Nov 17, 2009 Added a table: Estimated Rejuvenation Times = T to Target Model Age t1
from Starting Age t0 for a B= -5.2 years/year rejuvenation rate,
with Chronological Age After Treatment = t0 + T. The table was appended to
Age Transformation and some other files.
This one helps aging witnesses look up or compute the estimated time to rejuvenate from a given starting age
to some target age using off-the-shelf astragalus extracts. For the cloud cover response to this news, see
VisionarySky46/Space Embrace (46.6).
Otherwise, some new links are being added to better furnish the index. Nov 13, 2009 Computed a Calvin B. Harley rejuvenation constant of about B = - 5.2 years per year
for astragalus extract, based on casual observations, and removed systematic errors from my table of associated
computed values in Age Transformation. B = -8 to -9 years per year
for TA-65 according to more careful measurements of telomere length done by
TA Sciences, where
at first Model_Age = Bt, until Model_Age = B'Δt + t0 at some breakpoint t0 downstream. Here
B < 0 for rejuvenation, B = 0 for zero aging, B > 1 for accelerated aging, and B = 1 for normal aging. Some day
we may find at B(t0) is a function of t0 for very old people, probably slower at older ages. In general,
we may modify B(t) by introducing medicines, exercise, and diet therapies at switch points t0, t1, t2,....
Of course, charts of measured telomere lengths and other variables relevant to rejuvenation as a function of time
in various tissues such as blood granulocytes and
leukocytes would convey a superior physical and realistic representation of the process useful
for feedback in treatment.
I think we are about to enter a domain in which longer life could be insured by a Gort-style suit of armour
to be worn in an underground shelter during tornadoes, perhaps a padded leather suit lined with kevlar and
selectively reinforced with metallic or durable hard plastic components. This would
protect against flying debris. Such a garment might also help reduce automobiles to bumpem cars
like we rode in amusement parks as children. Components of the suit might be carried in the trunk of
a car, or be packed away in a closet. I think of Gort from
The Day the Earth Stood Still (1951). Someday
soon perhaps most human deaths will be due to storms, accidents, collisions, and disasters, since heart attack, stroke, cancer, and
death from old age may be decisively beaten.
I am also reminded of the movie Forbidden Planet (1956),
in which the id-monster of Dr. Edward Morbius continually renews its molecular structure. Don't miss Jim Green as Cal Mecham in This Island Earth (1955).
Phase I: For 0 < t < 57.967123 = t0, B = 1, Model Age = Bt. 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. Phase III: For 64.3 < t < infinity, B = 0, Model Age = 25. October 22-23, 2009 Developed an index entry on Telomere t-loop control
proteins (the shelterin complex, or the telosome) with
associated structures and molecules. Also found another
telomerase activator(67)
that is fairly available,
Terminalia chebula
[Links,
Images,
Papers]
(Combretaceae) [Links],
Haritaki [Links,
Images,
Papers],
to be precise, the ethanolic extract from the fruit of Terminalia chebula (Combretaceae), or Haritaki,
also termed chebulic myrobalan
[Links,
Images,
Papers,].
See MinKyun Na, KiHwan Bae, Sam Sik Kang, Byung Sun Min, Jae Kuk Yoo,
Yuko Kamiryo, Yu-ichiro Senoo, Seiichi Yokoo, Nobuhiko Miwa, (2004),
Cytoprotective effect on
oxidative stress and inhibitory effect on cellular aging of Terminalia chebula fruit,
Phytotherapy Research, Volume 18 Issue 9, Pages 737 - 741, Published Online: 11 Oct 2004.
This one is a popular panacea in Aryurvedic Medicine and is available from specialty pharmacies.
See also
[Links/Terminalia chebula fruit extract,
Images/Terminalia chebula fruit extract].
Also known as Haritaki [Links].
See Haritaki Extract [Images,
Links].
Chebuloside II, a pentacyclic triterpene glucoside also described as a triterpenoid glycoside,
[Links/Chebuloside II,
Article including the molecular structure of chebuloside II (p.113)]
is used as a marker for the quality of the ethanolic extract.
Note: "Haritaki" is described as
"alterative" by
PharmacyEscrow.com. Neurobiology of Aging 29(9), 1,404-1,411 - Mice that took
creatine monohydrate lived 10% longer than
mice that did not take creatine monohydrate. - recently quoted in Muscle & Fitness.
Bender, A, et al. Creatine Improves Health and Survival of Mice.
Neurobiology of Aging, 2008; 29(9): 1404-1411, quoted
in Simply Shredded. "In brains of Cr-treated mice, there was a trend towards a reduction of reactive oxygen species
and significantly lower accumulation of the "aging pigment" lipofuscin.
Expression profiling showed an upregulation of genes implicated in neuronal growth,
neuroprotection, and learning. These data show that Cr improves health and longevity in mice.
Cr may be a promising food supplement to promote healthy human aging.
" - from Bender A, et al., 2008. October 13, 2009 - The Day After Columbus Day.
Discovered the role of zinc in maintaining long telomeres and the associated mysteries, which are
now recounted in the Index entry for Z. Most men get about 14 mg/day,
women 9 mg, while the optimal dosage is perhaps 45 mg Zinc/day, which is sometimes used to
improve the size of a load of semen, which is rich in both zinc and cells with long telomeres. Note that "oysters" are
the food richest in zinc.
On the other hand, 80 mg/day of Zinc increases
hospital admissions in older men, and large doses of several hundred milligrams or more can expose the role of zinc as a neurotoxin and/or
unacceptably lower copper levels. October 5-6, 2009
The first edition of the new 2009 release will be on-line today, featuring 5 huge files (4 of them index files) changed
into 10 shorter ones, with some search code optimization, expansions, a better index,
more search options, and other improvements. The new system is more expandable and should
fit into systems that require files < 256 Kb in length, which was getting to be a stumbling block.
It may be a week or two before any new internal bugs have been corrected. Off-line code
review and optimization may continue for a week or two yet. Oct.6: code-optimized index ab,cd,eh,il. September 29, 2009
The longevity system is being overhauled off-line with redivision into smaller files and
recompilation to reset internal pointers. At the same time, some sections are being expanded or rewritten.
Expect a new release in mid-October, 2009. September 15, 2009
Added index section on sesame oil and sesame seeds, while investigating the effect of toasting on toasted sesame oil,
which is said by some to convert oleic acid into relatively harmful trans fats.
I thought perhaps some AGEs might be present in brown toasted sesame oil. Earlier,
I added Biocarta Pathway information
on telomerase activation via IGF-1 and Epidermal Growth Factor receptors in cell walls. September 4, 2009
Deduced today that beta ecdysterone
(20-hydroxyecdysone) may be a
telomerase activator like
ecdysone, because the molecules closely resemble each other.
Beta Ecdysterone is found in spinach and is sold in concentrated from as an anabolic steroid to improve protein
synthesis in bodybuilding applications. Beta ecdysterone is now telomerase activator candidate
(54), whereas ecdysone is (16). September 2, 2009
Improved the IGF-1 index entry. IGF-1 is a
telomerase activator
that has anti-aging effect.
NOW IGF-1 Liposomal Spray
(NOW,
about $25.00 at Whole Foods) and
NOW IGF-1 Lozenges for Anti-Aging
[NOW]
are available. Side effects have not been a problem when the products are used as specified by the manufacturer
[A1], and anti-aging effects are reported.
See IGF-1 from deer antler [Links].
Since IGF-1 increases the risk of prostate cancer by about 4x, a Prostate Specific Antigen (PSA) test is
recommended in connection with the use of this class of product
[LifeExtension/IGF-1 and Aging]. August 31, 2009
According to Erusalimsky, 2009,
Vascular endothelial senescence: from mechanisms
to pathophysiology, nitric oxide (NO) seems not to upregulate telomerase in endothelial cells after all,
but to get its benefits by upregulating SIRT1. See also Hong Y, Quintero M, Frakich NM, Trivier E, Erusalimsky JD, 2007,
Evidence
against the involvement of nitric oxide in the modulation of telomerase activity or replicative capacity
of human endothelial cells, Exp Gerontol 42: 904–910, 2007. August 27, 2009 RevGenetics now markets the
telomerase activator
cycloastragenol as Astral Fruit-C,
with 5 mg/dose of cycloastragenol and added chitosan to improve bioavailability,
now for under $70/month. Cycloastragenol
[Links]
is the common alglycone of the astragalosides. August 15, 2009
Peanuts are a good source of
gamma tocopherol, but sesame seed oil also contains sesamin,
a sesame lignan. August 13-14, 2009
Updated longevity3.html (10): Daily grape juice consumption reduces DNA damage
and plasma free radical levels.
[Mutation Research, 2003.]
[Links/DNA age damage reduction,
Links/reducing DNA damage]. See
Tocotrienols Could Reduce DNA Damage That Leads To Cancer.
Folic acid
[Links/Folic Acid & DNA repair,
Links/Folic Acid,
Folic acid supplements could boost DNA repair, says study (1.2 mg folic acid/day used)] and
Cat's Claw Extract
[AC-11] are also useful as
DNA repair supplements. "
DNA Repair Adjuvants (article):DNA repair promoters or
adjuvants can be divided into three categories:
(1) minerals (e.g. selenium and
selenomethionine),
(2) carboxyl alkyl esters i.e.
