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All the latest hype in anti-aging lately has been the research on senolytics. I learned about the astounding drug FOXO4-DRI after talking to Tristan from Ascendence Biomedical.

This led me to De Keizer's research in targeting "senescent cells", the findings so far of the efficacy of a peptide they have created called FOXO-DRI is astounding. It may be the most promising life extension chemical on the horizon right now, that can be sourced and bought if you had the right contacts.

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Peptide targeting senescent cells restores stamina, fur, and kidney function in old mice | EurekAlert! Science News

Regular infusions of a peptide that can selectively seek out and destroy broken-down cells that hamper proper tissue renewal, called senescent cells, showed evidence of improving healthspan in naturally aged mice and mice genetically engineered to rapidly age. The proof-of-concept study, published March 23 in Cell, found that an anti-senescent cell therapy could reverse age-related loss of fur, poor kidney function, and frailty. It is currently being tested whether the approach also extends lifespan.

Removing Senescent Cells from the Lungs of Old Mice Improves Pulmonary Function and Reduces Age-Related Loss of Tissue Elasticity – Fight Aging!

The open access paper linked below provides another reason to be optimistic about the therapies to clear senescent cells from old tissues that are presently under development. Here, the researchers created genetically engineered mice in which they could selectively trigger senescent cell death in lung tissues. In older mice, the result was improved pulmonary function,...

Cleara Biotech Launches to Develop Senolytic Therapies Based on FOXO4-DRI – Fight Aging!

The accumulation of senescent cells is thought to be one of the root causes of aging, and a growing body of evidence points to their direct contribution to numerous age-related conditions. Removing senescent cells is a narrow form of rejuvenation, capable of turning back measures of aging and age-related disease. Last year researchers published data...

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“This is the paper that started it all...

Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging.

The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability.

We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging XpdTTD/TTD and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.

What is FOXO4 and What is FOXO4-DRI?

FOXO4 is a protein in humans associated with longevity and linked to cancer, it is important for many cellular pathways, a lot of these pathways have modulating effects on lifespan.

The protein is encoded by the FOXO4 gene. To elaborate, genes are sections of code that exist in the DNA strands that encode and trigger production of the said protein - if expressed. The name for both the gene and the protein is exactly the same which can cause some confusion with people, as such FOXO4 the protein and FOX04 the gene is not the same thing.

Genes have specific locations on the genome. In this case, FOXO4 is located on the long arm of the X chromosome from base pair 71,096,148 to 71,103,533.

FOXO4 is a member of a family of chemicals all which use a winged helix domain for DNA binding. The family includes FOXO1, FOXO3 and FOXO6.

This family's proteins are modified by many activities after construction, such as phosphorylation, ubiquitination, and acetylation, which affects FOXO3's binding affinity for DNA.

This lets FOXO4 act on many pathways such as cell cycle progression, oxidative stress, insulin signaling, life span/longevity and cell death (apoptosis).

FOXO4's effects have been shown to include the IGF signaling pathway, by deactivating insulin, this turns on many pathways associated with longevity. Many types of cancers have been documented to contain mutations that deactivate FOXO4, prohibiting proper cell cycle progression and regulation.

FOXO4-DRI, full name Foxo4 D-Retro-Inverso Peptide. Was first reported in the paper 'Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxcity and Aging'  is a synthetic protein designed to disrupt the FOX04's proteins interaction with p53, this kill senescent cells (by triggering them to destroy themselves) which are one of the major causes of aging.

^ In the study the elderly rats restored fitness, fur density and renal function in both genetically aged mice and naturally aged mice, thus proving a REVERSAL of aging after the loss of healthy function has already occurred.

This breakthrough research is the basis of all the work and money being poured into FOXO4-DRI at the moment.

What Are The Potential Benefits of FOXO4-DRI Gene Therapy?

FOXO4-DRI was originally developed as a senolytic.

What is a Senolytic? Why would they be beneficial?

A senolytic is a substance that clears senescent or aged cells that do not multiply anymore from the body.

A senescent cell is a cell that has reached its aging limit, known as the Hayflick Limit. All human cells reach the Hayflick Limit unless they are cancer cells. A human cell has a limited amount of times it can undergo mitosis and replicate because DNA damage occurs everytime it does.

Usually, at this point, cells undergo apoptosis. Sometimes, cells don't.

A cell that gets to this point has entered a phase known as senescence. Senescent cells do not undergo normal cell death (apoptosis - programmed cell death). 

Full details of senescent cells are too detailed to cover entirely here, but they no longer replicate, however, remain metabolically active and often become pro-inflammatory by expressing genes that create inflammatory signaling. Senescent cells increase with age, and are purportedly one of the main drivers of aging.

As we age, senescent cell numbers get to a tipping point where it disrupts healthy cells due to the chemical messages sent from them, causing an increasing amount of cells turning senescent. This is thought to be why aging speeds up rapidly towards the later years of life.

Therefore, a senolytic that clears senescent cells would, in theory, reverse the many ill effects of aging such as deteriorated hair, skin, muscle, athletic performance, sleep, cognitive alertness, and so on.

Basically, whilst a senolytic is not going to cure aging, it is a treatment to one of the major contributors to the aging process (if it works). 

Lab results on mice so far as shown that FOXO4-DRI extends the life of mice exactly in the way a senolytic should hypothetically reverse and slow down aging. 

Early results are promising, but exactly to what extent and what benefits a human would gain from using FOXO4-DRI is currently unknown.

Also in theory, as far as I can understand it, senescence cells would only be needed to be cleared away every now and then to counter aging, it would not be a continuous treatment, which may make high cost worth it.

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Mechanism of Action of FOXO4-DRI - How does It Work?

FOXO4-DRI is a safe but broken version of the FOXO4 protein, when introduced to the body it works by interfering with a mechanism called P53.



