Comparative diagnostic efficacy of cranial CT, CTA, and DSA in subarachnoid hemorrhage management: A systematic review and meta-analysis.

INTRODUCTION: Subarachnoid hemorrhage (SAH) is a critical medical condition associated with high morbidity and mortality rates. Timely and accurate diagnosis is crucial for optimal patient outcomes. Cranial computed tomography (CT), computed tomography angiography (CTA), and digital subtraction angiography (DSA) are commonly used imaging modalities for diagnosing SAH, but their comparative diagnostic efficacy remains debated. METHODS: A systematic review and meta-analysis was conducted to evaluate the diagnostic performance of cranial CT, CTA, and DSA in identifying SAH. PubMed, Google scholar, Cochrane Library databases were searched for relevant studies published up to January 2024. Pooled sensitivity, specificity, and the summary receiver operating characteristic (SROC) curve were calculated using Review Manager 5.4. RESULTS: A total of 31 studies involving 10,287 patients were included in the analysis. The pooled sensitivity of cranial CT for detecting SAH was 94.7 % (95 % Confidence Interval, CI) with a specificity of 98.3 % (95 % CI). CTA demonstrated a pooled sensitivity of 94.1 % (95 % CI) and specificity of 93.4 % (95 % CI). DSA showed a pooled sensitivity of 87.7 % (95 % CI) and specificity of 95.8 % (95 % CI). The SROC curve demonstrated discriminatory ability for all modalities. CONCLUSION: Cranial CT, CTA, and DSA are valuable imaging modalities for diagnosing SAH, with high sensitivity and specificity. Cranial CT serves as an initial screening tool, while CTA offers superior sensitivity in detecting aneurysmal SAH. DSA remains essential in specific clinical scenarios. Further prospective studies are needed to validate these findings and refine diagnostic guidelines for SAH.

The haploinsufficient Col3a1 mouse as a model for vascular Ehlers-Danlos syndrome.

Vascular Ehlers-Danlos syndrome is a rare genetic disorder resulting from mutations in the α-1 chain of type III collagen (COL3A1) and manifesting as tissue fragility with spontaneous rupture of the bowel, gravid uterus, or large or medium arteries. The heterozygous Col3a1 knockout mouse was investigated as a model for this disease. The collagen content in the abdominal aorta of heterozygotes was reduced, and functional testing revealed diminishing wall strength of the aorta in these mice. Colons were grossly and histologically normal, but reduced strength and increased compliance of the wall were found in heterozygotes via pressure testing. Although mice demonstrated no life-threatening clinical signs or gross lesions of vascular subtype Ehlers-Danlos syndrome type IV, thorough histological examination of the aorta of heterozygous mice revealed the presence of a spectrum of lesions similar to those observed in human patients. Lesions increased in number and severity with age (0/5 [0%] in 2-month-old males vs 9/9 [100%] in 14-month-old males, P < .05) and were more common in male than female mice (23/26 [88.5%] vs 14/30 [46.7%] in 9- to 21-month-old animals, P < .05). Haploinsufficiency for Col3a1 in mice recapitulates features of vascular Ehlers-Danlos syndrome in humans and can be used as an experimental model.

Adenovirus-mediated VEGF(121) gene transfer stimulates angiogenesis in normoperfused skeletal muscle and preserves tissue perfusion after induction of ischemia.

BACKGROUND: Administration of angiogenic factors stimulates neovascularization in ischemic tissues. However, there is no evidence that angiogenesis can be induced in normoperfused skeletal muscles. We tested the hypothesis that adenovirus-mediated intramuscular (IM) gene transfer of the 121-amino-acid form of vascular endothelial growth factor (AdCMV.VEGF(121)) could stimulate neovascularization in nonischemic skeletal muscle and consequently attenuate the hemodynamic deficit secondary to surgically induced ischemia. METHODS AND RESULTS: Rabbits and rats received IM injections of AdCMV.VEGF(121), AdCMV.Null, or saline in the thigh, 4 weeks (rabbits) or 2 weeks (rats) before femoral artery removal in the injected limb. In unoperated rats, at the site of injection of AdCMV.VEGF(121), we found 96% and 29% increases in length density of arterioles and capillaries, respectively. Increased tissue perfusion (TP) to the ischemic limb in the AdCMV.VEGF(121) group was documented, as early as day 1 after surgery, by improved blood flow to the ischemic gastrocnemius muscle measured by radioactive microspheres (AdCMV.VEGF(121)=5.69+/-0.40, AdCMV.Null=2.97+/-0.50, and saline=2.78+/-0.43 mL x min(-1) x 100 g(-1), P<0.001), more angiographically recognizable collateral vessels (angioscore) (AdCMV. VEGF(121)=50.58+/-1.48, AdCMV.Null=29.08+/-4.22, saline=11.83+/-1.90, P<0.0001), and improvement of the bioenergetic reserve of the gastrocnemius muscle as assessed by (31)P NMR spectroscopy. Follow-up studies showed that superior TP to the ischemic limb in the AdCMV.VEGF(121) group persisted until it was equalized by spontaneous collateral vessel development in untreated animals. CONCLUSIONS: IM administration of AdCMV.VEGF(121) stimulates angiogenesis in normoperfused skeletal muscles, and the newly formed vessels preserve TP after induction of ischemia.

