Telomeres, Telomerase, Dehydroepiandrosterone, and Cancer and Aging

James Michael Howard jmhoward at anthropogeny.com
Sun Dec 5 14:45:28 EST 2004



Telomeres, Telomerase, Dehydroepiandrosterone, and Cancer and Aging

Copyright © 2004, James Michael Howard, Fayetteville, Arkansas, U.S.A.

Telomerase increases the length of telomeres.  During early growth and
development telomere length is longest, then declines with cell
division through adulthood and declines in old age.  It is thought
that reductions in telomere length inhibit cell division and maintain
the state of differentiation of cells.  That is, lengthy telomeres
within cells are connected with cell division.  As cell division
occurs, telomere length shortens, is maintained for a while, then
declines.  Often telomere length is increased in cancer.  This occurs
because the enzyme, telomerase, increases the length of telomeres and
is found in about 90% of human cancers.  DHEA levels may be directly
connected with normal growth and development and cancer and aging,
including the characteristics of telomerase / telomere length therein.
(My principle hypothesis is that evolution selected DHEA because it
may optimize replication and transcription of DNA.  Therefore, DHEA
may be involved in all cellular and tissue activities.  I suggest high
levels of DHEA are connected with high levels of cellular activity
including telomerase.)

DHEA levels during the human life span parallel changes in telomerase
activity and telomere length.  At birth DHEA levels are highest, about
920 ng, Period A.  During the first year, these levels fall
significantly producing Period B.  DHEA begins to increase around age
three to five beginning the increase of Period C.  This increase in
DHEA continues until around ages twenty to twenty-five when the levels
begin to decline producing Period E,  reaching very low levels in old
age, Period F.

DHEA enters cells through their surfaces.  If cellular surface area
decreases, then the ability of the cell to absorb DHEA decreases and
the effects of DHEA on DNA are decreased.  Therefore, I suggest cell
differentiation is directly affected by levels of absorbable DHEA and
the experiences of the cell with other cells and earlier levels of
higher DHEA.  Therefore, the cell will reach a state of
differentiation and remain relatively stable according to the
absorbable DHEA during its existence.  That is, the level of DHEA
maintains the state of replication and transcription of a particular
cell's differentiation.  Therefore, Period A should be a time of rapid
cell divisions and tissue formation.  As this occurs, measurable
levels of DHEA decline because they are absorbed from the blood.  As
tissues increase in mass and differentiation, the surface areas of the
cell are reduced with time and measurable DHEA is increased.  I
suggest Period B and part of Period C and part of Period D represent
this increase in measurable DHEA as the adult phenotype is approached.
This would be caused by tissues of the brain, especially, and the
body.

When DHEA is readily available to cell surfaces, telomerase should be
more active and telomere length should be longest. This is reported in
the following citations.  I suggest that DHEA and the levels of
telomerase are not simply parallel but that the effects of DHEA levels
on levels of telomerase are causal, subject to type of differentiated
cell and their characteristics.

"
we measured telomere lengths in peripheral blood leukocytes (PBLs)
from 75 members of 12 families and in a group of unrelated healthy
children who were 5-48 months old. Here we report the surprising
observation that rates of telomere attrition vary markedly at
different ages. Telomeric repeats are lost rapidly (at a rate of >1
kilobase per year) from the PBLs of young children, followed by an
apparent plateau between age 4 and young adulthood, and by gradual
attrition later in life." (Proc Natl Acad Sci U S A. 1998; 95:
5607-10)  In this case I suggest my hypothesis is supported.  As the
peripheral blood leukocytes, which are bathed in the DHEA of the
blood, differentiate, I suggest this reduces the ability to absorb
DHEA, therefore, maintaining the differentiated state of the PBLs.
Once the PBLs are differentiated, they absorb levels of DHEA which
maintain their state of differentiation until the decline of DHEA of
old age does not support this level.

