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The Laboratory Rat: Relating Its Age With Human's

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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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International Journal of Preventive Medicine, Vol 4, No 6, June, 2013
624
The Laboratory Rat: Relating Its Age with Human’s
Pallav Sengupta
ABSTRACT
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 ndings 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.
Keywords: Adult, human age, laboratory rat, physiology, puberty,
rat age
INTRODUCTION
The laboratory rat is an inevitable part of today’s biomedical
research. They are recognized as the preeminent model in numerous
fields, including neurobehavioral studies, cancer and toxicology.[1] It
is difficult to evaluate the number of animals employed in scientific
experiments every year. An estimation suggests some dozens of
millions per year, being 15 million in the United States, 11 million
in Europe, five million in Japan, two million in Canada and less
than one million in Australia. Almost 80% of the experimental
animals are rodents that include mice, rats, guinea pigs and
others (10% are fish, amphibians, reptiles and birds). A third
group includes rabbits, goats, bulls and in smaller amounts, dogs,
cats and some species of primatess.[2] They substitute the human
being as an experimental object in scientific researches. Among
the rodents, rats are the mostly used animals for experimental
purposes (accounting for approximately 20% of the total number
Department of Physiology, Vidyasagar College
for Women, University of Calcua, Kolkata,
West Bengal, India
Correspondence to:
Dr. Pallav Sengupta,
Department of Physiology, Vidyasagar
College for Women, 39, Sankar Ghosh
Lane, University of Calcua,
Kolkata - 700 006, West Bengal, India.
E-mail: sunny_pallav_1984@yahoo.co.in
Date of Submission: Sep 09, 2012
Date of Acceptance: Nov 11, 2012
How to cite this article: Sengupta P. The laboratory
rat: Relating its age with human’s. Int J Prev Med
2013;4:624-30.
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Sengupta: Rat age versus human age
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International Journal of Preventive Medicine, Vol 4, No 6, June, 2013
of mammals used for scientific purposes), followed
by mouse, rabbit, dog, pig and primate, especially for
in vivo studies. About 85% of the articles in Medline,
and 70.5% of the articles in Lilacs, employed rats
and mice.[3] All over the past 80 years, rats have
been utilized in investigations in almost every aspect
of biomedical and behavioral research. A recent
publication dealing with biomedical research
applications lists the following areas of biomedical
investigation as ones in which the rat is widely
used and is particularly useful in: Toxicology,
teratology, experimental oncology, experimental
gerontology, cardiovascular research, immunology,
dental research immunogenetics and experimental
parasitology.[4] The rat is also the most widely used
laboratory mammal in behavioral studies, for which,
incidentally, the mouse is not well suited. Rats have
traditionally been the animal of choice in much
nutritional research, although it should be noted that
their natural habit of coprophagy may limit their
suitability for certain of these studies.
Their use in scientific research started in the
16th century, although the development of the
laboratory rat as an experimental model really began
in 1906 when the Wistar Institute developed the Wistar
rat model (Rattus norvegicus).[5] They are thought to
have originated in some parts of Asia. Rattus rattus
was well established in Europe by 1100 A.D., with
Rattus norvegicus commonly found in Europe in the
1700s. By the 1800s, these animals were used for
neuroanatomy studies in the United States and in
Europe. It was in the late 1800s and early 1900s that
individual stocks and strains had their beginnings.
Today, there are 51 known species of the Rattus of
both albino and pigmented types that are available.
There are recognized differences between wild and
laboratory rodents. For example, laboratory rats
have smaller adrenals and preputial glands, earlier
sexual maturity, no reproductive cycle seasonability,
better fecundity and a shorter lifespan than their
free‑ranging wild counterparts.[6] Currently, Wistar
rats and Sprague‑Dawley rats are gradually becoming
the most used laboratory animals worldwide.
AGE DETERMINATION OF A
LABORATORY RAT: COMMON
METHODS
Numerous methods have been investigated
in several studies to correlate the ages of small
mammals with that of a human, i.e. using the weight
of the eye lens,[7] growth of molar teeth,[8] counting
of endosteal layers in the tibia,[9] musculoskeletal
growth along with the closure and thickening of
the epiphyses,[10] etc., but, all of the techniques
are relative methods and do not exactly define the
absolute age; thus, researchers generally employ
more than one method at a time to have a proper
idea about the age of the experimental animal.