Age comparisons of body temperature and cold tolerance among different strains of Mus musculus.

The age-related declines in colonic temperature (Tco) and cold tolerance (ability to maintain Tco when exposed to 10 degrees C for 3 h) described for C57BL/6J mice are compared to other mouse strains. Assessment of young and aged male mice of the C57BL/6J and A/J inbred strains and their F1 hybrid, B6AF1/J, as well as a pen-bred strain of Mus musculus captured from the wild revealed an aged-related decline in thermoregulation among all these strains. The degree of decline in thermoregulation was roughly correlated to differences in strain-specific lifespan. Aged mice of the relatively short-lived genotype, A/J (mean lifespan of 22 months), had the lowest Tco and poorest cold tolerance. The long-lived hybrids, B6AF1/J (mean lifespan of 29 months), demonstrated the highest Tco and the best cold tolerance among aged mice. C57BL/6J (mean lifespan of 26 months) showed an intermediate level of thermoregulation. Aged pen-bred mice demonstrated a significant decline in cold tolerance, but not a significant decline in Tco. The thermoregulatory responses of the pen-bred mice were superior to those observed among the domesticated strains. These data suggest that the age-related impairment in thermoregulation is a general phenomenon of aging in Mus musculus that is correlated with strain-specific lifespan but is possibly affected by the level of hybridization and domestication.

Effects of voluntary and forced exercise on thermoregulation and survival in aged C57BL/6J mice.

To evaluate the effect of exercise on thermoregulation in senescent animals, three groups of male C57BL/6J mice aged 28-30 months were tested for cold tolerance, defined as the rate of decline in colonic temperature during 3 h exposure to 10 degrees C ambient temperature. Following this test, the mice were exposed to one of the following exercise conditions: forced exercise on a treadmill for 60 min daily at a rate of 5 m/min; continuous access to voluntary exercise in wheel-activity cages, which resulted in a mean rate of 1.1 m/min; or no expressed exercise with 60 min daily placement on the non-activated treadmill. After 3 weeks, assessment of cold tolerance was repeated. A combined mortality rate of 36% was observed in the exercise groups for this period, while there were no deaths in the non-exercised group. The high mortality rate among exercised animals indicated that these regimens were hazardous for aged mice. Moreover, between tests the non-exercised group exhibited a 0.6 degree C increase in body temperature and 38% improvement in cold tolerance which could be interpreted as a normal adaptation for repeated cold exposure. In contrast, no significant change in either of these variables was observed among survivors in the exercise groups. Thus, introduction of these exercise regimens in senescent mice decreased survival and did not improve the age-related impairment in thermoregulation.

Relationship of body temperature stability to mortality in aging mice.

An age-related decline in the capacity for thermoregulation among homeothermic animals has been observed frequently under conditions of extreme ambient temperatures. We investigated the temporal stability of the internal body temperature of 69 C57BL/6J mice from 25 months of age until death in a controlled, neutral thermal environment. Estimates of temporal variability were calculated over consecutive 1-month intervals using (colonic) body temperature data collected weekly. The results of this longitudinal analysis indicated that the regulation of body temperature, as measured by its temporal stability, became increasingly less precise with advancing age. Body temperature exhibited a significant decline as the animal approached death. Individual differences in body temperature and the temporal regulation of body temperature were significantly correlated with lifespan, although the direction of the relations were opposite. Body temperature correlated positively with lifespan, whereas the temporal stability of body temperature correlated negatively with lifespan. Thus, animals exhibiting higher body temperatures and greater temporal stability also tended to live longer than their cohorts.

