.
Initial reports suggest that the expression of UCP in
Fischer 344 Male 5 vs. 27
(6C for2h)
Cold exposure
(6C for2h)
110
brown fat isolated from rats maintained at thermoneutrality
is unaffected by age (127, 153). These investigators
observed that under cold exposure condition causing hypothermia
in old (24 mo) but not young (3 mo) male F344
there appeared to be fewer preadipocytes per milligram
tissue in the 6- and 26- than in 1-mo-old rat, significant
differences did not exist between 6- and 26-mo animals,
nor did the total number of BAT preadipocytes isolated
from the 6- and 26-mo-old rats differ from each other.
Thus blunted proliferation in the 26- vs. 6-mo-old rats
cannot be explained by fewer preadipocytes in BAT of
the 26-mo-old rats. Additionally, brown preadipocytes isolated
from 26-mo-old rats responded to fetal bovine serum-supplemented
culture media with a comparable level
of cellular proliferation as did those from 6-mo-old rats,
displaying no attenuated responsiveness of the cells.
Rather, our data suggest that the diminished in vivo prolif-
erative response in 26-mo-old rats reflects altered availability
of extracellular trophic factor(s) in the old animals.
Neither norepinephrine nor insulin, factors thought to
play a role in in vivo brown preadipocyte proliferation in
young animals, stimulated in vitro proliferation of brown
preadipocytes above basal levels. These results suggest
that norepinephrine or insulin does not directly initiate
proliferation of preadipocytes in BAT of F344 rats.
rats, UCP mRNA increases significantly in both age groups
compared with animals maintained at thermoneutrality.
The results described by Scarpace et al. (153) in rats are
consistent with observations in aging mice (85, 166); that
is, 10-, 12-, and 24- to 26-mo-old C57BL/67 male mice main-
tained at thermoneutrality (29C) or acclimated to 22C
had significantly greater UCP concentration after a cold
stress than did mice not exposed to cold. Both Scarpace
et al. (153) and Kirov et al. (85) concluded that the decrease
in heat production previously reported is not be-
cause of nonshivering thermogenesis of brown fat.
The finding that UCP levels are not affected by age
is surprising, since several investigations report that the
thermogenic potential of this tissue, as measured by GDP
binding to brown fat mitochondria, is decreased signifi-
cantly in older versus younger rodents. One explanation
may be that the efficiency of UCP mRNA translation may
be altered during aging and that UCP mRNA may not be
directly correlated with UCP levels in the tissue (189).
Gabaldon et al. (51) demonstrated that cold exposure elic-
ited an increase in brown fat UCP levels of young and
mature, but not old, male F344 rats, although precold
2. GDP binding
exposure levels were similar in all age groups. The attenuated
levels of brown fat UCP observed in the old versus
Before the isolation and identification of the UCP,
the binding of GDP to brown fat mitochondria was used
as an index of thermogenesis in this tissue. Several investigations
(71, 107, 111, 150, 189) have reported an age-re-
lated decline in brown fat thermogenesis, as indicated by
GDP binding in mitochondria isolated from brown fat in
resting or cold-exposed rats or in rats administered a b-
adrenergic agonist (see Table 3). McDonald et al. (111)
observed that the age-related attenuation in nonshivering
thermogenic capacity was associated with a large decrease
(60% lower) in the level of brown fat GDP binding.
young animals were associated with a greater drop in
cold-exposed core temperature; that is, BAT does not ap-
pear to maintain the ability to increase nonshivering ther-
mogenic capacity (UCP levels; see also Fig. 4B) in response
to a cold stimulus, and this may contribute to
the decline in cold tolerance during aging. The specific
mechanism responsible for the age-related attenuation in
UCP levels has not been well defined but may involve
an alteration in the efficiency of neuroregulation and/or
regulatory hormones involved in UCP production.