Weight of eye lens: A useful measure
Several studies have been performed using
the weight of the eye lens in an attempt to
use the development and growth of the lens
throughout the mammalian life as an indicator
that could help correlate the ages of different
species.[7] The weight of an eye lens increases
along an asymptotic curve throughout the normal
life span of many mammals.[11] In laboratory rats,
this increase in lens weight has been found to be
largely independent of the nutritional status of
the animals. This technique was taken as a useful
measure in the late 1980s to correlate the ages of
different mammalian species at different stages
of life. However, this method proved a useful
indicator only up to 3‑4 months; beyond that point,
the technique is not precise enough to determine
the exact age of the rat.[12]
Teeth: A test of age
Some researchers have developed methods to
determine the ages of smaller mammals by using
the growth of molar teeth, mostly by the molar
ageing method or the crown method.[8] In rodents,
the first upper molars clearly show age‑dependent
changes. The molar of young animals consists solely
of a specialized prismatic part (i.e. crown), which
is compensated by the growth of the roots that
starts approximately at the age of 2.5 months, and
is continuous, pushing the crown upwards. In aged
animals, most of the crown worns away and the roots
are long. On account of differences in diet and also
in primary molar hardness, molar wear may differ
geographically; therefore, the molar ageing methods
are perhaps not directly applicable outside the area
in which they are developed. If accurate assessment
of dental development is possible, this method
should be given more emphasis in age estimates.
In the absence of dental information, assessments
of skeletal maturation (including long bone lengths
and maturation of other skeletal elements) can be
used.[13]
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Counting endosteal layers in tibia
Although many age determination techniques
have been developed, the most widely used method
in vertebrates involves a technique of counting
endosteal layers in the tibia that allows to accurately
determine the age of the experimental animals. It
has been reported in several studies that, in younger
animals, more lamellae were found than their age
in years.[9,14]
Musculoskeletal examination: Epiphyseal
closure
Because dental development is minimal in
fetal animals, most estimates of age rely on bone
formation, especially long bone lengths, and
also other bones such as the assessment of the
development of the ilium and the petrous portion
of the temporal. If accurate measurements can
be taken, formulae exist to allow the calculation
of body length and subsequently, the age. Mostly,
bones of the upper and lower limbs and hip joint
are used to determine the age of the experimental
animal. In the childhood of the animal, closure of
metopic suture and appearance of ossific centers
are used.[10] During the first 6 years of human life,
appearance of ossific centers are observed mainly
in the bones of the humerus, femur, tibia, radius,
patella and ulna. In addition, closures of epiphyseal
plates are an indicator of the adolescent period.
Closures of epiphysis in the bones of the upper
limbs (wrist, shoulder joint, humerus, ulna, radius,
metacarpals and phalanges) are found during the
age of 14‑18 years of human life, while epiphyseal
closure lower limbs (femur and tibia) are found
during 18‑25 years of age. During early adulthood,
bone remodeling and maintenance is the prime
indicator, while in late adulthood bone wears and
tears help in the determination of the animal age;
two pubic rami of the hip are found at the age
of 6 years, suture at the acetabulum at 15 years,
ischeal tuberosity with the ischium at 21 years and
iliac crest with the ilium at 23 years. In addition
to skeletal measurements and dental evaluation,
the extent of formation and union of epiphyses is
important. Epiphyseal evaluation involves gross
examination in skeletal remains and radiological
assessment in fleshed material.[15]
Rat age and human age: Revealing the relation
Biomedical researchers who use rats as an
experimental model often face numerous questions
like “what is the relationship between age of the rat and
human?,” “when are these animals considered adults or
aged?” or “how old is a rat in people years?.” Only a
few research works have attempted to answer these
questions. These questions could be answered in
various ways. Most of the researchers used to relate
human and rat age by simply correlating their life
span, which is not acceptable, because, for a specific
research work, one uses a particular developmental
phase of rat‑life. Thus, one should consider different
phases of their life to have an accurate correlation.
What is the relation between their “life periods”?
Laboratory rats live about 2‑3.5 years (average
3 years),[16] while the worldwide life expectancy of
humans is 80 years, with variations in countries in
accordance with their socioeconomic conditions.[17]
Therefore, taking their life span together, it can
be calculated as:
(80×365) ÷ (3×365) =26.7 human days=1 rat
day; and
365 ÷ 26.7=13.8 rat days=1 human year.
Thus, one human year almost equals two rat
weeks (13.8 rat days) while correlating their entire
life span.[18,19]
However, while considering the different phases
of rat life, including weaning to aged phase, it
could be easily noticed that rats have a brief and
accelerated childhood in respect of humans.
Rats develop rapidly during infancy and become
sexually mature at about 6 weeks of age. Humans,
on the other hand, develop slowly and do not hit
puberty until about the age of 11‑12 years. Social
maturity is obtained in 5‑6 months of age.[19,20]
When do the baby rats weaned?
The unique bond between mammalian mothers
and their infants, whom they create and maintain
by nursing, is irrevocably broken during weaning.
In a strict sense, the weaning process involves
a developmental reorganization of ingestive
behavior. Infant altricial mammals subsist entirely
on mother’s milk; as adults, they independently
select and ingest solid foods. Weaning is the
transition between these two forms of subsistence,
and constitutes an essential element in the
progression to adult function in all mammals.