Body temperature of C57BL/6J mice with age.

On the basis of a study of rectal temperature in a group of 180, C57BL/6J male mice, ranging in age from 3 months to 30 months, the following conclusions were drawn: 1) The positive correlation between body weight and body temperature typical for rodents was found only for young adults of the C57BL/6J strain; 2) body temperature of male C57BL/6J did not appear to decline until about 23.5 months, after which there was a significant negative correlation (r = -0.53) between age and temperature.

The effect of exercise training in cold on shivering and nonshivering thermogenesis in adult and aged C57BL/6J mice.

To understand the mechanisms of improvement of cold-induced heat production in aged mice following exercise training, the relative contributions of shivering and nonshivering thermogenesis to cold-induced metabolic responses were assessed in adult and aged C57BL/6J male mice, which inhabited sedentarily at room temperature, or were subjected either to a regimen of moderate intensity exercise training at 6 degrees C, or to sedentary repeated exposures to the same temperature. The main findings were that (1) aged mice had greater cold-induced nonshivering thermogenesis, but lower shivering than adult mice; (2) exercise training in a cold environment enhanced cold-induced nonshivering thermogenesis in adult mice, but suppressed it in aged animals; (3) exercise training in a cold environment increased shivering thermogenesis in both age groups, but this increase was much greater in aged mice; (4) the increase of cold-induced shivering thermogenesis was mainly responsible for increased cold tolerance in aged mice after exercise training in a cold environment.

An improved cold stress test for aging mice.

Tolerance to cold stress is a simple and reliable test which can be used longitudinally to study age-related differences or changes in thermoregulation of C57BL/6J mice. Neither prior food deprivation nor permanently inserted thermoprobes are necessary conditions for eliciting reliable age differences. However, restraint during the test is important and does elicit reliable age differences.

Metabolic heat production and cold tolerance during cold stress of different intensity of adult and aged male C57BL/6J mice.

Adult and aged male C57BL/6J mice were subjected to a 3-h cold stress test at either 24 degrees C, 18 degrees C, 12 degrees C, or 6 degrees C. Body mass was measured before the test, and colonic temperature, O2 consumption, and CO2 production were measured during the test. The slopes of colonic temperature over time of test and the mean metabolic heat production were calculated for each animal. While adult mice had a relatively small reduction in colonic temperature during the test at all four ambient temperatures, in the aged mice ambient temperatures resulted in steeper reductions of colonic temperature. In adult mice, an increase in metabolic heat production was proportional to ambient cold. The thermogenic response of aged mice at 24 degrees C and at 18 degrees C was similar to adult mice, suggesting that the ability of aged mice to respond to cold by increasing heat production does not diminish with age. However, in aged mice metabolic heat production at 12 degrees C and 6 degrees C was significantly below that of adult mice, which indicated a reduced capacity for thermogenesis.

Metabolic heat production during repeated testing at 24 degrees C and 6 degrees C in adult and aged male C57BL/6J mice: the effect of physical restraint before cold stress.

Adult (9-14 month) and aged (29-31 month) male C57BL/6J mice were subjected to 3 baseline tests (BASE), 3 cold tests (COLD), or 3 baseline immediately followed by cold tests (BASE/COLD). All tests consisted of partial restraint, and baseline tests were at 24 degrees C for 1 h while cold tests were at 6 degrees C for 3 h. All tests were started at 0900 and were repeated every 2 weeks. Mice were weighed before each test and colonic temperature, O2 consumption, and CO2 production were measured every 4 min for the duration of the test. Mean metabolic heat production during baseline and/or cold and slopes of colonic temperature over time during cold were calculated for each animal. Metabolic heat production at 24 degrees C in both BASE and BASE/COLD was the same in aged mice as adults, however, at degrees C BASE/COLD adult mice increased metabolic heat production compared to 24 degrees C, while aged mice produced a similar amount of heat at both 6 degrees C and 24 degrees C. When comparing metabolic heat production at 6 degrees C between COLD and BASE/COLD mice, adult COLD mice demonstrate an habituation to repeated cold exposure accompanied by increasing heat production, while BASE/COLD adults produce higher heat in all 3 cold exposures. The authors suggest that this is due to a priming of heat production in adults by restraint before the cold. In aged mice, neither COLD nor BASE/COLD groups demonstrate habituation, but BASE/COLD mice produce more heat than COLD during cold exposure, again indicating baseline priming of heat production. The data imply that aged mice have an impairment in specific cold-induced thermogenesis, while their abilities to produce heat in response to restraint-induced sympathetic activation remains intact.

