#23

Some good news for UNITY Biotech on their senolytics:

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#24

My view is that senescent and dedifferentiated cells are on the core aging system, but i think making them function correctly is better than killing them off.

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#25

So it seems. But the thing is that we don’t have any means currently to reverse cellular senescence (correct me if I’m wrong). Meanwhile SC’s and SASP are bringing about pathological consequences. So what is the alternative if you don’t want to keep waiting for a therapy that may not be available for a long time?

(Indeed there are the studies about the potential effects of Rapa on SASP and senescence, but in light of an ever increasing senescent cell burden, we likely need more rigorous interventions).

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#26

My own project is orientated around getting senescent cells to function.

One thing that is supposed to attenuate senescence is Rapamycin

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#27

This isn’t current, but it clarifies what Dr. Green’s opinion on senolytics was in January of 2021:

LE: What are some effective senolytics?

Dr. Green: The main three senolytics I use are dasatinib, fisetin, and quercetin. Dasatinib is the generic name for Sprycel®, a drug approved since 1996 for the treatment of leukemia. Fisetin and quercetin are flavonoids present in fruits and vegetables. They’re sold over the counter and are known to be very safe.

My method is to use all three: 100 mg dasatinib for three days, 1,000 mg of regular quercetin for three days, 1,500mg of regular fisetin for three days. That’s a maximum dose. Patients can begin with a smaller dose and determine sensitivity.

There are now two human studies and more than 20 animal studies regarding dasatinib’s role as a senolytic. Quercetin has been used in two human studies, and all mouse studies with dasatinib included quercetin. Fisetin had an excellent result in a 2018 mouse study. It was even more effective than quercetin, and there are several human studies using fisetin now listed on: www.clinicaltrials.gov. There have been no apparent harmful effects from long-term removal of senescent cells.

LE: What do studies of senolytics show?

Dr. Green: In mouse studies, removal of senescent cells improves cardiac function and reduces cardiovascular disease, alleviates frailty and muscle weakness, decreases osteoporosis, improves running endurance, decreases fatty liver disease and lung disease, decreases Alzheimer’s-like dementia, and in old mice, increases lifespan by 36%.

The two most recent human studieswere done at the Mayo Clinic in 2019. One showed that a combination of 100 mg of dasatinib and 1,000 mg of quercetin, given orally for three days, removed senescent cells in people with diabetic kidney disease. This showed that senolytics may work similarly in humans as they do in mice.

The other study showed that 100 mg of dasatinib and 1,250 mg of quercetin, given for three consecutive days each week for three weeks, alleviated physical dysfunction and improved walking distance and speed in patients with idiopathic pulmonary fibrosis (a lung disease that makes it difficult to breathe). This demonstrated that some of the results in mice can be seen in humans.

LE: What conditions do you think can be treated with senolytics?

Dr. Green: In general, any condition or disease that gets worse with age or has increased incidence with age is likely a senescent-cell-related condition and may respond to treatment with senolytics.

This includes:

  • Aging,
  • Cancer,
  • Cardiovascular disease,
  • Alzheimer’s disease and neurodegeneration,
  • Chronic lung disease and emphysema,
  • Chronic kidney disease,
  • Non-alcoholic fatty liver disease,
  • Obesity and metabolic syndrome,
  • Osteoarthritis and osteoporosis,
  • Eye cataracts,
  • Muscle frailty,
  • And more.

LE: Besides senescent cells, you mentioned that the protein mTOR plays a role in aging. Can you explain that?

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#28

Blagosklonny condemned senolytics in tweets a few hours ago. He said “senolytics are hoax of the century” and “it was never shown they extend life by KILLING senescent cells”

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#29

The solution is to ensure that senescent cells function, not to kill them.

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#30

I just bought some Grapeseed extract and Fisetin. Pretty cheap on Amazon. Was going to take them three days in a row once a month or so. Not worth it?

#31

I did a few rounds of the “Mayo Protocol” (2 days 15g of fisetin each).

But that was before I read the creator of the protocol, Dr James Kirkland, strongly advising people to not do it yet because there may be negative effects to clearing senescent cells.

Someone had a great metaphor for senescent cells as if they were movie zombies. Sure it’s great to start killing zombies with a blowtorch until you see the zombies that used to be your family and friends. Then you might want to look for a cure, rather than just killing them.

In the same way, some of these cells really would be great to return to healthy functioning rather than killing them off. Neurons and cardiac cells rarely get replaced. If you kill off bad ones, that’s it. You don’t really get more.

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#32

I turned against senescent cells when I learnt they spread through your body like cancer. They then imbed themselves and create little lumps or tumors of non functioning cells that spread to those around them causing dysfunction.

When you are young, your body cleans them up and disposes of them. Why wouldn’t you want to continue to do what your young body did?

Now, whether or not senolytics are effective is another matter. I believe that Kirklands hesitation is about effectiveness and not necessity.

I will continue to take senolytics until they are proven to be either harmful or ineffective. Remember that the SASP these senescent cells are exuding are calling for your immune system to come and remove them. The more SASP floating around your system, the less healthy you are.

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#33

Damn, I hate these for and against arguments between smart and qualified people. It makes it difficult for a layman to choose.

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#34

I would love to make sure senescent cells function. And I have heard you can save some of them. I would love to do that. Anything I can do to prevent senescence is fantastic. However, if they are past the point of no return, get rid of them.

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#35

No disagreement there.

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#36

The absence might be worse than the presence in some situations. What happens structurally to your heart if you have a large number of senescent cells and clear them without the ability to regenerate new ones? Maybe those cells, as bad as they are, were the thing keeping your heart from triggering cardiomyopathy and progressing to heart failure. We just don’t know yet.

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#37

Seems senescent cells in the heart are linked to CVD.

Senescence mechanisms and targets in the heart - PubMed.

Senescent cells are screaming for your body to go and remove them through SASP. If you don’t remove them, the SASP does unpleasant things to your body. I see no reason not to remove them.

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#38

I would agree that suddenly removing a large number of otherwise non functional cells could cause a problem, but best to get those that can to work.

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#39

Maybe another metaphor could be a house with wooden beams that are being weakened by termites

It’s definitely not great that the wood has termites and of course you want to get rid of it. But in some situations, some of that wood might be the only thing that is keeping your house from falling over. Removing the wood wouldn’t return your house to its original state, it might just collapse the house.

So that’s what needs to be researched. When is it ok to clear out these cells and when, as bad as they are, could it be worse to remove them?

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#40

That analogy isn’t quite right. When you are young, senescent cells get cleaned up quickly as your immune system is drawn to the SASP they release. So those termite infested boards get replaced quickly and the house doesn’t collapse.

As you get older, your immune system takes longer to clean them up. Sometimes they don’t get cleaned up at all. That’s like seeing termite riddled boards and procrastinating to replace them. We can all guess what happens to the house when that happens.

Most senescent cells signal to your body to clean them up using SASP. The cells know they need to be taken out. Why not help your body out with senolytics. Also, Rapamycin is a senomorphic compound that prevents senescence.

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#41

I am not sure that is right. I think when people are younger senescent cells are created at a smaller rate.

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#42

The literature I have read states as you get older your immune system gets less effective at removing senescent cells. Here is one such article.

https://www.geigerlab.com/research/immune-system/standard-titel-1

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