83 replies to this topic

[niner]

Then there is the small matter of increasing or decreasing these proteins in the blood..?!

Yeah, if I understand the graph, it looks like the problem might be more one of proteins being upregulated in the old. Most of them look like inflammation-related cytokines and chemokines, so maybe that's a red herring. In a heterochronic parabiosis experiment, everything upregulated in the old would be diluted. But it might be more important to learn about the smaller number of proteins that are high in the young and low in the old, like GDF11. At any rate, this is really exciting work.

[VidX]

Very interesting. Now I can't help but wonder how many more organs can be at least partially "rejuvenated" by this method of young vs old blood.

[niner]

Very interesting. Now I can't help but wonder how many more organs can be at least partially "rejuvenated" by this method of young vs old blood.

probably some, given a constant supply of young blood. However, GDF11 is probably only going to help for hypertrophic hearts. For other organs, or for the entire organism, perhaps there are other key proteins or other factors that could be identified and supplemented. Doing heterochronic parabiosis with humans is pretty much out of the question, and faking it with transfusions probably isn't very practical either. I hope they start looking at everything that is differentially expressed in young and old blood.

[smithx]

Here's 50ug for $325. A bargain?
http://www.biovision...inant-3209.html

[Elus]

Very interesting. Now I can't help but wonder how many more organs can be at least partially "rejuvenated" by this method of young vs old blood.

probably some, given a constant supply of young blood. However, GDF11 is probably only going to help for hypertrophic hearts. For other organs, or for the entire organism, perhaps there are other key proteins or other factors that could be identified and supplemented. Doing heterochronic parabiosis with humans is pretty much out of the question, and faking it with transfusions probably isn't very practical either. I hope they start looking at everything that is differentially expressed in young and old blood.

I'm interested to know why GDF11 diminishes with age, and what its mechanism of action is.

Also, couldn't we use bacteria or yeast to manufacture GDF11 in much the same way we use bacteria to manufacture insulin? Alternatively, one could use a gene therapy encoding perhaps transcription factors for GDF11.

Also, this whole thing raises a much larger question for me: Is protein depletion during aging a form of damage that SENS must address?

Edited by Elus, 11 May 2013 - 08:40 AM.

[VidX]

Very interesting. Now I can't help but wonder how many more organs can be at least partially "rejuvenated" by this method of young vs old blood.

probably some, given a constant supply of young blood. However, GDF11 is probably only going to help for hypertrophic hearts. For other organs, or for the entire organism, perhaps there are other key proteins or other factors that could be identified and supplemented. Doing heterochronic parabiosis with humans is pretty much out of the question, and faking it with transfusions probably isn't very practical either. I hope they start looking at everything that is differentially expressed in young and old blood.

Yes, exactly... If identified even a few key proteins, which could keep some of the main organs in a better shape - it'd be a huge leap forward. Esp. as it's a simple "intervention", I mean - regular injections, like these of HGH or similar..

[smithx]

Also, couldn't we use bacteria or yeast to manufacture GDF11 in much the same way we use bacteria to manufacture insulin?

That's how the commercially available products are manufactured -- from bacterial fermentation with engineered E.coli.

[niner]

I'm interested to know why GDF11 diminishes with age, and what its mechanism of action is.

Also, this whole thing raises a much larger question for me: Is protein depletion during aging a form of damage that SENS must address?

GDF11 is related to myostatin, which probably gives a hint as to MoA. The bigger question, as you point out, regards the reason for depletion. Is it a consequence of simpler forms of damage that SENS already considers, is it an entirely new form of damage, or is it "programmed"?

[Avatar of Horus]

I'm interested to know why GDF11 diminishes with age, and what its mechanism of action is.

Also, this whole thing raises a much larger question for me: Is protein depletion during aging a form of damage that SENS must address?

... The bigger question, as you point out, regards the reason for depletion. Is it a consequence of simpler forms of damage that SENS already considers, is it an entirely new form of damage, or is it "programmed"?

It's an important question imo.

Something like this is the subject of my recent post (#15) in the 'Human and Mouse Life Extension DIYBio Stem Cells Experiment' topic, it can be read here:
http://www.longecity...post__p__586398

[Avatar of Horus]

...
The ageing systemic milieu negatively regulates neurogenesis and cognitive function

Nature. 2011 Aug 31;477(7362):90-4. doi: 10.1038/nature10357.
by Dr. Villeda and others.
Available on Pubmed too, its code is: 21886162.

