Publications

Cell-autonomous and non-autonomous roles of daf-16 in muscle function and mitochondrial capacity in aging C. elegans.
Wang H#, Webster P#, Chen L, Fisher AL
Aging (Albany NY). 2019 Apr 24;11(8):2295-2311. doi: 10.18632/aging.101914.

Abstract:

Sarcopenia, defined as the loss of skeletal muscle mass and strength, contributes to disability and health-related conditions with aging. In vitro studies indicate that age-related mitochondrial dysfunction could play a central role in the development and progression of sarcopenia, but because of limitations in the methods employed, how aging affects muscle mitochondrial function in vivo is not fully understood. We use muscle-targeted fluorescent proteins and the ratiometric ATP reporter, ATeam, to examine changes in muscle mitochondrial mass and morphology, and intracellular ATP levels in C. elegans. We find that the preserved muscle function in aging daf-2 mutants is associated with higher muscle mitochondrial mass, preserved mitochondrial morphology, and higher levels of intracellular ATP. These phenotypes require the daf-16/FOXO transcription factor. Via the tissue-specific rescue of daf-16, we find that daf-16 activity in either muscle or neurons is sufficient to enhance muscle mitochondrial mass, whereas daf-16 activity in the muscle is required for the enhanced muscle function and mobility of the daf-2 mutants. Finally, we show through the use of drugs known to enhance mitochondrial activity that augmenting mitochondrial function leads to improved mobility during aging. These results suggest an important role for mitochondrial function in muscle aging.


Hyperadrenocorticism of calorie restriction contributes to its anti-inflammatory action in mice.
Allen BD, Liao CY, Shu J, Muglia LJ, Majzoub JA, Diaz V, Nelson JF
Aging Cell. 2019 Jun;18(3):e12944. doi: 10.1111/acel.12944. Epub 2019 Apr 1.

Abstract:

Calorie restriction (CR), which lengthens lifespan in many species, is associated with moderate hyperadrenocorticism and attenuated inflammation. Given the anti-inflammatory action of glucocorticoids, we tested the hypothesis that the hyperadrenocorticism of CR contributes to its attenuated inflammatory response. We used a corticotropin-releasing-hormone knockout (CRHKO) mouse, which is glucocorticoid insufficient. There were four controls groups: CRHKO mice and wild-type (WT) littermates fed either ad libitum (AL) or CR (60% of AL food intake), and three experimental groups: (a) AL-fed CRHKO mice given corticosterone (CORT) in their drinking water titrated to match the integrated 24-hr plasma CORT levels of AL-fed WT mice, (b) CR-fed CRHKO mice given CORT to match the 24-hr CORT levels of AL-fed WT mice, and (c) CR-fed CHRKO mice given CORT to match the 24-hr CORT levels of CR-fed WT mice. Inflammation was measured volumetrically as footpad edema induced by carrageenan injection. As previously observed, CR attenuated footpad edema in WT mice. This attenuation was significantly blocked in CORT-deficient CR-fed CRHKO mice. Replacement of CORT in CR-fed CRHKO mice to the elevated levels observed in CR-fed WT mice, but not to the levels observed in AL-fed WT mice, restored the anti-inflammatory effect of CR. These results indicate that the hyperadrenocorticism of CR contributes to the anti-inflammatory action of CR, which may in turn contribute to its life-extending actions.


Phosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochrome bc1 complex function.
Calzada E, Avery E, Sam PN, Modak A, Wang C, McCaffery JM, Han X, Alder NN, Claypool SM
Nature Communications. 2019 Mar 29;10(1):1432. doi: 10.1038/s41467-019-09425-1.

Abstract:

Of the four separate PE biosynthetic pathways in eukaryotes, one occurs in the mitochondrial inner membrane (IM) and is executed by phosphatidylserine decarboxylase (Psd1). Deletion of Psd1 is lethal in mice and compromises mitochondrial function. We hypothesize that this reflects inefficient import of non-mitochondrial PE into the IM. Here, we test this by re-wiring PE metabolism in yeast by re-directing Psd1 to the outer mitochondrial membrane or the endomembrane system and show that PE can cross the IMS in both directions. Nonetheless, PE synthesis in the IM is critical for cytochrome bc1 complex (III) function and mutations predicted to disrupt a conserved PE-binding site in the complex III subunit, Qcr7, impair complex III activity similar to PSD1 deletion. Collectively, these data challenge the current dogma of PE trafficking and demonstrate that PE made in the IM by Psd1 support the intrinsic functionality of complex III.


