RE: forgetting to be young

From: Don Klemencic (
Date: Thu Apr 06 2000 - 22:24:37 MDT

This is a rather longish excerpt from Nanotechnology: Research and
Perspectives; Papers from the First Foresight Conference on Nanotechnology,
published in 1992 by the MIT Press, Dr. Gregory Fahy wrote:

DNA polymerase alpha (DPA) DNA polymerase alpha is required for most
DNA repair and DNA synthesis. Like the processes of energy metabolism and
immunity already discussed, DNA repair and synthesis are obviously
fundamental life processes without which we would die quite quickly. It is
therefore bizarre but true that we each have a gene for a defective version
of DPA that switches on as we get older. The senescent or "old-age" form of
the enzyme is called A1 DPA. It binds to DNA much more weakly than the
youthful or A2 form of DPA and, consequently, it synthesizes and repairs DNA
ten times more slowly than A2 DPA. In addition it makes an alarming number
of mistakes. As we age, A1 DPA replaces more and more of our A2 DPA, until
we have almost no A2 DPA at around the age of 65.

Equally amazing, it is possible to convert the senescent A1 DPA into a form
that closely resembles A2 DPA by treating it with inositol-1,4-biphosphate,
a sugar phosphate produced by the hormonal stimulation of cells. (9) The
natural transition from A2 DPA to A1 DPA is a programmed aging phenomenon
that is measurably more advanced in 40-year-olds compared to 30-year-olds.
We should be able to do something to prevent this process, presumably by
altering the control regions for the A1 and A2 DPA genes or by adequately
maintaining particular hormone levels such as growth hormone.

Although it has been suggested that shutting down cell division is a
protective device for minimizing cancer, thereby making the A2 to A1
transition good for us, misincorporation of DNA bases can only promote
cancer. Furthermore, cancer may not be a problem regardless of DNA damage if
we can maintain the immune systems of 18-year-olds, which probably eradicate
cancer all the time without our awareness.

Elongation Factor One (EF-1) George Webster has shown that there is a
massive drop in protein synthesis in all tissues just before the age at
which animal death rates accelerate. (10) By studying (directly or
indirectly) all of the more than 50 molecular machines involved in the
complex biosynthesis of proteins, he identified one molecule that was
responsible for about half of this drop in protein synthesis in most
organisms (rats, mice, and flies). (11)

Protein synthesis from available mRNA consists of three component processes:
initiation, elongation, and termination. The portion of the protein
synthesis process that decreases precipitously with age is elongation.
Elongation in turn consists of three steps: (1) the amino acyl tRNA binds to
the A site of the ribosome; a new peptide bond forms that links the new
amino acid with the nascent peptide chain, thereby transferring the nascent
peptide to the A site and releasing the cleaved tRNA (the transpeptidase
reaction), and (3) the peptide with the added amino acid moves from the A
site to the P site so that the next amino acyl tRNA can bind to the A site.
With aging, the gene for elongation factor one (EF-1) is selectively shut
off, effectively blocking the first step of the elongation process.

EF-1 is a major constituent of the cell; it comprises between 3 and 11
percent of the total protein of a nonsenescent cell. We would like to be
able to prevent the specific repression of this protein with age. The
decreased protein synthesis caused by the repression of EF-1 may cause a
drop in RNA synthesis since RNA polymerase is a protein. Indeed, global
drops in RNA synthesis are usually seen with aging.

Webster has shown that administration of centrophenoxine can fully restore
the massive drop in RNA synthesis that takes place with aging. In
preliminary unpublished experiments, he has also found evidence that this
drug can specifically reactivate transcription of EF-1 genes. Although
Webster's results were obtained using a chromatin assay system in a test
tube, centrophenoxine has also been shown to reactivate RNA and protein
synthesis in vivo, in mammals, and to extend mammalian life span. However,
its effectiveness is limited by its rapid hydrolysis in the body. The most
elementary form of interventive molecular engineering imaginable would be to
design a stable version of centrophenoxine that lacks a labile ester linkage
yet still possesses the biological effects of centrophenoxine. This single
trivial accomplishment could lead to major gains against aging.


