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There are sex differences in vulnerability and resilience to the stressors of aging and subsequent age-related cognitive decline. Cellular senescence occurs as a response to damaging or stress-inducing stimuli. The response includes a state of irreversible growth arrest, the development of a senescence-associated secretory phenotype, and the release of pro-inflammatory cytokines associated with aging and age-related diseases. Senolytics are compounds designed to eliminate senescent cells. Our recent work indicates that senolytic treatment preserves cognitive function in aging male F344 rats. The current study examined the effect of senolytic treatment on cognitive function in aging female rats. Female F344 rats (12 months) were treated with dasatinib (1.2 mg/kg) + quercetin (12 mg/kg) or ABT-263 (12 mg/kg) or vehicle for 7 months. Examination of the estrus cycle indicated that females had undergone estropause during treatment. Senolytic treatment may have increased sex differences in behavioral stress responsivity, particularly for the initial training on the cued version of the watermaze. However, pre-training on the cue task reduced stress responsivity for subsequent spatial training and all groups learned the spatial discrimination. In contrast to preserved memory observed in senolytic-treated males, all older females exhibited impaired episodic memory relative to young (6-month) females. We suggest that the senolytic treatment may not have been able to compensate for the loss of estradiol, which can act on aging mechanisms for anxiety and memory independent of cellular senescence.

Muscle wasting and weakness are critical clinical problems that limit mobility and independence, reduce health span, and increase the risk of physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho-null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic GPDH enzymatic activity also increased. Klotho-deficient mice showed impaired muscle contractility, with reduced twitch force, torque, and contraction–relaxation rates. RNA sequencing revealed upregulation of synaptic and fetal sarcomeric genes, prompting us to examine muscle innervation. Klotho deficiency led to neuromuscular junction remodeling, myofiber denervation, and functional motor unit loss. Loss of motor units correlated with absolute torque. Collectively, these findings reveal a novel mechanism through which systemic Klotho deficiency disrupts muscle synapses and motor unit connectivity, potentially contributing to muscle wasting and weakness.

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others’ lifespans outlast their “mindspans.”

JC virus (JCV) can cause a lytic infection of oligodendrocytes and astrocytes in the central nervous system (CNS) leading to progressive multifocal leukoencephalopathy (PML). JCV can also infect meningeal and choroid plexus cells causing JCV meningitis (JCVM). Whether JCV also infects meningeal and choroid plexus cells in PML patients and other immunosuppressed individuals with no overt symptoms of meningitis remains unknown. We therefore analyzed archival formalin-fixed, paraffin-embedded brain samples from PML patients, and HIV-seropositive and seronegative control subjects by immunohistochemistry for the presence of JCV early regulatory T Ag and JCV VP1 late capsid protein. In meninges, we detected JCV T Ag in 11/48 (22.9%) and JCV VP1 protein in 8/48 (16.7%) PML patients. In choroid plexi, we detected JCV T Ag in 1/7 (14.2%) and JCV VP1 protein in 1/8 (12.5%) PML patients. Neither JCV T Ag nor VP1 protein could be detected in meninges or choroid plexus of HIV-seropositive and HIV-seronegative control subjects without PML. In addition, examination of underlying cerebellar cortex of PML patients revealed JCV-infected cells in the molecular layer, including GAD 67+ interneurons, but not in HIV-seropositive and HIV-seronegative control subjects without PML. Our findings suggest that productive JCV infection of meningeal cells and choroid plexus cells also occurs in PML patients without signs or symptoms of meningitis. The phenotypic characterization of JCV-infected neurons in the molecular layer deserves further study. This data provides new insight into JCV pathogenesis in the CNS.

We examine similar and differential effects of two senolytic treatments, ABT‐263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT‐263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood–brain barrier (BBB) integrity, and prevented the age‐related decline in hippocampal N‐methyl‐D‐aspartate receptor (NMDAR) function associated with impaired cognition. Senolytic treatments decreased senescence‐associated secretory phenotype (SASP) and inflammatory cytokines/chemokines in the plasma (IL‐1β, IP‐10, and RANTES), with some markers more responsive to D + Q (TNFα) or ABT‐263 (IFNγ, leptin, EGF). ABT‐263 was more effective in decreasing senescence genes in the spleen. Both senolytic treatments decreased the expression of immune response and oxidative stress genes and increased the expression of synaptic genes in the dentate gyrus (DG). However, D + Q influenced twice as many genes as ABT‐263. Relative to D + Q, the ABT‐263 group exhibited increased expression of DG genes linked to cell death and negative regulation of apoptosis and microglial cell activation. Furthermore, D + Q was more effective at decreasing morphological markers of microglial activation. The results indicate that preserved cognition was associated with the removal of peripheral senescent cells, decreasing systemic inflammation that normally drives neuroinflammation, BBB breakdown, and impaired synaptic function. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential access. The results of the current study demonstrate that senolytic treatment reduced morphological evidence of microglial activation, decreased expression of immune response genes in the dentate gyrus, and rescued hippocampal‐dependent spatial memory. Further, senolytic intervention preserved the blood‐brain barrier integrity. Finally, senolytic treatment prevented the age‐related decline in hippocampal N‐methyl‐D‐aspartate receptor‐mediated synaptic function associated with impaired cognition.

