\r\n\tAnimal food additives are products used in animal nutrition for purposes of improving the quality of feed or to improve the animal’s performance and health. Other additives can be used to enhance digestibility or even flavour of feed materials. In addition, feed additives are known which improve the quality of compound feed production; consequently e.g. they improve the quality of the granulated mixed diet.
\r\n
\r\n\tGenerally feed additives could be divided into five groups: \r\n\t1.Technological additives which influence the technological aspects of the diet to improve its handling or hygiene characteristics. \r\n\t2. Sensory additives which improve the palatability of a diet by stimulating appetite, usually through the effect these products have on the flavour or colour. \r\n\t3. Nutritional additives, such additives are specific nutrient(s) required by the animal for optimal production. \r\n\t4.Zootechnical additives which improve the nutrient status of the animal, not by providing specific nutrients, but by enabling more efficient use of the nutrients present in the diet, in other words, it increases the efficiency of production. \r\n\t5. In poultry nutrition: Coccidiostats and Histomonostats which widely used to control intestinal health of poultry through direct effects on the parasitic organism concerned.
\r\n
\r\n\tThe aim of the book is to present the impact of the most important feed additives on the animal production, to demonstrate their mode of action, to show their effect on intermediate metabolism and heath status of livestock and to suggest how to use the different feed additives in animal nutrition to produce high quality and safety animal origin foodstuffs for human consumer.
",isbn:"978-1-83969-404-2",printIsbn:"978-1-83969-403-5",pdfIsbn:"978-1-83969-405-9",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"8ffe43a82ac48b309abc3632bbf3efd0",bookSignature:"Prof. László Babinszky",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10496.jpg",keywords:"Technological Feed Additives, Feed Industry, Quality of Compound Feed, Non-Antibiotic Growth Promoter, Product Quality, Additive Enzymes, Digestibility of Nutrients, NSP Enzymes, Farm Animals, Livestock, Immunity, Microbiome",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 24th 2020",dateEndSecondStepPublish:"December 22nd 2020",dateEndThirdStepPublish:"February 20th 2021",dateEndFourthStepPublish:"May 11th 2021",dateEndFifthStepPublish:"July 10th 2021",remainingDaysToSecondStep:"a month",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Professor Emeritus from the University of Debrecen, Hungary who authored 297 publications (papers, book chapters) and edited 3 books. Member of various committees and chairman of the World Conference of Innovative Animal Nutrition and Feeding (WIANF).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"53998",title:"Prof.",name:"László",middleName:null,surname:"Babinszky",slug:"laszlo-babinszky",fullName:"László Babinszky",profilePictureURL:"https://mts.intechopen.com/storage/users/53998/images/system/53998.jpg",biography:"László Babinszky is Professor Emeritus of animal nutrition at the University of Debrecen, Hungary. From 1984 to 1985 he worked at the Agricultural University in Wageningen and in the Institute for Livestock Feeding and Nutrition in Lelystad (the Netherlands). He also worked at the Agricultural University of Vienna in the Institute for Animal Breeding and Nutrition (Austria) and in the Oscar Kellner Research Institute in Rostock (Germany). From 1988 to 1992, he worked in the Department of Animal Nutrition (Agricultural University in Wageningen). In 1992 he obtained a PhD degree in animal nutrition from the University of Wageningen.He has authored 297 publications (papers, book chapters). He edited 3 books and 14 international conference proceedings. His total number of citation is 407. \r\nHe is member of various committees e.g.: American Society of Animal Science (ASAS, USA); the editorial board of the Acta Agriculturae Scandinavica, Section A- Animal Science (Norway); KRMIVA, Journal of Animal Nutrition (Croatia), Austin Food Sciences (NJ, USA), E-Cronicon Nutrition (UK), SciTz Nutrition and Food Science (DE, USA), Journal of Medical Chemistry and Toxicology (NJ, USA), Current Research in Food Technology and Nutritional Sciences (USA). From 2015 he has been appointed chairman of World Conference of Innovative Animal Nutrition and Feeding (WIANF).\r\nHis main research areas are related to pig and poultry nutrition: elimination of harmful effects of heat stress by nutrition tools, energy- amino acid metabolism in livestock, relationship between animal nutrition and quality of animal food products (meat).",institutionString:"University of Debrecen",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Debrecen",institutionURL:null,country:{name:"Hungary"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"25",title:"Veterinary Medicine and Science",slug:"veterinary-medicine-and-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"185543",firstName:"Maja",lastName:"Bozicevic",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/185543/images/4748_n.jpeg",email:"maja.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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1. Introduction
In many circumstances of practical concern, thermal sources are encapsulated into closed cavities containing a fluid, such as in the case of fuel tanks. In other applications it is the heat source itself which needs to be thermally controlled, such as in electronic packaging, passive cooling, space heating, nuclear design, and geophysics; another example is the natural convection around a horizontally-placed or vertically-positioned radiator, which can be used for a centralized heating and cooling system to regulate the air temperature in a cavity. The location of the radiator affects the temperature distribution and heat transfer in a cavity. Normally, a higher position of the radiator is reasonable when the radiator is used as a cooling device, while a lower position for the radiator is reasonable when the radiator is used for a heating one. It is worth studying the temperature distribution and heat transfer in thermal management and design. Whether the radiator is used as a cooling device or a heating device, the heat transfer of a object in a cavity can be simplified and dominated by natural convection heat transfer mechanism in an enclosure with an isolated plate.
Shyy and Rao [1] conducted an investigation of transient natural convection around an enclosed vertical plate. Numerical simulations and experimental data of natural convection air cooling of an array of two-dimensional discrete flush heaters on a vertical wall of a rectangular enclosure were performed by Ho and Chang [2]. Yang and Tao [3] developed a computational method to deal with the internal isolated islands (set the main diagonal element coefficient big values in velocity discrete equations)for natural convection in an enclosure. Experimental work and numerical simulation were studied by Wang [4] regarding natural convection in an inclined cube enclosure with multiple internal isolated plates. Also, numerical analysis on a 3×3 array of discrete heat sources flush-mounted on one vertical wall of a rectangular enclosure filled with various liquids was done by Tou and Tso [5]. Natural convection from a discrete bottom flush-mounted rectangular heat source on bottom of a horizontal enclosure was studied by Sezai and Mohamad [6]. Deng et al. [7] investigated numerically the steady state natural convection induced by multiple discrete heat sources (DHSs) in horizontal enclosures. Unsteady convection numerical modelling in a vertical channel with a square cylinder was studied by Saha [8], Static bifurcation was found by Liu and Tao [9,10] who performed numerical computations for the heat transfer and fluid flow characteristics of an internal vertical channel composed by a pair of parallel plates situated in an enclosure. Barozzi and Corticelli [11,12] investigated the two-dimensional buoyant flow in a closed cabinet containing two vertical heating plates with a time-accurate finite method. The predictions showed the long-term behavior of numerical solution is time-dependent. The studies mentioned above have not been concerned with the effect of location for heat source or heat sink on the fluid flow and heat transfer.
Following the pioneering numerical works mentioned above, the present study represents a further effort to extend the studies with numerical simulation. The main objective of this study is to analyze the variation effect of the horizontal and vertical location ratios, a/H and b/H, respectively (defined in the following section) for different cold and hot isolated vertical plates in an enclosure, with respect to the flow configuration, temperature distribution, temperature difference distribution (defined in the following section) and heat transfer characteristics of the natural convection. Effect of Rayleigh number on the fluid flow and heat transfer is also presented.
2. Physical model and numerical method
The physical configuration and boundary conditions of problems investigated in this study are shown in Fig. 1. The two horizontal walls are considered to be insulated, and the two vertical walls which have the same temperatures, as well as the isolated vertical plate are maintained at T1 andT2, respectively. In this study, the investigations are carried out through the variation of horizontal location ratio a/H and vertical location ratio b/H in the cases of T1>T2(in this caseT1=Th,T2=Tc) and T1<T2(in this caseT1=Tc,T2=Th ).
In the present model, the flow is simulated as a two dimensional phenomenon with the following assumptions or simplifications: a) the fluid (air) is Newtonian, incompressible and the flow is laminar, and; b) the temperature difference T1−T2 is small, so that the effect of temperature on fluid density is expressed adequately by the Boussinesq approximation. Next, we consider the following dimensionless variables:
where the reference velocity is defined asUR=(RaPr)1/2a/H.
The governing equations, that express the conservation of mass, momentum and energy in the fluid domain, become:
∂U∂X+∂V∂Y=0E2
U∂U∂X+V∂U∂Y=−∂P∂X+Pr(RaPr)1/2⋅∇2UE3
U∂V∂X+V∂V∂Y=−∂P∂Y+Pr(RaPr)1/2⋅∇2V+ΘE4
U∂Θ∂X+V∂Θ∂Y=K(RaPr)1/2⋅∇2ΘE5
where ∇2=∂2/∂X2+∂2/∂Y2 andK=k/kf, with kand kf being the vertical block location conductivity and thermal conductivity of the fluid, respectively.
No-slip condition is imposed on all the walls for the velocities. Thermal boundary conditions are that ∂Θ/∂Y=0 for the horizontal insulated walls, and Θ=1 for the inner heat source and Θ=0 for the vertical cold walls or Θ=0 for the inner heat sink and Θ=1 for the vertical hot walls.
The average Nusselt number is given below:
Nu=H2(H+W)(∫0L/H−∂T∂X|X=0dY+∫0L/H∂T∂X|X=L/HdY)E6
Figure 1.
