IUBio

how we age?

Hang-Jun Jang IAM at CHOLLIAN.DACOM.CO.KR
Mon Feb 19 04:40:45 EST 1996


From: 102726.1511 at compuserve.com                                          
                                                  
Date: 17 Feb 96 05:55:13 EST
Subject: telomeres

Dear Mr. Hang Jun Jang,

Greetings! I apologize for a delay in responding to your post. I check the
usenet posts once a week or so because of the limited accessibility as 
provided
by my internet server, Compuserve. I prefer to communicate through e-mail
because I check it daily. I was very happy to read your post. I share your
vision, though with some doubts involving socio-economic effect of 
artificial
prolongation of life beyond the natural span. I don't want dissuade from 
your
current interest in telomeres; that is not my intent. I want to share with 
you
what have been going on in the telomere research in more detail. 
Definitely, I
am excited by current telomere research, but many do not involve aging.

Before I get into the specifics concerning the telomere and aging 
research, I
would like introduce myself. I am 24-years-old and have been out of a 
college
for 1.5 years now. I will be matriculating into a PhD program in
molecular-cellular biology this coming fall. My senior thesis project was 
in
programmed cell death, and that was how I began examining the 
aging/cellular
senescence research. I wanted to apply to USC where Caleb Finch is 
teaching. He
wrote a massive book called "Senescence, Longetivity and the Genome." It 
was
printed before the results showing a  (not robust) correlation between age 
and
telomere length, so the book does not contain information related to 
telomeres
as a natural biological clock. But, the book is a compendium of aging 
research
in various organisms including humans; it is a book that you might want to 
get a
hold of.

I changed my mind concerning my graduate study since my graduation, 
realizing
that currently gerontology and geriatrics suffer from ill-definition of 
many of
the phenomena related to aging. Most of the research activity focuses on 
the
clinical aspects, and I decided that the clinical research is far too 
removed
from my basic research interests. I am now more interested in cell cycle 
control
and chromatin regulation of transcription and differentiation, as well as 
the
mechanisms of DNA damage and repair. I think these research areas must be
understood to the fullest before any rigorous scientific investigations of 
aging
and cellular senescence can take place. So, that is my take on the whole 
issue
of aging in terms of what I want to do as a biologist. 

I must point out that neurons and heart muscle cells are understood as 
being
terminally differentiated, rather than as having reached their Hayflick 
limit.
The ability to divide further in neurons and heart muscle cells are 
believed to
be disabled by an active programming, and not by some natural limit that 
they
reached via exhaustion of some molecule or rather, as in the telomere 
length. To
my knowledge, there is no direct evidence that telomeres shorten as the 
cells
divide. 

The main focus of telomere research has been in cancer therapeutic 
research. It
has been reported that some significant portion of cancer cells show 
telomerase
activity. Efforts are being made for developing cancer therapeutic agents 
that
would act via inactivation of telomerase, in hopes of killing the immortal
cancer cells. I think there are increasing doubts as to whether this type 
of
therapy would work. I don't think cancers cells are immortal solely 
because of
telomerase activity.

I do not know whether a transgenic mice with enormous telomeres has been
produced and whether it would have a longer life span just because its 
cells are
able go through many more mitosis than in normal. I think having longer
telomeres probably won't increase the life span. Moreover, longer 
telomeres
might create an averse negative effect of reducing the life span by 
interfering
with the DNA replication and mitosis. If you do run into some report on 
this
matter, please let me know--I would be very interested.

I want to interject some interesting note here. There is a correlation 
between
metabolic rate and life span in animals, as well as a correlation between 
body
mass and life span. So, a simple correlation like these hide enormous 
amount of
complexities involved in aging process. I think, if I stayed home doing 
nothing
and ate only vegetables, I would live for quite a long time.

Besides the telomere issue, there has been interesting reports concerning 
other
possible determinants of aging, such as oxygen radicals. One interesting 
result,
reported two years ago in Science, showed increase in life-span of a 
recombinant
drosophila flies with increased levels of Superoxide Dismutase (SOD). I 
think a
similar result was shown for a nematode, C. elegans. This aspect of aging
research facinates me more than telomere for now.

I will be going to Princeton in two weeks for an interview, and hopefully 
I will
get a chance to talk with Dr. Virginia Zakian, a telomere expert.

