Berberine as an mTOR Inhibitor that Reduces Generation of Senescent Cells and Extends Life Span in Mice

Today's open access paper is an interesting look at berberine as an mTOR inhibitor and its effects on cellular senescence in cell culture and animal models. This is particularly interesting in the context of recent work on rapamycin, showing low doses to reduce the burden of cellular senescence in aged skin. In both cases this appears to be the result of reducing the pace at which cells become senescent, allowing natural clearance mechanisms to catch up - though there is always the question of whether or not the various protein markers used to identify senescence are reduced because the number of senescent cells are reduced, or are reduced because the drug causes a lowering of expression of these proteins.

Is it a good idea to prevent cells from becoming senescent? Cellular senescence halts replication and encourages programmed cell death or destruction via the immune system. It is way to remove damaged and potentially damaged cells from tissues. If a method of preventing senescence gives cells a chance to repair themselves, then fine, but otherwise it starts to sound like a way to increase cancer risk - to have damaged cells remain active while damaged. To refute that proposition, one has to run life span studies, as the researchers did here. Clearly, in these mice, preventing entry into senescence is beneficial, since it increases life span. This may again be a matter of allowing natural clearance processes a chance to catch up and reduce the overall level of cellular senescence. Or it may be that the harmful inflammatory signals produced by senescent cells are, on balance, far worse that the raised cancer risk resulting from prevention of senescence.

Studies of this nature must lead us to think about the right dosing schedule for senolytic therapies capable of destroying senescent cells. If natural clearance of senescent cells is taking place in late life, and accumulation is a matter of too much creation versus a slowed pace of clearance, then senolytic treatments should be delivered every few months. If, on the other hand, accumulation is a matter of a small fraction of all senescent cells managing to linger for years or more, senolytic treatments can be much less frequent. At present there is all too little evidence, but the evidence that does exist suggests that the former scenario is more likely.

Berberine ameliorates cellular senescence and extends the lifespan of mice via regulating p16 and cyclin protein expression

Cellular senescence is one of the most important in vivo mechanisms related to aging. Senescent cells impair tissue function by irreparable cell damage resulting from acute stress or natural aging, consequently restricting the lifespan. Cellular senescence can be categorized into two groups. The replicative senescence, seen after approximately sixty rounds of cell division in cultures (the Hayflick limit), results from the progressive erosion of telomeres following each cell division. This progressive erosion leads to telomere dysfunction and irreversible cell-cycle arrest.

The second category is defined as premature cellular senescence. It is unrelated to telomere shortening but is related to persistent cellular stress. Thus, replicative stress caused by oxidative DNA damage, activation of oncogenes, and loss of tumor suppressor genes also results in premature senescence. Furthermore, premature senescence includes irreversible impairment of tumor cell reproductive capability via chemotherapy or radiotherapy-induced apoptosis which is defined as a drug or radiation-induced senescence. The in vivo stress-induced premature senescence of normal cells is considered to be a critical mechanism affecting organismal aging and longevity.

Berberine (BBR), a natural alkaloid found in Coptis chinensis, has a long history of medicinal use. Furthermore, BBR possesses anti-cancer, anti-inflammatory, and anti-neurodegenerative properties. Although the biological properties of BBR are well-documented, there is little evidence of its role in anti-aging processes. It was previously observed that BBR inhibited mTOR/S6 signaling concurrent with the reduction in the level of endogenous oxidants and constitutive DNA damage response. Thus, it was hypothesized that BBR, with its potential anti-aging effects, could treat the senescence in aging cells.

This study presents the effects of berberine (BBR) on the aging process resulting in a promising extension of lifespan in model organisms. BBR extended the replicative lifespan, improved the morphology, and boosted rejuvenation markers of replicative senescence in human fetal lung diploid fibroblasts. BBR also rescued senescent cells with late population doubling (PD). Furthermore, the senescence-associated β-galactosidase (SA-β-gal)-positive cell rates of late PD cells grown in the BBR-containing medium were ~72% lower than those of control cells, and its morphology resembled that of young cells. Mechanistically, BBR improved cell growth and proliferation by promoting entry of cell cycles from the G0 or G1 phase to S/G2-M phase.

Most importantly, BBR extended the lifespan of chemotherapy-treated mice and naturally aged mice by ~52% and ~16.49%, respectively. The residual lifespan of the naturally aged mice was extended by 80%, from 85.5 days to 154 days. The oral administration of BBR in mice resulted in significantly improved health span, fur density, and behavioral activity. Therefore, BBR may be an ideal candidate for the development of an anti-aging medicine.


"If a method of preventing senescence gives cells a chance to repair themselves, then fine, but otherwise it starts to sound like a way to increase cancer risk - to have damaged cells remain active while damaged."

From the same study, third to last paragraph of the discussion.

