Tetramethylpyrazine is Senolytic in Bone Marrow: Reduces Inflammation and Improves Stem Cell Function in Mice
Today's open access paper reports on a new senolytic drug candidate, with good-looking data on its effects on the bone marrow environment in aged mice - reducing inflammation, and improving the hematopoietic stem cell pool, among other benefits. Senolytic drugs are those that selectively destroy senescent cells. Cells become senescent constantly, but near all either self-destruct or are destroyed by the immune system. Unfortunately, a tiny fraction linger, and their behavior produces chronic inflammation and degrades tissue function in a variety of ways. Their growing presence is one of the root causes of aging, directly implicated in the progression of many age-related diseases. If, however, senescent cells could be periodically culled, safely and efficiently, this contribution to degenerative aging could be removed entirely.
In recent years, researchers have found a dozen or so senolytic compounds. These are largely well-known to the research community, and most have been tested in dozens of studies, usually for anti-cancer effects. Yet next to no-one was looking for effects on cellular senescence much before six or seven years ago, more is the pity. The best of these senolytics have since been demonstrated to clear out between 25% and 50% of senescent cells in some tissues in old mice. A few are proceeding into human studies, the first of which is a pilot conducted by Betterhumans, alongside a fair degree of quiet self-experimentation. Here is a question to consider: given this, just how many more senolytics should we expect to exist in the body of compounds that are already well explored, with good data on side-effects and pharmacokinetics in mice and humans? I think it quite likely that the number is large.
This is a good thing, because we should expect these senolytic pharmaceuticals to be quite varied in their effectiveness by tissue type. The accumulation of evidence is beginning to suggest that senescent cells have their differences, and thus any given mechanism that can tip them over into self-destruction will work well for some tissues, poorly or not at all for others. The best pharmaceutical approach to senescent cells will likely involve a mix of several different classes of compound. This is distinct from the non-pharmaceutical approaches, such as the Oisin Biotechnologies gene therapy or SIWA Therapeutics immunotherapy, that will likely be more broadly effective and reliable, capable of clearly a much higher faction of senescent cells, but at greater expense.
The compound examined here, tetramethylpyrazine, is well studied and widely used in various forms. Take a look at PubMed and you will find a flood of papers from just the past few years, as well as a lengthy period of study over the few decades prior, assessing the benefits of tetramethylpyrazine for a range of age-related conditions. Researchers think it promising for stroke, neurodegeneration, reduction of chronic inflammation, and more. Like a number of the other established compounds that have turned out to be meaningfully senolytic, it is inexpensive and widely available for purchase in the open marketplace. If a compound this well studied can turn out to be senolytic to a significant degree, what else is right underneath the noses of the scientific community, lurking in the sizable batch of promising compounds that are under evaluation at any given time? Equally, if a widely used compound can be senolytic to this degree, that should perhaps temper our expectations on the size of the gains that this approach alone can achieve in humans.
During aging, bone homeostasis is interrupted with the chaos of the marrow microenvironment, including a disrupted hematopoietic stem cell (HSC) niche, decreased vessel formation and abnormal inflammation factor release. As a result, increased cellular senescence in bone marrow can be induced by cellular damage or environment changes. It is reported that senescent cells (SnCs) accumulate in bone marrow with aging and contribute to age-related pathologies through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Although cell senescence has been well studied in recent decades, the mechanisms and local treatment targets for SnCs-induced bone degenerative disease are not well understood.
Mesenchymal stromal cells (MSCs), including mesenchymal stem/progenitor cells (MSPCs), play an essential role in bone metabolism and HSC maintenance. MSC senescence during aging markedly impairs the HSC niche, decreases osteoblast numbers and disrupts epithelial-mesenchymal transition. LepR+ cells in bone marrow were a major source of MSPCs in adult and formed bone, cartilage, and adipocytes in culture and upon transplantation. Additionally, LepR+ cells are essential for maintaining the HSC niche. However, little is known about whether LepR+ cells are senescent and dysfunctional during aging.
