The University of Oklahoma Health Sciences Center is a public medical school in Oklahoma City, Oklahoma. It is the health sciences branch of the University of Oklahoma and serves as the primary place of instruction for many of Oklahoma's health professions. It is one of only four health centers in the United States with seven professional colleges.The nineteen buildings that make up the OUHSC campus occupies a fifteen block area in Oklahoma City near the Oklahoma State Capitol. Surrounding these buildings are an additional twenty health-related buildings some of which are owned by the University of Oklahoma. The Health Sciences Center is the core of a wider complex known as the Oklahoma Health Center. The major clinical facilities on campus are part of OU Medicine and include the OU Medical Center hospital complex, The Children's Hospital, OU Physicians and OU Children's Physicians clinics, Harold Hamm Diabetes Center and the Peggy and Charles Stephenson Oklahoma Cancer Center. Also part of the major clinical facilities is the Oklahoma City VA Medical Center.
Aging is accompanied by a progressive decline in skeletal muscle mass and function, culminating in sarcopenia, a major contributor to frailty, disability, and mortality in older adults. While skeletal muscle aging has traditionally been attributed to cell-autonomous and local tissue mechanisms, increasing evidence suggests that systemic, cell non-autonomous processes play a central role in coordinating aging across organs. The brain, particularly the hypothalamus, has emerged as a key regulator of organismal aging, yet its contribution to skeletal muscle aging remains poorly defined. Here, we tested the hypothesis that senescence confined to the brain is sufficient to induce aging-like molecular remodeling in skeletal muscle via systemic mechanisms. To model brain senescence, young mice were subjected to fractionated whole-brain irradiation (WBI), a well-established approach that induces widespread cellular senescence and neuroinflammation in the brain while sparing peripheral tissues. Two months after WBI, transcriptomic profiling of quadriceps muscle was performed and compared with that of naturally aged mice. WBI-induced robust gene expression changes in skeletal muscle that closely mirrored those observed during chronological aging. Pathway-level analyses revealed marked downregulation of mitochondrial organization, respiratory chain assembly, and metabolic processes, alongside enrichment of remodeling- and stress-associated pathways. Upstream regulator analysis identified FOXO1, FOXO3, KLF15, and STAT3, which are key drivers of muscle catabolism and atrophy, as central mediators of the observed transcriptional program. Semantic similarity analysis further demonstrated a high concordance between WBI-induced and aging-associated biological processes. Collectively, these findings demonstrate that brain senescence is sufficient to drive sarcopenia-like transcriptomic remodeling in skeletal muscle, implicating central nervous system aging as an upstream regulator of peripheral muscle decline. This brain-muscle aging axis may contribute to frailty in individuals with accelerated brain aging and in cancer survivors exposed to cranial irradiation, highlighting brain senescence as a potential therapeutic target to mitigate systemic aging and skeletal muscle dysfunction.
Aging profoundly alters the neuromotor and cognitive systems that support gait control, leading to increased variability and instability that predict functional decline and dementia risk. In this pilot study, conducted to inform the design of the Semmelweis Study gait assessment pipeline, we examined how aging and cognitive load influence the magnitude and temporal organization of gait fluctuations. The Semmelweis Study is a large, prospective workplace cohort at Semmelweis University designed to identify the determinants of unhealthy aging and the mechanisms that preserve functional resilience across the life course. One hundred three adults aged 23–87 years completed single- and dual-task walking trials on a 20-foot pressure-sensitive walkway. Gait variability was quantified using the median absolute deviation (MAD) and coefficient of variation (CoV) of key spatiotemporal parameters, while permutation entropy (PE) captured the complexity of stride-to-stride dynamics. Aging was associated with progressive increases in both the variability (MAD, CoV) and changes in orderliness (PE) of gait fluctuations, particularly under dual-task conditions, suggesting a dual contribution of neuromotor degradation and compensatory recruitment of higher-order control processes. The amplification of these effects during cognitive load highlights the vulnerability of cognitive–motor integration with advancing age. By integrating robust, relative, and nonlinear variability metrics within a unified analytical framework, this study provides a multidimensional characterization of gait control and establishes sensitive indicators for detecting early functional decline. Within the translational framework of the Semmelweis Study, these quantitative gait measures—together with vascular, metabolic, and cognitive assessments—are expected to serve as informative components of a comprehensive biomarker system aimed at identifying early determinants of unhealthy brain aging and guiding preventive strategies to promote healthy longevity.
