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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 57:B193-B197 (2002)
© 2002 The Gerontological Society of America

Physical Performance and Longevity in Aged Rats

Christy S. Cartera, William E. Sonntagb, Graziano Ondera and Marco Pahora

a Departments of Internal Medicine, Section on Gerontology and Geriatrics
b Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Christy S. Carter, Wake Forest University School of Medicine, PTCRC Building, Winston-Salem, NC 27157 E-mail: chrcarte{at}wfubmc.edu.

Decision Editor: John A. Faulkner, PhD


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
In humans, physical performance declines with increasing age, and in nondisabled older persons, scores on standardized performance measures, such as walking speed, repeated chair stands, and a balance test, predict the incidence of disability and reduced longevity. Here we show in aged rats (24-month-old Brown Norway x Fischer 344 male rats; n = 48) that conceptually similar performance measures, such as swimming speed and an inclined plane procedure, can be assessed longitudinally, and that over 6 months of follow-up from the age of 24 to 30 months, performance declines progressively with increasing age. High baseline performance scores predict long-term longevity, a relationship that is also found in humans. The application of standardized physical performance measures to a variety of animal models of aging may help to define similarities between species in the underlying mechanisms of the age-related decline in performance, disability, and longevity.

IN humans, physical performance declines with increasing age, and in nondisabled older persons, low scores on standardized performance measures, such as walking speed, repeated chair stands, and a balance test, predict the incidence of disability and reduced longevity. For example, Onder and colleagues (1) have shown that physical performance (as measured by a balance test, chair stand, and walking speed) declines continuously in a population of aged women as measured across 3 years of follow-up; in a separate study involving individuals over 70 years of age, Guralnik and colleagues (2) demonstrated that the individuals with the poorest performance scores at baseline (standing balance, walking speed, ability to rise from a chair quickly five times) also had a higher incidence of activities of daily living disability, institutionalization, and mortality at a 4-year follow-up. This type of assessment provides a method for early identification of conditions that precede the occurrence of disability and establishes a point in time when interventions could be helpful. The application of such standardized physical performance measures to a variety of animal models of aging may help to define similarities between species in the underlying mechanisms of the age-related decline in performance, disability, and longevity.

There is an expansive literature documenting age-related declines in physical function in rodent species. In the rat, the majority of these studies are cross-sectional and employ such tasks as used in locomotor activity (3), the inclined plane (4)(5)(6), swimming speed (6), and wire hanging procedures (7), among others. There is a similar literature for the mouse (8)(9). However, longitudinal data regarding age-related changes in physical performance, and the association between performance and longevity, are limited (see (10) for current review). Such information may be useful for developing future studies to clarify the mechanisms underlying the decline in performance. Therefore, the purpose of the present study is to assess the face validity of physical performance measures in aged rats for the following outcomes: longitudinal changes in standardized performance and the association of baseline performance with long-term longevity. Specifically, we demonstrate, in apparently healthy older rats, that performance on two performance measures (swimming speed and inclined plane procedures), alone or as a composite, predicts longevity such that animals that demonstrate superior performance in these procedures at baseline exhibit increased longevity over 9 months of follow-up.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Subjects
Brown Norway x Fischer 344 (F1) male rats (n = 48) were obtained from the National Institute on Aging colony at Harlan Industries (Indianapolis, IN) at 22 months of age and were housed in a specific pathogen-free facility throughout testing until mortality. These facilities are accredited by the American Association for Accreditation of Laboratory Animal Care. Testing began when the rats were 24 months of age and continued for 6 months, after which animals were followed for an additional 3 months. These time points were chosen based on survival curve data collected as part of the Biomarkers of Aging Program (11), which shows an 80% survival probability for F1s at 24 months of age and a 50% survival probability 6 months later.

Thirty-six animals survived the 6 months of the study; however, all animals are included in all analyses. Rats were maintained on a 12-hour light, 12-hour dark cycle with food and water available ad libitum. Animals were assessed on a weekly basis for signs of overt health problems by using a standardized form. Measures included, but were not limited to, checking for sudden decline in body weight, redness around the eyes and nostrils, ruffled coat, open sores on the tail, and haunched posture. Animals were also palpated during these assessments as a way to monitor for symptoms of disease and gross tumors. Animals were necropsied for gross pathologies whether they died spontaneously or were sacrificed during the course of the study. The causes of mortality in these animals ranged from pituitary tumors (n = 11), indeterminate cause (n = 4), rapid loss of more than 20% body weight in 1 week (n = 3), abscesses on the stomach (n = 1), paralysis in hindlimbs of indeterminate cause leading to the animal being unable to feed itself (n = 1), large subcutaneous tumors on hindlimbs leading to the animal being unable to feed itself (n = 1), open tumor on testicle (n = 1), possible stroke (n = 1), and large internal abdominal tumor (n = 1).

