Further Work on Small Molecules that Can Induce Cell Reprogramming
Cell reprogramming was first induced by expression of the Yamanaka factors, a way to access the program of rejuvenation and dedifferentiation that takes place in the early embryo. A small fraction of cells in culture exposed to reprogramming factors will change into induced pluripotent stem cells while ohers will undergo an epigenetic reset to adopt a youthful set of behaviors and capabilities. This involves removing age-related changes in gene expression that lead to mitochondrial dysfunction, for example. By virtue of the way in which cellular biochemistry is very interconnected, there should be many ways to access the embryronic program of rejuvenation, and hopefully ways to separate the process of dedifferentiation from the epigenetic reset. It is just a matter of finding those other ways.
An important part of the reprogramming field as it stands today is the expansion from genetic means of provoking reprogramming to the discovery of small molecules that can achieve the same outcome. While gene therapy is the future of medicine, the gene therapy industry of today remains a rounding error next to the size of the small molecule industry. With this in mind, most of the noteworthy organizations involved in the development of reprogramming therapies have a small molecule program. Today's open access paper is a illustrative report from one of the associated research groups in the field, a starting point for a small molecule drug discovery program aimed at producing efficient reprogramming without genetic modification.
Chemically induced reprogramming to reverse cellular aging
Starting in 1962, researchers demonstrated that nuclei contain the necessary information to generate new individuals with normal lifespans. In 2006, researchers demonstrated that the expression of four transcription factors, OCT4, SOX2, KLF4, and c-MYC (collectively known as the Yamanaka factors or OSKM), reprograms the developmental potential of adult cells, enabling them to be converted into various cell types. These findings initiated the field of cell reprogramming, with a string of publications in the 2000s showing that the identity of many different types of adult cells from different species could be erased to become induced pluripotent stem cells, commonly known as "iPSCs".
The ability of the Yamanaka factors to erase cellular identity raised a key question: is it possible to reverse cellular aging in vivo without causing uncontrolled cell growth and tumorigenesis? Initially, it didn't seem so, as mice died within two days of expressing OSKM. But later work confirmed that it is possible to safely improve the function of tissues in vivo by pulsing OSKM expression or by continuously expressing only OSK, leaving out the oncogene c-MYC. In the optic nerve, for example, expression of a three Yamanaka factor combination safely resets DNA methylomes and gene expression patterns, improving vision in old and glaucomatous mice. Numerous tissues, including brain tissue, kidney, and muscle, have now been reprogrammed without causing cancer. In fact, expression of OSK throughout the entire body of mice extends their lifespan. Together, these results are consistent with the existence of a "back-up copy" of a youthful epigenome, one that can be reset via partial reprogramming to regain tissue function, without erasing cellular identity or causing tumorigenesis.
Currently, translational applications that aim to reverse aging, treat injuries, and cure age-related diseases, rely on the delivery of genetic material to target tissues. This is achieved through methods like adeno-associated viral (AAV) delivery of DNA and lipid nanoparticle-mediated delivery of RNA. These approaches face potential barriers to them being used widely, including high costs and safety concerns associated with the introduction of genetic material into the body. Developing a chemical alternative to mimic OSK's rejuvenating effects could lower costs and shorten timelines in regenerative medicine development. This advancement might enable the treatment of various medical conditions and potentially even facilitate whole-body rejuvenation.
In this study, we developed and utilized novel screening methods including a quantitative nucleocytoplasmic compartmentalization assay (NCC) that can readily distinguish between young, old, and senescent cells. We identify a variety of novel chemical cocktails capable of rejuvenating cells and reversing transcriptomic age to a similar extent as OSK overexpression. Thus, it is possible to reverse aspects of aging without erasing cell identity using chemical rather than genetic means.
New Limit is putting a massive effort into maybe the gene therapy version of this. if you listen to their talks you'll realize it's very unlikely Sinclair et al managed to come up with a usable method to do the same with small molecules.
The claims seem like a bunch of baloney. The role of senescent cells is still poorly understood and their increased prominence with age even less so. Reversal of age related transcriptomic changes is claimed, yet what is actually shown in this study is the partial reprogramming of senescent cells using small molecules.
Age related transcriptomic changes within non-senescent cell types is neither addressed, nor distinguished from what the study is targeting. The authors seem to me to define "cellular age" as if all cell types experience the same changes in response to chronological age. The authors obviously know this is not the case, and there's nothing which explicitly claims this is the case, but the language seems unnecessarily inflammatory and broad, which appears to be a recurring theme with this particular clique.
The most interesting statement in this study for my unscientific mind is " Sodium butyrate, a histone deacetylase inhibitor, was one of the most effective additives in both human and mouse cocktails …. it has been reported to improve the expression of genes associated with reprogramming, supporting the model that the regulation of histone acetylation marks is crucial for rejuvenation via reprogramming"
David Sinclair conquers Aging, gets pooh-poohed by competitors
https://forbetterscience.com/2023/07/21/schneider-shorts-21-07-2023-i-write-and-revise-every-single-paper-myself/#sinclair
The paper was published on 12 July 2023 in the papermill-infested trash-bin Aging, where Sinclair 'is one of co-Editors-in-Chief. Also the penultimate author, the Harvard russian Vadim Gladyshev, is member of the editorial board which is full of infamous bullshitters and fraudsters. Basically, the paper ended in Aging after it was rejected by more serious journals despite the Harvard credentials.'
Btw... the 'peer review' @ Aging took 4(four!) days after submisson. Not all of them workdays!
