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Since the late 18th century, the murine model has been widely used in biomedical research (about 59% of total animals used) as it is compact, cost-effective, and easily available, conserving almost 99% of human genes and physiologically resembling humans. Despite the similarities, mice have a diminutive lifespan compared to humans. In this study, we found that one human year is equivalent to nine mice days, although this is not the case when comparing the lifespan of mice versus humans taking the entire life at the same time without considering each phase separately. Therefore, the precise correlation of age at every point in their lifespan must be determined. Determining the age relation between mice and humans is necessary for setting up experimental murine models more analogous in age to humans. Thus, more accuracy can be obtained in the research outcome for humans of a specific age group, although current outcomes are based on mice of an approximate age. To fill this gap between approximation and accuracy, this review article is the first to establish a precise relation between mice age and human age, following our previous article, which explained the relation in ages of laboratory rats with humans in detail.
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Review article
Men and mice: Relating their ages
Sulagna Dutta
a
, Pallav Sengupta
b,
a
Ex-guest Teacher, Department of Physiology, Post-graduation Section, Serampore College, University of Calcutta, Kolkata, West Bengal, India
b
Department of Physiology, Vidyasagar College for Women, University of Calcutta, Kolkata, West Bengal, India
abstractarticle info
Article history:
Received 20 July 2015
Received in revised form 19 October 2015
Accepted 22 October 2015
Available online xxxx
Keywords:
Age
Developmental biology
Human age
Laboratory mice
Mice age
Physiology
Since the late 18th century, the murine model has been widely used in biomedical research (about 59% of total
animals used) as it is compact, cost-effective, and easily available, conserving almost 99% of human genes and
physiologically resembling humans. Despite the similarities, mice have a diminutive lifespan compared to
humans. In this study, we found that one human year is equivalent to nine mice days, although this is not the
case when comparing the lifespan of mice versus humans taking the entire life at the same time without consid-
ering each phase separately. Therefore, the precise correlation of age at every point in their lifespan must be de-
termined. Determining the age relation between mice and humans is necessary for setting up experimental
murine models more analogous in age to humans. Thus, more accuracy can be obtained in the research outcome
for humans of a specic age group, although current outcomes are based on mice of an approximate age. To ll
this gap between approximation and accuracy, this review article is the rst to establish a precise relation be-
tween mice age and human age, following our previous article, which explained the relation in ages of laboratory
rats with humans in detail.
© 2015 Elsevier Inc. All rights reserved.
Contents
1. Introduction............................................................... 0
2. Agedeterminationoflaboratorymice:commonmethods........................................... 0
2.1. Weightofeyelens......................................................... 0
2.2. Musculoskeletalexamination:epiphysealclosure........................................... 0
2.3. Bodyweightassessment...................................................... 0
2.4. TWpattern............................................................ 0
3. Relationbetweenmiceageandhumanage................................................. 0
3.1. Relationbetweentheirlifespans................................................... 0
3.2. Weaningperiodofmiceandhuman................................................. 0
3.3. Miceandhumanagetoattainpuberty................................................ 0
3.4. Ageofadulthoodonsetinmiceanditsrelationtohumanageofadulthood............................... 0
3.5. Reproductivesenescenceinmiceandhumans ............................................ 0
3.6. Post-senescencephaseinmiceandhumans ............................................. 0
4. Conclusions............................................................... 0
Conictofinterest............................................................... 0
Fundingsource................................................................ 0
References.................................................................. 0
1. Introduction
Most studies in the eld of life science (almost 59% of the experi-
mental studies [1]) use experimental murine models (Mus musculus)
for investigating the implications on human health and body (Fig. 1).
In terms of their maximum lifespan, mice (4 years) and humans (120
Life Sciences xxx (2015) xxxxxx
Corresponding author at: Department of Physiology, Vidyasagar College for Women,
University of Calcutta, Kolkata, India.
E-mail address: pallav_cu@yahoo.com (P. Sengupta).
LFS-14535; No of Pages 5
http://dx.doi.org/10.1016/j.lfs.2015.10.025
0024-3205/© 2015 Elsevier Inc. All rights reserved.
Contents lists available at ScienceDirect
Life Sciences
journal homepage: www.elsevier.com/locate/lifescie
Please cite this article as: S. Dutta, P. Sengupta, Men and mice: Relating their ages, Life Sci (2015), http://dx.doi.org/10.1016/j.lfs.2015.10.025
years) differ signicantly, although murine models have been widely
used to analyse human body functioning and its modulation (see Ref.
[2]). In two pioneering studies, Sir L. Demeritus (published in 2005
and 2006) documented their similarities and differences in diverse met-
abolic processes, describing the molecular process of ageing in detail
(see Refs. [2,3]), but not the precise correlation of their ages in different
phases of their lifespan.
Despite the large differences in their lifespan, humans and mice
show similarpatterns in disease pathogenesis as well as organ and sys-
temic physiology. Their cells contain similar molecular structures that
regulate the functioning of cells, differentiation. Moreover, the molecu-
lar mechanism of ageing in mice is similar to that in humans (see Ref.
