$54,000
$19,257

An Example of the Early Stages of Antisenescence Drug Development

The presence of senescent cells is a contributing cause of aging; the number of such cells grows over time as a consequence of the normal operation of metabolism, and collectively they cause considerable harm to tissue and organ function. The most important lines of research on cellular senescence aim at the production of senolytic therapies capable of removing these unwanted cells, but a sizable fraction of the researchers involved in this part of the field are more interested in antisenescence treatments, those that minimize the bad behavior of these cells, or reduce the number of cells that become senescent.

It would perhaps be more accurate to say that there is an ongoing reassessment of protein and drug candidate libraries in order to categorize known effects in terms of their influence on cellular senescence; all too much of medical research involves repurposing of existing drugs where there is any small positive outcome rather than building better technologies from first principles. When it comes to looking at existing outcomes from the drug and protein libraries in search of modifications to the behavior of senescent cells, my impression is that this is a road to marginal therapies only, those that slightly reduce the impact of senescent cells rather than solving the problem completely. This is a widespread problem in the research community, in which too many people are devoting resources to projects that are unlikely to have a sizable impact on aging.

Kallistatin, an endogenous protein, protects against vascular injury by inhibiting oxidative stress and inflammation in hypertensive rats and enhancing the mobility and function of endothelial progenitor cells (EPCs). We aimed to determine the role and mechanism of kallistatin in vascular senescence and aging using cultured EPCs, streptozotocin (STZ)-induced diabetic mice, and Caenorhabditis elegans (C. elegans). Human kallistatin significantly decreased TNF-α-induced cellular senescence in EPCs, as indicated by reduced senescence-associated β-galactosidase activity and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked TNF-α-induced superoxide levels, NADPH oxidase activity, and microRNA-21 (miR-21) and p16INK4a synthesis. Kallistatin prevented TNF-α-mediated inhibition of SIRT1, eNOS, and catalase, and directly stimulated the expression of these antioxidant enzymes.

Moreover, kallistatin inhibited miR-34a synthesis, whereas miR-34a overexpression abolished kallistatin-induced antioxidant gene expression and antisenescence activity. Kallistatin via its active site inhibited miR-34a, and stimulated SIRT1 and eNOS synthesis in EPCs, which was abolished by genistein, indicating an event mediated by tyrosine kinase. Moreover, kallistatin administration attenuated STZ-induced aortic senescence, oxidative stress, and miR-34a and miR-21 synthesis, and increased SIRT1, eNOS, and catalase levels in diabetic mice. Furthermore, kallistatin treatment reduced superoxide formation and prolonged wild-type C. elegans lifespan under oxidative or heat stress, although kallistatin's protective effect was abolished in miR-34 or sir-2.1 (SIRT1 homolog) mutant C. elegans. Kallistatin inhibited miR-34, but stimulated sir-2.1 and sod-3 synthesis in C. elegans. These in vitro and in vivo studies provide significant insights into the role and mechanism of kallistatin in vascular senescence and aging by regulating miR-34a-SIRT1 pathway.

Link: http://dx.doi.org/10.1111/acel.12615

Comments

I seriously hope that unity and Osin biotechnologies are working clearing out the senescent cells rather than the approach illustrated in this article

Posted by: Akschith at May 31st, 2017 8:11 AM

We all know why the re-purposing of old drugs is the goal. Its easy low-hanging fruit. These drugs have already cleared regulatory approval so running a few studies for an old drug that can be used for say.... 7 billion people is a win. There is no way the suits can ignore this given the high cost of new drug development. There is some good news from this, if the old drug works, the studies will often tell us what its mechanism is that enables its secondary effect. Once you have that, you can build a better drug, more specific, and far more powerful.

Truth be told, I have a lot more faith in biological drugs, CRISPR based therapies, and other gene editing tools than I have in small molecules. I don't like the idea of my life hanging in the balance of a suite of products with a 95% failure rate.

Posted by: mborbely at May 31st, 2017 10:19 AM

mborbely:

Crispr has recently been shown to be far less accurate than we thought. It creates hundreds of unwanted and inintended mutations. It was hype all along.

Posted by: MissKaioshin at May 31st, 2017 5:29 PM

Link please, about how CRISPR was "hype all along"?

Posted by: Barbara T. at May 31st, 2017 5:54 PM

Barbara:

Im sure youve seen the study by now, about how CRISPR induces far more mutations than we thought. But just in case, here's a URL: https://phys.org/news/2017-05-crispr-gene-hundreds-unintended-mutations.html

So CRISPR was thought to be the "next gen" of genetic editing technology and everyone was so excited about the future of genetic technology. And then reality happened. Looks like we're back to the drawing board.