In addition, Horan et al. (71) observed a significant decline 4. Neural signaling and brown fat
(5-fold lower) in brown fat GDP binding of old versus thermogenic potential
young BN/BiRij rats.
Norepinephrine promotes the synthesis of brown fat-
3. Uncoupling protein
specific mitochondrial UCP (62, 129, 137, 158). Because
thermogenesis in brown fat is regulated, to a large degree,
Lin and Klingberg (95) were the first to publish a by sympathetic activity, it is possible that age-related atreport
describing the procedures for preparing a purified tenuation of BAT thermogenesis may be associated with
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April 1998 COLD-INDUCED THERMOREGULATION AND BIOLOGICAL AGING 351
there was an overall age-related decline in the density of
both b 1- and b 2-receptors in the BAT of F344 rats, the b 1adrenergic
receptor density decreased to a greater extent.
These findings are consistent with several investigations
reporting age-related declines in b-adrenergic responsiveness
in other tissues such as myocardium, cerebral
microvessels, brain, and kidney (119, 146, 157, 163, 188).
The age-related reduction in BAT b-adrenergic receptors
occurs concomitantly with an attenuation of adenylyl cyclase
activity (151). It is unknown if this age-related decline
in BAT adenylyl cycalse activity also involves alterations
in the G s protein or adenosine 3,5-cyclic monophosphate
production.
The preponderance of evidence strongly suggests
that BAT b-adrenergic number and responsiveness de-
FIG. 5. Interscapular sympathetic neural activity and change in cline significantly with age. Recent evidence suggests that
colonic temperature (T CO) in 10- and 30-mo-old C57BL/6J mice during
the major alterations in b-adrenergic receptor types occur
acute cold exposure followed by a reheating period. [From Kawate et
al. (79).] in the atypical b 3-receptor. Scarpace et al. (147) used a
unique compound, CGP-12177, that is both a b 3-agonist
and b 1-antagonist to evaluate the contribution of each
a similar decline in sympathetic nervous activity during receptor type to the overall decrease in adrenergic numaging.
However, age has been associated with an increase, ber in brown fat. Increases in O 2 consumption and body
not a decrease, in the activity of the sympathetic nervous temperature after administration of CGP-12177 were 60%
system (66, 96, 122, 164). Elevated plasma norepinephrine less in old versus young F344 rats maintained at thermolevels
have been observed in aged versus younger individ- neutrality throughout their life. Moreover, this b3-adreneruals
at rest and in response to stress (106, 130, 145, 193). gic agonist failed to increase mitochondria GDP binding
Moreover, sympathetic signaling to brown fat, as indi- and UCP mRNA expression and was diminished by 54%
cated by neural recordings in aged male C57BL/6J mice, in the senescent compared with young rats. These results
is significantly greater than that observed in younger mice, strongly imply that 1) b3 is the adrenergic receptor reboth
at thermoneutrality and during cold exposure (79; sponsible for thermogeneic response in brown fat and 2)
Fig. 5). McDonald et al. (109) report an elevation in sympa- a decrease in b 3-receptor in older rats may account for
thetic signaling to brown fat in old versus young cold- altered BAT thermogenesis during senescence.
exposed male F344 rats, as determined by norepinephrine To test the latter possibility, Scarpace and colleagues
turnover rates. The preponderance of evidence suggests (149, 152) carried out two investigations designed to evalthat
the neural signaling to aging brown fat is intact. uate the effects age, cold exposure, and CGP-12177 administration
have on b3-mediated BAT mitochondria GDP
5. Signal transduction in brown adipose tissue
Despite the apparent elevation in sympathetic signaling
to brown fat during aging, this tissue does not maintain
the capacity to respond to norepinephrine with increased
thermogenesis. Infusion of norepinephrine at levels adjusted
to the body mass of rats results in greater oxygen
consumption in young versus old male rats (111, 150);
that is, given a similar sympathetic stimulus, old animals
do not increase nonshivering thermogenesis to the same
extent as younger animals. These observations, together
with the finding that sympathetic signaling to the tissue
does not decline with age, suggest that postsignal factors
are more likely to be involved in the age-related decline
in brown fat nonshivering thermogenesis. Age-related attenuation
in signal transduction in BAT may include
binding and mRNA UCP expression. In the first experi-
ment, there was no age-related difference in the coldexposed
increase of GDP binding and mRNA UCP expres-
changes in the signal transduction pathway (Fig. 6).