...
also they tried to identify the factors with proteomic screening, and they've found some things,
which they also found in humans:
"We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans.
...
CCL11, at the top of this list, is a chemokine involved in allergic responses and not previously linked to aging, neurogenesis, or cognition. Relative levels of CCL11 were increased in plasma of mice during normal aging and within young mice during heterochronic parabiosis Furthermore, we detected an age-related increase in CCL11 in plasma and cerebrospinal fluid; from health human individuals between 20 and 90 years of age, suggesting that this age-related systemic increase is conserved across species."

and they also tested it:

"... increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors."
...

Some new results on this line of research from the BioscienceNews:
Inhibiting IFN-1 to Partially Restore Lost Cognitive Function
http://www.longecity...itive-function/

the qouted study's abstract:
Systemic factors mediate reversible age-associated brain dysfunction
Mendelsohn and Larrick
Rejuvenation Research - November 15 2014

Brain function declines in aging mammals. Recent work has identified dysregulation of key blood-borne factors whose altered expression during aging diminishes brain function in mice. Increased chemokine CCL11 expression with aging is detrimental to brain function. On the other hand, plasma levels of trophic factor GDF11 decrease with aging. Restoration of youthful levels of GDF11 by injection partially restores brain function and neurogenesis by improving endothelial cell function and vasculature. Moreover, GDF11 has a rejuvenative effect on cardiac and skeletal muscle.

Decreased IFN-II and increased IFN-I signaling during aging at the choroid plexus (CP), which constitutes the brain-cerebrospinal fluid barrier (B-CPF-B), negatively effects brain function. Blood from young mice contains factors that restore IFN-II levels. IFN-II is required for maintenance of the CP and low IFN-II levels are associated with decreased cognitive abilities.

IFN-1 levels appear to drive increased CCL11 expression through the cerebrospinal fluid (CSF). Blood from young animals does not restore IFN-1 levels. However, injecting anti-IFNAR antibodies into the CSF inhibits downstream IFN-I gene and protein expression, and decreases expression of CCL11, partially restoring neurogenesis and cognitive function. These results suggest that IFN-1 plays a critical role to increase CCL11 during aging of brain. An emerging theme is that aging-associated loss of function in mammals may involve a set of defined, potentially reversible changes in many tissues and organs, including the brain, permitting development of potential rejuvenative therapies.

Link: http://dx.doi.org/10...9/rej.2014.1643

[Avatar of Horus]

Another result in line with the previous ones: old environment/plasma is bad, young is good; also a new constituent was identified, haptoglobin:
 

Aging Systemic Milieu Impairs Outcome after Ischemic Stroke in Rats
Pan & Wang et al. 2017 Oct
https://www.ncbi.nlm...pubmed/28966798

Abstract
Compelling evidence indicates that factors in the blood can profoundly reverse aging-related impairments, as exposure of aged mice to young blood rejuvenates adult stem cell function, improves cognition, and ameliorates cardiac hypertrophy. Systemic factors from mice can also extend the life span of a partner exposed to a lethal treatment or disease. These findings suggest that the systemic milieu of a healthy young partner may be beneficial for an aged organism. However, it is unknown whether a healthy young systemic milieu can improve functional recovery after ischemic stroke. Intraperitoneal administration of young plasma into aged rats after ischemic stroke induced by distal middle cerebral artery occlusion (dMCAO) reduced infarct volume and motor impairment, compared with vehicle group. On the contrary, intraperitoneal administration of plasma from aged rats into young ischemic rats worsened brain injury and motor deficits. Using a proteomic approach, we found that haptoglobin levels were significantly increased in serum of aged rats and that intraperitoneal administration of haptoglobin impaired outcome after ischemic stroke in young rats. Our data suggest that the aging systemic milieu plays a critical role in functional outcome after ischemic stroke.

