39 replies to this topic

[APBT]

http://www.dailymail...ing-brains.html

 

 

It is not quite the fountain of eternal youth, but researchers have found a drug they say can rejuvenate ageing brain and muscle tissue.

The small-molecule drug simultaneously perks up old stem cells in the brains and muscles of mice.

The scientists hope the drug could lead to a treatments for old age, making ageing tissues throughout the body act young again.

 

 

 

Researchers at the University of California, Berkeley, found a a small-molecule drug simultaneously perks up old stem cells in the brains and muscles of mice, a finding that could lead to drug interventions for humans that would make tissues throughout the body act young again.

'We established that you can use a single small molecule to rescue essential function in not only aged brain tissue but aged muscle,' said David Schaffer.

'That is good news, because if every tissue had a different molecular mechanism for ageing, we wouldn't be able to have a single intervention that rescues the function of multiple tissues.'

The drug interferes with the activity of a growth factor, transforming growth factor beta 1 (TGF-beta1), that Schaffer's UC Berkeley colleague Irina Conboy showed over the past 10 years depresses the ability of various types of stem cells to renew tissue.

'Based on our earlier papers, the TGF-beta1 pathway seemed to be one of the main culprits in multi-tissue aging,' said Conboy, an associate professor of bioengineering.

'That one protein, when upregulated, ages multiple stem cells in distinct organs, such as the brain, pancreas, heart and muscle. 

'This is really the first demonstration that we can find a drug that makes the key TGF-beta1 pathway, which is elevated by ageing, behave younger, thereby rejuvenating multiple organ systems.

 

The UC Berkeley team reported its results in the current issue of the journal Oncotarget.Aging is ascribed, in part, to the failure of adult stem cells to generate replacements for damaged cells and thus repair the body's tissues. 

Researchers have shown that this decreased stem cell activity is largely a result of inhibitory chemicals in the environment around the stem cell, some of them dumped there by the immune system as a result of chronic, low-level inflammation that is also a hallmark of aging.

In 2005, Conboy and her colleagues infused old mice with blood from young mice - a process called parabiosis - reinvigorating stem cells in the muscle, liver and brain/hippocampus and showing that the chemicals in young blood can actually rejuvenate the chemical environment of aging stem cells.

Last year, doctors began a small trial to determine whether blood plasma from young people can help reverse brain damage in elderly Alzheimer's patients.

Such therapies are impractical if not dangerous, however, so Conboy, Schaffer and others are trying to track down the specific chemicals that can be used safely and sustainably for maintaining the youthful environment for stem cells in many organs. One key chemical target for the multi-tissue rejuvenation is TGF-beta1, which tends to increase with age in all tissues of the body and which Conboy showed depresses stem cell activity when present at high levels.

 

Five years ago, Schaffer, who studies neural stem cells in the brain, teamed up with Conboy to look at TGF-beta1 activity in the hippocampus, an area of the brain important in memory and learning. Among the hallmarks of aging are a decline in learning, cognition and memory. In the new study, they showed that in old mice, the hippocampus has increased levels of TGF-beta1 similar to the levels in the bloodstream and other old tissue.

Using a viral vector that Schaffer developed for gene therapy, the team inserted genetic blockers into the brains of old mice to knock down TGF-beta1 activity, and found that hippocampal stem cells began to act more youthful, generating new nerve cells.

The team then injected into the blood a chemical known to block the TGF-beta1 receptor and thus reduce the effect of TGF-beta1. This small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent, successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever, Conboy said.

'The key TGF-beta1 regulatory pathway became reset to its young signaling levels, which also reduced tissue inflammation, hence promoting a more favorable environment for stem cell signaling,' she said. 'You can simultaneously improve tissue repair and maintenance repair in completely different organs, muscle and brain.'

The researchers noted that this is only a first step toward a therapy, since other biochemical cues also regulate adult stem cell activity. Schaffer and Conboy's research groups are now collaborating on a multi-pronged approach in which modulation of two key biochemical regulators might lead to safe restoration of stem cell responses in multiple aged and pathological tissues.

'The challenge ahead is to carefully retune the various signaling pathways in the stem cell environment, using a small number of chemicals, so that we end up recalibrating the environment to be youth-like,' Conboy said. 'Dosage is going to be the key to rejuvenating the stem cell environment.'

