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).

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.

Glucose-lowering drugs, cognition, and dementia: The clinical evidence.

Type 2 diabetes mellitus (T2DM) is an important risk factor for dementia. The possibility to mitigate this risk by controlling T2DM is compelling; however, different glucose-lowering drugs have different effects on the brain by virtue of their different mechanisms of action. The clinical and epidemiological data appear mixed, warranting careful critical evaluation of the human studies. Here we examine the evidence in the context of dementia prevention and treatment, both for people with and without T2DM. We discuss the evidence on this scaffold of research directions, identifying methodological complexities in the extant literature (e.g. comparator discrepancies, changes in the therapeutic landscape), and the implications of different outcome measures (e.g. neuropsychological). We consider possible implications of cerebrovascular protection vs. effects on progression of neurodegenerative proteinopathy, and we present a research roadmap for glucose-lowering drugs in cognitive neurology, including neuroimaging, and fluid biomarkers. We conclude that there is great potential to advance personalized strategies to prevent and treat dementia with glucose-lowering drugs.

Elevated atherogenic lipid profile in youth with bipolar disorder during euthymia and hypomanic/mixed but not depressive states.

OBJECTIVE: Abnormal blood lipid levels are common in individuals with bipolar disorder (BD). Previous studies have revealed lipid-mood associations in adults with BD, but no data on this relationship is available in youth populations. This cross-sectional study examined the associations of lipid levels with mood states and symptoms in a cohort of youth with BD. METHODS: Participants were youth with BD and healthy controls (HCs) between the ages of 13-20 years. We compared the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), and TG/HDL-C ratio between 4 participant episode groups: BD-euthymic (n = 28), BD-depressed (n = 29) BD-hypomanic/mixed (n = 31), and HCs (n = 89). We also examined for dimensional associations of lipids with mania and depression scores in the overall BD group and within BD episode subgroups. RESULTS: TG levels were significantly higher in the BD-euthymic group (p = 0.008, d = 0.59) and in the BD-mixed/hypomanic group (p = 0.03, d = 0.44) compared to the HC group. TG/HDL-C ratio was also higher in the BD-euthymic group compared to the HC group (p = 0.01, d = 0.51). No dimensional associations were found between lipids and mood symptom scores in the overall BD group. However, within the BD-mixed/hypomanic subgroup, higher mania scores were associated with higher TG (ß = 0.42, p = 0.04), TG/HDL-C ratio (ß = 0.59, p = 0.002), and lower HDL-C (ß = 0.56 p = 0.002). CONCLUSIONS: Youth with BD demonstrate atherogenic lipid profiles. Higher atherogenic lipids were associated with hypomanic but, contrasting adult BD studies, not depressive symptoms. Future prospective studies are warranted to evaluate the temporal association between lipids and mood among youth with BD.