[albedo]

Another result in line with the previous ones: old environment/plasma is bad, young is good; also a new constituent was identified, haptoglobin:
 

Aging Systemic Milieu Impairs Outcome after Ischemic Stroke in Rats
Pan & Wang et al. 2017 Oct
https://www.ncbi.nlm...pubmed/28966798

Abstract
Compelling evidence indicates that factors in the blood can profoundly reverse aging-related impairments, as exposure of aged mice to young blood rejuvenates adult stem cell function, improves cognition, and ameliorates cardiac hypertrophy. Systemic factors from mice can also extend the life span of a partner exposed to a lethal treatment or disease. These findings suggest that the systemic milieu of a healthy young partner may be beneficial for an aged organism. However, it is unknown whether a healthy young systemic milieu can improve functional recovery after ischemic stroke. Intraperitoneal administration of young plasma into aged rats after ischemic stroke induced by distal middle cerebral artery occlusion (dMCAO) reduced infarct volume and motor impairment, compared with vehicle group. On the contrary, intraperitoneal administration of plasma from aged rats into young ischemic rats worsened brain injury and motor deficits. Using a proteomic approach, we found that haptoglobin levels were significantly increased in serum of aged rats and that intraperitoneal administration of haptoglobin impaired outcome after ischemic stroke in young rats. Our data suggest that the aging systemic milieu plays a critical role in functional outcome after ischemic stroke.

 

Interesting. I also came across haptoglobin genotyping as predictive of cardiovascular disease: it could be a genotype screening test for the CVD risk profile and easy treatment with Vitamin E.

[Avatar of Horus]

A recent study from rats:

 

Young plasma reverses age-dependent alterations in hepatic function through the restoration of autophagy

Liu et al. 2018

https://www.ncbi.nlm...pubmed/29210183

Abstract

Recent studies showing the therapeutic effect of young blood on aging-associated deterioration of organs point to young blood as the solution for clinical problems related to old age. Given that defective autophagy has been implicated in aging and aging-associated organ injuries, this study was designed to determine the effect of young blood on aging-induced alterations in hepatic function and underlying mechanisms, with a focus on autophagy. Aged rats (22 months) were treated with pooled plasma (1 ml, intravenously) collected from young (3 months) or aged rats three times per week for 4 weeks, and 3-methyladenine or wortmannin was used to inhibit young blood-induced autophagy. Aging was associated with elevated levels of alanine transaminase and aspartate aminotransferase, lipofuscin accumulation, steatosis, fibrosis, and defective liver regeneration after partial hepatectomy, which were significantly attenuated by young plasma injections. Young plasma could also restore aging-impaired autophagy activity. Inhibition of the young plasma-restored autophagic activity abrogated the beneficial effect of young plasma against hepatic injury with aging. In vitro, young serum could protect old hepatocytes from senescence, and the antisenescence effect of young serum was abrogated by 3-methyladenine, wortmannin, or small interfering RNA to autophagy-related protein 7. Collectively, our data indicate that young plasma could ameliorate age-dependent alterations in hepatic function partially via the restoration of autophagy.

 

[Avatar of Horus]

A review article from october 2017:

 

The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation

Conese et al. 2017

https://www.ncbi.nlm...pubmed/29104943

 

Abstract

Transfusion (or drinking) of blood or of its components has been thought as a rejuvenation method since ancient times. Parabiosis, the procedure of joining two animals so that they share each others blood circulation, has revitalized the concept of blood as a putative drug. Since 2005, a number of papers have reported the anti-ageing effect of heterochronic parabiosis, which is joining an aged mouse to a young partner. The hallmark of aging is the decline of regenerative properties in most tissues, partially attributed to impaired function of stem and progenitor cells. In the parabiosis experiments, it was elegantly shown that factors derived from the young systemic environment are able to activate molecular signaling pathways in hepatic, muscle or neural stem cells of the old parabiont leading to increased tissue regeneration. Eventually, further studies have brought to identify some soluble factors in part responsible for these rejuvenating effects, including the chemokine CCL11, the growth differentiation factor 11, a member of the TGF-ß superfamily, and oxytocin. The question about giving whole blood or specific factors in helping rejuvenation is open, as well as the mechanisms of action of these factors, deserving further studies to be translated into the life of (old) human beings.