Schematic diagram of configuration
Equations (1) to (5) are solved using a finite volume method (FVM) on a staggered grid system [13]. In the course of discretization, QUICK scheme is adopted to deal with convection and diffusion terms. The equations from the discretization of Eqs. (1) to (4) are solved by the line-by-line procedure, combining the tri-diagonal matrix algorithm (TDMA) and successive over-relaxation iteration (SOR) and the Gauss-Seidel iteration technique with additional block-correction method for fast convergence. The SIMPLE algorithm [13] is used to treat the coupling of the momentum and energy equations. Pressure–correction and velocity-correction schemes are implemented in the model algorithm to arrive at converged solution when both the pressure and velocity satisfy the momentum and continuity equations. The solution is considered to converge when the sum of the normalized residuals for each control equation is of order 10-6.
Special attention is paid to treatment of the isolated solid region. The presence of isolated area is accounted for by a strategy [3, 14] in which a part of solution domain is located in the flow field, therefore, the governing Eqs. (1) to (4) apply to both the fluid and the solid regions. Both the velocity and the dimensionless temperature in it remained zero in iteration process. For details, Ref.[3] may be consulted.
Non-uniform staggered grid system is employed with denser grids clustering near the plate and walls so as to resolve the boundary layer properly. Test runs are performed on a series of non-uniform grids to determine the grids size effects for the Rayleigh numbers 104, 105and 106 at grid systems 40×40, 60×60 and 80×80, respectively. For each calculation case, a grid independent resolution is obtained. The maximum difference in average Nusselt number between grid (40×40) and grid (60×60) is 5%, the difference in average Nusselt number between grid (60×60) and grid (80×80) is less than 0.2%, so the 60×60 non-uniform grids are used.
The developed computational model is validated against benchmark computational results and is also compared with experimental data. Accuracy of the numerical procedure is validated by the comparison between the predicted results with the benchmark solutions of de Vahl Davis [15] for pure natural convection model in a square cavity with opposite heated and cooled side walls. As shown in Table 1, good agreements are achieved for both the maximum velocity and the average Nusselt number in a broad range of Rayleigh numbers Ra=104 to 106. Another comparison is also made with respect to the experimental work of Wang [4]. The computationally obtained flow patterns for Ra=2×105 are compared with the flow visualization in Fig. 2. It is seen that the model adequately predicts the flow patterns obtained in the visualizations.
Ra
Present
Benchmark
Umax
Nu
Umax
Nu
104
0.192
2.231
0.193
2.245
105
0.129
4.50
0.132
4.510
106
0.078
8.817
0.077
8.806
Table 1.
Comparisons between the predicted results and the benchmark resolutions of de Vahl Davis[15]
Figure 2.
Flow field (a) Flow visualization [4], (b) Computation
3. Results and discussion
The configuration dimension is in the proportion ofL:H:W=80:15:3.We will examine the fluid flow and heat transfer characteristics under the circumstances of heating or cooling at various locations, followed by the dependence to the Rayleigh number.
3.1. Effect of location on the fluid flow and heat transfer
Numerical simulations have been conducted to elucidate the effect of location ratios variation a/H (0.3≤a/H≤2.7, b/H=0.3) and b/H(0.3≤b/H≤4.0, a/H=0.3) on the natural convection of a cold isolated vertical plate and hot isolated vertical plate in an enclosure, Rayleigh number is fixed at Ra=2.5×104 in both cases.
3.2. Flow and temperature fields
The buoyancy-driven flow and temperature fields in the enclosure for a cold plate and a hot plate with the variation of location ratios a/H and b/Hare illustrated by means of contour maps of streamlines and isotherms, respectively, as exemplified in Figs. 3 to 6.
For Fig.3 (a-f), there are two vortices flow where the directions are different for cold plate and hot plate. With the increase of horizontal location ratioa/H near the middle of the enclosure, the two vertices structure around the vertical plate tend to be more symmetric for cold plate and hot plate. The spaces at the two sides of the plate are large enough for the flow within it to develop, so buoyant convection flow is strong on the upper surface of hot plate, indicating the strong effect of the natural convection, while convection is weak in the case of cold plate relatively.
Figure 3.
Streamlines for different horizontal locations at Ra=2.5×104
Dimensionless temperature distributions, plotted against the variation of the horizontal location ratioa/H, are displayed in Fig.4 (a-f). From this plot, it can be seen that isotherms near walls are almost vertical up to the upper and lower walls. This is due to the conduction effect. The figures reveal also that dimensionless temperature distributions of cold plate are more stratified than those of the hot plate.
Figure 4.
Isotherms for different horizontal locations at Ra=2.5×104
For Fig. 3(a and b),\n\t\t\t\t\tFig. 5 and Fig. 6, we observe significantly different fluid flow and temperature distribution phenomena: the larger of the vertical location ratiob/H, the stronger the flow below the cold plate surface, and the more stratified temperature distribution for the hot plate.
Figure 5.
Streamlines for different vertical locations at Ra=2.5×104
It is apparent from the comparison of fluid flow configurations and dimensionless temperature distributions of the cold plate and hot plates that the vertical location ratio b/H has a substantial effect on the flow configuration and temperature profile.
3.3. Temperature difference distribution
Uniform temperature difference in an enclosure may have practical importance, particularly in electronics and air conditioning. In order to describe the uniformity of temperature difference in an enclosure we define TD, which means difference of node temperature and average temperature where average temperature is obtained by a weighted area method.
Figure 6.
Isotherms for different vertical locations at Ra=2.5×104
TD=tij−∑tijAij∑AijE7
Two cases are studied atRa=2.5×104, case 1: a/H=0.3 and b/H=0.3, and case2: a/H=0.3 and b/H=2.0. Figure 7 shows the temperature difference distribution, marked as TD and plotted against the height of enclosure, while the width is fixed for heating and cooling conditions.
It can be seen that, in case 1, the temperature difference of heating condition along the height of enclosure is more uniform (the maximum dimensionless temperature difference is 0.11) than that for cooling condition (the maximum dimensionless temperature difference is 0.48). While with the increase of height, the dimensionless temperature differences between heating condition (the maximum dimensionless temperature difference is 0.203) and cooling condition (the maximum dimensionless temperature difference is 0.245) are not great along the height of enclosure in case 2. It implies that the requirement of heating and cooling in case 2 for same component can be met.
Figure 7.
Variation of temperature difference with the height of enclosure for heating and cooling condition
3.4. Heat transfer
Next, attention is focused on the role which the location ratio can play in the heat transfer rate. Figures 8 and 9 present results of the average Nusselt number defined by Equation (5).
For both the cold and the hot plates, b/His fixed at 0.3. Results show that the same trend occurs with the increase of a/H for both cold plate and hot plate. When the plate is within a wide range of enclosure values, 0.3<a/H<4.8, the effect of its location on heat transfer is small. The variation character of Nu vs. a/Himplies that in a wide range ofa/H, the spaces at the two sides of the plate are large enough for the flow within it to develop, therefore, the average heat transfer rate is not sensitive to the distance from the side wall. Indeed, the average hot plate Nusselt number is 20% to 39% higher as compared to that of the cold plate. The fact that the average Nusselt number of the hot plate is higher than the corresponding cold plate, can be explained if we consider the streamlines shown in Fig. 3 and temperature profiles in Fig. 4. From these figures we note that the natural convection occurs easier for the hot plate, due to a higher heat transfer than for the cold plate under the same boundary conditions. The steep increase of average Nusselt number near walls for the cold and hot plates in Fig. 8 is referred to as the “chimney effect”. The present results confirm the fact that the stronger chimney effect enhances the heat transfer [16, 17]. For Pr≈1, the boundary layer thickness for the plate scales as [18],
δ=δT≈y(gβΔTy3aν)−1/4E8
Which indicates that δincreases asy1/4.
Figure 8.
Variation of Nu with horizontal location
The convection is enhanced due to the instability of thermal boundary layers near the left plate and right wall (0<a/H<0.3) or right plate and left wall (4.8<a/H<5). In this spacing, the thermal boundary layers of wall and plate merge with each other, so the boundary layer thickness is thin leading to the increase of Nusselt number. Therefore, the characteristics of the fluid flow and heat transfer in enclosure are very sensitive to the distance between the wall side and the plate.
Different trends occur when the cold plate and the hot plate are at different vertical location which is shown in Fig. 9. Study of Fig. 9 reveals that for cold plate, as the vertical location ratio increases from 0.3 to 3.3 the average Nusselt number increases from 4.33 to 5.68, and slightly decreases from 5.68 to 5.52 when location ratio increases to 4. That means there exists a maximum average Nusselt number when cold plate location (b/H)opt is 3.3. For the hot plate, average Nusselt number slightly increases from 5.47 to 5.61 when location ratio increase from 0.3 to1.33, and decreases from 5.61 to 4.3 when vertical location ratio increases from 1.33 to 4. There is an appropriate location which corresponds to a maximum heat transfer density for the hot plate also. This can be attributed to two different flow patterns. However, the average Nusselt number variation is not significant for cold and hot plates.
By comparison of Fig. 3(a and b),\n\t\t\t\t\tFig. 5(c and d),\n\t\t\t\t\tFig. 6(c and d), and Fig. 9, it can be seen that the symmetry phenomenon appears, i.e. the identical problems of natural convection in an enclosure [19].
Figure 9.
Variation of Nu with vertical location
3.5. Effect of Ra on the fluid flow and heat transfer
The procedure is then repeated over the range102≤Ra≤108. The effect of the Rayleigh number on the average Nusselt number by setting a/H=0.3 and b/H=0.3 under the circumstances of heating or cooling the block is shown in Fig. 10.
The flow patterns and isotherms are drawn for two typical Rayleigh numbers: Ra=1.0×102and Ra=1.0×107 for one geometrical configuration a/H=0.3 and b/H=0.3. These are presented in Figs. 11 and 12.