Physical Performance Measures
Inclined plane procedure.-- This test is a measure of muscle tone and stamina (7). The rat was placed facing upward in one compartment of a 60° tilted, 1-cm mesh screen. The time taken for the animal to fall onto two 7.6-cm foam pads was divided by the animal's weight and recorded with a maximum latency of 30 minutes.

Swimming speed procedure.-- Swim speed is a measure of how well an animal is able to navigate in the Morris water maze (6). During a trial, the rat was placed in the pool and allowed to swim for 60 seconds. Swim distance was recorded in centimeters by using an automated tracking system, and this score was divided by 60 seconds to determine speed within each trial (Poly-Track Video Tracking System, San Diego Instruments, San Diego, CA).

Walking speed procedure.-- Walking speed was assessed in Plexiglas test chambers (42 x 42 x 30 cm). Animals were habituated to the chambers for 60 minutes on the day prior to testing. Testing consisted of a 60-minute session in which walking speed was measured in meters per second by electronic counters that detect interruptions of eight independent photocell beams (Omnitech, Columbus, OH). Photocell counts were recorded at 6-minute intervals.

Summary performance score.-- A summary performance score was calculated based on the swimming speed and the latency to fall from the inclined plane (corrected for weight). The timed scores of the performance tests were rescaled to values ranging from 0 to 1, where 1 indicates the best performance and 0 the worst performance. For swim speed we applied the following formula: 1 - (24/swim speed), where 24 represents the value in centimeters per second of the worst performer. For the inclined plane procedure we applied the following formula: 1 - [(0.05/latency to fall)/weight], where 0.05 represents the value in seconds per gram of the worst performer. A summary performance score that ranged from 0 to 2 was calculated by adding these rescaled scores.

Statistical Analyses
To examine the 6-month decline in swimming and walking speed and inclined plane performance, we used a mixed model analysis of covariance (SAS PROC MIXED). This analysis uses the random effects generalized least-squares model, which accounts for the correlations between all follow-up outcomes and for subject-specific effects, and it uses all available follow-up data. We obtained adjusted means of the outcome variables from the parameter estimates of the generalized least-squares models. The analysis for swimming speed was adjusted for baseline weight.

Cox's proportional hazard regression analyses were fitted to assess the associations of physical performance measures (swim speed and inclined plane) and the summary performance score with survival. Data were censored at 9 months. The assumption of proportionality of hazard was assessed with log minus log plots and by tests of the interaction of exposure with time. The analyses were adjusted for baseline weight.

In order to compare survival time across different levels of performance, we created four groups according to quartiles of baseline summary performance score (SPS): group 1 = SPS < 0.71 (n = 12), group 2 = SPS 0.71–0.93 (n = 12), group 3 = SPS 0.93–1.03 (n = 12), and group 4 = SPS > 1.04 (n = 12). Because the variable of days of survival showed a normal distribution, an analysis of variance was performed to calculate least-square means of days of survival for each performance group. The analysis has been censored at 9 months.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Physical Performance
Fig. 1 shows the least-square means of inclined plane latency and swim speed over the 6-month period of the study. Overall, these performance measures demonstrate a significant 6-month decline (swim speed decline 7.0 cm/s, p < .001; incline plane decline 0.08 s/g, p = .002). Newman–Keuls post hoc analyses indicated that performance began to decline as early as the second month in the inclined plane procedure and in the fourth month in the swimming procedure, and reached asymptote at 4 months in both procedures. In contrast, there was no significant change during this same time period in walking speed (data not shown).



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  		Figure 1. Least-square means of (A) inclined plane and (B) swimming speed procedures, over a 6-month time period (24–30 months).

 
Survival Analyses
Overall, 24 rats died in the 9 months of the observation period (6 months testing and 3 months of extended observation; see Methods for causes of death). Baseline weight was included in the model as a covariate and did not differ significantly between the different performance groups [F(3,47) = .98, p = .411 (means ± standard error of the mean: group 1 = 573.83 ± 16.35; group 2 = 552.52 ± 12.83; group 3 = 556.10 ± 7.61; group 4 = 543.49 ± 13.07)]. Longevity was significantly predicted by higher baseline swim speed (hazard ratio 0.88 for 1 cm/s increase; 95% confidence interval 0.81–0.97; p = .009), but the association did not reach the conventional level of significance for the inclined plane test (hazard ratio 0.78 for 10 s/g increase; 95% confidence interval 0.56–1.08; p = .139). A higher baseline summary physical performance score based on these two measures significantly predicted longevity (hazard ratio 0.15 for 1-point increase; 95% confidence interval 0.05–0.60; p = .007). As shown in Fig. 2 (top panel), the mean survival time progressively increased with increasing quartiles of the baseline SPS (p for trend = .033). Specifically, the survival time of rats in the highest quartile of baseline performance (number of deaths = 1) was significantly longer than that observed among rats in the lower quartile of baseline performance (number of deaths = 8) (highest vs lowest quartile p = .031). When plotted as a continuous variable (Fig. 2, lower panel), survival probability of rats in the first and fourth quartiles of baseline SPS (first quartile SPS < 0.71; fourth quartile SPS >= 1.04; p for the comparison = .017) began to diverge at the third month of testing.