In a general sense, weaning also represents a
milestone in the achievement of more global
forms of independence, a prominent and universal
discontinuity in mammalian development that
marks a significant change in life pattern.[10,11]
Weaning (or nursing) is the first phase of rat
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life, which is a developmental process unique to all
mammalian young. It is the process of gradually
introducing a mammalian infant to an adult
diet (solid food) and withdrawing the supply of
its mother’s milk [Table 1]. In Rattus norvegicus, a
species important in laboratory studies of ingestive
behavior, the young begin to reliably ingest solid
food on about Day 18 (P18). Time spent suckling
begins to decline around P20, while time spent
ingesting solid food increases. By about P34, the
young no longer suckle and weaning is essentially
complete. The average weaning age for humans is
approximately 6 months (180 days),[21] while it is
3 weeks for laboratory rats (~P21).[22]
Thus,
180 ÷ 21=8.6 human days=1 rat day and
365 ÷ 8.6=42.4 rat days=1 human year.
Therefore, in this developmental phase, one
human year equals 42.4 rat days.[18,19]
Is my rat going through “puberty”?
The second phase of rat‑life is its puberty,
when reproduction first becomes possible,
i.e., when germ cells are released. Research on the
reproductive physiology using pubertal and adult
rats as experimental animal began in the 1930s.
Since then, the species has been more thoroughly
characterized in these research fields than any
other laboratory animal model. This biomedical
field basically employs pubertal or adult rats.[23‑25]
Long and Evans[26] found that rats reached puberty
at an average age of 50 days after birth (P50).
Humans, on the other hand, develop slowly and
do not reach puberty until about the average
age of 11.5 years (11.5×365=4198 days). Rats,
on the other hand, become sexually mature at
6 weeks (P42).[27] However, it has been reported in
several studies that have compared birth weight of
rat and human that, rats are not “born” until Day 12
after birth (P12). This means that rats reach sexual
maturity at approximately 38 days (i.e. 12 days less
than their actual pubertal age at P50).
Thus, it could be easily calculated that in the
pre‑pubertal phase:
4198 ÷ 38=110.5 human days=1 rat day, and
365 ÷ 110.5=3.3 rat days=1 human year.
Thus, in this phase, one human year equals 3.3
rat days.[18,19]
When rats are considered “adult”?
To determine when an animal is an adult, it is
also important to review the developmental stages
the animal progresses through to reach adulthood.
Both rats and mice show a similar developmental
profile [Figure 1]. At P21, rodents are weaned,
i.e. separated from their mother. After that, they begin
to undergo sexual maturation.[1,19] Sexual maturity
is generally defined by vaginal opening (females)
or balanopreputial separation (males). This
point is reached in female rats at approximately
P32‑P34 but, in males, maturity occurs much later
at around P45‑P48. However, the age of sexual
maturity varies considerably between individuals,
ranging from as young as P40 to as old as P76 in
male rats.[28] It is also important to note that sexual
maturity itself does not mark the beginning of
adulthood, but rather denotes the beginning of
adolescence. Like humans, rats progress through a
Table 1: General physiology and reproductive data of
Rattus norvegicus
Common physiological data
Body temperature 37°C
Respiratory rate 75-115 breaths/min
Heart rate 260-400 beats/min
Daily water consumption 10-12 ml/100 g body weight
Daily food consumption 10 g/100 g body weight
Litter size 6-12
Birth weight 5 g
Weaning age 21 days
Sexual maturity 7 weeks (~P49)
Breeding duration 12-16 months
Male adult weight 450-550 g
Female adult weight 250-300 g
Life span 2.5-3.5 years
Reproduction parameters
Male rats
Age at pairing (mating) 8-10 weeks
Weight at pairing 250-300 g
Female rats
Age at pairing (mating) 8-10 weeks
Weight at pairing 180-225 g
Length of oestrous cycle 4-5 days
Duration of oestrus 10-20 h
Time of ovulation 8-11 h after onset of estrous
Menopause 15-18 months
Gestation
Time of copulation Near midpoint of
previous dark cycle
Time sperm is
detected in vagina
Day 1
Time of implantation Late day 5
Length of gestation 21-23 days
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period of adolescence characterized by behaviors
such as increased risk‑taking and social play. These
behaviors extend well beyond the pubertal period
through the transition to adulthood,[29] which begins
after the eighth week of post‑natal life (~P63). The
body weight of an animal is sometimes considered
an indicator of its age. However, weight is not an
accurate surrogate marker for age. It has been reported
that male rats weighing between 250 g and 274 g
differed in age by 3 weeks, from P49 (periadolescent)
to P70 (young adulthood). In addition, male rats of
the same exact age showed up to 100 g variation in
body weight [Figure 2]. Weight is, therefore, only
an approximate marker of age. Similarly, to identify
adulthood by musculoskeletal maturity with rats is
problematic as there is no epiphyseal closure in the
long bones.[30,31] At approximately 7‑8 months of
age (~210 days), skeletal growth tapers off in male
and female Sprague‑Dawley rats.[22] In humans
growth plate closure is rather inconsistent among
individuals and among different growth plates
within the body. One of the last growth plates to
fuse is in the scapula, which closes at about 20 years
of age on average (365×20=7300 days).[32]
Therefore, from this data, it can be calculated that:
7300 ÷ 210=34.8 human days=1 rat day,
which indicates that 365 ÷ 34.8=10.5 rat
days=1 human year.