FIG. 6.b-Adrenergic signal transduction pathway leading to an
The density of brown fat b-adrenergic receptors de- intracellular response. b-Ar, b-adrenergic receptor; Gs, stimulatory G
clines with age. Scarpace et al. (151) noted that although protein; AC, adenylyl cyclase.
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MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
sion. Given that they previously observed a decrease in sure (159). In turn, UCP mRNA production increases
b3-receptor number of older versus younger rats, these (159). Together, BAT T5D activity and plasma T4 provide
investigators suggested that BAT thermogenesis in an indication of ‘‘T3 availability’’ in BAT. Gabaldon et al.
younger but not senescent animals is mediated by this (51) measured T3 availability in cold-exposed young and
unique receptor. Results from the second experiment old male and female F344 rats. Older cold-exposed rats
tended to contradict the suggestion that BAT thermogene- that experience hypothermia (1.2C drop in colonic temsis
in older rats is governed by a mechanism other than perature) do not increase total brown fat UCP or T3. These
the b3-adrenergic pathway. CGP-12177 administration to data imply that the reduced ability of the older male rat
older rats after a 48-h cold exposure increased signifi- to generate sufficient UCP production during cold expo-
cantly GDP binding to BAT mitochondria; that is, exsure is limited, at least in part, by a reduced T3 availability
tended cold exposure restored the b3-adrenergic responsiveness
in BAT from senescent rats. Clearly, further in-
in brown fat.
vestigations designed to elucidate the contribution of the
b3-receptor to BAT thermogenesis in senescent rats are
warranted.
V. COLD-INDUCED THERMOREGULATION AND
THE RATE OF AGING
6. Nonshivering thermogenesis and regulation
of uncoupling protein production
This review has focused on possible mechanisms responsible
for the age-related decline in CIT. Although
these reports have provided substantial new information
Although thermogenesis in brown fat is stimulated concerning the influence of age on thermoregulation, the
primarily by norepinephrine, it unlikely that this neural physiological mechanisms have yet to be clearly identi-
hormone is the only factor involved in UCP production. fied. At least part of the problem in elucidating the causes
Several other factors, such as corticosteroids, insulin, and of the age-related diminution in CIT reflects the inability
thyroid hormones, may participate in promoting the pro- to precisely define biological senescence. Most investigaduction
of UCP either directly or by modulating the im- tions reported here use chronological time to define aging.
pact of norepinephrine on UCP production. Glucocorti- The use of chronological rather than biological time poses
coids, such as corticosterone, have been shown to pro- problems of interpretation because it assumes that age-
duce a decrease in brown fat GDP binding (50, 70, 143). related loss will occur to all animals at a specific time.
The inhibitory role of corticosterone in reducing UCP pro- However, the rate of aging is specific to the individual.
duction is due primarily to its inhibitory influence on sym- For example, we generally use 24- to 26-mo-old F344 rats
pathetic nervous system activity (190). More recent evi- to evaluate the affect of age on CIT and have considered
dence suggests that corticosterone has a direct inhibitory this group to be senescent. These ages are chosen because
action on UCP expression (121). The exact mechanism the mean life span of the F344 is Ç24 mo. Mean core
responsible for the inhibition is unclear and merits further temperature is consistently lower in cold-exposed 26-mo-
investigation before conclusions regarding the effect of old male F344 rats compared with 6- and 12-mo-old ani-
corticosterone on UCP production during aging can be mals. There is, however, significant heterogeneity in the
drawn. response of the oldest rats to the cold exposure; that is,
Insulin may also play a significant role in the regula- some rats do not display significant alterations in coldtion
of UCP expression (53, 98). It is unlikely that the exposed core temperature, whereas others develop severe
effect of insulin on UCP involves an increase in adipocyte hypothermia.
