BACKGROUND:Alzheimer's Disease and Related Dementia (ADRD) affects 10.9% of people above 65 years old in the US. Disease modifying and symptomatic therapies for ADRD have marginal clinical value; thus finding effective treatments is paramount. Inflammation and proteotoxicity are two hallmarks of aging implicated in the pathophysiology of ADRD. We previously screened 2700 FDA approved drugs in two models of ADRD (C. elegans and microglia) for their ability to reduce inflammation and proteotoxicity and identified phenothiazines among the most protective class of drugs. This study aimed to use a pharmacoepidemiological approach with Medicare claims data to assess if phenothiazines could be repurposed in humans to treat ADRD. METHODS:To test our hypothesis that phenothiazines were protective for ADRD, we examined 1 year of cross-sectional Medicare fee-for-service claims data of 1 million Medicare beneficiaries >65 years. We performed multivariable analysis adjusted for demographics and ADRD risk factors to evaluate the association between ADRD prevalence and phenothiazine exposure. Our principal outcome was ADRD as defined by a modified Bynum algorithm (unavailable Amyloid documentation in our dataset). RESULTS:33,600 (3.5%) beneficiaries (70.0% women) were exposed to the drugs of interest. The mean age of exposed beneficiaries was 74 years (SD 6.6) versus 75 years (SD 7.3) for unexposed beneficiaries. The multivariable analysis revealed a significantly lower ADRD prevalence in phenothiazines exposed (≥1phenothiazine) vs unexposed beneficiaries (Incident Rate Ratio 0.9; 95%CI 0.9-0.97). Some protective phenothiazines in our dataset included amitriptyline (IRR 0.8; 95%CI 0.8-0.9) and prochlorperazine (IRR 0.8; 95%CI 0.7-0.8). CONCLUSIONS:By leveraging real-world data with Medicare fee-for-service claims, phenothiazine exposure was associated with a lower risk of ADRD in US individuals >65 years, suggesting a potential benefit of phenothiazines in reducing the risk of ADRD. This study is strengthened by real world data including selection of a target population and studying the interaction of age and ADRD in a short timespan. A limitation of our study is the lack of information on amyloid documentation inherent with the nature of administrative claims data from CMS. Further studies are warranted to determine whether the observed association between phenothiazine exposure and protection against ADRD in humans is confirmed longitudinally.

Despite increasing knowledge of the etiology of neurodegenerative diseases, translation of these benefits into therapeutic advances for Alzheimer’s Disease and related diseases (ADRD) has been slow. Drug repurposing is a promising strategy for identifying new uses for approved drugs beyond their initial indications. We developed a high-throughput drug screening platform aimed at identifying drugs capable of reducing proteotoxicity in vivo (Aß toxicity in Caenorhabditis elegans ) AND inhibiting microglial inflammation (TNF-alpha IL-6), both implicated in driving AD(figure attached with sample of results in C. elegans ). These screens led us to prioritize 50 potentially protective FDA-approved drugs. We propose to test our screening results in humans using administrative claims data collected from the Centers for Medicare and Medicaid Services This is an observational retrospective pharmaco-epidemiological longitudinal cohort study. The cohort is a random sample of 1,000,000 beneficiaries, aged 65-75 years, followed for 10 consecutive years, requested from CMS. Files include MedPar, Outpatient, Carrier, Hospice to maximize inclusion of AD beneficiaries according to Bynum algorithm, and Part D event for drug prescription details. We will use Cox regression, to compute Hazard Ratios and associated 95% confidence intervals, of the association between drug exposure status and the risk of ADRD. We will examine potential confounding by indication, drug target, and competing risks. 1/We propose to assess if drugs which reduce Ab toxicity in a C. elegans model of AD AND reduce microglial inflammation reduce the risk of developing ADRD in humans, using Medicare claims. 2/We propose to assess if drugs which reduce inflammation, reduce the risk of developing ADRD in humans, using the Medicare claims. The end goal of the study is to identify drugs to be repurposed to treat ADRD and to accumulate strong epidemiological evidence in addition to the existing evidence from the model organism C. elegans and cell culture studies.

