31 replies to this topic

[G-e-e]

Discussion?

 

 

Scientists have made a breakthrough towards creating a pill that can reverse signs of ageing.

A compound that could have a dramatic effect in restoring hair loss, kidney function and physical energy has been discovered.

It 'seeks and destroys' broken, ageing cells that accumulate as we get older, Dutch researchers claim.

Known as senescent cells, they are widely considered to contribute to many age-related diseases.

 

Full Article here 

http://www.dailymail...l#ixzz4cDmOgInF

 

 

So.... what is this modified FOX04 peptide? Anyone here trailing it and/or can recommend vendors?

 

 

[bitstorm]

Interested in this also

 

[elfanjo]

subscribing

[Mind]

Remember that mouse studies rarely translate into anything actionable for humans. Mouse studies are just the first small step in a long process to determine whether or not any particular substance is valuable for human health. Instead of gambling with your health buying peptides, you should be donating money to continuing research...seriously.

 

(normal caveat, of course, if you are old and/or dying, try anything you wish, throw caution to the wind).

[Rocket]

If there is a group buy, I'm in!

[G-e-e]

Remember that mouse studies rarely translate into anything actionable for humans. Mouse studies are just the first small step in a long process to determine whether or not any particular substance is valuable for human health. Instead of gambling with your health buying peptides, you should be donating money to continuing research...seriously.

 

(normal caveat, of course, if you are old and/or dying, try anything you wish, throw caution to the wind).

 

I would absolutely agree.

 

It seems that human trials though are starting in Australia in a couple of months and it's set to hit the shelves in a few years however.

2nd News article and video: https://thewest.com....y-ng-b88424326z

 

The scientists in the article are referencing something called: nicotinamide mononucleotide.

 

Exciting times ahead!

Edited by G-e-e, 25 March 2017 - 01:55 AM.

[Valijon]

The Fox04 peptide is available from some labs. Even if you can get it you don't know how much needs to be injected. How much is enough and how much is either dangerous or a waste of money. I'd read up on more clinical trials before trying anything.

Nmn has been discussed for some time here. It all centers on increasing NAD+

[HaplogroupW]

The Fox04 peptide is available from some labs.

 

OK spill the beans Valijon.
 

[HaplogroupW]

 

So.... what is this modified FOX04 peptide?

 

It's a senolytic.

 

FOX04-DRI:

 

http://www.cell.com/...8674(17)30246-5

 

They're talking about it over in the Dasatinib group buy thread. It turns out Dasatinimib + Quercetin is not selective against senescent cells, whereas this new FOX04-DRI peptide is. If you believe the referenced article.

 

 

Edited by Postprandial, 27 March 2017 - 05:12 AM.

[MikeDC]

Taking NAD+ precursors like Nicotinamide Riboside is probably a much better way to attack aging.

[Valijon]

I'll compile a list of places I saw selling Fox04 when I can. NR should only be one tool in our arsenal of polytherapy.

[Valijon]

https://us.vwr.com/s...-peptide-prosci

https://www.thermofi...eptide/PEP-1088

https://www.novoprol...ide-318716.html

[Valijon]

We should examine leptomycin B for inhibition of fox04. It looks like it could inhibit fox01 and fox0e. I don't know if we should be doing this yet.

[pieter cloete]

Peptide targeting senescent cells restores stamina, fur, and kidney function in old mice.

The Link:-   https://www.scienced...70323141414.htm

Very interesting

 

[Alpharius]

The peptide which is disrupting Foxo4-P53 binding has been made with d-aminoacids and has been constructed with the mice gene/protein sequence, plus it has been tagged with an additional protein to enhance the  absorption into cells.

[Logic]

This is being discussed in the links below.

http://www.longecity...lthspan/page-15

http://www.longecity...m-nyles/page-13

[Rocket]

So.... what is this modified FOX04 peptide?

It's a senolytic.

FOX04-DRI:

http://www.cell.com/...8674(17)30246-5

They're talking about it over in the Dasatinib group buy thread. It turns out Dasatinimib + Quercetin is not selective against senescent cells, whereas this new FOX04-DRI peptide is. If you believe the referenced article.

What do you mean by not selective? It works in all tissues or it doesn't target only senescent cells?

[HaplogroupW]

 

What do you mean by not selective? It works in all tissues or it doesn't target only senescent cells?

