Reduced Expression Of Myc Increases Longevity And Enhances Healthspan Pdf

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This state-of-the-art review on longevity focuses on centenarians, studied as a model of positive biology. The extraordinary rise in the elderly population in developed countries underscores the importance of studies on ageing and longevity in order to decrease the medical, economic and social problems associated with the increased number of non-autonomous individuals affected by invalidating pathologies.

The gene desert upstream of the MYC oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. The mice are viable and show no overt phenotype.

Centenarians

Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Its scope is unique. The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. The term was introduced in the inaugural Editorial , Introducing OncoTarget.

Sponsored Conferences. Impact Journals is a member of the Society for Scholarly Publishing. Lia R. Edmunds , P. Beck , Jerry Vockley , Satdarshan P. Monga , Erin E. Kershaw , Robert M. Kratz , Nathan A. Yates , Eric P. Goetzman , Donald Scott , Andrew W. Edmunds 1,2 , P. Beck 8 , Jerry Vockley 8 , Satdarshan P. Monga 9 , Erin E.

Kershaw 4 , Robert M. Kratz 10 , Nathan A. Yates 6,11 , Eric P. Goetzman 8 , Donald Scott 5 , Andrew W. Duncan 3 and Edward V. Prochownik 1,2, We used a model of hereditary tyrosinemia whereby the affected parenchyma can be gradually replaced by transplanted hepatocytes, which replicate fold, over several months. KO mice also consumed more oxygen, produced more CO 2 and generated more heat.

Although WT and KO hepatocytes showed few mitochondrial structural differences, the latter demonstrated defective electron transport chain function.

RNAseq revealed differences in transcripts encoding ribosomal subunits, cytochrome p members and enzymes for triglyceride and sterol biosynthesis. KO hepatocytes also accumulated neutral lipids. WT and KO hepatocytes repopulated recipient tyrosinemic livers equally well although the latter were associated with a pro-inflammatory hepatic environment that correlated with worsening lipid accumulation, its extracellular deposition and parenchymal oxidative damage.

Our results show Myc to be dispensable for sustained in vivo hepatocyte proliferation but necessary for maintaining normal lipid homeostasis. This has been subsequently supported by studies documenting recurrent MYCC de-regulation in human tumors, from animal models of Myc over-expression and from demonstrations that Myc silencing in these models promotes tumor regression [ 2 , 3 ].

Although Myc supervises many of the pathways that are commonly perturbed in cancer such as those regulating differentiation, proliferation, survival and metabolism [ 4 , 5 ], its precise role in these processes and its function s in normal cells have been somewhat more controversial and, at times, subject to conflicting experimental outcomes.

Postnatally, Myc silencing is compatible with long-term survival and is associated with only mild and reversible toxicities in proliferative tissues such as the bone marrow and gastrointestinal track [ 7 ]. Moreover, haplo-insufficiency of Myc actually slows the onset of numerous age-related pathologies and prolongs life span [ 8 ]. In contrast, the in vitro proliferation of primary murine embryonic fibroblasts declines progressively as Myc levels are reduced [ 9 ]. Thus, the consequences of Myc loss in normal cells appear to be more tissue- and context-dependent and variable than in transformed cells [ 9 ].

However, the actual requirement for Myc in this process has varied among different studies, which have not always assessed identical parameters or used similar methods for achieving myc gene deletion [ 11 - 13 ]. For example, while Sanders et al. These reports also relied exclusively on PH, which, in addition to the short duration of the regenerative response, is further hampered by the fact that fewer than 2 population doublings occur during the process [ 11 ]. Additionally, previous reports relying on PH were also largely dependent on indirect measurements of liver regeneration such as the expression of Ki, PCNA and cyclin A levels or liver:body weight ratios [ 11 , 12 , 14 ].

Type I hereditary tyrosinemia is a metabolic disorder caused by defective production of fumarylacetoacetate hydrolase FAH , which catalyzes the final step in hepatic tyrosine catabolism.

In HT, the toxic upstream metabolites fumaryl- and maleyl-acetoacetate accumulate and cause liver failure [ 15 ]. Deletion of the murine fah gene faithfully mimics the human disease [ 16 ]. The ability of WT and KO hepatocytes to proliferate identically under highly demanding conditions may explain why a more global long-term silencing of Myc is associated with only mild side effects or may even be beneficial [ 8 ]. WT and KO hepatocyte sizes were also similar Figure S2C indicating that, as previously reported, KO livers contain fewer rather than smaller hepatocytes to account for their reduced mass [ 8 , 9 ].

