A revolution in life extension

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Thomas Carter

ungelesen,
17.12.2011, 18:07:1417.12.11
an
As of now in Dec. 2011 a revolution in understanding and controlling
of aging has occurred. The three papers below portend a blueprint for
rapid advancement in life extension which could be at least partly in
the clinic before 2020.

Most human aging is caused by a programmed repression of four genes.
(4) This repression can be eliminated by simple miRNA treatment (4)
with consequent reversal of even 100 year old cells to a juvenile
state. (8) Mitochondria? Not to worry, Mother Nature does all the
work. (16)

While follow up studies will likely mitigate the claims of these three
reputable teams, the fundamentals seem very likely to stand, and
mitigating details likely to be overcome.

Notably the treatment may even work in vivo with simple injection of
the miRNAs. But at any rate rejuvenation in the lab with
reimplantation could be here shortly after the FDA runs out of excuses
to outlaw it.

Thomas

(4) University of Pennsylvania School of Medicine

A new way to make reprogrammed stem cells
Penn study eliminates the use of transcription factors and increases
efficiency 100-fold

PHILADELPHIA - Researchers at the University of Pennsylvania School of
Medicine have devised a totally new and far more efficient way of
generating induced pluripotent stem cells (iPSCs), immature cells that
are able to develop into several different types of cells or tissues
in the body. The researchers used fibroblast cells, which are easily
obtained from skin biopsies, and could be used to generate patient-
specific iPSCs for drug screening and tissue regeneration.

iPSCs are typically generated from adult non-reproductive cells by
expressing four different genes called transcription factors. The
generation of iPSCs was first reported in 2006 by Shinya Yamanaka, and
multiple groups have since reported the ability to generate these
cells using some variations on the same four transcription factors.

The promise of this line of research is to one day efficiently
generate patient-specific stem cells in order to study human disease
as well as create a cellular "storehouse" to regenerate a person's own
cells, for example heart or liver cells. Despite this promise,
generation of iPSCs is hampered by low efficiency, especially when
using human cells.

"It's a game changer," says Edward Morrisey, PhD, professor in the
Departments of Medicine and Cell and Developmental Biology and
Scientific Director at the Penn Institute for Regenerative Medicine.
"This is the first time we've been able to make induced pluripotent
stem cells without the four transcription factors and increase the
efficiency by 100-fold." Morrisey led the study published this week in
Cell Stem Cell.

Before this procedure, which uses microRNAs instead of the four key
transcription factor genes, for every 100,000 adult cells re-
programmed, researchers were able to get a small handful of iPSCs,
usually less than 20. Using the microRNA-mediated method, they have
been able to generate approximately 10,000 induced pluripotent stem
cells from every 100,000 adult human cells that they start with.
MicroRNAs (miRNAs) are short RNA molecules that bind to complementary
sequences on messenger RNAs to silence gene expression.

The Morrisey lab discovered this new approach through studies focusing
on the role of microRNAs in lung development. This lab was working on
a microRNA cluster called miR302/367, which plays an important role in
lung endoderm progenitor development. This same microRNA cluster was
reported to be expressed at high levels in embryonic stem cells, and
iPSCs and microRNAs have been shown to alter cell phenotypes.

The investigators performed a simple experiment and expressed the
microRNAs in mouse fibroblasts and were surprised to observe colonies
that looked just like iPSCs. "We were very surprised that this worked
the very first time we did the experiment," says Morrisey. "We were
also surprised that it worked much more efficiently than the
transcription factor approach pioneered by Dr. Yamanaka."

Since microRNAs act as repressors of protein expression, it seems
likely that they repress the repressors of the four transcription
factors and other factors important for maintaining the pluripotent-
stem-cell state. However, exactly how the miRNAs work differently
compared to the transcription factors in creating iPSCs will require
further investigation.

The iPSCs generated by the microRNA method in the Morrisey lab are
able to generate most, if not all, tissues in the developing mouse,
including germ cells, eggs and sperm. The group is currently working
with several collaborators to redifferentiate these iPSCs into
cardiomyocytes, hematopoietic cells, and liver hepatocytes.

"We think this method will be very valuable in generating iPSCs from
patient samples in a high-throughput manner" says Morrisey. microRNAs
can also be introduced into cells using synthetically generated
versions of miRNAs called mimics or precursors. These mimics can be
easily introduced into cells at high levels, which should allow for a
non-genetic method for efficiently generating iPSCs.

"The upshot is that we hope to be able to produce synthetic microRNAs
to transform adult cells into induced pluripotent stem cells, which
could eventually then be redifferentiated into other cell types, for
example, liver, heart muscle or nerve cells" says Morrisey.
[THIS RELATED AB SHOWS HUMAN CELLS ARE ALSO TRANSFORMABLE.]
Cell Stem Cell. 2011 Apr 8;8(4):376-88.
Highly efficient miRNA-mediated reprogramming of mouse and human
somatic cells to pluripotency.
Anokye-Danso F, Trivedi CM, Juhr D, Gupta M, Cui Z, Tian Y, Zhang Y,
Yang W, Gruber PJ, Epstein JA, Morrisey EE.
SourceDepartment of Medicine, University of Pennsylvania,
Philadelphia, PA 19104, USA.

Abstract
Transcription factor-based cellular reprogramming has opened the way
to converting somatic cells to a pluripotent state, but has faced
limitations resulting from the requirement for transcription factors
and the relative inefficiency of the process. We show here that
expression of the miR302/367 cluster rapidly and efficiently
reprograms mouse and human somatic cells to an iPSC state without a
requirement for exogenous transcription factors. This miRNA-based
reprogramming approach is two orders of magnitude more efficient than
standard Oct4/Sox2/Klf4/Myc-mediated methods. Mouse and human
miR302/367 iPSCs display similar characteristics to Oct4/Sox2/Klf4/Myc-
iPSCs, including pluripotency marker expression, teratoma formation,
and, for mouse cells, chimera contribution and germline contribution.
We found that miR367 expression is required for miR302/367-mediated
reprogramming and activates Oct4 gene expression, and that suppression
of Hdac2 is also required. Thus, our data show that miRNA and Hdac-
mediated pathways can cooperate in a powerful way to reprogram somatic
cells to pluripotency.

