Chemokine CX3CL1 (Fractalkine) Signaling and Diabetic Encephalopathy.

Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron-microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle.

CX3CL1 (Fractalkine)-CX3CR1 Axis in Inflammation-Induced Angiogenesis and Tumorigenesis.

The chemotactic cytokine fractalkine (FKN, chemokine CX3CL1) has unique properties resulting from the combination of chemoattractants and adhesion molecules. The soluble form (sFKN) has chemotactic properties and strongly attracts T cells and monocytes. The membrane-bound form (mFKN) facilitates diapedesis and is responsible for cell-to-cell adhesion, especially by promoting the strong adhesion of leukocytes (monocytes) to activated endothelial cells with the subsequent formation of an extracellular matrix and angiogenesis. FKN signaling occurs via CX3CR1, which is the only known member of the CX3C chemokine receptor subfamily. Signaling within the FKN-CX3CR1 axis plays an important role in many processes related to inflammation and the immune response, which often occur simultaneously and overlap. FKN is strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokine release, and it may act locally as a key angiogenic factor in the highly hypoxic tumor microenvironment. The importance of the FKN/CX3CR1 signaling pathway in tumorigenesis and cancer metastasis results from its influence on cell adhesion, apoptosis, and cell migration. This review presents the role of the FKN signaling pathway in the context of angiogenesis in inflammation and cancer. The mechanisms determining the pro- or anti-tumor effects are presented, which are the cause of the seemingly contradictory results that create confusion regarding the therapeutic goals.

The failure of biological treatment in axial spondyloarthritis is linked to the factors related to increased intestinal permeability and dysbiosis: prospective observational cohort study.

BACKGROUND: A significant number of patients with axial spondyloarthritis (axSpA) do not respond to biological therapy. Therefore, we decided to investigate the specificity of this group of patients and, in particular, whether haptoglobin (Hp), its polymorphism and zonulin, in addition to other clinical features, are predictors of poor response to biological treatment. METHODS: 48 patients with axSpA who were unsuccessfully treated with standard drugs were converted to biological treatment, and from this time on, a 12-week follow-up was started to assess the failure of biological treatment (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decrease < 2 points). Predictors of treatment failure were identified using logistic regression analysis. RESULTS: 21% of subjects had biological treatment failure. Patients who had a higher zonulin level, a history of frequent infections, were older, had inflammatory bowel disease (IBD), had a lower Hp level at the time of inclusion in biological therapy showed an increased risk of treatment failure. CONCLUSIONS: The results of the study support the hypothesis that the effectiveness of biological treatment of axSpA is limited by changed microbiota and intestinal epithelial barrier dysfunction, as an increased risk of biological treatment failure was observed in patients who were older, had higher zonulin level, IBD and repeated courses of antibiotics due to frequent infections. Therefore, starting biological treatment should be followed by reducing intestinal permeability and regulating the disturbed gut microbiome.

Reproductive Immunology and Pregnancy 2.0.

This Special Issue comprises original articles in the field of clinical studies whose major topics concern the genetic and immunological aspects of miscarriage and pre-eclampsia, the isolation of decidua macrophages and Hofbauer cells in the placenta for diagnostic purposes, and epigenetic mechanisms that trigger labor [...].

Expression of Placental Lipid Transporters in Pregnancies Complicated by Gestational and Type 1 Diabetes Mellitus.

The objective of the study was to assess the expression of proteins responsible for placental lipid transport in term pregnancies complicated by well-controlled gestational (GDM) and type 1 diabetes mellitus (PGDM). A total of 80 placental samples were obtained from patients diagnosed with PGDM (n = 20), GDM treated with diet (GDMG1, n = 20), GDM treated with diet and insulin (GDMG2, n = 20), and a non-diabetic control group (n = 20). Umbilical and uterine artery blood flows were assessed by means of ultrasound in the period prior to delivery and computer-assisted quantitative morphometry of immunostained placental sections was performed to determine the expression of selected proteins. The morphometric analysis performed for the vascular density-matched placental samples demonstrated a significant increase in the expression of fatty acid translocase (CD36), fatty acid binding proteins (FABP1, FABP4 and FABP5), as well as a decrease in the expression of endothelial lipase (EL) and fatty acid transport protein (FATP4) in the PGDM-complicated pregnancies as compared to the GDMG1 and control groups (p < 0.05). No significant differences with regard to the placental expression of lipoprotein lipase (LPL) and FATP6 protein between GDM/PGDM and non-diabetic patients were noted. Maternal pre-pregnancy weight, body mass index, placental weight as well as the expression of LPL and FABP4 were selected by the linear regression model as the strongest contributors to the fetal birth weight. To conclude, in placentas derived from pregnancies complicated by well-controlled PGDM, the expression of several lipid transporters, including EL, CD36, FATP4, FABP1, FABP4 and FABP5, is altered. Nonetheless, only LPL and FABP4 were significant predictors of the fetal birth weight.