We discuss below possible reasons for the larger liver:body mass ratio of older KO mice. To rectify this, they up-regulate pyruvate dehydrogenase PDH , presumably to maximize pyruvate conversion to acetyl CoA [ 20 ]. Finally, we noted that while Myc alters the susceptibility to multiple intrinsic and environmental pro-apoptotic factors [ 22 , 23 ], no increase in apoptosis in KO livers was found based on lack of cleaved caspase 3 Figure S2I. Figure 1: Increased metabolic activity of KO mice.

Mice were maintained in metabolic cages that quantified oxygen consumption rate VO 2 , carbon dioxide production rate VCO 2 and heat production mice per group. L and D indicate cyclic periods of light and dark. Other monitoring showed no differences in the overall activity, food consumption, total fat mass or glucose tolerance between groups of WT and KO mice not shown. KO mice were noted to have increased oxygen consumption, carbon dioxide production and heat generation Figure 1 when maintained on a high fat diet.

These studies suggested that the increased metabolism of KO mice is due to abnormalities in lipid metabolism. In addition to altering cellular metabolism, Myc also affects mitochondrial structure and function [ 20 , 21 , 24 ].

Respirometry measurements showed basal O 2 flux of WT and KO liver mitochondria to be low but otherwise equivalent prior to and after priming with the Complex I substrates glutamate, pyruvate and malate G,M,P Figure 2A.

However, the magnitude of O 2 flux change in response to ADP was less pronounced in KO mitochondria Figure 2A and 2B , indicating that they reduced molecular oxygen to water via complex IV less efficiently. The provision of succinate resulted in additional but similarly unequal increases in O 2 flux.

Taken together we conclude that, while KO liver mitochondria have defects in Oxphos, they are not severe enough to compromise ATP production. We next employed a recently described targeted proteomics assay using liquid chromatography-tandem mass spectrometry to assess the relative abundance of the 93 known subunits of the ETC plus an additional 46 mitochondrial metabolism-related proteins [ 25 ].

Based on a p-value cut-off of 0. In total, peptide ions features were matched to mitochondrial proteins. Together with the results shown in Figure S3, we conclude there to be no major quantitative differences in the composition of the mitochondrial proteomes of WT and KO livers.

Typical respirometry profiles from WT and KO liver homogenates. WT and KO liver preparations were simultaneously assayed in parallel with 10 sets of mice.

Cytochrome c was added to test mitochondrial outer membrane integrity. Note that the large, spike in O 2 flux seen upon adding G,M,P is an artifact resulting from injecting a large volume of diluted substrates and transiently disturbing the O 2 concentration. Graphic representation of succinate responses. The results in A. Assays were performed on 8 sets of WT and KO livers from littermate controls. Thus, endogenous Myc maintains normal levels of a subset of ribosomal protein transcripts.

Of pathways queried, 5 of the top 7 involved the regulation of cholesterol, sterol or bile acid synthesis Figure 3D and 3E. Thus, KO hepatocytes also up-regulate multiple pathways involved directly in sterol and bile acid bio-synthesis. A trend toward lower fasting cholesterol levels was also noted and increased significantly following re-feeding Figure S5C. However, profiling a series of intermediates in the biosynthetic pathway leading from lanosterol to cholesterol, and including the bile acid intermediate cholestenol, showed no differences between WT and KO mice when adjusted either to total protein or total sterol content Figure S5E and S5F.

Bile acids consist of conjugates between taurine or glycine and cholic or chenodeoxycholic acid [ 33 ]. When measured in the livers of non-fasted animals, secondary bile acids, which are formed within the small intestine by the action of enteric bacteria, make a larger contribution to the total bile acid pool.

Therefore, we measured total bile acid levels in the livers of fasted WT and KO mice. As seen in Figure S5G, no significant differences were observed. Differences in cyp member transcript expression between WT and KO hepatocytes.