"One possible concern about BBR would be if it increases the risk
of cancer by promoting cell proliferation. Though we showed BBR
promotes cell proliferation in WI38, it is reported previously BBR
treatment promotes cell-cycle arrest and death in human cancer
cell lines, coupled to an increased expression of apoptotic factors
(Sefidabi et al., 2017). BBR was reported to leading to apoptosis in
around 20 types of cancers through various mechanisms. Thus, BBR
is evident to rejuvenate aging cells and inhibit cancer cells at the
same time."

Berberine seems to be the real deal. My main concern was all the other reports of it being great to combat cancer due to it's ability to inhibit telomerase in cancer cells. Until this study was published, I could not find an answer as to whether or not this occured in healthy cells as well. Based on the aforementioned passage and the fact that replicative lifespan in human cells increased, it would appear that this is not the case.

Posted by: Alan at December 27th, 2019 1:26 AM

@Alan: the same is the case with silibinin (the main constituent of sylimarin). It was tested on many cancer cell types where it works as hiper strong telomerase inhibitor (switches it off completely in many cancer types), and as such inhibitor it made into official textbook tables. And then (in a search against hepatic toxicity of rapamycin btw) it was tested against HEALTHY liver cells and tissue... and it works in them as a strong telomerase ACTIVATOR - elevates telomerase level by about 3 fold. I would choose silibin over berberine as berberine accumulates in tissue and at some point this level becomes highly toxic and demages many tissues, including heart and liver.

Posted by: SilverSeeker at December 27th, 2019 8:40 AM

Bererine accumulates in tissue ? Tell me more! Been using at s metformin substitute for anti aging purposes.

Posted by: August3e at December 27th, 2019 11:54 AM

Hi there! Just a 2 cents.

I hate to be the bringer of bad news and break the holiday spirit/party, but lesser news bear here (not entirely, there is lots of positive but there is also a Truth):

''BBR extended the lifespan of chemotherapy-treated mice and naturally aged mice by ~52% and ~16.49%, respectively''

This is all you need know, chemotherapy mice are just like chemotherapy cancer patients (had I known that way back then I would have given berberine to my mother whom died of cancer), aging in acceleration due to massive ROS from chemo; the fact it increased their lifespan substantially is truly great; but, on the 'regular naturally-aged' mice, it's a different story, a sad one but still better than 0 also so we'll take it nyway...

16.49%, large difference compared to 52%. That is not doubling of lifespan. In human years (translated to human) it would be half to a 1/5th of that (sometimes up to a 1/10th of that). 8.25% to 1.65% lifespan extension (or 8 years to 1.5 years of extension) because translation to humans is nearly always Less than the Results in mice (simply because redundant and we are Already optimized for extreme lifespan, we don't benefit much; short-living mice do). It is what I was saying, we have to temper our hopes of senolytics doing substantial lifespan extension in regular healthy people - in sick people (chemo) - Yes, 100%...they are unhealthy already and probably aging in acceleration (due to ROS). Why?

Because, senescent cells are not the main driver of aging - in their totality - rather the contribute to loss of health homeostasis. Senescent cells are like '2nd layer' (of inflammation) - on top of regular intrinsic aging (which is much more caused of mitochondrial/telomeric/nuclear DNA loss/hayflick problems); their SASP is what causes disarray and chronic inflammation/disease. Does not change things much on 'your maximal clock/telomeres/'. IF you have less of them where you give your chance to reach your MLSP; but that changes very little to it/human specie max lifespan limit. Senolytic reduce expression of oncogenes and favors apoptosis over senescence; and then clearance of these senescent cell via autophagy. Health can then improve 'to control/regular health' levels...and thus live a full normal 'healthy' lief again, almost; just like that 52% increase in avg lifespan in chemo mice after senolytic; but only 16% in normal healthy ones. That is not 16 years in a human (16%, 16 out of 100 years); divide it by 2 to 10; thus 8 to 1.5 years.

Health-Wise these mTOR/senescent cell reducers or senoyltics are great....they improve your health and your average lifespan. Like CR or methionin/protein restriction or certain rapamycin like supplements (quercetin) already found in nature/food (we already cosume senolytics), basically. Not much better than it.

I'll repeat what I said previously (not to sound a parrot but) lifespan elongation over maximum, for now (until True rejuvenation happens, of which senolytic is better than nothing but not that in the sense of the term) is only feasible if you were youngER whole life (if you had kept a yougner biophenotype (on epicloc) your whole life -do you secure 'later 'centenarian' lifespan' (elongative above avg people living avg life) in late years). What happeNED in your Young life has Dramatic say in your Total lifespan and your 'Life Curve' on the graph over decades. The 'graphs' show it - it is linear loss with age (in accelerated aging it is faster downward curve), always going down, year after year. Senolytics change not much of this fact. True rejuvenation (damage repair, epigenetic reversal, telomere change, nuclear change, junk clearing (besides SASP p16 cells), chromosome recompaction, stem cell niche recreation, etc) would change this though. IT's why I am surprised that researchers put so much effort (and money) on senlytics (when they should be puttingeffort Something bigger (true rejuvenation), as if it is the 2nd coming[resuscitation] of Christ. The approach has to give results (beyong pure average health lifespan extension). For now, I think the reasons are because of imperativity to defeat diseases and improve health (in older diseased mice/people); not so much max lifespan elongation (especially, maximum one in Young healthy people, who are Young Right now (like us people in our 30s-40s...), and want to stay so the longest so that Later (in decades) they live 'later' too an Do go above their Maximum human MLSP). It's great that aging (and dying of it) will, finally, be classified as a disease per se that is recognized -as the most Dangerous/lethal of all- and needs fixing now because 'it'S happening' non-stop each sec. This way more funding will come and accelerate therapy creation in near distant future.

