The insulin utilization theory
Links/Insulin and Aging
can be used to
metabolize extra insulin
Treatment with chromium picolinate
] has been shown to
the life span
of mice 15%.
There are some reports that chromium picolinate
may be harmful to DNA
and is primarily useful in losing weight.
Perhaps some other source of the
should be used to impact insulin metabolism
help with the weight loss factor related to the caloric restriction
See also insulin
Insulin and Aging
and Life Extension Magazine
It is desirable to avoid or deemphasize sugary foods and consume foods with a low
) that cause glucose to rise more slowly to
and insulin resistance
problems. Glucose has a glycemic index of 100.
makes cells less
injections, or stick-on patches
prevents and treats
(excess insulin in the blood
has been implicated as a major risk factor"
in numerous age-related diseases
such as Alzheimer's disease
(See Fantastic Voyage
and Terry Grossman
, Ray & Terry's
Alpha lipoic acid
has been shown to improve
at 100-300 mg twice a day,
and drugs used to treat metabolic syndrome
200 mcg x 2 or 3/day,
alpha lipoic acid
) 1000 mg/day,
60-100mg x 2,
500 mg x 2,
500-1,500 mg x 2/day, 500-1,500 mg x 2,
600 mg x 2 or 3 per day,
3 grams x 3,
25 mg x 2, and
500 mg x 2/day.
Otherwise, the glycemic index of food
may be effectively lowered by dietary fiber
or by Precose
which slow down
absorption of carbohydrates from the digestive tract
and by methods from
The more sugar insulin
transports into cells
the more vulnerable the cell to
producing carbonylated proteins
that may clog up proteasomes
Glycation reactions with DNA
may also take place.
This is probably the reason that genes like daf-16 [Links
in C. Elegans
Note that for bodybuilding
it is desirable to elevate insulin
levels after an evening workout
before bedtime to sweep nutrients into cells and restore muscle glycogen with insulin-boosting drugs such as
using a two-week on/off cycle to prevent breast enhancement. Elevating
makes one tired as
blood glucose goes down, and eventually hungry, too.
The advanced Hayflick
division limit theory based on telomeres
Mechanisms of Aging/telomeres
End Replication Problem
History of Telomeres and Telomerase
History of Telomerase Activators
His Limit, and Cellular Aging
by Jerry Shay
telomeres & mortality
Ben Best/Telomeres and Aging
the Unbeliever: SenescenceInfo/Telomeres & Telomerase
Peter M. Lansdorp
Telomeres and Aging
88: 557-579, 2008.]
- Revolutionary advanced methods based on
or alternate technology for allowing mitotic cell division to continue indefinitely
gene therapy or
treatment to re-extend telomeres with
In vertebrates, telomeres
consist of tandem arrays of minisatellite [5'-GGTTAG-3']n
repeats from 4,000 to 15,000 bp long.
These are often described as T2
repeats in the literature (5'-TTAGGG-3')
(E. Blackburn, 2001
I have specified the sequence as [5'-GGTTAG-3']n
the template region
the hTR RNA molecule
(W Klapper et al, 2001
in Mark P. Mattson, 2001
"The template region of TERC is 3'-CAAUCCCAAUC-5'.
This way, telomerase can bind the first few nucleotides of the template to the last telomere sequence
on the chromosome, add a new telomere repeat (5'-GGTTAG-3') sequence, let go,
realign the new 3'-end of telomere to the template, and repeat the process.
TERC Template RNA (hTR template RNA)
New Telomere Hex Repeat DNA
The first 5 nucleotides of the RNA
) template bind to the last 5
GTTAG nucleotides (shown in red) of the last hex repeat.
After formation of the new DNA hex repeat GGTTAG
the TERC (hTR) template steps right 6 nucleotides
to align the next new hex repeat.
"Normal human cells
stably expressing transfected telomerase can maintain the length of their telomeres, and exceed their
maximum lifespan by more than fivefold."
Furthermore, normal cells immortalized with
do not become cancerous
although 85% of known cancer cells
express telomerase to enable them to keep
In fact, it is believed that cellular telomeric crisis
due to shortening of cellular telomeres causes
[in breast cancer,
Cytological observations of broken
by McClintock in maize
in the 1940s [Books]
led to the suggestion that telomeres functioned to prevent
chromosomal end-point fusions,
which have been recently shown to sometimes lead to cancer.
Sperm cells and
manifest high telomerase levels without showing cancer problems.
telomerase is applied exogenously
to mitotic human cell cultures, they become
Telomerase therapy even works to improve life span in long-telomere animals such as mice
[Ref, 2012]. Note that the
magnesium ion Mg++
is a necessary cofactor for the telomerase-controlled DNA synthesis that lengthens telomeres
[Elizabeth H. Blackburn and Kathleen Collins (2010)].
The Structure and Location of hTERT and hTR telomerase components
The hTERT component
I note that the hTERT protein
of telomerase is generated by the
consisting of 16 exons and 15 introns spanning ~37 kb of genomic sequence
(Wick et al., 1999)
near the distal end of chromosome 5p at
5p15.33, probably the most distal
the chromosome, which contains 609 genes.
The half-life of the associated molecule
mRNA transcript half-life (1-3 hours),
hTERT protein half-life (4 weeks),
of the active telomerase complex (24 hours)) is up to 4 weeks.
(See Xiaoming Yi,
Jerry W. Shay, and
Woodring E. Wright,
of telomerase components and hTERT mRNA splicing patterns in immortal human cells,
Nucleic Acids Res,
2001 December 1; 29(23): 4818–4825).
The hTERT protein,
catalytic component of telomerase,
includes 1132 amino acids
with a total
molecular mass of 127 kDa.
The information for the transcribed part of hTERT mRNA
is contained in 1132 x 3 nucleotides + 3 stop nt + 3 start nt = 3402 nt, and together with the 5' cap, the 5' UTR,
the 3' UTR and the poly(A) tail of
mRNA structure, hTERT mRNA is contained in 4015 nt.
One microgram of 20 nt of
yields 9.17 x 1013 molecules, so
1 microgram of 4015 nt of hTERT mRNA yields (20/4015) x 9.17 x 1013
= 457 x 109 hTERT mRNA molecules.
For purposes of viral or
it may be useful to prepare condensed
hTERT cDNA with various promoters.
Adding the 16 exon lengths of hTERT together,
I find 3396 nt length, 3.396 Kb.
The CMV promoter length is 508 nt, so that
hTERT cDNA with a CMV promoter and without introns should come to 3904 nt or 3.904 Kb. Using the
canonical 181-bp hTERT core promoter 19 bp upstream of the first nucleotide
in the cDNA sequence instead would yield hTERT cDNA + core promoter = 3396+181+19 nt = 3596 nt = 3.596 Kb.
The hTERT protein structure
is highly similar to retrotransposons
and includes the motifs
E characteristic of the
active sites of retrotransposons.
In addition, telomerases contain
the hTERT T-motif and show a
larger distance between the
motifs than is found in retrotransposons.
Our problem of telomerase activation
to repair shortened old telomeres and allow more cell divisions is primarily dependent on our ability to supply,
use, or activate transcription factors that interact with
the hTERT promoter to produce hTERT mRNA used to
produce the catalytic component of telomerase.
This process may be accelerated by HDAC inhibitors
that act to expand chromatin by acetylating DNA, promoting transcription and
counteracting gene silencing.
Otherwise, telomerase activation is typically produced by
phosphorylating cytoplasmic hTERT
with kinases (such as AKT1 kinase) for import into the nucleus.
Fast telomere extension
using purified nucleoside-modified hTERT mRNA in liposomes
was announced in 2013.
This method extends telomeres in six days by an amount by which
telomeres shorten over approximately 15 years of normal human aging.
The hTR component
The hTR sequence for the
RNA polymerase II-transcribed
RNA part of
is located on chromosome 3 (1,436 genes) at 3q26.3,
and the associated
hTR mRNA exhibits a half-life
of about 5 days.
length of the hTR mRNA transcript.
All vertebrate hTR RNA
uses the template yielding the hex nucleotide DNA extension sequence
includes up to 35 RNA
sequences, and features 4
conserved structural domains:
the CR/C5 region,
the H/ACA box (for localization of
telomerase hTR RNA to the nucleolus),
and the CR7 region
R Parwaresch and G Krupp, 2001).
It seems likely that
the H/ACA domain of hTR RNA binds to
H/ACA proteins formed by snoRNAs
such as dyskerin, which is found in
nucleolar telomerase complex.
In adult tissues, hTR is present and most
highly expressed in the spermatocytes
and Sertoli cells of the testis,
moderate expression is observed in
germinal center lymphoid follicles,
and weak expression is present in
regenerative cellular epithelia,
but is not seen in the nervous system and
mesenchymal derived tissues
cartilage, and the
circulatory system and
lymphatic system cells.
Treatment with mesenchymal stem cells
is one method of handling their eventual failure due to low hTR expression
in regenerative medicine.
See Nedime Serakinci, Stacey F Hoare, Moustapha Kassem, Stuart P Atkinson & W Nicol Keith (2006),
Telomerase promoter reprogramming and
interaction with general transcription factors in the human mesenchymal stem cell,
Jan 2006, vol.1, No.1, pp 125-131
"It is shown that repression of hTERT expression in hMSCs
(human Mesenchymal Stem Cells) is due to promoter-specific histone hypoacetylation
coupled with low Pol II and TFIIB trafficking.
This repression is overcome by treatment with
Trichostatin A (TSA),
an HDAC inhibitor,
concomitant with increases in promoter-specific histone acetylation and increases in Pol II and TFIIB tracking.
hTR expression is also increased in TSA-treated hMSCs, concomitant with changes in Pol II and TFIIB dynamics."
It is probably true that hyperacetylation with
sodium butyrate or
sodium butyrate chicken feed
would produce equivilant results.
Garlic improves the
Hayflick limit of dermal fibroblasts, probably due to the
HDAC inhibitor properties of
diallyl disulfide and allyl mercaptan metabolites of allicin from garlic,
which expand chromatin for better transcription of hTR and hTERT mRNA.
properties have recently been discovered for L-carnitine,
so that this common nutraceutical (obtainable from methionine from fish in the presence of lysine and vitamin C)
might also be used to overcome poor expression of hTR and hTERT in mesenchymal-derived tissues via
hyperacetylation of chromatin.
See hTR and the hTR Promoter.
Several "putative" binding sites
for the glucocorticoid,
steroid hormones have been found in the 5' flanking region of the hTR gene and may also be present in
the hTERT gene
(C.J. Cairney and W.N. Keith, 2007, 2008).
Expression of hTR
in adult tissues
is predominantly limited to
postmitotic cells express hTR.
[Yashima K, Wright WE, Shay JW, et al., 1998,
Papers/small molecule hTR activators,
J. Zhao, et al, 2003,
RNA gene activation, Links/hTR plasmids,
The hTR or
hTERC promotor is silenced via methylation
(binding at GC boxes)
and HIF-1 are positive regulators of hTR transcription
Cairney and W.N. Keith, 2007).
Note HIF-1 can be upregulated by hypoxia from
ginkgo biloba, or by
fenugreek seed, while
by sodium butyrate
and down-regulated by insulin deprivation.
Perhaps these can be applied to solve the special problems involving mesenchymal-derived tissues.
Note, however, that
induces growth arrest (in cancer cells) by inhibiting DNA synthesis,
arresting actively proliferating cells in G1 to induce differentiation.
that perhaps it should not be used continuously.
Sodium butyrate supplements
are sometimes shown with a rooster-waggle neck picture, probably to suggest that they may be good for neck wattles
composed of old connective tissue derived from mesenchymal cells by boosting the expression of
hTR there via elevated Sp1.
Increased Sp1 binding to promoter regions
in cells that overexpress the endogenous antioxidants
and curcumin has been
observed to increase
Recently it has become clear that hTERT and hTR are better expressed in mesenchymal-derived
tissues when HDAC inhibitors such as
sodium butyrate or
L-carnitine are used to expand chromatin for
Fractionation of the
with a glycol gradient
yields a size of about 1000 kDa for
the native enzyme and about 550 kDa
for affinity purified telomerase,
the difference being due to loosely associated
factors lost during
et al 2001).
A single hTERT
molecule accounts for just 127 kDa.
In addition, we have the
the shelterin or
telosome proteins, and associated
mammalian telomere protein factors.
Two molecules of dyskerin,
two molecules of hTERT
protein catalytic component of telomerase, and 2 molecules
of telomerase RNA are found in telomerase
according to recent research.
This may be two molecules of telomerase bound at the RNA template, however.
See Scott B. Cohen, Mark E. Graham, George O. Lovrecz, Nicolai Bache, Phillip J. Robinson, Roger R. Reddel, (2007),
Composition of Catalytically Active Human Telomerase from Immortal Cells,
Science, 30 March 2007: Vol. 315. no. 5820, pp. 1850 - 1853.
"Dyskerin is a component
of a small
nucleolar ribonucleoprotein (snoRNP) that is highly conserved throughout evolution....
findings indicate that dyskerin plays a role in
telomere maintenance by stabilizing
- H.-Y. Du et al.
Mutations and Premature Aging in Humans.
Molecular Densities of Telomerase
The abundance of
is low in cells, featuring for instance 3000-5000
copies of hTR
and 30 copies
of hTERT protein per cell in in vitro cultures of growing tumor cells that are the richest source
et al. 2001).
Of course, we may also inquire concerning the
molecules in sperm cells, dermal fibroblasts, hemopoietic stem cells, immortalized cells,
and other types of cells under varying conditions at
a function of age.
The lengths of different chromosomes
directly with telomere length
are shorter the closer they are to the centromere
are shorter than q-arm telomeres
The lengths of telomeres may vary between
alleles at the same
telomere in a diploid cell.
shortest telomere in human cells
is at 17p
Genes & Disease].
catalytic component of telomerase
available is the primary
in telomerase expression,
and transcriptional regulation
of hTERT gene expression
rather than of hTR for the RNA component of telomerase
is central in replicative senescence and
Replicative senescence is pro-inflammatory
and pro-carcinogenic, although it limits uncontrolled tumor growth.
Inhibiting telomerase causes
cancer cells to
self-destruct via apoptosis unless telomerase control
is via the ALT mechanism, so that
are often useful in squelching cancers.
telomeres of maximum reported length 30,000 base pairs shorten by
50-200 base pairs with each S phase of
the cell cycle,
starting with typically 15,000 to 20,000 base pairs in the germ line with typically 7,000-10,000 base pairs in
human adults, and counting down
to 4,000-7000 base pairs in senescent cells at
the M1 senescent
cell checkpoint preceding a conditionally triggered countdown to the
crisis state before apoptosis,
end-point fusions, and
other phenomena associated with cell death or
cancer set in.