Those encoding members of the CLAN 2 family [ 26 ] are indicated by asterisks. RPL12 is from A. Differential gene expression profiling of genes involved in the top 7 deregulated pathways identified by Ingenuity Pathway Analysis. Note that the cyp members shown in B are not repeated here but were included and found to be significant in the pathway analysis of cholesterol metabolism. The top axis represents the percentage of genes comprising that pathway whose transcripts were differentially expressed between WT and KO hepatocytes.

Green bars indicate transcripts that were up-regulated in KO hepatocytes and red bars indicate down-regulated transcripts. Some transcripts are included in more than one pathway. Orange circles indicate the log 10 p value indicating the probability that the differentially expressed transcripts within a specific pathway would have been selected randomly.

Numbers on the right indicate the number of transcripts assigned to the indicated pathway. This approach therefore provides a superior alternative to PH as the transplanted hepatocytes are subject to a more intense and prolonged replicative stress. The time needed to permanently re-establish pre-transplant weights was similar in the two groups suggesting that WT and KO hepatocytes possessed equal repopulation potential Figure 4C.

This was supported by the presence of numerous macroscopic and microscopic foci of regenerating hepatocytes in both groups of animals Figure 4D and by extensive focal FAH immuno-positivity Figure 4D , FAH.

Additional immuno-histochemical staining showed Myc-positive hepatocytes only in regenerating nodules derived from WT donors Figure 4D , c-Myc. Thus, liver regeneration by KO hepatocytes was not due to the selective expansion of a minority sub-population of hepatocytes with non-excised myc loci. This was independently confirmed using the PCR-based strategy shown in Figure S1B and S1C black and blue arrows to amplify different sized segments of donor and recipient myc loci. KO hepatocytes therefore are not at a proliferative disadvantage even when competing directly with their WT counterparts.

Pathway of hepatic tyrosine catabolism. Livers have been flushed with PBS to facilitate visualization of regenerating nodules arrows. Tissues were counterstained with DAPI blue.

Reducing Myc gene increases lifespan of mice by 15% on average

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Address correspondence to Haim Y. E-mail: Haim. Cohen biu. The extension in human lifespan in the last century results in a significant increase in incidence of age related diseases. It is therefore crucial to identify key factors that control elderly healthspan. However, it is as yet unknown whether SIRT6 also affects various healthspan parameters. In comparison to their wild-type WT littermates, old MOSES mice showed amelioration of a variety of age-related disorders, including: improved glucose tolerance, younger hormonal profile, reduced age-related adipose inflammation and increased physical activity.

Reducing Myc gene increases lifespan of mice by 15% on average

Loss of gut integrity is linked to various human diseases including inflammatory bowel disease. However, the mechanisms that lead to loss of barrier function remain poorly understood. Using D. Reduction of dMyc in enterocytes induced cell death, which leads to increased gut permeability and reduced lifespan upon DR. Genetic mosaic and epistasis analyses suggest that cell competition, whereby neighboring cells eliminate unfit cells by apoptosis, mediates cell death in enterocytes with reduced levels of dMyc.

Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Bats are the longest-lived mammals, given their body size.

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism.

Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Its scope is unique.

 Четыре умножить на шестнадцать, - спокойно сказал Дэвид.  - Вспомни арифметику, Сьюзан. Сьюзан посмотрела на Беккера, наблюдавшего за ней с экрана. Вспомнить арифметику. Он сам считает как фокусник. Она знала, что он перемножает цифры и намертво запоминает словари, не хуже ксерокса. - Таблица умножения, - сказал Беккер.

 Дэвид. - Это Стратмор, - прозвучал знакомый голос. Сьюзан плюхнулась обратно в ванну. - Ох! - Она не могла скрыть разочарование.  - Здравствуйте, шеф.

Если бы он тогда знал… ГЛАВА 9 Техник систем безопасности Фил Чатрукьян собирался заглянуть в шифровалку на минуту-другую - только для того, чтобы взять забытые накануне бумаги. Но вышло. Пройдя помещение шифровалки и зайдя в лабораторию систем безопасности, он сразу почувствовал что-то неладное. Компьютер, который постоянно отслеживал работу ТРАНСТЕКСТА, оказался выключен, вокруг не было ни души. - Эй! - крикнул Чатрукьян. Ответа не последовало. В лаборатории царил образцовый порядок, словно здесь никто не появлялся уже много часов.