Reducing activity of the mechanistic/mammalian target of rapamycin (mTOR) with rapamycin extends lifespan and healthspan in many species. The mechanisms by which mTOR regulates lifespan and healthspan, however, are still unknown. Understanding how mTOR signaling in different cell types regulates lifespan and aspects of healthspan is urgently needed if we are to harness the potential individual and societal benefits of healthspan extension by mTOR attenuation. mTOR kinase can form two complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The regulatory associated protein of mTOR (Raptor) is required for the assembly of mTORC1, the primary target of rapamycin. To define the role of mTORC1 and mTORC2 signaling during development in the regulation of healthspan we either ablated or reduced expression of Rptor (Raptor) or Mtor (mTOR) in neurons of mice. Developmental knock-down of Mtor (mTORKD) exclusively in neurons, had no significant impact on embryonic survival, but significantly increased adult mortality. In contrast, neuronal knockdown of Rptor (RaptorKD) during development reduced embryonic viability, but did not appear to impact adult survival, suggesting that reducing mTORC1 may confer a survival advantage after birth. Reduction of either Rptor or Mtor (mTORKD, RaptorKD) during development, however, significantly decreased growth rates, body weight, fat mass, resting and fasting blood glucose, and exercise capacity. Taken together, our studies indicate that neuronal mTORC1 plays a critical role in the determination of body size during development, as well as fat mass, metabolic states and exercise capacity during adulthood.
Purpose. To assess the chemopreventive effect of oleanolic acid (ONA) and its synthetic analog 18 alpha-olean-12-ene-3 beta-23,28-triol (OT) on azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in F344 rats and understand anti-inflammatory properties and apoptosis effects in HT29 colon cancer cells and Raw 264.7 macrophage cell lines.Methods. Five week-old male F344 rats were fed a control diet or experimental diets containing two doses of ONA (750 and 1,500 ppm) and OT (250 and 500 ppm). After 1 week, all animals were s.c. injected with AOM (15 mg/kg body weight, once weekly for 2 weeks). At 14 weeks of age, all rats were killed and colons were evaluated for ACF. Cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expressions and apoptosis were assessed in cell lines exposed to OT using western blots and 4',6-diamidino-2-phenylindole staining.Results. Administration of ONA and OT inhibited mean colonic ACF and multi-crypt AC/foci in a dose dependent manner (p < 0.001-0.0001). OT blocked the COX-2 expression induced by phorbol 12-myristate 13-acetate in a dose-dependent manner and induced apoptosis in HT-29 cancer cells, and suppressed iNOS activation in RAW264.7 macrophages.Conclusions. ONA and OT possess chemopreventive activity against colon carcinogenesis in rat and OT inhibits the COX-2 and iNOS and induces apoptosis in cell lines.
Chemotherapy-related cognitive impairment is increasingly recognized as a long-term consequence of cancer treatment, yet the contribution of the cerebrovascular system remains poorly defined. In this study, we investigated the long-term effects of clinically relevant treatment regimens with cyclophosphamide (CP) and vincristine (VIN) on cerebrovascular cellular senescence, associated molecular signatures, and downstream functional outcomes, including disruption of blood–brain barrier (BBB) integrity in a mouse model. Our results showed that CP induces a persistent cerebrovascular endothelial phenotype characterized by increased cellular senescence, upregulation of mRNA expression of DNA damage checkpoint regulators, and concomitant downregulation of key DNA repair genes. BBB integrity was preserved after CP treatment for larger molecular tracers (40 kDa and 3 kDa) but exhibited increased permeability to small tracers (0.3 kDa), measured by in vivo two-photon microscopy, indicating a subtle yet persistent disruption of barrier function. In contrast, VIN elicited a markedly attenuated and heterogeneous transcriptional response and did not produce detectable BBB impairment, underscoring agent-specific cerebrovascular effects of chemotherapy. Collectively, these findings suggest that chemotherapy induces a persistent cerebrovascular injury phenotype with features resembling vascular aging and reduced vascular resilience, providing a potential mechanistic link between systemic cancer therapy and long-term adverse effects on brain health.
