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lecture 5 1st hour \ by : Deema Yahya

Atrophy :

- sometimes we use a term clinically , but it has different meaning in the

pathological way .
E.g. atrophy of the breast :
decrease in the size of the breast itself
pathologically some of the cells will undergo apoptosis because they are
not needed , and the remaining ones will undergo atrophy
and remain viable .
( so clinically , atrophy is the combination of both of these 2
And that will vary depending on the duration of the
stimulus and the type of the tissue itself ).

E.g. a broken arm will be fixed for 2-3 months , and the muscles of that arm will
undergo atrophy , due to decrease in the size of the cells due to decrease of
the organelles , with minimal if any apoptosis .
But after physiotherapy , it will be back to its normal form in no time.

E.g. a paralyzed arm , for about 2-3 years , the cells are not going to be used for a
long time , atrophy might be associated with more and more apoptosis for
these cells .

- long duration atrophy, less reversible :\

thats why we use physiotherapy in patients who are paralyzed for long period of
time , to keep the viability of these cells , because if these cells are not stimulated
for a long period of time , some of them will undergo apoptosis .
- so the atrophy as clinical term is apoptosis and the actual atrophy and the
percentage is going to depend on the organ and the severity of the stimulus itself.

E.g. Skeletal muscle atrophy :

decrease of the size of the cells , later on death of these cells and gradual
replacement of these skeletal muscle cells with fatty tissue !
E.g. breast atrophy after menopause :
wont be just a temporarily event , the women after 50 years will have
menopause which will last for years , so the atrophy definitely is going to be
associated with ongoing apoptosis of the cells and the remaining ones will
become atrophy .
if we give her hormones , the breast wont return to normal form .
- so , whether the atrophy is reversible or not , it depends on the duration of the
disease itself .

- the atrophy might be irreversible clinically because we have a higher percentage

of cells undergoing apoptosis .

Hypertrophy :

- we use it to note the enlargement of the size of the organ , but later on we
discovered that some organs are going to increase in size not due to the
increase of the size of the cells , but due to the number of the cells
( hyperplasia not hypertrophy ) , but unfortunately we still use it as in the past :\

- pathologically , hypertrophy means that we have increase in the size of the

organ because we have increase in the sizes of the cells as they are going to
have more organelles in their cytoplasm .

- this is not just a reflex !

this process is really complicated and it has to go through certain processes
that eventually are going to end in delivering the signal to the nucleus and the
nucleus is going to express different genes or different expression of the genes
leading to more synthesis of organelles and causing hypertrophy .

- the hypertrophy could be physiologic or pathologic , depending on the cause :

if the cause is physiologic , then the hypertrophy is going to be physiologic .
E.g. the uterus can undergoes hypertrophy & hyperplasia at the same time .
E.g. exercises can cause physiological hypertrophy for the skeletal muscles
while extreme exercises can be associated with pathological hypertrophy.
E.g. the hypertension is considered as a training to the heart , because the
hypertension is an increase of the work demand of the heart itself so the
heart will undergo hypertrophy .

- so , different genes are going to be expressed , and this expression is going to

be associated with transcription of different proteins .

- So , if we take the heart for example , our heart fibers are going to contain
actine as well as the myosin light chains , and these can be from different types
depending on the genes are transcribed ,
so in the fetal life , we are going to have different myosin and actually actine
filaments than we have in our adult life , because the environment of the fetal
heart is different from that of the adult heart .
The fetal heart there is no high loud because there is no physical effort
floating in a weightless condition
so the effort of the heart is minimal
But there is a problem in the fetus , because we are going to get enough
oxygenation of the heart , because the blood is not going to be oxygenated in
the lungs as adults ( The blood saturation of oxygen is about 99% in the adults ),
But the fetus is going to have the oxygen from the maternal arteries , not from
the lungs themselves , so the heart will be affected will less oxygen ( just like it
is hypoxic )
So those fibers are going to be adapted more to that decreased concentration
of oxygen and actually they can coop with that .

When the heart is hypertrophic , these cells have to have more work load yet
they might also be affected by the hypoxia as we mentioned before ,
They need more oxygen , they have less oxygen themselves and they might be
more vulnerable to hypoxia as compared to the normal non hypertrophic
myocytes .