Human germline cell telomeres
are maintained at about 15 kbp.
thousands of base pairs long are uncapped to reach the
M1 senescence checkpoint, when the length of telomere has
shrunk so that the loop tries to close at a spot where non-canonical
are encountered differing from the tandem telomeric hexanucleotide repeats [5'-GGTTAG-3']n, so that the
formation protein [Index]
closing the t-loop cannot find a proper binding site.
In experiments, fibroblasts
shortening up to 200 base pairs per cell division
were found to loose only 5-20 bp per cell division when the cell was equipped with the most effective
(This might motivate using
along with water-soluble oxidants like
vitamin C, or
in lipids and water like alpha lipoic acid,
the recommended alternative.)
Cells of the healthy
colon mucosa typically
loose 44 base pairs
On the other hand, patients 77.5 years old were shown to have
white blood cells that lost 71 telomeric base pairs per year
[Nazmul Huda, et.al, 2007],
perhaps showing some
in telomere erosion.
The same paper showed that
nearly matched between elderly twins.
In one 2003 study, patients over 60 years old with shorter
telomeres in blood DNA had poorer survival than patients with longer telomeres, attributable in part
to a 3·18-fold higher mortality rate from heart disease and an 8·54-fold higher mortality rate
from infectious disease.
(Richard M. Cawthon,
Ken R. Smith, Elizabeth O'Brien, Anna Sivatchenko, Richard A. Kerber, 2003).
Other studies have pictured more precisely how
varies with telomere length in blood leukocytes, and shown how
cancer incidence and mortality vary as a function
of telomere length.
Telomerase and Aging in Non-Mitotic Cells and Mitochondria
Note that replicative senescence
does not apply in quite the same way to non-mitotic cells such as
muscle satellite cells
and most nerve
cells, which appear to
via other mechanisms involving
the cell membrane,
membrane permeability changes from hydroxyl radical reactions,
membrane damage from
accelerated ROS from
(Sometimes such cells are
renewed by stem cells from
as in the the case
[77s], so that the telomeric state of mitotic stem cells
may be behind the continued health of non-mitotic tissue.)
However, Geron claims that in vitro
cultures of non-mitotic
nerve and muscle cells as well as
mitotic cells are
benefited by telomerase
activation, listing 20 cellular types [81s].
It was later discovered that
the hTERT protein
defends mitochondrial DNA and
DNA repair in nuclear DNA.
"In many cases, introduction of
also increases the capacity of cells
to withstand stress due to high or low levels of oxygen, toxic molecules, or
abnormal growth conditions."
Experiments in 2007 have succeeded in immortalizing muscle cells
in in vitro culture using a combination of
and cyclin-dependent kinase 4.
See cyclin-dependent kinase 4
Books], which uses ATP to
phosphorylate proteins and is subject to inhibition by
p16INK4A and other INK4 family members
When grown in in vitro cultures, human (73-78 year lifespan) embryonic cells divide
about 50 times
before reaching their telomere-imposed cell division limit,
mouse (3 year life span) cells divide 15 times, and the cells of Galapagos tortoises (175 year life span)
divide 90 times.
Cells from human adults, on the other hand, were observed to typically divide 20 times,
or 50 times from the embryonic stage of development.
Telomerase activation by
small molecule telomerase activators
Index] such as
astragalus root extract,
Nitric Oxide (NO)
or CGK1026, however,
can confer an immortal phenotype on cells by bypassing the usual
cellular senescence pathway,
and can restore a youthful phenotype to aging cells with short
Carnosine and Antioxidant Telomere Defense
"In 1999, Australian researchers confirmed
that carnosine increases the longevity of human fibroblast cells in the laboratory.
Carnosine extended the Hayflick limit (the maximum number of times a cell can divide), from
a "normal" 50 by up to an additional 10 times!"
See Life Extension on
and Cellular Senescence and
The Barron Report.
Zglinicki et al. showed that
grown in a high oxygen atmosphere experience increased telomere loss
and increased single-stranded telomere breaks, then prematurely senesce.
So any drug protecting telomeres against
oxidative stress should help,
including the "super antioxidant"
Reducing oxygen in a cell culturing system sometimes yielded cells capable of 3x as many cell divisions
[Zs. Nagy, The
Membrane Hypothesis of Aging, p.8.].
Aging without Telomere Shortening
Also, note that the fibroblasts
of the mouselike dunnart
double 170 times, but the animal only lives 3 years, no doubt because the other mechanisms of
cellular senescence kill it
before replicative senescence does [Zs. Nagy, p.8].
Similarly, it is surprising that the mouse has telomeres > 25,000 base pairs long;
typically dying not of replicative senescence,
but of mitochondrial failure,
which is typical of animals very subject to predation.
The relatively safe mouse-like bat lives 40 years, enjoying telomere-controlled longevity.
Mice with the hTR RNA component of
knocked out show no old-age effects due to telomere shortening
until the 6th generation.
Coincidentally, the mouse is more prone to cancer
than humans; mouse telomeres are so long that they rarely
catch runaway cell division.
Telomeres sometimes stop the runaway cell division
associated with cancer unless the cancer causes the gene
to express telomerase.
Syrian hamster embryo cells express telomerase to keep their cellular telomeres long for 20-30 population
doublings until they senesce by another mechanism.
"Normal somatic cells are generally
telomerase negative, except for bone marrow stem cells."
Note that germ cells express the most telomerase, maintaining their telomere length constant,
while stem cells senesce more slowly than normal somatic cells because they intermittantly express telomerase
Aging, and Human Disease, p.54].
Neygeront and Kinetin
Another Hayflick limit extender is the RNA and B-vitamin complex
which may boost the number of possible cell divisions by 20%.
in carefully controlled doses, may be another
Hayflick Limit extender.
pioneered in anti-aging research by Dr. Suresh Rattan,
(also a student of zeatin)
is presently being used on skin cells.
Mind you, we are sometimes up against the problem:
phenotype was not prevented... although telomerase activity was induced...",
the solution to which we must seek in other sections of this and similar essays.
telomerase to lengthen telomeres saves fibroblasts, but not
pancreatic islet cells,
P16INK4A and the Reversibility of Senescence
P16INK4A can be too high
for replicative senescence to be reversed by
but can sometimes be kept within bounds by
nerve growth factor, which produces
Id-1 helix-loop-helix transcription factor limiting P16INK4A.
Note that vitamin A or
retinol from carrots,
sources of the telomerase inhibitor
reduce P16INK4A expression.
However, retinoic acid represses hTERT transcription,
so that vitamin A, carrots,
retinol, and retinoic acid
are to be taken during telomerase activation OFF phases of treatment.
P16INK4A is a ubiquitinated protein
that is devoured
(the rate of ubiquitination depending on P16INK4A density),
so that reducing its expression really reduces P16INK4A levels in the cell.
See (Ronen Ben-Saadon, Ifat Fajerman,
Tamar Ziv, et al, 2004). Resveratrol's heightened
SIRT1 expression downregulates
P16INK4A expression, retarding the onset of irreversible
Also note that exercise can bring P16INK4A expression down
by 2 binary orders of magnitude.
High P16INK4A levels are often associated with aging, smoking, and physical inactivity.
Heat Shock Proteins Increase Telomerase Levels
Another method of increasing telomerase levels in the cell is via
heat shock proteins,
which mediate the assembly of telomerase
Morin, DO Toft, JW Shay, WE Wright, MA White, et al., (1999)).
Note that HSP90 levels may be elevated for
transport of nuclear transcription factors
into the nucleus via the action of alpha lipoic acid
or via interleukin 6
produced by exercise.
HSP90 also guides
protein folding as a
Telomerase Activation by Nitric Oxide in Endothelial Progenitor Cells
A technique described by
Vasa, et. al.,
used Nitric Oxide to activate
telomerase and delay
See Nitric Oxide Activates Telomerase
and Delays Endothelial Cell Senescence and
Hayashi, et.al, 2006.
Since NO reacts with the superoxide anion to form
peroxynitrite, which produces hydroxyl radicals,
it is probably a good idea to use the
gamma-tocopherol when using
NO to promote telomerase activation.
Nitric Oxide synthase production,
and in the presence of arginine
this leads to Nitric Oxide generation
suitable for telomerase activation and promotion of
Nitric Oxide generation is also promoted by
release of NO in endothelial tissues is promoted by
acetylcholine, which may be boosted with
or acetyl L-carnitine.
Nitric Oxide release for
purposes of telomerase activation might be best promoted in the
by bodybuilding workouts in presence of
huperzine A, or
acetyl L-carnitine as
supplements, to which we might add
gamma tocopherol to
Small Molecule Telomerase Activators
Deacetylase Inhibitors and Small Molecule Telomerase Activators,
Molecule Telomerase Activators,
Endogenous Telomerase Activators;
Exercise-Induced Telomerase Activators;
History of Telomerase Activators].
Geron Telomerase Activators
Investor Guide] and a subsidiary
TA Therapeutics have announced a
small molecule telomerase-activator TAT0002
in AIDS therapy that may become useful in life extension work, say
on T-lymphocytes and on
on the skin
[article], now to involve
activation therapies [Index]
Geron has also determined that its telomerase activators
promote wound healing.
Concentrations of astragalosides
at 1 μg/ml are typical for topical applications or in testing
for telomerase activation effectiveness using a
telomerase TRAP assay
has a half-life of about 24 hours.
formulas [See also A' alternate-source version
Compositions and Methods for Increasing Telomerase Activity,
Hong Kong Univ. formulas
and Patent Lens] for a small-molecule
telomerase activator is
(molecular diagram, vendors
which the firm claims is associated with an optimal dosage of 50 mg to 100 mg per day
(p.39-40). This looks like an overdose by a factor of 10 or 20,
but that may be due to reduced bioavailability of
astragaloside IV by itself.
Astragaloside IV is more
bioavailable when taken in
astragalus root extract,
which is typically used to
the immune system.
The bioavailability of
can also be increased by
The small-molecule telomerase activator
TA-65, a product of
TA Sciences, primarily composed of
has also been announced
by Geron along with several other formulas based on
astragalus root extract molecules
[Geron European Patent and
Hong Kong University European Patent].
TA-65 was initially prescribed at 5 mg/day, then finally at 25 mg/day.
The 5 mg dose was recommended by
in their European patent
A 1/08/2011 email source quotes a chemical analysis showing that TA-65 is:
5.47 mg cycloastragenol + 0.27 mg
astragaloside IV + < 0.01 mg
astragenol per serving.
(See page 65
for the molecule, and note that "cycloastragenol
is the common genuine aglycone of the astragalosides", the smallest of
the astragaloside-related telomerase activator molecules,
resembling astragaloside IV with its
two lower ball-like carbon rings off,
as does likewise small astragenol
"One-nut" versions of astragaloside IV
are described on page 66,
cycloastragenol 6-β-D-glycopyranoside and cycloastragenol 3-β-D-xylopyranoside.)
TA Sciences at first claimed that
"one single, potent molecule"
from astragalus extract,
thus probably cycloastragenol, and not
astragaloside IV, which required 50 to 100 mg per day
doses to be effective without excipients to improve
TA-65 might have been
astragenol, the dosage of which was
unspecified in the Geron European patent, until chemical analysis emanating from
determined that it was primarily cycloastragenol.
singles out cycloastragenol
as having very low toxicity and excellent
bioavailability on page 40 of
and Methods for Increasing Telomerase Activity
(or see A' alternate-source version Compositions
and Methods for Increasing Telomerase Activity, or
and emphasizes a procedure for converting
astragaloside IV chemically to
TA-65 is applied by
in staggered fashion 3 months on, three months off, and again three months on
during a period of one year in the
It seems that after 3 months using TA-41 astragalus extract
to test the Patton Protocol,
TA Sciences saw 230 base pairs of telomere growth in their early studies
By May 2012, it seems
was more effective in producing increases in average telomere length than
according to studies carried out by
the VIDA Institute,
Calvin B. Harley, et al. (2011), in
Product Telomerase Activator As Part of a Health Maintenance Program,
Rejuvenation Research, 14(1), 2011.
"Results of an informal, but scientifically conducted, several month trial with laboratory
analysis of biomarkers, in fact, showed that a combination of whole astragalus root,
and natural astragalus extract was an order of magnitude more effective than
either cycloastragenol or astragaloside IV
at increasing the telomere length of immune system (NK) cells in the blood....
Using Standardised Astragalus Root Extract
(+ physical training, meditation, less work, gingko biloba, orlistat and LCHF ).... The median telomere
length of my NK cells increased in length by a whopping 1,800 base pairs (in 3 months)."
- VIDA Institute.
The VIDA Institute
recommends taking ginkgo biloba
(which makes blood platelets less sticky)
and gotu kola (Centella Asiatica) with
astragalus root extract
to improve its access to the fine structure of the circulatory system, so that it can reach more cells.
About 50-200 telomere base pairs are lost per cell division,
a number than can be reduced to from 20 bp to 5 bp
by taking antioxidants.
Note that humans typically have about 50 cell divisions available at the embryonic stage (except for stem cells),
so that such a program of treatment might go on for years.
Geron's preferred embodiments in 2005 for a small molecule telomerase activator are based on
astragenol, and astragaloside IV 16-one, although they have named several other effective
compounds also obtained from astragalus root extract,
including cycloastragenol 6-β-D-glucopyranoside and cycloastragenol 3-β-D-xylopyranoside.
Relatively highly bioavailable cycloastragenol
may be obtained from astragaloside IV
[RevGenetics] or by other methods from
By the Spring of 2011,
seemed rather less effective than described above, working
best as telomerase activators on NK cells,
explaining why astragalus is good at deflecting viral infections.
Approaches based on several telomerase activators
in parallel, plus exercise
with HGH secretagogues and
support for endogenous telomerase activators,
now seem more promising than total reliance on astragalosides or
TA-65, based on studies of
TA-65 performance by
Calvin B. Harley
and other leading investigators on data gathered since
the spring of 2007.
Geron has also described a "formula III" telomerase activator embodiment,
Red Korean Ginseng Extract may include some
[molecule], but on the whole
the extract turns out to be a telomerase inhibitor.
Astragalus Preparations from Vendors
In 2007 I thought the best and safest commonly available medicine for telomerase activation was
Astragalus Root Extract featuring 30 drops/mg
of astragalosides, given at
5 mg of astragalosides/day during 2-week activation time cells alternating with 2 week
periods of telomerase inhibition with telomerase inhibitors like
green tea EGCG, and
fish oil's EPA.
Herbs Astragalus Root Extract
was no longer available at 1 mg astragalosides per 30 drops,
I at first (2008) substituted 1200 mg/day of
Solaray Astragalus Root Extract
to cover the 5 mg of astragalosides,
which requires 6 x 200 mg capsules per day in a cyclic protocol featuring 15 days on, then 15 days off.
By December 2009, I had to substitute 5 droppers of
Herb Pharm Astragalus Root Extract
plus 6 x 200 mg capsules of
Solaray Astragalus Root Extract
to approach the 5 mg of astragalosides per day
requirement, adding 4 to 8 capsules of
Natural Balance Chitosan to
improve bioavailability. This was for the
first two-week part of the cycle, which features telomerase activation. During the 2nd part of the month-long
cycle, telomerase inhibitors are used instead, as described above.
