Hepatic posttranscriptional network comprised of CCR4-NOT deadenylase and FGF21 maintains systemic metabolic homeostasis
Morita M, Siddiqui N, Katsumura S, Rouya C, Larsson O, Nagashima T, Hekmatnejad B, Takahashi A, Kiyonari H, Zang M, St-Arnaud R, Oike Y, Giguère V, Topisirovic I, Okada-Hatakeyama M, Yamamoto T, Sonenberg N
PNAS. 2019 Mar 29. pii: 201816023. doi: 10.1073/pnas.1816023116. [Epub ahead of print]
Whole-body metabolic homeostasis is tightly controlled by hormone-like factors with systemic or paracrine effects that are derived from nonendocrine organs, including adipose tissue (adipokines) and liver (hepatokines). Fibroblast growth factor 21 (FGF21) is a hormone-like protein, which is emerging as a major regulator of whole-body metabolism and has therapeutic potential for treating metabolic syndrome. However, the mechanisms that control FGF21 levels are not fully understood. Herein, we demonstrate that FGF21 production in the liver is regulated via a posttranscriptional network consisting of the CCR4-NOT deadenylase complex and RNA-binding protein tristetraprolin (TTP). In response to nutrient uptake, CCR4-NOT cooperates with TTP to degrade AU-rich mRNAs that encode pivotal metabolic regulators, including FGF21. Disruption of CCR4-NOT activity in the liver, by deletion of the catalytic subunit CNOT6L, increases serum FGF21 levels, which ameliorates diet-induced metabolic disorders and enhances energy expenditure without disrupting bone homeostasis. Taken together, our study describes a hepatic CCR4-NOT/FGF21 axis as a hitherto unrecognized systemic regulator of metabolism and suggests that hepatic CCR4-NOT may serve as a target for devising therapeutic strategies in metabolic syndrome and related morbidities.
Age-related changes in the marmoset gut microbiome
Reveles KR, Patel S, Forney L, Ross CN
American Journal of Primatology. 2019 Feb;81(2):e22960. doi: 10.1002/ajp.22960. Epub 2019 Feb 25.
The gut microbiome is known to play a significant role in human health but its role in aging remains unclear. The objective of this study was to compare the gut microbiome composition between young adult and geriatric non-human primates (marmosets) as a model of human health and disease. Stool samples were collected from geriatric (8+ years) and young adult males (2-5 years). Stool 16S ribosomal RNA V4 sequences were amplified and sequenced on the Illumina MiSeq platform. Sequences were clustered into operational taxonomic units and classified via Mothur’s Bayesian classifier referenced against the Greengenes database. A total of 10 young adult and 10 geriatric marmosets were included. Geriatric marmosets had a lower mean Shannon diversity compared with young marmosets (3.15 vs. 3.46; p = 0.0191). Geriatric marmosets had a significantly higher mean abundance of Proteobacteria (0.22 vs. 0.09; p = 0.0233) and lower abundance of Firmicutes (0.15 vs. 0.19; p = 0.0032) compared with young marmosets. Geriatric marmosets had a significantly higher abundance of Succinivibrionaceae (0.16 vs. 0.01; p = 0.0191) and lower abundance of Porphyromonadaceae (0.07 vs. 0.11; p = 0.0494). In summary, geriatric marmosets had significantly altered microbiome diversity and composition compared with young adult marmosets. Further studies are needed to test microbiome-targeted therapies to improve healthspan and lifespan.
Rapamycin and Alzheimer’s disease: Time for a clinical trial?
Kaeberlein M, Galvan V
Science Translational Medicine. 2019 Jan 23;11(476). pii: eaar4289. doi: 10.1126/scitranslmed.aar4289.
The drug rapamycin has beneficial effects in a number of animal models of neurodegeneration and aging including mouse models of Alzheimer’s disease. Despite its compelling preclinical record, no clinical trials have tested rapamycin or other mTOR inhibitors in patients with Alzheimer’s disease. We argue that such clinical trials should be undertaken.
Microtubule regulators act in the nervous system to modulate fat metabolism and longevity through DAF‐16 in C. elegans.
Aiping Xu, Zhao Zhang, Su‐Hyuk Ko, Alfred L. Fisher, Zhijie Liu, Lizhen Chen
Aging Cell. 14 January 2019. doi: 10.1111/acel.12884. [Epub ahead of print].
Microtubule (MT) regulation is involved in both neuronal function and the maintenance of neuronal structure, and MT dysregulation appears to be a general downstream indicator and effector of age‐related neurodegeneration. But the role of MTs in natural aging is largely unknown. Here, we demonstrate a role of MT regulators in regulating longevity. We find that loss of EFA‐6, a modulator of MT dynamics, can delay both neuronal aging and extend the lifespan of C. elegans. Through the use of genetic mutants affecting other MT‐regulating genes in C. elegans, we find that loss of MT stabilizing genes (including ptrn‐1 and ptl‐1) shortens lifespan, while loss of MT destabilizing gene hdac‐6 extends lifespan. Via the use of tissue‐specific transgenes, we further show that these MT regulators can act in the nervous system to modulate lifespan. Through RNA‐seq analyses, we found that genes involved in lipid metabolism were differentially expressed in MT regulator mutants, and via the use of Nile Red and Oil Red O staining, we show that the MT regulator mutants have altered fat storage. We further find that the increased fat storage and extended lifespan of the long‐lived MT regulator mutants are dependent on the DAF‐16/FOXO transcription factor. Our results suggest that neuronal MT status might affect organismal aging through DAF‐16‐regulated changes in fat metabolism, and therefore, MT‐based therapies might represent a novel intervention to promote healthy aging.
