Note: Even if you don't read German, you may still wish to visit George's
website at www.methusalem.com , since a lot
of his material has already been translated into English. By the way, "Methusalem" is the
German spelling for the Biblical patriarch we call Methuselah who allegedly lived
to age 969. At our suggestion, George has just informed me that clicking on
www.methuselah.org now leads one to the very
same site. [Note2: the "www.methuselah.com" site had already been taken by another company.]
Early popular theories of aging haven't lead to measurable successes in
anti-aging research, as might have been expected, in part because these theories merely described
the side effects of aging or other theories like The Free Radical Theory" (popular
since 1956 and which has been tested for many years) - still didn't achieve significant results
because they didn't have a rigorous theoretical foundation. Of course, many questions posed by
these theories still remain unanswered. Nevertheless, I believe it is time to seek a new
In my opinion, we can distinguish at least two approaches to extending the
overall healthy human lifespan:
1. Stimulating the replacement of old, mitotically-challenged cells by new
2. Achieving a longer healthy cell life for post-mitotic cells.
For both of these strategies, I believe that new ways of looking at
Programmed Cell Death (PCD) and oxygen metabolism are
Reprogramming the nucleus is sometimes referred to as the "tape recorder"
theory. Based on experiments by Prof. Ernst Hadorn
of Switzerland Scientific American 1968; National Cancer Institute; 1969], Prof.
Leonard Hayflick of the USA, and Prof. John B.
Gurdon of the UK [several papers in the 1970's], Martina Steinhardt conducted a number of
experiments using the South African
frog Xenopus laevis [papers published in both English and German].
Her thesis was that nuclear DNA in the chromosomes, wrapped in histones, can
be recorded and played back by specific proteins
attached to the DNA. It is suggested that the "biological clock" is not along the DNA string itself
but depends on how far the
differentiation program of the cell has been executed. The difference between the experiments of
Gurdon and Hayflick's cell
nuclear transplantations is that the cytoplasm of young fibroblasts is a different 'tape recorder',
incapable of playing back the
nuclear program while egg protoplasm apparently can do it right. So the DNA is not a string,
spliced time after time, but more like
a magnetic tape . From the abstract of one of her papers, "These results lead to the
conclusion that nuclear transplantation into
an enucleated egg yields a 'reprogramming' of the nucleus, including the reprogramming of its
replicative capacity as much as the
biological age of the nucleus."  I am not aware as to whether this experiment was ever
followed up. Does anyone know?
Since Dr. Denham Harman first proposed The Free Radical Theory, the role of
oxygen has been relegated to more and more of an
enemy rather than a life-sustaining element. Several authors have written papers about this
ambiguous state-of-affairs [5, 11].
Oxygen is absolutely necessary for cell energy production but with the side effect of having to
ameliorate the effects of
self-produced free radicals. Despite several papers on the damaging effects of free radicals, there
is still no definite result relating to
the overall topic - cellular aging. Some long-lived strains of Drosophila show high
concentrations of SOD, but there is not yet a
coherent picture [5, 8, 11]. Contrary to what one might expect, there is an indication that
long-lived species have a lower
antioxidant level than short-lived ones [6, 7]. For example, birds have a much higher oxygen
consumption and metabolic rate than
non-flying animals with same body size [5, 14]. Thus, according to this theory, they should die
sooner. However, this does not
appear to be the case. On the one hand, this could be the result of a highly effective defense
system. But it also could suggest an
entirely different view of oxygen itself.
I believe our whole position on oxygen must be revised. Unfortunately,
positive papers on the value of oxygen seem to be rare in
comparison to papers on the deleterious effects of free radicals. Therefore, the following is only a
We all know that oxygen and H2O2 destroy
viruses, bacteria, and other infectious organisms . Also, oxygen is absolutely
necessary for energy production. Free Radicals are seen as a byproduct of this process. Cell
repair systems are put in place to
prolong cell life. But the equation:
is just an assumption. Conversely,
is equally valid [9,10].
It makes more sense to view free radicals as just another front-line
immune-system defense. I predict that PCD only occurs
whenever a certain threshold is reached. As a result of this process, we should expect to find two
biological clocks in place:
Artificially fighting free radicals with antioxidants may prolong cell life, but
ultimately I believe that this will lead to a kind of
'unhealthy' cell which, with age, will start to accumulate pigmented residues and lipid fragments
(lipofusin) significantly more than
it would have during a normal biological lifetime. As the volume of junk grows within the
cytoplasm, it begins to crowd out the
functional important machinery of the cell. Maybe there is also a connection between these
proposed biological "clocks" and
Within the connective tissue of our bodies, mesenchymal stem
cells are present and provide a nearly limitless reservoir of fresh cells
. With high oxygen levels over the course of the cell's life, mitotic divisions are constantly
taking place. This is also the
explanation for why several different antioxidation therapies may work: they stimulate the
cellular system, respiration (oxygen)
and the hematopoietic system, and therefore assists the body in eliminating ineffective
Even Caloric Restriction Theory can be explained in a like
manner: Blood flow is vigorous, nutrition optimal, and old cells are
destroyed and replaced quickly due to low caloric intake. It has also been established that high
body weight reduces oxygen supply.