glucose uptake (156); rather, insulin may act peripherally Close inspection of our data reveals a correlation
to promote UCP production via stimulation of the sympa- between body weight loss and core temperature. The
thetic nervous system (97). Because insulin secretion de- greater the body weight loss before the cold exposure,
clines during cold exposure, it is unlikely that this hor- the greater the decline in cold-exposed core temperature.
mone plays a major role in the age-related decline in cold- In previous investigations, rats showing marked body
induced thermal homeostasis in the aging rat.
weight loss were eliminated from the study because we
Thyroid hormones are also thought to be important believed that they were ‘‘sick’’ and did not represent nor-
in regulating the production of UCP, although the sympamal biological aging. However, when rats were examined
thetic signal must also be present (11, 158). Specifically, pathologically to determine the cause of death, a consis-
3,5,3-triiodothyronine (T3) promotes UCP production by tent ‘‘disease’’ accounting for the well-characterized rapid
increasing the level of transcriptional precursors for loss in body weight near the end of life was not detected
mRNA as well as by stabilizing the mature UCP mRNA (123). These observations led us to hypothesize that a
(136). The activity of thyroxine 5-deiodinase (T5D) in loss in body weight near the end of life may represent a
brown fat, an enzyme which converts thyroxine (T4) to transition from gradual aging to rapid senescence and may
the more potent T3, increases in response to cold expo- be a normal age-related phenomenon.
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April 1998 COLD-INDUCED THERMOREGULATION AND BIOLOGICAL AGING 353
imately the same time. Recently collected preliminary
data support the suggestion that regions of the hypothalamus
may be associated with ‘‘end-of-life’’ physiology. We
evaluated endogenous circadian rhythm of body temperature
(CRT), a function known to be regulated by the suprachiasmatic
nuclei region of the hypothalamus (120), in
rats from 23 mo of age until natural death. Measures of
CRT, daily mean body temperature, rhythm period, and
amplitude do not differ significantly within each rat during
the time when body weight was stable. However, at the
onset of rapid weight loss, daily mean temperature and
rhythm amplitude decreases, and the strength of the CRT
period is significantly less. These data are consistent with
the suggestion that the hypothalamus may be an important
regulator of the rate of aging.
FIG. 7. Colonic temperature of weight-stable vs. weight-unstable
old male Fischer 344 rats during resting conditions in a thermoneutral VI. SUMMARY AND CONCLUSIONS
environment and during cold exposure (4 h at 6C). * Significant difference
from weight-stable group (P õ 0.05). [Adapted from McDonald et
al. (108).]
A. Summary
To test this hypothesis, we exposed rats to 6C for 4 Aging is associated with diminished CIT. The mechah
every 14 days beginning at 24 mo of age and until the nisms accounting for this phenomenon have yet to be
onset of rapid spontaneous weight loss (108). The age of clearly elucidated but most likely reflect a combination
onset of the rapid spontaneous weight loss ranged from of increased heat loss and decreased metabolic heat pro-
24.5 to 29 mo of age. All rats displaying spontaneous rapid duction. The increase in heat loss during cold exposure
weight loss had significant hypothermia during the acute of older mammals may be due to altered perception of
cold exposure. The development of hypothermia in the changes to ambient temperature. This suggestion is sup-
spontaneous rapid weight loss group was not, in general, ported by the observation that cold-induced cutaneous
observed before their weight loss. Moreover, weight-sta- vasoconstriction and blood flow, measures of heat loss,
ble rats of identical age maintained normal core tempera- are delayed significantly in older versus younger humans
ture during cold exposure (Fig. 7). The rapid weight loss and rodents. Some reports suggest that an age-related
was associated with significant changes in body fat and diminution in the response of the arterial smooth muscle
protein, a 30% reduction in food intake, and lower levels to neural and hormonal stimuli results in decreased cuta-
of brown fat UCP that was not observed in the weight- neous vasoconstriction during cold exposure. Most evi-
stable animals.