 

HOW IT WORKS 

The drug interferes with the activity of a growth factor known as growth factor beta 1 (TGF-beta1).

Researchers have shown over the past 10 years this can depresses the ability of various types of stem cells to renew tissue.

They believe it effectively causes ageing - and blocking it can stop the process. 

 

[nightlight]

As always with any new "youth elixir" discovery, the ancient panacea, tobacco smoke, pushes the same biochemical levers the right way, toward rejuvenation. For example in this paper tobacco smoke was found to inhibit TGF-beta1 in human smokers, while this paper finds the same effect in vitro on human cell lines. No wonder big pharma and the rest of sickness industry are so eager to suppress this ancient medicinal plant and scare public away from it (by producing & peddling antismoking pseudo-science as well as buying antismoking laws & regulations). For further examples see also links to the highlights of the earlier Longecity thread Smoking is good for you.

[APBT]

Here’s another write-up on the study:  http://newscenter.be...d-aging-brains/

 

Here’s the abstract:  http://www.impactjou...iew&path[]=3851

 

 

ABSTRACT

Stem cell function declines with age largely due to the biochemical imbalances in their tissue niches, and this work demonstrates that aging imposes an elevation in transforming growth factor β (TGF-β) signaling in the neurogenic niche of the hippocampus, analogous to the previously demonstrated changes in the myogenic niche of skeletal muscle with age. Exploring the hypothesis that youthful calibration of key signaling pathways may enhance regeneration of multiple old tissues, we found that systemically attenuating TGF-β signaling with a single drug simultaneously enhanced neurogenesis and muscle regeneration in the same old mice, findings further substantiated via genetic perturbations. At the levels of cellular mechanism, our results establish that the age-specific increase in TGF-β1 in the stem cell niches of aged hippocampus involves microglia and that such an increase is pro-inflammatory both in brain and muscle, as assayed by the elevated expression of β2 microglobulin (B2M), a component of MHC class I molecules. These findings suggest that at high levels typical of aged tissues, TGF-β1 promotes inflammation instead of its canonical role in attenuating immune responses. In agreement with this conclusion, inhibition of TGF-β1 signaling normalized B2M to young levels in both studied tissues.

 

 

[xEva]

ok, so Galunisertib CAS# 700874-72-2 is one such "small molecule, an Alk5 kinase inhibitor already undergoing trials as an anticancer agent", which "successfully renewed stem cell function in both brain and muscle tissue of the same old animal, potentially making it stronger and more clever". Taken orally, too (!!)

The other one is TEW-7197 CAS# 1352608-82-2, also taken orally.

dosages unclear. The compounds are available from various labs for reasonable prices.

Who will be the first?

Edited by xEva, 14 May 2015 - 05:40 AM.

[Florian Xavier]

pentoxiflline inhibit tgf b1 in humans

[APBT]

Here's a link to the full text of the study:  http://www.impactjou...851&path[]=8731

 

 

[Turnbuckle]

As always with any new "youth elixir" discovery, the ancient panacea, tobacco smoke, pushes the same biochemical levers the right way, toward rejuvenation. For example in this paper tobacco smoke was found to inhibit TGF-beta1 in human smokers, while this paper finds the same effect in vitro on human cell lines. No wonder big pharma and the rest of sickness industry are so eager to suppress this ancient medicinal plant and scare public away from it (by producing & peddling antismoking pseudo-science as well as buying antismoking laws & regulations). For further examples see also links to the highlights of the earlier Longecity thread Smoking is good for you.

 

 

It was certainly not good for people in the study you linked to--

 

This study demonstrates that, after fracture, TGF-β1 serum concentrations are reduced by smoking, and this reduction is statistically significant during the 4th week after surgery. Our findings may help reveal the mechanism by which smoking impairs fracture healing.

 

 

 

Or in this one--

 

Conclusions: Nicotine is a potent regulator of bFGF and TGF-β1 production and release by aortic SMC, and it seems to play an important role in the development and progression of atherosclerosis and neointimal fibrous hyperplasia. 