AC-11 (formerly known as
C-MED-100 derived from Cat’s Claw [Uncaria tomentosa]) and
(3) Dimericine, a DNA repair enzyme,
(T4 endonuclease V) encased in
liposomes."
Also see Human DNA Repair Genes.
Ubiquinol CoQ10 [Links/ubiquinol,
LifeExtension/ubiquinol,
Biosynergy Ubiquinol,
Kaneka QH Ubiquinol]
shields nuclear and mitochondrial DNA against free radicals, regenerates vitamins C and E, and is used to eliminate
lipofuscin, eliminating old age spots and lipofuscin from heart muscle. It helps mitochondria process fatty acids,
improving neurological energy levels and vitality in general. The anti-aging effect of ubiquinol on
experimental rodents and their pelts can be very noticible indeed
[LifeExtension/ubiquinol]
making ubiquinol a credible mainstay in treatment of mitochondrial factors in aging. August 12, 2009
Improved index entry for Telomerase Regulation.
Added WISTAR Instiute to the lifexlabs.html list of
Academic Labs and Programs.
Novel Telomerase Activators [Links]
have been proposed in Israel at
the WISTAR Institute based on the design
of molecules to regulate telomerase. See WISTAR professor
Emmanuel Skordalakes PhD
[Links,
Papers,
Images].
August 11, 2009
Located some new telomerase activators for T-cells and filed them in lifexnotes3.html
under Telomerase Activators as entries
(50), (51), and (52):
(50) Anti-CD3 monoclonal antibody (mAb)
induces telomerase activity in human peripheral T cells.
(51) Ca ionophore,
a stimulant that bypasses T-cell receptor (TCR) signaling, induces telomerase activity in human peripheral T-cells.
(52) Phorbol 12, 13-dibutyrate (PDB)
[special hazard: tumor promoter], another stimulant that bypasses T-cell receptor (TCR) signaling,
inducing telomerase activity
in human peripheral T-cells. August 10, 2009
Added improvements to Trichostatin A and IGF-1 entries in the index.
Added Richard M. Cawthon's Feb 2009 paper in Nucleic Acids on new technique for measuring telomere lengths
to lifexlabs.html. August 8, 2009
Ran out of Tripod memory, froze site at August 6, 2009 on Tripod. The longevity.html site continues to develop
at AngelCities and S5. Today I discovered
Juvetea, which contains ginseng and other components that make it a telomerase activator.
It was entered in the index and under telomerase activators in lifexnotes3b.html. July 21, 2009
Added index material added on arthritis,
a condition that becomes aggravated in old age
(roughly mirroring cardiovascular disease,
which is related to the progressive senescence of the vascular endothelial cells)
as chondrocytes become senescent and joint injuries heal less readily. July 14, 2009
Added a section on cancer prevention via telomerase activation to produce long-telomere cells more resistant to cancer,
especially carcinomas, in agetransformation.html, and updated my photo collection
of dry and wet age transformation photos. July 12, 2009
Considered higher doses of astragalus extract and alternatives in
agetransformation.html, and embellished Reprogramming Height
in the same file. July 11, 2009
Upgraded Mortality Charts
with more links to relevant charts. July 8-9, 2009
Upper Bound and lower bound estimates with relevant ratios:
New calculations estimated 27.44 mg of astragaloside IV
per 6 x 200 mg Solaray Astragalus Root Extract pills, using figures from hairy roots of astragalus membranaceus
prepared in bioreactors. This upper bound figure must be quite high due to the choice of
hair roots raised in reactors. Earlier calculations based on ethanolic extracts from the
big plant roots (radix astragali) of astragalus membranaceus suggested 5 mg of astragalosides per 6 Solaray
capsules. July 2, 2009
Added more material and reference links to my somewhat speculative remarks on
Reprogramming Height at the conclusion of
Age Transformation. June 25, 2009 - June 26, 2009
The S index entries for Senescence and Senescence Pathway
were updated to include more material on details of
cell cycle arrest at M1, p53 tumor suppressor and p16/Rb cell cyle involvement in the
halting of the cell cycle, possible frustration of the M1 cell cycle halt at about
4000 base pairs of telomere length leading to the still shorter-telomere crisis
state M2, and cancer. References were included for telomerase activators such as
astragalus extracts,
TA-65,
cycloastragenol
(Medicass), Astragaloside IV
[RevGenetics,
Terraternal,
Links]
for escaping from the M1 senescent state by lengthening telomeres to close the telomere t-loop to remove the
double-strand DNA damage signal leading to the halting of the cell cycle. June 15, 2009
Nicotinamide:
[Links/extends replicative
lifespan of human cells,
Links/nicotinamide,
Links/nicotinamide supplements,
Amazon,
Life Extension/nicotinamide].
With regard to human fibroblast telomere shortening experiments, "
Continuous treatment with nicotinamide, which led to lower ROS generation
and changes in mitochondrial function, has been reported to extend lifespan
(a remarkable 1.6-fold increase) and decelerate telomere shortening (Kang, et al., 2006)", from
Telomeres
and Telomerase in Ageing, Disease, and Cancer: Molecular Mechanisms of Adult Stem Cell Aging,
ed. K. Lenhard Rudolph. See Kang HT, Lee HI, Hwang ES (2006),
Nicotinamide extends replicative lifespan of Human Cells, Aging Cell, 5(5): 423-36. June 13, 2009
Added material on
the IGF-1 pathway and
IGF-1 telomerase activation for anti-aging to the
index under IGF-1, including NOW IGF-1 Lozenges
for Anti-Aging and NOW IGF-1 Lipospray for sublingual administration.
See also the IGF-1 receptor [Wikipedia,
Links].
IGF-1 is a risk factor in prostate cancer and breast cancer
(Wikipedia).
IGF-1 can induce hypertrophy of skeletal muscle and other target tissues. May 16-19, 2009
Refined the newly added
Astragalus Extract Program 2 Year Point,
added the movies SixtyFortyTwo, YouTube,
51 seconds,
Astragalus Extract
Treatments, Daily Motion, 2 minutes, 32 seconds, and
HairClippings,
Daily Motion, 1 minute, 05 seconds. May 8, 2009
Added Einstein Greying
(with Physiological Factors of Aging). May 2, 2009
Upgraded agetransformation.html
and other files. March 16-26, 2009
GAIA Herbs Astragalus Root Extract was formerly available at 1 mg of astragalosides per 30 drops to
support our experimental program for cellular rejuvenation using small molecule telomerase activators
to reconstruct chromosomal telomeres featuring 5 mg/day astragalosides for two weeks on,
then two weeks off. Since it is no longer available, I have 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. Although this exceeds the recommended dose
according to Solaray, I believe from toxicology studies that it is safe enough. Reconstructing cellular telomeres
using activation of telomerase closes chromosomal t-loops in senescent cells, restoring the youthful phenotype
and patterns of gene expression at a rejuvenation rate approaching 0.75 years per month. Another alternative
is Herbal Remedies Astragalus 1.25 mg
astragalosides per 250 mg cap, via Nature's Way,
( 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. January 26, 2009 hTERT promoter
[Links,
Books,
Patents/hTERT promoter,
Papers,
Amazon,
Books/human
gene promoter and repressor design,
Books/transcription promoters].
See Morin, et.al, the Aug. 17, 2004 Geron patent
Telomerase promoter
driving expression of therapeutic gene sequences. See also M Wick, D Zubov, G Hagen, 1999,
Genomic
organization and promoter characterization of the gene encoding the human telomerase reverse transcriptase (hTERT),
Gene, Volume 232, Issue 1, 17 May 1999, Pages 97-106. Furthermore, don't miss Cong, YS,
The Human Telomerase Catalytic Subunit hTERT:
organization of the gene and characterization of the promoter, Human Molecular Genetics, 1999, vol.8, no.1, 137-142.
See also Yu-Sheng Cong, Woodring E. Wright, and Jerry W. Shay,
Human Telomerase and Its Regulation and
Izumi Horikawa, P. LouAnn Cable, Cynthia Afshari and J. Carl Barrett, 1999:
Cloning and
Characterization of the Promoter Region of Human Telomerase Reverse Transcriptase Gene , Cancer Research,
59, 826-830, February 1, 1999
[Papers,
Books].
See also
Telomerase,
Aging and Disease (Advances in Cell Aging and Gerontology) by M.P. Mattson, Elsevier, 2001.
Note c-Myc activates hTERT promoter [Wu,
Nature Genetics, 1999,
Links,
Links,
Books,
Papers].
Dr. Michael Fossel suggests using
c-Myc plasmids
(perhaps with supplemental controls, such as telomerase inhibitors,
of course) to activate hTERT in human cells for life extension in
Cells, Aging, and Human Disease. "The hTERT promoter lacks
TATA
and CAAT boxes and is in a
CpG island with an
E-box (CACGTG) binding site
and sites for Sp1
and several for c-Myc...
hTERT and c-Myc are expressed in actively dividing cells, but down-regulated in non-dividing cells. ...