Copyright © 2011 Elsevier Inc. All rights reserved.

Comment in
Cell Stem Cell. 2011 Jun 3;8(6):599-601.
PMID: 21474102


XX

(8) Genes Dev. 2011 Nov 1;25(21):2248-53. doi: 10.1101/gad.173922.111.
Rejuvenating senescent and centenarian human cells by reprogramming
through the pluripotent state.
Lapasset L, Milhavet O, Prieur A, Besnard E, Babled A, Aït-Hamou N,
Leschik J, Pellestor F, Ramirez JM, De Vos J, Lehmann S, Lemaitre JM.
SourceLaboratory of Plasticity of the Genome and Aging, Institute of
Functional Genomics, Montpellier Cedex, France.
Abstract
Direct reprogramming of somatic cells into induced pluripotent stem
cells (iPSCs) provides a unique opportunity to derive patient-specific
stem cells with potential applications in tissue replacement therapies
and without the ethical concerns of human embryonic stem cells
(hESCs). However, cellular senescence, which contributes to aging and
restricted longevity, has been described as a barrier to the
derivation of iPSCs. Here we demonstrate, using an optimized protocol,
that cellular senescence is not a limit to reprogramming and that age-
related cellular physiology is reversible. Thus, we show that our
iPSCs generated from senescent and centenarian cells have reset
telomere size, gene expression profiles, oxidative stress, and
mitochondrial metabolism, and are indistinguishable from hESCs.
Finally, we show that senescent and centenarian-derived pluripotent
stem cells are able to redifferentiate into fully rejuvenated cells.
These results provide new insights into iPSC technology and pave the
way for regenerative medicine for aged patients. PMID: 22056670

(16) Stem Cells. 2010 Apr;28(4):721-33.
The senescence-related mitochondrial/oxidative stress pathway is
repressed in human induced pluripotent stem cells.
Prigione A, Fauler B, Lurz R, Lehrach H, Adjaye J.
SourceDepartment of Vertebrate Genomics, Molecular Embryology and
Aging Group, Max Planck Institute for Molecular Genetics, Ihnestrasse
73, D-14195 Berlin, Germany.

Abstract
The ability of stem cells to propagate indefinitely is believed to
occur via the fine modulation of pathways commonly involved in
cellular senescence, including the telomerase, the p53, and the
mitochondrial/oxidative stress pathways. Induced pluripotent stem
cells (iPSCs) are a novel stem cell population obtained from somatic
cells through forced expression of a set of genes normally expressed
in embryonic stem cells (ESCs). These reprogrammed cells acquire self-
renewal properties and appear almost undistinguishable from ESCs in
terms of morphology, gene expression, and differentiation potential.
Accordingly, iPSCs exhibit alterations of the senescence-related
telomerase and p53 signaling pathways. However, although treatments
with antioxidants have been recently shown to enhance cellular
reprogramming, detailed information regarding the state of the
mitochondrial/oxidative stress pathway in iPSCs is still lacking.
Mitochondria undergo specific changes during organismal development
and aging. Thus, addressing whether somatic mitochondria within iPSCs
acquire ESC-like features or retain the phenotype of the parental cell
is an unanswered but relevant question. Herein, we demonstrate that
somatic mitochondria within human iPSCs revert to an immature ESC-like
state with respect to organelle morphology and distribution,
expression of nuclear factors involved in mitochondrial biogenesis,
content of mitochondrial DNA, intracellular ATP level, oxidative
damage, and lactate generation. Upon differentiation, mitochondria
within iPSCs and ESCs exhibited analogous maturation and anaerobic-to-
aerobic metabolic modifications. Overall, the data highlight that
human iPSCs and ESCs, although not identical, share similar
mitochondrial properties and suggest that cellular reprogramming can
modulate the mitochondrial/oxidative stress pathway, thus inducing a
rejuvenated state capable of escaping cellular senescence.

PMID: 20201066

Paul Antonik Wakfer

ungelesen,
17.12.2011, 23:09:3117.12.11
an
Hi Thomas,

While I had seen/read most of these new developments, thanks for posting them in focused form.

On Saturday, December 17, 2011 4:07:14 PM UTC-7, Thomas Carter wrote:
> As of now in Dec. 2011 a revolution in understanding and controlling
> of aging has occurred.

IMO, this is an exaggeration. First, these results do not much enhance understanding of why and how aging dysfunction occurs, and, second, any result of them will not so much as "control" aging, but rather enable major amounts of rejuvenation. Whether such a method will enable in situ rejuvenation of the body's most important organ, the brain, still remains to be seen.

> The three papers below portend a blueprint for
> rapid advancement in life extension which could be at least partly in
> the clinic before 2020.

I am not nearly that optimistic and I certainly will not be stopping any of my current approaches and ongoing enhancement of them as a result of these new discoveries.

>
> Most human aging is caused by a programmed repression of four genes.
> (4) This repression can be eliminated by simple miRNA treatment (4)
> with consequent reversal of even 100 year old cells to a juvenile
> state. (8) Mitochondria? Not to worry, Mother Nature does all the
> work. (16)

I can fully accept the miRNA results since they are essentially the effective surrogates for larger gene transcription factors. However, I think some additional work needs to be done to show in more detail that restoring the cellular environment to an essential embryonic state will automatically eliminate all mitochondrial accumulated damage.