 

 

Or this one--

 

Abstract We have recently shown that tobacco smoking, like ultraviolet A radiation, is an important factor contributing to premature skin aging. We found that tobacco smoke extract decreased type I and III procollagen, increased tropoelastin mRNA, and induced abnormal accumulation of proteoglycans and matrix metalloproteinase (MMP)-1 and MMP-3 in cultured skin fibroblasts. This indicated that common molecular features might underlie the premature aging of the skin induced by tobacco smoke extract, including abnormal regulation of extracellular matrix deposition through elevated MMPs, reduced collagen production, abnormal tropoelastin accumulation, and altered proteoglycans. With the exception that reactive oxygen species were mediated in the aging process, transforming growth factor (TGF)-β1 was found to play a crucial role in the age-related alterations induced by tobacco smoke extract. Here we report that tobacco smoke extract blocks cellular responsiveness to TGF-β1 through the induction of a non-functional latent form of TGF-β1, and downregulation of the TGF-β1 receptor. This paper shows the evidence for the role of tobacco smoking in skin aging and describes how modulation of TGF-β1 levels might retard premature skin aging.

 

[Kalliste]

As always with any new "youth elixir" discovery, the ancient panacea, tobacco smoke, pushes the same biochemical levers the right way, toward rejuvenation. For example in this paper tobacco smoke was found to inhibit TGF-beta1 in human smokers, while this paper finds the same effect in vitro on human cell lines. No wonder big pharma and the rest of sickness industry are so eager to suppress this ancient medicinal plant and scare public away from it (by producing & peddling antismoking pseudo-science as well as buying antismoking laws & regulations). For further examples see also links to the highlights of the earlier Longecity thread Smoking is good for you.

Maybe you should start a separate topic to debate this weird tobaccoconspiracy?

[nightlight]

 

It was certainly not good for people in the study you linked to--

 

This study demonstrates that, after fracture, TGF-β1 serum concentrations are reduced by smoking, and this reduction is statistically significant during the 4th week after surgery. Our findings may help reveal the mechanism by which smoking impairs fracture healing.

 

 

 

"Our findings may [or may not] help reveal the mechanism by which smoking impairs fracture healing. Furthermore, these results may [or may not] help to establish a serological marker that predicts impaired fracture healing soon after the injury."

 

It a nutshell, a wishful speculation spun out of the observation that tobacco smoke (also, nicotine alone) inhibits TGF-β1, which is the only pertinent observation. Note also that they don't claim causal role of TGF-β1 levels, but merely of being a marker e.g. like firetruck or firemen presence in front of a house being a marker for fire damaged houses.

 

Can you point to any study where the same objection to this TGF-β1 effect of nicotine (which is BTW hailed in the top post as the latest "youth elixir" candidate and the rest of thread is discussion how to lower it after all) has been raised regarding pharma's nicotine products (nicotine replacement "therapy")?

 

"Or in this one--"

 

That link doesn't point to your quote but to the article I brought up. Your actual link should have gone here.

 

Conclusions: Nicotine is a potent regulator of bFGF and TGF-β1 production and release by aortic SMC, and it seems to play an important role in the development and progression of atherosclerosis and neointimal fibrous hyperplasia. 

 

Nicotine is growth stimulant in variety of tissues (one aspect being the rejuvenation effect discussed). Of course, if you deliberately smear any growth stimulant locally in high concentration over cells you don't wish to grow, the result is predictably undesirable. I would be also curious to see any "study" of this kind on pharma nicotine (NRT) which the same doctors will push on their smoking patients without a second thought about the above effect on aortic SMC. In case you bring it up, they'll have a ready explanation how the concentration on aortic SMC are not nearly at the levels used in above experiments.

 

Or this one--

 

Abstract We have recently shown that tobacco smoking, like ultraviolet A radiation, is an important factor contributing to premature skin aging. We found that tobacco smoke extract decreased type I and III procollagen, increased tropoelastin mRNA, and induced abnormal accumulation of proteoglycans and matrix metalloproteinase (MMP)-1 and MMP-3 in cultured skin fibroblasts. This indicated that common molecular features might underlie the premature aging of the skin induced by tobacco smoke extract, including abnormal regulation of extracellular matrix deposition through elevated MMPs, reduced collagen production, abnormal tropoelastin accumulation, and altered proteoglycans. With the exception that reactive oxygen species were mediated in the aging process, transforming growth factor (TGF)-β1 was found to play a crucial role in the age-related alterations induced by tobacco smoke extract. Here we report that tobacco smoke extract blocks cellular responsiveness to TGF-β1 through the induction of a non-functional latent form of TGF-β1, and downregulation of the TGF-β1 receptor. This paper shows the evidence for the role of tobacco smoking in skin aging and describes how modulation of TGF-β1 levels might retard premature skin aging.