Posted by: MissKaioshin at May 31st, 2017 6:37 PM

Can you read?

"CRISPR-Cas9 editing technology-by virtue of its speed and unprecedented precision-has been a boon for scientists trying to understand the role of genes in disease. The technique has also raised hope for more powerful gene therapies that can delete or repair flawed genes, not just add new genes".

"Dr. Bassuk says the researchers didn't notice anything obviously wrong with their animals. "We're still upbeat about CRISPR," says Dr. Mahajan. "We're physicians, and we know that every new therapy has some potential side effects-but we need to be aware of what they are."

"We hope our findings will encourage others to use whole-genome sequencing as a method to determine all the off-target effects of their CRISPR techniques and study different versions for the safest, most accurate editing," Dr. Tsang says".

And this is the MOST NEGATIVE article on CRISP that you've found. Jesus.

Posted by: Barbara T. at May 31st, 2017 6:43 PM

@Barbara,

Please don't give in to MissKaioshin attention, every time she pops up, as it is ALWAYS with something negatives to say or comment on. She looks for attention every time. Just ignore her.

Posted by: Robert at May 31st, 2017 8:20 PM

Are any of you surprised that she posted that? She knows nothing about the topic. And always conveniently leaves out important detail. But why include detail when you can push your own weird "everything is hype" agenda.

Posted by: Ham at May 31st, 2017 8:33 PM

Barbara:

It shows that CRISPR is far, far less accurate than we thought. CRISPR has been hyped as being very accurate but now we see that it just isnt true. Genetic technology is still very primitive. Gene editing is decades and decades away. The technology is moving so slowly. Yes the scientists try to give a positive message but anyone can see that CRISPR is still very primitive. We wont see it used in humans in our lifetimes. Not successfully anyway.

Posted by: MissKaioshin at May 31st, 2017 8:35 PM

And yet they have therapies going to clinical trials next year. Read. The. Article. Especially where it talks about whole genome sequencing. Good grief, you really are one of the most ignorant people on the internet. Why post when you know nothing about a topic?

Posted by: Ham at May 31st, 2017 8:38 PM

Ham:

Clinical trials dont mean that they will become available. Most clinical trials fail. Again, the scientists are trying to be positive because CRISPR is still being researched and they dont want to make it sound hopeless. But the fact remains that we're still in the very early stages of this and its going to take decades, not years, for this to mature. Many decades. First successful CRISPR-based therapies may not appear before 2050.

Posted by: MissKaioshin at May 31st, 2017 8:46 PM

I'm full well aware of how clinical trials work. I'm also fully aware that you're an internet layman with literally zero scientific credentials. Anything you say is to be taken with a grain of salt. So again, I ask: why post on things you know little about? Your speculation is meaningless and not backed by anything tangible. They might not appear before 2050. But then again they might. Does me saying they'll appear in 2037 make me any more credible than you? Learn to read context in articles. This article is a perfect example of you trying way too hard to find a shred of negativity. I know you have some weird agenda and all, but really, why? I actually kind of feel sad for you.

Posted by: Ham at May 31st, 2017 8:53 PM

@Ham,

Yes, thankfully we have positive people who believe good things can happen if we make an effort. Elon Musk is a prime example. And, Audrey DeGrey is another. Why bitch about how things are vs what we can do to change them. I really hate negative people who offer zero in this world.

Posted by: Robert at May 31st, 2017 9:05 PM

Ham:

Its not me that's saying it, its scientists. CRISPR has been hailed as this wonderful new biotechnology thats gonna revolutionize genetics, and now we see that it's not. Skepticism of "breakthroughs" is warranted. Skepticism of overly optimistic timelines for the arrival of CRISPR-based therapies and medicines is warranted. 2037 is way too early.

You may think i'm being negative for no reason but again, go read the latest findings. It doesn't look good for CRISPR.

Posted by: MissKaioshin at May 31st, 2017 9:09 PM

@MissKaioshin

Cas9 is just one of the proteins you can use for gene editing. They have already found superior ones. Truthfully I doubt we will see many Crispr/Cas9 therapies. The Crispr part, oh yeah, that's the keeper, the guiding Cas9 has already been proven inferior to other RNA guides. The important discovery with CRISPR/Cas9 was the basics... how the bacteria pulled off the trick in the first place.

Now we the intelligent naked primates know how it works, and more importantly we know where to look for other/better options. This is now an engineering problem. We stole the trick and now we can mule it to make money. Once mankind finds a crack in natures armor, and figures out the basics, it doesn't take long before we dominate it. Flight is an excellent example. Once we figured out it was the shape of the birds wings that provided lift, it took all of 50 years to put a naked primate on the moon.