Anti-Inflammatory Action of Resveratrol in the Central Nervous System in Relation to Glucose Concentration-An In Vitro Study on a Blood-Brain Barrier Model.

Unbalanced blood glucose levels may cause inflammation within the central nervous system (CNS). This effect can be reversed by the action of a natural neuroprotective compound, resveratrol (RSV). The study aimed to investigate the anti-inflammatory effect of RSV on astrocyte cytokine profiles within an in vitro model of the blood-brain barrier (BBB) under varying glucose concentrations (2.2, 5.0, and 25.0 mmol/L), corresponding to hypo-, normo-, and hyperglycemia. The model included co-cultures of astrocytes (brain compartment, BC) and endothelial cells (microvascular compartment, MC), separated by 0.4 µm wide pores. Subsequent exposure to 0.2 µM LPS in the brain compartment (BC) and 50 µM RSV in the microvascular compartment (MC) of each well was carried out. Cytokine levels (IL-1 α, IL-1 ß, IL-2, IL-4, IL-6, IL-8) in the BC were assessed using a Multi-Analyte ELISArray Kit before and after the addition of LPS and RSV. Statistical analysis was performed to determine significance levels. The results demonstrated that RSV reduced the concentration of all studied cytokines in the BC, regardless of glucose levels, with the most substantial decrease observed under normoglycemic conditions. Additionally, the concentration of RSV in the BC was highest under normoglycemic conditions compared to hypo- and hyperglycemia. These findings confirm that administration of RSV in the MC exerts anti-inflammatory effects within the BC, particularly under normoglycemia-simulating conditions. Further in vivo studies, including animal and human research, are warranted to elucidate the bioavailability of RSV within the central nervous system (CNS).

Current Insights in Prolactin Signaling and Ovulatory Function.

Prolactin (PRL) is a pleiotropic hormone released from lactotrophic cells of the anterior pituitary gland that also originates from extrapituitary sources and plays an important role in regulating lactation in mammals, as well as other actions. Acting in an endocrine and paracrine/autocrine manner, PRL regulates the hypothalamic-pituitary-ovarian axis, thus influencing the maturation of ovarian follicles and ovulation. This review provides a detailed discussion of the current knowledge on the role of PRL in the context of ovulation and ovulatory disorders, particularly with regard to hyperprolactinemia, which is one of the most common causes of infertility in women. Much attention has been given to the PRL structure and the PRL receptor (PRLR), as well as the diverse functions of PRLR signaling under normal and pathological conditions. The hormonal regulation of the menstrual cycle in connection with folliculogenesis and ovulation, as well as the current classifications of ovulation disorders, are also described. Finally, the state of knowledge regarding the importance of TIDA (tuberoinfundibular dopamine), KNDγ (kisspeptin/neurokinin B/dynorphin), and GnRH (gonadotropin-releasing hormone) neurons in PRL- and kisspeptin (KP)-dependent regulation of the hypothalamic-pituitary-gonadal (HPG) axis in women is reviewed. Based on this review, a rationale for influencing PRL signaling pathways in therapeutic activities accompanying ovulation disorders is presented.

The Role of Rosavin in the Pathophysiology of Bone Metabolism.