[3]). For instance, mice acquire mutations in the spectrum of proto-
oncogenes and tumour suppressor genes, similar to those affected in
human cancers (see Ref. [4]). Almost 99% of mouse genes resemble
the human genome, thus making the murine model an ideal candidate
for studying the functions of human genes in health as well as in the reg-
ulation ofmultifactorialdiseases such as cancer, cardiovasculardiseases,
diabetes and arthritis (Table 1). Acute promyelocytic leukaemia (APL),
although previously untreatable, is currently treated in humans after
successful experimentation in murine models. Although certain larger
mammals can better simulate human genotypic and phenotypic fea-
tures, they can be expensive and difcult to maintain or handle [5].
Mice provide analogous experimental conditions and comparable
results to humans. Findings of general experiments with mice, pharma-
ceutical trials for newly designed drugs in murine models, or studieson
different developmental phases of mice are intended to be applied on
human health and life. In all such cases, using mice of an approximate
age rather than precisely correlated age or phase with humans limits
the accuracy of experiments and their implications for human physiol-
ogy. It is imperative that researchers consider the phase and age of ani-
mals used in experiments in relation to human physiology, which was
explained in detailin our previous review work on therelation between
the age of rats and humans (see Ref. [6]). Thus, the aim of this compre-
hensive review is to precisely analyse the relation between mice age
and human age in various life stages to bridge the gap between the ap-
proximation and accuracy of future research in the biomedical eld.
2. Age determination of laboratory mice: common methods
Various methods havebeen used to correlate the ages of small mam-
mals with human age, for example, by determining the weight of eye
lens (see Refs. [711] and [12]), epiphyseal closure (see Refs. [13,14]),
tooth wear (TW) pattern [15], and body weight correlation [15].As
these methods provide a relative age that does not exactly coincide
with the exact age, more than one method is required for a closer
Fig. 1. (A) Use of animals in research and other scientic purposes and (B) animals cited in biomedical research papers (19502010).
Table 1
Commonly used strains of laboratory mice and their research applications.
Mostly
used
strains
Strain
abbreviation
Rotation
length
(weeks)
a
Mean
litter
size
Wean to
born
ratio
Research applications
BALB/C Cby 30 4.40 0.88 Mostly in immunological research
C3H/HEJ C3 22 4.60 0.90 In a wide variety of research including cancer, infectious disease, sensoneural and cardiova scular research
C57BL/6 J B6 30 4.90 0.80 General purpose, cardiovascular research, background strain for mice carrying transgenes, spontaneous or
targeted mutations
DBA/2 J D2 26 4.70 0.80 General purpose, atherosclerosis, glaucoma research.
SWR SW 22 4.6 0.80 General purpose, highly susceptible to experimental allergic encephalomyelitis
129P3/J 129P 26 5.0 0.90 Spontaneous testicular teratomas, targeted mutagenesis
NZB/B1NJ NZB 26 4.5 0.90 Autoimmunity
a
The average length of time a breeding unit reliably delivers progeny (also called the optimum reproductive lifespan).
2S. Dutta, P. Sengupta / Life Sciences xxx (2015) xxxxxx
Please cite this article as: S. Dutta, P. Sengupta, Men and mice: Relating their ages, Life Sci (2015), http://dx.doi.org/10.1016/j.lfs.2015.10.025
approximation of the age of the experimental animal. To relate the life
stages of humans and mice scientically, we used methods of age deter-
mination in mice by reviewing previous articles.
2.1. Weight of eye lens
Several studies have used the weight of the eye lens across mamma-
lian life stages as an indicator of the age correlation among different spe-
cies [710]. The increase in the weight of the eye lens follows an
asymptotic curve throughout the lifespan of most mammals [11].In
the late 1980s, this technique was considered a vital tool to correlate
the ages of different mammalianspecies at various lifestages. However,
it serves as an important indicator only up to 34 months, beyond
which the precision is not sufcient to determine the exact age of
small mammals (see Refs. [12]).
2.2. Musculoskeletal examination: epiphyseal closure
As dental developmentis minimal in foetal animals, their age can be
estimated based on bone formation such as long bone lengths, the de-
velopment of the ilium, and the petrous portion of the temporal bone.
Provided the measurements are accurate, formulae involving the corre-
lation between bone length and age can be usedto determine the corre-
spondingage of the animal. The bones of the upper and lower limbs and
hip joint are mostly used to analyse the age of the experimental animal.
In young animals, metopic suture closure and the emergence of ossic
centres are indicators of age. In addition, the growth of epiphyseal
plates, and closure of the same in some species, is an indicator of the
onset of sexual life in mammals, as observed in different mammalian
species (see Ref. [13]). In humans, closure of the epiphysis in the
bones of the upper body (namely, wrist, shoulder joint, humerus, ulna,
radius, metacarpals and phalanges) is observed at the age of 1418
years, whereas that of the lower body (femur and tibia) is detected at
the age of 1825 years. Bone remodelling and maintenance of bone in-
dicate early adulthood, whereas late adulthood is marked by observa-
tions of bone wear and tear. Epiphyseal evaluation requires detailed
examination of skeletal remains along with radiological assessment in
eshed material [14].
2.3. Body weight assessment
In studies using laboratory animals of varying unknown ages, it is
important to differentiate the cohort groups according to their age. For
this purpose, the frequency distribution of their body weights can be
plotted to represent different cohorts. Then the statistical models in
the body weight distribution are determined, from which the different
age classes can be predicted [15]. The approximate age of mice pups
can also be determined by their physical characteristics during the
rst 2 weeks of their life (Fig. 2).