C-Myc rapidly and directly induces hTERT expression."
(M.Fossel, p.286). See also
Theodora R. Devereux, Izumi Horikawa, Colleen H. Anna, Lois A. Annab, Cynthia A. Afshari and J. Carl Barrett, 1999.
DNA Methylation Analysis of the Promoter Region
of the Human Telomerase Reverse Transcriptase (hTERT) Gene, Cancer Research 59, 6087-6090, December 1, 1999.
See also Joseph C. Poole, Lucy G. Andrews and Trygve O. Tollefsbol,
Activity,
function, and gene regulation of the catalytic subunit of telomerase (hTERT), Gene,
Volume 269, Issues 1-2, 16 May 2001, Pages 1-12. Note that the hTERT promoter for the catalytic component of
telomerase contains binding sites for the transcription factor Sp1
[Links,
Papers,
Books]
and for the transcription factor c-Myc
[Links,
Papers,
Books;
Wikipedia/C-myc].
Binding sites for the estrogen receptor
[Links]
and the progesterone receptor [Links]
are also found in the hTERT promoter, and it has also been reported that protein kinase C
[Links,
Books,
Books/protein kinase C and telomerase]
is involved in the regulation of telomerase activity. It has also been shown that Akt Protein Kinase
[Links;
Links/Akt Protein Kinase and telomerase,
Books]
is associated with two receptor sites on the hTERT promoter. See Sang Sun Kang, Taegun Kwon, Do Yoon Kwon,
and Su Il Do, Akt Protein Kinase Enhances Human
Telomerase Activity through Phosphorylation of Telomerase Reverse Transcriptase Subunit,
J Biol Chem, Vol. 274, Issue 19, 13085-13090, May 7, 1999.
Fixing up this hTERT promoter section seemed to have psychic impact:
I woke up on the morning after its preparation with
Deck
the Halls joyously ringing in my ears as like a distant response from pleased readers, as if from
a chapter scene
in A Christmas Carol by Charles Dickens. January 6, 2009
Our program for eliminating senescent cells by restoring their youthful phenotype with telomeric DNA repair
enzyme activators
[Books,
Papers,
Amazon/telomeric DNA repair]
that lengthen the telomere until its terminal
t-loop closes, removing the
DNA damage signal leading to
cellular senescence
(such as ethanolic astragalus
root extract) seems to work. (It may also be useful to supplement with
DNA double-strand break repair
acceleration products like
AC-11 as well as
DNA damage defense products
like L-carnosine,
vitamin C, and
homocysteine shields,
although these have mainly foot-dragging effect on aging rather than the backwards-in-time rejuvenation effect
associated with
telomere reconstruction).
However, the rejuvenation rate of 0.667 to 0.75 years/month corresponding to 400 to 460 base pairs of telomere growth
per year seems glacially slow,
and it seems obvious that in the future deeper knowledge concerning dose dependence, cofactors, alternate drugs,
and other factors will accelerate
cellular rejuvenation rates.
Our present program (7)
is conservatively specified for safety. Later, we may find that dose dependence is linear and safe over a wider region.
Whether 4x as much extract gets rejuvenation 4x as fast safely is unknown. Relatively large doses of
TA-65 or astragaloside IV
[RevGenetics] may be effective and safer than astragalus extract.
Improving the bioavailability
of astragalosides with Chitosan or
sodium deoxycholate is a related issue.
I presently take my astragalus root extract at 5 mg of
astragalosides per day for half of the month, with 4 capsules of
Natural Balance
Chitosan (250 mg x 4) at each serving. On the other hand, we may find that
astragalus root extract rejuvenation
is limited by hTR transcription rates
for the RNA component of telomerase.
It may be useful to accelerate this with HDAC inhibitors
that acetylate chromatin DNA and expand the
chromatin for transcription like
sodium butyrate or
Trichostatin A. Finally, it seems that
astragalosides are treated like
nuclear superfamily
transcription factors complexed with the
heat shock protein Hsp90
[Links,
Wikipedia,
Books,
Amazon,
Papers] before tranfer into the nucleus of the cell.
It may accelerate matters to
improve Hsp90 expression by some means,
perhaps by raising Interleukin 6 levels
[Links,
Books,
Papers,
Amazon]
via exercise. We might pump up just before taking our astragalus root extract with Chitosan to facilite its march
into the nucleus complexed with Hsp90 elevated by the exercise session. Magnesium is a cofactor for the DNA helicase
found in telomeric chromatin, so magnesium
supplementation may be a factor in getting results more quickly. Availability of
inexpensive telomere
length measurements should help us determine scientifically what the facts of the matter are,
and as results are published to Internet our program for rejuvenation may improve.
Incidentally, the telomerase inhibitors used in the
2nd two weeks of the telomere remodeling cycle
(when telomerase activators are not used)
should include the well-established longevity enhancers
resveratrol and
melatonin. Of course, a program that fixes
the entire problem forever with just one application of a cleverly designed
viral vector to modify host DNA
may emerge, making all these alternate approaches obsolete and creating new races of physically ageless men. December 30, 2008
Note that Terraternal sells telomerase-activating Astragaloside IV
skin cream. I note that lipophilic substances can get through the skin for transdermal drug application
[Books] without liposomes,
otherwise a liposome cream [Books] is used.
Incidentally, I get the impression that orally ingested small molecule telomerase activators also finally get
through to dermal fibroblasts, so that application in skin creams may not be absolutely required for skin rejuvenation
when using astragalosides or astragalus polysaccharides. The reconstruction of the extracellular matrix
controlling skin quality and wrinkles takes somewhat longer than refreshing grey hair melanocytes,
since it happens after the number density of senescent cells has declined (due to telomere reconstruction)
to the point that substances attacking the extracellular matrix such as collagen and stromelysin are much less
abundant in tissue, while collagen and elastin return from newly restored fibroblasts for skin restructuring.
At a telomere reconstruction rate of 400 to 460 base pairs per year corresponding to a 8 to 9 years per year
rejuvenation rate, results register more slowly in old skin than in hair root melanocyte replacements originating
from rejuvenated adult stem cells. December 23, 2008
Activation of telomerase via NO (nitric oxide) activation
[Links,
Books,
Papers]
in endothelial cells lining the arteries
[Vasa, et al., 2000,
Hayashi, et. al, 2006,
Haendeler, 2006]
can be implemented by taking 3 grams of L-arginine prior to a workout.
(Nobelist Louis B. Ignarro recommends 4-6 grams in NO More Heart Disease, together with
L-citrulline and 4 antioxidants.)
At this dosage, we also often experience thymic gland reactivation
[Links],
so that the thymus renews its production of T-lymphocytes. The range of telomerase activation with Nitric Oxide
produced via nitric oxide synthases is short, because of the short half-life of nitric oxide amounting to
just a few seconds [Links],
but it seems likely that rejuvenation of the thymus gland may be due to telomerase activation, and that
components of the blood such as the primary hematopoietic stem cells
[Wikipedia] may also experience telomerase
activation via this mechanism.
"Endothelial progenitor cells
(EPCs)...are considered to derive from hematopoietic stem cells".
Perhaps working out twice a day with 3 grams or more of L-arginine prior to each workout will turn out
to be a useful rejuvenating strategy for cells derived from hematopoietic stem cells
[Links],
such as brain microglial cells as well as the endothelial cells. L-Arginine, L-citrulline
[Links], and antioxidants
(vitamin C and E) have been useful in generating NO for endothelial rejuvenation
[Hayashi, et. al, 2006].
L-arginine and L-citrulline may
be more useful when taken together, and applicable in skin creams to skin rejuventation applications.
Nobel Prize winner Dr. Louis J. Ignarro recommends 4 to 6 grams of L-arginine per day for physiologically
effective NO generation, plus L-citrulline to maximize it's effect, together with 4 antioxidants in his book
NO More Heart Disease and in his advanced technical books on nitric oxide in physiology and medicine [Books/Louis Ignarro nitric oxide]. The amino acid, L-arginine, is an immune system enhancer that stimulates the thymus gland, boosts white blood cell production and stimulates release of growth hormone. Note: Nitric Oxide,
in aging
[Patents,
Books,
LifeExtension],
in mitochondrial function
[LifeExtension,
Books],
[112],
Nitric Oxide (NO) production stimulated by resveratrol
[Books].
NO levels may be raised by taking arginine with whey protein in bodybuilding exercise, which
has the effect of activating telomerase
[Vasa, et. al, 2000;
Hayashi, et.al, 2006]
in the endothelial cells of the vascular system, and of promoting mitochondrial biogenesis
[Links,
Books,
Papers].
Nitric oxide may also be stimulated using cocoa
[Links].
