Frailty is a state of high vulnerability to adverse health outcomes. This concept is used to explain the heterogeneity in rates of aging in people of the same age. Frailty has important clinical implications, because even minor stressors can lead to adverse outcomes, including death, in frail individuals. Although frailty mechanisms are not well understood, advances in our ability to qualify frailty have encouraged efforts in this area. Quantification of frailty with both “frailty phenotype” and “frailty index” approaches has begun to highlight putative frailty mechanisms and new animal models of frailty are inspiring preclinical research. These models either adapt frailty phenotype and frailty index tools for use in animals or they use genetically manipulated mice that mimic conditions seen in frailty (eg, inflammation, sarcopenia, weakness). This review: describes commonly used tools to quantify frailty clinically, discusses potential frailty mechanisms, and describes animal models of frailty. It also highlights how these models have been used to explore frailty mechanisms and potential frailty interventions, including pharmacological treatments, diet, and exercise. These exciting new developments in the field have the potential to facilitate translational research, improve our understanding of mechanisms of frailty, and help develop new interventions to mitigate frailty in our aging population.

We investigated effects of age, sex and frailty on contractions, calcium transients and myofilament proteins to determine if maladaptive changes associated with aging were sex-specific and modified by frailty. Ventricular myocytes and myofilaments were isolated from middle-aged (~12 mos) and older (~24 mos) mice. Frailty was assessed with a non-invasive frailty index. Calcium transients declined and slowed with age in both sexes, but contractions were largely unaffected. Actomyosin Mg-ATPase activity increased with age in females but not males; this could maintain contractions with smaller calcium transients in females. Phosphorylation of myosin-binding protein C (MyBP-C), desmin, tropomyosin and myosin light chain-1 (MLC-1) increased with age in males, but only MyBP-C and troponin-T increased in females. Enhanced phosphorylation of MyBP-C and MLC-1 could preserve contractions in aging. Interestingly, the age-related decline in Hill coefficients (r = −0.816; p = 0.002) and increase in phosphorylation of desmin (r = 0.735; p = 0.010), tropomyosin (r = 0.779; p = 0.005) and MLC-1 (r = 0.817; p = 0.022) were graded by the level of frailty in males but not females. In these ways, cardiac remodeling at cellular and subcellular levels is graded by overall health in aging males. Such changes may contribute to heart diseases in frail older males, whereas females may be resistant to these effects of frailty. Diseases of impaired myocardial contractile function, including heart failure, increase with age in both men and women 1. This may not be surprising. Studies suggest that the heart undergoes maladaptive changes during normal aging that may set the stage for the development of heart failure 2. However, a key challenge to understanding the milieu in which such diseases develop is that, while older men and women are most likely to develop heart diseases as they age 1 , current preclinical research studies typically use young, mostly male animals 3-5. Although few experimental studies have investigated the influence of age on cardiac contractile function, emerging evidence suggests this may differ between the sexes both in humans and in animal models 6-9. To understand the underlying reasons, it is important to identify cellular and subcellular mechanisms that are involved in cardiac aging in both sexes. Although age modifies the heart, such changes are average responses that may not be present, or present to the same extent, in all individuals of the same age 10. For example, on average ventricular contractility declines with age, even though some older men and women perform at the same or even at higher levels when compared to younger adults 11. This suggests that aging is heterogenous. The concept of "frailty", used by demographers in 1979 to describe unmeasured heterogeneity in mortality risk in people of the same age 12 , is now used to describe unmeasured heterogeneity in the risk of many age-related adverse outcomes in both humans and animals 13. While there is no consensus definition of frailty 14 , it is clinical...

Aerobic exercise is a promising intervention to attenuate frailty, but preclinical studies have used only male animals. We investigated the impact of voluntary aerobic exercise on frailty, biological age (FRIGHT clock), predicted life expectancy (AFRAID clock) and mortality in both sexes and determined whether exercise was associated with changes in inflammation. Older (21-23 months) male (n=12) and female (n=22) C57Bl/6 mice matched for baseline frailty scores were randomized into exercise (running wheel) and sedentary (no wheel) groups. Frailty index scores were measured biweekly (13 weeks), and 23 serum cytokines were measured at midpoint and endpoint. Exercise levels varied between mice but not between the sexes. Exercise had no effect on mortality, but it attenuated the development of frailty in both sexes (female=0.32±0.04 vs 0.21±0.01; p=0.005; male=0.30±0.02 vs. 0.22±0.02; p=0.042) and reduced frailty in older females after 10 weeks. FRIGHT scores were unaffected by exercise but increased with time in sedentary males indicating increased biological age. Exercise prevented the age-associated decline in AFRAID scores in older females such that exercised females had a longer life expectancy. We investigated whether aerobic exercise was associated with changes in systemic inflammation. Cytokine levels were not affected by exercise in males, but levels of pro-inflammatory cytokines were positively correlated with the frequency of exercise in females. Despite increases in systemic inflammation, exercise reduced frailty and increased lifespan in older females. Thus, voluntary aerobic exercise, even late in life, has beneficial effects on health in both sexes but may be especially helpful in older females.

