We previously quantified frailty in aged mice with frailty index (FI) that used specialized equipment to measure health parameters. Here we developed a simplified, noninvasive method to quantify frailty through clinical assessment of C57BL/6J mice (5–28 months) and compared the relationship between FI scores and age in mice and humans. FIs calculated with the original performance-based eight-item FI increased from 0.06±0.01 at 5 months to 0.36±0.06 at 19 months and 0.38±0.04 at 28 months (n = 14). By contrast, the increase was graded with a 31-item clinical FI (0.02±0.005 at 5 months; 0.12±0.008 at 19 months; 0.33±0.02 at 28 months; n = 14). FI scores calculated from 70 self-report items from the first wave of the Survey of Health, Ageing and Retirement in Europe were plotted as function of age (n = 30,025 people). The exponential relationship between FI scores and age (normalized to 90% mortality) was similar in mice and humans for the clinical FI but not the eight-item FI. This noninvasive FI based on clinical measures can be used in longitudinal studies to quantify frailty in mice. Unlike the performance-based eight-item mouse FI, the clinical FI exhibits key features of the FI established for use in humans.

Fitness and frailty form a continuum and predict survival. Exercise influences survival, even in old age. Relative fitness and frailty can be determined quickly in a clinical setting, are potentially useful markers of the risk for adverse health outcomes, and add value to traditional medical assessments that focus on diagnoses.

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BackgroundOlder adults are at an increased risk of death, but not all people of the same age have the same risk. Many methods identify frail people (that is, those at increased risk) but these often require time-consuming interactions with health care providers. We evaluated whether standard laboratory tests on their own, or added to a clinical frailty index (FI), could improve identification of older adults at increased risk of death.MethodsThis is a secondary analysis of a prospective cohort study, where community dwelling and institutionalized participants in the Canadian Study of Health and Aging who also volunteered for blood collection (n = 1,013) were followed for up to six years. A standard FI (FI-CSHA) was constructed from data obtained during the clinical evaluation and a second, novel FI was constructed from laboratory data plus systolic and diastolic blood pressure measurements (FI-LAB). A combined FI included all items from each index. Predictive validity was tested using Cox proportional hazards analysis and discriminative ability by the area under receiver operating characteristic (ROC) curves.ResultsOf 1,013 participants, 51.3% had died by six years. The mean baseline value of the FI-LAB was 0.27 (standard deviation 0.11; range 0.05 to 0.63), the FI-CSHA was 0.25 (0.11; 0.02 to 0.72), and the combined FI was 0.26 (0.09; 0.06 to 0.59). In an age- and sex-adjusted model, with each increment in the FI-LAB, the hazard ratios increased by 2.8% (95% confidence interval 1.02 to 1.04). The hazard ratios for the FI-CSHA and the combined FI were 1.02 (1.01 to 1.03) and 1.04 (1.03 to 1.05), respectively. The FI-LAB and FI-CSHA remained independently associated with death in the face of the other. The areas under the ROC curves were 0.72 for FI-LAB, 0.73 for FI-CSHA and 0.74 for the combined FI.ConclusionsAn FI based on routine laboratory data can identify older adults at increased risk of death. Additional evaluation of this approach in clinical settings is warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0171-9) contains supplementary material, which is available to authorized users.

This study developed an approach to quantify frailty with a frailty index (FI) and investigated whether age-related changes in contractions, calcium transients, and ventricular myocyte length were more prominent in mice with a high FI. The FI combined 31 variables that reflect different aspects of health in middle-aged (∼12 months) and aged (∼30 months) mice of both sexes. Aged animals had a higher FI than younger animals (FI = 0.43 ± 0.03 vs 0.08 ± 0.02, p < .001, n = 12). Myocyte hypertrophy increased by 30%-50% as the FI increased in aged animals. Peak contractions decreased more than threefold from lowest to highest FI values in aged mice (p < .037), but calcium transients were unaffected. Similar results were seen with an FI based on eight noninvasive variables identified as underlying factors. These results show that an FI can be developed for murine models and suggest that age-associated changes in myocytes are more prominent in animals with a high FI.

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A novel group of racemic isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-pyridinylpyridine-5-carboxylate isomers [(+/-)-12-14] were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with isopropyl 3-aminocrotonate and 2-, 3-, or 4-pyridinecarboxaldehyde. Determination of their in vitro calcium channel-modulating activities using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays showed that the 2-pyridinyl isomer (+/-)-12 acted as a dual cardioselective calcium channel agonist (GPLA)/smooth muscle selective calcium channel antagonist (GPILSM). In contrast, the 3-pyridinyl [(+/-)-13] and 4-pyridinyl [(+/-)-14] isomers acted as calcium channel agonists on both GPLA and GPILSM. The agonist effect exhibited by (+/-)-12 on GPLA was inhibited by nifedipine and partially reversed by addition of extracellular Ca2+. In anesthetized rabbits, the 4-pyridinyl isomer (+/-)-14 exhibited a hypertensive effect that was qualitatively similar to that exhibited by the nonselective agonist Bay K 8644 and the 3-pyridinyl isomer (+/)-13, whereas the 2-pyridinyl isomer (+/-)-12 induced a hypotensive effect similar to that of the calcium channel antagonist nifedipine. Similar results were obtained in a spontaneously hypertensive rat model. In vitro studies showed that the (+)-2-pyridinyl enantiomer (+)-12A exhibited agonist activity on both GPILSM and GPLA, but that the (-)-2-pyridinyl enantiomer (-)-12B exhibited agonist activity on GPLA and antagonist activity on GPILSM. Whole-cell voltage-clamp studies using isolated guinea pig ventricular myocytes indicated that (-)-12B inhibited the calcium current (ICa), that (+)-12A increased slightly ICa, and that (+/-)-12 inhibited ICa but the latter inhibition was less than that for (-)-12B. (-)-12B effectively inhibited ICa at all membrane potentials examined (-40-50 mV), whereas (+)-12A exhibited a weak agonist effect near the peak of the I-V curve. The 2-pyridinyl isomers (enantiomers) 12 represent a novel type of 1,4-dihydropyridine calcium channel modulator that could provide a potentially new approach to drug discovery targeted toward the treatment of congestive heart failure and probes to study the structure-function relationships of calcium channels.

the FI-Lab detected an increased risk of adverse health outcomes alone and in combination with a clinical FI; further evaluation of the feasibility of the FI-Lab as a frailty screening tool within hospital care settings is needed.