Novel small molecules inhibit proteotoxicity and inflammation: Mechanistic and therapeutic implications for Alzheimer's Disease, healthspan and lifespan- Aging as a consequence of glycolysis.

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).

Nocturnal hypoglycemia is underdiagnosed in older people with insulin-treated type 2 diabetes: The HYPOAGE observational study.

BACKGROUND: There is a lack of real-life data regarding the frequency and predictive factors of hypoglycemia in older patients with type 2 diabetes (T2D). This study aimed to determine the frequency and predictors of hypoglycemia in older patients with insulin-treated T2D. METHODS: This prospective multicenter study included 155 insulin-treated T2D patients aged 75 years and older with ≥2 self-monitoring of blood glucose (SMBG) daily controls. Participants underwent a geriatric and diabetic assessment and received ambulatory blinded continuous glucose monitoring (CGM) for 28 consecutive days with FreeStyle Libre Pro® sensor. Study population (n = 141) has >70% CGM active time. Multivariable logistic regressions were used to identify factors associated with SMBG confirmed hypoglycemia (≥70 mg/dL) and with nocturnal level 2 time below range (glucose concentration <54 mg/dL during ≥15 consecutive min between 0.00 and 6.00 am). RESULTS: The mean age of the 141 analyzed patients was 81.5 ± 5.3 years and 56.7% were male. The mean baseline HbA1c was 7.9% ± 1.0%. After geriatric assessment, 102 participants (72.3%) were considered as complex and 39 (27.7%) as healthy. The primary endpoint (confirmed SMBG <70 mg/dL) occurred in 37.6% patients. In multivariable analysis, the risk of SMBG-confirmed hypoglycemia was positively associated with a longer duration of diabetes (OR (+1 year) =1.04, (1.00-1.08), p = 0.04) and glycemic variability assessed by CGM (CV %) (OR (+1%) = 1.12, [1.05-1.19], p = <0.001). Nighty-two patients (65.2%) experienced nocturnal time in hypoglycemia (i.e., <54 mg/dL during ≥15 consecutive min between midnight and 6 a.m.). In multivariable analyses, cognitive impairment (OR: 9.31 [2.59-33.4]), heart failure (OR: 4.81 [1;48-15.6]), and depressive disorder (OR: 0.19 [0.06-0.53]) were associated with nocturnal time in hypoglycemia. CONCLUSION: Nocturnal hypoglycemia is very common and largely underdiagnosed in older patients with insulin-treated T2D. CGM is a promising tool to better identify hypoglycemia and adapt diabetes management in this population.

Diets, genes, and drugs that increase lifespan and delay age-related diseases: Role of nutrient-sensing neurons and Creb-binding protein.

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.

A retrospective study on the etiological exploration of osteoporosis in aging men in a French geriatric setting.

INTRODUCTION: Osteoporosis in older men is common and causes significant mortality and morbidity. Some data suggest that conditions leading to bone fragility, including osteoporosis, are under-identified and undertreated in men. Additionally, 50% of the causes of osteoporosis are secondary in men. The latest Endocrine Society and different Rheumatology Societies Guidelines recommend additional laboratory investigations in men with osteoporosis so as to treat them more efficiently. MAIN GOAL OF THE STUDY: Our aim was to determine whether men managed in our geriatrics center, diagnosed with osteoporosis, underwent investigations to determine the aetiology of osteoporosis and other bone fragility conditions and what the secondary causes were. MATERIALS AND METHOD: We conducted a monocentric, retrospective study including all men seen at the geriatric consult in 2016 diagnosed with osteoporosis. For each patient, we evaluated our clinical practice, whether common secondary causes were sought-after and what these aetiologies were. RESULTS: Among the 121 men with a diagnosis of osteoporosis seen at the geriatric consult at the Lille University Hospital in 2016, only 51 had undergone further investigations. Among the 3 major secondary causes were identified: 17.6% glucocorticoid induced, 13.7% treatment induced hypogonadism, 11.7% late onset hypogonadism. CONCLUSIONS: A more efficient etiological assessment of osteoporosis in older men could be achieved and would improve management for our patients. This can be achieved by a better knowledge of the recommendations for etiological assessment of bone fragility and osteoporosis and a dedicated consultation within the geriatric sector.

Biological age and environmental risk factors for dementia and stroke: Molecular mechanisms.

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.

Exposure of Caenorhabditis elegans to Dietary Nε-Carboxymethyllysine Emphasizes Endocytosis as a New Route for Intestinal Absorption of Advanced Glycation End Products.

The impact of dietary advanced glycation end products (dAGEs) on human health has been discussed in many studies but, to date, no consensual pathophysiological process has been demonstrated. The intestinal absorption pathways which have so far been described for dAGEs, the passive diffusion of free AGE adducts and transport of glycated di-tripeptides by the peptide transporter 1 (PEPT-1), are not compatible with certain pathophysiological processes described. To get new insight into the intestinal absorption pathways and the pathophysiological mechanisms of dAGEs, we initiated an in vivo study with a so-called simple animal model with a complete digestive tract, Caenorhabditis elegans. Dietary bacteria were chemically modified with glyoxylic acid to mainly produce Nε-carboxymethyllysine (CML) and used to feed the worms. We performed different immunotechniques using an anti-CML antibody for the relative quantification of ingested CML and localization of this AGE in the worms' intestine. The relative expression of genes encoding different biological processes such as response to stresses and intestinal digestion were determined. The physiological development of the worms was verified. All the results were compared with those obtained with the control bacteria. The results revealed a new route for the intestinal absorption of dietary CML (dCML), endocytosis, which could be mediated by scavenger receptors. The exposure of worms to dCML induced a reproductive defect and a transcriptional response reflecting oxidative, carbonyl and protein folding stresses. These data, in particular the demonstration of endocytosis of dCML by enterocytes, open up new perspectives to better characterize the pathophysiological mechanisms of dAGEs.