 

KEYWORDS: Blood; Brain; CCL11; GDF11; Liver; Muscle; Oxytocin; Parabiosis; Rejuvenation

 

 

[albedo]

Interesting Avatar. Just in case you wish to also contribute to an interesting thread on a different path of rejuvenation by in vivo reprogramming where, only indirectly though, also touched heterochronic parabiosis, see  here.

[YOLF]

Certain types of CRISPER can reduce resistance to cancer. Simple base editing, or methods which don't create double strand breaks don't. So gene editing just becomes more of a project than previously expected.

[Major Legend]

So if somebody paid for treatments for young blood like in Ambrosia, do they need infusions daily? That would be my understanding, as the benefits from youthful plasma would wear out fast, wouldn't it? Perhaps weekly would be good.

Also, would it be possible for young plasma to be mixed with other anti-aging chemicals and be infused together? Anyone tried IV therapy here? I tried a Vitamin B one once, didn't seem to do much.

[YOLF]

What you really want is an immortal culture of young or rejuvenated cells and daily transdermal or subQ administration of an extract of the factors and hormones that come from it. So grow alot of cells, preferably your own, and have a process that allows you to make an extract from them daily without too much work and inject them subQ... maybe up to 3-4 times daily. Or maybe do it in big batches. It'll be like the homemade alcohol of the future!

 

Is Ambrosia a movie? Book? Never heard of it and can't find it...

[Major Legend]

What you really want is an immortal culture of young or rejuvenated cells and daily transdermal or subQ administration of an extract of the factors and hormones that come from it. So grow alot of cells, preferably your own, and have a process that allows you to make an extract from them daily without too much work and inject them subQ... maybe up to 3-4 times daily. Or maybe do it in big batches. It'll be like the homemade alcohol of the future!

 

Is Ambrosia a movie? Book? Never heard of it and can't find it...

Keeping mammalian (especially human) cells intact and not contaminated is extremely hard, it's so hard that many small labs simply can't do it. Perhaps in time such wetware technology would be available, but it is very far off at the moment

 

For example they can hardly culture muscle cells for food because you need so much antibiotics (which you know what problems can lead to). Mammalian cells are simply not equipped to survive without a active immune system protecting them, so they are very hard to culture and keep pure.

[YOLF]

Keeping mammalian (especially human) cells intact and not contaminated is extremely hard, it's so hard that many small labs simply can't do it. Perhaps in time such wetware technology would be available, but it is very far off at the moment

 

For example they can hardly culture muscle cells for food because you need so much antibiotics (which you know what problems can lead to). Mammalian cells are simply not equipped to survive without a active immune system protecting them, so they are very hard to culture and keep pure.

Well, there's obviously a way to do it if someone is... 

 

About a year ago, I looked into culturing 4F cells, the materials that were being used could be purchased prepackaged and ready to use even. It came complete with chemical indicators that would change color depending on pH... after that, it's just temperature and taking a sterile sample. Skin cells might be more difficult, but blood is fairly sterile afaiaa. I think the labs that can't do it, just don't have a clean rooms and don't use disposable wetlab equipment like this.

 

I could be overly optimistic... If I am, that's where we aught to be fundraising.

 

Of course, I seem to recall good results from simply doing periodic 4F IVs.

[Avatar of Horus]

Interesting Avatar. Just in case you wish to also contribute to an interesting thread on a different path of rejuvenation by in vivo reprogramming where, only indirectly though, also touched heterochronic parabiosis, see  here.

Thanks for the thread suggestion, I will check it out.

 

 

Very interesting. Now I can't help but wonder how many more organs can be at least partially "rejuvenated" by this method of young vs old blood.

 

Here is another one, the kidney:

Youthful systemic milieu alleviates renal ischemia-reperfusion injury in elderly mice
Liu et al. 2018 Aug
https://www.ncbi.nlm...pubmed/29935950