dence, however, indicates that the delay in the response
These data indicate that the diminished CIT of the of the cutaneous vasculature to cold reflects increased
aging F344 rat more closely reflects body weight loss arterial wall stiffness, the cause of which is unknown.
rather than chronological age. Although it is premature Increased heat loss of cold-exposed older versus younger
to conclude that body weight loss is a biomarker of aging, humans and rodents does not appear to be associated
these data point out that definitions of aging based on with a reduction in insulation capacity caused by changes
chronological markers may significantly affect data inter- in percent body fat.
pretation; that is, the use of chronological benchmarks as An increase in heat loss in cold-exposed older versus
predictors of senescence are less than optimal and may younger humans and rodents is associated with a signifi-
cause significant heterogeneity within the data. Moreover, cant decline in core temperature. Attenuated metabolic
our data suggest that older rats of identical age and ge- heat production during cold exposure is also proposed to
netic backgrounds may be in different physiological states occur in the older animal, but the data supporting this
depending on their biological age.
effect are more subject to controversy than those associ-
With the use of CIT as a general model of aging, our ated with heat loss. Results from several investigations
data suggest that the transition from gradual aging to rapid imply that reduction in cold-induced shivering thermogen-
senescence involves centrally mediated regulation. This esis of skeletal muscle may account for the age-related
area of regulation may include the hypothalamus. For ex- decline in core temperature observed in aging mammals.
ample, we find that CIT and energy balance (body weight These relationships are, for the most part, correlational
and food intake), two systems that involve hypothalamic rather than causal. For example, chronological aging is
regulation, appear to undergo rapid senescence at approx- associated with alterations in skeletal muscle such as
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354
MARIA FLOREZ-DUQUET AND ROGER B. MCDONALD Volume 78
such as mass, blood flow, metabolic substrate uptake and teristics of the species, i.e., age-specific mortality rate or
utilization, and oxidative capacity. The effect that these mean life span. This method does not account for individ-
variables may have on cold-induced skeletal muscle meta- ual differences in the rate of aging and thus results in
bolic heat production have not been widely evaluated. significant variation in the outcome variables. In turn,
Increased cold-exposed whole body metabolic heat pro- comparisons among investigations are difficult, and conduction
after exercise training of previously sedentary inclusion on specific mechanisms is impossible. It is undividuals
suggests that the exercise-induced increases in likely that the mechanisms accounting for the decline in
mass and metabolic capacity of skeletal muscle signifi- CIT during aging will be determined until biological aging
cantly increase heat production compared with the pre- is precisely defined.
training period; that is, decreases in shivering thermogenesis
implied by the age-related reduction in skeletal muscle
metabolism may reflect environmental factors rather
than biological aging per se.
We thank Rodney Ruhe and Carol Murtagh-Mark for com-
ments on the manuscript and Barbara Horwitz for insightful
comments and the many years of helpful discussions and de-
lightful collaboration.
Metabolic heat production from nonshivering ther- Research in the laboratory of R. B. McDonald is supported
mogenesis in BAT is significantly attenuated during aging by National Institute on Aging Grant AG-06665 and a gift from
and may play an important role in blunted CIT. Several the California Age Research Institute. M. Florez-Duquet is supstudies
report that decreased brown fat nonshivering ther- ported by National Institute of General Medical Sciences Minor-
mogenesis is associated with diminished mass and/or UCP
levels. The mechanism responsible for this age-related
ity Access to Research Careers Grant GM-15929.
reduction in brown fat mass is not well understood but
has been shown to involve decreased cell proliferation.
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