Rosavin, a phenylpropanoid in Rhodiola rosea's rhizome, and an adaptogen, is known for enhancing the body's response to environmental stress. It significantly affects cellular metabolism in health and many diseases, particularly influencing bone tissue metabolism. In vitro, rosavin inhibits osteoclastogenesis, disrupts F-actin ring formation, and reduces the expression of osteoclastogenesis-related genes such as cathepsin K, calcitonin receptor (CTR), tumor necrosis factor receptor-associated factor 6 (TRAF6), tartrate-resistant acid phosphatase (TRAP), and matrix metallopeptidase 9 (MMP-9). It also impedes the nuclear factor of activated T-cell cytoplasmic 1 (NFATc1), c-Fos, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways and blocks phosphorylation processes crucial for bone resorption. Moreover, rosavin promotes osteogenesis and osteoblast differentiation and increases mouse runt-related transcription factor 2 (Runx2) and osteocalcin (OCN) expression. In vivo studies show its effectiveness in enhancing bone mineral density (BMD) in postmenopausal osteoporosis (PMOP) mice, restraining osteoclast maturation, and increasing the active osteoblast percentage in bone tissue. It modulates mRNA expressions by increasing eukaryotic translation elongation factor 2 (EEF2) and decreasing histone deacetylase 1 (HDAC1), thereby activating osteoprotective epigenetic mechanisms, and alters many serum markers, including decreasing cross-linked C-telopeptide of type I collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRACP5b), receptor activator for nuclear factor κ B ligand (RANKL), macrophage-colony-stimulating factor (M-CSF), and TRAP, while increasing alkaline phosphatase (ALP) and OCN. Additionally, when combined with zinc and probiotics, it reduces pro-osteoporotic matrix metallopeptidase 3 (MMP-3), interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α), and enhances anti-osteoporotic interleukin 10 (IL-10) and tissue inhibitor of metalloproteinase 3 (TIMP3) expressions. This paper aims to systematically review rosavin's impact on bone tissue metabolism, exploring its potential in osteoporosis prevention and treatment, and suggesting future research directions.

Predictors of treatment failure of non-steroidal anti-inflammatory drugs in patients with axial spondyloarthritis with focus on haptoglobin, haptoglobin polymorphism and zonulin.

According to the Assessment of SpondyloArthritis International Society-European Alliance of Associations for Rheumatology (ASAS-EULAR) recommendations for the management of axial spondyloarthritis (axSpA), patients should undergo at least two courses of non-steroidal anti-inflammatory drugs (NSAIDs) therapy. In our study, we enrolled axSpA patients both at onset and in a flare who had already been treated with NSAIDs ineffectively. Subsequently, according to the recommendations, they received modified NSAID treatment as another attempt to the first-line drug therapy and were monitored from there. We aimed to identify risk factors for treatment failure after 4 weeks (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4) especially amongst zonulin and haptoglobin concentrations, and haptoglobin polymorphism. Treatment failure was observed in 71% of patients, and the following variables were contributed for occurrence of this state: higher zonulin levels, ankylosing spondylitis, X-ray sacroiliitis, magnetic resonance imaging sacroiliitis, long duration of symptoms, high BASDAI, and high value of spinal pain intensity on visual analogue scale. In addition, the following positive correlations were found: haptoglobin concentration with C-reactive protein (r = 0.56; p = 0.0004), and erythrocyte sedimentation rate (r = 0.62; p < 0.0001), as well as between zonulin levels and white blood count (r = 0.5; p = 0.0003). The results of the study presented the identified factors related to the standard treatment failure in axSpA, amongst them zonulin levels. They might be applied to point out the patients for whom the search for a more appropriate method of treatment should be considered.

Reproductive Immunology and Pregnancy 3.0.

This Special Issue, the third dedicated to reproductive immunology and pregnancy, is another review of the latest trends in research topics in this field [...].

The Role of Sirtuin-1 (SIRT1) in the Physiology and Pathophysiology of the Human Placenta.

Sirtuins, especially SIRT1, play a significant role in regulating inflammatory response, autophagy, and cell response to oxidative stress. Since their discovery, sirtuins have been regarded as anti-ageing and longevity-promoting enzymes. Sirtuin-regulated processes seem to participate in the most prevalent placental pathologies, such as pre-eclampsia. Furthermore, more and more research studies indicate that SIRT1 may prevent pre-eclampsia development or at least alleviate its manifestations. Having considered this, we reviewed recent studies on the role of sirtuins, especially SIRT1, in processes determining normal or abnormal development and functioning of the placenta.

The Role of Glucose Concentration and Resveratrol in Modulating Neuroinflammatory Cytokines: Insights from an In Vitro Blood-Brain Barrier Model.

BACKGROUND The prevalence of type 2 diabetes mellitus is rising, presumably because of a coexisting pandemic of obesity. Since diabetic neuropathy and neuroinflammation are frequent and significant complications of both prolonged hyperglycemia and iatrogenic hypoglycemia, the effect of glucose concentration and resveratrol (RSV) supplementation on cytokine profile was assessed in an in vitro model of the blood-brain barrier (BBB). MATERIAL AND METHODS The in vitro model of BBB was formed of endothelial cells and astrocytes, which represented the microvascular and brain compartments (MC and BC, respectively). The BC concentrations of selected cytokines - IL-10, IL-12, IL-17A, TNF-alpha, IFN-γ, GM-CSF in response to different glucose concentrations in the MC were studied. The influence of LPS in the BC and RSV in the MC on the cytokine profile in the BC was examined. RESULTS Low glucose concentration (40 mg/dL) in the MC resulted in increased concentration of all the cytokines in the BC except TNF-alpha, compared to normoglycemia-imitating conditions (90 mg/dL) (P<0.05). High glucose concentration (450 mg/dL) in the MC elevated the concentration of all the cytokines in the BC (P<0.05). RSV decreased the level of all cytokines in the BC after 24 h following its administration for all glucose concentrations in the MC (P<0.02). The greatest decline was observed in normoglycemic conditions (P<0.05). CONCLUSIONS Both hypo- and hyperglycemia-simulating conditions impair the cytokine profile in BC, while RSV can normalize it, despite relatively poor penetration through the BBB. RSV exhibits anti-neuroinflammatory effects, especially in the group with normoglycemia-simulating conditions.