 

 

That statement was made based on this from the paper:

 

 

Quercetin and Dasatinib have been reported to be non-specific (Chang et al., 2016). We found no selectivity toward senescent IMR90 (Figure S3B), and therefore this cocktail was not explored further.

 

So they didn't find it to be selective toward senescent lung cells, and I don't know what Chang et al found. Perhaps it is too much to conclude from that they're not selective towards senescent cells in any tissue.

[ClarkSims]

It looks like someone else had the same idea of making a peptide chain that inhibits FOXO4, and patented it. I wonder what became of this? https://www.google.c...s/US20130288981

Edited by ClarkSims, 01 April 2017 - 03:47 PM.

[ClarkSims]

I am having a hard time understanding the effects of FOXO4 expression and inhibition. It sounds like fasting upregulates FOXO4, while these senolytics bind to FOXO4, and inhibit expression via RNA transcription.  It seems odd that fasting, which increases lifespan and healthspan, would upregulate a gene that is associated with senescence. https://pdfs.semanti...df5ed61f76b.pdf

To clarify the mechanisms involved in the regulation of these factors in vivo, we investigated in the present study whether or not, and if so how, their mRNA levels in rat liver respond to the stimuli of several nutritional and hormonal factors. Imposed fasting for 48 h significantly elevated mRNA levels of FoxO1 (1.5-fold), FoxO3 (1.4-fold), and FoxO4 (1.6-fold).

[ClarkSims]

Here is a FOXO3 inhibitor that reduces muscle atrophy in animals with tumors. I wish there was more research on Zhimu and Huangbai. It appears to have similar effects as the FOXO4 inhibitor.

http://www.mascc.org...rch_2016-18.pdf

[Nate-2004]

FOX03 is long known for its anti-aging effects when activated, I'm baffled as to why inhibiting it would do anything positive. I have the GG alleles on my FOX03 gene which is a good sign I'll live past 100, so why would inhibiting FOXO3 have any kind of anti-aging effect??

[MikeDC]

FOX03 is long known for its anti-aging effects when activated, I'm baffled as to why inhibiting it would do anything positive. I have the GG alleles on my FOX03 gene which is a good sign I'll live past 100, so why would inhibiting FOXO3 have any kind of anti-aging effect??

I think one third of people have FOXO3 gene activated and live longer. Others can take astaxanthin to activate it.

[ClarkSims]

The authors believe that FOXO4 is "stuck" and needs to be downregulated.

The FOXO's are usually discussed together. After I reread this several times I realized they are talking about FOXO4 and only FOXO4.

 

IMR90 fibroblasts and IMR90 induced to senesce by ionizing
radiation (IR) (Rodier et al., 2011). As senescent cells are report-
edly apoptosis-resistant (Wang, 1995), we expected pro-
apoptotic genes to be repressed. Surprisingly, however, senes-
cent IMR90 showed an upregulation of prominent pro-apoptotic
‘‘initiators’’ PUMA and BIM while the anti-apoptotic ‘‘guardian’’
BCL-2 was reduced (Figures 1A and S1A). This suggested se-
nescent IMR90 are primed to undergo apoptosis but that the
execution of the death program is restrained. We reasoned
such a brake could potentially be a transcriptional regulator
and focused on transcription factors that have previously
been linked to apoptosis, including STAT1, 2, and 4; RELB;
NFkB; TP53; and FOXO4 (Figures 1B and S1B). Interference
with JAK-STAT signaling is known not to affect the viability of
senescent cells (Xu et al., 2015), and we have previously
observed similar effects for NFkB and p53 inhibition (Freund
et al., 2011; Rodier et al., 2009). Our interest was therefore
directed to a factor that has not yet been studied as such,
FOXO4 (Figure 1B). FOXO4 belongs to a larger mammalian fam-
ily, with FOXO1 and 3 being its major siblings. FOXOs are well
studied in aging and tissue homeostasis as targets of insulin/
IGF signaling and as regulators of reactive oxygen species (de
Keizer et al., 2011; Eijkelenboom and Burgering, 2013; Martins
et al., 2016). Whereas senescence-inducing IR showed only
mild effects on the expression of FOXO1 and 3, both FOXO4
mRNA and protein expression progressively increased (Figures
1C and 1D). We therefore wondered whether FOXO4 could
function to balance senescence and apoptosis.