- because the hypertrophic cell are thick , so they need more oxygen , and the
chance to suffer from hypoxia is more as well ,
So in order to have fibers that can tolerate with hypoxia , the hypertrophy will be
associated with switching on certain genes for the fetal type proteins , This will
make the heart adapt with the hypoxia in better way but it will be more vulnerable
to injury than the normal muscle fibers .

- Hypertrophy is an adaptational method that the body undergoes after certain

events , but it is not the optimal way that the body should be in , because if thats
so , then all our cells would be hypertrophic in the normal situation .
So the hypertrophic cells are not that healthy

- Hypertrophic nice-looking muscle of body builders are not healthy

even though they look photogenic , physiologically its not healthy and these
muscles will be more vulnerable to damage for a certain stimulation .

- Hypertrophy in the heart , the ventricle will be thick , and you can guess that the
remarkable thickening of the myometrium of the heart , make in tough to get
enough oxygen, so infraction is more likely to happen .

- And the hypertrophic muscles will have enlarged nuclei , what we referred to as
box car nuclei , because of their enlarged appearance due to protein transcription
and synthesis in the nuclei of the muscle fibers of the heart .

- As we mentioned before , sometimes it is misused :

The most common wrong term we use is benign prostate hypertrophy
this is totally wrong ,
its not benign because its not cancer \ neoplastic ,
and its not hypertrophy , it is hyperplasia .
nowadays , we try our best to substitute that term with nodular
hyperplasia of the prostate.
Also , another term that is misused is gingival hypertrophy ,
the gingiva is composed if mucus membrane , connective tissue (
fibrocytes , fibroblasts ) and blood vessels
all of these are cells that can replicate , so the enlargement of the size
of the gingiva is mostly because hyperplasia not hypertrophy ,
this is usually seen in patients who are on anti-epileptic drugs.
another confusing term is organo-megaly
E.g. hepatomegaly , spleenomegaly , .
these are old terms that we used to describe the enlargement of the
size of the organ as we get to see by palpation or by imaging
techniques .
nowadays , we have to be more precise , so we have to describe the
increase of the size of that organ with a reflex to hypertrophy or

- for cells that can divide , it is better for them to go for adaptation by increase
the number of cells in that condition , and this is what we referred to as
hyperplasia .

Hyperplasia :

- Usually , all tissues have what we call , constant cell pool ,

we get to have constant number of cells per tissue and that is going to be
regulated by different factors .
- we have proliferation of the cells and some of these cells are going to be lost
by differentiation , shedding or by apoptosis .

Proliferation of the

Differentiation , shedding

cell pool

- so in order to have the normal anatomy and normal histology and normal
functionality , we have to have constant number of cells in our tissue\ organ ,
and that is going to be controlled by also genes .

- so we have genes that are responsible for the proliferation , and genes that are
responsible for differentiation and genes that are responsible for apoptosis as
we mentioned .

- so in order to increase the sizes of tissues per tissue volume , we have also to
manipulate the genetic control over that population .
- so again that is not just a reflex enlargement or a reflex increase in the number
of cells , its also include certain genetic re-arrangement that will maintain more
cells in that tissue .
- the increase of the number of cells can be either physiologic or it can be
compensatory or it can be pathologic :
1. Physiologic :
E.g. Breast feeding , in pregnancy , the endometrium after each cycle
this is hormonally dependent , the estrogens affecting certain genes that
will lead to increase proliferation of these cells as to have more cells to
perform more function
2. Compensatory :
E.g. liver transplantation , we go to partial hepatic removal , and the
remaining liver is going to undergo hyperplasia which is adaptational
compensatory hyperplasia , its not pathological .
3. Pathologic :
if the cells are not there to perform a specific function , this will be
pathologic hyperplasia , especially when its not controlled by genes .
- So in order to increase the number of cells , we have to activate \ switch on
certain genes responsible for proliferation or inactivate genes responsible for
apoptosis , and this again should change the control of genes that are
responsible for cell cycle .

Signaling activation of certain genes that are going to increase the cellular
proliferation increase the number of cells in that tissue

Q] till when the cell will proliferate and increase in number ?