Although this exceeds the recommended dose according to Solaray, I believe from
that it is safe enough.
By 2011 I was able to obtain Astragaloside IV
at 100 mg/day from vendors like RevGenetics and
at up to 25 mg/day from several vendors. By 2012
I dropped astragaloside IV and cycloastragenol, returning to 1/2 bottle of GAIA Herbs green label
astragalus root extract per day (15 x 30 drops = about 15 mg astragalosides at the time) with 50 x 500 mg = 25 g) of
NOW astragalus root powder in capsules,
as it became clear that this was both more effective and more inexpensive. I put 3-5 droppers of the 1/2 bottle
of GAIA Herbs green label astragalus extract into my scalp to stimulate hair follicle cycles. Then the
cost is approximately 15 x ($10.50/2) = $78.75/month for the astragalus extract and
((50) x $5.91/100) x 15 = $44.32 for the astragalus root powder capsules, for a total of $123.08/month.
Using just 5 mg of astragalosides/day from the extract,
I might have cut the cost to ($78.75/3) + $21.00 = $47.45/month. Using exclusively
NOW astragalus root powder
capsules at 33 grams/day, the maximum dose of astragalus root powder used in Chinese medicine, I would have spent
15 x (66 caps) x ($5.91/100 500 mg caps) = 15 x $3.90/day = $58.51/month. To this one would typically
add 3-5 droppers (30 drops/dropper = 1 mg astragalosides)
per day of the GAIA Herbs green label astragalus extract for the scalp. This would cost
3-5 droppers x ($10.50/30 droppers per bottle) x 15 days, or $15.75/month for 3 droppers/day in 15 days of a month,
up to $26.25/month for 5 droppers/day for 15 days of the monthly cycle. Then the cost would be less than
$84.76/month for 33 grams/day of astragalus root plus a deluxe astragalus root extract scalp rub.
See the complete current program for 2013, which features a number of
telomerase activators and booster supplements for them.
Combinations of Telomerase Activators [List]
Combinations of other telomerase activators
also became available, such as
RevGenetics Astral Fruit NF
and custom combinations including
Fenugreek extract for
for an insulin boost
to provide improved access by telomerase to
by phosphorylating tankyrase 1 for stripping
TRF1 telomere loop closure protein from telomeres in
the presence of a NAD+ substrate
provided by early morning niacinamide
See Age Transformation for a logbook of this experiment.
Telomerase inhibitors and
telomerase activators are not to be taken at the same time.
Reconstructing cellular telomeres using activation of telomerase closes chromosomal
telomere t-loops in
restoring the youthful phenotype and patterns of gene expression
at a rejuvenation rate of up to 0.75 years per month (9 years/year, or
460 bp/year of telomere growth using
the cyclic Patton Protocol).
Another alternative is
Herbal Remedies Astragalus
Root Extract 1.25 mg astragalosides per 250 mg cap, via
( Standardized 0.5% Astragalosides ), 60 VCapsules per bottle, incuding Astragalus, dried extract 250mg
(root) 0.5% astragalosides, with
Astragalus (root) 250mg.
Four capsules yield 5 mg astragalosides
plus 1 gram of astragalus membranaceus root,
which improves bioavailability of astragalosides.
Note that Ginsenoside RH2, a
may also be present in ginseng extracts,
in addition to telomerase activator
This may be why Korean Red Ginseng is
a telomerase inhibitor (31).
Note that the ginsenosides
are distinct from the astragalosides, being
One starting material from ginseng is
Geron also names
astragalosides A, 1, 2, 7, and
astraverrucins I and II,
which can be obtained from
as telomerase activators.
TA-65 "is a naturally
occurring molecule extracted from the well known Traditional
Chinese herb Astragalus membranaceus
GAIA Astragalus extract, 1 mg of astrogalosides per 30 drops]",
Milk Vetch Root, or
However, there are indications that
astragalus extract works best to increase telomere length in Natural Killer
Geron seems to have tested
nutraceuticals known to boost the immune system
in its search for small molecule telomerase activators
as both astragalagus root
[Index] had been used in traditional
medicine for the immune system.
Both contain saponins
Perkins Coie has recently filed a patent application on behalf of Geron's Chief Scientific Officer
Calvin B. Harley
B. Harley, Papers/Calvin B.
anti-aging skin creams using astragalosides.
Liposome delivery systems
 in connection with small molecule telomerase
activator delivery look quite interesting.
Cut-Rate Telomere Therapy with Fenugreek, Black Cohosh, Exercise, HGH Secretagogues, Garlic, and Onions
Perhaps Fenugreek seed alone at 3 grams/day just
before bedtime for 20 days of the month
can preserve us at a specific age. Then telomere length might be held constant for just $5.00/month
for 100 caps of 610 mg/cap Fenugreek seed from Wal-Mart, taken 5 caps/day for 3 grams/day for 20 days.
Black cohosh for 25 days at 4 caps/day
from a 100 caps for $5.00 bottle might also help stabilize telomere length at a reasonable price,
or the two could be combined. Thus low-cost telomerase activators exist that may allow us to hang
on as well-preserved cut-rate fellow travelers for 5 to 10 dollars/month,
even when we can't afford $100/month for basic
rejuvenation treatment with astragalus formulations.
Exercise can be free and is a source of
endogenous telomerase activators
that can be boosted with nutraceuticals such as
HGH secretagogues in
combination with exercise may be most useful, as virtually human cells have
about the same density of HGH receptors in their
[List] improves the Hayflick limit for dermal fibroblasts, and
[List], which has some telomerase inducing power.
Another firm, (now-defunct)
[SEC data 11/7/06], also developed
products based on telomerase activation, and was developing products
including rejuvenating skin creams
based on telomerase activation.
According to now-defunct Telomolecular Nanotechnologies
youthful "telomerized cells" seem immune to free
radical damage and glycation, due partly to the telomerase position effect described in subsequent section.
"...Cells with sufficiently elongated
energetically produce, in high levels,
elastin and many other
proteins important in tissue formation,
cell repair, and
that become scarce as telomeres shorten."
(See Overexpression of
by Armstrong, G. Saretzki, and Peters, et. al.)
DNA Rolling Nanocircle Encoding
Telomolecular Nanotechnologies proposed
Produced by a DNA synthesizer,
DNA rolling nanocircle encoding
for telomere rejuvenation was
invented by Dr. Eric Kool
of Stanford University.
See Dr. Kool's patent,
Telomere-Encoding Synthetic DNA Nanocircles, and Their Use for the Elongation of Telomere Repeats
However, DNA nanocircles
for telomere extension are not ready for internal use at this time,
but are only used for special applications and in the study of
ALT mechanisms in cancer.
that nanocircles might work efficiently in living animals."
Direct hTERT Delivery to Cells
Another firm, Phoenix Biomolecular,
has specified a cell penetrating peptide scheme
to deliver hTERT directly to cells.
It is subsequently necessary to
then for transport into the cellular nucleus.
Liposome preparations that
the cell via endocytosis
are promising both for large molecules and plasmids.
Plasmids in which
Green Fluorescent Protein is driven by
a copy of the hTERT promoter
on the plasmid may be used to guide cancer surgery, and finite-lifetime
plasmids expressing C-myc
may be used to
hTERT transcription levels.
hTERT mRNA Delivery to Cells
Fast telomere extension using HPLC-purified, nucleoside-modified hTERT mRNA
to escape from the innate immune system, uses mRNA with amplified poly(A) tails that gradually shrink to a minimum length before the mRNA is consumed by an enzyme.
The therapeutic hTERT mRNA may be transfected in liposomes. It is capable of lengthening telomeres in 6 days by the amount that telomeres shrink in 15 years of aging,
so that it should be useful for stem cell transplants and rejuvenation.
Sierra Sciences Identifies 858 Telomerase Inducers
[Wikipedia] is also working to develop
telomerase activation techiques
More than one
has been found.
I list 185 substances
under investigation as
Some of them are hTERT transcription activators
binding to the
hTERT promoter producing hTERT mRNA
transcripts and others are
hTERT phosphorylation kinases
phosphorylate hTERT in the cytoplasm to import it to the cell nucleus.
Both seem to produce telomerase activity.
In addition, there are HDAC
like Tricostatin A and
CGK 1026 that improve hTERT transcription by expanding chromatin,
and cofactors such as HSP90 that are required for hTERT assembly.
Sierra Sciences claims to have identified
858 telomerase activity-producing
substances after screening 254,593 compounds, more
than the 185 telomerase activators I have listed,
some of which were identified from Product B.
The relative speed with which alternative telomerase activators
can be used to achieve rejuvenation is being
measured by Sierra Sciences,
RevGenetics, and other firms.
For Sierra Sciences
(President William H. Andrews PhD) and
telomerase inducer test results for 27 phytochemical extracts
and associated Product B
telomere enlongation results, see the
Product B PatentScope.pdf
developed by Master
Formulator John Anderson. Also see
telomerase activator (121) Product B and
The Product B Explorer.
Endogenous and Exercise-Induced Telomerase Activators
Note that I have also identified
endogenous telomerase activators and
15 exercise-induced telomerase activators together
with supplements for promoting their expression. Note that
cyclic AMP from exercise and
certain supplements such as forskolin can lower
caveolin-1 expression in senescent cells
by sequestering FOXO factors away
from the cellular nucleus in a way
that can produce recovery from cellular senescence plus telomere enlongation.
HDAC Inhibitor Telomerase Activators
See papers on telomerase activation,
for instance by histone deacetylase inhibitors
"Treatment with tricostatin A (TSA)
Epigenetic Protocols, chap.8,
Hsp22 level with life extending effect] induced significant activation of hTERT mRNA expression and
telomerase activity in normal cells, but not in cancer cells."
Histone deacetylase inhibitor
"activates the hTERT promoter
in normal cells", thus enabling
I stated above that
is an activator for SIRT1, a histone deacetylase enzyme
the activation of which results in gene silencing that keeps
DNA more tightly wound on
histone cores, preventing
Perhaps resveratrol can be used as a
gene silencer to shut down telomerase transcription from hTERT following treatment with a small-molecule telomerase
activator like tricostatin A
a histone deacetylase inhibitor
which is genotoxic at some dosages, however.
Resveratrol turns out to activate hTERT protein in the cytoplasm via
hTERT phosphorylation with the
AKT protein kinase (Index/AKT),
enabling the import of cytoplasmic hTERT protein into the nucleus,
but not improving the number of
hTERT mRNA transcripts via
activation with a
nuclear transcription factor
such as HIF-1 or
dimerized with Mad,
Both bind to the same type of 5'-CACGTG-3'
E-box promoter site on the
[Telomerase Activators/CGK 1026,
ChemBank/CGK 1026 molecule],
discovered in 2004, is said to
"derepress" hTERT expression,
and has been used as an orally bioavailable substitute for
CGK 1026 is thought to inhibit the recruitment of
protein complexes assembled on the
It is described by several sources:
Directory of Immunological and Biological Reagents, as catalog # 565730,
Merck CGK 1026 -
Order # 565730-5MG, and EMC Biosciences CGK1026.
See also SP1 on
the hTERT promoter
(hTERT promoter/SP1) for
derepression of hTERT transcription.
A more detailed look at the situation shows that
commonly available foods contain histone deacetylase inhibitors that
may prove valuable in life extension via telomere extension by telomerase
For instance, diallyl
sulphide (garlic) and
sulphoraphane (broccoli) are
(meats, seafood, oysters)
class I histone deacetylase inhibitors (HDAC inhibitors).
enhances hTERT transcription
by upregulating Bcl-2
(a telomerase activator) and may be used up to 45 mg/day.
compound from garlic or deodorized garlic [Wikipedia/garlic,
that is more active as a histone deacetylase inhibitor than allyl sulphide
is allyl disulphide
and a still stronger one is allyl mercaptan
I note that allicin from
inhibits telomerase expression in
often inducing apoptosis.
Garlic extends the Hayflick limit in dermal fibroblasts, so that allicin
metabolites diallyl disulfide and
are thought to improve hTERT mRNA expression in normal cells.
Note that overdoses of garlic and allyl compounds can have toxic effect;
consuming 5 garlic cloves in a tomato soup with chopped onions can induce
is also a histone deaceylase inhibitor
or chromatin-remodeling factor
that may lengthen telomeres by enabling
telomerase transcription and is known to extend the life span of Drosophila 40%.
Images] is an
available now in pill form that may be able to accelerate
hTERT transcription by keeping chromatin expanded and available for transcription, so that it
might be taken together with astragalosides or other
improves the transcription of Sp1,
which markedly improves the expression of the
telomerase activator epiregulin, a ligand of the
epidermal growth factor receptor.
is a typical new histone
deacetylase inhibitor [Links,
being investigated by Japanese scientists that is known to activate telomerase transcription.
(red grapes, Japanese Knotweed root) is a class III histone
deacetylase activator via its ability to turn on SIRT1
deacetylase enzyme, collapsing
chromatin and inhibiting transcription of hTERT mRNA.
phosphorylates hTERT molecules in the cytoplasm for import into the nucleus, activating telomerase.
described as a deacetylation activator, and
activates the gene SIRT1,
yielding the corresponding
SIRT1 deacetylase enzyme for gene silencing via
NAD, incidentally, is found in tuna, and
may be synthesized in the body
(nicotinamide), a form of
By 2011 we were using
TA Sciences TA-65,
astragalus extract, or
in parallel with other telomerase activators
List] such as
Nitric Oxide and
fenugreek extract to
to cover our telomere elongation requirements,
with feedback from telomere length testing
The histone deacetylase inhibitors
DNA for transcription with
dissociating the histones from DNA prior to
Some, like sodium butyrate,
may be useful for accelerating transcription.
There are 4 types of
modifications of histone proteins -
Histone deacetylation inhibitors
allow chromatin to expand and become
Histone deacetylation causes compaction of chromatin, silencing genes.
Histone acetylation expands chromatin, while histone deacetylation compacts it.
HDACs may activate p53,
while activation of SIRT1 (human SIR2)
with resveratrol prevents p53 activation
with chromatin compaction and gene silencing,
causing extended life span, since
telomere shorting itself finally induces a
DNA damage detection pathway
leading to the senescent state of the cell.
activates telomerase by phosphorylating cytoplasmic hTERT for import into the nucleus,
also tending to inhibit senescence.
What we need most are hTERT transcriptional activators
that make the correct sections of
transcriptionally active for hTERT mRNA production, such as
astragalus root (33 grams/day),
astragalus root extract (for application to the scalp),
colostrum solution (for transdermal application),
bacopa (1-2 grams/day),
fenugreek seed (3 grams orally before bedtime),
arginine (5-10 grams/day
for Nitric Oxide),
DHEA (4 x 50 mg/day for higher
assist hTERT transcriptional activators by expanding chromatin and may themselves induce transcription of hTERT mRNA.