Tetramethylpyrazine (TMP), the bioactive component extracted from Ligusticum wallichii Franchat (Chuanxiong) which is widely used for the treatment of ischaemic stroke, cerebral infarction, and degenerative diseases of the central nervous system, has been reported to have anti-inflammatory and anticancer effects in certain cell types. In this study, we aimed to investigate the local effect of TMP on the bone marrow of aging mice and to determine whether the senescent phenotype of MSCs could be eliminated. Our findings revealed that local delivery of TMP eliminates the senescent phenotype of LepR+ MSCs via epigenetically modulating angiogenic environment in aging mice.
Senescent cell (SnC) accumulation in bone marrow with aging leads to aging-related pathologies, and local ablation of SnCs attenuates several pathologic processes and extends a healthy lifespan. In this study, we found that senescent LepR+ MSPCs accumulated in the bone marrow of aging mice with bone degeneration and that local delivery of TMP in bone marrow inhibited LepR+ MSPC senescence. In this study, we just began to understand that local elimination of senescent MSPCs in bone marrow is critical to aging-related bone degenerative change and microenvironment disruption. Identification of the local treatment for cellular senescence and the underlying mechanism of the crosstalk between SnCs and niche cells in maintaining whole bone homeostasis remain interesting for further investigation, which will provide insight into extensive clinical studies in use of local treatment for bone degenerative and regenerative applications.
"Equally, if a widely used compound can be senolytic to this degree, that should perhaps temper our expectations on the size of the gains that this approach alone can achieve in humans."
Yeah but, wouldn't someone have to take the senolytic compound at 1 or 3 year intervals over 30-40 years for a lifespan effect to show up? I don't think anyone is taking these compounds like that.
@Jim: This is killing 50% of senescent cells in a mouse bone marrow population, going by the paper, given an 8 week course of 3/week injections. The amounts of the compound used are very, very low in comparison to other senolytic compounds. I'm thinking that looking at the normal human use of this, ingested as an extract, injected as an extract, and in the original unextracted herbal form, is needed to understand whether or not past treatments would be expected to result in this sort of exposure.
A related question is the degree to which things can be missed. Can there be a case of a widely used treatment having a meaningful effect on function and longevity that isn't noticed for a very long time because it isn't the subject of the common usage, or just isn't being surveyed, or the fact that most people being treated are old and significantly impacted in many ways? The situation for bisphosphonate treatments for osteoporosis (one study showing a five year life expectancy difference, but seemingly little interest in doing more work on that topic) would seem to suggest the answer is maybe yes.
Ah, I see an important detail I missed yesterday, which is that the injections are intramedullary, or into the bone marrow. That may well be an important difference, and one that can explain why other forms of administration do not have a similar effect. Equally, wouldn't one expect anything in the bloodstream to also show up in the bone marrow?
Why would the scientists bother injecting directly into the bone marrow, if they could achieve the same effect with an intra-venous injection instead?
Yes you are right that this treatment may be having a longevity effect that simply hasn't been measured (although keeping track of trial participants for decades is no easy task). Perhaps this is a case like that of the Amish PAI-1 mutants who live on average 7 years longer than their peers? And that result somewhat supports the case for removal of senescent cells having a significant effect.
It's always good to have realistic expectations.
HSCs get exhausted with age, Isn't that the general consensus currently?
So how does stem cell exhaustion play into this is my question?
Obviously just clearing out the senescent cells won't have a tremendous effect on the exhausted pool and as far as I know methods to increase proliferation in old HSCs has actually produced faster exhaustion of the niche in other experiments.
So all in all, I'd be surprised if this produced amazing outcomes in humans or any other animal. It wouldn't make sense with the currently accepted knowledge to expect miracles. Of course in biology theories can be overturned quickly but in this case it doesn't look like that is the case, instead the data seems to support previous observations.
"So all in all, I'd be surprised if this produced amazing outcomes in humans or any other animal."
Senolytics produce 25% life extension in mice.
@Antonio
Uhhh. No they don't.
Trasgenic mice with a specific suicide gene which cleared out multiple types of senescent cells in multiple tissues had about 22% longer median lifespans. But not maximal. And their senescent cells were cleared every 2 weeks from the age of 1 year onward.
Can a drug mimic this effect and be taken safely by humans in their mid 30s? Highly improbable. I wouldn't bank on it, but I actually use my brain unlike Unity biotech investors which are very much driven by hype for instance.
I've been trying to bring some realism to the conversation here and elsewhere for months pointing out a lot of these experiments show continuous reduction of senescent cell population is need, starting out early is important and most of all - we'll probably need a gene therapy to achieve the same overarching effects unless you want to start your morning with a handful of pills - and good luck fidning drug combos with minimal side effects and interactions.
