Procyanidin C1 as a Senotherapeutic

This open access paper runs through a range of data for the assessment of procyanidin C1 as a senolytic compound capable of selectively destroying senescent cells, both in cell studies and in animal studies. Procyanidin C1 clearly isn't as good as dasatinib and quercetin (or fisetin alone) in mice, but it does extend mouse life span by a little under 10%. The mechanism of action appears to involve induction of mitochondrial dysfunction in senescent cells, leading to programmed cell death, but there is a good deal of work remaining in order to fully understand how procyanidin C1 achieves this outcome, and whether or not it is synergistic with other senolytics.

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction.

In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted, or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate, or prevent age-related pathologies.

Link: https://doi.org/10.1038/s42255-021-00491-8

Comments

It is interesting to see what would be the combined effect for C1, D+Q and F. Will it be any better than D+Q alone.

Posted by: Cuberat at December 14th, 2021 11:25 AM

@cuberat, Not sure if you mean simultaneously or sequentially as part of a regimen. I view senolytics as a version of chemotherapy. That one takes as large a dose of a chemical agent at one time that one can safely tolerate. The developing school of thought in cancer chemotherapy is that the chemical agent should be changed frequently, that is the way I view Senolytics, D&Q in December, F in January, piperlongumen in February, etc..

Posted by: JohnD at December 14th, 2021 1:15 PM

@JohnD

Why do you have this belief? Chemotherapies must be cycled or modified because cancer cells are highly adaptable, and mutate away from sensitivity to chemotherapeutics. It seems highly unlikely that senescent cells are likewise capable of adapting to protect themselves from senolytics, since (by definition) they do not reproduce (and so cannot mutate the way that cancer cells do), and (so far as I know) there is no empirical evidence that they are so adaptable.

Posted by: gheme at December 14th, 2021 3:55 PM

@gheme
In theory there will be a selection pressure that keeps only the ones that survive. However, the ones that survive have to be healthier , i.e. less senescent. But ultimately we want to stop SASP and remove the cancer -prone cells.

Anyway, C1 is generation one senolytic and not a very strong one.

What will make a difference are generation two and other approaches, which are already published. Beta galactose attached pro drug can increase the precision 100 fold.

Posted by: Cuberat at December 14th, 2021 7:18 PM

I recommend an interview on Youtube with James Kirkland, one of the authors of this paper, on the NUS Medicine Youtube channel, uploaded a week ago. He says that there is a network of about 10 chemical reactions that senescent cells use to survive. Some are redundant so for some types, it may be necessary to disable more than one of the reactions at the same time. His trials use a hit and run strategy, of large doses over a two day period. It takes about a day for senescent cells to die, so I guess they are just making sure they go past that. I agree there is an urgent need to test combinations of senolytics, but Dr Kirkland explains there is no money to be made in this area, which mainly involves things that aren't patentable. So governments have to step in and to fund the trials.

Posted by: Paul Wolf at December 18th, 2021 8:43 PM

And here is a big problem. If you cannot directly monetize a treatment you are getting only academic and government funds plus a some non-profit/charity. This might be the reason Unity Bio is fooling around with some small-molecule compounds whith questionable efficacy instead of using D+Q directly.

And we all know how quick and efficient the governments can be. If there are some left-over funds it could take 2 decades to have widely available senolytics

Posted by: Cuberat at December 20th, 2021 9:22 AM

The article above states:

" Procyanidin C1 clearly isn't as good as dasatinib and quercetin (or fisetin alone) in mice"

However, it seems that researchers may have come to an opposite conclusion:

"Fisetin, another natural flavonoid reported as a senolytic agent, displays modest effects on senescent HEFs and pre-adipocytes only at high concentrations20,21. By contrast, PCC1 has the potential to overcome these limitations, including cell type dependency, high toxicity in nonsenescent cells and low efficiency against senescent cells. Although, when used alone, quercetin (another flavonoid in GSE) per se displayed cytotoxicity against senescent stromal cells, its efficacy is generally lower than that of PCC1 (compare Fig. 2a,c and Supplementary Figs. 3n and 4n). Together, PCC1 has a superior senolytic activity with high specificity and efficiency for a wider range of cell types than many reported senolytics such as ABT-263, dasatinib, quercetin and fisetin and can target senescent cells generated by several major types of senescence inducers."

