NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Fang, Evandro Fei; Y, Hou; Lautrup, Sofie; Jensen, Martin Borch; Yang, Bing; SenGupta, Tanima; Caponio, Domenica; Khezri, Rojyar; Demarest, Tyler G.; Aman, Yahyah; Figueroa, David M.; Morevati, Marya; Lee, Ho‐Joon; Kato, Hisaya; Kassahun, Henok; Lee, Jong Hyuk; Filippelli, Deborah; Okur, Mustafa Nazir; Mangerich, Aswin; Croteau, Deborah L.; Maezawa, Yoshiro; Lyssiotis, Costas A.; Tao, Jun; Yokote, Koutaro; Rusten, Tor Erik; Mattson, Mark P.; Jasper, Heinrich; Nilsen, Hilde; Bohr, Vilhelm A.

doi:10.1038/s41467-019-13172-8

Cited by 180 publications

(169 citation statements)

References 91 publications

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“…6). This observation is consistent with defective mitophagy being a prominent feature in age-related disorders (80), including AD (81), and contributing to premature aging such as observed in Werner’s syndrome patients and invertebrate Werner’s disease models (82). It is also particularly intriguing that the T231E and K274/281Q do not appear to exhibit the same age-dependence as Dendra2, TauT4, or T231A.…”

Section: Discussionsupporting

confidence: 83%

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Guha

Fischer

Johnson

et al. 2020

Preprint

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21 Background: A defining pathological hallmark of the progressive neurodegenerative 22 disorder Alzheimer's disease (AD) is the accumulation of misfolded tau with abnormal 23 post-translational modifications (PTMs). These include phosphorylation at Threonine 231 24 (T231) and acetylation at Lysine 274 (K274) and at Lysine 281 (K281). Although tau is 25 recognized to play a central role in pathogenesis of AD, the precise mechanisms by which 26 these abnormal PTMs contribute to the neural toxicity of tau is unclear.27Methods: Human 0N4R tau (wild type) was expressed in touch receptor neurons of the 28 genetic model organism C. elegans through single-copy gene insertion. Defined 29 mutations were then introduced into the single-copy tau transgene through CRISPR-Cas9 30 genome editing. These mutations included T231E and T231A, to mimic phosphorylation 31 and phospho-ablation of a commonly observed pathological epitope, respectively, and 32 K274/281Q, to mimic disease-associated lysine acetylation. Stereotypical touch response 33 assays were used to assess behavioral defects in the transgenic strains as a function of 34 age, and genetically-encoded fluorescent biosensors were used to measure the 35 morphological dynamics and turnover of touch neuron mitochondria. 36Results: Unlike existing tau overexpression models, C. elegans single-copy expression 37 of tau did not elicit overt pathological phenotypes at baseline. However, strains 38 expressing disease associated PTM-mimetics (T231E and K274/281Q) exhibited 39 reduced touch sensation and morphological abnormalities that increased with age. In 40 addition, the PTM-mimetic mutants lacked the ability to engage mitophagy in response to 41 mitochondrial stress. 42 Conclusions: Limiting the expression of tau results in a genetic model where 43 pathological modifications and age result in evolving phenotypes, which may more closely 44 resemble the normal progression of AD. The finding that disease-associated PTMs 45 suppress compensatory responses to mitochondrial stress provides a new perspective 46 into the pathogenic mechanisms underlying AD. 47 modifications 49 BACKGROUND 50Alzheimer's disease (AD) is the most common degenerative brain disease in the aged 51 population. It is characterized by the progressive decline of cognition and memory, as 52 well as changes in behavior and personality (1). One of the key pathological hallmarks of 53 AD is neurofibrillary tangles (NFTs), which are primarily composed of abnormally modified 54 tau (2). Tau isolated from AD brain exhibits a number of posttranslational modifications 55 (PTMs); including increases in phosphorylation and acetylation at specific residues (3, 4). 56While it is clear that tau is central to AD pathogenesis, the concept of large insoluble NFTs 57 in AD and other tauopathies being the principle mediators of neuronal toxicity has been 58 gradually abandoned (5). Instead, toxicity appears to result from soluble or oligomeric 59 forms of tau that exhibit increased, disease-associated phosphorylation and acetylat...