For the low Rayleigh numbers (Ra=102—104), the flow field consists of a single big vortex in the half domain of cavity. With an increase in Rayleigh number, the heat transfer process is dominated successively by conduction mode, combined mode of conduction-convection and convection mechanism. When the Rayleigh number increases to as high as1.0×107, it indicates the convection mode is predominated, these can be seen from Figs. 11 and 12.
At the lower Rayleigh numbers (Ra=102—104), Nusselt number of heating condition is a little bit higher than that of cooling condition which can be explained that convection of the hot plate is easier to establish than that of cold plate, conduction mechanism is prevailed and hence heat transfer is mainly dominated by conduction. That is why the Nu values shown in Fig. 10 are almost constant in the low Ra number range.
With the increase in Rayleigh number, Eq. (7) shows that at high Rayleigh numbers, the boundary layers on the enclosure right wall and plate left surface become very thin, leading to a significant increase in Nusselt number. It can be seen from Figs. 10 to 12 that in the convection regime (Ra>104), the flow fields difference between the cold plate and the hot plate is appreciable, and the deviations of the Nusselt number between the cold plate and the hot plate are greater. The reason is that heat convection of the hot plate is easier to establish than that of the cold plate.
Figure 10.
Nu versus Ra for heating and cooling cases
3.6. Special case -non steady state prediction
When the isolate is located in the middle of the enclosure,i.e. L:H:W:b=80:15:4:5, After giving definition of dimensionless timeF=aτH2(RaPr)12, it is easy get the dimensionless non-steady governing equation based on Equation(1)-(4).
The boundary conditions for this system are as same as steady system above.
Figure 11.
T1<T2flow patterns (left) and isotherms (right) at different Rayleigh numbers
The zero initial conditions set for velocity and temperature fields.
A perfectly time-periodic solution is predicted shown in Fig. 13 for different Raleigh number(Ra=104, Ra=5x104, Ra=105 and Ra=106). Fig. 13a reports the time dependent behavior of dimensionless temperature at the monitoring point (x,y)=(1.3,1.53)of the cavity, and the average Nusselt number result is depicted in Fig. 13c. The first noteworthy feature of Fig. 13 is that, except low value of Ra number(Ra=10000,50000),after a few time units, a transition to oscillatory flow occurs. the symmetric solution breaks down as instabilities grow, and the time behaviors of quantities relative to geometrically symmetric points begin to differ, The quantities at location (x,y)=(1.3,1.53) exhibit a clearly periodic behavior for Ra=100000(Fig. 13c,d), the period being about 10 time unit.
Figure 12.
T1>T2flow patterns (left) and isotherms (right) at different Rayleigh numbers
The isotherms are plotted in Fig. 14 for approximately equal time interval in one periodic circle When analyzing the macroscopic nature of the flow configurations, We observe the isotherms are not centrosymmetric at any point in time. The flow configurations manifest themselves in same pattern—the rolls movie to the left or right with the oscillation.
Figure 13.
Time history of the dimensionless temperature and Nusselt number at the monitoring point (x,y)=(1.3,1.53)of the cavity
Figure 14.
Series of instantaneous streamlines for Ra =105
4. Concluding remarks
A numerical study has been presented to unveil primarily the effect of location ratio variation of cold isolated vertical plate and hot isolated vertical plate on the natural convection in an enclosure. We conclude as follows from the numerical results.
The flow configurations and dimensionless temperature profiles of cold plate and hot plate are different;
The stratification is found to be strong for cold plate, while for the hot plate is relatively weak;
The temperature difference along the height of the enclosure in heating conditions is more uniform than that obtained in cooling conditions;
The increase of vertical location near the middle of enclosure leads to small temperature differences in heating and cooling conditions;
The trend of the average Nu number variation is the same for the cold and hot plates, when the plate is fixed at different horizontal locations. However, the average Nu number of the hot plate is about 20% to 39% larger than that of cold plate at the same Rayleigh number of 25000. For narrow distances between the inner plate and the bounding wall, the inner plate Nusselt number is enhanced, aside from this, the plate average Nusselt number is insensitive to the plate position;
The average Nu numbers tend to decrease with the increase of vertical location ratio (1.33<b/H<4) for hot plate, but for the cold plate the average Nu number tends to augment with the increase of vertical location ratio (0.3<b/H<3.3);
An optimum vertical location ratio exists at which the heat transfer is maximum for both cold and hot plates at a specific Rayleigh number;
Non-steady modeling simulations reveals that solutions are unique for values of Rayleigh number 104 and 5×104 where the flow and heat transfer is steady state. While unsteady state flow and heat transfer is appeared as a function of Ra=105 and Ra=106 for the rectangular block located in the middle of the cavity.
Nomenclature
a horizontal location
A node(i,j) based control volume area
b vertical location
F non-dimensional time
g gravitational acceleration
H height of vertical plate
k vertical block location thermal conductivity
kf fluid thermal conductivity
K relative thermal conductivity
L characteristic length of the enclosure
Nu Nusselt number
p pressure
P non-dimensional pressure
Pr Prandtl number
Ra Rayleigh number
t node(i,j) temperature
T temperature
TD temperature difference
u,v velocity components
U,V dimensionless velocity
W width of vertical plate
x,y Cartesian coordinates
X,Y dimensionless coordinates
Greek. symbols
a thermal diffusivity
β coefficient of thermal expansion
δ velocity boundary layer thickness
δT thermal boundary layer thickness
ρ density of the fluid
ν kinematic viscosity of the fluid
Θ dimensionless temperature
Subscipts
c cold
h hot
opt optimization
R reference
Acknowledgement
This work is supported by National Natural Science Foundation of China(No.51176132)
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Results and discussion",level:"1"},{id:"sec_3_2",title:"3.1. Effect of location on the fluid flow and heat transfer",level:"2"},{id:"sec_4_2",title:"3.2. Flow and temperature fields",level:"2"},{id:"sec_5_2",title:"3.3. Temperature difference distribution ",level:"2"},{id:"sec_6_2",title:"3.4. Heat transfer",level:"2"},{id:"sec_7_2",title:"3.5. Effect of Ra on the fluid flow and heat transfer",level:"2"},{id:"sec_8_2",title:"3.6. Special case -non steady state prediction",level:"2"},{id:"sec_10",title:"4. Concluding remarks",level:"1"},{id:"sec_10_2",title:"Nomenclature",level:"2"},{id:"sec_12",title:"Greek. symbols",level:"1"},{id:"sec_12_2",title:"Subscipts",level:"2"},{id:"sec_13_2",title:"Acknowledgement",level:"2"}],chapterReferences:[{id:"B1",body:'Shyy, W., and Rao, M.M., Simulation of Transient Natural Convection around an Enclosed Vertical Plate, ASME J. Heat Transfer, vol. 115, pp. 946-953, 1993.'},{id:"B2",body:'Ho, C.J., and Chang, J.Y., A Study of Natural Convection Heat Transfer in a Vertical Rectangular with Two-dimensional Discrete Heating: Effect of Aspect Ratio, Int. J. Heat Mass Transfer, vol. 37, pp. 917-926, 1994.'},{id:"B3",body:'Yang, M., and Tao, W.Q., Numerical Study of Natural Convection Heat Transfer in a Cylindrical Envelope with Internal Concentric Slotted Hollow Cylinder, Numerical Heat Transfer, Part A, vol. 22, pp. 281-305, 1992.'},{id:"B4",body:'Wang, Q.W., Natural Convection in an Inclined Cube Enclosure with Multiple Internal Isolated Plates, Ph.D.Dissertation., Xi’an Jiaotong University,China,1996'},{id:"B5",body:'Tou, S.K.W., and Tso, C.P., 3-D Numerical Analysis of Natural Convective Liquid Cooling of 3x3 Heater Array in Rectangular Enclosure, Int.J. Heat Mass Transfer,42323132441999'},{id:"B6",body:'Sezai, I., and Mohamad, A.A., Natural Convection from a Discrete Heat Source on the Bottom of a Horizontal Enclosure, Int.J. Heat Mass Transfer, 42225722662000'},{id:"B7",body:'Deng, Q.H., Tang, G.F., and Li, Y.G., Interaction between Discrete Heat Source in Horizontal Natural Convection Enclosures, Int.J. Heat Mass Transfer, 45511751322002'},{id:"B8",body:'SahaA. K.Unsteadyfree.convectionin. a.verticalchannel.witha.built-inheated.squarecylinder.NumericalHeat.TransferPart. A.vol87958182000'},{id:"B9",body:'Liu, J.P., and Tao, W.Q., Numerical analysis of natural convection around a vertical channel in a rectangular enclosure.Heat and Mass Transfer; 3153133211996\n\t\t\t'},{id:"B10",body:'Liu, J.P., and Tao, W.Q., Bifurcation to oscillatory flow of the natural convection around a vertical channel in rectangular enclosure, International Journal of Numerical Methods for Heat and Fluid Flow, vol.21701851999\n\t\t\t'},{id:"B11",body:'Barozzi, G.S., and Corticelli, M.A., Natural convection in cavities containing internal heat sources, Heat and Mass Transfer, vol.4734802000\n\t\t\t'},{id:"B12",body:'BarozziG. S.CorticelliM. A.NobileE.Numerical simulation of time-dependent buoyant flows in an enclosed vertical channelHeat Mass Transfer, 3589991999\n\t\t\t'},{id:"B13",body:'Patankar, S.V., Numerical Heat Transfer and Fluid Flow, McGraw-Hill, New York, pp.1461521980'},{id:"B14",body:'Tao, W.Q., Numerical Heat Transfer (2ed edition) Xi’an Jiaotong University Press, pp.2442452001in Chinese)'},{id:"B15",body:'de Vahl Davis G., Natural Convection of Air in a Square Cavity: a Benchmark Numerical Solution, Int.J. Meth. Fluids, 32492641983'},{id:"B16",body:'KazanskyS.DubovskyV.ZiskindG.LetanR.Chimney-EnhancedNatural.Convectionfrom. a.VerticalPlate.ExperimentsNumericalSimulations.IntJ. Heat Mass Transfer,464975122003\n\t\t\t'},{id:"B17",body:'Auletta, A., and Manca, O., Heat and Fluid Flow Resulting from the Chimney Effect in Symmetrically Heated Vertical Channel with Adiabatic Extensions, Int.J. of Thermal Sciences, 41110111112002'},{id:"B18",body:'BejanA.ConvectionHeat.TransferWiley.NewYork, 1984'},{id:"B19",body:'Yang, M., Tao, W.Q. and Wang, Q.W., On the Identical Problems of Natural Convection in Enclosures and Applications of the Identity Character, Int.J. of Thermal Sciences, 21161251993'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Xiaohui Zhang",address:null,affiliation:'
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1. Introduction
Skin, the largest vital organ in the body, is made of three distinct layers from the top to the depth: the epidermis, which is a fine layer of epithelial keratinized cells called keratinocytes; the dermis consisting of fibroblasts in an intracellular matrix with various additional structures such as hear follicles, sweat glands, nerve endings, and capillaries; and the profound subcutaneous tissue called hypodermis. As a physical barrier between the body and the environment, the skin is affected by both intrinsic and extrinsic aging. Intrinsic or chronological aging is a natural continuous dynamic process that normally begins in the mid-1920s. During this inexorable process, the skin undergoes a physiological deterioration characterized by skin atrophy, increased physical and immunological vulnerability, with a reduced capacity of tissue repair in case of wounding. More precisely, intrinsic aging is leading to a 10–50% thinning of the epidermis, the flattening of the dermal-epidermal junction, an atrophy of the dermis with disorganization of the collagen and elastic fibers, a reduction of the microvasculature, and a loose of adipose tissue [1]. The thinning of the epidermis and the reduction of the skin regeneration capacities are mainly linked to the dysfunctions of the epidermal stem cell compartment, which progressively lose its capacity to generate progenitor cells that are able to ensure the physiological renewal of the epidermis or to sustain wound repair [2].