Thus, during the adolescent phase, 10.5 rat days
equals one human year.[18,19]
Reproductive senescence: The rat is no longer sexually
active!
Reproductive senescence in female rats occurs
between 15 and 20 months of age. During the fertile
period in a female’s life in most species, mating usually
only occurs when a female is fecund (at the time of
ovulation in spontaneous ovulators or when primed
to ovulate in reflex ovulators). But, this integration
of behavior and physiology can break down during
aging in female rats. Most aging female rodent
exhibits periods of persistent estrus (constant sexual
receptivity) that are associated with tonic blood titers
of estrogen and low levels of progesterone. Because
the tonic estrogen secretion stimulates cornification
of the vaginal epithelium, this state is also referred to
as persistent vaginal cornification. This is the most
common state of acyclicity in laboratory rats.[19]
Similarly, the traditional marker of reproductive
senescence in women is menopause, characterized
by loss of menstrual or fertility cycles at midlife.
According to the American Medical Association,
the average age of menopause in women is
51 years (51 × 365=18615 days),[33] and female
rats enter menopause between the ages of 15 and
20 months (600 days).[34]
Thus, 18615 ÷ 600=31.0 human days=1 rat
day, and
365 ÷ 31=11.8 rat days=1 human year.
Thus, during reproductive senescence, 11.8 rat
days equals one human year.[18,19,34]
Post senescence: When the rat is aged!
If the periods of post‑senescence to death are
Figure 1: Correlation of body weight with different phases of postnatal days
Figure 2: Variations in body weight of male rats throughout
the lifespan
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International Journal of Preventive Medicine, Vol 4, No 6, June, 2013
compared, the following is found: Female rats
live an average of 485 days after senescence and
female humans live an average of 10,585 days after
senescence.
Thus, 10585 ÷ 495=21.4 human days=1 rat
day,
meaning 365 ÷ 21.4=17.1 rat days=1 human
year.
Thus, in the aged phase, 17.1 rat days equals
one human year.[18,19,34]
CONCLUSIONS
Thus, the findings of this review suggest that
although rats are indispensable elements of
biomedical research,[35‑42] they are not a miniature
form of humans;[18,19] differences in anatomy,
physiology, development and biological phenomena
must be taken into consideration when analyzing
the results of any research in rats when age is a
crucial factor [Table 2]. Special care should be
taken when the intention is to produce correlation
with human life. It is important for a researcher
to understand that the relative ages are different
depending upon the stage of life; therefore, one has
to determine the relevant age under investigation
and what factors are being analyzed. For this,
special attention is needed to verify the phase in
days of the animal and its correlation with age in
years of humans.
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36 months (3.0) 90
42 months (3.5) 105
45 months (3.75) 113
48 months (4.0) 120
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37. Sengupta P, Chaudhuri P, Bhattacharya K. Male
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39. Sengupta P. Chemosterilization: Spermatogenesis,
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40. Sengupta P, Goswami H, Chandra AK. Environmental
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41. Sengupta P, Bhattacharya K. Effects of high altitude
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Source of Support: Nil, Conict of Interest: None declared.
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... 1. Group I: In which seven rats (six months old, equivalent to eighteen years in humans) [ 9] . They were kept in a normal, healthy state throughout the experiment, for eight consecutive weeks and fed ad libitum. ...
... This group consisted of fourteen rats aged 18 months (equivalent to 45 years in humans) [ 9] , and was equally subdivided into 2 subgroups seven rats each as follows: ...
... 66 Multiple experiments were performed during our study, using both repeat measures and interval testing. While there is evidence of differences in FST behavior between distinct phases of a rat's life, prepubertal (<4 weeks), adult (2−18 months), and aged rats (18 months), 56 all tests in this study occurred during the same phase, young adulthood (9−15 weeks), 67 during which time FST behaviors are known to be consistent. Thus, we chose to reduce animal resources in studies with repeat measures by comparing our interval-tested treatment groups with the first FST of the repeatedly tested saline groups. ...
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