A larger molecule of about 15,500 Daltons (still capable of passing through
the nuclear pore) worth exploring is
or interleukin 2
TA/Interleukin 2], a
the expression of mRNA for human telomerase in T-cell lymphocytes.
"has been approved by the Food and Drug Administration (FDA) for the
treatment of cancers (malignant
renal cell cancer), and is in
clinical trials for the treatment of
chronic viral infections, and as a
booster (adjuvant) for vaccines." - [Wikipedia].
role in T-lymphocytes has been noted by other investigators.
There is evidence that DHEA acts as a
physiological regulator of interleukin-2 biosynthesis
(Yu, 1995, citing in Arking,
The Biology of Aging, p.233.),
so supplementation with DHEA may help interleukin-2
maintain T-lymphocyte telomeres.
Preliminary data suggest estrogen
activates telomerase in T-lymphocytes
of Models for Human Aging, p.37].
and its receptor activate telomerase in estrogen-responsive cells through the estrogen response
element sites in the hTERT promoter".
Another group in Russia at the
Petersburg Institute of Bioregulation and Gerontology announced in 2003 that
Telomerase Activators/Epithalon Peptide,
aka epitalon], a small 4-peptide protein
made from the sequence
aspartic acid, and
glycine, (Ala-Glu-Asp-Gly), activates
telomerase and extends telomeres [Links,
Biogerontology article 1,
sources and costs].
Epithalon peptide has been
5 times weekly into mice, resulting in 34.2% prolongation of life span in
mice without cancers.
Liposomal or sublingual (under the tongue) administration is probably possible with such short peptide molecules,
and perhaps it can be topically applied like a skin cream,
taken sublingually under the tongue,
in buccal fashion in the pouch of the cheek, or otherwise.
HGH and IGF-1 as Telomerase Activators
Mice overexpressing IGF-1 showed higher levels of phospho-Akt
leading to increased
telomerase activity and more effective
cardiac stem cells,
creating a better supply of new
myocytes for the heart.
(Torella et.al., 2004,
cited by Arking).
Telomerase activity can be stimulated by improving our levels of
IGF-1 (Telomerase Activators/IGF-1) by
direct input of the hormone or by stimulating it via
exercise in the presence of amino acid stacks
[Human IGF-1 stimulator,
I note that Human Growth Hormone
has been shown to
upregulate telomerase in ovaries and in liver cells
(which improves transcripiton of hTERT mRNA)
is partially converted by the liver into IGF-1
(which phosphorylates hTERT protein
for import into the nucleus). Note that
IGF-1 are both upregulated by
as are at least 12 other endogenous
telomerase activators and at least 15 telomerase-activating
human growth factors found in
growth factor skin creams.
On the other hand, an antagonist of growth hormone-releasing hormone has dramatically decreased telomerase
in experimental xenografted transplants
has been achieved in cord blood using
IGF-1 in the presence of
PHA (phytohaemagglutinin; 1 μg/ml, Sigma, St Louis, Mo., U.S.A.).
Note that while attempting telomere extension via a
hormone strategy for telomerase activation
one should avoid ingesting telomerase inhibitors,
which can sometimes be produced in the body from high-polyphenol diets.
However, some telomerase activators
for normal cells (such as silymarin)
behave like telomerase inhibitors when applied to cancer cells.
Evidently, there has also been some progress in hTERT activation using the insect hormone
transcription from hTERT and
in human fibroblasts [article].
Finally, I note that US Patent
6787133 has been granted to Geron for a
to purify telomerase for the purpose of identifying
telomerase activators and
Increased telomere length, more telomerase activity, and active
meristematic stem cell
presence have been identified
as important factors in
long life spans of 2000-5000 year old bristlecone pine trees .
telomerase activity in embryonic stem cells seems to improve their defenses.
Although telomerase expression is up-regulated in cancer,
and used to detect cancer, the
for telomerase is not an oncogene and its activation does not induce
cancerous growth deregulation by itself.
Inhibition of telomerase in human tissues
helps suppress run-away cancer cells by inducing
massive apoptosis in tumors, so
telomerase activation treatments to lengthen our telomeres for life extension purposes
Cyclic Telomerase Activation]
should be periodic and short-term,
or done ex vivo prior to an adult stem cell transplant, and not continuously in vivo.
Telomerase activators are weakly
as they inhibit telomerase inhibition as an anticancer defense.
TA Sciences proposes using their
telomerase activator 3 months on, 3 months off, and 3 months on again for a year (the Patton Protocol).
Cyclic Telomerase Activation with Readily Available Nutraceuticals
I expect that monthly cycles
of 2 weeks of telomerase activation
followed by two weeks of
telomerase inhibition plus treatment with
anticancer nutraceuticals is an adequately safe approach.
This may allow stronger telomerase activation than is feasible with the Patton Protocol.
In the future we may prefer to use Product B,
astragalus root extract with
telomerase-activating growth factors and
ginkgo biloba for
fenugreek extract (for
Nerve Growth Factor boosters
carnosic acid from
promote ID-1 helix-loop-helix transcription factor,
telomerase activators under investigation to
lengthen our telomeres, along with telomerase-activating foods
like whey protein
(for IGF-1 and to boost cAMP),
apples and onions (for quercetin), and
(for HDAC inhibitors improving hTERT mRNA expression).
Some of these, such as astragalus root extract,
black cohosh, may be taken orally and
also rubbed in to the skin and scalp directly for best effect, rubbed into the gums and oral cavity,
or even applied in suppository form (astragalus extract in glycerin). Telomerase-activating drops
for the eyes (similar to carnosine
drops for the eyes) should be researched. Perhaps colostrum spray mist would be suitable,
although it must be refrigerated and verified as useful and safe.
Essential oil of rosemary
may have telomerase-activating effect in the sinuses via
nerve growth factor activation of
where we might also consider
using colostrum spray mist or astragalus extract nasal spays.
Hilariously, no mouse has ever died from telemere shortening, or suffered from a shortage of telomerase, however.
In mice the
dominant aging mechanism seems to be
via lipid peroxidation.
On the other hand, relatively cancer-resistant humans can die from telomere shortening;
as telomere length goes to zero once-mitotic bone marrow, human skin, liver, colon mucosa and
lymphocyte cells become senescent and chromosomally unstable.
Lymphocytes then suffer irreversible
cell cycle arrest.
Cell death follows, sometimes after a lengthy delay.
Progress on small molecules for
activation is also proceeding from research on plants.
Recently it has been shown that telomere shortening is aggravated in each cell division of
mitotic cells by high homocysteine levels,
so that a homocysteine shield
featuring TMG (trimethyglycine)
500 Mg - 720 mg, folic acid 400 Mcg,
vitamin B6 perhaps 25 Mg, and
vitamin B12 250 Mcg is effective at
preserving telomere length, in addition to preserving the
linings of the veins and arteries of the heart and the brain and fending
[See Dr. Phillip Lee Miller,
Life Extension Revolution.]
antioxidant treatment preventing
single-strand DNA breaks (repaired by
Cat's Claw extract (AC-11)
[Index] along with
and photochemical DNA damage) and
featuring a homocysteine protection formula
preventing more telomere loss per cell division tend to preserve telomere length, so that
some centenarians seem to have rather long telomeres.
Another possibility for lengthening telomeres, Alternative Lengthing of Telomeres
may be implemented with DNA nanocircles,
which seem to be generated in cancer cells from long telomeres
via recombination of long telomeres achieved by
homologous DNA repair.
Researchers picture the small telomeric circles forming through the resolution of an intratelomeric strand
invasion resembling a t-loop during
homology-directed repair (HDR) of telomeric DNA usually repressed by the
POT1 component of
the telomere nucleoprotein complex shelterin, also termed
Two recent papers demonstrated that human alternative lengthening of telomere (ALT) cells
have abundant t-circles similar to
(Corporate Video) DNA
nanocircles, pointing to their potential role
in promoting telomere replication in the absence of telomerase.
"Analysis of telomere restriction fragments
from human cells that rely on ALT for telomere maintenance revealed that they possess telomeric tracts that
are extremely heterogeneous in length, ranging from undetectable to abnormally long (Bryan et al., 1995),
which would also point towards a recombinational origin (see also Henson et al., 2002)."
Intense interest in the ALT pathway
exists partly because it is a stumbling block to the application of
telomerase inhibition as cancer therapy.
Without telomere extension via small molecule
or synthetic nanocircle ALT, however, it seems death is finally certain, as telomeres will be consumed eventually
T-lymphocytes in the immune system,
microglial cells in the brain associated with
clean-up operations, the skin, the lining of the internal organs,
and all other mitotic cells including the lining of
I might add that the consequence of cloning an animal from a mature specimen with
shorter-than-embryonic telomeres is that the clone dies young, as in the case of
Dolly the sheep, the first cloned mammal
to make headlines.
To successfully clone an adult requires pre-extension of telomeres prior
to nuclear transfer or cloning from embryonic tissues, otherwise, the cloned offspring may die ahead of time
In practice, cattle are typically cloned
from embryonic or fetal cells to avoid the short-telomere early death syndrome.
However, recently we have found out that cloning from
at the end of their lifespan
strong telomerase activation in a way that produces potentially very long-lived offspring in cattle
longer than ever!
It is also noteworthy that people having a longer telomere length (upper half of the population) live longer
than those in the lower half of the population, who have 1.86 times the mortality rate,
with 3.2 times the heart disease and 8.5 times the infectious disease of the long telomere upper half.
[Cawthon, et.al., 2003,
cited in The Biology of Aging
by Robert Arking, p.442.]
Breast Cancer, Cell Division, and Astragalus Root
The average age for breast cancer in males is 67,
and in women 62, afflicting 1 in 8 women over a lifetime.
During each menstrual cycle, estrogen
together with other ovarian hormones signals cells in the breast to divide and
Breast enlargement involving estrogens
and other ovarian hormones in males or females may result in
cell divisions sufficient to drive cells closer to the
when they become senescent
and genomically unstable
after telomeres become uncapped,
Thus anti-senescence drugs like the small-molecule
telomerase activators in
astragalus root extracts
or silymarin may be useful
in preventing breast cancer arising from
genomic instabilities in breast cells
that have divided many times and
eventually become senescent
ahead of other cells as a consequence of estrogen
and ovarian hormone signaling.
I note that telomerase activator black cohosh improves the stability of
breast tissue against cancer.
Busty aging mates might take
astragalus root extract to ward off
breast cancer before it is
observed, it seems.
We wonder if the term "astragalus"
itself did not signify originally
this set of patients that could benefit from the use of the herb.
"Recent studies show that more than 90% of all cancer
is caused by critical telomere shortening
due to critical telomere shortening,
for example, in 97% of premalignant
critical telomere shortening is observed
John Hopkins University 2005,
- Telomolecular Corporation SEC statement.
In the breast, progesterone also acts as a
chemical messenger that tells breast cells to divide, hence
and estrogen are applied in female transformations
which can become ultimately dangerous when finally cells approach
the Hayflick cell division limit.
Chromosome 17 has short telomeres
implicated in breast cancer.
Perhaps astragalus extract
in glycerin or in liposomes would be useful if applied
topically to the breast, in addition to astragalosides
or other small molecule
such as black cohosh
taken orally to apply telomerase activation in a cyclic manner
for improving stem cell and tissue
genomic stability against malignant transformations.
The Telomere Positioning Effect & Youthful Patterns of Gene Expression
Also see the telomere positioning
Long telomeres silence genes
close to the telomere, and
the telomere shrinks genes proximate to the telomere are more expressed.
Therefore to obtain youthful patterns of gene expression in mitotic, dividing cells, it is desirable to
maintain long telomeres
Telomeres are transcribed
to produce TERRA telomeric RNA,
starting from subtelomeric DNA and moving toward the end of the chromosome,
when telomeres become uncapped.
This reduces the telomere position effect inhibition of the transcription of genes near the telomere,
and may improve telomeric DNA repair, since
some DNA repair
is only done during transcription.
A good deal of work is now going on to identify
I note that the shortest telomere on human chromosome
Genes & Disease;
at 17p13.1 seems to be fairly close (within 7,512,445 bp out of 80 million bp) to the gene for the
tumor suppressor gene p53,
so that more tumor suppressor
should produced when this telomere gets
This way shorter telomeres would work together with the tumor-suppression system and
apparatus for stopping the cell cycle and to induce the senescent state
of the cell when telomeres shorten.
telomere position effect and tumor suppressor gene p53.
"The level of p53 protein increases in near
senescent cultures" of cells
and Benchimol, 1996].
It turns out that subtelomeric DNA contains genes
for zinc fingers
and olfactory receptors
that should be more actively transcribed when telomeres are short.
fingers in cellular senescence] may be transcribed in clusters that activate or deactivate promotors
for genes like fingers applied to a piano keyboard.
Their telomere position effect
activation in subtelomeric DNA
when telomeres become short may directly impact
to produce some of the observed aging effects.
Perhaps someday RNA interference
or RNAi, may be applied to oppose undesirable effects
caused by the expression of mRNA controlled by zinc fingers
in subtelomeric DNA.
Genes involved in the wrinkled skin,
graying hair, and
healing abilities may be
involved, as Geron has shown that these are
improved by lengthening telomeres
"Cells with sufficiently elongated telomeres energetically produce, in high levels,
elastin and many other
proteins important in tissue formation, cell repair, and antioxidation, that become scarce
as telomeres shorten."
[From Telomolecular Corp/case studies,
see also LifeExtension/Telomere
Control and Cellular Aging, the papers of
Dr. Woodring Wright
and Dr. Jerry Shay.]
"As the hTERT gene is only a few hundred kilobases from the end of
one could speculate that TPE (silencing) of
hTERT limits the maximal length of human telomeres during
[JW Shay & WE Wright, 2005.].
(In earlier 2002 work [Cong, Shay, and Wright, 2002],
the hTERT gene was stated to be
the most distal gene on 5p, but 2 million base pairs from the telomere, so that
the telomere position effect
would have little effect on hTERT.)
Evidently, the telomere position effect
should cause the body to automatically resist aging by more strongly activating telomerase as we age,
a tendency we must supplement to achieve a longer-than-usual lifespan.
Perhaps proteins mediating telomerase assembly such as
Hsp90 are less available as time goes on.
The location of the hTERT gene
(TERT) in other species
with different lifespans becomes an interesting question.
Species may be engineered in the future with extra distal hTERT genes on other chromosomes to extend their
Perhaps the telomere position effect is also involved in
and the withering of
the thymus gland, which is involved in
and connected to the immunological theory of aging
of thymus gland function
is sometimes observed when a patient
is treated with 10 grams of arginine per day to produce
Nitric Oxide, a telomerase-activating
On the other hand, as we shall see according to the
Membrane Hypothesis of Aging
to obtain youthful patterns of gene expression may also require modifying the cell membrane permeabilities
(modified by cross-linking of membrane-imbedded proteins) to ionic species such as potassium that modify
the dehydration, colloidal properties, and density of cellular material,
factors which should apply to both mitotic
and non-mitotic cells.
