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. [I found this using Google, but it does not appear in PubMed April 20, 2005: The concentration of DHEA-S (230 ng/ml) in our patient with WS was lower than that seen in age matched female controls (normal range, 400–3500 ng/ml).  (Journal of Clinical Pathology 2002;55:195-199)]  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