Just a 2 cents.

Posted by: CANanonymity at December 27th, 2019 5:09 PM

We don't know whether the human Max lifespan will be extended by the senolytics. To know that they we will need at least 10- 20 years after the senolytic therapies go mainstream. But if we look at mean LS there night be a quite noticable difference. After all, there are very few trully healthy individuals. So most of the people have already some extra damage due to lifestyle , environmental or infection factors. But even if they just make people in average a bit healthier without affecting the life expectancy that would already mean billions of adjusted health life years. Not too shabby...

Posted by: Cuberat at December 28th, 2019 9:59 PM

I know I am late to the conversation but I wanted to update on SilverSeekers assertion that Berberine accumulates in tissues and become toxic. A quick google search found nothing on that subject. But also the fact that most dosing suggestions say to break it into two or three doses daily suggests it has short lifespan in the body.
As far as senolytics role in life extension, there is a great article on Singularity Hub that ties senescent cells to NAD depletion. It is a great read. The team involved in the study found that senescent cells excrete CD38 that "chews up and destroys NAD". Removing the senescent cells increased NAD significantly.
I also recently read an article about sylimarin increasing bio availability of of BBR up to 30%.
Personally, I take a cocktail of supplements rather than focusing on one exclusively. The cocktail milk thistle(sylimarin), berberine, NAC, turmeric/currcumin with piperine, quercitin, NAC, alpha lipoic acid, carnitine and COQ-10 along wit Omega 3s and a food based multivitamin.
As for whether this cocktail is working or not I can only give this anecdote as an answer. One year after starting this regimen I went in for my first carotid ultrasound because as my doctor suggested, due to my history (ex-smoker, who had been obese and with a family history of heart disease) I was the poster child for having a blockage so I shouldn't be shocked when they found a blockage but I had treatment options. As it turns out, my carotid was clean. My doctor even cancelled our follow up saying there was no need because there was nothing to discuss. Since that first I've gotten tested every couple of years and still no blockages. Does that mean I will live to be 120? No, but I do think along with the lifestyle changes I've made it means I should live free of coronary disease at least.

Posted by: rob at November 25th, 2020 2:08 PM

@rob "most dosing suggestions say to break it into two or three doses daily" - without breaking it you get diarrhea. With 0,7 grams of pure sylimarin I was able to elevate significantly the dose of berberine without diarrhea. If it is so safe why some people complain about heart problems after overdosing berberine? I've studied only mahonia aquifolium, but it is a close relative to berberis vulgaris, and the safety precautions warn not to take it for prolonged periods because of berberine and it's toxicity compunding effect over longer periods.

Posted by: SilverSeeker at November 26th, 2020 8:36 AM

I obviously haven't been back in a while. But I would like to point out that there is a difference between BBR accumulating in tissue and overdosing on it. Overdosing on a substance mean taking too much of it all at once. Again, turning to a google search found only one article on BBR acute toxicity and that study seems to indicate that due to bioavailability factors it would be difficult to reach potentially toxic levels by taking BBR orally.

I would also like to point out that the "some people complain" argument is a straw man argument that is meritless If there is any credible science based articles on the harmfulness of BBR then I for one would love to have them cited by anyone.

Posted by: rob at October 29th, 2021 12:30 PM

I take berberine about once every four days, on my rest days from exercise. If I can avoid injuries, I would like to be exercising 6 days a week, with one rest day, which would leave me with a weekly berberine dosing regime.

The recommended daily dose is 1000 mg, in two 500 mg doses. I am taking three 600 mg doses, one in the AM, one at mid day, and one before bed. That's a high dose but it's not every day. I had also read somewhere that berberine is rapidly cleared from your system, which is why the doses are broken up during the day.

I've never noticed any effects from berberine - no nausea, weight loss, or anything. It should work similarly to rapamycin, but rapamycin is illegal in the U.S. without a prescription. Rapamycin may be more effective but if they both work by inhibiting mTOR, then berberine is the common man's remedy.

Posted by: Paul Wolf at November 23rd, 2021 2:12 PM

FYI, rapamycin and berberin are synergistic. Reduce both if taken together.

Posted by: djswarm at January 12th, 2022 5:00 PM
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