In dense, dehydrated cells enzyme reactions are inhibited, so that
and protein synthesis
are retarded, tending to produce more ceroid wastes and
lipofuscin that choke the cell and increase free
radical production, eventually leading to
inflammation and processes involving
that are ultimately poisonous to the cell.
of chromatin restores its youthful low DNA strand separation temperature, so that restoring
patterns of gene expression
may be assisted by undoing
or other protein properties in chromatin that inhibit DNA strand separation
[Books] and gene
and gene expression]. See Maria A. Blasco on the telomere position effect in
Maria A. Blasco (2007), The
epigenetic regulation of mammalian telomeres, Nature, April 2007.
Telomere Capping Proteins
[Index/Telomere Loop Control Proteins,
Index/Mammalian Telomere Protein Factors,
Extension by Telomerase,
Components in Cell Signaling,
The telomere t-loop
may be opened to make it accessible to telomerase by phosphorylating
tankyrase 1 with
insulin using insulin-boosters
such as Gymnema Sylvestre,
Fenugreek seeds, or
This may be amplified
somewhat in the presence of dextrose.
Tankyrase 1 levels may also be boosted with
(nicotinamide, a form of
uses NAD as a substrate in
may be useful when applying tankyrase 1
to enable telomerase access to the end points of otherwise closed
Note that nicotinamide
elevates NAD+ (NADH,
Nicotinamide Adenine Dinucleotide) levels,
but should be taken early in the morning on telomerase activation days to build up NADH levels,
since it has inhibiting effect on
PARP enzymes such as
tankyrase 1 that I prefer to phosphorylate via evening doses
such as Fenugreek extract.
Tankyrase 1 opens the telomere t-loop
via telomeric PARP activity involving poly(ADP-ribo)sylation with a NAD+ substrate
that strips the telomere of the telomere binding protein
Once the loop is open, the
the telomere to extend it.
Uncapped telomeres [Links,
Books] terminate in a
100-300 nucleotides in length bound to the
telomere loop along its length by
POT1 and at its starting point by
Dr. Yie Liu's lab at the National
Laboratory of Molecular Gerontology
has illustrated that the proteins
and MSH2 [Index,
a DNA mismatch repair protein,
play a role in
telomere capping function
in which a telomere t-loop
configuration many thousands of base pairs long is believed to protect chromosome ends from being
recognized as broken DNA.
As I note in section 10 on DNA Repair,
the maximum life span of 13 species
is directly correlated to the activity of
Disruption of the telomere loop
and subsequent exposure of
the 3' overhang
uncapped state of telomeres.
The ability to
from being recognized as damaged DNA is crucial to maintaining normal cellular function,
as uncapped telomeres directly associate with many DNA damage response proteins
Telomere integrity depends on the ability to maintain telomere length and/or the ability
to mask telomeres from being recognized as damaged DNA via telomere capping
have been observed to provide an enhancement of the associated
telomere protection biology
but are often avoided due to certain
In certain experiments
(0.1 mol/L) and mevastatin
(1.0 mol/L) both led to a more than 3-fold increase in the expression of the telomere capping protein
(telomere repeat-binding factor, Index/Telosome),
as shown by immunoblotting.
(Zocor) is even more effective in promoting TRF2.
Today atorvastatin is available by prescription,
but mevastatin is not used due to
multiple side effects.
Uncapping of telomeres
may be detected by the loss of TRF2,
and the effect of the statin drugs
has been produced by application of exogenous
which protects human telomeres from end-to-end fusions. TRF2 binds to double-stranded telomeric DNA.
PARP1 interacts with TRF2 and is
in repairing damaged telomeres.
"As the length of telomeres in leukocytes shortened the risk of coronary heart disease
increased... the risk was substantially attenuated by
Since statins have been shown to increase the production of a protein-telomere capping protein that prevents
telomeres from shortening it is a potential hypothesis that statins bring about some benefits by this mechanism.
This is very early research but it implies that statins could well have the ability to slow certain aging
processes." - ErinPharm Gazette, Jan. 2007.
I note that my friends have warned me not to meddle with
due to side effects [article,
such as lowering the body's level of CoQ10.
Furthermore, work by Woodring E. Wright and
Jerry W. Shay showed that
TRF2 overexpression can degrade telomeres.
Effective treatment to
levels of telomere-capping associated proteins
is, however, definitely on the horizon.
Overexpression of TRF2, which stabilizes
the telomeric loop,
telomere length threshold for senescence
towards shorter telomeres (Karlsreder et al. 2002),
so that TRF2 overexpression has been observed to delay senescence.
Furthermore, TRF2 overexpression improves
double-strand DNA repair (Mao et al. 2007).
Recent research shows that TRF2 is a factor in telomere length regulation, and in preventing
telomere fusion between chromosomes
(Smogorzewska et al. 2000,
van Steensel et al. 1998,
Celli and de Lange 2005).
By 2011, however, there were more indications that
TRF2 overexpression may be dangerous
Lenhard Rudolf, 2008, p.283).
upregulated in some
human carcinomas, along with
(Oh et al. 2005,
Matsutani et al. 2001,
Munoz et al. 2005,
Nakanishi et al. 2003,
Bellon et al. 2006).
TRF2 overexpressing mice show increases in
chromosomal instability and
(Munoz et al. 2005,
Blanco et al. 2007) and also
rapid and dramatic loss of telomere sequences where skin is exposed to light
(Munoz et al. 2005).
Also note that expression of telomerase protects
the telomere cap, so that small-molecule
telomerase activators such as
or cycloastragenol defend telomere capping.
Telomere uncapping induces the state of
cellular growth arrest termed
mortality state M1.
[Senescence and Immortalization:
The Role of Telomeres and Telomerase, Jerry W. Shay and
Woodring E. Wright, from
If the genes
maintaining the senescence checkpoint M1 are blocked, say by a
oncogene, the cells continue to divide
and proceed to the crisis state M2,
typically followed by cellular apoptosis.
Both M1 and M2 can be prevented by introducing telomerase.
[Telomere Regulation in Eucaryotic Cells, from
Instability and Aging: Basic Science and Clinical Implications By Fuki M. Hisama,
Sherman M. Weissman, George M. Martin,
Informa Health Care, 2003.]
The telomere t-loop closes closer to non-canonical sequences
differing from GGTTAG repeat
as cell divisions proceed and the telomere shortens.
The telomeres are reduced by 50-200 bp per division until the telomere tail fails to close into a
(bound with a small
when TRF2 cannot find a proper binding site due to the non-canonical nature of the repeat there,
for instance and typically GGTGAG.
See also Carol W. Greider's
Do D-Loop T-Loop Minireview, IMGENEX on
Jerry Shay's turn-of-the-century article in
on telomeric t-loops and d-loops,
Dr. Connie Nugent's lab, and
Joao Pedro de Magalhaes on telomeres and telomerase.
Recent work shows that
protein POT1 is involved in
the single-stranded overhang at the tip end of
the telomere to close the t-loop and
is required for
telomere length regulation and
chromosomal end protection
[Yang, et.al, 2007].
Humans have one POT gene,
mice have two.
Telomeres are bound to a set of
numerous interacting proteins
including 6 shelterin subunits
POT1, which insure proper maintenance of telomeres
It has been described as the telomere binding complex
or more recently shelterin
Note that telomeric protein complexes are also being investigated by
Dr. Zhou Songyang
and Dr. Zhou Songyang].
Jesse Fender and other investigators including
Woodring E. Wright and
Jerry W. Shay have been exploring the
interaction of the protein Ku and telomerase.
which is involved in
telomeres to the nuclear membrane,
is also important in
assisting telomerase function,
lack of Ku leading
to telomere-telomere fusions
and cellular dysfunction.
factors in telomere lengthening
and corresponding therapeutic possibilities, see
Blackburn: Telomerase Does Not Act on Capped Telomeres
Incidentally, according to a model propounded by E. Blackburn in
and Signaling at the Telomere (2001),
telomerase does not act
on capped telomeres, but
only on telomeres that
have become short enough to become uncapped.
Telomere enlongation via telomerase then provides telomeres long enough to cap themselves. This seems to
be supported by TA-65 testing in 2010.
Calvin B. Harley,
William H. Andrews,
Laura A. Briggs, and
Joseph M. Raffaele (2010),
A Natural Product Telomerase Activator
As Part of a Health Maintenance Program,
September 7, 2010.
However, telomerase activation can easily result in telomere growth > 55 bp/year.
Retinal pigment epithelial cells transfected with hTERT plasmids show telomeres
lengthening at 115-255 bp per population doubling, and we find that BJ foreskin fibroblasts similarly
transfected show a telomere length increase of 340-370 bp per population doubling, the same order
of magnitude (400-460 bp/year telomere growth, corresponding to roughly 1 cell division per year)
originally observed at TA Sciences
in 2007 by Bob Waskom and Greta Blackburn.
Andrea G. Bodnar,
Shawn E. Holt,
Gregg B. Morin,
Calvin B. Harley,
Jerry W. Shay,
Serge Lichtsteiner, and
Woodring E. Wright (1998),
of Life-Span by Introduction of Telomerase into Normal Human Cells,
vol. 279, 16 January 1998. Normally, human fibroblasts can divide for about 49 population doublings.
expressing the catalytic component of human telomerase (hTERT)
have been followed for 250–400 population doublings.
As expected, telomerase activity declined in long term culture of stable transfectants.
Surprisingly, however, clones with average telomere lengths several kilobases shorter
than those of senescent parental cells continued to proliferate.
Although the longest telomeres shortened, the size of the shortest telomeres was maintained.
Cells with subsenescent telomere lengths proliferated for an additional 20 doublings
after inhibiting telomerase activity with a dominant-negative hTERT mutant.
These results indicate that, under conditions of limiting telomerase activity,
may recruit telomerase to act on the shortest telomeres..."
Michel M. Ouellette,
Shawn E. Holt,
Heidi S. Liss,
Jerry W. Shay and
Woodring E. Wright (2000),
Subsenescent Telomere Lengths in Fibroblasts
Immortalized by Limiting Amounts of Telomerase,
The Journal of Biological Chemistry,
April 7, 2000, vol. 275, 10072-10076.
See also telomerase artist's conceptions
[telomerase & proteins database,
Note that telomerase inhibitor
article] acts through stabilization of
formed by single-stranded telomeric DNA found at
the end of the t-loop structure,
so that telomerase does not act on
the closed telomere loop.
I get the impression that the percentage of senescent cells in a tissue determines how old it looks,
so that the macroscale human phenotype can be rejuvenated by merely making telomeres long enough to
close the t-loops, as far as mitotic cells are concerned.
However, recovery from replicative senescence
can be frustrated by high levels of P16INK4A,
which is down-regulated by the Id-1 helix-loop-helix transcription factor,
itself upregulated by Nerve Growth Factor (NGF),
upregulated by acetyl L-carnitine,
rosemary tea, and other nutraceuticals.
P16INK4A can also be reduced by
exercise, carrots, and retinol.
It is certainly true that maintaining long telomeres supports closed-loop telomere structure
that frustrates the arrival of replicative senescence,
especially in the absence of oxidative stress leading to
The best way to to keep telomere loops lengthy is probably to use
telomerase activators, which have closure possibilities
for telomere t-loops to help cells rejuvenate and avoid
However, as cells accumlate more and more P16INK4A,
recovery from the state of replicative senescence
becomes more difficult.
Eventually, perhaps a healthy adult stem cell
with vigorously long telomeres can fill a spot where a senescent cell has become apoptotic in such cases.
In time, rejuvenated cells secrete collagen,
elastin, and endogenous
antioxidants in a way that restores a youthful look, although
lipofuscin deposits may have to be removed with
CoQ10, alpha lipoic acid,
or other drugs to completely finish the job. Note that
collagen and elastin
can both be restored in the extracellular matrix
colostrum skin creams or by
telomerase-inhibiting TGF-beta skin creams.
There may be milage in unlocking closed
telomeric loops for telomerase activation,
then resealing them, to achieve even longer telomeres for a still more
youthful patterns of gene expression
associated with longer telomeres.
Can telomeres be made as long as desired by the continued application of telomerase activation?
Or does everything stop when the t-loop closes and the cell assumes the immortal phenotype?
It is certain that continued application of telomerase activation can supply hundreds of
additional cell divisions, and that immortal cells continue to divide in a
way that maintains fairly constant or increasing telomere length.
Atorvastatin (Lipitor), Simvastatin (Zocor), TRF2, T-Loop Closure, and Rejuvenation
should be life-extending via its activation of telomere binding protein
at the M1 state with 4000 remaining base pairs
might yield about 4000/50 = 80 further cell divisions and lifetimes on the order of 220 years.
The additional cell division capacity should
strengthen the immune system.
The closure of telomere t-loops
by TRF2 should remove
It could be that Lipitor
(atorvastatin) is more rapidly
rejuvenating than anything else we have at just
$65/month for the prescription drug.
A cheaper version, lovastatin, is available,
and Zocor (simvastatin) is more powerful.
pravastatin, which should produce similar results.
Extra CoQ10 or
ubiquinol should be taken, along with a
shield and antioxidants, including mitochodrially effective antioxidants like
alpha lipoic acid and protective drugs like
Perhaps the most effective program for antiaging will begin with
atorvastatin and end with
cycles. This analysis, however, needs experimental verification and requires
more study, including side-effects analysis.
Some studies maintain
damages telomeres, however, so TRF2 overexpression is unlikely to become a preferred life extension strategy.
Telomere Enlongation with Replication Protein A and hEST1A
Other control proteins associated with telomere maintenance include
Replication Protein A and
Replication Protein A
on human Chromosome 17
YeastGenome/Telomere Maintenance)], which
is present in all eucaryotic cells, has been observed to activate telomerase in yeast.
See Vera Schramke,
Maria Pia Longhese,
Eric Gilson &
RPA regulates telomerase
action by providing Est1p access to chromosome ends,
Nature Genetics 36, 46 - 54 (2004)
Published online: 21 December 2003.
has been conserved in evolution and is present in humans as
"Overproduction of hEST1A
cooperated with hTERT to lengthen telomeres." - See
Harrington L., (2003),
Functional conservation of the telomerase protein Est1p in humans,
Current Biology 2003 Apr 15;13(8):698-704.
hEST1A recruits telomerase
holoenzyme by binding to hTERT.
Links/SMG6] is identical to
(See Lingner Joachim, Senior scientist,
and chromosome end replication,
ISREC.) According to Gene Cards,
overexpression of SMG6 (in humans hEST1A) results in telomere uncapping.
Therefore perhaps hSMG6 or hEST1A
can be used to extend t-loop capped telomeres, opening them so that they can be extended by telomerase.
Telomerase does not act on telomeres unless the telomere is uncapped, as we saw in the last paragraph.
Thus large telomere t-loops corresponding to very youthful cells may be prepared by using
with telomerase, probably by stopping SMG6
towards the end of a treatment period to reseal telomere t-loops.