Thus, Jean Calment's extremely long lifetime of 122 1/3 years may have been due to telomerase activation
from nitric oxide activation, reversing the cellular senescence of endothelial cells lining veins and arteries,
cutting off atheroscelerosis causing heart attacks and strokes, two of the most common causes of death
in aging adults. Nitric Oxide generation is also promoted by pomegranate, an ingredient Life Extension's
Endothelial Defense
product. See the journal Nitric Oxide
[Wikipedia,
Links,
Books]. November, 2008 - December 16, 2008
For our notes on GAIA Herbs astragalus root extract ratings, comparing the "1 mg astragalosides per 30 drops"
version with the approximately 1/13.2 weaker "500 mg crude herb equivalent" version, see
longevitysupplementvendors.html#TOXICOLOGY. October 23-October 29, 2008, Updated December 16, 2008: The Outer Limits
The primary thing to take for longevity turned out to be something like a delicious cough syrup,
an ethanol and water extract of astragalus made available in glycerin, say
GAIA Astragalus root extract in glycerin,
rated at 1 mg astragalosides per 30 drops. Basically, less than
1 tablespoon of this stuff
per day (150 drops is the actual amount taken of 180 drops per tablespoon), half of the month, repeated every month,
will turn a 60 year old man into a 25 year old man in 3.9 to 4.4 years, less than 4.5 years.
That is the main thing to remember, really it is, although some weight-lifting is probably also
required in many cases. Astragalus extract works by lengthening telomeres via telomerase
activation (7) until telomere t-loops in senescent cells
close, eliminating senescent cells. This revivifies adult stem cells, so that they can get in there and fix everything.
Virtually everything else we had in our antiaging medicine chest was footdragging by comparison with
small molecule telomerase activator treatments based on compounds
derived from astragalus extracts. The pioneering research in the matter was done by
Geron [Geron Patent,
A',
A''],
TA Sciences,
Telomolecular Nanotechnologies and other firms including
Sierra Sciences. They are still trying to develop faster, more
effective telomerase activators that get results quicker. Also see
astragaloside IV
from RevGenetics or Terraternal.
Otherwise, we fine-tune the system against cancer with antioxidants
like cocoa powder in water, taken 2 tablespoons at a time from a crystal goblet chilled in the fridge for
several hours. We fine-tune mitochondrial aging with acetyl L-carnitine taken with alpha lipoic acid.
We eliminate lipofuscin with alpha lipoic acid and CoQ10. We exercise daily with 3 grams of arginine in our
systems to generate nitric oxide that lengthens the telomeres in the vascular endothelium, warding off heart attack
and stroke consequences of atherosclerosis. We are careful to take 2000 mg or more vitamin C daily to have plenty of
it to support collagen synthesis and other metabolic reactions. We get our daily multiple vitamins and take
a homocysteine blocker featuring vitamins B6, B12, folic acid, and trimethylglycine to further ward off atherosclerosis.
However, if you want to see the clock of time turn the other direction,
so that you really do seem to get younger, don't forget the astragalus extract.
It will cost you perhaps $25.50 per month for two bottles of it to support two weeks of treatment per month,
including taxes. You'll be glad you did. The exact rate at which it works for you is less important than the fact
that it rejuvenates at something resembling 8 years/year to 9 years/year, that is, 0.667 years/month to 0.750 years per
month. This seems glacial at first, but stick to it. After 9 months, you can usually detect some improvement.
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 = $25.50(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
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-8 Rejuvenation time, B = -8 yrs/yr
0.625
1.25
1.875
2.5
3.125
3.75
4.375
5
Δt-9 Rejuvenation time, B = -9 yrs/yr
0.556
1.111
1.667
2.222
2.778
3.333
3.889
4.444
Actual Age at Final Model Age tFM,
< 60.63
< 61.26
< 61.88
< 62.51
< 63.13
< 63.76
< 64.38
< 65.1
t = t0 + Δt
> 60.55
> 61.11
> 61.66
> 62.22
> 62.77
> 63.33
> 63.88
> 64.4
Cost at $25.50 per month (dollars)
< 191.25
< 382.5
< 573.8
< 765.1
< 956.3
< 1148
< 1339
< 1531
= $25.50(12)Δt
> 170.12
> 339.97
> 510.1
> 679.9
> 850.07
> 1019
> 1190
> 1359
The Time Machine.
Also consider the age transformation table associated with
my personal program for rejuventation with astragalus
extract. As you can appreciate, we need more measurements of telomere growth via telomerase activation therapy
done with off-the-shelf, inexpensive astragalus extracts
to get better oriented.
My measurements using grey hair counts might also be compatible with a 7 years/year rejuvenation rate,
or 0.583 years per month. It's really a life or death issue for millions of people
[See old Outer Limits TV show intros
and The Twilight Zone].
I theorize that formerly astragalus extracts were not widely recognized for their rejuvenating properties
because results seem glacial at first, and because the medicine is fairly expensive, so that few experiments were done.
If you want the most deluxe treatment associated with this technique, see
TA Sciences. There you have the opportunity to make a contribution to science
and use the astragalus-derived TA-65, which seems to probably be cycloastragenol obtained from astragaloside IV
[Geron Patent,
A',
A''].
Making measurements via Repeat Diagnostics for about $650.00 each might
also help you contribute to the calibration of the astragalus extract telomerase activation effect and to the history
of science in this domain. Otherwise, I recommend keeping a file of undyed hair clippings from all over your head,
taken every several months, so you can have a record of the rejuvenation process. Don't forget to include photos and
movies. Life extension on the order of 8 times the normal human lifetime seems feasible with this technique,
since telomerase activation can easily extend mitotic cell division potential by a factor of 8, and
with all we now know, we might be able to extend human life indefinitely.
Music: Love Potion Number 9. Also may make a wonderful rejuvenating personal lubricant. October 17, 2008
Cocoa Polyphenols may have been the primary factor behind Jeanne Calment, the 122 1/3 year-old aging record holder
[Links,
Images,
Photo Gallery], who seems to have gotten some life extension
milage from her consumption of 5 lb. of chocholate per week, although perhaps absorption of antioxidant hydroxytyrosol
from olive oil rubbed into her skin was similarly impacting. See Life Extension's
Endothelial
Defense with "CocoaGold". Cocoa inhibits undesirable platelet aggregation leading to atherosclerosis
associated with heart attack and stroke and promotes blood flow for 8 hours after ingestion.
Since cocoa promotes nitric oxide generation, cocoa may turn out to activate telomerase in endothelial cells
via NO (nitric oxide) activation [Vasa, et al., 2000,
Hayashi, et. al, 2006],
although this is so far unconfirmed. Thus Jeanne Calment's long life span may be due in part to telomerase activation
in the vascular endothelium due to ingestion of cocoa in chocolate. I myself take two tablespoons of cocoa powder
(chilled in a wine goblet of water for two hours or more) 4 times a day.
Finally, note that Jeanne Calment's resveratrol from red wine is also nitric oxide activating and therefore
also probably contributes to telomerase activation in endothelial cells.
Pomegranate, also found in endothelial defense preparations, is another nitric oxide activator.
It is remarkable how sharply the cut-off in human aging seems to be focused at 110, so that Jeanne Calment's
barrier-penetrating extra 12 1/3 years beyond it as a supercentenarian seems to deserve special scrutinty.
Chocolate boosts the blood supply in the brain, according to
Life Extension Magazine, reducing the risk of dementia, another good reason for
aging record holder Jeanne Calment to take 5 lb. per week of it. Increased chocolate consumption
improves blood flow to the brain for 2 to 3 hours. Dark chocolate is superior to milk chocolate because
it contains more cocoa flavonols per gram. September 30, 2008
Upgraded astragaloside IV vendors list in index and in supplement vendors file.
Telomolecular demonstrates Bimene, a new product using nanotechnology
to restore collagen to aging skin. Reviewed telomerase inhibition for anticancer treatment using resveratrol. September 11, 2008
I noted in longevity2.html that a telomeric chromosomal rejuvenation rate of 9 years per year
(460 telomere base pairs per year) amounts to 0.75 years/month, and that 8 years per year (400 bp/year)
amounts to 2/3 years/month. Both of these rejuvenation rates have been measured for TA-65 on different
TA Sciences customers, according to communications from TA Sciences.
Rejuvenation may be continued cyclicly for as long as required to produce a young adult pattern of gene expression
and the corresponding immortal phenotype for most specimens, although it doesn't
restore your teeth. My impression from relatively crude experiments here is that
ethanol-and-water astragalus extracts such as
GAIA astragalus extract taken at 5 mg/astragalosides
per day during the activation part of
telomerase-activation-deactivation cycles produce roughly
the same result. See also TA-41 (a TA Sciences ethanol and water astragalus extract)
test results. Note that TA Sciences makes precise telomere measurements
available from 2 university labs along with their TA-65 rejuvenation pill molecule, no doubt the smallest-molecule
astagaloside, the metabolite found in the blood after ingestion of TA-41. TA-65 is probably cycloastragenol,
which Geron can produce from astragaloside IV (RevGenetics,
Terraternal) by removal of 2 ring structures.
Astragaloside IV is a larger molecule exhibiting the rejuvenation effect based on telomerase activation.