2.4. TW pattern
As laboratory mice experience constant attrition of their molar teeth
when grinding food, the degree of TW is proportional to the age of the
mice [15]. The skulls of mice have been observed under a dissecting mi-
croscope for dental eruption and wear patterns of the upper molar
(M) (whichare used in determining the age classes). Based on theseob-
servations, a standardized age chart is formulated:
TW age 1: M3 is partly erupted and unworn.
TW age 2: M3 is completely erupted and slightly worn, whereas M1
and M2 show negligible wear on their occlusal surface.
TW age 3: M3 is visibly roughly worn with a concave occlusal sur-
face; M1 shows a protocone and paracone, and fused anterolingual
and anterolabial conules; and M2 shows a protocone and paracone,
as well as fused hypocone and metacone.
TW age 4: M3 becomes at or concave; M1 shows a completely
worn occlusal surface; and M2 shows greatly decreased
anterolingual and anterolabial conules.
TW age 5: all cusps of M1 become more diminutive; the connections
between the M2 protoconeparacone and hypoconemetacone are
completed; and the anteroloph and anteroconule are considerably
reduced.
TW age 6: M3 is concave; M1 shows connected protoconeparacone
and hypoconemetacone; and all cusps of M2 are reduced further.
3. Relation between mice age and human age
Currently, biomedical studies achieve the highest accuracyand spec-
icity due to the advances in technology. Therefore, in experiments
with mice representing humans, the mice age must be precisely deter-
mined in relation to human age, in terms of both the lifespan and indi-
vidual life stages. In the following section, we present human age in
relation to different developmental stages of mice.
3.1. Relation between their lifespans
Mice have a shorter and accelerated early life, compared with
humans. As the developmental stages of mice are not uniform com-
pared with humans, the correlation between their entire lifespans can-
not be used to determine human days in terms of mice days and vice
versa, at every life stage.
Studies on the broad distributions of age at death within inbred
strains and variances in the mean survival rate of mice under diverse
conditions revealed the signicant effect of environmental factors on
longevity. Intercurrent infections, parasitismand ghting lead to unpre-
dictable deaths. Three specic non-genetic factors (mammary tumour
virus, breeding history and diet) affecting lifespan have been identied
in controlled investigations. Individual alterations in these factors may
result in differences in lifespan within a single colony of a particular
strain. Other perceptible within-strain life-history variables,such as sea-
son of birth, age of parents at birth, or lifespan of parents, have no dis-
cernable effect on mouse lifespan. Differences between strains have
also demonstrated the signicance of genetic factors for lifespan.
Fig. 2. The approximate age of mice can be determined by their physical attributes during the rst 2 weeks of life.
3S. Dutta, P. Sengupta / Life Sciences xxx (2015) xxxxxx
Please cite this article as: S. Dutta, P. Sengupta, Men and mice: Relating their ages, Life Sci (2015), http://dx.doi.org/10.1016/j.lfs.2015.10.025
The average lifespan of laboratory mice is about 24 months [16]
(Table 2), whereas the life expectancy of humans globally is about 80
years, which varies among countries based on economic status [17].
Therefore, considering both lifespans, the correlation can be calcu-
lated as follows:
80 365ðÞ2365ðÞ¼40 human days ¼1miceday;
and
365 40 ¼9:125 mice days ¼1 human year:
Thus, one human year is almost equivalent to 9 mice days when cor-
relating their entire lifespan.
3.2. Weaning period of mice and human
Mammals are altruistic as they nurse and feed their young ones,
which later withdraw from mother's milk and learn independent feed-
ing habits and survival strategies in their environment. According to the
medical dictionary, weaning is the transition of the human infant from
breast-feeding or bottle nursing and commencement of nourishment
with other food(see Ref. [18]).
Mice are weaned at 34 weeks, approximately on 28th days (P28),
after birth. While weaned, the pups become robust, active, their eyes
open up, teeth and fur develop well and are able to jump, feed them-
selves and drink on their own [19]. On the other hand the average
weaning age for humans is about 6 months (180 days) (see Ref. [6]).
Thus,
180 28 ¼6:43 human days ¼1 mice day and 365 6:43
¼56:77 mice days ¼1 human year:
Therefore, in this developmental phase, one human year equals
56.77 mice days.
3.3. Mice and human age to attain puberty
Puberty is the peak phase of maturation of the hypothalamo
pituitarygonadal axis, which is characterized by alterations in gonado-
tropin levels in circulation and elevated levels of sex steroids. The most
common markers of puberty onset in mice are vaginal cornication and
onset of the oestrous cycle in females and balanopreputial separation
(BPS) in males [20]. At birth, the pituitary glands of mice are physiolog-
ically undifferentiated from gonadotropins. Moreover, the ovaries are
unresponsive to gonadotropin. Sex differentiation of the pituitary usu-
ally occurs by day 6 (P6) in males and before day 12 (~P12) in females.
Typically, sexual maturity coincides with rising titres of circulating go-
nadotropin after 4 weeks of age. The rst observable signs of puberty
in females are oestrogen dependent: vaginal introitus and a cornied
vaginal smear. The vagina may open as early as day 24 (P24), and it is
often reported open by 4 weeks (~P28) of age. In addition, oestrus,
that is, the willingness to mate, does not always occur on schedule.