 

Luckily most smokers don't gratuitously smear concentrated "tobacco smoke extract" over their skin fibroblasts. With pack a day smoker of full strength cigarettes, there is about ~100mg of tobacco smoke matter (like 1/3 of aspirin in a tiny tablet consisting of mostly fillers, or 2 drops of water) absorbed from that pack spread out across the 70-90 square yards of internal lung surface. That's concentration comparable to taking 2 drops of water and spreading them over back yard deck or a swimming pool.

 

 

 

[xEva]

well, as a struggling with addiction ex-(almost!)-smoker, I'm not too keen to see this kinda info, but thanks anyway.

The other down-regulator of TGF-β signaling pathway is Ganoderma lucidum (reishi) -- BTW, I have a few extra pounds of Ganoderma tzugae (north-American equivalent of reishi, collected personally in local hemlock woods), whole, dried, great stuff. PM me if interested.

[Florian Xavier]

pentoxifylline, quercertain, dasatinib for a cocktail :D

[Turnbuckle]

@nightlight

 

I hope you've included that photographic comparison of a movie star with the leader of Germany as a joke. The only useful such comparison is with closely related people in statistically relevant numbers, like with twins. And speaking of twins, here is a paper comparing mortality for identical and non-identical twins--1515 twin pairs where one twin smoked and the other did not. The relative risk for all-cause mortality after 24 years was 2.5 for the smokers as compared to the non-smokers, and it didn't matter much if they were identical. Heavy smokers had a worse risk ratio than light smokers, as expected. So smoking is not "good for you." Now, if you want to make some argument about nicotine alone, that might be a different story.

Edited by Turnbuckle, 15 May 2015 - 11:00 AM.

[Florian Xavier]

I mean, there are many compounds that alone, seems to somewhat reverse signs of aging.

 

quercertain, dasatinib

Pentoxifylline (tgf-b1 inhibitor)

 

Are they others ? 

[Avatar of Horus]

in muscle:

Follistatin improves skeletal muscle healing after injury and disease through an interaction with muscle regeneration, angiogenesis, and fibrosis
Zhu et al. 2011
http://www.ncbi.nlm....pubmed/21689628
 
... The findings of this study suggest that follistatin is a promising agent for improving skeletal muscle healing after injury and muscle diseases, such as the muscular dystrophies.
...
In response to traumas and disease, the local secretion of transforming growth factor (TGF)-ß1, a potent fibrotic cytokine, induces the formation of fibrosis in various tissues and organs, including skeletal muscles.1, 2, 3, 4, 5, 6, 7, 8, 9 Various agents, including suramin,10, 11 interferon-γ,12 decorin,5, 8, 13, 14, 15 relaxin,16, 17 and losartan,9,18 have been shown to significantly enhance skeletal muscle regeneration, reduce fibrosis in injured muscles, and, in a broad spectrum of myopathic diseases, partially block TGF-ß1.
...
Myogenic differentiation, in particular, involves sequential steps where myoblasts initially retract from the cell cycle and thereafter differentiate and fuse into multinucleated myotubes. TGF-ß1 inhibits myoblast differentiation, and although muscle cells are able to withdraw from the cell cycle when cultured in fusion induction medium supplemented with TGF-ß1, these cells fail to fuse into myotubes as is evidenced by the lack of muscle creatine kinase and nicotinic acetylcholine receptor expression.47 Here, we have shown that TGF-ß1 inhibits the myogenic differentiation of C2C12 myoblasts in fusion induction medium. In contrast to the extensive myotube formation observed in the control C2C12 cells not treated with TGF-ß1, there were only a few small myotubes interspersed among numerous nuclei (blue) in cell cultures treated with TGF-ß1 (Figure 7A). In cell cultures treated with both TGF-ß1 and increasing concentrations of follistatin, follistatin was observed to counteract TGF-ß1's inhibition of the C2C12 myoblast's myogenic capacity (Figure 7A). The fusion indices indicated that follistatin significantly increased the myogenic differentiation capacity of the C2C12 myoblasts and that TGF-ß1 significantly decreased their myogenic differentiation capacity. Moreover, follistatin prevented TGF-ß1 from inhibiting myogenesis and partially restored the myogenic differentiation capacity of the C2C12 myoblasts exposed to TGF-ß1 (Figure 7B). Follow-up experiments demonstrated that follistatin also decreased TGF-ß1 expression by the C2C12 myoblasts with and without the exogenous application of TGF-ß1 (Figure 7C). In addition, the TGF-ß1 signaling pathway relies on the activation of an intracellular SMAD signaling cascade, and our results indicated that follistatin blocks this pathway by reducing the expression and phosphorylation of SMAD2 (Figure 7D). ...