> While follow up studies will likely mitigate the claims of these three
> reputable teams, the fundamentals seem very likely to stand, and
> mitigating details likely to be overcome.
>
> Notably the treatment may even work in vivo with simple injection of
> the miRNAs. But at any rate rejuvenation in the lab with
> reimplantation could be here shortly after the FDA runs out of excuses
> to outlaw it.

This last is likely the biggest problem, particularly since it does not serve the interest of the FDA nor any State and the moneyed power been it to have a society of long-lived health people. The rational among them want longer healthier lives for themselves, but they definitely do not want such for the populace of which they are overlords, or they would not long retain their ruler status.

--
--Paul Wakfer

MoreLife for the rational - http://morelife.org
Reality based tools for more life in quantity and quality
The Self-Sovereign Individual Project - http://selfsip.org
Self-sovereignty, rational pursuit of optimal lifetime happiness,
individual responsibility, social preferencing & social contracting

Thomas Carter

ungelesen,
18.12.2011, 06:28:5618.12.11
an
Hi Paul,

I guess your're still working those weird hours, Kitty too?

On Dec 17, 11:09 pm, Paul Antonik Wakfer <p...@morelife.org> wrote:
> Hi Thomas,
>
> While I had seen/read most of these new developments, thanks for posting them in focused form.
>
> On Saturday, December 17, 2011 4:07:14 PM UTC-7, Thomas Carter wrote:
> > As of now in Dec. 2011 a revolution in understanding and controlling
> > of aging has occurred.
>
> IMO, this is an exaggeration. First, these results do not much enhance understanding of why and how aging dysfunction occurs, and, second, any result of them will not so much as "control" aging, but rather enable major amounts of rejuvenation. Whether such a method will enable in situ rejuvenation of the body's most important organ, the brain, still remains to be seen.
>
Cellular aging dysfuntion occurs because the four genes are repressed.
QED That's the whole point of Yamanata's work. The brain's another
matter. We need a breakthru badly. Gozes now has NAP in phase III
after a very successful phase II. Nasal insulin spray seems poised for
clinical use. These may be very helpful. In the meantime you might
think of adding low dose ibuprofen to your hi dose vitamin C and E.
Here's an article.

Vitamins E and C plus ibuprofen may protect against Alzheimer's
Last Updated: 2006-04-07 14:47:20 -0400 (Reuters Health)
By Karla Gale
SAN DIEGO (Reuters Health) - For patients at high risk of Alzheimer's
disease, taking a combination of vitamins E and C plus ibuprofen
significantly reduces their risk, results of a longitudinal study
suggest.
"We found that for people at low risk, taking vitamin C and E alone is
sufficient to further reduce their risk. But for those with
apolipoprotein epsilon-4 (APOE-epsilon-4) alleles, the combination
exerts a synergistic benefit," Dr. Majid Fotuhi told Reuters Health.
Dr. Fotuhi, from Johns Hopkins University in Baltimore, and his
associates prospectively followed nearly 5000 elderly residents of
Cache County in Utah for 8 years, taking into account their regular
consumption of vitamins C and E, ibuprofen, or a combination of the
three. Dr. Fotuhi reported the findings at the American Academy of
Neurology's 58th Annual Meeting here in San Diego.
They identified 127 subjects who regularly consumed all three agents.
Results showed that this group exhibited significantly less decline in
Modified Mini-Mental State Exam scores. After adjusting for age,
gender, APOE genotype, hypertension, cholesterol, stroke, coronary
artery bypass surgery, and MI, those who used all three agents
performed better than non-users by approximately 1 point every 2
years. [The range is 0-28 and the zero point is quite extreme, while
the 28 doesn’t really indicate good mental ability, since this test is
generally only given to people with dementia.]
"With this approach, we've advanced a 2-point attack on the cascade of
events that leads to Alzheimer's disease pathology," Dr. Fotuhi said.
"On the one hand, we reduce inflammation (with vitamins E and C), and
on the other hand, we reduce the amount of amyloid in the brain (with
ibuprofen), the substrate that causes inflammation."
As noted, APOE-epsilon-4 carriers experienced the greatest benefit
from the triple-combination treatment. According to the researchers'
presentation, this subset of patients in their late 60s or 70s
exhibited no decline in cognitive function during the 8-year follow-up
when they took all three agents. Subjects who took just one of these
agents had worsening memory over time.
"So if patients seem to be at high risk, such as having several family
members with Alzheimer's disease or with early memory loss, they are
likely to benefit the most from the triple-combination therapy," the
researcher said.
As to what dose of ibuprofen to use, Dr. Fotuhi urges caution, since
the drug is associated with gastric ulcers. He recommends a dose no
higher than 100 mg/day.
He is so encouraged by these findings that he has patented a
combination pill containing vitamins A and C, ibuprofen, and "a small
amount of omega-3 fatty acid." [Analysis of the full text, now free
on line reveals some flaws in this study, but still it's impressive.]
Alzheimer’s vs vitamin C
Alzheimer’s vs vitamin E
Alzheimer’s vs ibuprofen




> > The three papers below portend a blueprint for
> > rapid advancement in life extension which could be at least partly in
> > the clinic before 2020.
>
> I am not nearly that optimistic and I certainly will not be stopping any of my current approaches and ongoing enhancement of them as a result of these new discoveries.
>
It would be 12 years after Yamanata published, not out of line with
other new protocols. You have reasons for thinking this could not
happen?
>
> > Most human aging is caused by a programmed repression of four genes.
> > (4) This repression can be eliminated by simple miRNA treatment (4)
> > with consequent reversal of even 100 year old cells to a juvenile
> > state. (8)  Mitochondria?  Not to worry, Mother Nature does all the
> > work. (16)
>
> I can fully accept the miRNA results since they are essentially the effective surrogates for larger gene transcription factors. However, I think some additional work needs to be done to show in more detail that restoring the cellular environment to an essential embryonic state will automatically eliminate all mitochondrial accumulated damage.
>

We know it's possible since oocytes have been doing it for eons. The
mechanism seems to be that "stem" mitochondria which remain attached
to the endoplasmic reticulum divide, producing daughter cells that
proceed along micro tubles (in mammalian cells) to lysomes for
recycling. The stem mitochondrium divides with help of ER proteins and
is apparently kept relatively pristine, maybe by not producing much
energy. (same tactic as stem cells) There may be proof reading ER
proteins that assure defective DNA goes to the daughter cells. The
defective mitochondria papers we've all read for decades have been
done on the daughter cells, and therefore not germain as to the status
of the "stem" organelle.

