Implementation of the mouse frailty index.

Frailty is considered a state of high vulnerability for adverse health outcomes for people of the same age. Those who are frail have higher mortality, worse health outcomes, and use more health care services than those who are not frail. Despite this, little is known about the biology of frailty, the effect of frailty on pharmacological or surgical outcomes, and potential interventions to attenuate frailty. In humans, frailty can be quantified using a frailty index (FI) based on the principle of deficit accumulation. The recent development of an FI in naturally ageing mice provides an opportunity to conduct frailty research in a validated preclinical model. The mouse FI has been successfully used across a wide range of applications; however, there are some factors that should be considered in implementing this tool. This review summarises the current literature, presents some original data, and suggests areas for future research on the current applications of the mouse FI, inter-rater reliability of the FI, the effect of observer characteristics and environmental factors on mouse FI scores, and the individual items that make up the FI assessment. The implementation of this tool into preclinical frailty research should greatly accelerate translational research in this important field.

Influence of age on intestinal bile acid transport in C57BL/6 mice.

Intestinal and hepatic bile acid transporters are important for enterohepatic bile acid circulation and pharmacokinetics. Based on previous literature, we hypothesized that the expression of bile acid transporters and intestinal bile acid absorption are lower in older individuals. Here, we measured active taurocholate absorption across the ileum of male C57BL/6 mice in two different age cohorts - young (age range of 89-224 days) and old (age range of 613-953 days). Also examined in these mice were mRNA expression of the major bile acid transporters - Asbt and Ostα/ß in the ileum, and Ntcp, Oatp1b2 and Bsep in the liver. Mean intestinal taurocholate absorption was significantly lower (~50%) in mice in the older cohort compared to those in the younger cohort. In the ileum, the expression of Asbt was significantly lower in the older cohort, but expression of Ostα/ß was not affected by age. The lower capacity for intestinal bile acid absorption in the older animals is consistent with their lower expression level of Asbt. Of the hepatic bile acid transporters examined, expression of Ntcp and Oatp1b2 were significantly lower in the older mice. This is the first study to directly measure intestinal bile acid absorption as a function of age. The data suggest a lower capacity for intestinal bile acid absorption in older animals. Also, lower expression of Asbt, Ntcp, and Oatp1b2 in older individuals could influence pharmacokinetics of drug substrates.

Acute exposure to progesterone attenuates cardiac contraction by modifying myofilament calcium sensitivity in the female mouse heart.

Acute application of progesterone attenuates cardiac contraction, although the underlying mechanisms are unclear. We investigated whether progesterone modified contraction in isolated ventricular myocytes and identified the Ca2+ handling mechanisms involved in female C57BL/6 mice (6-9 mo; sodium pentobarbital anesthesia). Cells were field-stimulated (4 Hz; 37°C) and exposed to progesterone (0.001-10.0 µM) or vehicle (35 min). Ca2+ transients (fura-2) and cell shortening were recorded simultaneously. Maximal concentrations of progesterone inhibited peak contraction by 71.4% (IC50 = 160 ± 50 nM; n = 12) and slowed relaxation by 75.4%. By contrast, progesterone had no effect on amplitudes or time courses of underlying Ca2+ transients. Progesterone (1 µM) also abbreviated action potential duration. When the duration of depolarization was controlled by voltage-clamp, progesterone attenuated contraction and slowed relaxation but did not affect Ca2+ currents, Ca2+ transients, sarcoplasmic reticulum (SR) content, or fractional release of SR Ca2+ Actomyosin MgATPase activity was assayed in myofilaments from hearts perfused with progesterone (1 µM) or vehicle (35 min). While maximal responses to Ca2+ were not affected by progesterone, myofilament Ca2+ sensitivity was reduced (EC50 = 0.94 ± 0.01 µM for control, n = 7 vs. 1.13 ± 0.05 µM for progesterone, n = 6; P < 0.05) and progesterone increased phosphorylation of myosin binding protein C. The effects on contraction were inhibited by lonaprisan (progesterone receptor antagonist) and levosimendan (Ca2+ sensitizer). Unlike results in females, progesterone had no effect on contraction or myofilament Ca2+ sensitivity in age-matched male mice. These data indicate that progesterone reduces myofilament Ca2+ sensitivity in female hearts, which may exacerbate manifestations of cardiovascular disease late in pregnancy when progesterone levels are high. NEW & NOTEWORTHY: We investigated myocardial effects of acute application of progesterone. In females, but not males, progesterone attenuates and slows cardiomyocyte contraction with no effect on calcium transients. Progesterone also reduces myofilament calcium sensitivity in female hearts. This may adversely affect heart function, especially when serum progesterone levels are high in pregnancy.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/acute-progesterone-modifies-cardiac-contraction/.