[xEva]

Yeah so it's interesting that there is a number of compounds, including natural ones, that downregulate or block this TGF-ß1 pathway in various ways. Yet in the study in question they use specifically "anticancer agent", presumably Galunisertib. Why?

And then "Conboy said. 'Dosage is going to be the key to rejuvenating the stem cell environment.'"

Any ideas on that?

Edited by xEva, 16 May 2015 - 11:40 PM.

[Steve H]

Irina is likely talking about the dosages of various compounds that will need balancing if the stem cell environment is to be rejuvenated. She talks about various pathways in her beyond parabiosis video on YouTube And it's worth a watch btw

[Avatar of Horus]

Yeah so it's interesting that there is a number of compounds, including natural ones, that downregulate or block this TGF-ß1 pathway in various ways. Yet in the study in question they use specifically "anticancer agent", presumably Galunisertib. Why?

And then "Conboy said. 'Dosage is going to be the key to rejuvenating the stem cell environment.'"

Any ideas on that?

 

I think they were using this, from the study:

"TGF-β1 Type I Receptor Kinase Alk5 inhibitor 2-(3-(6-Methylpyridin-2-yl)-1H-pyrazol-4-yl)-1,5-naphthyridine (Enzo Life Sciences) diluted in sunflower seed oil to a concentration of 57.4 μM."

 

ALK5 Inhibitor II - ALX-270-445 - Enzo Life Sciences

http://www.enzolifes...5-inhibitor-ii/

 

Irina is likely talking about the dosages of various compounds that will need balancing if the stem cell environment is to be rejuvenated. She talks about various pathways in her beyond parabiosis video on YouTube And it's worth a watch btw

Yes I think it is something similar.
Also their paper writes:

...

Various studies have demonstrated that not just one signaling pathway, but a network of highly interactive pathways including Notch, Wnt, BMP, Shh, TNF-α, IGF, and IL-6 are affected by the aging process [1, 2, 46]. For example, Wnt signaling has been demonstrated to decrease in aged hippocampi and contribute to the decline of adult hippocampal neurogenesis [1, 44, 58, 59]. Furthermore, IL-6 becomes elevated in the old and especially at the sites of tissue damage [60], is secreted by activated microglia, and is known to promote inflammation in part via support of Th17 cells and up-regulation of MHC class I and class II gene expression [32, 61, 62]. Therefore, it is possible that the age-specific increase in TGF-β1 signaling may contribute to the excess of IL-6 or other inflammatory cytokines such as IL-17, and consequentially experimental attenuation of TGF-β1 may result in lower levels of inflammatory cytokines and normalized levels of MHC I proteins. The detailed understanding of the age-specific cytokine interplay in the neurogenic and myogenic niches would be interesting to uncover in future comprehensive studies.

 

BTW one of my own research works is focusing on this, the various cell signaling and communication mechanisms and interactions in the multiple layers, but with biological modelling/simulation and systems biology approach. So I agree that such "comprehensive studies" may produce good insights and results.

[Steve H]

I am a friend of Dr katcher and he has worked on parabiosis in the past. He essentially says the problem we have with signals is there are potentially so many that targeting and regulating the levels would be very tricky. Irina and others have identified some key pathways that would no doubt boost health and lifespan.

I take the view that gene expression is controlled significantly by telomeres and the effect they have on gene expression via the telomere position effect (Wright and Shayne & Fossel).as they shorten through replication and damage this reprograms the cell and the histone and methylation patterns then begin to drift increasingly promoting dysfunction. Studies like these are very interesting as it shows aging is malleable but I suspect they are downstream effects of damage and telomere attrition/gene expression changes.

Imo whilst they spend decades working out all the pathways to produce a therapy it might be a good idea to intervene upstream with telomeres and see how much of an effect it has and if it slows or stops the epigenetic drift.