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Джабба взглянул на часы. - Странное? - Он начал беспокоиться.  - Можешь выражаться яснее. Две минуты спустя Джабба мчался вниз к главному банку данных. ГЛАВА 85 Грег Хейл, распластавшись, лежал на полу помещения Третьего узла. Стратмор и Сьюзан отволокли его туда через шифровалку и связали ему руки и ноги толстым кабелем от одного из лазерных принтеров.

Он спрятал свой ключ, зашифровав его формулой, содержащейся в этом ключе. - А что за файл в ТРАНСТЕКСТЕ? - спросила Сьюзан. - Я, как и все прочие, скачал его с сайта Танкадо в Интернете. АНБ является счастливым обладателем алгоритма Цифровой крепости, просто мы не в состоянии его открыть. Сьюзан не могла не восхититься умом Танкадо. Не открыв своего алгоритма, он доказал АНБ, что тот не поддается дешифровке.

Стоя возле креста, он слушал, как приближаются шаги Халохота, смотрел на распятие и проклинал судьбу. Слева послышался звон разбитого стекла. Беккер повернулся и увидел человека в красном одеянии. Тот вскрикнул и испуганно посмотрел на Беккера. Как кот, пойманный с канарейкой в зубах, святой отец вытер губы и безуспешно попытался прикрыть разбившуюся бутылку вина для святого причастия.

Само ее существование противоречило основным правилам криптографии. Она посмотрела на шефа. - Вы уничтожите этот алгоритм сразу же после того, как мы с ним познакомимся.

Какое-то время Стратмор задумчиво нажимал на клавиши мышки, вмонтированной в столешницу письменного стола. После долгой паузы он наконец посмотрел ей в глаза и долго не отводил взгляда. - Назови мне самое большое время, которое ТРАНСТЕКСТ затрачивал на взламывание кода. Что за чепуха.

Сегодня же суббота. Найди себе какого-нибудь парня да развлекись с ним как следует. Она снова вздохнула. - Постараюсь, Джабба. Поверь мне, постараюсь изо всех сил.

Нуматака чуть не расхохотался во весь голос. Он знал, что это трюк. Корпорация Нуматек сделала очень крупную ставку на новый алгоритм Танкадо, и теперь кто-то из конкурентов пытается выведать ее величину. - У вас есть ключ? - сказал Нуматака с деланным интересом. - Да.

 - С руки Танкадо исчезло кольцо. - Да. К счастью, Дэвид это обнаружил. Он проявил редкую наблюдательность. - Но ведь вы ищете ключ к шифру, а не ювелирное изделие.

 Больше трех часов. Стратмор кивнул. Она не выглядела взволнованной. - Новая диагностика. Что-нибудь из Отдела обеспечения системной безопасности.

Это. - Si.

Стратмор поднял глаза вверх, собираясь с мыслями. - Сьюзан, - наконец произнес он еле слышно.  - У меня нет семьи.

 Вы этого не сделаете! - крикнул Хейл.  - Я все расскажу. Я разрушу все ваши планы. Вы близки к осуществлению своей заветной мечты - до этого остается всего несколько часов.

 Почему вы ушли из парка? - спросил Беккер.  - Умер человек. Почему вы не дождались полицейских.

Он смотрел на нее с недоумением. - Доктор, - повторила.  - Скажи первое, что придет в голову.

Дэвид молчал. - Расскажи.  - Она надулась.

В этом нет никакого смысла, - размышляла.  - Если он не знал, что мы его убиваем… Ничего не понятно. Слишком поздно. Мы упустили что-то очень важное. На экране ВР у входа толпились и множились хакеры, число их за последние минуты удвоилось.

Не останавливаясь, он отстегнул телефон от брючного ремня. - Говорите. - Где мой ключ? - прозвучал знакомый голос. - Кто со мной говорит? - крикнул Стратмор, стараясь перекрыть шум. - Нуматака! - огрызнулся сердитый голос.

3 Response
  1. Povevenma

    A team of scientists based at Brown University has found that reducing expression of a fundamentally important gene called Myc significantly increased the healthy lifespan of laboratory mice, the first such finding regarding this gene in a mammalian species.

  2. Theosubronu1967

    So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone GH , IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate.

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