 

[Florian E.]

As fantastic this news is, to finally have a proper senolytic agent like FOXO4-DRI, just keep in mind:

 

1. The FOXO4 in humans is slightly different then in mice. So, maybe there have to be some peptide differences for humans as well concerning the mentioned mice peptide formular: "LTLRKEPASEIAQSILEAYSQNGWANRRSGGKRP"

2. There are currently also a lot of other senolytic agent tests ongoing. And everybody is eager to report some success reports. So waiting a bit longer for serious results is probably not a bad idea.

3. The problem of senescent cells does usually only affect older people !! Senescent cells increase exponentially from Age 15 = ~4% senescent cells to a maximum of about 20% senescent around age 90.

    Graph would look like this:

 

 

 

 

So, i personally would't start with senolytics under age 60. Also a small amount of senescent cells (about 4-5 %) should remain because small percentage is needed for different purposes (e.g. wound healing, and other, partly unknown functions) 

 

 

[MikeDC]

Senescent cells can be rejuvenated with Niagen. So use Niagen for 6 months, then use senolytics. If you use senolytics first, you will unnecessarily kill tons of good cells.

[Nate-2004]

I don't know what I'm ill informed about with regards to FOXO3 but it was highly unnecessary to mark my post as being ill informed, since I was asking a question and stating my confusion about the matter.

 

I just finished a round of D+Q at age 42 so you're probably right, I should just wait till 55 but if "inflammaging" is related to SASP from senescent cells, why do people begin to show signs of age so much sooner than 40? I realize there are other factors to aging than just senescent cells but it's something I would question given the above graph.

Edited by Nate-2004, 10 April 2017 - 03:39 PM.

[Florian E.]

I don't know what I'm ill informed about with regards to FOXO3 but it was highly unnecessary to mark my post as being ill informed, since I was asking a question and stating my confusion about the matter.

 

I just finished a round of D+Q at age 42 so you're probably right, I should just wait till 55 but if "inflammaging" is related to SASP from senescent cells, why do people begin to show signs of age so much sooner than 40? I realize there are other factors to aging than just senescent cells but it's something I would question given the above graph.

 

Someone also just gave me a "ill informed" vote, without uttering what's actually wrong...

Maybe it's because the senescent cell statistics is based on primates.(?)

If someone has accurate data on age + %-percent of senescent cells based on humans, you're welcome ! I personally couldn't find information about that.

 

To do senolytics you first have to know how much of senescent cells you have at which age.

So I made this exponential graph according to data from this article:

https://www.fightagi...t-cells-anyway/

Quote:

the Brown team began to study aging animals - baboons living on a research preserve that ranged in age from 5 to 30. In human years, that age range is roughly 15 to 90. ... For replicative senescence, the most important biomarker is telomere dysfunction-induced foci, or TIFs. Presence of these structures signals that the protective chromosome caps called telomeres have dwindled enough to halt cell division. ... What they found: The number of senescent cells increased exponentially with age. TIF-positive cells made up about 4 percent of the connective tissue cell population in 5-year-olds. In 30-year-olds, that number rose as high as 20 percent.

 

 

Regarding your question on inflammation... As you said, lets not forget that there are also other pro-inflammatory factors while aging.

And that should not be a surprise since we know that for expample NAD+ and Glutathion levels go done after age 30, just to name 2 important.

(if my data is correct regarding humans) Significant inflammation by senescent cells is (imho) only a factor later in life, triggered by the degradation of other systems (for example autophagy).

But maybe someone has better intel about age and amount of senescent cells and at which age it would make sense to do senolytics. 

Edited by Florian E., 10 April 2017 - 05:37 PM.

[Nate-2004]

Well I already did D+Q so I'm guessing it can wait a few years till they find something far more effective. I don't know what other pro inflammatory factors there are besides SASP. I was under the assumption that NAD+ falls, hypothetically due to SASP which also involves a rise in CD38, Stephen says he's testing the hypothesis now. I don't know about glutathione though. That's news to me. I recall glutathione was a balancing act and mentioned in de Gray's book on Ending Aging.

[Nate-2004]

Here is the fighting aging article posted last month on this FOXO4 - P53 stuff:

 

https://www.fightagi...-p53-crosstalk/