DHEA, Calorie Restriction, Aging, and Cancer
jmhoward at sprynet.com
Thu Jul 17 05:23:05 EST 1997
DHEA, Calorie Restriction, Aging, and Cancer
James Howard, July 17, 1997
July 7, 1996, and May 16, 1996, I posted a couple of explanations of the
connection of DHEA, calorie restriction, and cancer (James Howard, old
email: phis at sprynet.com) at sci.life-extension. Today I found
supporting work that my hypotheses may be correct. In my past post, I
refer to reducing DHEA, which is derived from the major source, DHEA
sulfate (DHEAS). In the recent publication, below, it has been
determined that " Most important is the finding that, in rhesus monkeys,
calorie restriction, which extends life span and retards aging in
laboratory rodents, slows the postmaturational decline in serum DHEAS
levels." This needs to be explained, to avoid confusion.
DHEA is the active form; DHEAS the reserve form. When calories are
consumed, more DHEA is recruited from DHEAS. So calorie consumption
reduce DHEAS, and calorie restriction will keep DHEAS levels higher
longer. I suggest DHEA is literally used up to maintain life. Keep
this explanation in mind as you read the following quotation, and my
posts of July 7, 1996, and May 16, 1996, also below.
J Clin Endocrinol Metab 1997 Jul;82(7):2093-2096
"Dehydroepiandrosterone sulfate: a biomarker of primate aging
slowed by calorie restriction."
Lane MA, Ingram DK, Ball SS, Roth GS
"The adrenal steroids, dehydroepiandrosterone (DHEA) and its sulfate
(DHEAS), have attracted attention for their possible antiaging effects.
DHEAS levels in humans decline markedly with age, suggesting the
potential importance of this parameter as a biomarker of aging. Here we
report that, as seen in humans, male and female rhesus monkeys exhibit a
steady, age-related decline in serum DHEAS. This decline meets several
criteria for a biomarker of aging, including cross-sectional and
longitudinal linear decreases with age and significant stability of
individual differences over time. In addition, the proportional
age-related loss of DHEAS in rhesus monkeys is over twice the rate of
decline observed in humans. Most important is the finding that, in
rhesus monkeys, calorie restriction, which extends life span and retards
aging in laboratory rodents, slows the postmaturational decline in serum
DHEAS levels. This represents the first evidence that this nutritional
intervention has the potential to alter aspects of postmaturational
aging in a long-lived species."
This is my post of July 7, 1996; there are others of a similar nature
that may be found with Deja News.
"Life-span must rely on the two most important aspects of DNA,
replication and duplication. My work suggests that DHEA is directly
involved in both of these. (You can read some applications of this at
http://www.naples.net/~nfn03605 on the web.) Since calorie restriction
reduces DHEA, calorie restriction would then reduce replication and
transcription of DNA. Also, it has been found "that mitochondrial
respiration is the earliest factor affected by DHEA..." (Journal of
Nutrition 1991; 121: 240). I put these together to suggest that
calorie restriction reduces DHEA, which reduces mitochondrial
respiration, which results in reduced temperature.
It is a known fact that cells, in culture, can only duplicate for a
limited number of divisions. It was reported some time last year, or
so, that this may be due to the fact that each cell division reduces the
size of a chromosomal structure involved in duplication of DNA (I think
it was the centromere). [It is the telomere. JMH July 17, 1997.] Once
this is reduced to a certain amount, it cannot participate in further
cell divisions; cell division stops. (Some "transformed" cell may
divide forever, but this is not the time to pursue this.)
If DHEA is involved in duplication of DNA, then reducing the supply of
DHEA, by reducing calorie intake, will reduce the number of cell
divisions. This reduces the time it takes to reach the end of cell
divisions caused by reductions in the centromere. Reducing calories
reduces DHEA, which reduces cell divisions, which lengthens the time it
takes to reach the cell division end point: reducing DHEA lengthens the
My work also suggests that cancer depends on DHEA. It is known that
reducing calorie intake also reduces cancer growth. This is the same
Some people think that aging results from a build up of free radicals.