I've long thought that proffessor Mother Nature should be getting most
of the Nobel prizes.

> > While follow up studies will likely mitigate the claims of these three
> > reputable teams, the fundamentals seem very likely to stand, and
> > mitigating details likely to be overcome.
>
> > Notably the treatment may even work in vivo with simple injection of
> > the miRNAs. But at any rate rejuvenation in the lab with
> > reimplantation could be here shortly after the FDA runs out of excuses
> > to outlaw it.
>
> This last is likely the biggest problem, particularly since it does not serve the interest of the FDA nor any State and the moneyed power been it to have a society of long-lived health people. The rational among them want longer healthier lives for themselves, but they definitely do not want such for the populace of which they are overlords, or they would not long retain their ruler status.
>

They would have to be very stupid then, since they are the ones
funding the reasearch. I don't believe there are nearly as many evil
overlords as you seem to. My take is for the most part that the issue
is far more complex. Despite the descrepancies of the ruling class we
seem to be making progress, and it seems to be accellerating. Saul
Kent's timeship may be our best hope, tho.


> --Paul Wakfer
>
> MoreLife for the rational -http://morelife.org
> Reality based tools for more life in quantity and quality
> The Self-Sovereign Individual Project -http://selfsip.org

Paul Antonik Wakfer

ungelesen,
18.12.2011, 14:59:2518.12.11
an
On Sunday, December 18, 2011 4:28:56 AM UTC-7, Thomas Carter wrote:
> Hi Paul,
>
> I guess your're still working those weird hours, Kitty too?

Obviously you have not been at all following our website personal updates. We have not been following a 28 hour day since 2005 when we moved from Toronto (where it was convenient and had some definite advantages) to make my cottage in Harcourt Park (160 miles north-east of Toronto) into our 6 month yearly (my legal) Canadian residence. We had already not followed it for the 2 previous half years that we spent in Arizona. For details see the link near the bottom of: http://morelife.org/personal/

The 28 hour day was merely an experiment lasting a short few years. While I did not have any noticeable biorhythm problems with it, Kitty's biorhythms never did completely resync. Since there were no studies of any such arrangement and since many studies suggested that it might even be harmful longterm, I was happy to have a reason for discontinuing it.

Finally, since we do almost everything together as team, there is no way that one of us would be following a different schedule than the other.

> On Dec 17, 11:09 pm, Paul Antonik Wakfer
> wrote:
> > Hi Thomas,
> >
> > While I had seen/read most of these new developments, thanks for posting
> > them in focused form.
> >
> > On Saturday, December 17, 2011 4:07:14 PM UTC-7, Thomas Carter wrote:
> > > As of now in Dec. 2011 a revolution in understanding and controlling
> > > of aging has occurred.
> >
> > IMO, this is an exaggeration. First, these results do not much enhance
> > understanding of why and how aging dysfunction occurs, and, second, any
> > result of them will not so much as "control" aging, but rather enable major
> > amounts of rejuvenation. Whether such a method will enable in situ
> > rejuvenation of the body's most important organ, the brain, still remains
> > to be seen.
> >
> Cellular aging dysfuntion occurs because the four genes are repressed.
> QED

That is your opinion and not proven conclusively. IMO there is a major difference between the increasing dysfunction of differentiated cells with time and the ability to revert a cell back to a pristine undifferentiated state.

> That's the whole point of Yamanata's work. The brain's another
> matter. We need a breakthru badly.

Exactly and until this problem is solved the rest is of lesser importance. A cognitively dysfunctional brain in a young virile body is not going to be attractive at all.

> Gozes now has NAP in phase III
> after a very successful phase II. Nasal insulin spray seems poised for
> clinical use. These may be very helpful. In the meantime you might
> think of adding low dose ibuprofen to your hi dose vitamin C and E.
> Here's an article.
>
> Vitamins E and C plus ibuprofen may protect against Alzheimer's
> Last Updated: 2006-04-07 14:47:20 -0400 (Reuters Health)
> By Karla Gale

I saw this when it first appeared, but it had little relevance to me since I am convinced that our entire lifestyle will completely prevent AD for me and Kitty.

[Snipped old article]

> > > The three papers below portend a blueprint for
> > > rapid advancement in life extension which could be at least partly in
> > > the clinic before 2020.
> >
> > I am not nearly that optimistic and I certainly will not be stopping any of
> > my current approaches and ongoing enhancement of them as a result of these
> > new discoveries.
> >
> It would be 12 years after Yamanata published, not out of line with
> other new protocols. You have reasons for thinking this could not
> happen?

Yes, and it will not be anywhere near a complete solution to aging dysfunction in any case.