The bioavailability of Astragaloside IV can be improved with chitosan. Note that some additional supplements,
careful diet, and exercise are beneficial to the rejuvenation process, and that
telomerase activators and
telomerase inhibitors should not be taken at the same time
for optimal telomere remodeling. Acetyl L-Carnitine with alpha lipoic acid should probably be taken
concurrently for mitochondrial rejuvenation and lipofuscin reduction, together with 2000 mg/day or
more of Vitamin C (at 500 mg/dose) and a homocysteine blocker including vitamin B6, vitamin B12,
and folic acid. Arginine at 3 grams/day with exercise produces Nitric Oxide that refreshes
the vascular endothelium by lengthening endothelial telomeres, also restoring thymic function,
allowing the body to create fresh T-lymphocytes and maintain youthful thymic hormone levels.
See Repeat Diagnostics and the
How Long are My Telomeres
article from RevGenetics, a manufacturer of
Astragaloside IV,
to measure your telomere length from a commercial lab for less than $700. July 14, 2008Section 15 on other aging processes now includes
wear and tear on the teeth and a strategy for defeating dental caries that also
reconstructs and remineralizes tooth enamel. See also my dental files. June 19, 2008 Perhaps histone deacetylase inhibitors, which expand chromatin for transcription,
may work effectively together with astragalosides or other small-molecule telomerase activators functioning
through nuclear transcription factors much as steroid hormones interact by binding with the
steroid receptor transcription factors
[Links/nuclear receptor superfamily]
attaching directly to the gene promoter. Broccoli sprouts for sulphoraphane, plus its zinc cofactor,
might work more effectively with astragalosides to promote hTERT transcription after chromatin expansion
via HDAC inhibitor sulphoraphane plus zinc. Such hypotheses will require testing. June 12, 2008DNA repair enhancement
[Links,
Books,
Papers,
Patents,
Amazon,
LifeExtension,
AC-11,
Links/AC-11].
Telomere Repair
[Links,
Books,
Papers,
Patents,
LifeExtension,
Amazon,
TA Sciences,
Telomolecular Nanotechnologies,
Sierra Sciences, Geron's
Compositions
and Methods for Increasing Telomerase Activity
(A',
A'') and
Formulations
Containing Astragalus Extracts and Uses Thereof], and via relevant hormone introduction,
[23s]. For a promising experimental program with readily available
GAIA astragalus extract, see
Telomere Remodeling via Cyclic Telomerase Activation,
(7). Telomere repair is fundamental in modern long-range life extension technology,
as telomere shortening routinely results in replicative cellular senescence in the human species. June 10, 2008SNPs - Single Nucleotide Polymorphisms
[Wikipedia,
Links,
Books]
in the human genome can create different scenarios for anti-aging nutritional supplementation
and medical treatment. See GeneLink, used by
Solgar NutrigenomX,
which provides a report on about 12 SNPs, together with tailored supplements from
Solgar. See also
Gene Essence, which prepares a personalized genetic information
"Gene Essence Report" on about 90 medically important disease association SNPs through
Biomarker Pharmaceuticals, using a DNA chip equipped
with 1.8 million DNA probes to detect over 1 million SNPs. See the April 2008 article
Genetic Polymorphisms and Human Aging:
Association Studies Deliver
[Links/Genetic
Polymorphism and Human Aging,
Books,
Papers,
Patents,
LifeExtension,
Amazon].
See also DNA microarrays [Wikipedia,
Links,
Books;
Affymetrix]. June 6, 2008
Improvements to the index: corpora amylacea, treatment of microglial activation,
improvements to curcumin, oleocanthal, ect. May 31, 2008
Testosterone enables reverse cholesterol transport
[Links,
Books,
Papers,
LifeExtension,
Amazon],
removing excess cholesterol from tissues and carrying it to the liver, thereby reducing the likelihood of atherosclerosis,
heart attack, and stroke. Reverse cholesterol transport works by augmenting scavenger receptor B1
[Links] in the liver,
which acts to stimulate cholesterol uptake, and by increasing the activity of hepatic lipase
[Links],
which removes phospholipids from the surface of HDL cholesterol,
enhancing the uptake by scavenger receptor B1. May 30, 2008
Alpha Lipoic Acid with Acetyl L Carnitine
[LifeExtension,
Links,
Books,
Papers]
has been shown to restore mitochondria to a youthful state, and is thought to be the answer to the
mitochondrial theory of aging. Recently, sodium-R-lipoic acid
[Links]
has been shown to be more bioavailable than lipoic acid (half active R-lipoic acid, half inactive S-lipoic acid)
or pure R-lipoic acid, capable of achieving 10-30 times higher levels in the blood than R-lipoic acid,
reaching peak plasma concentrations in just 10-20 minutes. See Life Extension's
Super R-lipoic Acid,
a brand of sodium-R-lipoic acid. May 10, 2008
Among mammals,
research suggests that the bowhead whale
(Balaena mysticetus,
or Greenland Right Whale)
may live up to 211 years.
Measurements
on the nuclei of the whale eye done with racemization techniques often show ages close to 100.
When this whale dives, I am reminded
by his tail of
Orion's battleaxe resume Gemini sinking in the West, crowned with his soaring
story of resurrection as a phoenix in the East. Also upgraded bibliography. May 6, 2008
Added material on hTR or hTERC, the gene for the RNA component of telomerase coding for TTAGGG tandem repeats,
including links to hTR plasmids and hTR transfection. Some tissues may require hTR plasmids or hTR transfection
if they cannot be served by adult stem cells for rejuvenation, because in some mesenchymal-derived tissues
the hTR promoter is methylated at CpG islands and plated over with a silencing protein. May 4, 2008 May the Fourth be with you.
YouTube: Telomolecular
Nanotechnologies Corporate Video on Telomeres and Telomerase in Life Extension,
Eucaryotic Cells,
Molecular Biology,
Molecular Medicine,
Medical
Nanotechnologies,
Visualization of DNA,
DNA Sequencing,
DNA Repair,
RNA,
RNA Sequencing,
The Cell Membrane,
The Nuclear Pore,
Viral Transfection,
DNA Plasmids,
The Human Genome,
Genome Design,
Drug Design,
Proteins,
Molecular Machines,
Gel Electrophoresis,
DNA Lab,
Polymerase Chain Reaction (PCR). April 30, 2008Epigenetic Regulation and Undesirable DNA Demethylation in Aging
[Links,
Books,
Papers,
Amazon,
LifeExtension;
Links/Epigenetic Dysregulation in Aging,
Books,
Papers,
Amazon;
Links/DNA methylation,
Books/DNA Demethylation,
Links,
Books,
Books/epigenetic regulation in senescent cells, Links/causes of DNA demethylation, LifeExtension/DNA demethylation]. Methylation of genes is used in the development of placental mammals to silence gene promoters after their developmental role is over, or to switch on genes controlled by an insulator in charge of an enhancer. Life Extension Magazine promotes SAMe [Links] as a cure for undesirable DNA demethylation, noting that "Cellular aging is partially caused by de-methylation".
(Added to the index and section (10) on DNA repair in aging.) April 28, 2008 Added hTERT transcription factors
[Links,
Books,
Papers,
Patents]
down-regulating hTERT, including E2F-1,
Mad1, TGF-β, and Menin to the list of telomerase inhibitors in lifexnotes3b.html. Also added hTERT transcription factors active in hTERT activation including c-Myc,
Sp1,
and Ets family
protein ER81,
and estrogen receptors
to telomerase activators in
lifexnotes3b.html. See Shuwen Wang and Jiyue Zhu, 2004:
The hTERT Gene is Embedded in a
Nuclease-resistant Chromatin Domain, Journal of Biological Chemistry, vol 279, No.53, Dec.31, 2004,
pp 55401-55410.
In addition, I added material on the "hTERT insulator" topic to
indexlongevity2.html. April 27, 2008
There are 5 RecQ DNA helicase genes
[Books/DNA helicases,
Books/RecQ DNA helicase genes]
used to unwind DNA, some or all requiring Mg+2 as a cofactor [Hu & Ellis, Bloom Syndrome,
in Chromosomal
Instabilty and Aging, by Hisama, et al, 2003]. Therefore, it may be that deficiencies in dietary
magnesium are connected with genomic instabilities in aging cells via the malfunctioning of DNA helicases.
The WRNp helicase [Books,
Books/cofactors]
associated with Werner Syndrome, for instance, is localized to the telomere, and may malfunction
if sufficient magnesium is not available as a cofactor
[Links,
Papers].
According to Life Extension magazine,
low levels of magnesium are chronic in the US population, and magnesium should be supplemented. YouTube Video:
Helicase in Action in
DNA Replication Process. April 26, 2008
Homocysteine blockers reduce the formation of micronuclei in aging cells, a symptom of chromosomal instability.
Folic acid and vitamin B12 alone reduce micronucleus formation, as does a general reduction in homocysteine levels,
obtained perhaps by consuming less red meat rich in methionine.