This isn't the cheap, easy and painless process a lot of people were envisioning for senolytics. The data never supported the idea.
The Baker et al. experiment is not that different from Oisin's approach.
I am a bit puzzled whether senolityc treatment in middle age is strongly beneficial.
SC population double every decade, so its sensible to say that halving SC cells count would result in shifting this progression by 10 years. Kinda promising... No data to support it yet, but this idea make sense. Or not? We don't have data on decreasing SC population, but we have data on increasing SC cell count, and one should expect that increasing SC cells 2 fold would shift SC progression by a decade and would have a detrimental effect on life expectancy.
Except its not..
Breast cancer chemotherapy increase SC cells marker(p16INK4a) by 1.9x, effectively adding 10 years to SC progression (https://www.sciencedirect.com/science/article/pii/S2352396416303784)
But life expectancy of breast cancer survivors doesn't differ from the general population.
This could mean that opposite thing - reducing SC cell count midlife would not affect lifespan either.
Maybe SC cells count progression doesn't depend on current count but more on other aging processes. Then it would make more sense to remove SC cells in a more advanced age when its became a huge factor by itself.
This senolytic compound should be studied further as it seems to have some amazing anti-aging possibilities. Perhaps mice are not the best animal to experiment on with this compound due to the short lifespan of mice and differences in aging from humans. It sounds like the compound is expressed epigenetically, so perhaps its main effect is on turning bone marrow genes on and off, particularly in turning inflammation pathways off. Contrary to what most commenters above have said, I am really excited about the anti-aging possibilities of this senolytic compound.
Hi, just a 2 cent,
''In this study, we aimed to investigate the local effect of TMP on the bone marrow of aging mice and to determine whether the senescent phenotype of MSCs could be eliminated. Our findings revealed that local delivery of TMP eliminates the senescent phenotype of LepR+ MSCs via *epigenetically modulating angiogenic environment in aging mice''
Not surprising, TMP (tetra*Methylpyrazine) acts through the methylation pathway, donating its own methyl which alters DNA epigenetic clock methylation; thus makes 5-methylcytosine loss be decelerated; DNMTs will take in the donated methyl and incorporate it. As said before, senescence is controlled by epigenetics and it is why no cancer can survive epigenetics; likewise for senescent cells, they cannot survive if the expressed signals change (which epigenetic do change them via methylation and commands senescent cells for apoptosis). TMP is akin to SAMe (S-AdenosylMethionine), or MSM (Methyl Sulfonyl Methane), and works through the same pathway; or rather, TMP or MSM activate/fuels SAMe, which the latter is the element responsible for methylation formation in the (de)methylation/trans-sulfuration pathway (methionine, homocysteine, cysteine, sulfur compounds). Either through methyl donating or through indirect participating with SAMe controlling this.
I think people have to realize that senescent cells are related to health, not aging (not in the way we think when we mean 'aging'...as in 'growing old'...senescent cells have Nothing do with this - If your health is kept in check - Otherwise, they Do have a say; which is the maintenance of your health (that threshold), if your health declines you can experience premature aging - Caused by senescent cells accumulation - But If you are not declining in health, you will not experience Premature Aging - But what you Will experience and - Continue - to experience is Regular Instrinsic Aging continuing its slow course - whether you have a little bit or almost No senescent cells). People have to distinguing the two and separate the two as two discting things (related, but indepedent too).
Senescent cells = your health (removing senescent cells will Not make you live above 122 years maximum lifespan, but it will allow you the chance to reach 122 if you have this genetic that allows it otherwise not only will you not reach 122, you will just live an avergage lifespan and senescent cell load will rise in your last few years; which will mean premature aging because you did not reach 122, you died earlier and it also means you had Limited replicated lifespan left on your cells). Stem cells alleviate tissue loss and provide temporary health boost; but have little say on MLSP (stem cell injection in mice for whole life give 20% lifespan extension). Damage is what matters, along with epigenetics/genomic fidelity.
