Frailty is a clinical syndrome associated with the aging process and adverse outcomes. The purpose of this short report was to initiate the development of a Frailty Index in 27- to 28-month-old C57BL/6 mice that matched the clinical criteria used in humans (weakness, slow walking speed, low activity level, poor endurance). The selected criteria included grip strength, walking speed, physical activity, and endurance. The criteria in mice were evaluated by the inverted-cling grip test, rotarod test, voluntary wheel running, and derived endurance scores. Each criterion had a designated cutoff point (1.5 SD below the cohort mean) to identify the mice with the lowest performance. If a mouse presented with three of the criteria scores below the cutoff points, it was identified as frail. Mild frailty was designated if two criteria were below the cutoff points. In this mouse cohort, one mouse was identified as frail and one was mildly frail. This prevalence of 9% frailty is consistent with the prevalence of frailty in humans at the same survival age. Collectively, our selected criterion, cutoff point, and Frailty Index provide a potential standardized definition for frailty in mice that is consistent with the operational definition of frailty in humans.

Developing a scoring system based on physiological and functional measurements is critical to test the efficacy of potential interventions for sarcopenia and frailty in aging animal models; therefore, the aim of this study was to develop a neuromuscular healthspan scoring system (NMHSS). We examined three ages of male C57BL/6 mice: adults (6–7 months old, 100% survival), old (24–26 months old, 75% survival), and elderly group (>28 months old, ≤50% survival)—as well as mice along this age continuum. Functional performance (as determined by the rotarod and inverted-cling grip test) and in vitro muscle contractility were the determinants. A raw score was derived for each determinant, and the NMHSS was then derived as the sum of the individual determinant scores. In comparison with individual determinants, the NMHSS reduced the effect of individual variability within age groups, thus potentially providing an enhanced ability to detect treatment effects in future studies.

Frailty is a major cause of disability and loss of independence in the elderly. Using clinically relevant criteria from our previously established mouse frailty index, we investigated the effects of aerobic exercise on frailty in male C57BL/6 mice. In order to measure the effect of treatment on the individual animals, we constructed a composite score, the Frailty Intervention Assessment Value. We hypothesized voluntary aerobic exercise would improve individual criteria and reverse or prevent frailty in the old mice. Five adult and 11 old mice (6 and 28+ months, respectively) were housed individually in cages with running wheels for 4 weeks. Controls (adult, n = 5 and old, n = 17) were housed without wheels. Inverted cling grip and rotarod tests were performed pre- and postintervention. Hind limb muscles were used for biochemical analysis and contractility experiments. We conclude that the exercise stimulus reversed frailty and was sufficient to maintain or improve functional performance in old mice, as well as to produce measurable morphological changes. In addition, the Frailty Intervention Assessment Value proved to be a valuable tool with increased power to detect treatment effects and to examine the intervention efficacy at the level of the individual mouse.

Quantification of key outcome measures in animal models of aging is an important step preceding intervention testing. One such measurement, skeletal muscle power generation (force * velocity), is critical for dynamic movement. Prior research focused on maximum power (P _max), which occurs around 30–40 % of maximum load. However, movement occurs over the entire load range. Thus, the primary purpose of this study was to determine the effect of age on power generation during concentric contractions in the extensor digitorum longus (EDL) and soleus muscles over the load range from 10 to 90 % of peak isometric tetanic force (P ₀). Adult, old, and elderly male C57BL/6 mice were examined for contractile function (6–7 months old, 100 % survival; ~24 months, 75 %; and ~28 months, 50 % P ₀). The shape of the force-velocity curve also changed with age (a/P ₀ increased). In addition, there were prolonged contraction times to maximum force and shifts in the distribution of the myosin light and heavy chain isoforms in the EDL. The results demonstrate that age-associated difficulty in movement during challenging tasks is likely due, in addition to overall reduced force output, to an accelerated deterioration of power production and contractile velocity under heavily loaded conditions.

The muscle protein anabolic response to contraction and feeding may be blunted in older adults. Acute bouts of exercise can improve the ability of amino acids to stimulate muscle protein synthesis (MPS) by activating mechanistic target of rapamycin complex 1 (mTORC1) signaling, but it is not known whether exercise training may improve muscle sensitivity to amino acid availability. The aim of this study was to determine if muscle protein anabolism is resistant to essential amino acids (EAAs) and whether resistance exercise training (RET) improves muscle sensitivity to EAA in healthy older adults. In a longitudinal study, 19 healthy older adults [mean ± SD age: 71 ± 4 y body mass index (kg/m²): 28 ± 3] were trained for 12 wk with a whole-body program of progressive RET (60–75% 1-repetition maximum). Body composition, strength, and metabolic health were measured pre- and posttraining. We also performed stable isotope infusion experiments with muscle biopsies pre- and posttraining to measure MPS and markers of amino acid sensing in the basal state and in response to 6.8 g of EAA ingestion. RET increased muscle strength by 16%, lean mass by 2%, and muscle cross-sectional area by 27% in healthy older adults (P < 0.05). MPS and mTORC1 signaling (i.e., phosphorylation status of protein kinase B, 4E binding protein 1, 70-kDa S6 protein kinase, and ribosomal protein S6) increased after EAA ingestion (P < 0.05) pre- and posttraining. RET increased basal MPS by 36% (P < 0.05); however, RET did not affect the response of MPS and mTORC1 signaling to EAA ingestion. RET increases strength and basal MPS, promoting hypertrophy in healthy older adults. In these subjects, a small dose of EAAs stimulates muscle mTORC1 signaling and MPS, and this response to EAAs does not improve after RET. Our data indicate that anabolic resistance to amino acids may not be a problem in healthy older adults. This trial was registered at www.clinicaltrials.gov as NCT02999802.