1. Behavioral battery in mice to model age-associated changes in human motor function
Jamie N. Justice, Ph.D. Department of Integrative Physiology, University of Colorado Boulder
Assessing physical function across species: Mice, monkeys and man
Gerontological Society of America, Nov 2013

2. Improve quality of clinical aging research Provide “common currency”
Standardized batteries of physical function tests have long been in use in clinical practice & aging research in humans
Improve quality of clinical aging research
Provide “common currency”

3. Though rodent behavior has long been used in aging research...
Analogous batteries in mice?
Validate against human declines?

4. Mouse models in aging research:
Mechanisms
-access to tissue
-signaling pathways
-genetic knock outs
-disease models
Screen interventions
-prevention
-treatment
-safety
-efficacy
Longitudinal Research
-survival studies
-optimal intervention time
Translation

5. Physical Function Aim:
Mouse Model
Aim:
To develop and assess the validity of a battery of tests to characterize motor function in mice
Strength
Endurance
Locomotion
Balance
face validity
wide spread use in behavioral testing
established use in aging research
economy of time and effort
Justice JN, Carter CS, Beck HJ, Gioscia-Ryan RA, McQueen M, Enoka RM, Seals DR. AGE, 2013.

6. Mouse Model of Physical Function
the ability to generate a maximal force against physical objects
- NIH Toolbox
Strength
Endurance
Locomotion
Balance
Grip Strength:
average force at forepaw release

7. Mouse Model of Physical Function
the ability to move from place to place
-NIH Toolbox
Strength
Endurance
Locomotion
Balance
Open Field Distance:
Distance traveled over 5 min
Rearing Counts:
Number of rears over 3 min
“Scurry” Speed:
average speed to cover straight walking track

8. Mouse Model of Physical Function
the ability to orient the body in space, maintain an upright posture under both static and dynamic conditions, and move and walk without falling
-NIH Toolbox
Strength
Endurance
Locomotion
Balance
Accelerating Rota-Rod:
average latency to fall from accelerating rotating rod
Hindlimb Grasp:
latency to grasp tightrope with hind limbs once suspended by forepaws

9. Mouse Model of Physical Function
how long a person (animal) can perform an activity at a particular intensity
-NIH Toolbox
Strength
Endurance
Locomotion
Balance
Tightrope:
maximum time suspended from tightrope
Rota-Rod Run:
maximum time and distance run until falling off the rota-rod

10. 3 month 20 month 26 month n = 87 n = 48 n = 42 Strength Locomotion
Fore-paw grip strength (g)
130 ± 14
96.7 ± 15.1*
79.7 ± 13.3*†
Grip strength per mass
5.58 ± 0.55
2.80 ± 0.44*
2.55 ± 0.44*
Locomotion
Open field distance (cm)
1859 ± 265
1740 ± 431
1357 ± 398*†
Rearing counts
25.4 ± 6.7
10.6 ± 6.3*
8.6 ± 8.2*
Walk speed (cm/s)
11.0 ± 4.2 -
8.2 ± 3.8*
Balance
Accelerating rota-rod time (s)
240 ± 57
181 ± 76*
164 ± 62*
Latency to hindlimb grasp (s)
5.0 ± 2.4
8.3 ± 7.2*
16.7 ± 13.1*
% capable of hindlimb grasp
100 77 36
Endurance
Tightrope hang score (s)
84.0 ± 32.5
62.4 ± 34
23.6 ± 24.2*†
Tightrope score per mass (s/g)
3.5 ± 1.4
1.8 ± 1.0*
0.8 ± 0.8*†
Endurance run time (s)
864 ± 356
670 ± 478
461 ± 328*
Endurance run distance (m)
24.4 ± 9.9
15.7 ± 8.6*
14.2 ± 11.6* 10

11. Normalized Scores (0-1 scale): 1 - (worst / current)
3 month
20 month
26 month
Normalized Scores (0-1 scale): 1 - (worst / current)
Strength
Forepaw grip strength
Grip strength per mass
Locomotion
Open field distance
Rearing counts
Walk speed
Balance
Avg accelerating rota-rod time
Latency to hindlimb grasp
Endurance
Tightrope hang score
Tightrope score per mass
Endurance run time
Endurance run distance
Average
Average
Average
Average

12. Physical function declines with age in mice* * * * *

13. Physical function declines with age
How do these subdomains relate to declines seen in humans?
Systematic Review
21 articles included with normative data from young and old humans
Percent declines from young were calculated for humans and mice
Determine relative lifespan points for mice and humans

14. Relative lifespans for mice and humans
100 75
Percentage of survivors
50% survivorship 50 25 1 6 12 18 24 30 36
Mouse age (months)
Human age equivalents (years) 12 30
42.5 56 69 81 94 1 1
Adapted from “The Mouse in Biomedical Research: Normative Biology, Husbandry, and Models” 14

15. Physical function declines with age
Strength
Locomotion
Human
Mice
Balance
Endurance

16. Physical Function
Strength
Endurance
Locomotion
Balance

17. Rachel Gioscia-Ryan, M.S.
Acknowledgements
Christy Carter, Ph.D.
Roger M. Enoka, Ph.D.
Douglas R. Seals, Ph.D.
Rachel Gioscia-Ryan, M.S.
Hannah J. Beck
Matthew McQueen, Ph.D.

18. Which tests are most reflective of Summary Score?
Performance Score
Part R2
Grip strength
0.16
0.83
Rota-rod distance
0.07
0.90
Tightrope time per mass
0.18
0.94
“Scurry” speed
0.97
Accelerating rota-rod
0.04
0.98
Rearing count
0.08
0.99
Rota-rod time
Time to hindlimb grasp
1.00
Open field distance
0.05

19. Which subdomains are most reflective of Summary Score?
Subdomain Score
Part R2
Endurance
0.38
0.65
Strength
0.22
0.85
Locomotion
0.30
0.93
Balance / Coordination
0.23
0.98

20. Order of test presentation
Day 1
Day 2
Day 3
Day 4
Open field distance
Rearing Counts
Accelerating rota-rod 1
Endurance rota-rod
Scurry speed
Tightrope
Accelerating rota-rod 2
Grip strength
Intro to Accelerating rota-rod
Accelerating rota-rod 3

21. Thank you Jamie Justice, IPHY Colloquium Presentation, 2013
“Put a bird on it”
Jamie Justice, IPHY Colloquium Presentation, 2013

22. Physical function at midlife is predictive of lifespan in rats
Swim Speed & Incline Plane
Task Dependency?
Normalized Scores (0-1 scale): 1 - (worst / current)
Best
Worst
Performance at Midlife
Best
Worst
Best
Carter CS, Sonntag WE, Onder G, Pahor M.
J Gerontol A Biol Sci Med Sci, 2002