"We found that the average rate of telomere shortening in peripheral
blood mononuclear cells (PBMCs) obtained longitudinally from nine
different infants during the first 3 years of life (270 bp per year)
is more than fourfold higher than in adults and does not correlate
with telomerase activity." (Blood. 1999; 93: 2824-30)  This dislinkage
of telomerase and telomere length may be due to temporal
disconnections between gene transcription for telomerase and other
genes.  Genes are turned on and off sequentially.

During aging levels of DHEA decline.  This reduces telomerase activity
and, therefore, telomere length.  Loss of telomere length has been
connected with adverse cellular phenomena.  "During normal ageing, the
gradual loss of telomeric DNA in dividing somatic cells can contribute
to replicative senescence, apoptosis, or neoplastic transformation. In
the genetic disorder dyskeratosis congenita, telomere shortening is
accelerated, and patients have premature onset of many age-related
diseases and early death. We aimed to assess an association between
telomere length and mortality in 143 normal unrelated individuals over
the age of 60 years. Those with shorter telomeres in blood DNA had
poorer survival, attributable in part to a 3.18-fold higher mortality
rate from heart disease (95% CI 1(.)36-7.45, p=0.0079), and an
8.54-fold higher mortality rate from infectious disease (1.52-47.9,
p=0.015). These results lend support to the hypothesis that telomere
shortening in human beings contributes to mortality in many
age-related diseases." (Lancet. 2003; 36: 393-5)  Research on the
effects of DHEA levels in old age are remarkably similar to the
connection of old age and telomeric loss in the foregoing citation.
Telomeres are very short in "Werner syndrome," a form of progeria, the
advanced aging in some children.  As far as I can determine, DHEA has
not been measured in progeria or Werner syndrome but "adrenal cortical
hypofunction" has been found in Werner's syndrome. The adrenal cortex
is the site of DHEA synthesis.  "Endocrinologic investigation revealed
nodular goiter, sub clinical primary hypothyroidism,
hypergonadotrophic hypogonadism, adrenal cortical hypofunction and GH
deficiency [in Werner's syndrome]." (Ann Endocrinol (Paris). 2003; 64:
205-9)  DHEA has not been determined in dyskeratosis congenita.

DHEA is very low in AIDS and declines with the decline of AIDS.  (It
is my hypothesis that vulnerability to infection by the HIV is due to
low DHEA, the actual symptoms of AIDS are due to the continued loss of
DHEA, and that death in AIDS is due to severe loss of DHEA.  I first
suggested that low DHEA was the cause of HIV infection and AIDS in
1985).  "Telomere loss correlated well with progression of AIDS
"
(AIDS 2000; 14: 771-80)

It is my hypothesis that cancer may be triggered by low DHEA (1994).
I suggested that the differentiated state of cells rests on the
ability to absorb a certain amount of DHEA necessary for that state.
It followed that conditions that reduce DHEA may first reduce the
ability of a cell to "stick" to other cells, that is, it reduces cell
adhesion.  Loss of cell adhesion is a characteristic of cancer.  Once
this occurs, the cell may then increase its surface area.  This sudden
increase in surface area increases levels of DHEA within the cell.
The increased DHEA could then activate genes normally turned off
because of lack of DHEA.  Some of these activated genes could include
telomerase.  "It is clear that telomerase is obligatory for continuous
tumour cell proliferation, clonal evolution and malignant
progression." (Mutagenesis. 2002; 17: 539-50)  Telomerase activity and
telomere length are increased in many cancers.  Therefore, low DHEA of
old age may expose more cancer but it will grow less rapidly because
of the low DHEA.  It is known that cancer occurs more in old age but
grows less rapidly.

Growth and development and telomerase may be dependent upon high DHEA.
Maintenance of the adult phenotype and the adult telomeric length
within cells may depend upon an adequate, continuous level of DHEA.
Aging may result from loss of DHEA and its support of the adult
phenotype.  As DHEA declines it may expose cells prone to uncontrolled
cell division which increase when their cell surface areas increase
and absorb increased DHEA.  Cachexia, the wasting of cancer, may
result from increased absorption of low levels of DHEA by cancer,
overall, at the expense of the rest of the body







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