Skin is also constantly exposed to environmental insults such as ionizing or UV radiations, chemicals, or climatic variations [3]. UV exposure is the main player in extrinsic skin aging and leads to phenotypic changes named photoaging. The photo-aged skin is characterized by a thickening of the epidermis with abnormal keratinocytes differentiation, an accumulation of abnormal elastic tissues (called solar elastosis) with a disorganization and degradation of the collagen fibers in the dermis, an abnormal pigmentation, and an activation of the immune response [4]. Skin is affected by both UV-A and UV-B radiations. UV-B rays are mainly limited to the superficial epidermal part of the skin and directly induce DNA lesions such as cyclobutane dimers and 6–4 photoproducts in exposed cells, leading to keratinocytes senescence, apoptosis, or carcinogenesis [5]. UV-A rays penetrate deeper into the dermis and induce DNA, protein, and lipid damages through the generation of reactive oxygen species (ROS), which in turn activate MAP-kinase p38, JNK, and ERK pathways with induction of the AP1 transcription factor resulting in the expression of the MMP1, -3, and -9 responsible for extracellular matrix degradation [6]. ROS also oxidate cellular components including proteins, lipids, DNA, and RNA, with altered metabolism and further damages.
ROS are also produced during the chronological aging process mainly through mitochondrial activity of the electron transport chain and this is the basis of the free radical theory of aging [7]. It states that mutations acquired in mitochondrial DNA (mtDNA) during life can disrupt metabolisms in the mitochondria and increase ROS. In the skin, mtDNA mutations accumulate with age and UV stress can accelerate this damage. Mitochondrial dysfunctions specifically contribute to skin aging phenotype especially through abnormal pigmentation and hair graying and loss [8]. More precisely, mitochondria play a pleiotropic role in pigmentation by modulating the melanin production through interacting with melanosomes [9]. Moreover, increased oxidative stress linked to mitochondrial dysfunction is observed in aged melanocytes and hair follicle epithelium [10].
Elimination of damaged mitochondria seems then to be a safety mechanism preserving cellular function, tissue homeostasis and organismal soundness. Selective mitochondrial autophagy, named mitophagy, has been described to ensure this function. Autophagy is a cellular quality control mechanism preliminary nonselective playing an essential role in cells for bulk proteins and organelle recycling. Mitophagy modulates the turnover of mitochondria under equilibrium conditions and adjusts the number of mitochondria according to the cellular needs. Increasing evidence suggest that impairment of mitophagy is involved in aging and age-related diseases [11] but the genetics and epigenetics mechanisms modulating mitophagy during aging remain to be better understood.
Multiple epigenetic changes are considered as reliable hallmarks of tissue aging such as modification of DNA methylation motifs, histone post-translational modifications, and modulation of noncoding RNA expression [12]. The latter is an emerging scientific domain in which an incredibly expanding number of studies have been published over the last decade, highlighting day after day the key roles of long noncoding RNAs, circular noncoding RNAs, and microRNAs (miRNAs) in the control of physiologic balances. For example, the stem cell function is governed by numerous factors such as growth factors, cellular metabolism, mediators of inflammation, extracellular matrix, interaction with niche cells, and so on. It has been clearly described that the imbalance between stem cells renewal and commitment can give rise to deleterious effects leading to pathologies or accelerated aging [13, 14]. Recent single-cell analyses from multiple tissues, including epidermis, revealed a clonal heterogeneity of gene expression level among a defined cell population [15, 16, 17], thus reflecting a distinct fluctuating transcriptome in individual cells which governs cell fate. Thus, cell fate decisions rely on the integration of dynamic regulatory networks of gene expression and these fluctuating transcriptomes are likely to be under the control of noncoding RNAs, which cooperate with each other and are co-regulated.
Isolated human primary keratinocytes are a valuable model for studying epidermal aging as they retain features of the tissue they are extracted from. Recently, we took advantage of this model to identify miRNAs modulated with chronological aging through a genome-wide expression analysis of cell extracted from skin biopsies of healthy infants (3–6 years old), young adults (20–40 years old), and aged adults (60–71 years old). This microarray screening allowed us to identify 60 miRNAs significantly modulated (P < 0.05, fold change >1.5) between at least two of the three sample groups analyzed [18]. Most of them were differentially expressed between the youngest group and the two adult groups. Considering that physiological aging starts as early as 20 years old and that our cell samples were prepared from photo-protected skin areas, one can speculate that constant modulation of miRNAs expression as soon as 20 years could constitute an epigenetic signature of intrinsic chronological aging. Thus, according to our miRNome analysis during aging, this signature would be constituted by the overexpression of miR-181d-5p, miR-1972, miR-200c-5p, miR-30a-3p, miR-30a-5p, miR-30c-2-3p, miR-30c-5p, miR-365a-5p, miR-4298, miR-6812-5p, and miR-6831-5p and the underexpression of miR-4443. Among these miRNAs of the epidermis aging signature, no mechanistic studies are referenced in the literature for miR-1972, miR-4298, miR-6812-5p, and miR-6831-5p, thus limiting any biological interpretation. Furthermore, if few studies are published to date for miR-365 and miR-4443, they mostly come from cancerology studies, as it is traditionally the case for miRNA studies. Considering the debate on the relevance of the cancer cell lines as reliable mechanistic models [19, 20, 21], we decided here to focus on data obtained from pathological and physiological models excluding the cancer field, as much as we can. Consequently, we will focus here our attention on miRNA members from three different families. Interestingly enough, the miR-30 family is highly represented in this signature, and a recurrent biological pathway targeted by miR-30 is autophagy. In addition, many members of the miR-200 family have been associated to oxidative damage. Finally, the miR-181 family is progressively enriched with overexpression of additional members (miR-181a-2-3p and miR-181b-5p) with elderly. Several published studies converge toward a control of mitochondrial homeostasis by miR-181. As described earlier, the autophagic flux, the response to oxidative stress and the maintenance of functional mitochondria are all affected with skin aging and thus constitute cellular processes of particular interest regulated by miRNAs.
2. The miR-30 family in the control of the autophagic flux
The miR-30 family is composed of six members (miR-30a, miR-30b, miR-30c-1, miR-30c-2, miR-30d, and miR-30e) transcribed from three clusters of two genes located on human chromosome 1 (miR-30c and miR-30e), chromosome 6 (miR-30a and miR-30c-2), and chromosome 8 (miR-30b and miR-30d) [22]. Each gene is able to produce two mature miRNA sequences, the 3p and 5p strands (Table 1), with various abundances. We specifically observed an induction of miR-30a-3p, miR-30a-5p, miR-30c-2-3p, and miR-30c-5p in aged human skin [18]. In our miRNome analysis, the miR-30a is the most overexpressed miRNA with aging, with a 4- to 6-fold increase depending on the mature strand. For a long time, mir-30a-5p has been associated with the regulation of autophagy in various cancer cells [24, 25] and, more recently, in other several types of normal cells such as cardiomyocytes [26, 27], endothelial cells [28, 29, 30], thymocytes [31], lens epithelial cells [32], or hepatic stellate cells [33].
Table 1.
Mature sequences of miRNAs from miR-30, miR-200, and miR-181 families.
Multiple sequence alignment of miRNA mature 5p or 3p strands was done for each family using Clustal Omega program [23]. Mature sequences with an asterisk (*) correspond to the passenger strand, whereas the seed sequences in the guide strand are indicated in bold. The identity between multiple miRNA strands is expressed as relative to the first miRNA for each guide or passenger strand within a family. Stars (*) are aligned with conserved nucleotides among the different members of either guide or passenger strands for each family.