> >
> > > Most human aging is caused by a programmed repression of four genes.
> > > (4) This repression can be eliminated by simple miRNA treatment (4)
> > > with consequent reversal of even 100 year old cells to a juvenile
> > > state. (8)  Mitochondria?  Not to worry, Mother Nature does all the
> > > work. (16)
> >
> > I can fully accept the miRNA results since they are essentially the
> > effective surrogates for larger gene transcription factors. However, I
> > think some additional work needs to be done to show in more detail that
> > restoring the cellular environment to an essential embryonic state will
> > automatically eliminate all mitochondrial accumulated damage.
> >
>
> We know it's possible since oocytes have been doing it for eons.

Not exactly, as far as I understand. 0ocytes are effectively dormant before they ripen and likely never accumulate much or any mitochondrial or nuclear damage.

> The
> mechanism seems to be that "stem" mitochondria which remain attached
> to the endoplasmic reticulum divide, producing daughter cells that
> proceed along micro tubles (in mammalian cells) to lysomes for
> recycling. The stem mitochondrium divides with help of ER proteins and
> is apparently kept relatively pristine, maybe by not producing much
> energy. (same tactic as stem cells) There may be proof reading ER
> proteins that assure defective DNA goes to the daughter cells. The
> defective mitochondria papers we've all read for decades have been
> done on the daughter cells, and therefore not germain as to the status
> of the "stem" organelle.

All this is still somewhat conjectural, so these mechanisms need to be more explored and firmed up before they are fully accepted. In addition more detailed analysis of all cellular aspects needs to be done (or the use of these apparently pristine stem cells to generate a cohort of new individuals with normal longevity) in order to more surely prove the complete reversion to effective ESC phenotype.

> I've long thought that proffessor Mother Nature should be getting most
> of the Nobel prizes.

No comment on an irrational anthropomorphic statement.

> > > While follow up studies will likely mitigate the claims of these three
> > > reputable teams, the fundamentals seem very likely to stand, and
> > > mitigating details likely to be overcome.
> >
> > > Notably the treatment may even work in vivo with simple injection of
> > > the miRNAs. But at any rate rejuvenation in the lab with
> > > reimplantation could be here shortly after the FDA runs out of excuses
> > > to outlaw it.
> >
> > This last is likely the biggest problem, particularly since it does not
> > serve the interest of the FDA nor any State and the moneyed power been it to

Note: "been" above should have read "behind".

> > have a society of long-lived health people. The rational among them want
> > longer healthier lives for themselves, but they definitely do not want such
> > for the populace of which they are overlords, or they would not long retain
> > their ruler status.
> >
>
> They would have to be very stupid then, since they are the ones
> funding the reasearch. I don't believe there are nearly as many evil
> overlords as you seem to. My take is for the most part that the issue
> is far more complex. Despite the descrepancies of the ruling class we
> seem to be making progress, and it seems to be accellerating. Saul
> Kent's timeship may be our best hope, tho.

I don't wish to continue this part of the discussion on this forum.
Die Nachricht wurde gelöscht

Thomas Carter

ungelesen,
20.12.2011, 12:20:0120.12.11
an
On Dec 19, 4:07 pm, MarkJ <Ma...@Use-Author-Supplied-Address.invalid>
wrote:
> Thomas Carter <tomcarter...@yahoo.com> wrote innews:4e431dfd-1f31-465f...@p9g2000vbb.googlegro
> ups.com:
Hi Paul,

After publication of Morrisey's data (4, reference above) it is known,
assuming his claims are valid, that all other postulated causes of
aging are irreversably causitive only when the cell permits. When the
cell does not cooperate in its aging by repressing the four Yamanaka
factors there is no aging, and in fact prior aging is reversed.

Therefore factors such as free radical damage, intracellular cross
linking, DNA damage, mtDNA damage, lipofuscin aggregration, autophagic
failure, etc, are secondary to "THE" cause of aging, which is
programmed repression of four genes.

The above reasoning is valid only for cellular aging, of course, in
fact at this point only for cellular aging in mitotic cells. and
strictly speaking only under the in vitro conditions used in the
Morrisey studies. Never the less we now know all drivers of the aging
process, long thought to be inevitable in somatic cells are reversible
and in fact easily reversed.

With this now known to apply to the cells of human centenarians (8),
and to their mitochondria (16) as well, we can indeed call this a true
revolution of epic proportions in the theory of human aging, assuming
the validity of the reports, of course. I note that the teams which
are American, French, and German respectively seem to be quite
reputable, as judged by subsequent reports such as that of Yamanaka,
himself, who said he will beging using the Morresey protocol in his
lab.

The more important question of practical application is one yet to be
answered, but a similar method has already be used to give elderly
mice reconstitued, youthful immune systems, and the same ability in
humans seems very probable and quite near, perhaps just five to ten
years.

Other tissues will be more problematic, but with aging theory now on
firm grounds and the new field of micro RNA (just three years old)
control of gene expression in its early period when geometric progress
is usually seen, who knows how fast we might now progress?

Nobably miRNA strands, which are normally just 20 base pairs long are
very easily incorporated by cells. The cell does all the work, there
is no toxicity due to the natural molecules, which are metabolised for
energy, and they have been reported to be very specific for thier
target genes (it's a process the cell itself uses). We really need to
do little more than develop methods for proper cellular targeting.
This field is also rapidly progressing as seen by the number of early
phase drug trials using it.

One caveat is that there are reports that the remethylation of
histones is a bit different in iPSC than the profile seen in embryonic
stem cells, and this may be a cause of less robust function. So
Morresey's claim of "complete" rejuvanation may be premature.