In physiologic situation , E.g. breast feeding :
the enlargement must be controlled by physiological control mechanisms ,
as these cells are going to compete for nutrients ( the nutrients wont be
enough for all these cells ) , or the continuous proliferation might be
associated with switching on other genes that are responsible for inhibition
for the proliferation .
then the cells are going to re-establish new homeostasis at a higher level of
cells per the new tissue volume .
so at this point we have constant cell pool at a higher level .
Q] are the hyperplasic cells , normal or abnormal ?
They are normal whether the stimulus normal or abnormal !
these cells are responding normally and physiologically , and responding as
they should to the stimuli .
if the stimulus is abnormal , its not the cell business :P
the cells do not investigate the origin of that stimulus , their response to
estrogen is proliferation whether that estrogen is physiologic or pathologic will
have the same response .
so these cells are still normal , and responsive for hormonal stimulation or
hormonal inhibition and they are under control of the cell cycling,
however, that stimulus is going to determine if that increase of number of
cells is physiologic or pathologic .

- Not all hyperplasia means cancer

Q] so what is the relationship between hyperplasia and cancer ?
cancer means uncontrolled cell division
hyperplasia is controlled cell division
hyperplasic cells are normal ,
* can these cells considered cancerous as such ? NO !
* is that process adaptational or not ? YES !
* reversible or not ? REVERSIBLE !
The stimulus of these cells might be abnormal , but the response is normal
So these cells as such cant be cancer , however , the more cells you have , the
more chances of one of these cells will acquire a mutation leading to
uncontrolled proliferation and neoplastic formation .
So hyperplasia is considered as a fertile soil for cancer
but hyperplasic tissue is not precancerous tissue ( not yet cancerous ) because
it depends on whether these cells acquired a mutation of not .

Pathological hyperplasia :
E.g. prostate hyperplasia :
- the function of the prostate is to contribute with the seminal fluid and in
the sexual activity to prevent retrograde ejaculation (the semen go to
the urinary bladder not the ejaculatory duct ) .
so the function of the prostate is going to be maintained by the
physiological demands and the hormonal stimulation because its not
functioning all day long ( unlike the heart , so the heart doesnt need
tropic hormone as the prostate does ) .

* tropic hormone : hormone that is necessary for the maintenance

of the cell *
- so the prostate have to be continuously stimulated by the testosterone ,
testosterone is not like the estrogen ,
the estrogen is going to affect the female in a cyclic fashion , thats why
females dont have endometrial hyperplasia; the estrogen level increases at
the beginning of the cycle then decreases .
at the menopause , the estrogen will disappear all together and the uterus
will undergo atrophy.
- the prostate will continuously be affected by testosterone , men dont have
cycle , and they dont have menopause , so the testosterone will
continuously keep stimulating the prostate cell for ever ! as long as that
person is alive ,
Q] Is that needed or not ??
testosterone is definitely needed for the normal development of the
prostate ,
after puberty , the prostate will be almost mature and it needs actually some
sort of hormonal support .
However , that hormonal support exceeds the physiological life expectancy
of that prostate , and it will continue to proliferate , eventually some of
those proliferative cells might form nodules , which will compress the
prostatic urethra , leading to urinary retention .
so at the end , this will become pathological .


Q] but the nodular prostate hyperplasia , is it a disease or not ?

All healthy men are going to have continuous testosterone stimulation and
all of them are going to have prostate hypertrophy , so its not a disease .
any man who doesnt have prostate hyperplasia , he has problem .
Some persons are going to be lucky enough so they dont have significant
hyperplasia obstructing the urethra , while other people will be less
fortunate and will have more level of that physiologically available
testosterone , leading to prostate nodular hyperplasia , leading to urinary
obstruction .
So it is normal , but if exceeds a certain level , it will considered as

E.g. Hyperplasia of the uterus :

the uterus is going to respond to estrogen and progesterone :
at the beginning of the menstrual cycle , the estrogen level increases ,
then the progesterone , after that both will decrease .
as a response to that hormonal change , the uterus will proliferate , and
when the estrogen level decreases , the proliferation stops .
these cells are going to be maintained by the other hormone , the
progesterone , which will maintain the viability of these cells , leading to
secretion .
if there is no conception , the level of these 2 hormones will decrease .
the endometrium is for implantation of the zygote , but no conception ,
so the endometrium is useless !

so the corpus lutium will undergo involution ( vanish ) , so the level of the
hormone decreases , and the endometrium wont have any hormonal
support , so that endometrium will undergo shedding , apoptosis and
necrosis !
the surface epithelial cells will undergo apoptosis .
the spiral arteries will be coiled , and that might be associated with ischemic
change of the Stroma itself , so what happened is that is physiological
necrosis !
its not legal to call it that way :P
but this is what it is ,
its not apoptosis , because we have death of scattered cells \ groups of cells,
we have an inflammatory reaction, but this is physiological not pathological !
and there is no term to call that condition with , its not necrosis as its not
pathological . and it exceeds what apoptosis is all about ,
this all will lead to menstruation , and the cycle will be repeated again.