The average age at which mice attain puberty is about 42 days (P42)
[21,22], and the average age in humans is about 11.5 years
(11.5 × 365 = 4198 days) [23].
Thus, in the prepubertal phase,
4198 42 ¼99:95 human days ¼1miceday;
and
365 99:95 ¼3:65 mice days ¼1humanyear:
Thus, in this phase, one human year is equivalent to 3.65 mice days.
3.4. Age of adulthood onset in mice and its relation to human age of
adulthood
Adulthood is biologically dened as the age at which sexualmaturity
is attained in the case of mice or other animals, but it is associated with
several psychological and social concepts in humans. Mice attain sexual
maturity at 812 weeks of age, with an average of 10 weeks (P70) [23].
Mice weigh about 12 g at birth, with adult male mice reaching2030 g
and adult female mice1835 g [23]. In humans, growth plate closure is
used to differentiate between adolescence and adulthood, as growth
plates in the scapula fuse last, at about 20 years of age on average
(365 × 20 = 7300 days) [13,24].
Therefore, from these data, it can be calculated that
7300 70 ¼104:3 human days ¼1miceday;
which indicates that
365 104:3¼2:60 mice days ¼1humanyear:
Thus, during the adult phase, 2.60 mice days are equivalent to one
human year.
3.5. Reproductive senescence in mice and humans
Although senescent changes in mice begin in middle age (1015
months), the biomarkers of ageing are not detected then. However, re-
productive functions cease at the end of middle age, and theupper limit
for the middle-aged group is considered to be 15 months (P450) of age
in mice [25]. In humans, menopause in women is a marker of reproduc-
tive senescence, which is associated with the termination of the fertility
cycle [26,27]. The average age ofmenopause in women,according to the
American Medical Association, is 51 years (51 × 365 = 18,615 days)
(see Ref. [6]).
Table 2
General physiology and reproductive data of laboratory mice.
Common physiological data Reproduction data
Body temperature 36.538 °C Age at pairing (mating) 68 weeks (male)
Respiratory rate 80230 breaths/min Weight at pairing 2030 g (male)
Heart rate 310840 beats/min Age at pairing (mating) 68 weeks (female)
Daily water consumption 58 ml/100 g body weight Weight at pairing 1835 g (female)
Daily food consumption 57 g/100 g body weight Length of oestrous cycle 45 days
Litter size 210 Duration of oestrus 816 h
Birth weight 12 g Time of ovulation 8.5 h after onset of oestrus
Breeding duration 1015 months Menopause 1718 months
Male adult weight 2030 g Time of copulation Midpoint of previous dark cycle
Female adult weight 1835 g Time sperm is detected in vagina 1648 h
Lifespan 13 years Time of implantation Late day 3.5
Blood volume 1.52.5 ml Length of gestation 1821 days
4S. Dutta, P. Sengupta / Life Sciences xxx (2015) xxxxxx
Please cite this article as: S. Dutta, P. Sengupta, Men and mice: Relating their ages, Life Sci (2015), http://dx.doi.org/10.1016/j.lfs.2015.10.025
Thus,
18;615 450 ¼41:37 human days ¼1miceday;
and
365 41:37 ¼8:82 mice days ¼1humanyear:
Thus, during reproductive senescence, 8.82 mice days are equivalent
to one human year.
3.6. Post-senescence phase in mice and humans
In mice, senescence is dened by a minimum age of at least 18
months [25], when thebiomarkers of old age are prominently detected,
with a lifespan of around 24 months, as stated in the previous sections.
Thus, the post-senescence period in mice is about 2 months (60 days),
and female humans may survive approximately for 10,585 days after
senescence.
Thus,
10;585 60 ¼176:4humandays¼1miceday;
365 176:4¼2:069 mice days ¼1humanyear:
Thus, in thesenescence phase, 2.069 mice days are equivalent to one
human year.
4. Conclusions
This article reveals the wide variations in the developmental dura-
tions and phases of mice versus humans, although murine models are
essential in biomedical science to study human physiology and its mod-
ulations. The relative ages of mice differ depending on the life stage.
Therefore, it is imperative that researchers know the precise correlation
between mice age and human age at a specic life stage of the mice
under their studies.
Conict of interest
The authors declare that there are no conicts of interest.
Funding source
None.
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Please cite this article as: S. Dutta, P. Sengupta, Men and mice: Relating their ages, Life Sci (2015), http://dx.doi.org/10.1016/j.lfs.2015.10.025
... Development from the embryo through the juvenile stage to adulthood, before changes related to ageing take place is considered here. This stage in human is equivalent to the embryo to adulthood (> 10 weeks) in mice ( Figure 47) (Dutta and Sengupta, 2016). ...
... Adapted from . From (Dutta and Sengupta, 2016). ...
... The animals used in the CXEM study described in this chapter are chosen to represent juvenile (4 weeks) and early adult (38 weeks) stages of development. Figure 47 illustrates the relationship between human and mouse developmental stages (Dutta and Sengupta, 2016). ...