Irina is one of my favourite scientists and if anyone can work it out she and Michael can. Her beyond parsbiosis talk on YouTube is very informative indeed.

I do believe signals are the key to age reversal but I think gene therapy not small molecule solutions will be the better and far faster answer to targeting pathways and telomeres. There have been many pathways identified but the question I have is how many are needed if telomeres are maintained and keeping gene expression tighter?

[Avatar of Horus]

I am a friend of Dr katcher and he has worked on parabiosis in the past. He essentially says the problem we have with signals is there are potentially so many that targeting and regulating the levels would be very tricky. Irina and others have identified some key pathways that would no doubt boost health and lifespan.

Yes, that's why imho the systems biology approach is needed, to see the overall picture, and what can be achieved by manipulating the signals.
 

Irina is one of my favourite scientists and if anyone can work it out she and Michael can. Her beyond parsbiosis talk on YouTube is very informative indeed.

It's possible that one or two people will be enough, but equally that it may need a collective of 10000 or more scientists in collaboration, or a strong AI, to achieve it.
 

... telomeres

Regarding telomeres:
I've argued, too, for the possible roles of telomeres in life extension, based on their ability to immortalize certain cell lines,
and also the initial mouse results are promising:

Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer
Bernardes de Jesus et al. 2012
http://www.ncbi.nlm....pubmed/22585399
Abstract
A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.

Comment in: Telomerase gene therapy: a novel approach to combat aging. EMBO Mol Med. 2012

But whether it will be enough in itself or not, I don't know.

BTW as TGFB1: "this cytokine also became elevated in old blood serum" (from the topic's paper), it is possible that it affects the telomeres too, because this growth factor can inhibit the telomerase:

Role of Smad3 in the regulation of rat telomerase reverse transcriptase by TGFbeta
Hu et al. 2006
http://www.ncbi.nlm....pubmed/16205635
 
Transforming growth factor β suppresses human telomerase reverse transcriptase (hTERT) by Smad3 interactions with c-Myc and the hTERT gene
Li et al. 2006
http://www.ncbi.nlm....pubmed/16785237

 

Transforming growth factor-β inhibits telomerase through SMAD3 and E2F transcription factors

Lacerte et al. 2008

http://www.ncbi.nlm....pubmed/17881189

 

[Steve H]

Dr Harold Katcher is going to do a HPE experiment this year with a person would this be something the community might be interested in supporting? I understand he has specific technique and has arranged for equipment, volunteers and someone to perform it apparently. He wants to use the following assays:

 

Blood tests
Cytokines and antibodies (some may not be feasible the first 8 are required, 11 is highly preferred as are 11 – 15.
1. CRP
2. TNF-alpha
3. TGF-beta
4. IL-10
5. IL-6
6. IL-1
7. Soluble TNF-receptor (type I)
8. Soluble TNF-receptor (type II)
9. Autoantibodies/ – against a variety of factors (RF, ANA, anti-thyroid Ab)
10. Immune complexes
11. BNP (brain natriuretic protein)
12. granulocyte colony-stimulating factor (G-CSF)
13. CCL-11 (‘eotaxin’)
14. MIG (monokine induced by gamma interferon)
15. macrophage colony-stimulating factor (M-CSF)
16. Exosomes RNA content (if only – would require ‘deep sequencing’)

Lymphocytes
1. FACS for distribution of b-cells, t-cells (CD-3, CD-28) CD4+, CD25+, CD8+ CD28+
2. P16INK4a expression in T – cells

Metabolism
1. Insulin and glucose
2. IGF-1
3. Lipids and apolipoproteins (apo A1, apoB, apoC, apoE)
4. Testosterone (free)
5. Hemoglobin concentration
6. DHEA
7. Free T3
8. Sedimentation rate

Other factors (cellular factors also in the blood (or liver, skin – we need an earlier marker than HSC rejuvenation)
1. Telomerase
2. Telomere length
3. MMP-9
4. miRNA expression profiling (qPCR)

Safety labs
1. CBC
2. LFT’s
3. BUN and creatinine

Functional Testing
1. Cognitive ability/memory testing (computerized?)
2. Physical strength, Up and Go
3. Presbyopia
4. FEV
5. Age-specific quality of life scale

Senescent Symptoms to be photographed (with a ruler alongside)
1. Balding patterns
2. Age spots
3. Senile fold (earlobe)

 

[Steve H]

Obviously those assays would be for a full on study but perhaps a small pilot hpe study is something we can grass roots fund.

