Accelerated Aging Induced by an Unhealthy High-Fat Diet: Initial Evidence for the Role of Nrf2 Deficiency and Impaired Stress Resilience in Cellular Senescence.

High-fat diets (HFDs) have pervaded modern dietary habits, characterized by their excessive saturated fat content and low nutritional value. Epidemiological studies have compellingly linked HFD consumption to obesity and the development of type 2 diabetes mellitus. Moreover, the synergistic interplay of HFD, obesity, and diabetes expedites the aging process and prematurely fosters age-related diseases. However, the underlying mechanisms driving these associations remain enigmatic. One of the most conspicuous hallmarks of aging is the accumulation of highly inflammatory senescent cells, with mounting evidence implicating increased cellular senescence in the pathogenesis of age-related diseases. Our hypothesis posits that HFD consumption amplifies senescence burden across multiple organs. To scrutinize this hypothesis, we subjected mice to a 6-month HFD regimen, assessing senescence biomarker expression in the liver, white adipose tissue, and the brain. Aging is intrinsically linked to impaired cellular stress resilience, driven by dysfunction in Nrf2-mediated cytoprotective pathways that safeguard cells against oxidative stress-induced senescence. To ascertain whether Nrf2-mediated pathways shield against senescence induction in response to HFD consumption, we explored senescence burden in a novel model of aging: Nrf2-deficient (Nrf2+/-) mice, emulating the aging phenotype. Our initial findings unveiled significant Nrf2 dysfunction in Nrf2+/- mice, mirroring aging-related alterations. HFD led to substantial obesity, hyperglycemia, and impaired insulin sensitivity in both Nrf2+/- and Nrf2+/+ mice. In control mice, HFD primarily heightened senescence burden in white adipose tissue, evidenced by increased Cdkn2a senescence biomarker expression. In Nrf2+/- mice, HFD elicited a significant surge in senescence burden across the liver, white adipose tissue, and the brain. We postulate that HFD-induced augmentation of senescence burden may be a pivotal contributor to accelerated organismal aging and the premature onset of age-related diseases.

Is the collateral circulation pattern in the hard palate affected by cleft deformity?

OBJECTIVES: To evaluate the influence of collateral vascularization on surgical cleft palate closure and deformities. MATERIALS AND METHODS: Corrosion casting was performed using red-colored acrylic resin in twelve fresh adult cadavers with a normal hard palate. Additionally, white-colored barium sulfate was injected into a fetus with a unilateral complete cleft palate, and layer-by-layer tissue dissection was performed. Both substances were injected into the external carotid arteries. Corrosion casting involved dissolving the soft and hard tissues of the orofacial area utilizing an enzymatic solution. RESULTS: In normal palates, bilateral intraosseous infraorbital arteries formed a network in the premaxilla with the intraosseous nasopalatine- and greater palatine arteries (GPAs). The perforating GPAs anastomosed with the sphenopalatine artery sub-branches. Bilateral extraosseous GPA anastomoses penetrated the median palatine suture. Complex vascularization in the retrotuberal area was detected. In the cleft zone, anastomoses were omitted, whereas in the non-cleft zone, enlarged GPAs were distributed along the cleft edges and followed the anatomical course anteriorly to initiate the network with facial artery sub-branches. CONCLUSIONS: The anatomical subunits of the palate exhibited distinct anastomosis patterns. Despite omitted anastomoses with collateral circulation in the cleft zone, arteries maintained their anatomical pattern as seen in the normal specimen in the non-cleft zone. CLINICAL RELEVANCE: Based on the findings in normal- and cleft palates, surgeons may expect developed anastomosis patterns in the non-cleft zone. Due to the lack of microcirculation in the cleft zone, the existent anastomoses should be maintained as much as possible by the surgical technique. This applies anteriorly in the incisive canal territory, alveolar ridges, and posteriorly in the retrotuberal area.

IGF1R deficiency in vascular smooth muscle cells impairs myogenic autoregulation and cognition in mice.

Introduction: Cerebrovascular pathologies contribute to cognitive decline during aging, leading to vascular cognitive impairment and dementia (VCID). Levels of circulating insulin-like growth factor 1 (IGF-1), a vasoprotective hormone, decrease during aging. Decreased circulating IGF-1 in animal models leads to the development of VCID-like symptoms, but the cellular mechanisms underlying IGF-1-deficiency associated pathologies in the aged cerebrovasculature remain poorly understood. Here, we test the hypothesis that vascular smooth muscle cells (VSMCs) play an integral part in mediating the vasoprotective effects of IGF-1. Methods: We used a hypertension-based model of cerebrovascular dysfunction in mice with VSMC-specific IGF-1 receptor (Igf1r) deficiency and evaluated the development of cerebrovascular pathologies and cognitive dysfunction. Results: VSMC-specific Igf1r deficiency led to impaired cerebral myogenic autoregulation, independent of blood pressure changes, which was also associated with impaired spatial learning and memory function as measured by radial arm water maze and impaired motor learning measured by rotarod. In contrast, VSMC-specific IGF-1 receptor knockdown did not lead to cerebral microvascular rarefaction. Discussion: These studies suggest that VSMCs are key targets for IGF-1 in the context of cerebrovascular health, playing a role in vessel stability alongside other cells in the neurovascular unit, and that VSMC dysfunction in aging likely contributes to VCID.

Relation between internal adaptation and degree of conversion of short-fiber reinforced resin composites applied in bulk or layered technique in deep MOD cavities.