Thomas

Paul Antonik Wakfer

ungelesen,
20.12.2011, 17:00:1820.12.11
an
On Tuesday, December 20, 2011 10:20:01 AM UTC-7, Thomas Carter wrote:
> On Dec 19, 4:07 pm, MarkJ <Ma...@Use-Author-Supplied-Address.invalid>
> wrote:
> > Thomas Carter <tomcar...@yahoo.com> wrote innews:4e431dfd-1f31-465f...@p9g2000vbb.googlegro
> > ups.com:
> >
> >
> >
> >
> >
> > > Hi Paul,
> >
> > > I guess your're still working those weird hours, Kitty too?
> >
> > > On Dec 17, 11:09 pm, Paul Antonik Wakfer
> > >
Thomas, I hope that you are right, but I don't think that such a conclusion is sufficiently proven as yet. IMO, such a conclusion is contrary to the very reasonable evolutionary disposable soma notion, and I find it hard to be convinced that the cause of aging is that simple. Remember that radical new ideas require a great deal of evidence both before they are accepted as likely valid and before they are acted upon.

I have no further interest in discussing this, but rather will wait and see what transpires, meanwhile following the work of Blagosklonny and others to be as healthy and long lived as I can, based on current reasonable knowledge and attainable methods.

--
--Paul Wakfer

MoreLife for the rational - http://morelife.org
Reality based tools for more life in quantity and quality
The Self-Sovereign Individual Project - http://selfsip.org

Thomas Carter

ungelesen,
20.12.2011, 18:05:3720.12.11
an
Not at all contrary. Organisms that fail to repress the Yamanaka
factors will die early like an ant colony with too many queens, not
enough workers. But I agree with your assesment. It's far too early
for Yamanaka to book passage to Swedan.

> I have no further interest in discussing this, but rather will wait and see what transpires, meanwhile following the work of Blagosklonny and others to be as healthy and long lived as I can, based on current reasonable knowledge and attainable methods.

Speaking along these lines, have you seen this? I suppose another
thread would be more appropriate for this, but I've already started
here.

J Clin Endocrinol Metab. 2011 Apr;96(4):1006-14. Epub 2011 Feb 2.
Osteoporosis medication and reduced mortality risk in elderly women
and men.
Center JR, Bliuc D, Nguyen ND, Nguyen TV, Eisman JA.
SourceGarvan Institute of Medical Research, and St Vincent’s Hospital,
Sydney, New South Wales, Australia. j.ce...@garvan.org.au
Abstract
CONTEXT: Osteoporotic fractures are associated with premature
mortality. Antiresorptive treatment reduces refracture but mortality
reduction is unclear.
OBJECTIVE: The objective of the study was to examine the effect of
osteoporosis treatment [bisphosphonates (BP), hormone therapy (HT),
and calcium ± vitamin D only (CaD)] on mortality risk.
DESIGN: This was a prospective cohort study (April 1989 to May 2007).
SETTING: The study was conducted with community-dwelling elderly (aged
60+ yr) subjects in Dubbo, a semiurban city, Australia.
SUBJECTS: Subjects included 1223 and 819 women and men in the Dubbo
Osteoporosis Epidemiology Study.
MAIN OUTCOME MEASURE: Mortality according to treatment group was
recorded.
RESULTS: There were 325 (BP, n = 106; HT, n = 77; CaD, n = 142) women
and 37 men (BP, n = 15; CaD, n = 22) on treatment. In women, mortality
rates were lower with BP 0.8/100 person-years (0.4, 1.4) and HT
1.2/100 person-years (0.7, 2.1) but not CaD 3.2/100 person-years (2.5,
4.1) vs. no treatment 3.5/100 person-years (3.1, 3.8). Accounting for
age, fracture occurrence, comorbidities, quadriceps strength, and bone
mineral density, mortality risk remained lower for women on BP [hazard
ratio (HR) 0.3 (0.2, 0.6)] but not HT [HR 0.8 (0.4, 1.8)]. For 429
women with fractures, mortality risk was still reduced in the BP group
[adjusted HR 0.3 (0.2, 0.7)], not accounted for by a reduction in
subsequent fractures. In men, lower mortality rates were observed with
BP but not CaD [BP 1.0/100 person-years (0.3, 3.9) and CaD 3.1/100
person-years (1.5, 6.6) vs. no treatment 4.3/100 person-years (3.9,
4.8)]. After adjustment, mortality was similar, although not
significant [HR 0.5 (0.1, 2.0)].
CONCLUSIONS: Osteoporosis therapy appears to reduce mortality risk in
women and possibly men.
PMID: 21289270


The numbers are simply sensational, about one fourth the mortality of
the nontreated group, and almost as good vs the standard mortality
rate of Austraila as a whole. Confounders suggest even better numbers
yet.

The numbers I quote above are for the treatment period of 3.5 years
and a few years after. (seen in fig. 2) The numbers quoted in the ab
are for the entire 15 years follow up period. The mortality rate is
still lower at the ten year mark and only becomes normal from the ten
to fifteen year period.

Five of the thirteen deaths were due to pneumonia. (and macrophage
inhibition is documented in other papers.) The low number of deaths
make the study seem smaller than it was. (116 people on
bisphosphanates) They suffered only two deaths in the treatment period
and only four in the first six years. (about 11 expected due to the
standard mortality rate for Austrailia)

They reiview the literature and it is less spectacular, but still
strongly indicative of a mortality rate that beats the standard for
the general population. Most of the cohort used Alendronate, but
zolendronate may be better.

We seem to be looking at another antiaging drug based on the same
reasoning as metoprolol.

The drugs, of course, are replete with phosphate groups and may affect
any signalling pathway in incalculable ways. But a little searching
turns up the fact that they are fanesyltransferas inhibitors and
strongly inhibit progerin which is now known to exist at low levels in
aged cells, and is hypothesized to be proaging in normal people, and
proven so in vitro.