The commercial potential of CRISPR is off the charts compared to any other invention by man. This blows away fire, the wheel and the transistor combined. The patent fight carried out right now between the U of C and the Broad will probably be completely meaningless.

Back in the 90's Microsoft got hit with an antitrust lawsuit over its Internet Explorer dominance when the web was just getting going. The lawsuit took too long to impact the technology and it moved on WAY faster than the slow wheels of the legal system. We are here now with CRISPR.

Just a sample of how fast this is moving. Some of these are from back in 2015.

http://www.bio-itworld.com/2017/2/22/beyond-crispr-cuts-five-complements-to-cas9.aspx

https://www.nature.com/news/alternative-crispr-system-could-improve-genome-editing-1.18432

http://cen.acs.org/articles/95/i1/Expanding-CRISPR-toolkit-render-patent.html

Now we know how it works, and we know where to look. It won't be long before we have a bucketload of guide proteins. This whole thing is just getting started. Barely scratched the surface. Best to look at at CRISPR like software now, with version numbers. CRISPR/CAS9 is version 1.0.

Buckle up... once man can alter life itself, our greed will take care of the rest. Trust in greed MissKaioshin. You are skeptical, and that is good, but one thing you can ALWAYS trust in is greed.

Posted by: mborbely at May 31st, 2017 9:20 PM

No. Just... no. Read the article. It's pretty obvious and explains what the problem was and what needs to be done. But you know what? You know best and better than everyone else. CRISPR won't be used for 50 years. Make that 150 years. Maybe never! It's all hype anyway, right? There, that should really get you going. I've no interest in arguing with someone that doesn't understand what they're arguing about. Enjoy your little circle jerk.

Posted by: Ham at May 31st, 2017 9:34 PM

Ham:

The point i'm trying to make is that CRISPR is far less of a breakthrough than everyone thought. Yes the science will keep improving. I never said it will stay in place and that we'll never ever improve. But the improvement will be much slower and more incremental than we hope. This study shows that CRISPR has a very, very, very long way to go, and the progress will be linear and incremental the whole way there. Not exponential or accelerating. Not revolutionary.

For the forseeable future, crispr will continue to be a useful tool for basic research. But for medicine, it's not even on the horizon. Perhaps in 50 years, we'll be a little closer. Perhaps.

Posted by: MissKaioshin at May 31st, 2017 11:35 PM

Whatever you say. Actual evidence doesn't fit your narrative, so I won't bother. No point in arguing with someone who doesn't understand what they're talking about and only sees what they want to see. But sure... 50 years! Let's make it 100! Yay uninformed arbitrary numbers!

Posted by: Ham at June 1st, 2017 12:44 AM

@Ham,

IMO, I see paradyne shifts in medical technology with relatively big discoveries, such as the electron microscope, mapping of the human genome, and yes, CRISPR, irregardless of what some uneducated (ignorant?) people comment on. It is these big events that propel us to remove previous roadblocks and speed up (new)discoveries.

As an Uber driver (hopefully temporarily), I picked up two young researchers from the Stanford medical research center and while driving them to their destination, I talked to them about their work and we engaged in topics such as stem cells and CRISPR. I am very convinced we have enough "tools" in our toolbox to make huge improvements in medical science over the next 10-15 years.

Posted by: Robert at June 1st, 2017 1:44 AM

"This study shows that CRISPR has a very, very, very long way to go, and the progress will be linear and incremental the whole way there. Not exponential or accelerating. Not revolutionary".

No it doesn't. The study shows that it will take 100-150 years to nail gene editing in the same way that it shows that coffee is good for watering begonias. You are cray cray.

Posted by: Barbara T. at June 1st, 2017 8:32 AM

Dont feed the troll it hasnt the slightest idea what its talking about and it isnt qualified in a relevant field.

Dont worry about this study. I have spoken to Oliver who is a CRISPR researcher at Copper U, whilst its a set back it isnt the disaster being claimed. This is a problem but it by no means a problem that cannot and will not be overcome. There are a number of techniques in development that improve accuracy and off target hits.

There are also other forms of CRISPR and other editing systems appearing as well. This is one study, it needs to be replicated and the problem isnt that serious.

Now please stop feeding the troll. If you have questions about this or CRISPR in general please ask me and I will consult with Oliver who is qualified to speak on the subject and is a genetic engineer.

Posted by: Steve Hill at June 1st, 2017 9:12 AM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.