[Maurer, et al., Chromosomal Instability in Normative Aging, from
Chromosomal Instability and Aging,
2003, p.138.] Werner Syndrome
cells thrive in vitro when hTERT is activated [Junko Oshima, Werner Syndrome, in
Chromosomal Instability and Aging,
2003, p.176], suggesting that perhaps small molecule telomerase activators such as TA-65 and astragalus
extract may be used to cure Werner Syndrome patients or alleviate their symptoms. April 18, 2008
Index improvements. C-myc
[Wikipedia,
Links,
Books,
Papers,
Patents,
Amazon,
LifeExtension] is a gene producing
the c-myc protein, a transcription factor that upregulates hTERT, which produces the catalytic component of the DNA repair
enzyme telomerase, the reverse transcriptase that extends telomeres. Dr. Michael Fossel has pointed out in
Cells, Aging, and Human Disease
that c-myc, or c-myc activators, may be useful in life extension applications for re-extending telomeres in order
to escape from replicative senescence. Ordinarily, we have no problems with c-myc, which is located towards
the q-end of chromosome 8. C-myc is normally expressed as a transcription factor in response to growth factors
such as EGF, Epidermal Growth Factor, which excites the proliferation of many types of cells, and which is
also a telomerase activator. However, c-myc is an oncogene
in Burkitt's lymphoma. This happens when c-myc
is translocated to an immunoglobin location toward the q-end of chromosome 14, in which case its expression
becomes unregulated. There are also Burkitt's lymphomas associated with c-myc translocation to immunoglobin
sites on chromosomes 2 and 22, in which c-myc becomes similarly unregulated. The translocation leading to
Burkitt's lymphoma usually occurs as a consequence
of a Herpes virus infection, or from infection with Epstein-Barr virus, and sometimes as a consequence of
infection with HIV. [Geoffrey M. Cooper, Ch.15, Cancer, The Cell, 1997, p.608, pp. 618-619.] April 16, 2008:
Realized that acetylcholine helps make nitric oxide available to endothelial cells,
so that acetylcholine boosters Ashwagandha and Huperzine A may be useful in connection with telomerase
activation using NO generated by nitric oxide synthase from arginine during bodybuilding exercise.
Also, the acetylated form of L-carnitine (acetyl-l-carnitine) facilitates the release and synthesis of
acetylcholine by donating its acetyl group towards the production of acetylcholine.
NO generation is also promoted by broccoli sprouts, genistein, and resveratrol.
Since NO reacts with the superoxide anion to form peroxynitrite, which produces hydroxyl radicals,
it is probably a good idea to use the peroxynitrite inhibitor gamma-tocopherol when using
NO to promote telomerase activation. (After or during.) See
Vasa, et al., 2000,
Hayashi, et al., 2006. March 24, 2008:
Located Mogfield JE, Liu WR, Reid R, 2006:
Adenoviral human telomerase
reverse transcriptase dramatically improves ischemic wound healing without detrimental immune response
in aged rabbit model., Human Gene Therapy,
2006; 17(6): 651-660. This shows how telomerase may be activated via gene therapy using a viral vector. March 22, 2008: Introduced 4-page structure into the main essay and the index,
also dividing the bibliography and the labs section into two pages. This makes
individual pages storable on S5, and leaves room for expansion. Requested an update for the local
Pico Search index. Coincidentally, the
forsythia bloomed today, two days after the
Spring Equinox, and tomorrow is Easter Sunday. March 21, 2008: Deuterium Theory of Aging
[article,
Links,
Books,
Papers].
Deuterium in water is thought to contribute to DNA damage, and deuterium-depleted water
[Links,
Papers],
or Dd-water, may be taken to reduce damage to DNA from deuterium
[Wikipedia].
Deuterium water is toxic, and the associated problems seem to stem from the effect of deuterium
on the hydrogen bond. Deuterium bonds are stronger and shorter than normal hydrogen bonds,
sometimes modifying the shape of an enzyme. Deuterium-depleted water has contributed to the
survival time of breast cancer patients after metastases have been observed.
Dd-water may be obtained from glaciers at high altitude, as for instance Hunza water
[Links].
Natives from this region report living extended lifespans on the order of 120-140 years.
Plants can be constructed to produce deuterium-depleted water on a large scale
[article],
and it is available
in liter bottles like a soda beverage. March 15, 2008 Noticed that PDGF, Platelet Derived Growth Factor
[Links],
is a telomerase activator. Upgraded lifexnotes5.html and other files. March 2, 2008 Refinements to the index. February 12, 2008 Astragaloside IV is more bioavailable when taken in astragalus root extract,
which is typically used to boost the immune system. The bioavailability of astragaloside IV
[Article,
Papers],
can also be increased by
chitosan
[Wiki/chitosan,
Links/chitosan] or
sodium
deoxycholate [Links,
Books].
The astragalosides are the safest and most readily available small-molecule telomerase activators for
telomere remodeling with cyclic telomerase activation
that I know of. Telomerase inhibitors including silymarin, curcumin, resveratrol, quercetin, green tea,
garlic, fish oil, and vitamin E should not be taken while trying to turn on hTERT with astragalosides
for telomerase activation, but may be taken in the next two weeks of a cyclic treament cycle.
Otherwise, NO from arginine works with nitric oxide synthase from exercise to lengthen telomeres
in endothelial cells and to promote mitochondrial biogenesis. Drug bioavailability
[Links,
Wikipedia,
Books]
of orally taken compounds is worst when the molecular weight is > 500, the calculated octanol/water partion is > 5,
the number of H-bond donors is > 5, and the number of H-bond acceptors is > 10.
(See van de Waterbeemd, Drug Bioavailability.) Hence, we concentrate on small-molecule telomerase activators,
and for the conjugate part of a telomere remodeling cycle, on small-molecule sirtuin activators with a
molecular weight < 500 such as resveratrol and quercetin, when small-molecule telomerase inhibitors
like silymarin, garlic, and curcumin may also be taken. February 8, 2008
Added a terminal section on the impact of extreme life extension with
rejuvenation included on reproduction and evolution in the future. A new entry on
telomere-telomere fusion in the index envisions human evolution from the great ape genome. Jan 25, 2007
Aging muscle regeneration via stem cells, young serum, signalling proteins,
NO, mechanisms for improving mitochondrial biogenesis in section (9).
See new telomerase activators or telomere-growth methodologies for that list in
lifexnotes3b.html. Also introduced improvements in
mortality charts. Dec. 11-12, 2007
Greying hair [Wikipedia/hair color,
Wikipedia/Grey Hair]
is sometimes described as due to stem cell failure that no longer renews a
melanocyte hair coloring cell in the hair follicle,
so that the melanocyte dies and the hair turns white. This was
a news story in 2004.
I am not sure yet whether stem cell renewal via telomerase activation can restore the melanocyte
to the hair follicle after the transition has taken place. (By November 2008 I am sure it can.)
I note that Geron and
Telomolecular Nanotechnologies
seem to believe that white hair can be restored to normal dark hair using telomerase activation
[Links/hair
restoration with telomerase, article].
(I have verified this by November 2008.). There are products on the market now that claim to
restore hair and hair color with telomerase activation, such as
iGrowHair Telomerase
[Links/telomerase excreting acidophilus,
Wikipedia/Lactobacillus Acidophilus:
improves immune function]. I sometimes imagine that my hair is getting darker as I experiment
with telomerase activation, but then my hair looks dark after a shower when it is wet, and greyer later...
perhaps explaining ancient popular belief in baptism. Just plunking a handful of water on the top of my head
makes me look 5-10 years younger - it must help!
(By November 2008 there can be no doubt, although I still look younger after a shower.)
See Lactobacillus Acidophilus improves immune function:
[Links,
Papers,
Books,
Links/Genome of Lactobacillus
Acidophilus]. The Lactobacillus Acidophilus genome consists of 1,993,564 bp on one DNA molecule
with no plasmids and shows 1864 genes. Dec. 9-10, 2007Gene Therapy sections expanded.
[Books,
Links,
Papers,
Wikipedia,
LifeExtension],
Adenovirus transfection - hTERT or other genes such as c-MYC for hTERT activation may be transfected
using adenovirus vectors or retroviral vectors.
[LifeExtension,
QbioGene/Adenovirus
for gene therapy applications,
Books/adenoviral transfections,
Links/Adenoviral Transfections,
Invitrogen/adenoviral transfections, Amaxa Biosystems,
Amazon/adenoviral transfections].
See also retroviral vectors in gene therapy
[Links,
Books,
Amazon,
LifeExtension].
Targeted introns may improve control of gene expression
[Links,
Books,
LifeExtension].
Sendai viral techniques may also be useful for our life extension application
[Books],
as well as other viral vector methods
[Books,
LifeExtension].
Micheal Fossel also mentions possible dendrimer
[Books]
and transcatheter application techniques
[Books]
in his 2004 textbook
Cells,
Aging, and Human Disease, and points out that high-pressure commercial gene guns
[Wikipedia,
Books] may be employed on the skin
[Books].
See also plasmid delivery in gene therapy
[Books,
Links,
Amazon,
LifeExtension].
Dec 6, 2007
Toxicology studies and experiments in progress seem to indicate that
GAIA astragalaus extract in glycerin may be
applied directly to the skin and scalp at 1 mg of astragalosides/30 drops for telomerase activation in the skin
and hair follicles. A superior solution may become available as astragalus extract in liposomes.
I note readings in Michael Fossel's
Cells, Aging, and Human Disease
make telomerase activation seem quite primary in anti-aging medicine, most other preventative treatments
rather palative by comparison. For instance, heart attack and stroke are primarily due to endothelial cell senescence
[Links], and elderly cancer
not due to carcinogens such as cigarette smoke is primarily due to genomic instability originating in short telomeres,
according to Fossel
[Links] and other researchers.