Alzheimer's Disease and Related Dementia (ADRD) affects 10.9% of people above 65 years old in the US. Disease modifying and symptomatic therapies for ADRD have marginal clinical value; thus finding effective treatments is paramount. Inflammation and proteotoxicity are two hallmarks of aging implicated in the pathophysiology of ADRD. We previously screened 2700 FDA approved drugs in two models of ADRD (C. elegans and microglia) for their ability to reduce inflammation and proteotoxicity and identified phenothiazines among the most protective class of drugs. This study aimed to use a pharmacoepidemiological approach with Medicare claims data to assess if phenothiazines could be repurposed in humans to treat ADRD. To test our hypothesis that phenothiazines were protective for ADRD, we examined 1 year of cross-sectional Medicare fee-for-service claims data of 1 million Medicare beneficiaries >65 years. We performed multivariable analysis adjusted for demographics and ADRD risk factors to evaluate the association between ADRD prevalence and phenothiazine exposure. Our principal outcome was ADRD as defined by a modified Bynum algorithm (unavailable Amyloid documentation in our dataset). 33,600 (3.5%) beneficiaries (70.0% women) were exposed to the drugs of interest. The mean age of exposed beneficiaries was 74 years (SD 6.6) versus 75 years (SD 7.3) for unexposed beneficiaries. The multivariable analysis revealed a significantly lower ADRD prevalence in phenothiazines exposed (≥1phenothiazine) vs unexposed beneficiaries (Incident Rate Ratio 0.9; 95%CI 0.9-0.97). Some protective phenothiazines in our dataset included amitriptyline (IRR 0.8; 95%CI 0.8-0.9) and prochlorperazine (IRR 0.8; 95%CI 0.7-0.8). By leveraging real-world data with Medicare fee-for-service claims, phenothiazine exposure was associated with a lower risk of ADRD in US individuals >65 years, suggesting a potential benefit of phenothiazines in reducing the risk of ADRD. This study is strengthened by real world data including selection of a target population and studying the interaction of age and ADRD in a short timespan. A limitation of our study is the lack of information on amyloid documentation inherent with the nature of administrative claims data from CMS. Further studies are warranted to determine whether the observed association between phenothiazine exposure and protection against ADRD in humans is confirmed longitudinally

Chronological age is not an accurate predictor of morbidity and mortality risk, as individuals’ aging processes are diverse. Phenotypic age acceleration (PhenoAgeAccel) is a validated biological age measure incorporating chronological age and biomarkers from blood samples commonly used in clinical practice that can better reflect aging-related morbidity and mortality risk. The heterogeneity of age-related decline is not random, as environmental exposures can promote or impede healthy aging. Social Vulnerability Index (SVI) is a composite index accounting for different facets of the social, economic, and demographic environment grouped into four themes: socioeconomic status, household composition and disability, minority status and language, and housing and transportation. We aim to assess the concurrent and combined associations of the four SVI themes on PhenoAgeAccel and the differential effects on disadvantaged groups. We use electronic health records data from 31,913 patients from the Mount Sinai Health System (116,952 person-years) and calculate PhenoAge for years with available laboratory results (2011–2022). PhenoAge is calculated as a weighted linear combination of lab results, and PhenoAgeAccel is the differential between PhenoAge and chronological age. A decile increase in the mixture of SVI dimensions was associated with an increase of 0.23 years (95

Inflammation drives many age-related, especially neurological, diseases, and likely mediates age-related proteotoxicity. For example, dementia due to Alzheimer's Disease (AD), cerebral vascular disease, many other neurodegenerative conditions is increasingly among the most devastating burdens on the American (and world) health system and threatens to bankrupt the American health system as the population ages unless effective treatments are developed. Dementia due to either AD or cerebral vascular disease, and plausibly many other neurodegenerative and even psychiatric conditions, is driven by increased age-related inflammation, which in turn appears to mediate Abeta and related proteotoxic processes. The functional significance of inflammation during aging is also supported by the fact that Humira, which is simply an antibody to the pro-inflammatory cytokine TNF-a, is the best-selling drug in the world by revenue. These observations led us to develop parallel high-throughput screens to discover small molecules which inhibit age-related Abeta proteotoxicity in a C. elegans model of AD AND LPS-induced microglial TNF-a. In the initial screen of 2560 compounds (Microsource Spectrum library) to delay Abeta proteotoxicity, the most protective compounds were, in order, phenylbutyrate, methicillin, and quetiapine, which belong to drug classes (HDAC inhibitors, beta lactam antibiotics, and tricyclic antipsychotics, respectably) already robustly implicated as promising to protect in neurodegenerative diseases, especially AD. RNAi and chemical screens indicated that the protective effects of HDAC inhibitors to reduce Abeta proteotoxicity are mediated by inhibition of HDAC2, also implicated in human AD, dependent on the HAT Creb binding protein (Cbp), which is also required for the protective effects of both dietary restriction and the daf-2 mutation (inactivation of IGF-1 signaling) during aging. In addition to methicillin, several other beta lactam antibiotics also delayed Abeta proteotoxicity and reduced microglial TNF-a. In addition to quetiapine, several other tricyclic antipsychotic drugs also delayed age-related Abeta proteotoxicity and increased microglial TNF-a, leading to the synthesis of a novel congener, GM310, which delays Abeta as well as Huntingtin proteotoxicity, inhibits LPS-induced mouse and human microglial and monocyte TNF-a, is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction, including induction of Cbp inhibition of inhibitors of Cbp, and genes promoting a shift away from glycolysis and toward metabolism of alternate (e.g., lipid) substrates. GM310, as well as FDA-approved tricyclic congeners, prevented functional impairments and associated increase in TNF-a in a mouse model of stroke. Robust reduction of glycolysis by GM310 was functionally corroborated by flux analysis, and the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. These results support the value of phenotypic screens to discover drugs to treat age-related, especially neurological and even psychiatric diseases, including AD and stroke, and to clarify novel mechanisms driving neurodegeneration (e.g., increased microglial glycolysis drives neuroinflammation and subsequent neurotoxicity) suggesting novel treatments (selective inhibitors of microglial glycolysis).