Effects of intravenous AICAR (5-aminoimidazole-4-carboximide riboside) administration on insulin signaling and resistance in premature baboons, Papio sp.
Blanco CL, Gastaldelli A, Anzueto DG, Winter LA, Seidner SR, McCurnin DC, Liang H, Javors MA, DeFronzo RA, Musi N
PLoS one. 2018 Dec 12;13(12):e0208757. doi: 10.1371/journal.pone.0208757. eCollection 2018.
Premature baboons exhibit peripheral insulin resistance and impaired insulin signaling. 5′ AMP-activated protein kinase (AMPK) activation improves insulin sensitivity by enhancing glucose uptake (via increased glucose transporter type 4 [GLUT4] translocation and activation of the extracellular signal-regulated kinase [ERK]/ atypical protein kinase C [aPKC] pathway), and increasing fatty acid oxidation (via inhibition of acetyl-CoA carboxylase 1 [ACC]), while downregulating gluconeogenesis (via induction of small heterodimer partner [SHP] and subsequent downregulation of the gluconeogenic enzymes: phosphoenolpyruvate carboxykinase [PEPCK], glucose 6-phosphatase [G6PASE], fructose- 1,6-bisphosphatase 1 [FBP1], and forkhead box protein 1 [FOXO1]). The purpose of this study was to investigate whether pharmacologic activation of AMPK with AICAR (5-aminoimidazole-4-carboximide riboside) administration improves peripheral insulin sensitivity in preterm baboons. 11 baboons were delivered prematurely at 125±2 days (67%) gestation. 5 animals were randomized to receive 5 days of continuous AICAR infusion at a dose of 0.5 mg·g-1·day-1. 6 animals were in the placebo group. Euglycemic hyperinsulinemic clamps were performed at 5±2 and 14±2 days of life. Key molecules potentially altered by AICAR (AMPK, GLUT4, ACC, PEPCK, G6PASE, FBP1, and FOXO1), and the insulin signaling molecules: insulin receptor (INSR), insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were measured using RT-PCR and western blotting. AICAR infusion did not improve whole body insulin-stimulated glucose disposal in preterm baboons (12.8±2.4 vs 12.4±2.0 mg/(kg·min), p = 0.8, placebo vs AICAR). One animal developed complications during treatment. In skeletal muscle, AICAR infusion did not increase phosphorylation of ACC, AKT, or AMPK whereas it increased mRNA expression of ACACA (ACC), AKT, and PPARGC1A (PGC1α). In the liver, INSR, IRS1, G6PC3, AKT, PCK1, FOXO1, and FBP1 were unchanged, whereas PPARGC1A mRNA expression increased after AICAR infusion. This study provides evidence that AICAR does not improve insulin sensitivity in premature euglycemic baboons, and may have adverse effects.
Translational and HIF-1α-Dependent Metabolic Reprogramming Underpin Metabolic Plasticity and Responses to Kinase Inhibitors and Biguanides.
Hulea L, Gravel SP, Morita M, Cargnello M, Uchenunu O, Im YK, Lehuédé C, Ma EH, Leibovitch M, McLaughlan S, Blouin MJ, Parisotto M, Papavasiliou V, Lavoie C, Larsson O, Ohh M, Ferreira T, Greenwood C, Bridon G, Avizonis D, Ferbeyre G, Siegel P, Jones RG, Muller W, Ursini-Siegel J, St-Pierre J, Pollak M, Topisirovic I
Cell Metabolism. 2018 Dec 4;28(6):817-832.e8. doi: 10.1016/j.cmet.2018.09.001.. Epub 2018 Sep 20.
There is increasing interest in therapeutically exploiting metabolic differences between normal and cancer cells. We show that kinase inhibitors (KIs) and biguanides synergistically and selectively target a variety of cancer cells. Synthesis of non-essential amino acids (NEAAs) aspartate, asparagine, and serine, as well as glutamine metabolism, are major determinants of the efficacy of KI/biguanide combinations. The mTORC1/4E-BP axis regulates aspartate, asparagine, and serine synthesis by modulating mRNA translation, while ablation of 4E-BP1/2 substantially decreases sensitivity of breast cancer and melanoma cells to KI/biguanide combinations. Efficacy of the KI/biguanide combinations is also determined by HIF-1α-dependent perturbations in glutamine metabolism, which were observed in VHL-deficient renal cancer cells. This suggests that cancer cells display metabolic plasticity by engaging non-redundant adaptive mechanisms, which allows them to survive therapeutic insults that target cancer metabolism.