Autophagy is well-conserved catabolic process across phyla that directs the degradation of either bulk or selective cellular components. Molecular mechanisms governing autophagy in mammals has been extensively reviewed [34]. Briefly, the process is regulated by a core machinery involving a step-by-step interaction of multiple molecular partners called autophagy-related (ATG) proteins. The initiation step is under the control of the protein kinase ULK1, which phosphorylates Beclin-1 (BECN1) on S14, thus boosting the activity of the VPS34-P150 complexes that induce the nucleation of the autophagophore. Subsequent phagophore extension requires first the intervention of ATG5-ATG12-ATG16L complexes. The closure of the autophagosome relies then on the activity of the ATG4-ATG3-ATG7 complexes that convert the inactive microtubule-associated protein LC3-I into the active LC3-II form by conjugation with phosphatidylethanolamine. Finally, LC3-II allows the autophagosomes to fuse with lysosomes to form autolysosomes where all contents are enzymatically digested (Figure 1).
Figure 1.
MiRNAs regulate multiple gene regulatory networks implicated in skin aging. Members of the miR-30, miR-181, and miR-200 families are overexpressed with skin aging and regulate critical cellular processes such as autophagy, oxidative stress, and mitochondria homeostasis. Autophagy is regulated by the interaction of multiple molecular partners called autophagy-related (ATG) proteins and leads to the enzymatic digestion of autophagosome content. Oxidative stress is characterized by an accumulation of reactive oxygen species (ROS), which disturbs cellular homeostasis and leads to DNA damage and apoptosis. Mitochondria homeostasis relies on an effective biogenesis and a proper elimination of compromised mitochondria. MiR-30, miR-181, and miR-200 directly or indirectly target multiple key proteins implicated in these different processes. Fusion between multivesicular bodies (MVBs) and cell membrane allows the liberation of exosomes and their miRNA cargo in the extracellular compartment. Red inhibitory arcs symbolize miRNA inhibitory effect by inducing mRNA decay or translation inhibition. Gray inhibition arcs indicate inhibition effect on proteins or processes. Continuous plain gray arrows represent activation effect on protein or process. Continuous straight gray arrows represent intracellular dynamics. Dotted straight gray arrows represent protein post-translational modifications.
Plethora of microRNAs have been shown to modulate the different proteins involved at each step of the autophagic process [35, 36, 37]. Although the six members of the miR-30 family have distinct mature sequences, the seed sequence is perfectly conserved (Table 1). Thus, it is not surprising that other members of the miR-30 family have been involved as well in the negative control of autophagy, such as miR-30b in vascular smooth muscle cell [38], miR-30c in neurons [39], miR-30d in astrocytes [40], and miR-30e in cardiomyocytes [41]. The different members of the miR-30 family have been primarily associated to the targeting of BECN1 [24, 25, 26, 27, 28, 29, 30, 31, 32, 33]. Importantly, this regulation of BECN1 by miR-30a has been established in vivo as well [30, 39, 41, 42]. ATG5 is another recurrent downstream target of all the members of the miR-30 family [43, 44, 45, 46, 47, 48, 49, 50, 51, 52]. Finally, BNIP3L (aka NIX) is an additional factors of the autophagy pathway negatively controlled by both miR-30c [53] and miR-30d [50, 51], whereas miR-30d also decreases the luciferase activity of reporter plasmids carrying the 3′UTR of ATG2B or ATG12 [50, 51].
The functional link between these miRNAs and the mechanisms of skin aging is not clarified yet; however, the decline in effectiveness of autophagy is clearly one of the hallmarks of aging [54]. This has been observed in diverse organisms from nematodes to rats, including human cells, and this is accompanied in part by a downregulation of ATG5 and BECN1 [55], which are notorious targets of the miR-30 family members. Accordingly, members of the miR-30 family have been shown to be induced in senescent cells, including aged keratinocytes [18, 56]. Apparent conflicting data exist in the literature as a recent study comparing gene expression from young (9–18 years old, average 12.7) and aged dermal fibroblasts (50–94 years old, average 67) revealed by RNA-seq analysis that the major autophagy-modulating genes (BECN1, MAP1LC3B, ATG5, ATG7, ULK1, PIK3C3, mTOR) were not differentially expressed [57]. However, the downregulation of mRNA target expression by miRNA binding in the 3′UTR occurs in two manners, either through mRNA decay or translation inhibition [58, 59]. Thus, the measure of mRNA levels does not simply reflect the final activity of the protein, and for example, miR-30a has been preferentially associated to BECN1 translation inhibition rather than mRNA decay in endothelial cells [29, 30]. Indeed, in the same study, even though the mRNA levels of multiple effectors of autophagy were not downregulated with aging in dermal fibroblasts, excessive residual autophagic bodies were found in these cells, thus exposing an impaired autophagic flux in aged skin [57]. This is consistent with a previous report showing a nearly 80% reduction in the autophagic flux, as determined by RT-qPCR and immunocytofluorescence analysis of LC3B expression in synchronized aged normal human skin fibroblasts and compared to young fibroblasts [60]. Likewise, accumulation of autophagic vacuoles containing debris and deformed mitochondria was found in both senescent human keratinocytes and aged dermal fibroblasts by transmission electron microscopy analysis [61, 62].
In fibroblasts, the defect in the autophagic flux was identified at the final degradation step of the autophagolysosome and was correlated with weakened turnover of dermal extracellular proteins, possibly leading to a collapse of the dermis structure and skin fragility [62]. In keratinocytes, the autophagic process, especially the nucleophagy, plays a key role in the control of the terminal differentiation [63, 64]. In addition, it has been demonstrated that Becn1 also plays a crucial role for skin development in mice [65]. Indeed, conditional knockout of Becn1 in the epidermis layer results in mice having stiff and shiny skin with extensive water loss and death within a day after birth. The silencing of BECN1 in human keratinocytes is associated with a considerable drop in expression of the keratins 1 and 10 (KRT1 and KRT10) together with puncta formation of the integrin alpha 6 (ITGA6), suggesting a failure in the normal endosomal trafficking. Since the skin phenotype is not observed in ATG5 or ATG14 KO mice, the authors suggested that BECN1 is required for normal mouse skin development through the regulation of the endocytic pathway but autonomously from the autophagy pathway. However, an ATG5/ATG7-independent alternative autophagy has been described earlier [66, 67, 68], and thus, we cannot totally exclude the direct contribution of the autophagy pathway in normal skin development.
The importance of the multiple autophagy pathways in skin function has been recently reviewed elsewhere [69]. The causative link between miR-30 members’ induction, autophagy reduction, and tissue aging still needs to be demonstrated especially in skin for miR-30a. Toward this aim, we already showed that a reduced epidermal differentiation is correlated with an abnormal barrier function in an organotypic skin models prepared with keratinocytes artificially overexpressing miR-30a [18]. Finally, the impairment of the various modes of autophagy (aggrephagy, lipophagy and mitophagy) leads to the accumulation of protein aggregates, to the aberrant handling of lipid droplets causing changes in lipid metabolism, and to the accumulation of dysfunctional mitochondria responsible for ROS production, which are all some features of aged tissue (Figure 2), including skin [70]. Interestingly, the upregulation of miR-30b and miR-30d (clustered at the same locus) significantly increases by about twofold in retinal epithelial cells treated with a sublethal dose of H2O2, a potent inducer of ROS [71]. All of these converging data from the literature strongly suggest that the negative regulation of the autophagic pathway by miR-30 could be an important mechanism contributing to tissue aging.
Figure 2.
Features of skin aging resulting of combined miRNA action. Overexpression of miR-30, miR-181, and miR-200 family members recapitulates many of the skin aging features. Each trait is directly regulated by one, two, or three of the families presented here. Some of the alterations related to miRNA regulation will also indirectly contribute to the exacerbation of the other traits. Colored lines represent direct effect of the corresponding miRNA. Dotted gray arrows symbolize indirect action of one feature on another.
3. The miR-200 family in the control of the oxidative balance
Oxidative stress results from an imbalance between the production of free radicals and their molecular scavengers aiming at the restoration of the redox equilibrium in the cell. At moderate levels, ROS induce biochemical modifications of lipids, proteins, and DNA and thus take part in the signaling cascades controlling cellular processes such as differentiation or trafficking of intracellular vesicles. However, a sustained excessive concentration of ROS will disturb the cellular homeostasis and eventually induces cell death or senescence. Every day, parts of the skin are directly exposed to solar radiations that induce the production of ROS. Since keratinocytes are exposed to both UV-A and UV-B, they display a powerful antioxidant system and an efficient DNA repair machinery compared to dermal fibroblasts.
Since the epidermis turnover takes about a month, even a little decline in this ROS scavenging mechanism will contrariwise strongly affect keratinocytes homeostasis and leads to a progressive accumulation of senescent cells that no longer participate in the regenerative process. Indeed, the steady-state ROS levels were found to be 2.6-fold higher in primary human keratinocytes from old donors (60–82 years) compared to young ones (2–45 years) [72]. This was correlated with a particular increase in 8-hydroxy-2′-deoxyguanosine (8-OH-dG) residues, a highly mutagenic DNA lesion leading to the transversion of GC to TA upon replication by a DNA polymerase [72, 73].
