Prevention of neuromusculoskeletal frailty in slow-aging ames dwarf mice: longitudinal investigation of interaction of longevity genes and caloric restriction

Abstract

Ames dwarf (Prop1 (df/df) ) mice are remarkably long-lived and exhibit many characteristics of delayed aging and extended healthspan. Caloric restriction (CR) has similar effects on healthspan and lifespan, and causes an extension of longevity in Ames dwarf mice. Our study objective was to determine whether Ames dwarfism or CR influence neuromusculoskeletal function in middle-aged (82 ± 12 weeks old) or old (128 ± 14 w.o.) mice. At the examined ages, strength was improved by dwarfism, CR, and dwarfism plus CR in male mice; balance/ motor coordination was improved by CR in old animals and in middle-aged females; and agility/ motor coordination was improved by a combination of dwarfism and CR in both genders of middle-aged mice and in old females. Therefore, extension of longevity by congenital hypopituitarism is associated with improved maintenance of the examined measures of strength, agility, and motor coordination, key elements of frailty during human aging, into advanced age. This study serves as a particularly important example of knowledge related to addressing aging-associated diseases and disorders that results from studies in long-lived mammals.

Figure 1. Body Weight Trajectories.

A. Graphical Representation of Experimental Design, Depicting Length of CR and Window of Neuromusculoskeletal (NMS) Testing for Male Ames Dwarf Mice. 30% caloric restriction attenuates body weight gain in the male littermate controls of the Ames Dwarf stock, and does so much later in the male Ames Dwarf mice themselves. B. Graphical Representation of Experimental Design, Depicting Length of CR and Window of NMS Testing for Female Ames Dwarf Mice. Matching the data from male mice of this stock, 30% CR dampens body weight gain in the female littermate controls of the Ames Dwarf stock, yet does so much later in the female Ames Dwarf mice themselves. All measures of central tendency are arithmetic means, and all depictions of variation (error bars) represent standard deviations (S.D.).

Figure 2. Grip Strength Testing at Middle-Age and Old-Age

A. Middle-aged Male Ames Dwarf Mice. Both Ames Dwarfism and caloric restriction maximized performance on the grip strength task in middle-aged males. B. Middle-aged Female Ames Dwarf Mice. By middle-age, there was no decline from perfect performance on the grip strength task for the littermate controls females. C. Old Male Ames Dwarf Mice. As was the case at middle-age, both Ames Dwarfism and CR maximized performance on the grip strength task in old males. D. Old Female Ames Dwarf Mice. Remarkably identical to the results observed at middle-age, there was still no decline from perfect performance on the grip strength task for old littermate controls females. (The red horizontal bars at neuromusculoskeletal scores of 1 demark perfect performance.) All measures of central tendency are arithmetic means, and all depictions of variation (error bars) represent standard deviations (S.D.).

Figure 3. Balance Testing at Middle-Age and Old-Age.

A. Middle-aged Male Ames Dwarf Mice. Neither Ames Dwarfism nor caloric restriction had any effect on the maintenance of equilibrium in middle-aged males. B. Middle-aged Female Ames Dwarf Mice. Caloric restriction, but not Ames Dwarfism, is beneficial to the maintenance of balance in middle-aged females. C. Old Male Ames Dwarf Mice. D. Old Female Ames Dwarf Mice. (The red horizontal bars at neuromusculoskeletal scores of 1 demark perfect performance.) All measures of central tendency are arithmetic means, and all depictions of variation (error bars) represent standard deviations (S.D.).

Figure 4. Motor Coordination/ Agility Testing at Middle-Age and Old-Age.

A. Middle-aged Male Ames Dwarf Mice. An additive effect of Ames Dwarfism and caloric restriction is observed during testing of motor coordination and agility in middle-aged males….. B. Middle-aged Female Ames Dwarf Mice. …..and the same results are observed for middle-aged females. C. Old Male Ames Dwarf Mice. D. Old Female Ames Dwarf Mice. Perfect performance is observed in old Ames Dwarf females on CR during testing of motor coordination and agility. (The red horizontal bars at neuromusculoskeletal scores of 1 demark perfect performance.) All measures of central tendency are arithmetic means, and all depictions of variation (error bars) represent standard deviations (S.D.).