NFκB Regulates Muscle Development and Mitochondrial Function.
Valentine JM, Li ME, Shoelson SE, Zhang N, Reddick RL, Musi N
J Gerontol A Biol Sci Med Sci. 2018 Nov 13. doi: 10.1093/gerona/gly262. [Epub ahead of print]
NFκB is a transcription factor that controls immune and inflammatory signaling pathways. In skeletal muscle, NFκB has been implicated in the regulation of metabolic processes and tissue mass; yet, its affects on mitochondrial function in this tissue are unclear. To investigate the role of NFκB on mitochondrial function and its relationship with muscle mass across the lifespan, we study a mouse model with muscle-specific NFκB suppression (MISR mice). In wild type mice there was a natural decline in muscle mass with aging that was accompanied by decreased mitochondrial function and mRNA expression of electron transport chain subunits. NFκB inactivation downregulated expression of PPARGC1A, while upregulating TFEB and PPARGC1B, as well as decreased gastrocnemius (but not soleus) muscle mass in early life (1-6 months old). Lower oxygen consumption rates occurred in gastrocnemius and soleus muscles from young MISR mice, whereas soleus (but not gastrocnemius) muscles from old MISR mice displayed increased oxygen consumption compared to age-matched controls. We conclude that the NFκB pathway plays an important role in muscle development and growth. The extent to which NFκB suppression alters mitochondrial function is age-dependent and muscle-specific. Lastly, mitochondrial function and muscle mass are tightly associated in both genotypes and across the lifespan.
Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
Cornelison GL, Levy SA, Jenson T, Frost B
Aging Cell. 2018 Nov 9:e12847. doi: 10.1111/acel.12847. [Epub ahead of print]
The nucleus is a spherical dual-membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the “nucleoplasmic reticulum.” Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer’s disease. While the presence of pore-lined, cytoplasm-filled, nuclear envelope invaginations has been proposed to facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. Here, we report that polyadenylated RNAs accumulate within and adjacent to tau-induced nuclear envelope invaginations in a Drosophila model of tauopathy. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations and reduces tau-induced neuronal death. These data are the first to point toward a possible role for RNA export through nuclear envelope invaginations in the pathogenesis of a neurodegenerative disorder and suggest that nucleocytoplasmic transport machinery may serve as a possible novel class of therapeutic targets for the treatment of tauopathies.
Marmoset as a model to study kidney changes associated with aging.
Lee HJ, Gonzalez O, Dick EJ Jr, Donati A, Feliers D, Goutam Ghosh C, Ross C, Venkatachalam M, Tardif SD, Kasinath BS
J Gerontol A Biol Sci Med Sci. 2018 Oct 13. doi: 10.1093/gerona/gly237. [Epub ahead of print]
We evaluated whether the marmoset, a nonhuman primate, can serve as a good model to study aging related changes in the kidney by employing healthy young and aged marmosets of both sexes. Aging was associated with glomerulosclerosis, interstitial fibrosis and arteriolosclerosis in both sexes; correspondingly, the content of matrix proteins was increased. Functionally, aging resulted in an increase in urinary albumin and protein excretion. There was a robust correlation between markers of fibrosis and functional changes. We explored signaling pathways as potential mechanistic events. Aging in males, but not in females, was associated with reduced renal cortical activity of AMP-activated protein kinase (AMPK) and a trend toward activation of mechanistic target of rapamycin complex 1 (mTORC1); upstream of AMPK and mTORC1, Akt and IGF-1 receptor were activated. In both sexes, aging promoted kidney activation of transforming growth factor β-1 signaling pathway. While the expression of cystathionine β-synthase (CBS), an enzyme involved hydrogen sulfide (H2S) synthesis, was reduced in both aged males and females, decreased H2S generation was seen in only males. Our studies show that the marmoset is a valid model to study kidney aging; some of the signaling pathways involved in renal senescence differ between male and female marmosets.
Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets.
Sills AM, Artavia JM, DeRosa BD, Ross CN, Salmon AB
American Journal of Primatology. 2018 Oct 12:e22927. doi: 10.1002/ajp.22927. [Epub ahead of print].
Interventions to extend lifespan and improve health with increasing age would have significant impact on a growing aged population. There are now several pharmaceutical interventions that extend lifespan in laboratory rodent models with rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) being the most well studied. In this study, we report on the hematological effects in a cohort of middle-aged common marmosets (Callithrix jacchus) that were enrolled in a study to test the effects of daily rapamycin treatment on aging in this species. In addition, we assessed whether sex was a significant factor in either baseline assessment or as an interaction with rapamycin treatment. Among our cohort at baseline, we found few differences in either basic morphology or hematological markers of blood cell counts, metabolism or inflammation between male and female marmosets. After dosing with rapamycin, surprisingly we found trough blood concentrations of rapamycin were significantly lower in female compared to male marmosets. Despite this pharmacological difference, both sexes had only minor changes in cellular blood counts after 9 months of rapamycin. These data then suggest that the potential clinical hematological side effects of rapamycin are not likely outcomes of long-term rapamycin in relatively healthy, middle-aged marmosets.