Consistently, a previous report has shown that about 3% of proliferating human keratinocytes contain these oxidized guanines versus 19% in senescent human keratinocytes [74]. The 8-oxoguanine DNA glycosylase (OGG1) is a key enzyme coordinating the removal of 8-OH-dG lesions by catalyzing the first step of the repair process (Figure 1), and its expression level is significantly decreased with aging in keratinocytes [72]. In silico analysis indicated that OGG1 was a potential target of miR-33a and miR-200a, with respectively two putative seed sequences and one putative seed sequence in its 3′UTR. In primary keratinocytes from human elderly donors, only miR-200a was strongly upregulated, whereas miR-33a was downregulated, suggesting that only miR-200a was responsible for OGG1 lower expression [72]. This prediction was confirmed as overexpression of miR-200a-3p mimics by transient transfection reduced both endogenous OGG1 expression and luciferase activity derived from a reporter plasmid exhibiting the OGG1 3′UTR sequence. Concomitantly with OGG1 downregulation, a significant increase of the senescence marker CDKN2A (aka P16INK4) was observed, thus showing a direct link between the redox balance and senescence in aged keratinocytes (Figure 2).
To note, we have not observed a differential expression of miR-200a-3p in our own miRNA sequencing between keratinocytes from young (3–6 years), adult (20–40 years), and elderly (60–71 years) human skin samples [18]. This difference may come from the differential segregation of young and old keratinocytes in the two studies and/or from the anatomical location of the biopsies as sun-exposed or photo-protected areas would present a different pattern of expression. Nevertheless, the miR-200 family is composed of five members, including miR-141, miR-200a, miR-200b, miR-200c, and miR-429 (Table 1), and we effectively detected a significant twofold increase in miR-200c-5p levels in both adult and aged keratinocytes as compared to the young cells from photo-protected skin biopsies [18]. The functional significance of the elevated level of expression of the so-called passenger strand still needs to be depicted. Recently, a study on miR-122 has opened up a new perspective in the miRNA field as it showed that the passenger strand is not always an innocent bystander but could also cooperates with the guide strand to achieve the same function through different mechanisms [75]. In agreement with our miRNome analysis in aged keratinocytes, miR-200c-3p was increased by about threefold in aged skin fibroblasts (65–80 years) as compared to young ones (4–6 years), isolated from skin biopsies protected from sun exposition [76]. Thus, overexpression of miR-200 family members cannot be solely interrelated to photo-aging but also to intrinsic chronological aging.
Interestingly, the existence of a crosstalk between the miR-200 family and oxidative stress has been investigated in other physiological contexts. Oxidative stress induced by H2O2 treatment in normal liver cells or normal endothelial cells triggers progressive overexpression of all of the five members, with discrepancy among them [77, 78]. Even if the five members of the miR-200 family are divided into two clusters, namely miR-200a/miR-200b/miR-429 on chromosome 1 and miR-200c/miR-141 on chromosome 12, it has been reported that the promoters of both miR-200 clusters comprise TP53-binding sites and that all of the three transcription factors TP53/TP63/TP73 are able to activate the transcription of the miR-200 family members [77, 78, 79, 80]. MiR-200c-3p has been shown to target SIRT1, FOXO1, and ZEB1, all of them being downmodulated in aged skin cells [76, 78, 81]. A complex regulatory loop exists between SIRT1 and FOXO1 as the latter is a direct target of the deacetylase SIRT1, and at the same time, FOXO transcription factors are regulating SIRT1 expression. MiR-200c-3p directly targets both SIRT1 and FOXO1 (Figure 1) [76]. Thus, by decreasing SIRT1 level, FOXO transcription factors become hyperacetylated, which in turn provokes their detachment from SIRT1 promoter, thus further decreasing SIRT1 expression [82]. FOXO1 hyperacetylation similarly decreases the expression of the ROS scavenger catalase (CAT) and superoxide dismutase 2 (SOD2) [83, 84].
Another consequence of miR-200c-induced SIRT1 downregulation is the increased acetylation of TP53, a post-translational modification associated to apoptosis induction via a TP53 transcription-independent pathway [85]. The overexpression of miR-200c-3p effectively enhances apoptotic DNA fragmentation and increases the percentage of senescent cells together with overexpression of CDKN1A (aka p21 WAF1/CIP1) [78]. Finally, miR-200c is also targeting the transcription factor ZEB1, which has been recently associated to ROS-induced senescence in human dermal fibroblast [86]. In physiological conditions, ZEB1 positively regulates the expression of the DNA methyltransferase DNMT1 that methylates CpG islands in the TP53 promoter, thus decreasing the transcription rate. In this study, the authors found that ZEB1 expression is strongly repressed by elevated ROS levels but they are still interrogating the mechanistic relationship between ROS and ZEB1 expression. One can speculate that miR-200c-3p overexpression during oxidative stress is one part of the answer.
Moreover, miR-200a-3p is regulating the ROS-stress response signaling by targeting the MAP kinase p38 alpha (aka MAPK14), which normally activates the expression of NRF2 (aka NFE2L2). NRF2 is a well-known master regulator of adaptive protection against oxidative stress in cells and especially in keratinocytes [87, 88]. Indeed, a gradient of Nrf2 expression was spotted in the murine epidermis, with higher levels of Nrf2 in the suprabasal differentiated cells and lower levels in the proliferating basal cells [89]. The gradient of Nrf2 expression and activity is crucial for long-term epidermis homeostasis. In one hand, high concentrations of Nrf2 will establish a safeguard for suprabasal keratinocytes daily assaulted by pollutants and radiations, thus maintaining the skin functional integrity. On the other hand, low concentrations of Nrf2 will preferentially orient basal transit amplifying keratinocytes toward apoptosis under stress conditions, which is imperative for the elimination of mutated stem/progenitor cells and potential malignant transformation. Furthermore, it has been demonstrated that NRF2 also improves human keratinocyte differentiation in vitro by increasing the expression of Keratin-10 and Loricrin, even if the underlying mechanism has not been addressed yet [90]. Finally, the inhibition of MAPK14 signaling targeted by miR-200a-3p triggers a lack of NRF2, which will directly affect keratinocyte differentiation together with an accumulation of ROS and the generation of mitochondrial injury resulting in cell death [77, 90]. A defective keratinocyte differentiation program and an increased keratinocyte apoptosis are two hallmarks of epidermis aging that may fit with the consequences of miR-200 overexpression (Figure 2).
4. The miR-181 family in the control of mitochondria homeostasis
In our microarray approach aiming at identifying modulated miRNA with epidermis aging, we found out that three members of the miR-181 family were significantly upregulated, namely miR-181-a (fold change 1.61), miR-181-b (fold change 1.54), and miR-181-d (fold change 2.40). Two of which were previously associated with keratinocytes replicative senescence: miR-181a (fold change 1.30) and miR-181b (fold change 1.38) and with human skin aging as well, although this latter result was not statistically significant in this particular study [81]. Additionally, miR-181a was also found to be tightly related to human dermal fibroblasts senescence [91], making it a consistent miRNA associated with skin aging. The miR-181a and miR-181b are two intronic clustered miRNAs existing in double copies on chromosome 1 (miR-181a-1 and miR-181b-1) and on chromosome 9 (miR-181a-2 and miR-181b-2), whereas the miR-181c and miR-181d constitute a third cluster on chromosome 19 (Table 1).
Multiple targets have been identified for the miR-181, including SIRT1, a key regulator of cell survival in the context of oxidative stress. The essential crosstalk between oxidative stress and SIRT1 has been fully reviewed elsewhere [92]. As discussed previously, SIRT1 deacetylates the FOXO transcription factors and subsequently stimulates the expression of antioxidants. In addition, the SIRT1-FOXO axis is also involved in autophagy induction. SIRT1 promotes the activation of FOXO transcription factors that positively regulate the expression of several autophagy-related genes such as ULK1, MAP1LC3A/B, GABARAPL1, ATG12, and BNIP3 [93, 94, 95, 96, 97]. Moreover, SIRT1 directly deacetylates the proteins ATG5, ATG7, and ATG8, thus controlling the dynamic of protein interaction and assembly requisite in the progression of the autophagic flux [98]. The importance of SIRT1 in regulating the autophagic flux was also demonstrated in vivo with a knockout mouse model. Indeed, the Sirt1−/− mice partially resemble the Atg5−/− mice, including the accumulation of damaged organelles and notably atypically shaped mitochondria, disturbance in energy homeostasis, and early perinatal mortality [98].
The disruption of the mitochondrial function is also retrieved when miR-181 are overexpressed, independently of Sirt1 expression. Indeed, miR-181 additionally targets several members of the BCL2 family: BCL2 and MCL1, two major antiapoptotic effectors, and to a lesser extent the proapoptotic effector BIM (Figure 1) [99]. BCL2 is the most famous member of the family, and it has a role in almost all the main pathways governing cell aging. First, BCL2 promotes longevity by favoring the antiapoptotic signaling [100]. Second, BCL2 has an antioxidant function as it relocates glutathione to the mitochondrial membrane [101]. Third, BCL2 inhibits starvation-induced autophagy both in vitro and in vivo by binding to BECN1. Importantly, only BCL2 proteins localized at the endoplasmic reticulum present an inhibitory effect on starvation-induced autophagy, whereas BCL2 proteins localized at the mitochondrial membrane do not play a role in this process [102]. Likewise, MCL1 has been shown to regulate the balance between apoptosis and autophagy under stress conditions [103]. Thus, the miR-181 family seems to finely control the cell fate by favoring the cell death via apoptosis over the cell survival through autophagy within oxidative environment.
Remarkably, consistent enriched expression of miR-181 is found in mitochondria across different cell models even though these miRNAs are not encoded in the mitochondrial genome but come from the nucleus [104, 105]. The precise subcellular localization of particular miRNAs at the mitochondria led to the classification of miRNAs such as “mitomiRs,” a group of approximately 60 members [106]. The miR-181a is one of the most consistent—if not the most consistent—mitomiR. Since mitochondria play a key role in the aging process, it is reasonable to assume that mitomiRs disrupt gene regulatory networks eventually contributing to tissue decline with aging. Very recently, a seminal study has demonstrated that miR-181a/b is controlling a group of elemental genes for mitochondrial biogenesis and function [107]. NRF1, a master regulator of mitochondrial biogenesis; the cytochrome c oxidase assembly protein COX11 and the coenzyme Q-binding protein COQ10B, two actors of the mitochondrial respiratory chain assembly; and the thioredoxin-dependent peroxide reductase PRDX3, another potent ROS scavenger, are newly validated direct targets of miR-181a/b (Figure 1). In accordance, the inactivation of miR-181a/b stimulates both the mitochondrial biogenesis and activity in a knock out mouse model.