Xu, Q., Fu, Q., Li, Z. et al. The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice. Nat Metab 3, 1706-1726 (2021)

Posted by: Brad at December 21st, 2021 3:41 PM

@Brad "Procyanidin C1 clearly isn't as good as dasatinib and quercetin (or fisetin alone) in mice". Fisetin at mice given at similar age was about 10%. Here it is 11%. About exactly the same. It was younger mouse that it was more than 30%.
BTW. Beyond grape seed extract where do we find Procyanidin C1? How similar/dissimilar is it to delphinidin (which is anthocyanidin)?

Posted by: SilverSeeker at December 22nd, 2021 7:43 AM

@SilverSeeker - According to the Nature article, Procyanidin C1 is found in smaller levels in extracts of apple peels, cocoa, and pine bark. I suspect it is also found elsewhere and that the Nature list was not an exhaustive list of sources.

Posted by: Brad at December 22nd, 2021 6:38 PM

@Brad Apple also contains fisetin, up to 40mg per 1 kg. So no matter how much you consume you won't reach fisetin senolytic dose. I'm afraid the same may be with PCC1. Pine bark aka pycnogenol contains bigger doses of procyanidins. But if this would be enough? Lately I've found cheaper (not using trademark) source of 65% OPC (aka pycnogenol) at 0,40$ per gram. Currently the max dose of pycnogenol I can take daily without excessive side effects is 0,5 gram divided into 3 doses :< But how much PCC1 does it contain and how much pycnogenol do you need to consume? Cinnamon also contains PCC1, but mixed with poisonous toxic subtance which mean it's questionable to reach safely senolytic dose with it.

Posted by: SilverSeeker at December 23rd, 2021 2:30 AM

Pycnogenol (and any other substance, as far as I know) contains less PCC1 than GSE.

Posted by: Florin at December 23rd, 2021 1:30 PM

This seems very promising. Much better than quercetin or fisiten. The supplementary table shows grape seed extract contains 6.3% PCC1 vs only 0.9% Quercetin. However that means that a standard 200mg GSE capsule only contains 11mg of PCC1 so you would have to take 100 pills to get 1000 mg to get in the range used for quercetin and fisetin!?? Need a more concentrated extract. But then you are getting significant levels of the other components which may be toxic?

Posted by: Malcolm L Klein at March 24th, 2022 10:27 PM

Here is the link to the table with the grape seed extract composition. file:///media/fuse/drivefs-c062b553cc2381b0be47b1afc8f008e1/root/42255_2021_491_MOESM1_ESM.pdf

Posted by: Malcolm L Klein at March 24th, 2022 10:28 PM

@Malcolm L Klein I've made a google search, various sources give PCC1 in range from 0,9% to 12,3% in grape seed extract. Which brand they use with measured 6.3% PCC1 content? Definitely to conduct any research/self experimentation one have to have exact content of PCC1 in OPC first... Going crude once a week a growing dose without measuring senolytic effect probably won't work. Luckily none of the other ingredients in grape seed extract is poisonous. I've eaten once one bottle of 60 capsules with 300mg OPC per capsule with no side effects. Cinnamon, the other source of PCC1, due to its' poisonous nature is not suitable for such a dose and such a test without refining PCC1 to highest purity. We need pure OPC1 and reliable test to check in vivo senolytic's effectiveness and then tries and guesses turn into reliable data :)

Posted by: SilverSeeker at April 1st, 2022 5:57 AM

Rather than concerning myself with which is the best senolytic, I've been taking rather high-dose quercetin, fisetin, and GSE (along with theaflavins and apigenin in lieu of dasatinib, per Life Extension Foundation theorists) all on the same day, once weekly, for the past several months. While I haven't detected any negative side effects, I haven't detected any positive ones either, but then perhaps we shouldn't expect to notice a reduced rate of aging.

Posted by: Brian Valerie at April 3rd, 2022 4:28 PM
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