Such cells may have superior staying power, lasting for more cell divisions before uncapping,
generating a DNA damage signal, and entering the state of
"TA-65 alone will reduce the percentage
of cells with short telomeres ( < 4 kbp) with minimal effects on mean telomere length..."
- Calvin B. Harley, et.al, 2010.
Perhaps other telomerase activators will turn out to gradually reduce the percentage of
short telomeres ( < 4kb) without modifying average telomere length.
To improve on average telomere length much with telomerase activation may require activation of
Replication Protein A,
so that t-loops can open for telomerase access.
The Telomere DNA Helicases and Co-Factor Magnesium
The WRNp helicase protein
(associated with Werner Syndrome)
that unwinds DNA
turns out to be complexed on the telomere
with other t-loop proteins
function of WRNp requires Mg2++ as a cofactor,
so that telomere
maintenance may be improved by taking
Cells lacking WRN helicase activity show
telomere lagging strand synthesis
[Crabbe, et al, 2004].
Life Extension Magazine has noted that
magnesium levels common in the population lead to high rates of hypertension and sudden death.
This is perhaps partially due to
endothelial senescence linked to WRNp helicase malfunction from
Mg2++ cofactor shortfall and associated with
high monocyte adhesion
and consequent formation of
The magnesium ion is also an essential
DNA polymerase whenever
is synthesized without a reverse transciptase like telomerase.
This was discovered by Arthur Kornberg in the 1960s.
(Magnesium is also a
Note that magnesium supplementation
may be used to decrease high blood pressure in non-senescent cases, lowering the risk of
The Time Machine Effect
Cosmic Humor and Pursuit of the Aquarian Soul:
Moonwalking Scattered Backwards in Time
Keratinocytes of the epidermis
live about as long as the period of the moon by
1000 stem cell divisions over a lifetime, and coincidentally the synced-up moon projects
the mythos of shedding one's "skin".
The book of Proclus on the moon-god's spine is thus a "telomere"
at the end of the line on the moon, a haunting "God Particle"
Hayflick and Moorhead
revolution of 1961 may be mirrored at the summit of NGC 2264
as our hero makes his way to eternal glory as Orion amid his amazing Winter Crescent
flying saucer of stars, shining on
smile of Andromeda in Perseus, the Pleiades, and Aries above like the first light of the Sun on the bottom
of the New Moon.
Note that TA Sciences, using
astragalus extract TA-41 in 2005
on a 3-month-on, 3-month-off cycle for a year
measured 460 bp/year telomere growth in blood granulocytes,
while aging normally subtracts about 50 bp/year, so that with TA-41 the telomere biotimer moved backwards
in time about 9 times as fast as it went forwards when "aging", after normal aging base pair losses were
That is, we observed a rejuvenation rate of about 9 years per year, or 0.75 years/month.
Adults may experience 1 to 2 cell divisions per year, since approximately 50 cell divisions
take place from the embryonic stage of development in mitotically active human somatic tissues excepting
stem cells and germ cells.
Persistence is required in de-aging using telomerase activators,
as the process takes place gradually, somewhat like aging itself.
However, instead of merely slowing the aging process,
telomere remodeling with cyclic telomerase activation
is expected to carry its practitioners all the way back to the young adult state, if telomeres measure
longer year by year.
Bear in mind that antioxidants and
DNA repair acceleration,
cell membrane treatments, and
vitamin C should help ensure a successful outcome with a
minimum population of senescent cells to threaten
cancer or susceptibility to
diseases of old age.
Note that there are 10 bp/turn in Watson-Crick
B-DNA, with 33.2 Angstrom units per turn,
or 3.32 nm/turn, so that in one year when 50 bp are lost, we typically lose 16.6 nm of telomere length.
On the other hand, using TA-41
according to the Patton Protocol, we should see 9 x 16.6 nm = 149.4 nm of
telomere growth per year, amounting to 1494/33.2 = 45 turns of the Watson-Crick
DNA double helix at each end of every
about 76.67 telomeric GGTTAG satellite DNA repeats/year.
149.4 nm is in the EUV extreme ulraviolet range of wavelengths,
and more than 2 years of growth are required for the telomere growth length
to approach the wavelength of violet light, 380-450 nm.
I note TA Sciences
TA-41 user Bob Waskom, aged 69,
observed a rejuvenation rate of B = By = -8 years per year,
based on 400 bp of telomere growth per year, which amounts a to a Bm =
- 0.667 years/month rejuvenation scenario.
See TA Sciences testamonials.
More recent studies of TA-65
(Calvin B. Harley, et. al., 2011)
do not show such dramatic lengthening of telomeres,
but rather closing of the shortest telomere t-loop to prevent cellular senescence.
It will be useful to measure the rejuvenation rate constant B in years/year for
telomerase activators in general,
in parallel, in the presence of
and while on specific diets targeted to improve by reducing the intake or expression of
For instance, it will be useful to test B
in connection with schemes for improving the rejuvenation rate such
as adding the chromatin-expanding histone deacetylase inhibitor
sodium butyrate to improve transcription speeds.
Moreover, sodium butyrate greatly enhances levels
of the wound-healing telomerase activator
exercise by upregulating the transcription factor
Also, it is expected that testing B
Test B!) will give better results when a
low polyphenol diet is used while
applying telomerase activators, because
high polyphenol diets tend to generate
Now that I have identified
endogenous telomerase activators and
15 exercise-induced telomerase activators together
with supplements to promote their expression, we have
still more measurements to do to define optimal therapy.
By February 2013, we have estimated that Product B
is associated with a maximum rejuvenation rate of
B = -8.218 years/year.
Of all animals, only Leach's Storm Petrel [Wikipedia,
has telomeres which lengthen with age.
The animal lives from 20 to 35 years and is black with a white mark
on the tail resembling a load of salt.
I get the impression that it dies of
mitochondrial aging preventable in humans by using
with alpha lipoic acid and/or pyrroloquinoline quinone (PQQ).
On the other hand, the
is a fish with high telomerase levels in all its tissues.
I might add that in humans
improving hTERT transcription in the nucleus
DNA protection in mitochondria, a surprising result.
hTERT transcription also improves DNA repair
in the nucleus generally, although it is most famous for managing DNA repair and regrowth of telomeres.
Tables for the rejuvenation times and costs may be deduced by linear analysis.
Let the final model age tFM be given by tFM = t0 + BΔt, where
t0 is the Initial Actual Chronological Age, and B is the aging rate. Let
B = -8 or -9 years per year aging rate for rejuvenation, so that
tFM = the model age at the end of rejuvenation. In the table below we choose tFM = 25.
Solving for the rejuvenation time Δt, we find Δt = (tFM - t0)/B years.
Then the Actual Age at Final Model Age tFM is t = t0 + Δt,
and we have Cost = $76.00(12)(Δt).
Note that B=1 corresponds to normal aging, B > 1 represents accelerated aging,
0 < B < 1 represents decelerated aging, and B < 0 corresponds to rejuvenation.
Rejuvenation Times to Model Age 25 from Initial Age in Years with Cost in Dollars
|Initial Actual Chronological Age t0||100||90||80||70||60||50||40||30|
|Δt-5 Rejuvenation time, B = -5 yrs/yr ||15.0.||13.0.||11.0||9.0||7.0||5.0||3.0||1.0|
|Δt-8 Rejuvenation time, B = -8 yrs/yr||9.375||8.125||6.875||5.685||4.375||3.125||1.875||0.625|
|Δt-9 Rejuvenation time, B = -9 yrs/yr ||8.333||7.222||6.111||5.000||3.888||2.777||1.666||0.556|
|t = t0 + Δt-5 = |
Actual Age-5 at Final Model Age 25
| 115.0 || 103.0 || 91.0 || 79.0 || 67.0 || 55.0 || 43.0 || 31.0 |
|t = t0 + Δt-8 = |
Actual Age-8 at Final Model Age 25
| 109.375 || 98.125 || 86.875 || 75.685 || 64.375 || 53.125 || 41.875 || 30.625 |
|t = t0 + Δt-9 = |
Actual Age-9 at Final Model Age 25
| 108.333 || 97.272 || 86.111 || 75.0 || 63.888 || 52.777 || 41.666 || 30.556 |
|Cost-5 = $76.00(12)Δt-5||13,680 || 11,856 || 10,032 || 8,208 || 6,384 || 4,560 || 2,736|| 912|
|Cost-8 = $76.00(12)Δt-8||8,550 || 7,410 || 6,270 || 5,185 || 3,990 || 2,850 || 1,710|| 570|
|Cost-9 = $76.00(12)Δt-9||7,597 || 6,586 || 5,573 || 4,560 || 3,546|| 2,533|| 1,519|| 507|
Left: Jeanne Calment, age 25. Right: Jeanne Calment, age 60.
see Einstein Greying,
Astragalus Extract Program at 2-Year Point,
"...and bending down beside the glowing bars, murmer a little sadly how love fled,
and paced the mountains overhead,
and hid his face amid a cloud of stars."
- When You Are Old, by William Butler Yeats.
Rejuvenation Times from 60 to Final Model Ages tFM in Years with Cost in Dollars
|Final Model Age tFM||55||50||45||40||35||30||25||20|
|Δt-5 Rejuvenation time, B = -5 yrs/yr ||1.0||2.0||3.0||4.0||5.0||6.0||7.0||8.0|
|Δt-8 Rejuvenation time, B = -8 yrs/yr||0.625||1.25||1.875||2.5||3.125||3.75||4.375||5.0|
|Δt-9 Rejuvenation time, B = -9 yrs/yr ||0.556||1.111||1.667||2.222||2.778||3.333||3.889||4.444|
|t = t0 + Δt-5 = |
Actual Age-5 at Final Model Age
| 61.0|| 62.0 || 63.0 || 64.0 || 65.0 || 66.0 || 67.0 || 68.0 |
|t = t0 + Δt-8 = |
Actual Age-8 at Final Model Age
| 60.625 || 61.25 || 61.875 || 62.5 || 63.125 || 63.75 || 64.375 || 65.0 |
|t = t0 + Δt-9 = |
Actual Age-9 at Final Model Age
| 60.556 || 61.111 || 61.667 || 62.222 || 62.778 || 63.333 || 63.889 || 64.44 |
|Cost-5 = $76.00(12)Δt-5|| 912 || 1,824 || 2,736 || 3,648 || 4,560|| 5,472|| 6,384|| 7,296|
|Cost-8 = $76.00(12)Δt-8|| 570 || 1,140 || 1,710 || 2,280 || 2,850|| 3,420|| 3,990|| 4,560|
|Cost-9 = $76.00(12)Δt-9|| 507 || 1,013 || 1,520 || 2,027 || 2,534|| 3,040|| 3,547|| 4,053|
The $76.00/month cost was derived from summing the cost of 3 bottles of
Solaray Astragalus Extract
(3 x $8.50),
2 bottles of
Herb Pharm Astagalus Extract
(2 x $11.59), 1 bottle of
Solaray Astragalus Root
(1 x $7.25),
1/2 bottle per month of Chitosan
(0.5 x $10.00),
and 1/2 bottle per month of
NOW FOODS IGF-1 Liposomal Spray
(0.5 x $30.00).
This is the basic cost of the
used during the 1st 15 days
of the two-part month-long treatment cycle.
Sometimes I also rub 4 droppers of
Astragalus Extract in glycerin
into my scalp every day during the first 15 days.
Recently in 2012
I have been taking 25 grams/day of
Now astragalus root
powder for the first 15 days plus
GAIA astragalus root extract (Green Label, 3 bottles for 15 days), mostly rubbed into the scalp.
In addition, during the first part of the cycle
I take 3000 mg/day of Vitamin C
5-10 grams of arginine
per day, a
4 x 400 mg Acetyl L-Carnitine
with 4 x 200 mg
Alpha Lipoic Acid
2 grams of CoQ10
4 x Super B-vitamin
and 4 x 25 mg DHEA
4 x 500 mg of NOW
5 x 500 mg of NOW
in 1/6 cup of water for skin cream,
2 grams of ginko biloba
3 grams of fenugreek seed
4 x 500 mg of black cohosh
and daily exercise
During the 2nd 15-day part of the cycle featuring
I drop the telomerase activators
and take telomerase inhibitors
including green tea
(3 x 60 mg ECGC
mixed with black pepper in water,
4 x 150 mg green tea extract
4 x 1000 mg omega-3 fish oil
, 4 x 200 mg
red wine complex,
and 1 x 300 mcg melatonin
, cacao bean products
, together with the
same basic supplements used in the first part of the cycle,
3000 mg/day of Vitamin C
5 grams of arginine
per day, a
4 x 400 mg Acetyl L-Carnitine
with 4 x 200 mg
Alpha Lipoic Acid
4 x Super B-vitamin
4 x 400 IU Vitamin D3
4 x 25 mg DHEA
Perhaps I spend $130/month (2007) to $230/month (2013) on supplements, altogether,
economizing my obtaining many from discount stores.
I also take 2 tablespoons of chocolate
powder stirred in water,
then heavily iced for antioxidant effect and for extra
, several times a day.
I believe from toxicology studies
that this is safe.
supplements help deflect cancer,
and Vitamin D3
is an anticancer
Another alternative is Herbal Remedies
1.25 mg astragalosides
per 250 mg cap,
via Nature's Way
( Standardized 0.5% Astragalosides ), 60 VCapsules per bottle, incuding
, dried extract 250mg
(root) 0.5% astragalosides
Astragalus (root) 250mg. Four capsules yield 5 mg astragalosides
plus 1 gram of astragalus membranaceus root
which improves bioavailability
Obviously, we need more measurements of actual results obtained with off-the-shelf
( < 33 grams/day),
and similar preparations such as TA Sciences TA-65
to verify tables like this table for rejuvenation
to effective telomeric chromosomal age 25.
The pioneering research in the matter was done by
, and other firms including
They are still trying to develop faster, more effective
that get results quicker.
Measurements of telomere growth
in base pairs may be done through
for less than $700 per pass
as suggested by
via TA Sciences
if one is enrolled in their program,
via Spectracell Laboratory
via Life Length
, or via kits and
software described in our labs section
See the rejuvenation tables for my self-experiment
in anti-aging therapy
, and my video
Therapy with Astragalosides
Note that decelerated aging with 0 < B < 1 corresponds to the usual program of anti-aging
medicine without telomerase activation, a footdragging delay in the aging process.
For instance, vitamin C
or homocysteine blockers
decelerate the aging process, slowing the removal of telomere base pairs from chromosome tip ends.
On the other hand, the aging regimes with B < 0 correspond to rejuvenation with telomerase activation.
Plotting the final model age
+ BΔt as a function of t = t0
yields charts of aging as controlled by stepwise modification of the aging rate B(t).