In order to keep up with redox equilibrium, the cell has to maintain a perfectly tuned balance between mitochondrial biogenesis and its recycling. The elimination of defective mitochondria is mediated by the BCL2-related outer membrane protein BNIP3L/NIX, which contains a conserved LC3-binding motif and acts as a receptor for addressing damaged mitochondria to autophagosomes, which then deliver the organelle to lysosomes for degradation and recycling. A recent in vitro study has shown that transient transfection of miR-181a decreases the colocalization of mitochondria with lysosomes after drug-induced mitochondria depolarization [108]. Under stress conditions, the depolarization of the mitochondria switches the localization of the PTEN-induced serine/threonine kinase 1 (PINK1) from the inner membrane to the outer membrane where it quickly accumulates, flagging the damaged organelle for elimination. From the outer mitochondrial membrane, PINK1 phosphorylates the cytosolic Parkin (PRKN) ubiquitin ligase, which in turn is recruited to the mitochondria (Figure 1). The addition of ubiquitin chains on several outer membrane mitochondrial proteins establishes a signal for the selective autophagic removal of the mitochondria, a process called mitophagy [109]. Interestingly enough, the TargetScan prediction algorithm shows no conserved putative binding site in the 3′UTR sequence of PINK1 mRNA, whereas only one putative miR-181 binding site is present in the 3′UTR sequence of PRKN. The direct targeting of PRKN by miR-181a was demonstrated in vitro both at the mRNA level and the protein level [108]. This inhibition of PRKN by miR-181a was further associated to a substantial inhibition of the entire mitophagy process.
Accumulating compromised mitochondria will ultimately lead to the failure of the respiratory chain to produce ATP and will alongside generate even more ROS affecting in cascade the global cell homeostasis. A positive feedback loop may exist between miR-181 and oxidative stress since a recent study has shown that H2O2 was able to boost the expression of miR-181a, probably through the activation of the NF-κB signaling [110]. Altogether, these data show that miR-181 overexpression observed with skin aging would exert a deleterious effect by simultaneously preventing mitochondrial turnover and overactivation of cell death through apoptosis (Figure 2). However, it is to be noted that miR-181a/b−/− mouse model shows normal lifespan, with no apparent skin defects and thus cannot solely recapitulate the aging process [111].
5. Circulating miRNAs in the spreading of the aging message
MiRNAs have been found in all biological fluids such as blood, saliva, urine, or breast milk. These circulating miRNAs are very stable as they are protected from RNAse degradation thanks to a packaging into extracellular vesicles (EVs) made of a lipid bilayer [112, 113] or through complexing with carrier proteins [114, 115]. Indeed, an important part of circulating miRNAs is bound to the argonaute (AGO) proteins and is released in the extracellular compartment after cell death [116]. As AGO proteins are very stable in the presence of both RNAses and proteases, conjugated miRNAs are secured [117]. EVs are classically divided into three different groups: (1) apoptotic bodies, with a diameter comprised between 1 and 5 μm, (2) microvesicles, formed by direct budding of the plasma membrane and ranging in size from 0.1 to 1 μm, and (3) exosomes, the smaller EVs derived from an endosomal origin with a diameter ranging between 30 and 150 nm (Figure 1). They represent a new class of paracrine factors mediating cell-to-cell communication [118]. They transfer a complex signal to more or less distant recipient cells through their composite cargo, including proteins, mRNAs, lipids, noncoding RNAs and particularly miRNAs, thus modulating their behavior [112, 118, 119]. Interestingly, miRNAs enclosed in exosomes do not necessarily reflect their relative abundance in the parent cell, indicating that the exosomal miRNA loading occurs through a selective sorting [120, 121]. This allows a controlled released of particular messages to the recipient cells depending on the biological context. The intercellular communication via circulating miRNAs is likely to be involved in aging and age-related diseases. It was recently observed that human senescent dermal fibroblasts, which progressively accumulate in aging tissues [122], release more exosomes than proliferating cells [123]. In accordance, unpublished data from our group suggest that aged keratinocytes also secrete more exosomes as compared to young keratinocytes.
It is now well admitted that exosomes from senescent cells and their miRNA cargo are part of the senescent-associated secretory phenotype (SASP) [123]. Indeed, most of the miRNAs contained in exosomes are predicted to silence proapoptotic pathways and so could be involved in the propagation of senescent cells in tissue, thus greatly contributing to the aging process [122]. In parallel with an increased secretion of exosomes, two recent studies have demonstrated that immune cells are more capable of exosome uptake by internalization in older people [124, 125]. Even if the molecular mechanisms behind these observations are not understood yet, the decreased clearance of senescent cells by the innate immune system is clearly another factor enforcing tissue aging [126].
Specific circulating miRNAs have already been associated with different age-related diseases. For example, a concordance has been noticed between miR-29-3p increase in exosomes released by bone marrow mesenchymal stem cells and aging [127]. This miR-29-3p increase leads to insulin resistance in adipocytes, myocytes, and hepatocytes by downregulation of SIRT1 protein level. Insulin resistance is often developing in elderly type 2 diabetes patients. This suggests a significant role of exosomal miRNAs in aging-associated insulin resistance and represents a new therapeutic target. Additionally, circulating miR-34a in plasma is also increased during aging. This increase is even more important in age-related hearing loss patients and has been correlated with a decrease of diverse miR-34a target expression (SIRT1, BCL2 and E2F3) in both plasma and hearing-related tissues [128]. Besides, circulating level of miR-130b was found raised with obesity, another metabolic disorder that accelerates the rate of aging by contributing to the accumulation of the pro-oxidative advanced glycation end-products and therefore shortening life span [129, 130]. The miR-130b directly regulates the expression of the master epidermis transcription factor ∆Np63, a predominant isoform of TP63, which controls the skin stem cell maintenance and longevity and which expression is decreased with skin aging [81, 131]. Interestingly, the miR-181 clustered genes, which expressions are increased with aging, are all negatively regulated by ∆Np63. If miR-130b is slightly increased with keratinocyte replicative senescence, its expression does not change in aged skin biopsies [18, 81], suggesting that the negative modulation of ∆Np63 with aging may come from exosomal release of miR-130b. Thus, the dissemination of local high concentration of miR-130b from other altered skin or body compartments with aging could lead to the increased expression of miR-181 family members in the epidermis through miR-130b-dependent inhibition of the ∆Np63 action at the genomic loci.
In skin, few things are known concerning implication of circulating miRNAs in aging. However, several studies have demonstrated age-related changes of circulating miRNAs expression level in biological fluids [128, 132], including a decrease of miR-181a, miR-200c, and miR-30b in serum of older individuals [133, 134], one representative from each miRNA family that we focused on here. The observation that these miRNAs are increased in aged human primary keratinocytes compared to young cells [18] but decreased in the serum of elderly people well illustrates the fact that the proportion of miRNAs released by cells does not necessarily reflect the variations in parent cells. In another pathological context, the acute myocardial infarction, miR-30a, is enriched in exosome from patient serum [135]. In vitro, miR-30a enrichment in exosomes released by cardiomyocytes is repeated during hypoxia and leads to a reduction of autophagy in cardiomyocytes. To date, very few studies have focused on modulation of exosomes content in miRNA in aged skin cells. A recent study demonstrates that miR-23a-3p, which is enriched in exosomes released by senescent fibroblasts, has an impact on skin homeostasis. Indeed, miR-23a-3p seems to improve the migration of keratinocytes on a scratch closure assay in vitro and impairs keratinocytes differentiation [136]. In addition, another study has demonstrated that exosomes, and more specifically miRNA cargo, released by keratinocytes after UV-B exposure influence the activity of melanocytes [119]. The UV-B irradiation changes the exosome composition and lead to the modulation of skin pigmentation by multiple pathways.
Taken together, all of these emerging data exemplify the theory that circulating miRNAs and particularly miRNA exosome cargo play a crucial role in cell-to-cell communication. They are implicated in multiple physiological and pathological mechanisms, including aging and age-related diseases. As they are present in all the biological fluids, and more interestingly in blood, they could be used as biomarkers for various human diseases that limit lifespan. Moreover, the capability of exosomes to transfer information and affect the behavior of distant cells is very interesting for the development of new therapies. In skin context, the exosomes of the different cell types and their roles in skin homeostasis are not really described for the moment. It could be also interesting to consider if some miRNAs implicated in the complementary aging processes, as the ones we described here, are present in exosomes derived from skin cells and how they could affect some gene regulatory networks in recipient cells.
6. Conclusion
Many miRNAs have been already described in the skin to be involved in either keratinocytes or fibroblasts senescence [137]. However, cellular senescence is only one parameter contributing to tissue aging. In this chapter, we described how miRNAs could drive tissue decline with aging, by regulating complex gene regulatory networks with a special focus on autophagy, oxidative stress, and mitochondria homeostasis. Indeed, since one miRNA is targeting multiple effectors at the same time, a dynamic buffering of inter-related pathways will ultimately tip the balance toward a cell fate or another. Here, we tend to demonstrate that some miRNAs are consistently found to be indirectly or directly associated to diverse mechanisms of aging, namely the members of the miR-30, miR-200 and miR-181 family. Interestingly, the three cellular processes detailed in here are closely nested. Autophagy is crucial to remove havocs due to oxidative stress, including damaged mitochondria. Mitochondria are also a direct source of ROS, so maintaining the homeostasis of this particular organelle ensures a good oxidative equilibrium. One particular finding when we gather different studies from the literature is the fact that the three miRNA families described here, miR-30, miR-200, and miR-181, are all upregulated following an oxidative stress. Since all of them could also worsen this oxidative stress by acting on different pathways, it is not clear what is the cause and what is the consequence so far. Finally, miRNAs are clearly exported out of the parent cell and could possibly diffuse into the whole body. According to all of the emerging data exposed in this chapter, it appears quite clear that circulating miRNAs have a central role in the propagation of functional defects associated to tissue aging. A central fundamental question still remains to date: What is driving in a first place the modulation of miRNAs expression with aging?
