Comparative Approaches to Understanding the Relation Between Aging and Physical Function

Abstract

Despite dedicated efforts to identify interventions to delay aging, most promising interventions yielding dramatic life-span extension in animal models of aging are often ineffective when translated to clinical trials. This may be due to differences in primary outcomes between species and difficulties in determining the optimal clinical trial paradigms for translation. Measures of physical function, including brief standardized testing batteries, are currently being proposed as biomarkers of aging in humans, are predictive of adverse health events, disability, and mortality, and are commonly used as functional outcomes for clinical trials. Motor outcomes are now being incorporated into preclinical testing, a positive step toward enhancing our ability to translate aging interventions to clinical trials. To further these efforts, we begin a discussion of physical function and disability assessment across species, with special emphasis on mice, rats, monkeys, and man. By understanding how physical function is assessed in humans, we can tailor measurements in animals to better model those outcomes to establish effective, standardized translational functional assessments with aging.

Keywords: Animal models; Behavior; Physical function; Translational.

Figure 1.

Translational outcomes in the disablement process across species. Functional measures observed in humans at each stage of the disability spectrum can be reverse translated to outcomes in rodents and nonhuman primates (adapted from references 23,41). Impairment: a loss or abnormality of an anatomical, physiological, mental, or emotional nature. Functional limitation: manifestations at the level of the organism as a whole. Disability: social rather than organismic functioning; the inability or limitation in performing socially defined roles and expected tasks within a specific sociocultural and physical environment. Definitions originally derived from the disability framework established by Nagi (1).

Figure 2.

Relative life spans and age-related declines in locomotor function across species. Analogous ages (A) in man (blue), old world monkeys (green), F1 344xBN rats (red), and C57Bl/6 mice (orange) are calculated based on percentages of mean life span for each species (10,83,84). The dotted line indicates the percent survival. The vertical bars indicate the relative ages, calculated as percent life span for each species. Declines in locomotor function (B) for each species are plotted at their respective relative ages determined by percentage of life span. Percent declines from young humans (20–29 y) were calculated from representative studies with normative data for gait speed (see Justice et al. for detail). Percent declines in locomotor function were determined from scored tests of open field distance, walking track scurry speed, and rearing ability in mice (8), swim speed in rats (11), and gait speed in old world monkeys (10).

Figure 3.

Keys to improving translation of preclinical physical function outcomes. Essential elements to improve our ability to translate findings to clinical trials include (i) prioritizing communication and use of clinically relevant domains of function in animal models of aging, (ii) an interdisciplinary and collaborative effort to standardize tests of physical function and performance, and (iii) a structured set of validation steps to improve the relation to clinical outcomes.