Lets suppose that this area is going to have unopposed estrogen

stimulation, so the estrogen will continue to stimulate the endometrium ,
{ like in cases where the woman is taking estrogen pill after the menopause ,
to protect the bones from osteoporosis and to maintain their young
appearance :P , or in case of estrogen-producing tumors , or in case of
polycystic ovaries ovaries that fail to ovulate and these follicles will
continue to produce estrogen- }
so we have a continuous stimulation ,
at the beginning , the endometrium will proliferate as usual , and this
suppose to end with secretions , but this is not what happened , the
estrogen level keeps high , so more proliferation of the endometrium ,
causing endometrial hyperplasia .

If we get to diagnose that condition , we give her progesterone to increase

the secretions and stop the proliferation .
If we didnt diagnose that , proliferation will continue until the endometrial
layers will close the cavity of the uterus !
so there would be no space for the blood vessels to grow in that area ,
and those new proliferated layers and now going to get ischemic , and when
they become ischemic , they will undergo apoptosis , necrosis and shedding .
This is called irregular vaginal bleeding ( which is different from
menstruation ) .
this bleeding depends on the level of hormones and the size and the
anatomy of the uterus .
some women takes 2-3 months before this bleeding , and some after 5
months .
In these cases we go for curettage of the endometrium by surgery , and in
the examination we get to see endometrial hyperplasia .

Q] is that cancerous ?
NO , not yet cancerous .
but having endometrial hyperplasia for a long time , this will create a
suitable circumstances for a mutation to emerge in those rapidly
proliferative cells leading to carcinoma .
The more cells we have , the more the chances for a mutations leading to
cancer , especially if these cells are proliferative cells .


E.g. Thyroid hyperplasia :

Q] how do we maintain a certain number of cells in our thyroid gland ?
The normal cell pool of the thyroid gland will remain anatomically normal
that we usually do not feel .
so no matter how accurate you palpate your thyroid , you wont get to feel.
Unless this thyroid is going to have more cells , that will be associated with
an enlargement of the size of that thyroid .
this is called clinically Goiter .
Goiter means that we are able to see and feel the thyroid !

Q] what are the mechanisms involved in the regulation of the normal cell
population in the thyroid gland ?
TSH , is going to activate the functional activity of the cells leading to
increase their secretion of T3\T4 on one hand , and on the other hand ,
increase the proliferation of the epithelial cells of the thyroid .
T3\T4 are going to have negative feedback on the pituitary gland
if we have low levels of T3\T4 , the TSH will continue to be produced
So this process is auto regulated .

Q] what are the cases that we have thyroid hyperplasia in ?

1. Increase of the TSH level , as in pituitary TSL- producing tumor , that
will continue to secrete TSH regardless the level of the normal values
of T3\T4. But this is very rare case .

the TSH will be inhibited from the normal cells but the tumor is going
to continue the secretion of TSH.
this will lead to elevation of the level of T3\T4 and also to hyperplasia.
2. TSH-like substance affecting the receptors n the thyroid cells , for
example : antibodies .
so the antibodies will continuously stimulate the cells of the thyroid
leading to increase T3\T4 secretion that will lead to thyrotoxicosis ,and
also increase in the cellular rate of proliferation leading to diffuse
that is called clinically Graves disease
3. Iodine deficiency , so T3\T4 will start to decrease , but this is a slow
process , so as soon as the level of T3\T4 are going to decrease , TSH
will increase leading to increase the proliferation of the thyroid gland ,
so increase the cells of the gland .
they will pick the iodine more efficiently and the level of T3\T4 might
get back to normal .
this will be associated with new thyroid state .
so more iodine deficiency , more proliferation of the glad ( become
larger ! )
eventually , these cells are not going to respond to TSH in the same
way , so in certain areas , there will be more proliferation than the
other areas , forming nodular goiter .
the gland will increase in size as long as there is iodine deficiency with
that patient .
the gland might be as big as it become retro-sternal !
nowadays , we dont see this anymore .