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  		Figure 2. A: least-square means and standard errors of days of survival according to quartiles of baseline summary performance score (SPS). The survival time of rats in the higher quartile of baseline performance (number of deaths = 1) was significantly longer than that observed among rats in the lower quartile of baseline performance (number of deaths = 8). The analysis has been adjusted for weight. *p vs lower quartile = .031. B: survival probability of rats with first ({blacksquare}) and fourth (•) quartiles of baseline SPS (first quartile SPS < 0.71; fourth quartile SPS >= 1.04). For the comparison, p = .017.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
The present study shows that standardized physical performance measures can be assessed longitudinally in aged rats. Similarly to findings in humans, scores on these measures decline progressively with increasing age, and higher baseline performance scores predict long-term longevity (reviewed in (12)(13)). Two procedures, the inclined plane and the swim test, provide a simple assessment of upper body muscle strength and endurance, respectively, without the necessity of invasive procedures. We also measured walking speed in a locomotor activity chamber. All these measures are sensitive to changes in performance during aging as measured by cross-sectional studies. The inclined plane is a widely used and reliable procedure that is sensitive to age-related declines in muscle strength (4)(5)(6). The inclined plane is a potentially important measure to include in our assessment, because in humans, grip strength, which is a conceptually similar measure, predicts the incidence of disability (14). Swim and walking speed are performance measures that are conceptually similar to walking speed in humans, in that they assess an animal's ability to navigate efficiently within the confines of the small area, in this case a pool or locomotor activity box. It is important to note that the age-related declines in physical performance were demonstrated only in the two high-motivation tasks (swimming and inclined plane procedures). In contrast, animals spent very little time actually moving within the locomotor activity chambers; therefore the absence of a decline in performance on this task could be masked by a floor effect in this measurement.

Another relevant finding is that physical performance measured at baseline predicts long-term longevity in aged rats. This finding shows that physical performance measures in older rats have similar predictive validity for longevity as that shown in human studies by Guralnik and colleagues (2). Although the immediate causes of death are substantially different in rats from those in humans, physical performance had similar predictive validity in both species, suggesting that the interspecies physical performance–survival association is independent of the immediate causes of death. It is unlikely that the lower performance in rats was a subclinical indicator of a premortal disease or condition. First, the baseline body weight, one of the best indicators of an animal's health, was similar among the four performance groups. Second, the survival curves comparing the animals in the first and fourth quartiles rating summary physical performance scores began to diverge well outside of the time frame of the initial baseline testing. This suggests that the health or disease status was similar among the groups.

There is substantial evidence to suggest that the cause of death in mammals is not only related to terminal disease status but is influenced by biological and genetic mechanisms as well. The remarkable progress in understanding the genetics of life-span determination in invertebrate models, mostly through targeted mutagenesis techniques, has allowed for the identification of specific genes and signaling pathways that modulate longevity (15)(16). Homologous pathways exist in mammals that are modified through caloric restriction, one of the most potent interventions known to increase life span (17)(18). Caloric restriction in rodents has also been shown to improve physical performance and mechanisms of muscle function in aged rodents (19)(20)(21)(22)(23). Therefore it is unlikely that the final determinant of physical performance was disease per se but rather was also genetically or biologically determined.

An important aspect of this research is that we have defined and provided face validity of an assessment process of physical function that can be applied to several models of aging in small animals. This assessment model can be used to study biological mechanisms that contribute to the age-related decline in physical function and possibly to the disabling process. For example, these assessments can be evaluated in rats deficient in growth hormone, an anabolic hormone known to play a vital role in maintaining tissue viability in old age (24), or rats treated with cytokines, which have been shown to induce muscle loss (25)(26)(27)(28)(29). These standardized assessments in small animals may also be used for preclinical testing of novel interventions for preventing age-related physical function decline. Preclinical testing in animals is an established step for testing interventions in several disease conditions, but it represents a novel step in the process of evaluating interventions to prevent the age-related decline in physical function and possibly disability. This approach is innovative, as such interventions are currently directly tested in humans, with no preclinical testing in an animal model of the condition these interventions are intended to cure or prevent. This research begins to address this important gap.


   Acknowledgments
 
This research is supported by the National Institutes of Health–National Institute on Aging under Grant P60 AG10484 from the Claude D. Pepper Older Americans Independence Centers.

We thank Ms. Jennifer Ledford and Ms. Jennifer McCorckle for their technical assistance. We also thank Dr. Drake Morgan for comments on earlier versions of this manuscript.

Received November 2, 2001

Accepted January 3, 2002


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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