Thesis
Osteocytes are stellate cells which form a network within hard bone matrix and play a key role for bone adaptation during development, ageing and bone diseases including osteoporosis. The mechanisms by which osteocytes sense loading and transmit signals to regulate remodelling are not well understood. Detailed knowledge of the three-dimensional (3D) structure of the osteocyte network and the surrounding lacuno-canalicular network is essential to elucidate these mechanisms. 3D imaging on cellular and sub-cellular scales will allow quantitative hallmarks of health and disease to be derived and will lead to improved computational models of bone mechanotransduction. Until now the location of the cells within calcified bone matrix and the submicrometre dimensions of the networks have posed challenges for 3D imaging. Serial block-face scanning electron microscopy (SBF SEM) is a novel imaging technique which produces high resolution 3D data of the osteocyte and lacuno-canalicular networks (ON&LCN) simultaneously. The objective of this project is to develop a correlative X-ray and SBF SEM (CXEM) workflow for mammalian bone tissue, providing quantitative data, which will enable realistic computational modelling of bone mechanobiology. This project aims to develop protocols for SBF SEM sample preparation and imaging and to combine SBF SEM with X-ray micro computed tomography in a correlative workflow which allows derivation of established and novel quantitative measures of the ON&LCN across length scales in relevant tissue volumes. CXEM imaging and image analysis workflows are applied to juvenile and adult murine bone tissue and to bone tissue from osteoporotic (OP) and osteoarthritic (OA) human donors. CXEM applied to juvenile and adult mouse tibia has produced data on osteocyte density, porosity, and cell measures including volume and number of processes. Pericellular space volume and width were quantified in 3D for the first time. The results show that values for pericellular space volume used in previous studies have been overestimated and that the width of the pericellular space is more irregular than values derived from 2D imaging methods and used in computational models, possibly leading to the underestimation of peak strain sensed by osteocytes. Tissue from OP and OA donors was imaged and analysed using CXEM. Osteocyte number density is 37% of lacunar number density and osteocyte porosity is 30% of lacunar porosity in these samples. These findings illustrate that using lacunar number density and porosity measures to represent osteocyte measures in diseased human bone tissue is misleading. 93% of lacunae contained a cell showing ultrastructural changes indicative of deteriorating health or cell death. This indicates that the cell network, crucial for mechanobiology and bone homeostasis, is compromised in OA and OP tissue, although not in significantly different ways. CXEM enables imaging of the hard and soft components of bone simultaneously, at high resolution and in 3D, producing unique quantitative measures. CXEM assessment of the ON&LCN in health and disease paves the way for the study of mechanotransduction mechanisms by computational models based on accurate geometries. This will lead to the identification of relevant features of healthy and diseased bone at the cell level, which could serve as targets for the diagnosis and treatment of bone-related diseases, impacting significantly on public health.
... In addition, the degenerate IVD is largely innervated by small nociceptors that express voltagegated sodium channels (VGSCs) or transient receptor potential cation channel subfamily V member 1 (TRPV1) that regulate neuronal activity (161). Persistent inflammation in the IVD can sensitize these neurons and induce changes, causing altered action potential duration, hyper-excitability, lowered thresholds to stimuli, and enhanced pain as observed in rodent models (50,(161)(162)(163). The activation of Protease-activated receptor 2 (PAR2) on DRG sensory neurons can regulate acute and chronic pain by activating the extracellular signal-regulated protein kinase (ERK 1/2) signaling pathway (162,164,165). ...
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Low back pain is a leading cause of disability worldwide and studies have demonstrated intervertebral disc (IVD) degeneration as a major risk factor. While many in vitro models have been developed and used to study IVD pathophysiology and therapeutic strategies, the etiology of IVD degeneration is a complex multifactorial process involving crosstalk of nearby tissues and systemic effects. Thus, the use of appropriate in vivo models is necessary to fully understand the associated molecular, structural, and functional changes and how they relate to pain. Mouse models have been widely adopted due to accessibility and ease of genetic manipulation compared to other animal models. Despite their small size, mice lumbar discs demonstrate significant similarities to the human IVD in terms of geometry, structure, and mechanical properties. While several different mouse models of IVD degeneration exist, greater standardization of the methods for inducing degeneration and the development of a consistent set of output measurements could allow mouse models to become a stronger tool for clinical translation. This article reviews current mouse models of IVD degeneration in the context of clinical translation and highlights a critical set of output measurements for studying disease pathology or screening regenerative therapies with an emphasis on pain phenotyping. First, we summarized and categorized these models into genetic, age-related, and mechanically induced. Then, the outcome parameters assessed in these models are compared including, molecular, cellular, functional/structural, and pain assessments for both evoked and spontaneous pain. These comparisons highlight a set of potential key parameters that can be used to validate the model and inform its utility to screen potential therapies for IVD degeneration and their translation to the human condition. As treatment of symptomatic pain is important, this review provides an emphasis on critical pain-like behavior assessments in mice and explores current behavioral assessments relevant to discogenic back pain. Overall, the specific research question was determined to be essential to identify the relevant model with histological staining, imaging, extracellular matrix composition, mechanics, and pain as critical parameters for assessing degeneration and regenerative strategies.
... All animal experiments were approved by the Institutional Animal Care and Ethics Committee of Ninth People's Hospital, Shanghai Jiaotong University School of Medicine (Shanghai, China). A total of 18 male Sprague-Dawley rats (3 months old) were euthanized using carbon dioxide, and then their spinal columns were harvested under aseptic conditions (Dutta and Sengupta, 2016). The coccygeal discs ...