Again, it is important to note FOXO4-DRI is NOT normal FOXO4. It is a MIMICK using D-amino acids in a retro-reversed sequence. FOXO4-DRI is a completely human engineered peptide that is designed for anti-aging. (This is really important). FOXO4-DRI also has a higher affinity for p53 than FOXO4 itself. It is also important to note that the molecule is not perfect, and lead scientist Dr. Keizer is trying to create a better version with a spin off company.

When scientists studied senescent cells they found that they lack proteins to trigger apoptosis (programmed cell death) and a high number of proteins which inhibit apoptosis, upon further research they identified FOXO4's P53 mechanism as the cause of stopping natural apoptosis.

Remember senescent cells no longer act like normal cells, so their gene expression is abnormal compared to healthy cells. In senescent cells, FOXO4 is elevated.

p53 is a protein that FOXO4 binds to. p53 is a tumor supressor, when it detects a mutation in the cell's DNA - it triggers apoptosis. p53 is VERY IMPORTANT! This means switching off p53 is very bad and is in fact one of the causes of cancer.

FOXO4 is in the nucleus and DOES NOT LEAVE whilst p53 works at the mitochondria, when FOXO4 is bound to p53, p53 gets STUCK in the nucleus because the p53 can't leave the nucleus where it was created. p53 needs to get to the mitochondria to trigger apoptosis. 

So how does FOXO4-DRI work?

FOXO4-DRI is a MODIFIED version of FOXO4 which looks and acts like FOXO4 but travels EVERYWHERE in the cell. 

So when FOXO4-DRI is introduced, it binds to p53 and allows the p53 to reach the mitochondria where it could do its function and trigger apoptosis. Allowing the senescent cells to die.

 

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The Results on Mice

FOXO4-DRI has had amazing results on mice. In the seminal publication they tested the peptide on 3 mouse models in vivo.

  1. In chemotoxicity, by damaging the mouse's organs using induced senescence.
  2. In mice that have had their aging accelerated.
  3. In mice that have aged naturally.

In all 3 models, FOXO4-DRI successfully reversed aging characteristics (such as hair loss, decreased renal function) and extended lifespan in mice significantly. Note FOXO-4 only addresses one of the 7 major pillars of aging, so the best result a good extension of lifespan not immortality of cells or mice. 

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What are the Risks of FOXO4-DRI?

For human use the current risk is pretty simple, there are simply no human studies for FOXO4-DRI. That hasn't stopped people from synthesizing the peptide and trying it on themselves.

Dr. De Keizer the lead scientists of the original study says he believes the molecule is too heavy-handed for every ten senescent cells FOXO4-DRI triggers apoptosis it drags one healthy cell to die. He believes this ratio could be drastically improved by designing an even better peptide, something that has a ratio of currently 10:1 to 100:1.

It is also unclear whether senescent cells are important for function or exactly what role they play. The fact they stay around and don't die could be a natural mechanism or it could be an accident of evolution, whilst FOXO4-DRI was safe in mice, this may not translate to humans. Humans are different and more complicated organisms even if they are both mammalian and share a large number of similar systems and organ designs.

An example Dr. De Keizer gives is, what if senescent cells in the brain and they are memories, wouldn't removing the cells "delete" a person's memory. If a person is of advanced age then there will be many senescent cells in the brain.

For people trying to get ahead of the race by sourcing and buying FOXO4-DRI the quality of the peptide may also be questionable, injecting the wrong peptide may risk the person's health if the FOXO4-DRI is not verified by third-party means.

FOXO4-DRI for Sale on the Internet and Human Experimentation

As human greed would have it, FOXO4-DRI is already for sale on the internet by Chinese manufacturers. Only Chinese manufacturers can sell this at a viable cost as western manufacturers usually keep prices very high to deter people from experimenting on themselves.

Whether the quality of FOXO4-DRI by Chinese manufacturing is of good quality or not depends on the manufacturer and is not subject to any form of guarantee and must be independently verified to validate that what they sell is exactly the peptide mentioned in the paper.

Biohackers have been experimenting this peptide on themselves with good anecdotal results, though the problem is, of course, certain aspects such as mental energy are incredibly subjective. People report feeling better younger,  improvement in sleep, better focus, improvements in cardiovascular endurance. Here is an example of somebody blogging about using it.

When I started adding the FOXO4-DRI in the past week I have noticed some definite changes. Weight loss, better sleep, more endurance and perhaps an improvement in lung function now well over 100% for the 3 measures, FVC, FEV and PEF, for a 63 yo. I know that the dose, a little less than 1 mg over 7 days, is a lot lower than the threshold dose indicated by the mouse model of .4 mg per kg of body weight for a human but I can’t reconcile my results with simply a placebo effect. The approx. 30 mg daily dose is a bit expensive, $3,000 p/day. But this peptide is meant, IMO, for only infrequent use. So, $25,000 to clear senescent cells once every 3-5 years might be worth the expense. Considering that I spend over $12,000 a year for insurance I never or rarely use FOXO4-DRI might be a bargain. But I hope price can be reduced by at least a factor of 4 as efficacy and safety can be better verified. I would love to have a protocol based on better patient data but for now, I’ll experiment. I might add another round of FOXO4-DRI in a month or so at a higher dose but again for only a week’s duration. - Steven Harris in 2017

My personal opinion is that there is simply not enough information at the moment to justify trying it like this unless absolutely desperate for a solution immediately. Quality control in China could be a problem. 

It is equally important to note, that even if FOXO4-DRI works it would only be solving 1 of the 7 pillars of aging, so it is unlikely to achieve miraculous results.

Of course, I am not the final authority on the subject, and if anyone has already seen amazing results from the peptide please DO share.

 

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