With respect to our global understanding of aging, at least two very
noteworthy developments have supported the notions I described. First, the
appearance of Caleb Finch's truly epic book, Longevity, Senescence, and the
Genome (Chicago: Chicago University Press, 1990), a treasure trove of aging
information, provides strong additional evidence for a predominantly genetic
basis of aging. Second, a most unexpected synthesis has been presented by
Sohal and Allen. (13) They posit that the progression of development, and
hence also the progression of aging, is regulated by a redox-stat that
gradually renders cytosol more oxidizing with time. Their synthesis, if
correct, would show how past evidence for wear and tear is actually evidence
for genetic control of aging.


My inference based on the DNA polymerase alpha story that it should be
possible to prevent replicative senescence and compromised DNA repair
appears to have been confirmed beyond all reasonable expectations by Mike
West's findings. West claims to have totally conquered the cellular aging
clock by using just two naturally occurring molecular triggers that can
restore the youthful phenotype to any one of four entirely different types
of senescent cell (endothelial cells, astrocytes, chondrocytes, and
fibroblasts). (17) Finally, the possible significance of elongation factor
one has been delightfully demonstrated by a paper of Shepard et al. In which
flies made transgenic for EF-1 so as to avoid or postpone its down
regulation with age were shown to have mean life spans equivalent to the
maximum life spans of control flies. (18) However, this experiment is not
yet definitive and awaits rigorous verification.

9. V. Sylvia, G. Curtin, J. Norman, J. Stec, D. Busbee, "Activation of a
low specific activity form of DNA polymerase alpha by
inositol-1,4-biphosphate," Cell 54 (1988): 651-658.

10. C. Blazejowski, G. Webster, "Decreased rates of protein synthesis by
cell-free preparations from different organs of aging mice," Mech. Ageing
Dev. 21 (1983): 345-356.

11. G. Webster, "Protein synthesis in aging organisms," Molecular Biology of
Aging, Gene Stability and Gene Expression, ed. R. Sohal, L. Birnbaum, R.
Cutler (New York: Raven Press, 1985), 263-289.

12. G. Webster, "Protein Synthesis," Drosophila as a Model Organism for
Ageing Studies, ed. F. Lints, M. Soliman(London,: Blackie, 1988), 119-128.

13. R. Sohal, R. Allen, "Oxidative stress as a causal factor in
differentiation and aging: A unifying hypothesis," Exp. Geront. 25
(1990): 499-522 R. Allen, "Oxygen-reactive species and
antioxidant responses during development: the metabolic paradox of cellular
differentiation," Proc. Soc. Exp. Biol. Med. 196 (1991): 117-129.

17. M. West, "Reversing cellular aging in connective tissues," Life
Extension Rep. 10 (1990): 73-75.

18. J. Shepard, U. Walldorf, P. Hug, W. Gehring, "Fruit flies with
additional expression of the elongation factor EF-1 alpha live longer,"
Proc. Natl. Acad. Sci. USA 86 (1989): 7520-7521.

-----Original Message-----
From: [] On
Behalf Of Damien Broderick
Sent: Thursday, March 30, 2000 9:45 PM
Subject: forgetting to be young

This is not entirely astonishing, but the report offers an interesting

Scripps Research Institute

The genetics of aging: New study says cell division errors may be the common

La Jolla CA., March 31, 2000 -- Gradual genetic changes may be the source of
many, if not all illnesses of aging, including breast cancer, osteoporosis,
Alzheimer's disease and arthritis. A new study by scientists in The Skaggs
Institute for Chemical Biology at The Scripps Research Institute (TSRI) in
Jolla and the Genomics Institute of the Novartis Research Foundation,
published in the latest issue of Science, concludes that human aging and its
associated diseases and conditions can be traced to a gradual increase in
cell division errors in tissues throughout the body. This functional change
begins slowly in middle age and increases gradually with advancing age.

According to Richard A. Lerner, M.D., an author of the paper, "Mitotic
Misregulation and Human Aging," "This represents a radical change in the way
people have thought about aging. While scientists have believed that aging
a disease in which cells stop dividing, this study suggests that aging is
really a disease of quality control. In this case the manufactured product
a new cell. As we get older, altered gene expression results in cells with
diminished function." [etc]

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