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Low back pain (LBP) caused by intervertebral disc degeneration (IVDD) is accredited to the release of inflammatory cytokines followed by biomechanical and structural deterioration. In our study, we used a plant-derived medicine, curcumenol, to treat IVDD. A cell viability test was carried out to evaluate the possibility of using curcumenol. RNA-seq was used to determine relative pathways involved with curcumenol addition. Using TNFα as a trigger of inflammation, the activation of the NF-κB signaling pathway and expression of the MMP family were determined by qPCR and western blotting. Nucleus pulposus (NP) cells and the rats’ primary NP cells were cultured. The catabolism status was evaluated by an ex vivo model. A lumbar instability mouse model was carried out to show the effects of curcumenol in vivo. In general, RNA-seq revealed that multiple signaling pathways changed with curcumenol addition, especially the TNFα/NF-κB pathway. So, the NP cells and primary NP cells were induced to suffer inflammation with the activated TNFα/NF-κB signaling pathway and increased expression of the MMP family, such as MMP3, MMP9, and MMP13, which would be mitigated by curcumenol. Owing to the protective effects of curcumenol, the height loss and osteophyte formation of the disc could be prevented in the lumbar instability mouse model in vivo.
... Article the defects even though they were tested in both male and female mice and that the mice reached sexual maturity during these experiments and would begin to secrete estrogen, progesterone, and testosterone. 91,92 The findings that changes in osteoblast number did not accompany the melatoninmediated increases in new bone formation indicate that melatonin, in this model, may be increasing osteoblast activity. This idea is supported in recent reports demonstrating that bone mass accrual around a prosthesis in response to melatonin occurs via an increase in osterix; osterix is an osteogenic protein, 93 which is increased in mature osteoblasts and promotes bone matrix mineralization. ...
Article
Melatonin, the primary hormone involved in circadian entrainment, plays a significant role in bone physiology. This study aimed to assess the role of MEK1/2 and MEK5 in melatonin-mediated actions in mouse and human mesenchymal stem cells (MSCs) and on bone using small-molecule inhibitors and CRISPR/Cas9 knockout approaches. Consistent with in vitro studies performed in mMSCs and hMSCs, nightly (25mg/kg, ip, 45 days) injections with PD184352 (MEK1/2 inhibitor) or Bix0202189 (MEK5 inhibitor) or SC-1-151 (MEK1/2/5 inhibitor) were the primary drivers underlying melatonin's actions on bone density, microarchitecture (i.e., trabecular number, separation, and connectivity density) and bone mechanical properties (i.e., ultimate stress) through increases in osteogenic (RUNX2, BMP-2, FRA-1, OPG) expression and decreases in PPARγ. Furthermore, CRISPR/Cas9 knockout of MEK1 or MEK5 in mMSCs seeded on PLGA scaffolds and placed into critical-size calvarial defects in Balb(c) mice (male and female) revealed that treatment with melatonin (15mg/L; p.o., nightly, 90 days) mediates sex-specific actions of MEK1 and MEK5 in new bone formation. This study is the first to demonstrate a role for MEK1/2 and MEK5 in modulating melatonin-mediated actions on bone formation in vivo and in a sex-specific manner. This article is protected by copyright. All rights reserved.
... Généralement, les jeunes souris de 6 à 14 semaines sont utilisées. En effet, si on compare les durées de vie entre l'humain et la souris, une année de vie humaine correspond approximativement à 9 jours dans la vie d'une souris (Dutta et Sengupta, 2016). Des études ont montré que des groupes de souris avec des âges différents présentent des réponses variées aux infections à pneumocoques (Borsa et al. 2019). ...
Thesis
La résistance aux antibiotiques est un problème majeur de santé publique qui affecte de nombreux pathogènes bactériens. Pour ralentir ce phénomène, des peptides antimicrobiens (PAMs), naturellement synthétisés et impliqués dans la défense immunitaire de différents organismes, est une approche thérapeutique prometteuse. Cependant, les bactéries présentent de nombreux mécanismes capables de contrecarrer l’action de ces peptides. L’un des mécanisme de résistance les plus importants implique une étroite collaboration entre un transporteur ABC et un système de régulation à deux composants (TCS). Pour comprendre le mécanisme de résistance aux PAMs chez Streptococcus pneumoniae, un important pathogène humain, nous avons identifié le TCS associé au transporteur ABC de PAMs. Le TCS01 en collaboration avec un transporteur ABC de type BceAB détecte et induit la résistance à des PAMs structurellement différents mais ciblant l’undécaprényl-pyrophosphate ou le lipide II, essentiels à la biosynthèse du peptidoglycane. Bien que les gènes codant le TCS01 et le transporteur BceAB ne soient pas adjacents, leurs délétions sensibilisent de la même manière S. pneumoniae aux mêmes PAMs. Nous avons montré par des expériences de fluorescence et de qPCR que le TCS01 régulait l’expression du transporteur BceAB. Afin de caractériser le mécansime moléculaire du transporteur BceAB, nous l’avons surexprimé et purifié à partir d’Escherichia coli. Après la reconstitution en liposomes, le transporteur présente des activités ATPase et GTPase significatives qui sont stimulées par les PAMs substrats du système de résistance.