Thomas

>
> --
> --Paul Wakfer
>

Ingo Heinscher

ungelesen,
21.12.2011, 03:15:4521.12.11
an
Am 18.12.2011 00:07, schrieb Thomas Carter:
> As of now in Dec. 2011 a revolution in understanding and controlling
> of aging has occurred. The three papers below portend a blueprint for
> rapid advancement in life extension which could be at least partly in
> the clinic before 2020.
>
> Most human aging is caused by a programmed repression of four genes.
> (4) This repression can be eliminated by simple miRNA treatment (4)
> with consequent reversal of even 100 year old cells to a juvenile
> state. (8) Mitochondria? Not to worry, Mother Nature does all the
> work. (16)
>
> While follow up studies will likely mitigate the claims of these three
> reputable teams, the fundamentals seem very likely to stand, and
> mitigating details likely to be overcome.
>
> Notably the treatment may even work in vivo with simple injection of
> the miRNAs. But at any rate rejuvenation in the lab with
> reimplantation could be here shortly after the FDA runs out of excuses
> to outlaw it.

This is marvelous. Thank you for sharing that observation!



Thomas Carter

ungelesen,
21.12.2011, 14:04:0821.12.11
an
> This is marvelous. Thank you for sharing that observation!- Hide quoted text -
>
> - Show quoted text -

Wellkommen, hier ist klene mehr.

Maybe we'll see mice that crave french fries instead of cheese
someday.


(30) Stem Cells Restore Cognitive Abilities Impaired By Brain Cancer
Treatment
Article Date: 14 Jul 2011 - 5:00 PDT

Human neural stem cells are capable of helping people regain learning
and memory abilities lost due to radiation treatment for brain tumors,
a UC Irvine study suggests.

Research with rats found that stem cells transplanted two days after
cranial irradiation restored cognitive function, as measured in one-
and four-month assessments. In contrast, irradiated rats not treated
with stem cells showed no cognitive improvement.

"Our findings provide solid evidence that such cells can be used to
reverse radiation-induced damage of healthy tissue in the brain," said
Charles Limoli, a UCI radiation oncology professor.

Study results appear in the July 15 issue of Cancer Research, a
journal of the American Association for Cancer Research.

Radiotherapy for brain tumors is limited by how well the surrounding
tissue tolerates it. Patients receiving radiation at effective levels
suffer varying degrees of learning and memory loss that can adversely
affect their quality of life.

"In almost every instance, people experience severe cognitive
impairment that's progressive and debilitating," Limoli said.
"Pediatric cancer patients can experience a drop of up to three IQ
points per year."

For the UCI study, multipotent human neural stem cells were
transplanted into the brains of rats that had undergone radiation
treatment. They migrated throughout the hippocampus - a region known
for the growth of new neurons - and developed into brain cells.

Researchers assessed the rats one month and four months after
transplantation, noting enhanced learning and memory abilities at both
intervals.

Additionally, they found that transplanting as few as 100,000 human
neural stem cells was sufficient to improve cognition after cranial
irradiation. Of cells surviving the process, about 15 percent turned
into new neurons, while another 45 percent became astrocytes and
oligodendrocytes - cells that support cerebral neurons.

Most notably, Limoli said, he and his colleagues discovered that about
11 percent of the engrafted cells expressed a behaviorally induced
marker of learning, indicating the functional integration of those
cells into memory circuits in the hippocampus.

"This research suggests that stem cell therapies may one day be
implemented in the clinic to provide relief to patients suffering from
cognitive impairments incurred as a result of their cancer
treatments," Limoli said. "While much work remains, a clinical trial
analyzing the safety of such approaches may be possible within a few
years, most likely with patients afflicted with glioblastoma
multiforme, a particularly aggressive and deadly form of brain
cancer."

Munjal Acharya, Lori-Ann Christie, Mary Lan and Erich Giedzinski of
UCI and John Fike and Susanna Rosi of UC San Francisco contributed to
the study, which was funded by the California Institute for
Regenerative Medicine, the National Institutes of Health and the U.S.
Department of Energy.




(32) Stem Cells Restore Cognitive Abilities Impaired By Brain Cancer
Treatment
Article Date: 14 Jul 2011 - 5:00 PDT

Human neural stem cells are capable of helping people regain learning
and memory abilities lost due to radiation treatment for brain tumors,
a UC Irvine study suggests.

Research with rats found that stem cells transplanted two days after
cranial irradiation restored cognitive function, as measured in one-
and four-month assessments. In contrast, irradiated rats not treated
with stem cells showed no cognitive improvement.

"Our findings provide solid evidence that such cells can be used to
reverse radiation-induced damage of healthy tissue in the brain," said
Charles Limoli, a UCI radiation oncology professor.

Study results appear in the July 15 issue of Cancer Research, a
journal of the American Association for Cancer Research.

Radiotherapy for brain tumors is limited by how well the surrounding
tissue tolerates it. Patients receiving radiation at effective levels
suffer varying degrees of learning and memory loss that can adversely
affect their quality of life.

"In almost every instance, people experience severe cognitive
impairment that's progressive and debilitating," Limoli said.
"Pediatric cancer patients can experience a drop of up to three IQ
points per year."

For the UCI study, multipotent human neural stem cells were
transplanted into the brains of rats that had undergone radiation
treatment. They migrated throughout the hippocampus - a region known
for the growth of new neurons - and developed into brain cells.

Researchers assessed the rats one month and four months after
transplantation, noting enhanced learning and memory abilities at both
intervals.

Additionally, they found that transplanting as few as 100,000 human
neural stem cells was sufficient to improve cognition after cranial
irradiation. Of cells surviving the process, about 15 percent turned
into new neurons, while another 45 percent became astrocytes and
oligodendrocytes - cells that support cerebral neurons.

Most notably, Limoli said, he and his colleagues discovered that about
11 percent of the engrafted cells expressed a behaviorally induced
marker of learning, indicating the functional integration of those
cells into memory circuits in the hippocampus.