The extended lifetime telomerase activation gives to the immune system and to adult stem cells
is seen as crucial in the long-range maintenance of neural and muscle tissue, too, so that both mitotic
and primarily non-mitotic tissues are benefited by telomerase activation of cells in the body.
Otherwise, Fossel reports on indications that Alzheimer's Disease may be primarily due to the
replicative senescence of epithelial and microglial cells, so that the primary
causes of death can be traced to replicative senescence
preventable with telomerase activation. Using a cyclic activation scheme
(TA Sciences) allows the telomeres to catch runaway cellular proliferation
in cancer during down-subperiods of the telomerase activation treatment cycle. Fossel's book envisions
boosting telomerase activation via hTERT gene therapy using viral vector transfection, or via c-MYC plasmid
activation of telomerase [Nature, 1999,
Papers],
and presents many stimulating new ideas and observations. More than 10x the usual 50 allowable human cell divisions
has been obtained in in vitro experiments when telomerase activation was employed, according to Fossel.
Perhaps Methuselah's legendary 969 year record will be broken hereafter. Note that extra copies of transfected
hTERT in the human genome can still have telomerase inhibited with standard
telomerase inhibitors if this is indicated in cancer treatment. Dec 4, 2007
Conflicting data on retinoic acid as a telomerase inhibitor or activator,
new index entries on matrix metalloproteinases, skin solutions. (Retinoic acid is a telomerase inhibitor.)
See Retinoic Acid [Links;
Links/retinoic acid telomerase]. Nov 20 & 24, 2007 Embryonic stem cells have recently been created by nuclear reprogramming
of skin cells, so that embryonic stem cells can be obtained without taking embryos apart
[article1,
article2,
Links/embryonic
stem cells via nuclear reprogramming,
Books,
Papers].
The results were seperately published by Dr. Shinya Yamanaka of Kyoto University in Cell
[Papers,
Links,
images]
and James Thomson of the University of Wisconsin in Science
[Papers,
Links,
images]. Nov 19, 2007
It may be useful to take whey protein, which ups HGH, and arginine, which ups NO levels,
while using astragalosides or astragalosides + chitosan to activate telomerase.
Nitric Oxide from arginine supplements causes anabolic effects, including telomerase activation
in epithelial tissue according to Vasa. HGH from whey protein intake ups IGF-1, also an anabolic stimulant
associated with telomerase activation, although it subsequently lowers HGH. Chitosan
improves telomerase activator astragaloside IV bioavailability.
[62s].
Searching uncovered more telomerase activators: Mre11 protein
[Links,
Books,
Papers]
has been noted to lengthen telomeres in plant and human cells.
(Bundock and Hooykaas, 2002.)
Also, Ependymin Peptide Mimetics work: a 14-amino acid ependymin peptide was effective.
Ependymin [Links,
Books,
Papers] is a secretory protein found
in the cerobrospinal fluid and extracellular fluid of goldfish brains. Ceremedix, Inc. makes
the 14-amino-acid ependymin peptide,
which has the sequence ESCKKETLQFRKHL, or Glu-Ser-Cys-Lys-Lys-Glu-Thr-Leu-Gln-Phe-Arg-Lys-His-Leu.
See (Hirsch, Erica, 2005. Telomerase Activity
and Telomere Lengths in Fibroblast Cells Treated with Ependymin Peptide Mimetics).
[Telomerase Activators]. Nov 13, 2007
Nitric Oxide from arginine is typically used in NO bodybuilding preparations
to improve blood supply and boost anabolic effects. Vasa's work on telomerase activation via NO in epithelial
tissues might apply to Nitric Oxide preparations used in bodybuilding based on the preparation of NO
from arginine by nitric oxide synthases
in the body. I note that NO has also been reported to activate mitochondrial genesis. Nov 11, 2007
Added more refinements to section (14)
on the proteasome and aging, and to the corresponding references. Nov 8, 2007
Oleuropein, a major constituent of olive oil and olive fruit, was shown to be effective in stimulating
and reviving proteasome activity, resulting in anti-senescence effects and 15% life extension.
[article] Of course,
this helps explain good results that Jean Calment got with olive oil. Also, ginsenoside Rh2
was shown to be a telomerase inhibitor, although Geron has shown ginsenoside Rh1 to be a telomerase activator.
Thus the effectiveness of anticancer ginseng extracts in activating telomerase is in question.
Another telomerase inhibitor recently uncovered is green marine algae extract.
[article] Oct 22, 2007
Breast cancer resulting from estrogen or ovarian hormone stimulated cell division
driving cells toward the Hayflick limit when cells become senescent and genomically unstable might be warded
off by "astragalus" extracts or other small molecule telomerase activators.
"Recent studies show that more than 90% of all cancer is caused by critical telomere shortening, for example,
in 97% of premalignant endothelial lesions critical telomere shortening is observed
(Meeker, John Hopkins University 2005)."
- Telomolecular Corporation SEC statement.
Note that estrogen affects the receptor levels of a female hormone called progesterone.
In the breast, progesterone also acts as a chemical messenger that tells breast cells to divide,
hence progesterone and estrogen are applied in female transformations which can become ultimately
dangerous when finally cells approach the Hayflick cell division limit. Oct 21, 2007
Added DNA Synthesizers to Labs page for
DNA nanocircle synthesis, ect.
with more from Telomolecular Nanotechnolgies. In particular, I address notch signalling and
muscle regeneration in (9) on exercise in anti-aging medicine. Oct 19, 2007
Added CGK733
to the telomerase activator list. It can produce 25% life extension by providing 20 more cell divisions.
Its precise mechanism differs from telomerase activation: it revives senescent cells, working
"by
blocking a protein checkpoint involved in sensing and slowing down cells in response to DNA damage.
Although Kim showed that cells whose aging was reversed by CGK733 didn't develop chromosomal abnormalities,
the long-term effect of blocking DNA repair mechanisms could lead to cancer."
Also Added 5-azacytidine (DANGER: may promote prostate carcinomas) to lifexnotes3b.html's small molecule
telomerase activator list in [81s].
The 5-azacytidine prostate cancer promoting problem is related to its methylating agent property,
whereas on the other hand Tricostatin A works around histone acetylation via histone deacetylation inhibition.
Added very-potent RHPS4, a Small-Molecule Pentacyclic Acridine, to the corresponding list of telomerase inhibitors.
RHPS4 is used in anticancer therapy. Oct 18, 2007
Upgraded [81s] list of telomerase activators. Oct 17, 2007
Concluded again after careful inspection that TA-65 is probably cycloastragenol,
and added improvements to lifexlabs.html and to the
bibliography. Also revealed that chitosan makes
astragaloside IV more bioavailable. Added CGK 1026 to the list of telomerase activators. Oct 16, 2007
Astragalus, which contains small molecule telomerase activating astragalosides,
was the first medicine discovered to be effective against lymphoma
night sweats
caused by the senescence of B-lymphocytes stimulated to divide many times in the presence of an antigen.
The astragalosides lengthened B-cell telomeres, preventing B-cell senescence and consequent genomic instability
and lymphoma night sweats. Inserted in section (11) on immunosenescence. Oct.11, 2007
The position of hTERT at the distal end of chromosome 5p has hTERT itself controlled by the
telomere position effect TPE. (JW Shay & WE Wright, 2005.) Oct.10, 2007
Index improvements: teeth problem correction, mole removal,
tatoo removal, blemish-removal, better coverage of telomerase activation therapies and astragalus. October 8, 2007
Added links to Hair Transplants in the Index
and in Sup Notes 3. Sept 20, 2007 Added BioProcess International
to journals, biotech firms to Labs. Sept 12, 2007TA Sciences gets 230 base pairs
of telomere growth per 3 months of Patton protocol treatment during the telomerase-on part of the cycle.
Added to (7)/small molecule telomerase activators
and to dosages at [62s]. Sept 10, 2007
Spell-corrected first two pages. Sept 5, 2007
Added reference articles page lifexrefs.html.
This under-construction piece will be updated and refined, and allow classical articles to be clicked
for reader access to the paper on Internet. Sept. 1, 2007
Added material in (4) on lipofuscin and ceroid removal. August 29, 2007
Added liposomal delivery product examples:
IQ Derma (rejuvenating),
Bodyshape by Hydroderm
(for cellulite) to index and footnotes. August 27, 2007
More historic articles were added to Telomere Articles in the
Labs section. Notes from "Telomere Damage in Aging" by von Zglinicki
from Aging at the Molecular Level
were used to improve (7) on telomere aging theory. August 23, 2007
Perkins Coie filed a patent application for anti-aging
skin creams including astragalosides on behalf of Geron's Chief Scientific Officer
Calvin B. Harley
[Forbes/Calvin B. Harley,
Papers/Calvin B. Harley,
Books,
Portrait],
news which was included in my section on Small Molecule
Telomerase Activators. August 22, 2007
Cosmetic anti-cellulite fat creams and references were added to the
index. August 13, 2007
Improved the toxicology of astragalus
and [81s/6b]. August 10, 2007
Improved Vendors file,
Jekyll-Hyde longevity beverages. August 9, 2007
Added toxicology to index, drug dosage info to dosages
[62s], and astragalus extract in water to my list of
Jekyll-Hyde longevity beverages. August 8, 2007
Added astragalus section in vendors,
added molecular diagram links to [81s/6b]. August 7,2007
Improved Bibliography/Journals and Vendors files. August 6, 2007
Added Bluebonnet supplements with low-cost ubiquinol, improved Cat's Claw extract discussions
in (10) and the index by
including material on CAEs (carboxyl alkyl esters) and oxindole alkaloids, which are not used
in Dr. Ron Pero's AC-11 Cat's Claw extract.