Let Δt be the treatment time for a desired age transformation from a
certain Chronological Age to a younger Desired Model Age. Then
(Chronological Age - Desired Model Age)/9 < Δt < (Chronological Age - Desired Model Age)/8,
where the ages are given in
years and 8 and 9 years per year are the limiting absolute B-factor magnitudes for the age transformation rates.
Deaging Plot: See the Model Age spread at the 58th, 60th,
Based on TA Sciences 8 years per year to 9 years per year
rejuvenation rate results
obtained for TA-65 at 5 mg/day using the Patton Protocol. B = - 5.2 years per year was initially estimated
for astragalus extract, and B = - 5.18684 shows that this was close enough for the data quality available.
All model ages in the above drawing correspond to May Day,
as treatment started on May 1, 2007, whereas my birthday is on May 13, 1949.
After 2.5 years at about 60.5 when bone dry I seemed to be 45 to myself, whereas with oiled hair
I seemed to restaurant help to be 40 at 60. This led to the B = - 5.2 years per year estimate
for the astragalus extract rejuvenation rate. By 2014, however, I note that with astragalus NK cells
rejuvenate much faster than other cell types. With exercise and
deaging can be more uniform, as all human cells have about the same density of
GHR, the HGH receptor,
in their cell membranes.
Deaging Plot Corresponding to Astragalus Extract Observations after about 2.5 years.
(From 58 to Model Age 45 at 60.5 in 2.5 years, projected to Model Age 25 at 64 in 6.33 years.)
The observed rejuvenation rate is computed at B = -5.18684 years per year, approximately B = -5.2,
corresponding to the top line on the chart.
At the present time, I may seem to be 45, so that at the B = -5.18684 rate I would achieve a
25 year old appearance
at about 64.33 years of age in 2013.
The dotted lines are for TA-65 at -8 and -9 years per year.
Basic cost is about $55/month, including
or $660/year, yielding $4,188 for 6.34 years to 25 at 64.
Extra money might be spent on
alpha lipoic acid
with acetyl L-carnitine,
for the off part of the cycle, and
Anti-Aging Flight Plan (reminiscent of My World Line by George Gamow). 64.3 = August 31, 2013.
Δt = 6.3 years.
Here Model_Age = Bt + Starting_Age, B=1 for normal aging, B > 1 for accelerated aging,
B=0 for no aging, and B < 0 for rejuvenation, or negative aging. Here initially B= 1 for
normal aging, then
B= - 5.2 years/year during the deaging phase, followed by B=0 zero aging
until Madame Jean Louise Calment's 122 years, 164 days
record is exceeded at 2071.9634 AD,
which should be right at the Winter Solstice when shadows are shortest about Dec 22, 2071.
About this time the S.Monocerotis skywalker
above the Cone Nebula crosses the meridian.
Note the "Cross of Years" formed by the 110 and 122.45 barriers.
There are thousands
of Americans over 100, of whom hardly any will get though the 110 year barrier without medicine.
See the associated response of the cloud cover to the inclusion of these charts including the sign of the
cross in Visionary Sky 46.5.
Note that the B = 0 line in the flight plan can be implemented by using astragalus extract one month out of six,
which would lead to a barely discernable jaggle on the B=0 line between 25 and 25 + 5/12 = 25.42 with a five-month
rise time and a one-month fall time, since (1/12)(-5.2) = -0.43.
Phase I: For 0 < t < 57.967123 = t0, B = 1, Model Age = Bt.
Ended May 1, 2007.|
Phase II: For 57.967123 < t < 64.3, B = - 5.2 years/yr,
Model_Age = B(delta_t) + t0 = (B/12)N + 57.967123,
N = 1, 2, 3,...,76 months,
using off-the-shelf astragalus extracts.
Started May 1, 2007. See Quick Summary for details.
Phase III: For 64.3 < t < infinity, B = 0, Model Age = 25. Starts at
August 31, 2013.
Note that the Flight Plan chart may be similar if the observed approximate B = -5 years per year rejuvenation rate
is due to a reduction in the number of short telomere ( < 4 kbp) cells, rather
than to an increase in average telomere length.
That this may be true is indicated
by recent research on TA-65
(Calvin B. Harley, et.al, 2010
Average telomere length growth may require
Replication Protein A
telomere t-loops when the length is greater than 4 kbp, or
phosphorylation of tankyrase 1
seeds to open telomere loops by
stripping telomere loop closure protein TRF1
On the other hand, Retinal pigment epithelial cells transfected with hTERT plasmids show telomeres
lengthening at 115-255 bp per population doubling, and we find that BJ foreskin fibroblasts similarly
transfected show a telomere length increase of 340-370 bp per population doubling, the same order
of magnitude (400-460 bp/year telomere growth, corresponding to roughly 1 cell division per year)
originally observed at TA Sciences in 2007
by Bob Waskom and Greta Blackburn.
- From Andrea G. Bodnar
Shawn E. Holt
Gregg B. Morin
Calvin B. Harley
Jerry W. Shay
Woodring E. Wright
of Life-Span by Introduction of Telomerase into Normal Human Cells
vol. 279, 16 January 1998.
Estimated Rejuvenation Times = T to Target Model Age t1
from Starting Age t0 for B= -5.2 years/year
with Chronological Age After Treatment = t0 + T.
Treatment Time T(t0, t1) = (t0 - t1)/5.2 years, T(ray, target) = Treatment Time
Chronological Age after Treatment = t0 + T = t0 + [(t0 - t1)/5.2] years = Final Age.
Treatment Time (yr), Age after Treatment | Treatment Time (yr), Age after Treatment (yr)
Start Target Duration Target Final Age | Start Target Duration Target Final Age
t0 t1 T t1 t0 + T | t0 t1 T t1 t0 + T
T(110, 25) = 16.346, Age(25) = 126.346; T(105, 25) = 15.385, Age(25) = 120.385,
T(100, 25) = 14.423, Age(25) = 114.423; T(95, 25) = 13.462, Age(25) = 108.462,
T(90, 25) = 12.500, Age(25) = 102.500; T(85, 25) = 11.538, Age(25) = 96.538,
T(80, 25) = 10.577, Age(25) = 90.577; T(75, 25) = 9.615, Age(25) = 84.615,
T(70, 25) = 8.654, Age(25) = 78.654; T(65, 25) = 7.692, Age(25) = 72.692,
T(60, 25) = 6.731, Age(25) = 66.731; T(55, 25) = 5.769, Age(25) = 60.769,
T(50, 25) = 4.808, Age(25) = 54.808; T(45, 25) = 3.846, Age(25) = 48.846,
T(40, 25) = 2.885, Age(25) = 42.885; T(35, 25) = 1.923, Age(25) = 36.923,
T(110, 35) = 14.423, Age(35) = 124.423; T(105, 35) = 13.462, Age(35) = 118.462,
T(100, 35) = 12.500, Age(35) = 112.500; T(95, 35) = 11.538, Age(35) = 106.538,
T(90, 35) = 10.577, Age(35) = 100.577; T(85, 35) = 9.615, Age(35) = 94.615,
T(80, 35) = 8.654, Age(35) = 88.654; T(75, 35) = 7.692, Age(35) = 82.692,
T(70, 35) = 6.731, Age(35) = 76.731; T(65, 35) = 5.769, Age(35) = 70.769,
T(60, 35) = 4.808, Age(35) = 64.808; T(55, 35) = 3.805, Age(35) = 58.805,
T(50, 35) = 2.885, Age(35) = 52.885; T(45, 35) = 1.923, Age(35) = 46.923,
T(40, 35) = 0.962, Age(35) = 40.962.
I think perhaps these effects can be reliably mobilized for $130 x 12= $1560/year,
so for each column of treatment time T,
Approximate Cost = $130 x 12 x T = $1560 x T = $9,828.00 after 6.3 years
Thus we may now have anti-aging medicine and associated technique to survive
hundreds of years, although the medicine acts very slowly, like aging itself,
to make us young again. Each month the expense of it satisfies
Cost/month > $130, perhaps $130 < Cost/month < $150,
depending on how thoroughly we treat every
variable. Of course, still more can be spent by very careful experimenters, especially if
they cautiously employ blood testing to measure their age variables and telomere lengths.
By the 22nd century, the merit of telomerase activation in connection
with anti-aging treatment will be obvious, but for decades to come until decisive
demonstrations are readily available from many experimenters,
time and expense may veil the solution.
A more effective, safe enough, fast-acting anti-aging
telomerase activation technique could save many lives merely by subtracting
the elements of expense, long suffering, and mystery.
rapid extracellular matrix
So far, one email correspondent
has suggested that 9.5 years per year rejuvenation results have been observed with schemes
like ours, and up to 460 bp/year of telomere growth has been observed with the cyclic Patton Protocol
at TA Sciences
the astragalus extract
absolute rejuvenation rates of up to 9 years per year.
(Calvin B. Harley, et.al, 2011
suggest that TA-65
merely closes the shortest
telomere in a cell to prevent replicative senescence
Fast rejuvenation rates may be possible with adequate safety.
Very high speeds have been reported
using nucleoside-modified hTERT mRNA.
We need to measure the telomere growth rates
for the safer of the 185 various
telomerase activators we have listed
at varying concentrations in order to gain more penetrating insight.
Also, mixtures of the telomerase activators
combined for parallel activation pathways may
yield superior results in the future.
Better methods for improving the
telomerase activators used may improve the cost/benefit ratio.
I note that dogs and rats can tolerate higher doses of
than we presently use.
See Shu-Yi Yua, Hong-Tao OuYanga, Ju-Yun Yanga, Xiao-Liang Huanga, Ting Yanga, Ju-Ping Duana,
Jun-Ping Chenga, Yu-Xiang Chen, Yong-Jia Yanga and Pang Qiong (2007),
toxicity studies of Radix Astragali extract in rats and dogs
Journal of Ethnopharmacology
Volume 110, Issue 2, 21 March 2007, Pages 352-355.
"In conclusion, our studies clearly demonstrated that
Radix Astragali Extract
was safe without any distinct toxicity and side effects, the safety dosage range is
5.7–39.9 g/kg for rats and 2.85–19.95 g/kg for beagle dogs,
which is equal to 70 or 35 times of that of human (0.57 g/kg, say, average BW 70 kg), respectively.
See also Astragalus Extract toxicity
Thus to rejuvenate more rapidly, it may be useful to take more
in divided doses throughout the day.
In addition, we may use
(perhaps 2 grams/dose)
to improve the bioavailability
Better measurements of astragaloside bioavailability improvements with varying doses of
would be helpful,
and perhaps Internet searches can help us locate more existing data.
Perhaps we can use a chromatin-expanding
from oysters or
or the HDAC inhibitor
transcription of hTERT mRNA
, although this is now only solidly established for
We may use a diet emphasizing low-polyphenol foods
during periods in
which astragalus extract
is taken, in order
to steer clear of telomerase inhibitors
generated by high-polyphenol foods
On the other hand,
short duration of the effects such telomerase inhibitors
may make this unnecessary.
Otherwise, we may take medicines or growth factors such as IGF-1
, tending to import hTERT protein from the
cytosol into the nucleus.
To this we can add Fenugreek extract
with < 3 grams
NAD+ substrate synthesis
to open telomere loops
phosphorylating tankyrase 1
closure protein TRF1
making telomere tips accessible to the telomerase holoenzyme,
and simultaneously stimulate hTERT mRNA transcription with
HIF-1 transcription factor
promoted by Fenugreek
Note that Ginkgo Biloba
also stimulates production of
Furthermore, we may use antioxidants
hTERT inside the nucleus
Parallel path activation
of hTERT transcription
may also help accelerate
hTERT mRNA transcription without causing unacceptable transformations due to gene mutation, gene translocation, or
gene amplification that can lead to cancer
Recovery from Cellular Senescence
I note that recovery from advanced cellular senescence
may be more difficult than merely defending ourselves against the arrival of
in the first place.
Patients should probably be encouraged to start early, at the fist sign of a grey hair, to conserve their sex appeal
and fortify them against
, and other
diseases of old age
Our insight into what may be achieved with small molecule
] and supporting therapies will change
as more and more very aged patients attempt rejuvenation.
Ultimately, it may be useful or necessary to take steps such as
inserting extra genes for antisense mRNA to oppose further accumulation of factors
supporting halt of the cell cycle like P16INK4A
Zinc Finger Nuclease
technology, for instance.
However, until we know whether or how fast these are consumed by ubiquitination, we will probably rely on
activating hTERT mRNA transcription or inserting the hTERT gene.
An extra gene
might be inserted at the 25th year, administered like an
oral liposomal spray or if need be like a flu shot.
However, we are approaching final victory over
death from degenerative diseases associated with aging (and otherwise) as
controlling factors from molecular biology come more clearly into focus and our
medical bioscience techniques evolve to meet the challenges.
Perhaps medicines, diet, and exercise alone will
usally be adequate to achieve physical immortality without modifying
the human genome
Therapy for recovering from cellular senescence
[Restoring Senescent Cells
| Refs 9
| Refs 10
allow us to restore youthful patterns of gene expression prior to
preventing replicative senescence
we also fortify the cell against
to protect telomeres against
[Fossel, (1998), JAMA
noted that telomerase can rejuvenate senescent cells.
points to rejuvenated skin experiments:
Walter D. Funk,
Dawne N. Shelton,
Calvin B. Harley
Garrett D. Pagon,
Warren K. Hoeffler (2000),
Expression Restores Dermal Integrity to in Vitro-Aged Fibroblasts in a Reconstituted Skin Model
Experimental Cell Research
"Telomerase activity not only confers replicative immortality to skin fibroblasts,
but can also prevent or
the loss of biological function seen in senescent cell populations.
However, after cells become senescent, telomerase activators are sometimes
incapable of rescuing the cell, and cells experience
growth arrest due to cell membrane communications failure from high
in which the cells are not responsive to
and they also experience the change to the larger senescent cellular phenotype, in which
they resist external stimuli and apoptosis, a survivalist response of the aging cell.
This seems to be partly due to a pinch-off of cell membrane caveolae with rising
and their subsequent internalization as detached vesicles, stopping signaling through open
flask-shaped caveolae on the cell membrane in which key signaling receptors are located.
behaves as a gatekeeper molecule for terminating signaling functions associated with
endocytosis, shutting down certain membrane communications associated with sensitivity to growth factors
such as EGF
as caveolin-1 levels rise, producing growth arrest.
expression, which acts to stop the cell cycle,
mediating cell cycle arrest through a p53/p21Waf1
status decreases p53
enabling recovery from the senescent state and restart
of the cell cycle by telomerase-activating
Senescent cells may be rejuvenated
FOXO transcription factors
away from the nucleus
This makes senescent cells once again responsive to
human growth factor
cures the sluggish hyporeactivity of senescent cells, and restores the youthful cellular phenotype.
After lowering caveolin-1 the cell cycle can be restarted with DNA synthesis
and lowered levels of cell cycle inhibitors p53 and p21 by stimulation with EGF
both components of colostrum
SJ Ryu, JS Park, IS Jang, JS Ahn, KT Kim, and SC Park, 2003
"Targeted down-regulation of caveolin-1 is sufficient to drive cell transformation...