"This research suggests that stem cell therapies may one day be
implemented in the clinic to provide relief to patients suffering from
cognitive impairments incurred as a result of their cancer
treatments," Limoli said. "While much work remains, a clinical trial
analyzing the safety of such approaches may be possible within a few
years, most likely with patients afflicted with glioblastoma
multiforme, a particularly aggressive and deadly form of brain
cancer."

Munjal Acharya, Lori-Ann Christie, Mary Lan and Erich Giedzinski of
UCI and John Fike and Susanna Rosi of UC San Francisco contributed to
the study, which was funded by the California Institute for
Regenerative Medicine, the National Institutes of Health and the U.S.
Department of Energy.



(34) Implanted Neurons, Grown In The Lab, Take Charge Of Brain
Circuitry
Main Category: Neurology / Neuroscience
Article Date: 22 Nov 2011 - 1:00 PST
Among the many hurdles to be cleared before human embryonic stem cells
can achieve their therapeutic potential is determining whether or not
transplanted cells can functionally integrate into target organs or
tissues.

Writing today (Monday, Nov. 21) in the Proceedings of the National
Academy of Sciences, a team of Wisconsin scientists reports that
neurons, forged in the lab from blank slate human embryonic stem cells
and implanted into the brains of mice, can successfully fuse with the
brain's wiring and both send and receive signals.

Neurons are specialized, impulse conducting cells that are the most
elementary functional unit of the central nervous system. The 100
billion or so neurons in the human brain are constantly sending and
receiving the signals that govern everything from walking and talking
to thinking. The work represents a crucial step toward deploying
customized cells to repair damaged or diseased brains, the most
complex human organ.

"The big question was can these cells integrate in a functional way,"
says Jason P. Weick, the lead author of the new study and a staff
scientist at the University of Wisconsin-Madison's Waisman Center. "We
show for the first time that these transplanted cells can both listen
and talk to surrounding neurons of the adult brain."

The Wisconsin team tested the ability of their lab grown neurons to
integrate into the brain's circuitry by transplanting the cells into
the adult mouse hippocampus, a well-studied region of the brain that
plays a key role in processing memory and spatial navigation. The
capacity of the cells to integrate was observed in live tissue taken
from the animals that received the cell transplants.

Weick and colleagues also reported that the human neurons adopted the
rhythmic firing behavior of many brain cells talking to one another in
unison. And, perhaps more importantly, that the human cells could
modify the way the neural network behaved.

A critical tool that allowed the UW group to answer this question was
a new technology known as optogenetics, where light, instead of
electric current, is used to stimulate the activity of the neurons.

"Previously, we've been limited in how efficiently we could stimulate
transplanted cells. Now we have a tool that allows us to specifically
stimulate only the transplanted human cells, and lots of them at once
in a non-invasive way," says Weick.

Weick explains that the capacity to modulate the implanted cells was a
necessary step in determining the function of implanted cells because
previous technologies were too imprecise and unreliable to accurately
determine what transplanted neurons were doing.

Embryonic stem cells, and the closely related induced pluripotent stem
cells can give rise to all of the 220 types of tissues in the human
body, and have been directed in the lab to become many types of cells,
including brain cells.

The appeal of human embryonic stem cells and induced pluripotent cells
is the potential to manufacture limitless supplies of healthy,
specialized cells to replace diseased or damaged cells. Brain
disorders such as Parkinson's disease and amyotrophic lateral
sclerosis, more widely known as Lou Gehrig's disease, are conditions
that scientists think may be alleviated by using healthy lab grown
cells to replace faulty ones. Multiple studies over the past decade
have shown that both embryonic stem cells and induced cells can
alleviate deficits of these disorders in animal models.

The new study opens the door to the potential for clinicians to deploy
light-based stimulation technology to manipulate transplanted tissue
and cells. "The marriage between stem cells and optogenetics has the
potential to assist in the treatment of a number of debilitating
neurodegenerative disorders," notes Su-Chun Zhang, a UW-Madison
professor of neuroscience and an author of the new PNAS report. "You
can imagine that if the transplanted cells don't behave as they
should, you could use this system to modulate them using light."







Sheng Li Xue Bao. 2010 Feb 25;62(1):79-85.

[Anti-aging effect of transplantation of mouse fetus-derived
mesenchymal stem cells.]
[Article in Chinese]

Li J, Zhang Y, Liu GX.

Institute of Hematonosis, Medical School, Jinan University, Guangzhou
510632, China. E-mail: tli...@jnu.edu.cn.

To determine the role of allogeneil graft of mesenchymal stem cells in
mammalian longevity, mesenchymal stem cells were isolated from BALB/c
mouse uterine-incision delivery fetus by two successive density
gradient centrifugations, and then were purified and amplified by
adherent culture. Identified P1 mesenchymal stem cells were injected
(i.v.) through vena caudalis into the 15-month-old female BALB/c mice
three times. The mice were evaluated with ultrasoundcardiogram,
autopsy, score of cardiac, skin, lung, kidney, colon histopathology
and serum total superoxide dismutase activity, maleic dialdehyde
content, glutathione peroxidase activity. The results showed that
after transplantation, the long-term surviving stem cells were found
to be located in many organ tissues with in situ Y chromosomal
hybridization dyeing. Median life span was increased in these animals
after transplantation. Skin, cardiac, lung, kidney and colon pathology
development were delayed. The retrogradation of heart function was
attenuated, the increase of heart mass index (the mass of heart/the
mass of the body), and serum maleic dialdehyde content, the decrease
of spleen mass index (the mass of spleen/the mass of the body), serum
total superoxide dismutase activity and glutathione peroxidase
activity were reduced three months after transplantation (all P<0.05).
These results support the idea that longevity can be enhanced by
transplantation of mesenchymal stem cells and reinforce the hypothesis
of mesenchymal stem cell as antiager.

PMID: 20179893

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