Abstract
The incidence of acute kidney injury (AKI) is high in elderly people, and is difficult to prevent and treat. One of its major causes is renal ischemia-reperfusion injury (IRI). A young systemic environment may prevent the senescence of old organs. However, it is unknown whether a young milieu may reduce renal IRI in the elderly. To examine this question, bilateral renal IRI was induced in old (24 months) mice three weeks after parabiosis model establishment. At 24 hours after IRI, compared to old wild-type mice, the old mice with IRI had significantly damaged renal histology, decreased renal function, increased oxidative stress, inflammation, and apoptosis. However, there was no increase in autophagy. Compared to old mice with IRI, old-old parabiosis mice with IRI did not show differences in renal histological damage, oxidative stress, inflammation, apoptosis, or autophagy, but did exhibit improved renal function. Compared to the old-old parabiosis mice with IRI, the old mice with IRI in the young (12 week)-old parabiosis showed less renal histological injury and better renal function. Renal oxidative stress, inflammation, and apoptosis were significantly decreased, and autophagy was significantly increased. Thus, a youthful systemic milieu may decrease oxidative stress, inflammation, and apoptosis, and increase autophagy in old mice with IRI. These effects ameliorated IRI injuries in old mice. Our study provides new ideas for effectively preventing and treating AKI in the elderly.

 
KEYWORDS: acute kidney injury; aging; ischemia-reperfusion injury; parabiosis animal model; young milieu

[Avatar of Horus]

Another result about the bad old environment, "as an underlying mechanism of impaired nerve regeneration during aging", and again the chemkine CCL11 was identified:
 

Inflammaging impairs peripheral nerve maintenance and regeneration
Büttner et al. 2018
https://www.ncbi.nlm...pubmed/30168637

Abstract
The regenerative capacity of peripheral nerves declines during aging, contributing to the development of neuropathies, limiting organism function. Changes in Schwann cells prompt failures in instructing maintenance and regeneration of aging nerves; molecular mechanisms of which have yet to be delineated. Here, we identified an altered inflammatory environment leading to a defective Schwann cell response, as an underlying mechanism of impaired nerve regeneration during aging. Chronic inflammation was detected in intact uninjured old nerves, characterized by increased macrophage infiltration and raised levels of monocyte chemoattractant protein 1 (MCP1) and CC chemokine ligand 11 (CCL11). Schwann cells in the old nerves appeared partially dedifferentiated, accompanied by an activated repair program independent of injury. Upon sciatic nerve injury, an initial delayed immune response was followed by a persistent hyperinflammatory state accompanied by a diminished repair process. As a contributing factor to nerve aging, we showed that CCL11 interfered with Schwann cell differentiation in vitro and in vivo. Our results indicate that increased infiltration of macrophages and inflammatory signals diminish regenerative capacity of aging nerves by altering Schwann cell behavior. The study identifies CCL11 as a promising target for anti-inflammatory therapies aiming to improve nerve regeneration in old age.

KEYWORDS: aging; inflammaging; macrophages; neural regeneration; peripheral nervous system; schwann cell

[Major Legend]

What info is there publically available for the company Ambrosia is actually planning?

[Avatar of Horus]

Another recent study about the kidney, where the "results demonstrated that a young blood environment significantly reduces kidney aging":
 

A Young Blood Environment Decreases Aging of Senile Mice Kidneys
Huang et al. 2018
https://www.ncbi.nlm...pubmed/29040401

Abstract
Whether changes in internal body environment affect kidney aging remains unclear. Specifically, it is unknown whether transplanted kidneys from older donors recover from tissue damage after placement in younger recipients. In this study, a parabiosis animal model was established to investigate the effects of a young internal body environment on aged kidneys. The animals were divided into six groups: young (Ycon) and old control (Ocon) groups, isochronic youth-youth group (Y-IP), elderly-elderly group (O-IP), and heterochronic youth (Y-HP) and elderly (O-HP) groups. After parabiosis, tubule and interstitial tissue scores in the O-HP group were significantly lower than in the Ocon and O-IP groups. The expression of aging-related protein p16 and SA-β-gal in the O-HP group was significantly reduced compared with the Ocon and O-IP groups. Autophagy factors Atg5 and LC3BII were significantly upregulated, whereas the expression of the autophagic degradation marker (P62) was significantly downregulated in the O-HP group compared with the Ocon and O-IP groups. With the same comparison, the positive cells of TUNEL staining and the expression of IL-6 and IL-1β were significantly reduced, whereas the total/cleaved caspase-3 and total/pNF-κB were significantly increased in the O-HP group. The results demonstrated that a young blood environment significantly reduces kidney aging. These findings provide new evidence supporting an increase in the upper age limit for human kidney transplantation donors.