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 Apr 16;116(16):7973-7981. doi: 10.1073/pnas.1816023116. Epub 2019 Mar 29.

Abstract

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.


Defective Phosphatidylglycerol Remodeling Causes Hepatopathy, Linking Mitochondrial Dysfunction to Hepatosteatosis.
Zhang X, Zhang J, Sun H, Liu X, Zheng Y, Xu D, Wang J, Jia D, Han X, Liu F, Nie J, Shi Y
Cellular and Molecular Gastroenterology and Hepatology. 2019;7(4):763-781. doi: 10.1016/j.jcmgh.2019.02.002. Epub 2019 Mar 1.

Abstract:

BACKGROUND & AIMS: Obesity promotes the development of nonalcoholic fatty liver diseases (NAFLDs), yet not all obese patients develop NAFLD. The underlying causes for this discrepancy remain elusive. LPGAT1 is an acyltransferase that catalyzes the remodeling of phosphatidylglycerol (PG), a mitochondrial phospholipid implicated in various metabolic diseases. Here, we investigated the role of LPGAT1 in regulating the onset of diet-induced obesity and its related hepatosteatosis because polymorphisms of the LPGAT1 gene promoter were strongly associated with susceptibility to obesity in Pima Indians.

METHODS: Mice with whole-body knockout of LPGAT1 were generated to investigate the role of PG remodeling in NAFLD.

RESULTS: LPGAT1 deficiency protected mice from diet-induced obesity, but led to hepatopathy, insulin resistance, and NAFLD as a consequence of oxidative stress, mitochondrial DNA depletion, and mitochondrial dysfunction.

CONCLUSIONS: This study identified an unexpected role of PG remodeling in obesity, linking mitochondrial dysfunction to NAFLD.


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.

Abstract

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.


Hepatocyte-Macrophage Acetoacetate Shuttle Protects against Tissue Fibrosis.
Puchalska P, Martin SE, Huang X, Lengfeld JE, Daniel B, Graham MJ, Han X, Nagy L, Patti GJ, Crawford PA
Cell Metabolism. 2019 Feb 5;29(2):383-398.e7. doi: 10.1016/j.cmet.2018.10.015. Epub 2018 Nov 15.

Abstract:

Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.


Altered bile acid profile in mild cognitive impairment and Alzheimer’s disease: Relationship to neuroimaging and CSF biomarkers.
Nho K, Kueider-Paisley A, MahmoudianDehkordi S, Arnold M, Risacher SL, Louie G, Blach C, Baillie R, Han X, Kastenmüller G, Jia W, Xie G, Ahmad S, Hankemeier T, van Duijn CM, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, Saykin AJ, Kaddurah-Daouk R; Alzheimer’s Disease Neuroimaging Initiative and the Alzheimer Disease Metabolomics Consortium.
Alzheimer’s & Dementia. 2019 Feb;15(2):232-244. doi: 10.1016/j.jalz.2018.08.012. Epub 2018 Oct 15.

Abstract:

INTRODUCTION: Bile acids (BAs) are the end products of cholesterol metabolism produced by human and gut microbiome co-metabolism. Recent evidence suggests gut microbiota influence pathological features of Alzheimer’s disease (AD) including neuroinflammation and amyloid-β deposition.

METHOD: Serum levels of 20 primary and secondary BA metabolites from the AD Neuroimaging Initiative (n = 1562) were measured using targeted metabolomic profiling. We assessed the association of BAs with the “A/T/N” (amyloid, tau, and neurodegeneration) biomarkers for AD: cerebrospinal fluid (CSF) biomarkers, atrophy (magnetic resonance imaging), and brain glucose metabolism ([18F]FDG PET).

RESULTS: Of 23 BAs and relevant calculated ratios after quality control procedures, three BA signatures were associated with CSF Aβ1-42 (“A”) and three with CSF p-tau181 (“T”) (corrected P < .05). Furthermore, three, twelve, and fourteen BA signatures were associated with CSF t-tau, glucose metabolism, and atrophy (“N”), respectively (corrected P < .05).

DISCUSSION: This is the first study to show serum-based BA metabolites are associated with “A/T/N” AD biomarkers, providing further support for a role of BA pathways in AD pathophysiology. Prospective clinical observations and validation in model systems are needed to assess causality and specific mechanisms underlying this association.


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.
PMID: 30674654

Abstract:

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].

Abstract:

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.


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