Background Cardiovascular disease increases with age in both sexes. Treatment can require cardiac surgery, where the hearts are pre-treated with protective cardioplegic solution before ischemia and reperfusion (I/R). While endogenous estrogen is beneficial in I/R, whether testosterone is involved is uncertain and whether age modifies responses to I/R is unclear. We investigated sex- and age-specific differences in I/R injury in the hearts pre-treated with clinically relevant cardioplegic solution. Methods The hearts were isolated from young (6–9 months) and old (20–28 months) mice of both sexes and perfused (Langendorff) with Krebs-Henseleit buffer (15 min, 37 °C), followed by St. Thomas’ two cardioplegia (6 min, 6–7 °C), global ischemia (90 min, 23–24 °C), and reperfusion (30 min, 37 °C). The hearts were perfused with triphenyltetrazolium chloride to quantify infarct area. Testosterone’s role was investigated in gonadectomized (GDX, 6–9 months) male mice; serum testosterone and estradiol were measured with ELISA assays. Results Left ventricular developed pressure (LVDP) recovered to 67.3 ± 7.4% in the old compared to 21.8 ± 9.2% in the young male hearts ( p < 0.05). Similar results were seen for rates of pressure development (+dP/dt) and decay (−dP/dt). Infarct areas were smaller in the old male hearts (16.6 ± 1.6%) than in the younger hearts (55.8 ± 1.2%, p < 0.05). By contrast, the hearts from young and old females exhibited a similar post-ischemic functional recovery and no age-dependent difference in infarcts. There was a sex difference in the young group, where ventricular function (LVDP, +dP/dt, −dP/dt) recovered better and infarcts were smaller in females than males. Estradiol levels were highest in young females. Testosterone was high in young males but low in females and old males, which suggested beneficial effects of low testosterone. Indeed, the hearts from GDX males exhibited much better recovery of LVDP in reperfusion than that from intact males (values were 64.4 ± 7.5 % vs. 21.8 ± 9.2%; p < 0.05). The GDX hearts also had smaller infarcts than the hearts from intact males ( p < 0.05). Conclusions Although age had no effect on susceptibility to I/R injury after cardioplegic arrest in females, it actually protected against injury in older males. Our findings indicate that low testosterone may be protective against I/R injury following cardioplegic arrest in older males. Electronic supplementary material The online version of this article (10.1186/s13293-019-0256-4) contains supplementary material, which is available to authorized users.

We investigated whether late-life changes in cardiac structure and function were related to high levels of frailty and inflammation in male and female mice. Frailty (frailty index), ventricular structure/function (echocardiography) and serum cytokines (multiplex immunoassay) were measured in 16 and 23-month-old mice. Left ventricular (LV) mass and septal wall thickness increased with age in both sexes. Ejection fraction increased with age in males (60.4±1.4 vs 68.9±1.8%; p&lt;0.05) but not females (58.8±2.5 vs 62.6±2.4%). E/A ratios declined with age in males (1.6±0.1 vs 1.3±0.1; p&lt;0.05) but not females (1.4±0.1 vs 1.3±0.1) and this was accompanied by increased ventricular collagen levels in males. These changes in ejection fraction (r=0.52; p=0.01), septal wall thickness (r=0.59; p=0.002), E/A ratios (r=-0.49; p=0.04) and fibrosis (r=0.82; p=0.002) were closely graded by frailty scores in males. Only septal wall thickness and LV mass increased with frailty in females. Serum cytokines changed modestly with age in both sexes. Nonetheless, in males, E/A ratios, LV mass, LV posterior wall thickness and septal wall thickness increased as serum cytokines increased (e.g. IL-6, IL-3, IL-1α IL-1ß, TNF-α, eotaxin and MIP-1α), while ejection fraction declined with increasing IL-3 and GM-CSF. Cardiac outcomes were not correlated with inflammatory cytokines in females. Thus, changes in cardiac structure and function in late life are closely graded by both frailty and markers of inflammation, but this occurs primarily in males. This suggests poor overall health and inflammation drive maladaptive changes in older male hearts, while older females may be resistant to these adverse effects of frailty