Insight into the Potential Mechanisms of Endocrine Disruption by Dietary Phytoestrogens in the Context of the Etiopathogenesis of Endometriosis.

Phytoestrogens (PEs) are estrogen-like nonsteroidal compounds derived from plants (e.g., nuts, seeds, fruits, and vegetables) and fungi that are structurally similar to 17ß-estradiol. PEs bind to all types of estrogen receptors, including ERα and ERß receptors, nuclear receptors, and a membrane-bound estrogen receptor known as the G protein-coupled estrogen receptor (GPER). As endocrine-disrupting chemicals (EDCs) with pro- or antiestrogenic properties, PEs can potentially disrupt the hormonal regulation of homeostasis, resulting in developmental and reproductive abnormalities. However, a lack of PEs in the diet does not result in the development of deficiency symptoms. To properly assess the benefits and risks associated with the use of a PE-rich diet, it is necessary to distinguish between endocrine disruption (endocrine-mediated adverse effects) and nonspecific effects on the endocrine system. Endometriosis is an estrogen-dependent disease of unknown etiopathogenesis, in which tissue similar to the lining of the uterus (the endometrium) grows outside of the uterus with subsequent complications being manifested as a result of local inflammatory reactions. Endometriosis affects 10-15% of women of reproductive age and is associated with chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility. In this review, the endocrine-disruptive actions of PEs are reviewed in the context of endometriosis to determine whether a PE-rich diet has a positive or negative effect on the risk and course of endometriosis.

Interplay between Systemic Glycemia and Neuroprotective Activity of Resveratrol in Modulating Astrocyte SIRT1 Response to Neuroinflammation.

The flow of substances between the blood and the central nervous system is precisely regulated by the blood-brain barrier (BBB). Its disruption due to unbalanced blood glucose levels (hyper- and hypoglycemia) occurring in metabolic disorders, such as type 2 diabetes, can lead to neuroinflammation, and increase the risk of developing neurodegenerative diseases. One of the most studied natural anti-diabetic, anti-inflammatory, and neuroprotective compounds is resveratrol (RSV). It activates sirtuin 1 (SIRT1), a key metabolism regulator dependent on cell energy status. The aim of this study was to assess the astrocyte SIRT1 response to neuroinflammation and subsequent RSV treatment, depending on systemic glycemia. For this purpose, we used an optimized in vitro model of the BBB consisting of endothelial cells and astrocytes, representing microvascular and brain compartments (MC and BC), in different glycemic backgrounds. Astrocyte-secreted SIRT1 reached the highest concentration in hypo-, the lowest in normo-, and the lowest in hyperglycemic backgrounds. Lipopolysaccharide (LPS)-induced neuroinflammation caused a substantial decrease in SIRT1 in all glycemic backgrounds, as observed earliest in hyperglycemia. RSV partially counterbalanced the effect of LPS on SIRT1 secretion, most remarkably in normoglycemia. Our results suggest that abnormal glycemic states have a worse prognosis for RSV-therapy effectiveness compared to normoglycemia.

Molecular Mechanisms for the Vicious Cycle between Insulin Resistance and the Inflammatory Response in Obesity.