... Recent advances in scRNA-seq techniques allow the detection of gene profiles of single cells under pathological conditions, providing a remarkable opportunity to understand disease mechanisms (Ofengeim et al., 2017;Armand et al., 2021). Chronic pain is pain that lasts more than 3 months (Treede et al., 2015), in this study, we selected 7 days after CFA injection in mice as one of typical time points to investigate preliminarily the mechanisms of chronic orofacial pain in humans (Dutta and Sengupta, 2016). After scRNA-seq analysis, we unbiasedly classified six clusters of TG sensory neurons based on their transcriptional characteristics, which were later assigned as PEP1, PEP2, NP1, NP2, cLTMR, and NF. ...
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Orofacial inflammation leads to transcriptional alterations in trigeminal ganglion (TG) neurons. However, diverse alterations and regulatory mechanisms following orofacial inflammatory pain in different types of TG neurons remain unclear. Here, orofacial inflammation was induced by injection of complete Freund’s adjuvant (CFA) in mice. After 7 days, we performed single-cell RNA-sequencing on TG cells of mice from control and treatment groups. We identified primary sensory neurons, Schwann cells, satellite glial cells, oligodendrocyte-like cells, immune cells, fibroblasts, and endothelial cells in TG tissue. After principal component analysis and hierarchical clustering, we identified six TG neuronal subpopulations: peptidergic nociceptors (PEP1 and PEP2), non-peptidergic nociceptors (NP1 and NP2), C-fiber low-threshold mechanoreceptors (cLTMR) and myelinated neurons (Nefh-positive neurons, NF) based on annotated marker gene expression. We also performed differential gene expression analysis among TG neuronal subtypes, identifying several differential genes involved in the inflammatory response, neuronal excitability, neuroprotection, and metabolic processes. Notably, we identified several potential novel targets associated with pain modulation, including Arl6ip1, Gsk3b, Scn7a, and Zbtb20 in PEP1, Rgs7bp in PEP2, and Bhlha9 in cLTMR. The established protein–protein interaction network identified some hub genes, implying their critical involvement in regulating orofacial inflammatory pain. Our study revealed the heterogeneity of TG neurons and their diverse neuronal transcriptomic responses to orofacial inflammation, providing a basis for the development of therapeutic strategies for orofacial inflammatory pain.
Article
Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders.
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Disseminated cancer cells from primary tumours can seed in distal tissues, but may take several years to form overt metastases, a phenomenon that is termed tumour dormancy. Despite its importance in metastasis and residual disease, few studies have been able to successfully characterize dormancy within melanoma. Here we show that the aged lung microenvironment facilitates a permissive niche for efficient outgrowth of dormant disseminated cancer cells—in contrast to the aged skin, in which age-related changes suppress melanoma growth but drive dissemination. These microenvironmental complexities can be explained by the phenotype switching model, which argues that melanoma cells switch between a proliferative cell state and a slower-cycling, invasive state1–3. It was previously shown that dermal fibroblasts promote phenotype switching in melanoma during ageing4–8. We now identify WNT5A as an activator of dormancy in melanoma disseminated cancer cells within the lung, which initially enables the efficient dissemination and seeding of melanoma cells in metastatic niches. Age-induced reprogramming of lung fibroblasts increases their secretion of the soluble WNT antagonist sFRP1, which inhibits WNT5A in melanoma cells and thereby enables efficient metastatic outgrowth. We also identify the tyrosine kinase receptors AXL and MER as promoting a dormancy-to-reactivation axis within melanoma cells. Overall, we find that age-induced changes in distal metastatic microenvironments promote the efficient reactivation of dormant melanoma cells in the lung.
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Unilateral ovariectomy (ULO) and its consequences with endocrine replacement in pregnant mice are important to examine both follicular dynamics as well as the outcome of implantation and pregnancy. In mice, ovariectomy on fourth day morning (D4), before pre-implantation estrogen secretion induces delayed implantation and embryonic diapauses, i.e. a state of suspended animation of embryos. The present study has beenundertaken to evaluate the effect of progesterone supplementation on rate of implantation in unilaterally ovariectomized superovulated mice. Our study reveals that progesterone (P4) may help to protect the loss of embryo before and after the implantation if ULO is done during pre-implantation period (D4).The present study also shows if ovary is present in one side of the animal, it secretes estrogen (E2) in circulation which acts systematically on the uterus rather than locally. The findings of the present study show that progesterone may help to avoid the loss of embryo before and after the implantation, if ULO is done during pre-implantation period (D4) and the serum estrogen (E2) acts systematically on the uterus. Thus, it can be concluded that implantation in the uterine horn where ovary is not there.
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By late 18th or early 19th century, albino rats became the most commonly used experimental animals in numerous biomedical researches, as they have been recognized as the preeminent model mammalian system. But, the precise correlation between age of laboratory rats and human is still a subject of debate. A number of studies have tried to detect these correlations in various ways, But, have not successfully provided any proper association. Thus, the current review attempts to compare rat and human age at different phases of their life. The overall findings indicate that rats grow rapidly during their childhood and become sexually mature at about the sixth week, but attain social maturity 5-6 months later. In adulthood, every day of the animal is approximately equivalent to 34.8 human days (i.e., one rat month is comparable to three human years). Numerous researchers performed experimental investigations in albino rats and estimated, in general, while considering their entire life span, that a human month resembles every-day life of a laboratory rat. These differences signify the variations in their anatomy, physiology and developmental processes, which must be taken into consideration while analyzing the results or selecting the dose of any research in rats when age is a crucial factor.
