The slow-aging growth hormone receptor/binding protein gene-disrupted (GHR-KO) mouse is protected from aging-resultant neuromusculoskeletal frailty

Abstract

Neuromusculoskeletal (physical) frailty is an aging-attributable biomedical issue of extremely high import, from both public health and individual perspectives. Yet, it is rarely studied in nonhuman research subjects and very rarely studied in animals with extended longevity. In an effort to address this relatively neglected area, we have conducted a longitudinal investigation of the neuromusculoskeletal healthspan in mice with two senescence-slowing interventions: growth hormone (GH) resistance, produced by GH receptor "knockout" (GHR-KO), and caloric restriction (CR). We report marked improvements in the retention of strength, balance, and motor coordination by the longevity-conferring GHR/BP gene disruption, CR regimen, or a combination of the two. Specifically, GHR-KO mice exhibit superior grip strength, balance, and motor coordination at middle age, and CR mice display superior grip strength at middle age. The advantageous effects established by middle-age are more pronounced in old-age, and these robust alterations are, generally, not gender-specific. Thus, we show that genetic and/or dietary interventions that engender longevity are also beneficial for the retention of neuromusculoskeletal health and functionality. The translational knowledge to be gained from subsequent molecular or histological investigations of these models of preserved functionality and decelerated senescence is potentially relevant to the efforts to reduce the specter of fear, falls, fracture, and frailty in the elderly.

Fig. 1

Graphical representation of experimental design, showing body weight trajectories for cohorts assessed longitudinally. a Male N mice on AL diet weigh substantially more than male KO mice on AL, and CR results in an attenuation of body weight gain for each phenotype. b Female N mice on AL weigh significantly more than female KO mice on AL, and CR results in a restraint of body weight gain for each phenotype

Fig. 2

Beneficial neuromusculoskeletal effects of the GHR/BP gene disruption and/or caloric restriction on grip strength. a Middle-aged male mice enjoy superior grip strength due to either the GHR/BP gene disruption or CR. b Old male mice enjoy superior grip strength due to either the GHR/BP gene disruption or CR. c Middle-aged female KO mice exhibit perfect grip strength, whereas their N counterparts show deficiencies. d Old female KO mice exhibit perfect grip strength, whereas their N counterparts show deficiencies. (All p values are for comparisons between the littermate control on AL (N on AL) group and the group whose bar the probability value is written over. The red horizontal bars at neuromusculoskeletal scores of 1 indicate the performance level of young-adult animals.)

Fig. 3

Advantageous neuromusculoskeletal effects of the GHR/BP gene disruption on balance/motor coordination. a Middle-aged male KO mice are better able to maintain physical equilibrium than their littermates. b Old male KO mice are better able to maintain physical equilibrium than their littermates. c Middle-aged female KO mice retain balance better than middle-aged female N mice. d Old female KO mice retain balance better than old female N mice. (All p values are for comparisons between the littermate control on AL (N on AL) group and the group whose bar the probability value is written over. The red horizontal bars at neuromusculoskeletal scores of 1 indicate the performance level of young-adult animals.)

Fig. 4

Limited beneficial neuromusculoskeletal effects of caloric restriction on motor coordination/agility. a Neither CR nor GHR/BP gene disruption affects motor coordination/agility in middle-aged male mice. b CR improves motor coordination/agility in old male mice, but the GHR/BP gene disruption does not. There is no CR or GHR/BP gene disruption effect on motor coordination/agility for either c middle-aged female mice or d old female mice. (The p value is for comparison between the littermate control on AL (N on AL) group and the group whose bar the probability value is written over. The red horizontal bars at neuromusculoskeletal scores of 1 indicate the performance level of young-adult animals.)