The effect of exercise training in a cold environment on thermoregulation in adult and aged C57BL/6J mice.

We studied the effect of exercise training in cold environment (six weeks of daily, one-hour runs on a treadmill at ambient temperature of 6 +/- 1 degrees C at 60-65% of VO2max) on cold-induced metabolic heat production, heat loss, and cold tolerance in adult and aged C57BL/6J male mice. In adult mice, exercise training in cold environment resulted in greater cold-induced heat production and cold tolerance without changes in heat loss, similar to the effects of daily cold exposure without exercise. In aged mice, daily cold exposures did not affect cold tolerance and cold-induced heat production, but exercise training in the cold resulted in greater cold-induced heat production and cold tolerance. Heat loss in aged mice increased similarly after both repeated cold exposures and exercise training in the cold. Therefore, mechanisms of effect of exercise training on cold tolerance are different in adult and aged animals. Exercise training in cold environment does not affect cold-induced heat production and cold tolerance in adult mice, but improves them in aged animals.

Change in heat loss as a part of adaptation to repeated cold exposures in adult and aged male C57BL/6J mice.

Previous studies have shown that adult mice increase cold-induced heat production as a result of repeated exposures to cold, but that aged mice do not. The objective of the present study was to investigate changes in heat loss during repeated cold exposures in adult and aged C57BL/6J mice. Mice were partially restrained for three hours at 6 degrees C, three times at one-week intervals. Dry heat loss was inferred from measurements of differential temperature between the incoming and outgoing air in the experimental chamber. During the first cold exposure, aged mice showed less heat loss (both total and adjusted for body temperature) than adult animals, suggesting greater peripheral vasoconstriction in aged mice. With repeated cold exposures, both age groups showed increased heat loss, but the aged mice showed greater increase of heat loss, so that by the third cold stress test, no significant differences in heat loss between adult and aged mice were observed. The increase of heat loss after repeated cold exposures in aged mice might reflect a lesser peripheral vasoconstriction, serving to reduce the possibility of tissue necrosis in the cold.

Oxygen consumption in adult and AGED C57BL/6J mice during acute treadmill exercise of different intensity.

Submaximal and maximal oxygen consumption was determined in untrained adult and aged male C57BL/6J mice during treadmill running. Each of 12-month-old (ADULT) and 24-month-old (AGED) male mice was tested on a motor-driven treadmill once at different speeds. VO2 was measured before, during, and after exercise by means of indirect calorimetry in metabolic treadmill chambers. The resting VO2 averaged 3064.67 +/- 87.71 mL/kg/h for ADULT mice and 2472.95 +/- 69.41 mL/kg/h for AGED mice. During exercise, VO2 increased linearly with work intensity (running speed): ADULT mice--from 5908.06 +/- 422.35 mL/kg/h at 3 m/min to 10861.99 +/- 174.03 mL/kg/h at 25 m/min; AGED mice--from 5217.25 +/- 263.26 mL/kg/h at 3 m/min to 7817.32 +/- 290.28 mL/kg/h at 20 m/min. Further increase of the running speed resulted in a decline of VO2 in ADULT and refusal to run in AGED mice. The results of this study demonstrated that in untrained C57BL/6J mice VO2max and maximal exercise capacity declined with age. At the same absolute and relative workloads, VO2 was lower in AGED mice.

Nonshivering thermogenesis in adult and aged C57BL/6J mice housed at 22 degrees C and at 29 degrees C.