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Section: Discussionsupporting

confidence: 83%

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Guha

Fischer

Johnson

et al. 2020

Preprint

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“…Interestingly, Sirt1 modulates the levels of the Forkhead Box O3A (FOXO3A) [73,74]. Accordingly, NAD + precursor supplementation induces mitophagy and improves healthspan and lifespan in Drosophila, C. elegans [75] and in mouse models of accelerated aging [76]. Thus, NAD + has emerged as a potent anti-aging factor, and the use of NAD + precursors has been proposed as a potent strategy to target age-associated diseases in old organisms and invertebrate models of premature aging syndromes [75].…”

Section: Nad + Precursorsmentioning

confidence: 99%

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Gabandé‐Rodríguez

Heras

Mittelbrunn

2019

Cells

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Mitochondrial metabolism and autophagy are two of the most metabolically active cellular processes, playing a crucial role in regulating organism longevity. In fact, both mitochondrial dysfunction or autophagy decline compromise cellular homeostasis and induce inflammation. Calorie restriction (CR) is the oldest strategy known to promote healthspan, and a plethora of CR mimetics have been used to emulate its beneficial effects. Herein, we discuss how CR and CR mimetics, by modulating mitochondrial metabolism or autophagic flux, prevent inflammatory processes, protect the intestinal barrier function, and dampen both inflammaging and neuroinflammation. We outline the effects of some compounds classically known as modulators of autophagy and mitochondrial function, such as NAD+ precursors, metformin, spermidine, rapamycin, and resveratrol, on the control of the inflammatory cascade and how these anti-inflammatory properties could be involved in their ability to increase resilience to age-associated diseases.

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“…Similar to other DNA repair-defective premature aging diseases, such as xeroderma pigmentosum (XP)[16], ataxia-telangiectasia (AT) [17], and Werner syndrome (WS) [18], mitochondrial dysfunction is implicated in many CS phenotypes [3, 4, 19]. The mechanisms of mitochondrial dysfunction underlying CS remain unclear but may involve the impairment of the NAD + (nicotinamide adenine dinucleotide, oxidized)-mitophagy axis [19-22].…”

Section: Introductionmentioning

confidence: 99%

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

Okur

Fang

Fivenson

et al. 2020

Preprint

Self Cite

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16Background: Cockayne syndrome (CS) is a rare premature aging disease, most 17 commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS 18 patients display cachectic dwarfism and severe neurological manifestations and have 19 an average life expectancy of 12 years. The CS proteins are involved in transcription 20 and DNA repair, with the latter including transcription-coupled nucleotide excision repair 21 (TC-NER). However, there is also evidence for mitochondrial dysfunction in CS, which 22 likely contributes to the severe premature aging phenotype of this disease. While 23 48 proteins. CSA [5, 6] and CSB [7] are DNA damage response proteins that are involved 49 in transcription-coupled nucleotide excision repair (TC-NER), as well as both nuclear 50 and mitochondrial base excision repair (BER) [8]. NER is a versatile DNA repair 51 pathway as it is responsible for the removal of a wide range of DNA adducts. CSA and 52 CSB are also important for transcription recovery after DNA damage [9][10][11]. Various 53 studies have shown that CSB plays a considerable role in transcription, and likely is a 54 transcription factor [12][13][14][15]. 55 56 Similar to other DNA repair-defective premature aging diseases, such as xeroderma 57 pigmentosum (XP) [16], ataxia-telangiectasia (AT) [17], and Werner syndrome (WS) 58[18], mitochondrial dysfunction is implicated in many CS phenotypes [3, 4, 19]. The 59 mechanisms of mitochondrial dysfunction underlying CS remain unclear but may involve 60 the impairment of the NAD + (nicotinamide adenine dinucleotide, oxidized)-mitophagy 61 axis [19][20][21][22]. NAD + is a fundamental molecule in cellular energy metabolism and 62 signaling pathways and is essential for adaptive responses of cells to bioenergetics and 63 oxidative stress; accordingly, there is an age-dependent depletion of cellular NAD + , 64 suggesting NAD + depletion as a major driver of both pathological and biological aging 65[23]. Many molecular mechanisms are involved in the multi-faceted effects of NAD + on 66 longevity and healthspan, including the induction of mitophagy, a cellular self-67 recognition, engulfment, degradation, and recycling of damaged and superfluous 68 mitochondria [24][25][26]. In CS, the accumulation of unrepaired DNA damage may lead to 69 to those observed in CS patients. After the selection of terms with p-values lower than 130 0.05 and an absolute value pathway Z-Score cut-off of 2.0, the remaining 39 GO terms 131and their respective Z-Scores were sorted by clustering in Fig 1b. Surprisingly, csa-1 132 and csb-1 worms had opposite pathway changes for a majority of the terms. Throughout 133 the dataset, csa-1;csb-1 worms partitioned more with csa-1 than csb-1 worms, 134suggesting that csa-1 drives the double mutant phenotype. However, there was a 135 shortlist of terms, including lysosome, where the csa-1;csb-1 worms segregated with 136 csb-1 worms. Other terms in this group included histidine catabolic process to glutamate 137 and formamide, oxidoreductase activity, an...

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NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Cited by 180 publications

References 91 publications

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling

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NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

Cited by 180 publications

References 91 publications

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Alzheimer’s disease-relevant tau modifications selectively impact neurodegeneration and mitophagy in a novelC. eleganssingle-copy transgenic model

Control of Inflammation by Calorie Restriction Mimetics: On the Crossroad of Autophagy and Mitochondria

Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+signaling

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Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD⁺signaling