Miller, Richard A.

Abstract Dynamic measures of resilience—the ability to resist and recover from a challenge—may be informative of the rate of aging before overt manifestations such as chronic disease, disability, and frailty. From this perspective mid-life resilience may predict longevity and late-life health. To test this hypothesis, we developed simple, reproducible, clinically relevant challenges, and outcome measures of physical resilience that revealed differences between and within age groups of genetically heterogeneous mice, and then examined associations between mid-life resilience and both lifespan and late-life measures of physiological function. We demonstrate that time to recovery from isoflurane anesthesia and weight change following a regimen of chemotherapy significantly differed among young, middle-aged, and older mice, and were more variable in older mice. Females that recovered faster than the median time from anesthesia (more resilient) at 12 months of age lived 8% longer than their counterparts, while more resilient males in mid-life exhibited better cardiac (fractional shortening and left ventricular volumes) and metabolic (glucose tolerance) function at 24 months of age. Moreover, female mice with less than the median weight loss at Day 3 of the cisplatin challenge lived 8% longer than those that lost more weight. In contrast, females who had more weight loss between Days 15 and 20 were relatively protected against early death. These data suggest that measures of physical resilience in mid-life may provide information about individual differences in aging, lifespan, and key parameters of late-life health.

Physical resilience, defined as the ability to resist and respond to challenges and return to homeostasis, has been postulated to be a determinant of healthspan and lifespan. To test this premise, we have begun to optimize a standardized, clinically relevant battery of resilience challenges, including anesthesia and cisplatin chemotherapy, and recovery outcome measures in younger (2–3 month) and older (26–29 month) mice. We have also started to test whether interventions shown to increase murine lifespan‐acarbose, rapamycin, and 17a‐estradiol‐impact the resilience of older mice. Our preliminary data demonstrate that younger mice (n = 10) have faster dorsal to sternal recumbence recovery time compared to older mice (n = 8) (39 ± 1 sec vs. 67 ± 6 sec, p < 0.001) following a 5‐minute 4% isoflurane anesthesia challenge. In response to a 5‐day cisplatin (2 mg/kg/day) challenge, both younger (n=5) and older (n=4) mice lost a significant percent of their baseline body weight (younger mice −10.6 ± 0.8% and older mice −13.2 ± 2.1%, p = 0.26), however, older mice failed to regain body weight 11 days after the challenge (younger mice −0.9 ± 0.8% and older mice −9.8 ± 0.8%, p < 0.01). Changes in body weight in younger and older mice were largely attributable to the loss/regain of fat mass. Interestingly, 8 weeks of either acarbose (1,000 ppm) or 17α‐estradiol (14.4 ppm) administration to older female mice improved body weight recovery after the cisplatin challenge, while rapamycin (14 ppm) had no appreciable effect. Our preliminary results demonstrate that younger mice, as expected, have greater resilience than older mice to clinically relevant physical challenges. The age at which physical resilience starts to decline requires further investigation. Our early observations suggest interventions that extend health‐ and lifespan may impact resilience in older mice. Ultimately, a standardized battery of resilience challenges may provide a new framework for testing and translating interventions that target the fundamental biology of aging. Support or Funding Information This work was supported by grant AG52958 from the National Institutes of Health. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

GH is an important regulator of body growth and composition as well as numerous other metabolic processes. In particular, liver plays a key role in the GH/IGF-I axis, because the majority of circulating “endocrine” IGF-I results from GH-stimulated liver IGF-I production. To develop a better understanding of the role of liver in the overall function of GH, we generated a strain of mice with liver-specific GH receptor (GHR) gene knockout (LiGHRKO mice). LiGHRKO mice had a 90% decrease in circulating IGF-I levels, a 300% increase in circulating GH, and significant changes in IGF binding protein (IGFBP)-1, IGFBP-2, IGFBP-3, IGFBP-5, and IGFBP-7. LiGHRKO mice were smaller than controls, with body length and body weight being significantly decreased in both sexes. Analysis of body composition over time revealed a pattern similar to those found in GH transgenic mice; that is, LiGHRKO mice had a higher percentage of body fat at early ages followed by lower percentage of body fat in adulthood. Local IGF-I mRNA levels were significantly increased in skeletal muscle and select adipose tissue depots. Grip strength was increased in LiGHRKO mice. Finally, circulating levels of leptin, resistin, and adiponectin were increased in LiGHRKO mice. In conclusion, LiGHRKO mice are smaller despite increased local mRNA expression of IGF-I in several tissues, suggesting that liver-derived IGF-I is indeed important for normal body growth. Furthermore, our data suggest that novel GH-dependent cross talk between liver and adipose is important for regulation of adipokines in vivo.