This study aimed to characterize the effects of laparotomy on postoperative physical function and skeletal muscle gene expression in male C57BL/6N mice at 3, 20, and 24 months of age to investigate late-life vulnerability and resiliency to acute surgical stress. Pre and postoperative physical functioning was assessed by forelimb grip strength on postoperative day (POD) 1 and 3 and motor coordination on POD 2 and 4. Laparotomy-induced an age-associated postoperative decline in forelimb grip strength that was the greatest in the oldest mice. While motor coordination declined with increasing age at baseline, it was unaffected by laparotomy. Baseline physical function as stratified by motor coordination performance (low functioning vs high functioning) in 24-month-old mice did not differentially affect postlaparotomy reduction in grip strength. RNA sequencing of soleus muscles showed that laparotomy-induced age-associated differential gene expression and canonical pathway activation with the greatest effects in the youngest mice. Examples of such age-associated, metabolically important pathways that were only activated in the youngest mice after laparotomy included oxidative phosphorylation and NRF2-mediated oxidative stress response. Analysis of lipid mediators in serum and gastrocnemius muscle showed alterations in profiles during aging and confirmed an association between such changes and functional status in gastrocnemius muscle. These findings demonstrate a mouse model of laparotomy which recapitulated some features of postoperative skeletal muscle decline in older adults, and identified age-associated, laparotomy-induced molecular signatures in skeletal muscles. Future research can build upon this model to study molecular mechanisms of late-life vulnerability and resiliency to acute surgical stress.

Since the development of antibiotics and vaccination, as well as major improvements in public hygiene, the main risk factors for morbidity and mortality are age and chronic exposure to environmental factors, both of which can interact with genetic predispositions. As the average age of the population increases, the prevalence and costs of chronic diseases, especially neurological conditions, are rapidly increasing. The deleterious effects of age and environmental risk factors, develop chronically over relatively long periods of time, in contrast to the relatively rapid deleterious effects of infectious diseases or accidents. Of particular interest is the hypothesis that the deleterious effects of environmental factors may be mediated by acceleration of biological age. This hypothesis is supported by evidence that dietary restriction, which universally delays age-related diseases, also ameliorates deleterious effects of environmental factors. Conversely, both age and environmental risk factors are associated with the accumulation of somatic mutations in mitotic cells and epigenetic modifications that are a measure of "biological age", a better predictor of age-related morbidity and mortality than chronological age. Here we review evidence that environmental risk factors such as smoking and air pollution may also drive neurological conditions, including Alzheimer's Disease, by the acceleration of biological age, mediated by cumulative and persistent epigenetic effects as well as somatic mutations. Elucidation of such mechanisms could plausibly allow the development of interventions which delay deleterious effects of both aging and environmental risk factors.

Discovery of interventions that delay or minimize age-related diseases is arguably the major goal of aging research. Conversely discovery of interventions based on phenotypic screens have often led to further elucidation of pathophysiological mechanisms. Although most hypotheses to explain lifespan focus on cell-autonomous processes, increasing evidence suggests that in multicellular organisms, neurons, particularly nutrient-sensing neurons, play a determinative role in lifespan and age-related diseases. For example, protective effects of dietary restriction and inactivation of insulin-like signaling increase lifespan and delay age-related diseases dependent on Creb-binding protein in GABA neurons, and Nrf2/Skn1 in just 2 nutrient-sensing neurons in C. elegans. Screens for drugs that increase lifespan also indicate that such drugs are predominantly active through neuronal signaling. Our own screens also indicate that neuroactive drugs also delay pathology in an animal model of Alzheimer's Disease, as well as inhibit cytokine production implicated in driving many age-related diseases. The most likely mechanism by which nutrient-sensing neurons influence lifespan and the onset of age-related diseases is by regulating metabolic architecture, particularly the relative rate of glycolysis vs. alternative metabolic pathways such as ketone and lipid metabolism. These results suggest that neuroactive compounds are a most promising class of drugs to delay or minimize age-related diseases.