The most common feature of goiter is neck masses !

especially in males and elderly females .
- hypothyroidism , when the thyroid gland has abnormal functionality ,
but this wont happen suddenly , unless the patient had a surgery to
remove the thyroid .
Q] when do we have hypothyroidism ?
1. After a surgery to remove the thyroid
2. Autoimmune disease , the antibodies and going to damage the
epithelial cell and follicles of the gland .
- destructive antibodies
3. If the patient doesnt have TSH , in case if pituitary necrosis .
4. if the patient is deficient to iodine .

- hyperplasia is misused also in the case of klinefelter syndrome,

these patients are going to have testicular atrophy , the testicle
will be small because of the loss of the somniferous tubules , while
the leydig cells in between will stay almost as normal ,
so their proportion will be much more prominent because of the
decrease of the size of the somniferous tubules .
so they appear like they are hyperplasic , but they are not .


Lecture 5 2nd hour \ by : Yara Quzmar

Metaplasia :

- Well talk about third kind of adaptation: Metaplasia

Q] What does Meta means?

it means position behind, after, or beyond
Something that will take the place of the cell after it becomes mature .

- Cells are going to survive in balance b/w stimulation and function

depending on environment ,
so if you stimulate cell more youll have increase in number of this cell or
increase in size ,
and if you stimulate less youll get less number and smaller size ,
but if you damage the environment around those cells ,i.e. you are not
going to stimulate them functionally but you are going to alter the
environment this kind of stimulation will not affect the physiological
pathway of the cell so it will need different kind of adaptational response .

- These cells are going to be adapted to their environment and to their

function , and their morphology will depend on: normal metabolism and
function which is going to determine what genes will be turned on and what
organelles will be working .


E.g. the respiratory lining :

Upper respiratory tract : stratified squamous
Bronchial : columnar ciliated psuedostratified with goblet cells
Alveolar : simple squamous
Different environment , different function imply different morphology

- In upper respiratory airways these cells are going to be affected more by

mechanical , physical and chemical irritation . the air we breathe in have
many different harmful particles so our epithelium will have to withstand
those damaging factors .
- So if one cell dies , its okay because the underlying cell layer will make It
up , but if the lining is single layered and one cell dies this will cause the
underlying basement membrane to be naked and ulceration will happen .
- So in areas where we have more mechanical , physical and chemical
irritation we need to have stratified epithelium and this will prevent the
damage of that epithelium by those noxious stimuli .
- But as we go deeper into respiratory tract , Bronchial lining will become
ciliated where we have goblet cells that produce mucin , we also will have
mucin located in the sub-epithelial connective tissue and that mucin will
stuck on the surface of that epithelial to pick up tiny particles from air we
breath .


- Particles carried by air we breathe will stuck to mucin on cilia and cilia will
get that mucus escalated and delivered to nasopharynx where its going to
be swallowed.
- By reaching alveolus , air will be clean and no particles will be find even
though bacteria , and that cell lining will allow the diffusion of gas .
so morphology has to keep up with function and environment .
- although all of these cells have same genes , different genes will be
expressed in order to have different morphology and functionality in keeping
with environment .
- if a person started to smoke and this will be associated with deep delivery
of those chemicals of those gases to respiratory tract not only nasophaynx,
he is going to inhale smoke and that is going chemically and mechanically
irritate respiratory epithelium .

Q] so now how cells are going to adapt ?

body will find a way that makes those epithelial cells more adapted and
more tolerant to that chemical irritation as squamous epithelium ,
metaplasia , new cells are going to differentiate and proliferate to make
squamous .
NOT mature cells that are going to be transformed , reserved cells are going
to . signals delivered to those cells are going to alter their line of
differentiation , they are going to make squamous instead of respiratory
epithelium that can better handle those irritations.

- But unfortunately we are going to pay the price </3 .

the more we irritate the respiratory epithelium more mucus epithelial glands
in the sub epithelial tissue are going to produce more mucin , but that mucin
is not going to be continuously escalated buy cilia because there is no cilia
anymore </3 , and it will accumulate and produce cough reflex , it builds up
during night and smoker cough in the morning .
So metaplasia is a double-edged sword
Its good , to keep the viability of those cells and that will definitely be better
than losing them
But at the long run it will lead to loss of function leading to more
inflammation that can be associated with bronchitis , and thats bad

- In order to have normal differentiation of the reserved cells to respiratory

epithelium we have to have Vitamin A and suitable environment .