Other body systems, like the Respiratory System for CO2 and acid/base balance
are involved. There are indications that chloride
ions are adversely related to the blood system .
With oxygen being everywhere, why has there been no oxygen-based theory of
longevity until now? And what role do mitochondria
play? Several systems must be functioning and maintained constantly throughout life. With the
need for oxygen, it is just not
enough to exercise - one must have correct nutrition, blood flow, body weight, and several other
parameters all of which are
necessary. And what about living at higher altitudes? Maybe someone has data about the
"oxygen status" of Centenarians? The
partial pressure of oxygen varies from 90 mmHg at age 30 to only 68 mmHg by age 70 .
Typical values for pO2 with age are as
To achieve a healthy life for our cells, and live longer than the current
maximum life span, I believe that it will be necessary to
titrate oxygen supplies in every cell to a higher level. Could this be accomplished by introducing
oxygen from outside the body or
by reducing oxygen's antagonists within? Catalase is present in every cell and constantly
refreshed by nutrition (milk products,
honey, etc.; in Asia, it must be present in other foods). 
Another anti-oxidant enzyme, Glutathione Peroxidase, appears to
be solely endogenic and probably could be influenced only
partially. However, higher oxygen levels would not result in the end of death! Birds
maintain a constantly high level until the end,
but nevertheless, the end does come . Therefore, I believe that birds will be a very interesting
group in which to search for the
ultimate cause(s) of death.
Of course, an extensive literature research has yet to be done. I'm sure that many
of these questions could have been answered
already simply by a thorough investigation of past work. The entire triggering system for
apoptosis and replicative replacement
must be scrutinized in detail. How does telomerase play a role? I believe that this
approach is far simpler to achieve than searching
for means to prolong the life of individual cells.
Chapter 1: In the final analysis, "genes are regulated by hormones and other
Chapter 2: For old cells, death can appear from out of the "clear blue sky."
Since even elderly individuals have young stem cells
that are perfectly capable of mitosis, shortened telomeres and apoptosis cannot be the sole
explanation for collective cell death
within a tissue. Where are the "housekeepers" or "gardeners" who are external to the cell?
Chapter 3: Changes to the mantle: What or who regulates the mantle? In the
final analysis, cells receives two kinds of signals: (1)
growth factors and/or hormones originated by external endocrine tissue and (2) from the
chromosomal telomeres themselves.
Ultimately, mitosis is carefully regulated by body growth, consistent with tissue architecture, and
by contact inhibition from
adjacent cells that may be disrupted by trauma, triggering a healing response. Local PCD and the
survival of adjacent cells must be
exquisitely orchestrated to preserve the underlying architecture of the tissue. When this
architecture is obliterated by disease, an
inflammatory fibrosis to preserve structural integrity seems to be the only reasonable response.
Even Prof. Fossel hints in his book at the existence of other regulatory
mechanisms for mitosis that are independent of the telomere.
He sometimes asks why germ cells, in contrast to somatic cells, don't show any sign of aging?
Prof. Fossel answers: "Because the
telomeres are constantly relengthening stimulated by the presence of the enzyme telomerase." On
the other hand, my answer would
be: Neither cancer cells nor germ cells age, since they are constantly being rejuvenated by a
process of regular mitosis. Aging, as we
observe it, only starts when the rapid-proliferative phase of development ends in early
adolescence (as explained by Steinhardt).
After a period of active proliferation, ova escape from the body by monthly ovulation plus
menstruation (or occasionally by birth),
while sperm cells continuously divide but later escape from the body by ejaculation. I suspect
that cancer cells wouldn't be
pathological (by forming tumors) either, were it not for the fact that they aren't regularly expelled
from the body. Unhappily, they
accumulate in situ . The problem of aging really lies in the lack of a
larger "architecture" program in the DNA to maintain a
cellular equilibrium of PCD and stem cell proliferation that would preserve the structural
integrity of the adult, say, at age 25.
Understanding the role of tissue-specific growth factors during embryogenesis and development
and their relation to histological
architecture is the secret. Wouldn't it be ironic if the key to experimental gerontology lay in
The notion that "regular mitosis" extends cellular lifespan is inconsistent with
the scientific literature. Cell senescence is correlated
with (and experimentally alterable by) telomere length and not with either the
number of divisions per se, nor the rate of those
divisions, nor the body's capacity for "ejecting" such cells. I appreciate Mr. Duve's comments,
but, as far as I am concerned, they
are inaccurate. I prefer to rely on data.
[Editor's Comment: If you, yourself, wish to participate in this discussion,
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Other interesting areas for aging research might be in the fields
Were you aware that certain cave-dwelling animals live much longer than their
closely-related cousins who hunt in daylight? For
example, bats are known to be nocturnal but are further shielded from the potential damage of
radiation by virtue of living in
thick-walled caves during their normal sleeping period.