Food produces powerful reinforcement that can lead to overconsumption and likely contributes to the obesity epidemic. The present studies examined molecular mechanisms mediating food-induced reinforcement in the model system C. elegans. After a 1-h training session during which food (bacteria) is paired with the odorant butanone, odor preference for butanone robustly increased. Glucose mimicked this effect of bacteria. Glucose-induced odor preference was enhanced similarly by prior food withdrawal or blocking glucose metabolism in the presence of food. Food- and glucose-induced odor preference was mimicked by serotonin signaling through the serotonin type-4 (5-HT4) receptor. Dopamine (thought to act primarily through a D1-like receptor) facilitated, whereas the D2 agonist bromocriptine blocked, food- and glucose-induced odor preference. Furthermore, prior food withdrawal similarly influenced reward produced by serotonin, dopamine, or food, implying post-synaptic enhancement of sensitivity to serotonin and dopamine. These results suggest that glucose metabolism plays a key role in mediating both food-induced reinforcement and enhancement of that reinforcement by prior food withdrawal and implicate serotonergic signaling through 5-HT4 receptor in the re-enforcing properties of food.

BACKGROUND:The safety and efficacy of brain parenchyma biopsy during minimally invasive (MIS) intracerebral hemorrhage (ICH) clot evacuation has not been previously reported. The objective of this study was to establish the safety and diagnostic efficacy of brain biopsy during MIS ICH clot evacuation and to validate the modified Boston criteria as a predictor of cerebral amyloid angiopathy (CAA) in this cohort. METHODS:From October 2016 to March 2018, superficial and perihematomal biopsies were collected for 40 patients undergoing MIS ICH clot evacuation and analyzed by the pathology department to assess for various ICH etiologies. Additionally, the admission magnetic resonance imaging or computed tomography scan of each patient was analyzed and evaluated for the likelihood of a CAA etiology based on the modified Boston criteria. Student t test was used to analyze intergroup differences in continuous variables, and a 2-tailed Fisher exact test was used to determine intergroup differences of categorical variables, with significance set at P < 0.05. RESULTS:Two of the 40 patients (5%) experienced postoperative rebleed. Four of the 40 patients (10%) had evidence of CAA on biopsy. Patients with CAA on biopsy were older (P = 0.005) and had a higher prevalence of parietal lobe (P = 0.02) and occipital lobe (P = 0.001) hemorrhage. The modified Boston criteria had a sensitivity of 100% (95% confidence interval [CI], 39.6%-100%) and a specificity of 72.2% (95% CI, 54.6%-84.2%) for predicting CAA on biopsy. CONCLUSIONS:Brain biopsy in MIS ICH clot evacuation is safe and allows for the diagnosis of various ICH etiologies.

During differentiation transient, inducers produce permanent changes in gene expression. A similar phenomenon, transcriptional hysteresis, produced by transient or prolonged exposure to glucose, leads to cumulative, persistent, and largely irreversible effects on glucose-regulated gene expression, and may drive key aspects of metabolic memory, obesity, diabetes, and aging, and explain the protective effects of dietary restriction during aging. The most relevant effects of glucose-induced transcriptional hysteresis are the persistent effects of elevated glucose on genes that control glucose metabolism itself. A key observation is that, as with the lac operon, glucose induces genes that promote glycolysis and inhibits gene expression of alternative metabolic pathways including the pentose pathway, beta oxidation, and the TCA cycle. A similar pattern of metabolic gene expression is observed during aging, suggesting that cumulative exposure to glucose during aging produces this metabolic shift. Conversely, dietary restriction, which increases lifespan and delays age-related impairments, produces the opposite metabolic profile, leading to a shift away from glycolysis and toward the use of alternative substrates, including lipid and ketone metabolisms. The effect of glucose on gene expression leads to a positive feedback loop that leads to metastable persistent expression of genes that promote glycolysis and inhibit alternative pathways, a phenomenon first observed in the regulation of the lac operon. On the other hand, this pattern of gene expression can also be inhibited by activation of peroxisome proliferator activating receptor transcription factors that promote beta oxidation and inhibit metabolism of glucose-derived carbon bonds in the TCA cycle. Several pathological consequences may arise from glucose-induced transcriptional hysteresis. First, elevated glucose induces glycolytic genes in pancreatic beta cells, which induces a semi-stable persistent increase in insulin secretion, which could drive obesity and insulin resistance, and also due to glucose toxicity could eventually lead to beta-cell decompensation and diabetes. Diabetic complications persist even after complete normalization of glucose, a phenomenon known as metabolic memory. This too can be explained by persistent bistable expression of glucose-induced glycolytic genes.