How cardiomyocyte excitation, calcium release and contraction become altered with age.

Cardiovascular disease is the main cause of death globally, accounting for over 17 million deaths each year. As the incidence of cardiovascular disease rises markedly with age, the overall risk of cardiovascular disease is expected to increase dramatically with the aging of the population such that by 2030 it could account for over 23 million deaths per year. It is therefore vitally important to understand how the heart remodels in response to normal aging for at least two reasons: i) to understand why the aged heart is increasingly susceptible to disease; and ii) since it may be possible to modify treatment of disease in older adults if the underlying substrate upon which the disease first develops is fully understood. It is well known that age modulates cardiac function at the level of the individual cardiomyocyte. Generally, in males, aging reduces cell shortening, which is associated with a decrease in the amplitude of the systolic Ca(2+) transient. This may arise due to a decrease in peak L-type Ca(2+) current. Sarcoplasmic reticulum (SR) Ca(2+) load appears to be maintained during normal aging but evidence suggests that SR function is disrupted, such that the rate of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA)-mediated Ca(2+) removal is reduced and the properties of SR Ca(2+) release in terms of Ca(2+) sparks are altered. Interestingly, Ca(2+) handling is modulated by age to a lesser degree in females. Here we review how cellular contraction is altered as a result of the aging process by considering expression levels and functional properties of key proteins involved in controlling intracellular Ca(2+). We consider how changes in both electrical properties and intracellular Ca(2+) handling may interact to modulate cardiomyocyte contraction. We also reflect on why cardiovascular risk may differ between the sexes by highlighting sex-specific variation in the age-associated remodeling process. This article is part of a Special Issue entitled CV Aging.

Reliability of a Frailty Index Based on the Clinical Assessment of Health Deficits in Male C57BL/6J Mice.

We investigated the reliability of a newly developed clinical frailty index (FI) that measures frailty based on deficit accumulation in aging mice. FI scores were measured by two different raters independently in a large cohort (n = 233) of 343-430 day-old male C57BL/6J mice. Inter-rater reliability was evaluated with correlation coefficients, the kappa statistic, and intra-class correlation coefficients (ICC) in three separate groups of mice (n = 45, 50, and 138 mice/group) sequentially over 3 months. After each group was evaluated, descriptions of techniques used to identify health deficits were amended. Mice had comparable overall FI scores regardless of rater (0.213±0.002 vs 0.212±0.002; p = .802), although discordant measures declined as techniques were refined. Correlation coefficients (r (2) values) between raters improved throughout the study and mean kappa values increased (mean ± SEM; 0.621±0.018, 0.764±0.017, and 0.836±0.009 for groups 1, 2, and 3; p < .05). Values for intra-class correlation coefficient also improved from .51 (95% confidence interval = 0.11-.73) to .74 (0.54-0.85) and .77 (0.67-.83). FI scores increased over 3 months (p < .05), but did not differ between raters. These results show a high overall inter-rater reliability when the clinical FI tool is used to assess frailty in a large cohort of mice.

State policy and funding of services to families of adults with serious and persistent mental illness.

A survey of state mental health programs was conducted to determine the extent to which states are facilitating the delivery of services to families of adults with severe and persistent mental illness. Of the 44 responding states, 73 percent did not have a policy about the types of services delivered to families, but 80 percent reported that they funded a family support intervention. The large majority of interventions supported by the states were family-to-family programs such as those sponsored by the National Alliance for the Mentally Ill. This study draws attention to the gap in services by mental health professionals to families and underscores the importance of the advocacy movement in obtaining funding and support for services to families.

The evolving role of the state hospital in the care and treatment of older adults: state trend, 1984 to 1993.

OBJECTIVE: To understand the current and potential role of state hospitals in serving geriatric patients, national trends in the use of state mental hospitals by adults age 65 and older were examined. METHODS: State hospital use by older adults in the 50 states and the District of Columbia was compared for the years 1984 and 1993 using published data from the Center for Mental Health Services. RESULTS: Nationally, the number of state hospital admissions and residents declined between 1984 and 1993, and the rate of decrease was greater for older adults than for younger adults. However, states varied considerably in the rate of decrease in the number of older adult state hospital residents and admissions and in the proportion of older adult patients diagnosed with an organic mental disorder. In ten states, the older-adult state hospital population increased. CONCLUSIONS: Although the national trend is toward a declining role for state hospitals in treatment and care of older adults, in several states the hospitals fill an important function in providing custodial care and acute care for this population.