The comprehensive anabolic effects of insulin throughout the body, in addition to the control of glycemia, include ensuring lipid homeostasis and anti-inflammatory modulation, especially in adipose tissue (AT). The prevalence of obesity, defined as a body mass index (BMI) ≥ 30 kg/m2, has been increasing worldwide on a pandemic scale with accompanying syndemic health problems, including glucose intolerance, insulin resistance (IR), and diabetes. Impaired tissue sensitivity to insulin or IR paradoxically leads to diseases with an inflammatory component despite hyperinsulinemia. Therefore, an excess of visceral AT in obesity initiates chronic low-grade inflammatory conditions that interfere with insulin signaling via insulin receptors (INSRs). Moreover, in response to IR, hyperglycemia itself stimulates a primarily defensive inflammatory response associated with the subsequent release of numerous inflammatory cytokines and a real threat of organ function deterioration. In this review, all components of this vicious cycle are characterized with particular emphasis on the interplay between insulin signaling and both the innate and adaptive immune responses related to obesity. Increased visceral AT accumulation in obesity should be considered the main environmental factor responsible for the disruption in the epigenetic regulatory mechanisms in the immune system, resulting in autoimmunity and inflammation.

Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood-Brain Barrier and the Risk of Dementia.

Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood-brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aß aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

Aberrant epigenetic regulation of estrogen and progesterone signaling at the level of endometrial/endometriotic tissue in the pathomechanism of endometriosis.

Endometriosis is a term referring to a condition whereby the endometrial tissue is found outside the uterine cavity. This progressive and debilitating condition affects up to 15% of women of reproductive age. Due to the fact that endometriosis cells may express estrogen receptors (ERα, Erß, GPER) and progesterone (P4) receptors (PR-A, PR-B), their growth, cyclic proliferation, and breakdown are similar to the processes occurring in the endometrium. The underlying etiology and pathogenesis of endometriosis are still not fully explained. The retrograde transport of viable menstrual endometrial cells with the retained ability to attach within the pelvic cavity, proliferate, differentiate and invade into the surrounding tissue explains the most widely accepted implantation theory. Endometrial stromal cells (EnSCs) with clonogenic potential constitute the most abundant population of cells within endometrium that resemble the properties of mesenchymal stem cells (MSCs). Accordingly, formation of the endometriotic foci in endometriosis may be due to a kind of EnSCs dysfunction. Increasing evidence indicates the underestimated role of epigenetic mechanisms in the pathogenesis of endometriosis. Hormone-mediated epigenetic modifications of the genome in EnSCs or even MSCs were attributed an important role in the etiopathogenesis of endometriosis. The roles of excess estrogen exposure and P4 resistance were also found to be crucial in the development of epigenetic homeostasis failure. Therefore, the aim of this review was to consolidate the current knowledge regarding the epigenetic background of EnSCs and MSCs and the changed properties due to estrogen/P4 imbalances in the context of the etiopathogenesis of endometriosis.

Modulation of the Inflammatory Response in Polycystic Ovary Syndrome (PCOS)-Searching for Epigenetic Factors.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite its incidence, the syndrome is poorly understood and remains underdiagnosed, and female patients are diagnosed with a delay. The heterogenous nature of this complex disorder results from the combined occurrence of genetic, environmental, endocrine, and behavioral factors. Primary clinical manifestations of PCOS are derived from the excess of androgens (anovulation, polycystic ovary morphology, lack of or scanty, irregular menstrual periods, acne and hirsutism), whereas the secondary manifestations include multiple metabolic, cardiovascular, and psychological disorders. Dietary and lifestyle factors play important roles in the development and course of PCOS, which suggests strong epigenetic and environmental influences. Many studies have shown a strong association between PCOS and chronic, low-grade inflammation both in the ovarian tissue and throughout the body. In the vast majority of PCOS patients, elevated values of inflammatory markers or their gene markers have been reported. Development of the vicious cycle of the chronic inflammatory state in PCOS is additionally stimulated by hyperinsulinemia and obesity. Changes in DNA methylation, histone acetylation and noncoding RNA levels are presented in this review in the context of oxidative stress, reactive oxygen species, and inflammatory signaling in PCOS. Epigenetic modulation of androgenic activity in response to inflammatory signaling is also discussed.

Sirtuins promote brain homeostasis, preventing Alzheimer's disease through targeting neuroinflammation.

Both basic pathomechanisms underlying Alzheimer's disease and some premises for stipulating a possible preventive role of some sirtuins, especially SIRT1 and SIRT3, protective against Alzheimer's disease-related pathology, are discussed in this article. Sirtuins can inhibit some processes that underlie Alzheimer's disease-related molecular pathology (e.g., neuroinflammation, neuroinflammation-related oxidative stress, Aß aggregate deposition, and neurofibrillary tangle formation), thus preventing many of those pathologic alterations at relatively early stages of their development. Subsequently, the authors discuss in details which mechanisms of sirtuin action may prevent the development of Alzheimer's disease, thus promoting brain homeostasis in the course of aging. In addition, a rationale for boosting sirtuin activity, both with allosteric activators and with NAD+ precursors, has been presented.