Q] So is metaplasia adaptational ?
Q] Reversible?
on the level of tissue yes , reserved cells when they differentiate in the
suitable environment and with the disappearance of noxious stimuli , will
have cilia
Q] Precancerous?
No, because they are mature cells which replaced another type of mature
cells .

E.g. Metaplasia of esophagus :

Esophagus is lined with squamous stratified to tolerate mechanical and
chemical irritation .
Stomach is affected by acid so it needs a special type of epithelium that
produces mucin to protect epithelial lining
If theres a gastro esophageal reflux disease , esophagus will have to adapt
by replacement of squamous epithelium by columnar that produces mucin.

E.g. Uterine cervix :

- Exocervix (faces vagina) is lined by on keratinized squamous stratified
epithelium to withstand mechanical and microbial irritation of vagina .
- Endocervix is lined by columnar mucinproducing , for lubrication , to close
cervical os , prevent the ascending of infection and to facilitate or prevent
the movement of spermatozoa .
- If inflammation happened , metaplasia from columnar to squamous will
happen and we can detect by pap smear that will show that the endocervix
is not lined by columnar anymore and its lined by squamous epithelium
which denotes prolonged ongoing injury to the endocervix.

Epithelial metaplasia can be :


E.g. Mesenchymal metaplasia :

- Mesenchyme is primitive connective tissue that can differentiate to
fibroblast , osteoblast , chondroblast , smooth muscle and adipose tissue.

Q] What determines the line of differentiation of mesenchymal cell?

Signals and certain genetic stimulation .

For example, fibroblast in CT exposed to prolonged cell injury , which can

lead to acidosis and accumulation of calcium which leads to calcification, the
environment had changed and fibroblast cannot handle it , so it has to
transform to something that can withstand this calcification Osteoblast .
So mesenchymal CT will undergo osseous metaplasia leading to bone
formation at the site of CT .
so you can actually find bone in muscle tissue .
this is often seen in aortic arch , when its exposed to a high pressure , lipids
and toxins of smoking , this will lead to prolonged injury for years leading to
acidosis , calcification & bone metaplasia .
so we can actually find bone in aortic arch

Q] is metaplasia precancerous ?
however , lets suppose a patient is smoking for years , he is going to have a
well developed squamous metaplasia of his respiratory tract .

Q] now is that metaplasia going to deal totally with that irritation ?

NO :\
irritation still exists , so does smoking .
eventually that patient is going to be exposed not to mechanical irritation
only , but also to certain carcinogens that might interfere with normal
expression of genetic apparatus leading to abnormal differentiation .

- previously we had proliferation with normal differentiation towards

squamous epithelium . now having continuous exposure to the noxious
stimuli will lead eventually to having some of these cells with abnormal
genes .

- this actually happens all the time but fortunately these cells that are going
to have abnormal genes either that genetic abnormality is so profound to
lead to severe metabolic abnormality leading to cell death APOPTOSIS or
viability of these cells is maintained with abnormal genes which can be
detectable and eliminated by p53 leading to APOPTOSIS .
but eventually after so many tries for many years , one of these cells is going
to have the right mutation allowing it to escape apoptosis and immune
system and its going to proliferate with irregular maturation , NO


- Adaptational mechanisms are to tolerate not to eliminate , so if that

patient is going to quit smoking his squamous metaplasia can be reversible
after months , but metaplasia not to going to eliminate stimulus .
metaplasia is not going only to change morphology but on the long run it
may cause damage the genes leading to abnormal maturation , dysplastic
We have differentiation but no maturation .

- Dysplasia can be :
1. mild , we didnt have maturation at early stage and we treated it
2. Moderate , abnormal maturation extends to middle third of lining
3. Severe , involving the whole lining from deep to surface

- Proliferating cells without maturation = carcinoma in sito.

Q] Is dysplasia adaptational ?
no . Its a problem , it doesnt serve any physiological benefit . Its a reflect to
a problem in genes .
Q] Premalignant ?
Q] Reversible ?
at the level of tissue yes it is at early stages of mild dysplasia , at the level of
cell no its not .

i.e. , lets get back to metaplasia , cells committed to be squamous and

theyll die squamous ,
cell that was squamous is not going to return respiratory , but newly growing
cells will be respiratory , so at the level of tissue well have new respiratory
cells and the squamous cells are just dead and gone .