Note that folic acid
, vitamin B9
stimulates the PI3K/AKT pathway
sequestering FOXO factors
away from the nucleus.
Thus a large dose of folic acid (1 to 5 mg,
along with a bodybuilding
workout set up to elevate
and supplements such as colostrum
might return a man's senescent cells rapidly to a rejuvenated state.
Exercise-intensive treatment is an experiment for patients without
Skin Creams for Rejuvenating Senescent Dermal Fibroblasts
A rejuvenating skin cream might be prepared with telomerase-activating
mixed with folic acid
(to inhibit caveolin-1
) to implement restoration of
senescent dermal fibroblasts. It is useful to mix it in green tea
Note that colostrum
, which upregulates survivin
to restore senescent cells.
This may be combined with treatment to simultaneously elevate cyclic AMP
(with glycyrrhiza extract
which also downregulates caveolin-1
alpha lipoic acid
may be added to
supply required cofactors including HSP90
to support telomerase assembly.
Treatment with retinol
[which converts into
might be added to this to inhibit P16INK4A
makes recovery from the senescent state
should be applied during the two-week telomerase inhibiting part of the
cycle of telomerase activation followed by telomerase inhibition
Small molecule caveolin-1 inhibitors
may be the most effective solution, because the senescent state of the cell
causes it to somewhat resist insulin stimulation and other stimulation from large molecules
such as IGF-1
interacting with membrane receptors.
Still, downregulating caveolin-1
has at least preventative value in resisting the onset
(which influences every cell in the body) can be used to
thus downregulate caveolin-1
prior to the onset of senescence.
may be produced in the liver
) stemming from, say,
elevates IGF-1 levels
as does orally ingested colostrum
restores levels of IGF-1
aging neural tissue. The growth-promoting effect of
on brain cells is potentiated by
alpha lipoic acid
Note that creatine monohydrate
also stimulates the production of IGF-1
, which activates
the PI3K/Akt pathway
from the nucleus to down-regulate
) expression and
prevent cellular senescence
However, senescent cell membrane caveolae
are required to communicate with IGF-1, but don't exist when caveolin-1 is too highly expressed,
so that IGF-1 is more useful for preventing senescence than for reversing it.
to inhibit FOXO
transcription factors via the IGF1/PI3K/Akt pathway,
thus inhibiting caveolin-1 transcription
to prevent senescence.
Note that the "PI3K–Akt pathway is a major
upstream signaling module leading to
phosphorylation of FOXO factors,
their exclusion from the nucleus
," and subsequent ubiquitination by proteasomes. -
from (Dominique A Glauser and Werner Schlegel (2007)
Treatment should be applied
on a cyclic basis with telomerase inhibitors
to guard against cancer.
Other telomerase activators
may be used on a cyclic basis with telomerase inhibitors
telomeres while striving (with colostrum
and caveolin-1 inhibitors
to overcome the sluggish hyporeactivity of
the senescent cell membrane associated with overexpression of
FOXO transcription factor
overexpression in senescence
and to regain youthful cell morphology while restarting the cell cycle and rejuvenating the senescent cell.
Note that caveolin-1
is up-regulated by low density lipoprotein free
so that high free cholesterol levels could lead to cellular senescence.
This may be controlled with pantethine
), which lowers LDL cholesterol.
den Heuvel, Schulze, and Burgering, 2005
See also Bist A., Fielding P. E., Fielding C. J. (1997),
sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to
low density lipoprotein free cholesterol
Proc. Natl. Acad. Sci. U.S.A.
This article defines
the caveolin-1 promoter
Note that when senescent cells are rejuvenated by downregulation of caveolin-1,
the restored cell not only recovers its youthful phenotype
and sensitivity to growth factors, but also lengthens its telomeres
quite substantially to a halfway point allowing typically 25 further cell divisions.
Further improvements in telomere length and replicative capacity can be obtained by applying suitable
Unfortunately, sometimes related
simple schemes can be upset by low levels of vitamin K2
resulting in aortic stenosis
which forbids regular hard exercise
Caveolin-1 is downregulated by c-Myc
It turns out that c-Myc
downregulates caveolin-1 expression
and that c-Myc
or more dangerously by estradiol
(Tsai L.-C., Hung M.W., et al, (1997)
is upregulated 1.55 times by
30 minutes of exercise
Note that estradiol
increases stroke incidence
and should be kept within 20 to 30 pg/ml in blood samples.
Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, Park SC (2003),
Senescent phenotype can be reversed by reduction of caveolin status
Journal of Biological Chemistry
, 2003 Jul 25;278(30):27789-95,
and also Park SC, Cho KA, Jang IS, Kim KT, Ryu SJ.(2004),
of the senescent cells: replace or restore?
Full Text pdf
Annals of the New York Academy of Sciences
, 2004 Jun;1019:309-16.
Also see A. Pieter J. van den Heuvel, Almut Schulze, and Boudewijn M. T. Burgering (2005),
control of caveolin-1 expression by FOXO transcription factors
. 2005 February 1; 385(Pt 3): 795–802.
See also Dominique A Glauser and Werner Schlegel (2007),
The emerging role of FOXO transcription factors in pancreatic b cells
Journal of Endocrinology
(2007) 193, 195–207.
See also Brain P. Ceresa and Sandra L. Schmid (2000),
Regulation of signal transduction by endocytosis
Opinion in Cell Biology
2000, 12:204–210, which explains
the role of caveolae in signal transduction
Survivin and Cellular Senescence Recovery
Note that cellular senescence
may also be recovered from by upregulating
is upregulated by VEGF
), both of which are contained in
which coincidentally contains insulin
and improves expression of
when taken orally.
Note that VEGF
is upregulated 1.36 times by 30 minutes
"Senescence is a reversible process
controlled by survivin:
by overexpressing survivin in senescent cells,
we are able to decrease senescent markers and increase cell proliferation.
(Caterina A. M. La Porta, Stefano Zapperi, James P. Sethna (2012),
Cells in Growing Tumors: Population Dynamics and Cancer Stem Cells
January 2012 Issue of PLoS
Survivin should be upregulated
on a cycled basis with telomerase inhibitors
to guard against cancer.
N-[2-(Cyclohexy-Loxyl)-4-Nitrophenyl]-Methanesulfonamide (NS-398) for Recovering from Senescence
inhibitor inhibits senescence in one case, and decreases
of caveolin-1 in the cell membranes of senescent cells
recovery from cellular senescence
cell is stimulated with telomerase-activating growth factors
such as EGF
The use of selective Cox-2
has been patented
for this application by S.C.Park
and J.A.Han (2008-2012).
This substance is believed to transcriptionally
inhibit caveolin-1 expression
still in question, although the
selective COX-2 inhibitors
lack the side effects of conventional NSAIDS.
See Restoring Senescent Cells
Therapy for Recovering from Cellular Senescence
molecule caveolin-1 inhibitors
Forskolin down-regulates levels of caveolin-1 via cyclic AMP to Rejuvenate Senescent Cells
is the active ingredient in
which activates the enzyme
which converts ATP
cyclic adenosine monoposphate
ATP for forskolin
to convert to
also acts to stimulate adenyl cyclase to produce
see epinephrine supplements
, such as
, which inhibits
the enzyme that metabolizes cyclic AMP
Two amino acids phenylalanine
sold as supplements, are converted into dopamine
, in turn, is converted into
, and then
, which produces more cAMP from ATP.
(after Ray Sahelian on Neurotransmitters
(a second messenger) acts by activating
protein kinase A
(cAMP-dependent protein kinase),
which can phosphorylate specific proteins that bind to promoter regions of DNA,
causing increased expression of specific genes,
or phosphorylate proteins that may act directly on a cell's ion channels,
or phosphorylate proteins that may become activated or inhibited enzymes.
"It is known that forskolin via
cAMP can down-regulate mRNA levels
in a dose-dependent manner.
- after A. Pieter J. van den Heuvel, Almut Schulze, and Boudewijn M. T. Burgering (2005),
Direct control of caveolin-1 expression by FOXO transcription factors
. 2005 February 1; 385(Pt 3): 795–802.
The "senescent phenotype, however,
can be reversed
by reducing the expression levels of
suggesting that either the senescent state is a reversible phenotype
or that these cells are actually quiescent, rather than senescent.
See upregulating cAMP
supplements for upregulating cAMP
is known to
increase cyclic AMP in the liver
promotes cyclic AMP
inhibits cAMP phosphodiesterase
which degrades cAMP
"The effect of one bout of intense swimming caused significant increases in the cyclic AMP
content of fast-twitch white skeletal muscle, liver, and heart.
Further investigation of the exercise-induced increase in myocardial cyclic AMP indicates
that the nucleotide content remained elevated long after (24 h)
termination of exercise. This increase in cyclic AMP was time dependent, with the level
increasing gradually throughout the work bout.
The increase in cardiac cyclic AMP seemed to be independent of work intensity,
provided that work time was of sufficient duration (greater than or equal to 30 min).
- After Palmer WK (1988),
Effect of exercise on cardiac cyclic AMP
Med Sci Sports Exerc
Note that 2 ligands of the EGF receptor,
are elevated by exercise
as is PDGF
, so that exercise
restoring senescent cell communications through the cell membrane,
then restores senescent cells with longer telomeres via
EGF family growth factors
(See also EGF
other telomerase activators from exercise
Negative effects of high cAMP
may include high body heat associated
with thermogenesis and weight loss, estrogenic side-effects from stimulation of aromatase activity,
and depression if dopamine
levels are not kept up.
therapy may be combined with
cyclic telomerase activation to induce telomere growth
and rejuvenate senescent cells.
See also Yamamoto M., Okumura S., Oka N., Schwencke C., Ishikawa Y. (1999),
of caveolin expression by cAMP signal
Note, however, that in some
types cAMP induces cell cycle arrest
den Heuvel, Schulze, and Burgering, 2005
For instance, forskolin
inhibits colon cancer cell growth and survival
may also suppress leukemia progression
(LEF, Nov 15, 2005
Experimental siRNA restoration of Senescent Cells
These experiments down-regulated caveolin-1 using
, targeting 5 regions of
caveolin-1 mRNA, using 21-nucleotide siRNAs obtained from
Caveolin-1 was also downregulated with
(TTTGCCCCCAGACAT) transfected with Lipofectamine
After lowering caveolin-1 the cell cycle can be restarted with DNA synthesis
and lowered levels of p53 and p21 by stimulation with EGF
(a component of colostrum
SJ Ryu, JS Park, IS Jang, JS Ahn, KT Kim, and SC Park, 2003
"Targeted down-regulation of caveolin-1 is sufficient to drive cell transformation...
Small interfering RNA oligonucleotides directed against caveolin-1 have
included siRNA described in
den Heuvel, Schulze, and Burgering, 2005
Arginylglycylaspartic acid for Senescent Cell Morphology Restoration
treatment with the tripeptide Arg-Gly-Asp (RGD
has transformed senescent human fibroblasts back to their "young-like phenotype"
morphology in 5 days. H. Choi, J.H. Rhim, S.J. Lee, K.A. Cho, S.C. Park (2012),
Induction of morphological restoration of senescent
Sens Foundation, 2012.
SIRT1 Deacetylates and activates Ku when Young Extracellular Matrix rejuvenates Senescent Cells
Young extracellular matrix can
rejuvenate senescent fibroblasts
During the process, SIRT1
influences DNA repair and
deacetylates and activates the chromosomal fusion protection and telomere protection
composed of Ku70
like caloric restriction
seem quite promising in connection with
recovery from the senescent state of the cell
of senescent human diploid fibroblasts by modulation of the extracellular matrix
, 2011 Feb;10(1):148-57.
See the related patent by Sang Chul Park, Kyung A Cho, Moon Kyung Ha and Hae Ri Choi, (2011 & 2009),
Control Composition Containing Extracellular Matrix Components
Tocotrienol-rich fraction can reverse senescence in human diploid fibroblasts
expression of collagenase from senescent fibroblasts, protecting the extracellular matrix,
and has favorable impact on gene expression in both senescent and normal fibroblasts, tending
to oppose aging.
tocotrienols alpha, beta, gamma, and delta
from rice bran, palm oil
, oat, or barley,
tends to produce telomerase activity in senescent fibroblasts, lengthens telomeres, restores fibroblast
morphology, and restarts the cell cycle.
fraction supplements with alpha-tocopherol from palm oil
fraction skin cream with alpha-tocopherol from palm oil
See Suzana Makpol, Azalina Zainuddin, Kien Hui Chua, Yasmin Anum Mohd Yusof, and Wan Zurinah Wan Ngah (2012),
modulation of senescence-associated gene expression prevents cellular aging in human diploid fibroblasts
Clinics (Sao Paulo)
2012 February; 67(2): 135–143, and also
Makpol S, Durani LW, Chua KH, Mohd Yusof YA, Ngah WZ (2011),
fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts
Journal of Biomedicine and Biotechnology
2011 Mar 30.
Gamma tocotrienol has increased animal lifetimes by up to 18%.
Astragalus Extract to the Scalp Darkens Hair in About 12 Months
Jim Green - Left: Jan 24, 2010, Age: 60.7. Right: Jan 18, 2011, Age: 61.68,
Math Model Age: 38.71.
After about a year of astragalosides to the scalp,
hair color improved as telomere cell DNA was
quiescent hair follicle stem cells
in the hair follicle bulge region,
initiating cycles of
proliferation and hair synthesis.
Human dermal fibroblasts
can divide about 50 times in culture, as
Hayflick & Moorhead discovered in 1961.
But with telomerase enzyme enough,
the cells become immortal, and have divided hundreds of times in culture.
I took Terraternal
Astragaloside IV 100 mg/day during the
activation part of the cycle during the last few months.
extract in glycerin
at 1 mg astragalosides per 30 drops was used for the scalp.
HGH to promote
hTERT mRNA transcription was boosted by 1200 mg/day
Alpha GPC plus
I decided it would be best to include direct topical application,
as Artandi Labs
at Stanford University reported positive hair restoration
results on experimental animals with direct application of astragalosides to hairy skin.
"Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition
(the resting phase of the
hair follicle cycle) to
anagen (the active phase),
robust hair growth.
TERT overexpression promotes this developmental transition by causing proliferation of quiescent,
stem cells in the
hair follicle bulge region.
after Sarin KY, Cheung P, Gilison D, Lee E, Tennen RI, Wang E, Artandi MK, Oro AE, Artandi SE (2005),
telomerase induction causes proliferation of hair follicle stem cells
, 2005 Aug 18;436(7053):1048-52.
Most recently (August 2011) I have tried using an ethanolic extract of
as a telomerase activator
on my scalp, which is relatively inexpensive.
solution was also under test for treating hair greying.
Nothing worked well except application of green flag
GAIA Herbs astragalus extract
in alcohol or glycerin to the scalp,
which takes about a year to modify hair color from the roots out. Further Remarks