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Exposure to stress during puberty can lead to long-term behavioral alterations in adult rodents coincident with sex steroid hormone-dependent brain remodeling and reorganization. Social isolation is a stress for social animals like mice, but little is known about the effects of such stress during adolescence on later reproductive behaviors. The present study examined sexual behavior of ovariectomized, estradiol and progesterone primed female mice that were individually housed from 25 days of age until testing at approximately 95 days, or individually housed from day 25 until day 60 (during puberty), followed by housing in social groups. Mice in these isolated groups were compared to females that were group housed throughout the experiment. Receptive sexual behaviors of females and behaviors of stimulus males were recorded. Females housed in social groups displayed greater levels of receptive behaviors in comparison to both socially isolated groups. Namely, social females had higher lordosis quotients (LQs) and more often displayed stronger lordosis postures in comparison to isolated females. No differences between female groups were observed in stimulus male sexual behavior suggesting that female "attractiveness" was not affected by their social isolation. Females housed in social groups had fewer cells containing immunoreactive estrogen receptor (ER) α in the anteroventral periventricular nucleus (AVPV) and in the ventromedial nucleus of the hypothalamus (VMH) than both isolated groups. These results suggest that isolation during adolescence affects female sexual behavior and re-socialization for 1 month in adulthood is insufficient to rescue lordosis behavior from the effects of social isolation during the pubertal period.
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Background: The people residing in coastal areas of Visakhapatnam are mostly engaged in fishery, which is always been a physically demanding job, and numerous factors have direct or indirect impact on the health of fishermen; but, the data about their physical fitness or health status is quite scanty. Thus, the present study was conducted to assess their cardiorespiratory fitness pattern, as well as morphometric characters, which may be influenced by their occupation. Methods: In this retrospective cohort study, 25 young fishermen (mean age of 22.8 ± 1.92 years) were randomly selected from Araku valley of Visakhapatnam District, Andhra Pradesh and compared with 25 subjects who were randomly selected from college students (mean age of 21.9 ± 2.25 years) of Kolkata, West Bengal. Some physical and physiological fitness variables including height, weight, body mass index, body surface area, physical fitness index, anaerobic power, and energy expenditure were measured along with their morphometric characters. Results: Analysis of data indicated a significant difference in blood pressure, physical fitness index, energy expenditure, body fat percent and anaerobic power among fishermen compared to controls. However, there were no changes in morphometric characters between the two groups. Conclusions: Findings of this small-scale population-based study indicated that health and physical fitness of young fishermen is under the influence of both occupational workload and nutritional status, as found by body composition and morphometric characters.
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Changes in body weight, lens weight, and the soluble and insoluble protein fractions of the eye lenses of a laboratory population of cotton rats (Sigmodon hispidus) were measured from 10 to 600 days of age. Body weight was found to be a reliable criterion for age determination for only the first 70 days. Soluble protein increased for about 120 days, but never was the most reliable indicator of age. Lens weight and insoluble lens protein were roughly equal as age indicators for the first 130 days, then insoluble protein became the best criterion as determined by narrowness of individual prediction limits calculated by regression techniques. It was concluded that any increase in accuracy of age estimation provided by the measure of insoluble lens protein should be evaluated carefully relative to the effort, time, and expense required by the technique. The relationship between apparent tyrosine and nitrogen in the soluble and insoluble protein fractions was investigated for young and old animals. The ratio was greater than 2:1 in all cases and differed in the soluble fraction between young and old animals and between the two fractions for younger animals. Decrease in the specific growth rates of the 4 parameters was similar for the first 100-150 days, then became negative for body weight and soluble protein but remained positive for lens weight and insoluble protein through 600 days of age.
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(1) Eye lens growth curves were obtained from 200 male and 208 female laboratory-reared wild house mice (Mus musculus L.) between 3 and 72 weeks of age. (2) The relationship between age and dried lens weight was derived by regression analysis. The equations fitted to data for males and females respectively were log10 (age + 20 days) = 1.019 + 0.175 (paired lens weight) and log10 (age + 20 days) = 1.004 + 0.182 (paired lens weight); the correlation coefficients of the relationships were 0.97 and 0.96 respectively. (3) Lens weights were also measured in 170 male and 194 female farm-living mice whose ages were accurately known. Lens weight-age relationships were comparable in captive and wild-caught animals. (4) The accuracy of the lens method in determining age was examined by comparison of known and predicted ages. Infant, juvenile and three age-classes of adult animals were reliably separated by lens weight. The technique thus appears to be useful in the analysis of population structure in wild house mice.
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(1) F1 litters from wild-caught Rattus norvegicus were maintained on surplus food and water in laboratory cages. (2) A relationship between age and dried lens weight was derived by regression analysis of data from ninety-six male and 105 female rats sacrificed at various known ages up to 18 months from birth. (3) A single predictive equation (combining males and females) is recommended for practical use which relates eylens weight to a transformed measure of age. The equation is log10 (age + 22 days) = 1·313 + 0·021 (paired lens weight) where 22 days is the gestation period and the correlation coefficient is 0.96.