Twelve- and 28-month-old C57BL/6J male mice were housed either at room temperature of 22 degrees C or at thermoneutrality (29 degrees C) during the two months prior to experiments. Acute experiments were conducted under anesthesia, myorelaxation, and artificial ventilation. We recorded efferent electrical impulse activity in one of the sympathetic nerves innervating the interscapular brown adipose tissue in response to acute cold stimulation, when body temperature was lowered 7.5 degrees C below control level. In separate experiments we measured O2 consumption and CO2 production and calculated the nonshivering thermogenesis. We also measured the concentration of uncoupling protein in interscapular brown adipose tissue before and after three-hour cold stress. In aged mice, both sympathetic nervous activity and nonshivering thermogenesis were lower in animals housed at thermoneutrality (29 degrees C) than in mice housed at 22 degrees. Among mice maintained at 22 degrees C, but not at thermoneutrality, aged animals had greater nonshivering thermogenesis and greater cold induced concentration of uncoupling protein in the brown adipose tissue than adults. Sympathetic nervous outflow to brown adipose tissue was always greater in aged mice, regardless of the temperature of acclimation. We concluded that aged mice, housed at 22 degrees C, showed the changes in nonshivering thermogenesis associated with cold acclimation. However, an increased sympathetic outflow to brown adipose tissue in aged animals reflects an age-related elevation of the tone and responsiveness of the sympathetic nervous system.

Heat loss during cold exposure in adult and aged C57BL/6J mice.

Metabolic heat production (MHP), colonic temperature (Tco), and nonevaporative (dry) heat loss were measured in ADULT and AGED C57BL/6J male mice during cold exposure. Dry heat loss was assessed as a differential temperature (Td) between incoming and outgoing air through the chamber for indirect calorimetry. The average Td during cold exposure normalized to surface area for ADULT mice was significantly higher than that for the AGED animals (0.0618 +/- 0.0003 degree C/cm2 and 0.0553 +/- 0.0005 degree C/cm2, respectively). Linear regression analysis showed that at the same Tco AGED mice showed lower values of Td normalized to surface area, indicating that at the same body temperature they were losing less heat than ADULT animals. It was concluded that age-related decline in cold tolerance in mice is not due to a lack of ability to reduce heat loss during cold exposure. On the contrary, AGED animals had lower heat loss in comparison with ADULT. We suggest that augmentation of heat conservation mechanisms is an adaptive response to diminishing cold-induced heat production.

Nonshivering thermogenesis during acute cold exposure in adult and aged C57BL/6J mice.

In C57BL/6J adult and aged mice, housed at room temperature (22.5 +/- 1 degrees C), we measured O2 consumption and CO2 production and calculated metabolic heat production under conditions of anesthesia and myorelaxation during acute cold stimulation when body temperature was lowered 7.5 degrees C below control level. An independent group of mice was subjected to a three hour partial physical restraint at 6 degrees C and concentration of uncoupling protein (thermogenin) was measured in interscapular brown adipose tissue mitochondria at different times after cold exposure. Heat production under anesthesia and myorelaxation was about 57-66% lower than in nonanesthetized conditions, but increased significantly during cold stimulation in both age groups. Under anesthesia and myorelaxation before and during cold stimulation aged mice produced about 20% more heat than adult mice. Because in these experiments all sources of facultative thermogenesis, except nonshivering, were suppressed by anesthesia and myorelaxation, and because brown adipose tissue is the major source of nonshivering thermoproduction, we concluded that aged mice housed at room temperature have an increased thermogenesis in brown adipose tissue. This conclusion was also supported by the finding that the concentration of uncoupling protein measured in the mitochondria of brown adipose tissue after single cold exposure was significantly higher in aged than in adult mice. Therefore, we propose that the lower, cold-induced, heat production typically observed in nonanesthetized aged mice may reflect reduced thermogenic capacity of skeletal muscles. While aged mice have less brown adipose tissue than adult animals, the remaining brown adipose tissue may compensate by increasing the concentration of uncoupling protein.

Vascular permeability effect of adenovirus-mediated vascular endothelial growth factor gene transfer to the rabbit and rat skeletal muscle.