Muscle wasting and weakness are important clinical problems that impact quality of life and health span by restricting mobility and independence, and by increasing the risk for physical disability. The molecular basis for this has not been fully determined. Klotho expression is downregulated in conditions associated with muscle wasting, including aging, chronic kidney disease, and myopathy. The objective of this study was to investigate a mechanistic role for Klotho in regulating muscle wasting and weakness. Body weight, lean mass, muscle mass, and myofiber caliber were reduced in Klotho-deficient mice. In the tibialis anterior muscle of Klotho null mice, type IIa myofibers were resistant to changes in size, and muscle composition differed with a higher concentration of type IIb fibers to the detriment of type IIx fibers. Glycolytic enzymatic activity also increased. The composition of the soleus muscle was unaffected and myofiber caliber was reduced comparably in type I, IIa, and IIx fibers. Muscle contractile function declined in Klotho-deficient mice, as evidenced by reduced absolute twitch and torque, and decreased rates of contraction and relaxation. RNA-sequencing analysis identified increased transcriptional expression of synaptic and fetal sarcomeric genes, which prompted us to test effects on muscle innervation. Klotho-deficiency induced morphological remodeling of the neuromuscular junction, myofiber denervation, and a functional loss of motor units. Loss of motor units correlated with absolute torque. Collectively, our findings have uncovered a novel mechanism through which Klotho-deficiency leads to alterations to the muscle synapse affecting motor unit connectivity that likely influences muscle wasting and weakness.

Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by skeletal muscle degeneration and cardiomyopathy without a cure. This study examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) on cardiac function in the dystrophin-deficient mouse model of DMD. Male mice were fed control chow or EMPA-containing chow (~25 mg/kg/day), and cardiac function was evaluated longitudinally by four-dimensional ultrasound imaging. EMPA did not alter left ventricular mass or chamber volume but preserved ejection fraction (EF) for 12 weeks, maintained significantly higher EF through 24 weeks, and attenuated global impairment of systolic and diastolic myocardial deformation. These functional improvements were accompanied by reduced cardiomyocyte hypertrophy and decreased expression of cardiac stress genes. EMPA reduced mitochondrial DNA damage, increased mitochondrial DNA copy number, and induced transcriptional signatures consistent with enhanced fatty acid and ketone metabolism, contributing to increased myocardial ATP content. Systemically, EMPA improved body mass trajectory, preserved relative lean mass, enhanced skeletal muscle torque, and did not adversely affect renal function. Together, these findings demonstrate that EMPA improves cardiac performance and mitochondrial integrity while enhancing myocardial energy availability in mice, supporting SGLT2 inhibitors as a promising therapeutic strategy for individuals with DMD.

Estradiol (E2) induces synaptic plastic processes in the hippocampus and enhances/protects cognition during aging. However, a time-dependent decline in E2 responsiveness following long-term E2 deprivation denotes a critical window for E2 therapeutic effects. We hypothesized that closing of the critical window is due to a shift in the expression of estrogen receptors and up-regulating the expression of estrogen receptor alpha (ERα) or estrogen receptor beta (ERβ) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2 induced hippocampal plasticity. We employed adeno-associated viral vectors to express ERα, ERβ, or green fluorescent protein (GFP) in the CA1 region of dorsal hippocampi of female rats (18.5 mo.) whose ovaries had been removed 14 weeks earlier. Animals were subsequently treated for five weeks with cyclic injections of 17β-estradiol-3- benzoate (EB, 10 μg) or oil vehicle. Spatial memory was examined 48 hours following EB/oil treatment. EB treatment in the GFP group (GFP+EB) failed to improve cognition relative to GFP+oil, indicating closing of the window for E2-mediated benefits. Expression of ERα was associated with a modest learning impairment regardless of EB/oil treatment. Cognitive benefits were specific to animals expressing ERα that received EB treatment (ERα+EB), such that memory was improved relative to ERα+oil and GFP+EB. Similarly, ERα+EB animals exhibited enhanced N-methyl-D-aspartate receptor mediated synaptic transmission compared to ERα+oil and GFP+EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2-responsiveness can be reinstated by increased expression of estrogen receptors.

In an attempt to assess the degree to which specific stimulus-response associations are gradually acquired in learning a serial list, the order of the middle items was altered during acquisition. Five groups with 16 Ss per group had either no items switched, two items switched after four or eight test trials, or four items switched after four or eight test trials. The nonsense syllables were presented with slide projectors by means of standard serial anticipation procedures. Contrary to hypotheses, there were no overall differences between the four experimental groups and the control in trials to criterion or in total errors. However, although few experimental Ss reported noticing the switch, they made more errors on the trials immediately following the switch in comparison with the control group. These results are interpreted as disconfirming continuous, stimulus-specific association assumptions and supporting noncontinuous, nonassociative approaches.

Scope and method of study. Vocational teacher education has not had guiding principles from which to base a redesign of teacher education. The University Council for Vocational Education (UCVE) has recognized the need for the identification of broad based principles that can be agreed upon by member institutions. Educators need principles to guide their development, implementation, maintenance, and evaluation of educational programs. With guiding principles, institutions could work from the same theoretical framework to develop future models in teacher preparation. The central focus and purpose of this study was to develop a research-based agreed upon set of contemporary principles for the redesign of vocational teacher education. These guiding principles will enable vocational teacher educators to take the next step toward the development of new vocational teacher education programs. A Delphi Technique via electronic mail was the vehicle for the development of an agreed upon set of principles. Three rounds were submitted and analyzed through the use of communication in electronic mail to 19 participants. The participants were nominated from representatives of UCVE institutions as known experts in vocational teacher education. Findings and conclusions. The consensus of Delphi experts resulted in 28 unique principles. After a comparative analysis, three distinct categories emerged: students, programs, and teacher educators. Within these three categories, several common themes were identified and were used as the basis for the development of 17 contemporary principles. These 17 contemporary principles organized in the three categories of Students in Vocational Teacher Programs, Programs of Vocational Teacher Preparation, and Vocational Teacher Educators can be used to guide the redesign and/or evaluation of vocational teacher education programs.