Intrinsic aging = Replicative senescence, this one decides that you can live max up 122 as specie,
epigenetic aging (transcription, translation, genomic integrity, DNA clock methylome changes), proteasome dysfunction (loss of autophagy), telomere loss or centromere/subtelomere changes/histone loss with progerin/lamin changes/chromosomal laxing (albeit it stil ambiguous but telomeres still do count the replicative rounds, but they do not stop aging either as was seen in epigenetic clock discrepancy vs telomeres), protein aggregation, mitochondrial DNA oxidative lesions (8-oxodG)/deletions/mt copy number loss, redox loss (mitochondrial subcompartment oxidized milieu) = ATP loss and oxidize thiols = an oxidatively stressed cell = faster replicative senescence by ATP production weakening over time in billions of mitos (energy crisis over time in the organ tissues)).
@CANanonymity: Thanks for the great explanation of the methylation pathway in your paragraph 2 above and the relation of this to epigenetics and aging in the rest of your comments. TMP (and SAMe and MSM) seems to be an especially good methylator of our chromatin, that epigenetically declines with aging if we do not replace the methyl groups on our chromatin. If our chromatin CpG Islands lose their methyl groups ((become hypomethylated) with aging, this loss allows hundreds of aging genes (aging genotype) to become expressed. Thus, we need to fight off the hypomethylation of our chromatin CpG Islands so that the aging genotype does not express, and our youthful highly methylated CpG Islands remain turned on. My own protochol to this epigenetic aging (turning off hundreds of youthful genes, and turning on aging genotype that normally occurs with aging, is to take TMG and milk thistle, both methylation agents. But maybe this is insufficient to reverse ongoing epigenetic aging and cell senescence. Maybe I need a stronger methylator like TMP or SAMe. Any thoughts on that?
Hi Biotechy ! Thanks for that too. Just a 2 cent,
Exactly, global hypomethylation is a very real phenomenon (while there is hypermethylation in inflammatory genes; the important anti-inflammatory genes are lost because of hypomethylation in them with age). TMP and milk thistle do improve methylation, milk thistle has even the double effect of improving the redox because it increases liver GSH and repairs the liver (it's an herb that was used since ancient times for hepatic detoxification and healing; and overall health; it's great also for alcoholics suffering hepatic cirhosis/hepatitis). TMP and SAMe will be stronger (for methylation purposes), especially SAMe because SAMe is the barometer and fuel of methylation; the substrate that is 'rate-limiting' in the methylation production process/necessary for DNMTs to do their jobs and add the methyls to these CpG poor-islands or CpG rich-islands. SAMe is the best bet for methylation improvement, there is also Vitamin B12, Vitamin B6, Folate/Folic acid, choline/betaine; these while simple, are strong methylators too especially, folic acid. That's because they directly activate DNMTs and you can increased activity of these methyl transferase enzymes when these methylators are taken exogenously. I would also include Vitamin D3 has another one. But for the strongest methylation, SAMe is up there, while MSM or TMP do both good for they donate their methyl; and that is the goal; get the methyls or make body produce much more methyls (though DNMTS/SAMe cascade). Truthfully, they will not Reverse or Stop demethylation process, but will definitely slow it (which is commendable, since epigenetics have Far and Wide reaching effects over a life time; starting methylators the soonest the best (as epigenetics is all about 'memory' events (thus what happens/happened - will affect what will happen Later (like many years later))). The more methylated epigenome/DNA epigenetic clock means, as you said, keeping our important genes expressed/activated and the ones we don't want (inflammation causing (p53/p16...) kept - silenced. Less inflammation/Methylated epigenome preserves a 'youth' signature, which means a longer lifespan. Studies with SAMe have been sadly inconclusive, mice receiving SAMe had improved healthspan but not much lifespan elongation. This tell me that it's not enough; demethylation continues (for mice, before dying, have lost 95% of their 5-methylcytosine level; thus, it means that SAMe is not capable/or enough to maintain the Global DNA methylation levels necessary to stop 5-methylcytosine levels to drop with age (and thus cause epigenetic deregulation/inflammation 'epiprogramm' activation).
Just a 2 cent.
@CANanonymity: Thanks for your further comments on methylators and their connection with epigenetics and the epigenetic clock. My other thought is that the formation of dense methyl groups around the chromatin, has a physical effect in keeping the chromatin zipped so that aging genes cannot easily be expressed as they stay wound tight in the chromatin and not available for transcription and expression. In fact, this may be their main function in slowing aging.