OBJECTIVE: Vascular endothelial growth factor has been used in preclinical studies and phase 1 and 2 clinical trials as a potent mediator of therapeutic angiogenesis; however, its ability to enhance the vascular permeability may be a source of potential complications. The objective of this work was to evaluate the effects of the intramuscular injection of an adenovirus vector coding for the 121-amino acid form of vascular endothelial growth factor (Ad.VEGF(121 )) on vascular permeability and edema development in rabbits and rats. METHODS: Different concentrations of Ad.VEGF(121 ) ranging from 10(5) to 10(10) plaque-forming units/mL (3 x 10(6)-3 x 10(11) particles/mL) were injected into hind limb or forelimb muscles of Wistar rats or rabbits. The size of the scrotum, the circumferences of limbs, and the concentration of vascular endothelial growth factor in the serum were measured daily after injection. RESULTS: The injection of different concentrations of Ad.VEGF(121 ) into the hind limb muscles of rabbits led to a dose-dependent scrotal edema in rabbits at concentrations higher than 10(7) plaque-forming units/mL (P =.002). The edema developed slowly, reached its maximum level 6 days after the injection, and spontaneously resolved thereafter. At concentrations higher than 10(9) plaque-forming units/mL the scrotal edema was accompanied by skin necrosis (P =.0001). No scrotal edema was observed in rats. CONCLUSIONS: The massive species-specific scrotal edema accompanied by skin ulceration and necrosis was observed only in rabbits treated with Ad.VEGF(121 ) in concentrations exceeding therapeutic doses. The therapeutic doses of Ad.VEGF(121 ) resulted in only moderate transient scrotal edema in rabbits, suggesting that the potential for side effects of vascular endothelial growth factor therapy as a result of increased vascular permeability should not be very alarming for generally healthy patients and may not cause a significant clinical problem in the treatment of peripheral vascular diseases.

Cold acclimation-induced increase of systolic blood pressure in rats is associated with volume expansion.

To investigate the mechanisms of cold-induced hypertension, the systolic blood pressure (SBP) and average daily water consumption were measured weekly in 6-month-old male Wistar rats; they were subsequently acclimated to thermoneutrality (26 degrees C for 7 weeks), to cold temperature (6 degrees C for 9 weeks), and then again reacclimated to 26 degrees C for 5 weeks. Circulating plasma volume and whole blood viscosity were measured in subgroups of rats at the end of acclimation to 26 degrees C after 2 days, after 1, 6, and 8 weeks of cold, and after 2 and 5 weeks of rewarming. The control values obtained at the end of thermoneutral period were: SBP = 130.8 +/- 18.6 mm Hg, plasma volume = 41.9 +/- 4.64 mL/kg, whole body viscosity at shear rate of 22.5 per sec = 6.7 +/- 0.48 cps, and daily water consumption = 42.25 +/- 16.81 mL. After 48 h of cold exposure there was almost a 50% increase in plasma volume that persisted to a lesser degree throughout the whole period of cold exposure (P < .05). After 2 weeks of cold exposure the daily water consumption increased and SBP began to increase. After 6 weeks of cold exposure the SBP was 30 mm Hg above that of the control level (P < .001) and was accompanied by a 25% increase in whole blood viscosity (P < .05). At the end of 8 weeks of cold exposure the plasma volume was 56.8 +/- 9.51 mL/ kg and the whole blood viscosity was 8.0 +/- 1.79 cps at the 22.5 per sec shear rate. During the 5 weeks of rewarming the elevation of SBP and increased whole blood viscosity persisted, whereas the increased daily water consumption and expanded plasma volume returned to normal. Therefore, the acclimation to cold is accompanied by the development of a volume-associated hypertension, which is sustained after rewarming without volume expansion.

The effect of exercise training on cold tolerance in adult and old C57BL/6J mice.

In order to ascertain the effect of aging on cross-adaptation between exercise training and cold tolerance, we studied cold tolerance in adult and old C57BL/6J male mice before and after 6 weeks of an exercise regimen of moderate intensity. There were two age groups of 32 mice each, including 12-month-old (adult) and 24-month-old (aged) mice equally divided into control and exercise groups. The exercise consisted of daily runs on a treadmill (1 hr/day, 5 days/week) for 6 weeks, while the control mice spent the same time on a stationary treadmill. All mice were subjected to a cold stress test (3-hr partial restraint at 6 degrees C) prior to and following the designated regimen. The results revealed a statistically significant interaction between age and exercise training. In adult mice, exercise resulted in a reduction of cold-induced heat production and weakening of cold tolerance, while in aged mice, the opposite effect was observed; i.e., an increase in cold-induced heat production accompanied by greater cold tolerance. However, only the attenuating effect on cold tolerance of adults was statistically significant. The results of our experiments do not support the existence of cross-adaptation between exercise training and cold tolerance. They indicate, however, that exercise training affects the cold tolerance in adult and old mice through different physiological mechanisms.