Mechanisms mediating protective effects of dietary restriction during aging are of great interest since activating such mechanisms protect against a wide range of age-related diseases. In mammals key metabolic responses to nutritional deprivation are mediated by the transcription factor PPAR-alpha, which is activated by free fatty acids and promotes lipid metabolism while inhibiting glucose metabolism. The C. elegans gene nhr-49 appears to function similarly in C. elegans. Here we report that protective effects of dietary restriction and inhibition of glucose metabolism to increase lifespan wild-type C. elegans and reduce toxicity in a polyQ model of Huntington's disease in C. elegans are dependent on NHR-49 and its co-activator CREB-Binding Protein (CBP). We have previously demonstrated that inhibition of cbp blocks protective effects of dietary restriction and blocks the molecular switch from glucose metabolism to alternative substrates. Conversely, increased glucose concentration and inhibition of cbp reduce lifespan and increase proteotoxicity. Lactate and inhibition of ETC complex II mimicked toxic effects of glucose on proteotoxicity whereas pyruvate and inhibition of ETC complex I protected against glucose-enhanced proteotoxicity. These results support that PPAR-alpha-like activity mediates protective effects of dietary restriction by reducing glucose metabolism via reducing production of NADH, and corroborate and extend recent studies demonstrating that PPPAR-alpha agonists increase lifespan in C. elegans dependent on NHR-49.

Aging constitutes the central risk factor for major diseases including many forms of cancer, neurodegeneration, and cardiovascular diseases. The aging process is characterized by both global and tissue-specific changes in gene expression across taxonomically diverse species. While aging has historically been thought to entail cell-autonomous, even stochastic changes, recent evidence suggests that modulation of this process can be hierarchal, wherein manipulations of nutrient-sensing neurons (e.g., in the hypothalamus) produce peripheral effects that may modulate the aging process itself. The most robust intervention extending lifespan, plausibly impinging on the aging process, involves different modalities of dietary restriction (DR). Lifespan extension by DR is associated with broad protection against diseases (natural and engineered). Here we review potential epigenetic processes that may link lifespan to age-related diseases, particularly in the context of DR and (other) ketogenic diets, focusing on brain and hypothalamic mechanisms.

Appetitive drive is influenced by coordinated interactions between brain circuits that regulate reinforcement and homeostatic signals that control metabolism. Glucose modulates striatal dopamine (DA) and regulates appetitive drive and reinforcement learning. Striatal DA D2 receptors (D2Rs) also regulate reinforcement learning and are implicated in glucose-related metabolic disorders. Nevertheless, interactions between striatal D2R and peripheral glucose have not been previously described. Here we show that manipulations involving striatal D2R signaling coincide with perseverative and impulsive-like responding for sucrose, a disaccharide consisting of fructose and glucose. Fructose conveys orosensory (ie, taste) reinforcement but does not convey metabolic (ie, nutrient-derived) reinforcement. Glucose however conveys orosensory reinforcement but unlike fructose, it is a major metabolic energy source, underlies sustained reinforcement, and activates striatal circuitry. We found that mice with deletion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) exclusively in D2R-expressing cells exhibited preferential D2R changes in the nucleus accumbens (NAc), a striatal region that critically regulates sucrose reinforcement. These changes coincided with perseverative and impulsive-like responding for sucrose pellets and sustained reinforcement learning of glucose-paired flavors. These mice were also characterized by significant glucose intolerance (ie, impaired glucose utilization). Systemic glucose administration significantly attenuated sucrose operant responding and D2R activation or blockade in the NAc bidirectionally modulated blood glucose levels and glucose tolerance. Collectively, these results implicate NAc D2R in regulating both peripheral glucose levels and glucose-dependent reinforcement learning behaviors and highlight the notion that glucose metabolic impairments arising from disrupted NAc D2R signaling are involved in compulsive and perseverative feeding behaviors.