OBJECTIVE: The purpose was to evaluate the degree of conversion (DC), internal adaptation (IA) and closed porosity (CP) of short-fiber reinforced resin composites (SFRC) associated with layered or bulk restorative procedures in deep MOD cavities. METHODS: Eighty third molars with standardized MOD cavities (5-mm-depth, 2.5-mm-width) were randomly divided into four groups and restored as follows: 1) bulk SFRC; 2) layered SFRC; 3) flowable bulk-fill resin-based composites (RBC); 4) layered conventional RBC. After one-month wet storage the samples were subjected to micro-computed tomography measurements and scanning electron microscopy to assess the IA and CP. Micro-Raman spectroscopy was used to determine the DC in different depths. Data were subjected to ANOVA and Tukey's post-hoc test, multivariate analysis and partial eta-squared statistics (p < 0.05). Pearson correlation coefficient was determined to assess the relationship among the parameters of interest. RESULTS: Gap/total interface volume ratio ranged between 0.22-0.47%. RBCs applied in bulk revealed significantly lower gap volume (p < 0.001) and CP (p < 0.05). Each group showed complete detachment on the pulpal and partial on the lateral walls, except for group3. While the highest DC% was achieved by the conventional RBC (87.2%), followed by the flowable bulk-fill (81.2%), SFRC provided the best bottom to top DC ratio (bulk: 96.4%, layered: 98.7%). The effect of factors studied (RBC type, filling technique) on IA and DC was significant (p < 0.001). SIGNIFICANCE: Bulk placement of RBCs exhibited lower interfacial gap volume and achieved satisfactory DC without significant correlation between these parameters. Incremental insertion of SFRC had no advantage over bulk placement in terms of IA and DC.

Splenectomy at early stage of autoimmune arthritis delayed inflammatory response and reduced joint deterioration in mice.

The spleen plays a role in innate and adaptive immunity, and autoimmune diseases like rheumatoid arthritis (RA). We investigated the effect of splenectomy in early and moderate stages of autoimmune arthritis in a mouse model. To induce recombinant human G1-induced arthritis (GIA), BALB/c mice were immunized intraperitoneally three times in 4-week intervals with the rhG1 antigen. Mice were splenectomized on day 7 (SPE1) or day 35 (SPE2) after the initiation of immunization; tested for clinical severity, joint radiological and histological changes, serum levels of inflammatory cytokines and autoantibodies, and rhG1-specific immune responses; and compared to those in control mice with spleen left intact. Circulating Tregs and T-helper subset ratios in the spleen and inguinal lymph nodes (LNs) were also examined using flow cytometry. The onset of severe inflammatory response was significantly delayed in SPE1 and SPE2 groups compared to control mice at early stages of GIA, which was associated with increased circulating Tregs. After the third immunization, as disease progressed, the severity scores were robustly increased in all mice. Nevertheless, in splenectomized mice, we observed reduced joint deterioration and cartilage damage, more Th2 cells in LNs, and reduced levels of pro-inflammatory cytokines and autoantibodies in their sera. Mesenteric LN cells of splenectomized mice exhibited weaker response in vitro against the rhG1 antigen compared to control mice spleen. In conclusion, splenectomy in the early stages of GIA delayed the inflammatory response, suggesting a protective effect against the development and progression of severe destructive arthritis.

Vascular smooth muscle cell-specific Igf1r deficiency exacerbates the development of hypertension-induced cerebral microhemorrhages and gait defects.

Cerebrovascular fragility and cerebral microhemorrhages (CMH) contribute to age-related cognitive impairment, mobility defects, and vascular cognitive impairment and dementia, impairing healthspan and reducing quality of life in the elderly. Insulin-like growth factor 1 (IGF-1) is a key vasoprotective growth factor that is reduced during aging. Circulating IGF-1 deficiency leads to the development of CMH and other signs of cerebrovascular dysfunction. Here our goal was to understand the contribution of IGF-1 signaling on vascular smooth muscle cells (VSMCs) to the development of CMH and associated gait defects. We used an inducible VSMC-specific promoter and an IGF-1 receptor (Igf1r) floxed mouse line (Myh11-CreERT2 Igf1rf/f) to knockdown Igf1r. Angiotensin II in combination with L-NAME-induced hypertension was used to elicit CMH. We observed that VSMC-specific Igf1r knockdown mice had accelerated development of CMH, and subsequent associated gait irregularities. These phenotypes were accompanied by upregulation of a cluster of pro-inflammatory genes associated with VSMC maladaptation. Collectively our findings support an essential role for VSMCs as a target for the vasoprotective effects of IGF-1, and suggest that VSMC dysfunction in aging may contribute to the development of CMH.

Irradiation-induced hair graying in mice: an experimental model to evaluate the effectiveness of interventions targeting oxidative stress, DNA damage prevention, and cellular senescence.

Hair graying, also known as canities or achromotrichia, is a natural phenomenon associated with aging and is influenced by external factors such as stress, environmental toxicants, and radiation exposure. Understanding the mechanisms underlying hair graying is an ideal approach for developing interventions to prevent or reverse age-related changes in regenerative tissues. Hair graying induced by ionizing radiation (γ-rays or X-rays) has emerged as a valuable experimental model to investigate the molecular pathways involved in this process. In this review, we examine the existing evidence on radiation-induced hair graying, with a particular focus on the potential role of radiation-induced cellular senescence. We explore the current understanding of hair graying in aging, delve into the underlying mechanisms, and highlight the unique advantages of using ionizing-irradiation-induced hair graying as a research model. By elucidating the molecular pathways involved, we aim to deepen our understanding of hair graying and potentially identify novel therapeutic targets to address this age-related phenotypic change.