Suggested investigating Solaray Korean Ginseng Extract for telomerase activation as an alternative
to astragalus extract oriented telomerase activation. Still inclined toward astragalus. August 4, 2007
Improvements in mitochondrial DNA repair in (10). August 3, 2007
Improvements in dosage list for anti-aging program [62s]. July 31, 2007
Telomere T-loop detail added to (7),
more refs to dosages [62s]. July 29, 2007
References added to (7)
to papers from Dr. Woodring E. Shay and Dr. Jerry Wright, with branching from them
to other papers on telomeres and telomerase in cellular aging and the telomere position effect. July 26, 2007
Improvements in optimum anti-aging program
and dosage reference [62s]. July 25, 2007
Improvements in immune theory of aging, section (11),
and associated footnote (94). July 22, 2007
Improvements in Telomere Position Effect in (7), Labs, and in Index M-Z. July 18-20, 2007
Highlight Links added, organizational enhancements introduced. July 16, 2007
Added info on telomere capping proteins to section 7,
after the discussion of telomerase activators. July 15, 2007
Added material on varicose veins and horse chestnut to index. July 11, 2007
Mostly organizational improvements in longevity2.html. July 9, 2007Telomerase inhibitors
[81s] to avoid while activating telomerase
[81s/6b] with astrogalosides from astragalus extract or other
telomerase activators include garlic, turmeric (curcumin), resveratrol, vitamin E, green tea,
melatonin, and fish oil EPA. June 30, 2007
Included more book searches on telomerase activators in
81s/6b. June 26, 2007
Indexed more material on phospholipid exchanges for cell membrane and skin repair,
skin clinics, infusion therapies. Bibliography improvements. June 24, 2007:
Added Activar AC-11 Cat's Claw Extract
[Links,
Books] for DNA repair
[Links,
Books,
Wikipedia], available from
Prothera
as C-MED-100. June 23, 2007:
The people's small molecule telomerase activator is probably GAIA Astragalus Extract,
taken at 5 mg of astragalosides per day, two weeks on and two weeks off,
continuing over the course of a year. During the two weeks on one must avoid telomerase inhibitors
such as garlic, turmeric (curcumin), resveratrol, vitamin E, green tea, melatonin, and fish oil EPA,
applying them during the next two weeks. This keeps the cost at about what it was before using
telomerase activation to re-extend your telomeres to repair the tip-ends of your aging chromosomes.
However, this program is not yet well established. Cycloastragenol at 5 mg/day is probably superior
in such a program, but cycloastragenol, the common structural element in the astragalosides,
is not readily available at this time. (Later, GAIA cut the strength of their extract to about
1/13 of its robust strength, abandoning an astragaloside-specific specification for the product
at the same time. This made it mandatory to switch to other brands to get 5 mg of astragalosides per serving.) June 13-16, 2007:
Added more links to section (8) subsection
on the role in aging and cloning of rising DNA strand separation temperature due to
DNA-protein crosslinking, regarding causes and repair. June 6, 2007:
Added links in (7) on Small-Molecule Telomerase Activators to the
molecular
structure of cycloastragenol (probably TA Sciences TA-65)
in the
Geron
European patent (p.65) (A',
A'')
and in on-line chemical refs on cycloastragenol [81s/6b,
Books,
Links,
Papers].
"Cycloastragenol
is the common genuine aglycone of the astragalosides". See the Geron European Patent,
(p.39-40). June 3, 2007:
Added [Books/DNA-protein crosslink repair]
to (8). June 2, 2007:
Book and Web links, bibliography links inserted for the
previous entry. June 1, 2007:
"Clones of animals with normal life spans are usually prepared via nuclear
transfer from embryonic tissues
[Books].
Perhaps the steadily increasing
cross-linking of aging DNA with proteins
[Books],
which causes the strand separation temperature of DNA to rise in old DNA, will turn out to
be an inhibiting factor in cloning from adults.
[See S. Dani, A. Hori and G. Walter,
Principles of Neural Aging,
Elsevier Press, 1997.] I have not determined whether or not cross-link breakers like
Alagebrium
(ALT-711,
Links) exist that can be used to alleviate this problem,
and the role of rising DNA strand separation temperature from
DNA-protein cross-linking
in aging remains somewhat unclear to me at this time.
[See Books/DNA-protein crosslink repair.]"
- Added at the end of section (8), after the entry below. May 31, 2007:
It will soon be possible to create and store your own embryonic stem cells
for personalized therapies via services available at
StemLifeLine in San Francisco
[TIME article],
starting with spare embryos prepared in an
IVF (In Vitro Fertilization) clinic.
However, the firm is not promoting this in connection with prior
nuclear transfer
for human cloning with precise tissue DNA matching or in combination with telomerase activation
for chromosomal telomere rejuvenation prior to nuclear transfer,
which would be necessary to produce a clone with a normal life span from adult DNA
[Wikipedia/human cloning,
Books/Human Cloning].
Clones of animals with normal life spans are usually prepared via nuclear transfer from embryonic tissues. May 1, 2007
Started my personal experiment with
telomere remodeling via cyclic telomerase activation
using GAIA Herbs Astragalus Extract.
TA Sciences announced that a chemical found in
astralagus extract was being used for TA-65 in March, 2007.
Geron announced that astragalus extracts and derivatives were
telomerase-activating in a patent
(A,
A',
A'')
published June 1, 2005. Hong Kong University also published on May 19, 2005
on telomerase activation with astragalus extract, in the Hong Kong University/Geron patent
B.
These were the first known orally bioavailable telomerase activators.
Calvin B. Harley, the chief scientific officer of Geron, has his name on both the Hong Kong University and the Geron patents. Calvin B. Harley established with A.B.Futcher and C.W. Greider in 1990 [Nature, 1990] that telomeres grow shorter with each cell division in human fibroblasts, and in 1998 was the leader of the team of Geron scientists including A.G.Bodnar, J.W.Shay, and W.E.Wright, et.al., that proved hTERT activation could lengthen telomeres and provide additional cell division [Science, 1998], extending life-span by introduction of telomerase into normal human cells. In the early 1998 work, a viral vector was used to produce extra copies of the hTERT gene in samples to increase telomerase levels. The first drug that was discovered to activate telomerase seems to have been the histone deaceylase inhibitor (HDAC inhibitor)
Trichostatin A, as described by Yu-Sheng Cong and Silvia Bacchetti in
Histone Deacetylation Is Involved
in the Transcriptional Repression of hTERT in Normal Human Cells, J. Biol. Chem.,
Vol. 275, Issue 46, 35665-35668, November 17, 2000. Tricostatin A
[Links]
can stop the cell cycle in early stages of development and is positioned as an antifunqual antibiotic
these days, usually presented as harmful and not for human consumption when taken orally.
Telomerase activator epithalon peptide (Ala-Glu-Asp-Gly) was isolated from the pineal gland
and announced in 2003 at the St. Petersburg Institute for Biogerontology in Russia.
Both Trichostatin A and Epithalon Peptide are taken by injection.
For the early time-table of the development of our insight into telomeres,
telomerase, and replicative senescence, see
Hayflick,
His Limit, and Cellular Ageing by Jerry W. Shay and Woodring E. Wright from Nature Reviews
Molecular Cell Biology in October, 2000. June 2000
Started these Longevity web pages.
Your corrections and remarks are welcome. Please write
to JimGreenHimself@gmail.com. Disclaimer:
These are student study notes for research on life extension,
not the prescription of a medical doctor. These customer investigations of
various anti-aging medicines and foods and associated disciplines are not
to be interpreted as a medical doctor's prescription or product
endorsement. Be sure to check a PDR
(Physician's Desktop Reference) regarding dosage, contraindications,
and side effects. See also Wal-Mart's checker for Drugs
and Drug Interactions and Google Books Pharmaceutical
References. It is best to use quality pharmaceuticals from reputable manufacturers
according to the instructions of the manufacturer, and to avoid using mere chemicals that may
be under investigation for pharmaceutical applications.
Many of the tips and clues in this document could benefit
from further testing and research.
May 6, 2008
Added material on hTR or hTERC, the gene for the RNA component of telomerase coding for TTAGGG tandem repeats,
including links to hTR plasmids and hTR transfection. Some tissues may require hTR plasmids or hTR transfection
if they cannot be served by adult stem cells for rejuvenation, because in some mesenchymal-derived tissues
the hTR promoter is methylated at CpG islands and plated over with a silencing protein.
May 4, 2008 May the Fourth be with you.
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