Hpe should have impressive results as it has in animals and very likely restores telomeres too.young Blood factors definitely do lengthen telomeres as shown in a study I could link but as a new member cannot. There is a 2009 study that shows telomerase expression increases in hscs exposed to androgens, these ofc would be in youthful blood and helps explain why we see rejuvenation in parabiosis and hpe studies.

Regards telomeres and their epigenetic control of gene expression I heard a project called telocyte is being planned to bring htert therapy to fda trials. This I believe is a joint project between Dr Fossel and Dr blasco, they are using the same aav gene therapy used by bioviva sciences apparently.

[niner]

Excuse my ignorance, but what's HPE?

[Steve H]

Sorry it is hetrochronic plasma exchange or in other words young plasma into an old system to rejuvenate the stem cells etc...

[niner]

And Katcher is doing this with a human?  How much plasma is the person going to get?   Unlikely to be enough, unless he has access to a LOT of young blood.

[ceridwen]

Would it be very expensive?

[Steve H]

Niner I am unsure but possibly a fair amount for a short while. Previous rodent studies showed liver regeneration and other organs in under five weeks and that was IIRC around a 5% infusion of plasma. Alkahest is doing a weekly whole blood transfusion but I suspect Dr Katcher is looking at a good amount for a few weeks. I will try to find out though it is likely to be a fair amount in order to sufficiently expose the system to the younger factors. I see no reason why we would not see some level of rejuvenation from this as as has been seen in rodent studies going back decades. It's a question about dosage and frequency and once he proves it works I think the hope is to assay the factors responsible of which we already know some.

 

The plasma will contain all the signals required to restore the system and Dr Katcher essentially believes it could even reboot the Endocrine system so the body begins secreting it's own youthful factors again. This does make some sense if the cells responsible for secreting those factors are told to get back to work again but it's an unknown until it is tested. We have certainly seen Thymus and other organs regenerate using factors, the big question is will those organs resume youthful secretion themselves if sufficiently exposed to young milieu?

 

I have seen papers that show factors can activate telomerase (eg, Adrogens to this in HSCs for example) and restore telomeres, if the telomeres are then restored then that would alter gene expression via TPE and could possibly encourage gene expression to revert back to a youth like state. I think that is the essence of what he is trying to prove or indeed disprove. 

He has also published a new paper here that is interesting:

 

http://www.ncbi.nlm....pubmed/25902455

 

As to cost a small proof of concept is likely within the reach of grassroots funding but a full on test with all the listed assays probably in the order of around a Million dollars at a guess.

 

 

Edited by Steve H, 20 May 2015 - 10:04 AM.

[Kalliste]

I like the idea but I still worry that he will use too little too infrequently, a negative result will probably kill of the idea for the time being which would be sad.

 

If he succeeds that will be another nail in the wall of the pro-death church.

[Steve H]

I will try to find out but I think he was talking about 1.5 plasma units every few days so we are talking about a roughly 80% exchange keeping the levels pretty high otherwise as he has said it will not be enough to make the epigenetic changes he suspects will happen as they have in rodent studies. I know he says that the Alkahest frequency is far too low so I suspect he has a lot more exposure in mind. Not without risks of course but not trying and aging is equally as risky he has pointed out.

 

I think Telomeres will also be reset via these factors as this 2009 study shows they do in hematopoietic cells and there is plenty of reason to suspect other factors would do likewise in other cells, but of course we will not know unless we try.

 

http://www.bloodjour...so-checked=true

 

I think a small scale study is certainly something grass roots could support and I think if done right and rejuvenation is demonstrated money for further studies would cease to be an issue IMO. 

[Kalliste]

Thats the kind of thing I would happily donate to. If he is worried about safety issues he could do a dose-escalation study. If money is the limiting problem for him he should ask for donations. It will be interesting to see how it works out, lets hope they don't get stuck in a lab for eternity looking for the synthetic version of this treatment.

[alc]

" I would happily donate to" - same here! and I'm sure lots of other people will do as we want to see results, besides papers.

 

Can Logecity community organize something like that?

 

So we can help Dr. Katcher to move on and have a study done, similar like Ichor Therapeutics have done with C60?