I am very glad that I have met you via internet. It has been very 
difficult find
any Koreans with similar research interests, and I am very happy and hope 
to
continue our correspondences long into the future. I am very impressed 
with your
career goals. I once had considered MD/PhD combined programs here in US, 
but I
decided to enter a straight PhD program instead because I wasn't made to 
be a
doctor.

1990's have been really bad for PhD candidates because of over-production 
of
PhD's in US for the last decade or so. Many programs are cutting back on 
their
admittees. Reducing the number of PhD students adversely affects 
prospective
international students more than the prospective students like myself. If 
you
would consider my advice, I would suggest that you develop a network of
professors and researchers in US whose research interests you. Once you 
know
these people well, I think it will be easier for you to get funding for 
your PhD
education as well as get accepted into a good program. Who knows? Maybe in 
three
years things will change drastically. 

Do write me about your experience as a doctor in rural districts in Korea! 
I
would be very interested. I have never been back to Korea in my 13 years 
in US.
Hopefully I will be able to visit this coming summer before entering the
graduate school. I don't know yet which school to go to. I have been 
accepted at
Washington University (in St Louis, Missouri) and Harvard University. I 
have to
go to interviews at Stanford, UC Berkeley, UCLA, Columbia and Princeton 
starting
next week. My parents want me to go to Harvard, but I have to see what 
other
schools have to offer, in terms of scholarships and stipend and the 
reputation
of their professors.

You sound very Romantic, like Victor Frankenstein who created life from 
death in
Mary Shelley's "Frankenstein..." I am like this as well. The notion of
immortality facinates me very very much, but I doubt it can happen within 
my
lifetime (or forever). On the other hand, I can't resist the lure of 
immortality
and I want to contribute some way to achieving a limited "eternal youth." 
I
think I will stop here because my message is getting really long and 
digressing
from telomeres. I apologize for this long message. I hope all goes well 
with
you. Hope to hear from you soon. Take care.

Regards,
Tae Hoon Kim
102726.1511 at compuserve.com




Dear Mr. Tae Hoon Kim

Greetings!  How are you?  It's my great pleasure 
to correspond with you. I luckily found your letter yesterday 
midnight when I came back from military doctor training camp 
because the commander gave us a very special vacation 
that has never ever been given before for the Lunar New Year's Day 
that is a big national holiday in Korea. I should take 
the physical exam and basic military training till 20th April, 1996.  
So, but for his favor,I couldn't read your post till April. 
After this training, I will be discharged from the military 
service at the same time as I become a first grade lieutenant. 
Then, One rural district is allocated to me for the 3 year-medical 
service. As you guess, I will use this period for my preparation 
for my study and going abroad for research.  
Do you know that I was surprised whenever I read your post? 
That's because we have many common features with each other
exactly speaking, common interests

I am very interest in many aspects of aging theories. 
One of them is a telomere issue. I have once thought that 
the aging process might be a cell cycle problem. 
In that time, I automatically got interested in telomere.  
Now I think it might be a regeneration problem. 
Aging can be best defined as a process that converts healthy 
adults into frail ones with diminished reserves in most 
physiological systems and an exponentially increasing 
vulnerability to diseases and death. 
I want to emphasize "diminished reserve".that has been a serious 
question to me a long time ago. Why and How are the physiological
reserves diminished as we age? Is it due to the limited capacity 
of cell division?  
Although I also think it's unlikely, I think that the only 
definitive proving method is to make a transgenic mice 
with longer telomere, then compare the maximum life span 
with that of control. I have never found such a paper yet. 
It seems very difficult to make all the chromosomes have 
the extended telomeres with the same length. 
I also read several papers about telomere and cancers. 
I am more interested in what mechanism makes the telomerase 
expressed in cancer cells because of the hope to rejuvenate the 
senescent tissues. I think it so early to make a hasty conclusion 
that telomere is not related with aging process because there are 
some evidences to suggest age-related changes in telomere. 
I want to recommend you a noteworthy paper [Proc. Natl. Acad. Sci. 
USA., Vol 91, pp. 9857-9860, October 1994] that suggests that 
the proliferative potential of most, if not all, human hematopoietic 
stem cells is limited and decreases with age. 
This article's title is " Evidence for a mitotic clock in human 
hematopoietic stem cells: Loss of telomeric DNA with age." 
Now I am waiting for the more advanced research result like you. 
We would better inquire of Dr. Leonid. A. Gavrilov about this 
matter who once asserted that Hayflick limit was wrong, 
so as to  promote our insights into the aging process. 

