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
.