Modifiable Risk Factors in Alzheimer Disease and Related Dementias: A Review.

PURPOSE: Although Alzheimer disease and related dementias (ADRDs) have long been considered nonpreventable and even an inevitable consequence of aging, recent findings from longitudinal studies indicate a downtrend in age-adjusted incidence and prevalence of ADRDs in Western countries. This remarkable trend might be the result of improved management of so-called modifiable risk factors. The aim of this review is to present evidence of modifiable factors of ADRDs in a life-course approach. METHODS: A PubMed database search was conducted between November and December 2020 to identify relevant studies evaluating the role of modifiable risk factors in the development of ADRDs. Key words (Alzheimer's disease and modifiable risk factors) were used and specific inclusion and exclusion criteria applied. FINDINGS: This review identifies modifiable factors for ADRDs divided into early-life, middle-life, and late-life risk factors, depending on the available window of preventive action. According to life course exposure, factors can be protective or deleterious for ADRDs that participate in the underlying pathophysiologic complexity of these diseases as well as the complexity for public health measures implementations. IMPLICATIONS: The available evidence derived from epidemiologic, preclinical, interventional studies suggest that modifiable risk factors for ADRDs offer opportunities for therapeutic and preventive actions.

[Caenorhabditis elegans as a model organism for aging: relevance, limitations and future]. / Caenorhabditis elegans, un modèle d'étude du vieillissement.

Aging is a physiological and complex process associated with increasing age of living organisms. Simple model organisms have brought significant advances in our understanding of the aging process. Caenorhabditis elegans, a nematode originally used to establish the genetic and molecular basis of development, has become one of the leading model organisms for research on aging. This invertebrate has allowed identifying a connection between cellular signaling pathways and longevity. Although C. elegans is not suitable for analysis of the complete process of human aging, it remains a model of choice to analyze specific aging mechanisms and phenotypes.

Kidney, heart and brain: three organs targeted by ageing and glycation.

Advanced glycation end-product (AGE) is the generic term for a heterogeneous group of derivatives arising from a non-enzymatic reaction between reducing sugars and proteins. In recent years, evidence has accumulated that incriminates AGEs in pathogenic processes associated with both chronic hyperglycaemia and age-related diseases. Regardless of their exogenous or endogenous origin, the accumulation of AGEs and their derivatives could promote accelerated ageing by leading to protein modifications and activating several inflammatory signalling pathways via AGE-specific receptors. However, it remains to be demonstrated whether preventing the accumulation of AGEs and their effects is an important therapeutic option for successful ageing. The present review gives an overview of the current knowledge on the pathogenic role of AGEs by focusing on three AGE target organs: kidney, heart and brain. For each of these organs we concentrate on an age-related disease, each of which is a major public health issue: chronic kidney disease, heart dysfunction and neurodegenerative diseases. Even though strong connections have been highlighted between glycation and age-related pathogenesis, causal links still need to be validated. In each case, we report evidence and uncertainties suggested by animal or epidemiological studies on the possible link between pathogenesis and glycation in a chronic hyperglycaemic state, in the absence of diabetes, and with exogenous AGEs alone. Finally, we present some promising anti-AGE strategies that are currently being studied.

Influence of glycaemic control on the outcomes of patients treated by intravenous thrombolysis for cerebral ischaemia.

Whether the glycaemic control during the first hours of cerebral ischaemia treated by thrombolysis influences outcomes remains unsettled. We aimed at evaluating the quality of the glycaemic control and whether patients with well-controlled glycaemia after thrombolysis for acute cerebral ischaemia have better outcomes. We retrospectively analysed data prospectively collected in consecutive stroke patients who received i.v. thrombolysis at the Lille University Hospital. Patients with glycaemia >1.6 g/l (8.9 mmol/l) at any point during the first 48 h received insulin. We used 2 definitions of well controlled glycaemia: (i) "well controlled 100 %" when 100 % glycaemia were <1.6 g/l (8.9 mmol/l), and (ii) "well controlled 70 %" when at least 70 % glycaemia were <1.6 g/l (8.9 mmol/l). The outcome measures at 3 months were (1) independence [modified Rankin scale (mRS) score 0 or 1], (2) absence of handicap (mRS 0-2), (3) death, and (4) symptomatic intracerebral haemorrhage (sICH). Of 875 consecutive patients, 657 (75.2 %) were considered as well controlled with a threshold at 100 % and 736 (84.2 %) with a threshold at 70 %. The glycaemic control was not independently associated with any of the four outcome measures. In patients treated by insulin, hypoglycaemic events were rare (2.1 % of all patients) and of moderate intensity [>0.5 g/l (2.8 mmol/l)]. The quality of the glycaemic control was not associated with outcomes in patients treated by thrombolysis. A possible explanation is that the glycaemic control after thrombolysis has minor influence compared with glycaemic control before thrombolysis when the artery is not yet re-open and the penumbra area at maximum.