The Aging theory that I was first affected is the free radical 
theory of aging, which seems to explain the correlation between 
the high metabolic rate and lower maximum life span.  
Actually I am taking anti-oxidant cocktail composed of vitamin E,
C, beta-carotene, and selenium everyday and sometimes melatonin 
in the bedtime in the hope for more healthier life!  
You know that Aging researchers should not age before the layman does!  
Hahaha!! :)) The pineal neurohormone melatonin has recently been 
proved to a most powerful anti-oxidant to be able to penetrate 
the cell membrane into the nucleus which is a totally 
different feature from other antioxidants. One report said that
administration of anti-oxidant into the mice increased the life 
span by about 30%.  I read one article that suggested that 
the oxygen radical is a signal to initiate apoptosis of neuron, 
but not the direct mediator of cell death.  As for SOD
(Superoxide Dismutase) in human, there are some report that 
the level increases as human age. I don't know why, 
but It may be a different matter in drosophilae. 
A certain company made a formula composed of endorphin and SOD 
forbetter heath in the elderly. It sounds interesting.  
Human beings seem not to age just because antioxidant power diminishes. 
In my opinion, Free radical may be a supporting player, but not a 
leading actor in aging process. 

Ok!  From now on, I will tell you about my recent favorite issues 
on aging research. First, the evolutionary model for aging gave 
me a great insight. This model can be summarized with 
"the antagonistic pleiotropy"  According to this theory, 
in the evolutionary process some pleiotropic genes have been 
selected that have beneficial effect early in life, but harmful later 
in the life span.  This means that aging process occurs with 
the late side effects of homeostasis genes, and also that 
God's most wonderful creature, human being's genes are not perfect. 
For example, lipoprotein-a is a LDL variant whose function is 
involved in normal lipid homeostasis, but in the late in life, 
it invariably causes coronary artery diseases, even if the blood 
level of cholesterol is normal. 
A gene that leads to calcium deposition, for example, 
may promote the rapid development of the bones, 
but predispose to arterial calcification in later life. 
A gene that promotes rapid cell division in embryogenesis may 
also render an animal vulnerable, in later life, to rapid growth 
of neoplastic tissue.  How interesting and plausible this theory 
sounds!  Isn't it?  Second, Disposable soma theory has been a long 
company because this theory is quite close to my viewpoint.  
In Nature, the more the organism reproduces,  the shorter the maximum 
life span is.  When I was a freshman in medical school, I have been 
very curious about this inverse correlation. I postulated my own 
theory to be able to explain this phenomenon.  
In my own theory, the master clock, in other word,  the biological
clock may exist somewhere maybe in the central nervous system 
to control the aging rate according to the reproductive activity. 
To explain this, I postulated a virtual feedback loop between 
the gonad and the pineal gland 4 years ago. 

My dear friend! I totally agree to your opinion that 
currently gerontology and geriatrics suffer from ill 
definition of many of the phenomenon related to aging 
and that most of the research activity focuses on the 
clinical aspects. When I took polyclinic training in 
hospital last year, I really appreciated the 
incompetence of modern medicine in curing the 
degenerative and age-related diseases very well 
every moment! Nevertheless  most of the doctors seem to 
be very proud of themselves, filled with self-satisfaction.  
It made me so angry that I decided to make a research 
to put my discoveries into the medical textbooks, not 
to just read and accept others' opinions passively. I am 
eager for becoming the man of destiny, instead of  walking 
on the rail road others built.  Friend!  Let's cooperate 
for making better world!  I hope that my long message 
doesn't make you feel bored!  Please understand my enthusiasm 
which is a token of my youth. :)  Thank you for your valuable 
advises. I should come back to military doctor camp this coming 
Friday when is the day of my graduation ceremony. 
Maybe, If another favor is not given from the commander, 
it's impossible to write for a while.  If you come to Korea,
Do remember to call me up and let me know it in advance. 
Can you speak Korean?  If not, don't worry,  I will try 
to speak English.  Take care.

Best regards and sincerely yours
Hang Jun Jang
iam at chollian.dacom.co.kr







 





 




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