Conflict of interest
The authors declare no conflict of interest.
Notes
All of the artworks used in Figure 1 were adapted from the illustration bank of Servier Medical Art (https://smart.servier.com) provided by Les Laboratoires Servier under a Creative Commons Attribution 3.0 Unported License.
\n',keywords:"skin, microRNA, epidermis, keratinocyte, fibroblast, aging, autophagy, oxidative stress, mitochondria, miR-30, miR-200, miR-181",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/69509.pdf",chapterXML:"https://mts.intechopen.com/source/xml/69509.xml",downloadPdfUrl:"/chapter/pdf-download/69509",previewPdfUrl:"/chapter/pdf-preview/69509",totalDownloads:328,totalViews:0,totalCrossrefCites:1,dateSubmitted:"March 4th 2019",dateReviewed:"September 12th 2019",datePrePublished:"November 26th 2019",datePublished:"March 4th 2020",dateFinished:null,readingETA:"0",abstract:"Humankind has always been intrigued by death, as illustrated by the eternal quest for the fountain of youth. Aging is a relentless biological process slowly progressing as life cycle proceeds. Indeed, aging traduces an accumulation of physiological changes over time that render organisms more likely to die. Thus, despite our mastery of advanced technologies and robust medical knowledge, defining the molecular basis of aging to control lifespan is still currently one of the greatest challenges in biology. In mammals, the skin is the ultimate multitasker vital organ, protecting organisms from the world they live in. As a preferential interface with the environment, the skin is reflecting the internal physiological balances. The maintenance of these balances, called homeostasis, depends on the concurrent assimilation of diversified signals at the cellular level. MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression by mRNAs degradation or translational repression. Their relatively recent discovery in 2000 provided new insights into the understanding of the gene regulatory networks. In this chapter, we focused on the role of three miRNA families, namely miR-30, miR-200, and miR-181, playing a key role in the progression of the skin aging process, with particular input in mechanistic considerations related to autophagy, oxidative stress, and mitochondrial homeostasis.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/69509",risUrl:"/chapter/ris/69509",signatures:"Fabien P. Chevalier, Julie Rorteau and Jérôme Lamartine",book:{id:"9377",title:"Non-Coding RNAs",subtitle:null,fullTitle:"Non-Coding RNAs",slug:"non-coding-rnas",publishedDate:"March 4th 2020",bookSignature:"Lütfi Tutar, Sümer Aras and Esen Tutar",coverURL:"https://cdn.intechopen.com/books/images_new/9377.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"158530",title:"Dr.",name:"Lütfi",middleName:null,surname:"Tutar",slug:"lutfi-tutar",fullName:"Lütfi Tutar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"101931",title:"Prof.",name:"Jérôme",middleName:null,surname:"Lamartine",fullName:"Jérôme Lamartine",slug:"jerome-lamartine",email:"jerome.lamartine@univ-lyon1.fr",position:null,institution:{name:"Claude Bernard University Lyon 1",institutionURL:null,country:{name:"France"}}},{id:"297823",title:"Dr.",name:"Fabien",middleName:"Pascal",surname:"Chevalier",fullName:"Fabien Chevalier",slug:"fabien-chevalier",email:"fabien.chevalier@univ-lyon1.fr",position:null,institution:null},{id:"309924",title:"Ph.D. Student",name:"Julie",middleName:"Sandra",surname:"Rorteau",fullName:"Julie Rorteau",slug:"julie-rorteau",email:"julie.rorteau@ibcp.fr",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. The miR-30 family in the control of the autophagic flux",level:"1"},{id:"sec_3",title:"3. The miR-200 family in the control of the oxidative balance",level:"1"},{id:"sec_4",title:"4. The miR-181 family in the control of mitochondria homeostasis",level:"1"},{id:"sec_5",title:"5. Circulating miRNAs in the spreading of the aging message",level:"1"},{id:"sec_6",title:"6. Conclusion",level:"1"},{id:"sec_10",title:"Conflict of interest",level:"1"},{id:"sec_7",title:"Notes",level:"1"}],chapterReferences:[{id:"B1",body:'Rittie L, Fisher GJ. Natural and sun-induced aging of human skin. Cold Spring Harbor Perspectives in Medicine. 2015;5:a015370-a015370'},{id:"B2",body:'Sharpless NE, DePinho RA. How stem cells age and why this makes us grow old. Nature Reviews Molecular Cell Biology. 2007;8:703-713'},{id:"B3",body:'Krutmann J, Bouloc A, Sore G, et al. The skin aging exposome. 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Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One;5. [Epub ahead of print Jul 27, 2010]. DOI: 10.1371/journal.pone.0011803'},{id:"B121",body:'Pigati L, Yaddanapudi SCS, Iyengar R, et al. Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS One;5. [Epub ahead of print Oct 20, 2010]. DOI: 10.1371/journal.pone.0013515'},{id:"B122",body:'Muñoz-Espín D, Serrano M. Cellular senescence: From physiology to pathology. Nature Reviews Molecular Cell Biology. 2014;15:482-496'},{id:"B123",body:'Terlecki-Zaniewicz L, Lämmermann I, Latreille J, et al. Small extracellular vesicles and their miRNA cargo are anti-apoptotic members of the senescence-associated secretory phenotype. Aging (Albany, NY). 2018;10:1103-1132'},{id:"B124",body:'Eitan E, Green J, Bodogai M, et al. Age-related changes in plasma extracellular vesicle characteristics and internalization by leukocytes. Scientific Reports;7. [Epub ahead of print May 2, 2017]. DOI: 10.1038/s41598-017-01386-z'},{id:"B125",body:'Picca A, Guerra F, Calvani R, et al. Mitochondrial dysfunction and aging: Insights from the analysis of extracellular vesicles. IJMS. 2019;20:805'},{id:"B126",body:'Prata LGPL, Ovsyannikova IG, Tchkonia T, et al. Senescent cell clearance by the immune system: Emerging therapeutic opportunities. Seminars in Immunology. 2019;11:101275. DOI: 10.1016/j.smim.2019.04.003. [Epub ahead of print]'},{id:"B127",body:'Su T, Xiao Y, Xiao Y, et al. Bone marrow mesenchymal stem cells-derived exosomal MiR-29b-3p regulates aging-associated insulin resistance. ACS Nano. 26 Feb 2019;13(2):2450-2462. DOI: 10.1021/acsnano.8b09375. [Epub 2019 Feb 11]'},{id:"B128",body:'Pang J, Xiong H, Yang H, et al. Circulating miR-34a levels correlate with age-related hearing loss in mice and humans. Experimental Gerontology. 2016;76:58-67'},{id:"B129",body:'Wang Y, Li Y, Wang X, et al. Circulating miR-130b mediates metabolic crosstalk between fat and muscle in overweight/obesity. Diabetologia. 2013;56:2275-2285'},{id:"B130",body:'Salvestrini V, Sell C, Lorenzini A. Obesity may accelerate the aging process. Frontiers in Endocrinology (Lausanne). 2019;10:266'},{id:"B131",body:'Beaudry VG, Attardi LD. SKP-ing TAp63: Stem cell depletion, senescence, and premature aging. Cell Stem Cell. 2009;5:1-2'},{id:"B132",body:'Huan T, Chen G, Liu C, et al. Age-associated microRNA expression in human peripheral blood is associated with all-cause mortality and age-related traits. Aging Cell. 2018;17:e12687'},{id:"B133",body:'Hooten NN, Fitzpatrick M, Wood WH, et al. Age-related changes in microRNA levels in serum. Aging (Albany, NY). 2013;5:725-740'},{id:"B134",body:'Hatse S, Brouwers B, Dalmasso B, et al. Circulating microRNAs as easy-to-measure aging biomarkers in older breast cancer patients: Correlation with chronological age but not with fitness/frailty status. PLoS One;9. [Epub ahead of print Oct 21, 2014]. DOI: 10.1371/journal.pone.0110644'},{id:"B135",body:'Yang Y, Li Y, Chen X, et al. Exosomal transfer of miR-30a between cardiomyocytes regulates autophagy after hypoxia. Journal of Molecular Medicine. 2016;94:711-724'},{id:"B136",body:'Terlecki-Zaniewicz L, Pils V, Bobbili MR, et al. Extracellular vesicles in human skin: Cross-talk from senescent fibroblasts to keratinocytes by miRNAs. Journal of Investigative Dermatology; [Epub ahead of print Jun 18, 2019]. DOI: 10.1016/j.jid.2019.05.015'},{id:"B137",body:'Mancini M, Lena AM, Saintigny G, et al. MicroRNAs in human skin ageing. Ageing Research Reviews. 2014;17:9-15'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Fabien P. Chevalier",address:null,affiliation:'
CNRS UMR 5305, Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, France
CNRS UMR 5305, Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique, France
Claude Bernard University Lyon 1, France
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Open Access publishing helps remove barriers and allows everyone to access valuable information, but article and book processing charges also exclude talented authors and editors who can’t afford to pay. The goal of our Women in Science program is to charge zero APCs, so none of our authors or editors have to pay for publication.
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