- so if these mild dysplastic cells are not going to be exposed to stimulus ,

generation after generation theyll lose their properties until after 2 months
theyll be replaced by new cells with normal genes and maturation , but if
smoker decided to stop smoking during severe dysplasia its not going to be
beneficial because these cells are now independent theyll be self sustaining
population and will not depend on stimulus anymore , then it either keep as
carcinoma in sito or become invasive .

Cellular aging :

- Biochemically , morphologically and on tissue level its going to be

characterized by certain features
- On metabolism level :
Decreased anabolism , increased catabolism , decreased synthesis of
enzymes and receptors , decreased capability of DNA repair , decreased
metabolism of cell itself , Which will be reflected on cell morphology :
* Distorted golgi apparatus
* Misfolded endoplasmic reticulum
* Dispersed chromatin and ribosomes
* Abnormal lobation of nuclei
*Tissue becomes little bit atrophic with autophagicvacule

* Accumulation of lipofuscin pigment

* Abnormal protein functionally due to glycosylation , reflected at tissue and
cellular level .

- Aging is preventable , it happens because our cells chose it to happen

We can repair our cells as long as we have DNA templates

- We have two approaches to answer why do we age ?


Theological approach

we age , we die , we are judged , either hell or heaven


biological approach

Q] can we be immortal ?
theoretically yes as long as we have DNA templates and resources we can
regenerate everything from scratch but we dont
Q] in another way , why do we live ?
to pass our genetic material to next generation !

- we live long enough theoretically and practically to have the ability to pass
our genes to the next generation and when we are supposed to have done
that genes are not going to sustain and repair organism anymore , theyll let
us die </3
this doesnt apply individually , its applied on race level . i.e. if someone
didnt had children that doesnt mean that hes going to live until he does .

- genes are not going to repair our damaged cells and DNA as long as we
have fulfilled our purpose
- at the age of 20 we are supposed to have passed our genes and then the
effect of aging will appear

- aging determined by 2 things : radicals and other noxious stimuli we are affected by
2. ability or desire of our genes to repair our own cells

- Projeria disease ,werner syndrome at the age of 6 theyll appear as if they

are at the age of 70 with HTN , MI and cancers and theyll die , Why ?
because genes responsible for repair are damaged already and the
physiologic damage of DNA is not going to be repaired and theyll age
prematurely .
Thats one mechanism of how can cells lose their ability to repair .

- But later on , other genes on our system will deliberately choose not to
repair .
- As our cells are going to divide telomere will become shorter and shorter
and after the vanish of telomere if the cell decided to divide it will die , so
why telomere becomes shorter ?
because gene responsible for telomerase will become gradually inactivated ,
and thats the normal state !


- If the gene had mutation telomere will not get shorter and cells will
become immortalized .
- So our genes will decide not to repair DNA and not to reproduce telomere
and this will be associated with a gradual but deliberated decrease of the
abilities of our cells to repair themselves and decrease in the ability to divide
until theyll eventually age and organism will die .

- If we want to decrease effect of aging :


decrease effect of toxins, free radicals and acetylation.


decrease calories intake , thats why fasting can be really good to

improve DNA repair .


growth factor receptors decreased activity may also be associated with

better DNA repair .


stress might also lead to activation of certain receptors Sir2 protein , if

that sir protein is deficient will lead to more effect of aging .

- aging process and rate will differ from one person to another

SLIDE 113 :
Telomerase activity will decrease in somatic cell , as long as they live and
divide and reach 50 times if division telomerase will vanish and any try to
division will fail and cell will die .


- When they cloned sheep dolly it aged and died before the supposed time ,
because they used somatic cells in cloning which already had decreased
activity of telomerase

Q] What if someone had a baby at the age of 60 ?is that going to affect its
baby telomerase activity ?
No its not , because germ cells have constant activity of telomerase activity.

- If cancer cells dont have continuous activity of telomerase , after 40 or 50

division it will die , unless this cell has switched on certain genes that will
reactivate telomerase .
So cancer cells either will keep constant activity of telomerase or increase
this activity , it will not decrease by time . thats why cancer cells are
immortalized .
And thats at the level of tissue not cell level .

- Theyll continue to proliferate because they have long life span but on the
level of individual cell of course its going to die

- If we took a normal hepatocyte and afford the suitable environment for it

to divide , it will divide until telomerase vanish .