These are known to cause damage to DNA, which results in cell death. I
suggest that the natural loss of DHEA of old age reduces the
transcription of DNA. One of the important losses of transcriptions of
old age, I suggest, is the loss of transcription of the genes that are
involved in gene repair. That is, the reduction of DHEA of old age
results in a loss of the repair of damage due to free radicals. It is
loss of DHEA that results in the increase of lack of repair of free
radical damage. Part of my work suggests that the rise of "warm blooded"
animals on this planet resulted from increases in DHEA in eukaryotic
organisms over time. I think this is why the mammals made it through the
period that caused the demise of the dinosaurs. I bring this up since
Brian mentions that lowering body temperature in fish extends their
life-spans. In this case, I suggest this reduces the number of DNA
replications. Reducing their temperature slows their chemical reactions
(metabolism) since they cannot regulate temperature. This reduces the
time to reach the cell division limit and extends the life-span.
Except for the fish, these increases in life-span are not due to reduced
temperature. In mammals, reducing calorie intake reduces DHEA
production which slows the numbers of cell divisions. This is how
calorie restriction and lowered temperatures increase life-span.
This is the post of May 16, 1996, that contains the connection of
smoking and cancer. (Some of this is redundant; browse through the
"My work suggests all tissues, including cancer, depend on DHEA for
transcription and replication of DNA. DHEA naturally begins to decline
around age 20 to twenty-five years. When DHEA declines in old age,
differentiated cells may revert to "embryonic" type cells because their
adhesive mechanisms break down, and this allows these cells to absorb
increased DHEA, even in the reduced DHEA of the older person. Cells
form tissues by differentiation into particular sets of cells that
participate in a particular kind of DNA transcription that represents a
particular tissue. (These usually include supporting tissues
intermixed, but these represent a particular kind of DNA
transcription for the purpose of the tissues they support.) These
tissues adhere to each other. This is done by production of cell
membrane proteins that "stick" cells together. This limits the amount
of free surface area available for absorption of oxygen, fuels, etc.
...and DHEA. Genes of the differentiated state require less DHEA,
because these genes are only involved in a DNA transcription of
only part of the entire DNA; cell division involves all of the DNA.
Hence, giving DHEA to the lab mice maintains the differentiated state of
breast tissues and maintains the cell adhesion within these tissues.
It has been proven that calorie or food restriction reduces cancer
development and growth. Calorie restriction reduces DHEA production.
Hence, food restriction reduces the amount of DHEA for any cells that
"de-differentiate." These potential cells cannot get enough DHEA in
this case for the higher useage of DHEA required for cell division.
Drugs that block the availability of DHEA will do the same thing, except
they will also affect the entire body, since the entire body needs DHEA.
They work because cells that require a lot of DHEA for cell division
will die before a cell that requires less to maintain the differentiated
state. This is why starvation, old age, and use of some anti-cancer
drugs all make the person look aged and malnurished: they all reduce the
avaialability of DHEA.
Women who exercise increase their DHEA. These women also have less
breast cancer. The mechanism is the same as giving DHEA to the lab
mice: extra DHEA protects against breast cancer.
It is known that many "oncogenes" are mutated genes. That is, they are
genes involved in normal cell division, but changes in their DNA
structure make them into cancer genes (oncogenes). These genes,
according to my theory, need more DHEA than genes of the differentiated
state. The mutations must reduce the amount of DHEA necessary to
stimulate cell division. The mutations would be transferred to daughter
cells in this case. This would explain metastasis of similar cells
throughout the body. This cells would be very malignant, especially in
young people. There is a truism in general that cancers occur more in
the elderly but grow more slowly. The would be due to low DHEA: low
DHEA would increase the breakdown of cell adhesions. Of those cancer
cell that are able to start cell division, they would grow less because
of the reduced DHEA of old age.
An interesting side note: Nicotine stimulates DHEA production. I think
this is why people smoke. Nicotine makes them feel better because it
stimulates DHEA. The problem is that the drug delivery system, the
cigarette, is full of carcinogens. These carcinogens are being pumped
into a person of low DHEA. (People low in DHEA will seek it, smoking is
a readily available method.) The combination of these carcinogens and
low DHEA make them particularly vulnerable to cancer in the lungs.
The proof of this is that cancer of the pancreas is also higher in
smokers; the reason has not been found yet. I suggest the connection is
the reduced DHEA in these folks.
More information about the Ageing