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or... "We won't get eternal life. Scientists who promise it are just selling BS"
https://www.calcalistech.com/ctechnews/article/hy4bzl2y3
"There is a perverse incentive structure in science to claim the most exciting things, including discoveries that will not only interest scientists but make the front pages of newspapers and magazines. Anxiety about aging means that there's a willing audience. There's been hype about aging for thousands of years. So no, I don't believe that Methuselah lived for over 900 years, nor do I believe that the latest claims about mice aging are likely to be replicable."
Lulz!
Assuming this research is valid it is relatively easy to obtain the ingredients. The 'cocktail' included 1) activator of adenylyl cyclase (forskolin). 2) broad spectrum histone deacetylase inhibitors (valproic acid & sodium butyrate). 3) GSK3α/β inhibitor (used CHIR99021, but Lithium is potent GSK3α/β inhibitor too), and 4) TGF-β inhibitor (used E-616452 aka RepSox; drugs in clinical use known to inhibit TGF-β include losartan, glitazones. Curcumin/Resveratrol do too).
So relatively easy to reproduce at least some of these effects w cocktail of OTC Lithium, Sodium Butyrate and Forskolin. Keeping too natural compounds kampferol, boswellia, panax ginsenoside and ginger have effects in same pathways). Could add rx valproate, losartan, pioglitazone. Obviously dose and duration are questions that also bear on risks (primarily cancer in my view). There are probably thousands of people prescribed all 3 of the prescription meds daily. For anyone else measuring DNA age before and after short cycle should give some idea of efficacy.
See links added to excerpt from article.
CHIR99021 is a GSK3α/β inhibitor (so is Lithium- https://www.nature.com/articles/labinvest2014132), an effective inducer of CiPSCs and promoter of certain stem cell characteristics [66, 67]. E-616452, also known as RepSox, is a TGF-β inhibitor (as are: drugs in clinical use, tranilast, losartan, glitazones and imatinib mesylate- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541793/#:~:text=Four%20such%20drugs%20in%20current,activity%20that%20are%20under%20development.) is used in experiments to replace SOX2 during epigenetic reprogramming [68, 69]. All the efficacious reprogramming chemical cocktails included these compounds. research groups observe that cocktails w CHIR99021 and E-616452 induce direct reprogramming between differentiated cell states [70, 71]. suggests that processes involved in both rewriting and replacing cellular epigenetic identity are affected by additive effects of these compounds. studies found associations w individual chemicals and reprogramming in various contexts, indicating that each likely contributes to rejuvenation through a broad range of mechanisms.
Valproic acid is a well-known broad-spectrum histone deacetylase inhibitor (so are kampferol, boswellia, ginsenoside- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274245/) that leads to a rapid and dramatic spread of histone acetylation marks across the genome. The fact that valproic acid is a critical component of many of the successful cocktails indicates that the spread of euchromatin may be an important component of partial epigenetic reprogramming [73]. Sodium butyrate is another histone deacetylase inhibitor that was effective in both human and mouse cocktails. It has been reported to improve the expression of genes associated with reprogramming, supporting the model that the regulation of histone acetylation marks is crucial for rejuvenation via reprogramming [54]. The final chemical in our most efficacious C1 cocktail, forskolin, is an activator of adenylyl cyclase that has been shown to drive reprogramming and trans differentiation, depending upon the combination of other compounds present [74, 75]. While the mechanism of action of forskolin in the context of rejuvenation remains to be identified, increasing cellular levels of cAMP and the triggering of signal cascades that are critical for adaptations in cell identity may be key.
@Jones:
I enjoy forbetterscience (and I am not a scientist), but is there a scientist out there whom they don't repute a scammer? Trashing everyone and everything is not very constructive.
@Barbara T.
I somewhat agree. It's the counterpart to the science 'cheerleading' crowd.
Let me add some constructive advice in Leonid's place. He probably assumes that scientists/his readers know this.
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To maintain a good reputation, scientists should avoid engaging in practices that can be detrimental to their credibility, integrity, and the overall trustworthiness of their research.
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Things that a scientist should avoid:
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Fabrication or Falsification of Data: Fabricating or falsifying data is a severe breach of scientific integrity and can lead to severe consequences, including loss of reputation and career.
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Plagiarism: Using someone else's work, ideas, or words without appropriate attribution is unethical and can damage a scientist's reputation.
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Misleading or Selective Reporting: Presenting research findings in a way that misrepresents the data or selectively reporting results to support a particular conclusion is dishonest and undermines the scientific process.
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Conflict of Interest: Scientists should disclose any potential conflicts of interest that could compromise the objectivity of their research or its interpretation.
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Poor Research Design and Methodology: Conducting research with flawed methodologies or inadequate experimental design can lead to unreliable results and harm a scientist's reputation.
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Inadequate Peer Review: Avoiding the peer review process or not adequately addressing reviewers' feedback can impact the quality and credibility of the research.
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Overhyping or Overstating Results: Making exaggerated claims about the significance or implications of research findings can mislead the public and erode trust in the scientific community.
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Ignoring or Dismissing Contrary Evidence: A reputable scientist should be open to new evidence and should not ignore or dismiss data that contradicts their hypotheses or beliefs.
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Lack of Transparency: Failing to provide access to data, methodologies, or research protocols can raise concerns about the reliability and reproducibility of the research.
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Ethical Violations: Engaging in any form of unethical behavior, such as mistreatment of research subjects or violating ethical guidelines, can have severe consequences for a scientist's reputation.
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Not Correcting Errors: If errors or inaccuracies are discovered in published work, it is essential for scientists to take prompt and appropriate actions to correct the record.
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Neglecting to Give Credit: Properly acknowledging the contributions of collaborators, mentors, and other researchers is crucial for maintaining integrity and fairness in scientific work.
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By avoiding these practices and upholding the highest standards of scientific integrity, a scientist can build and preserve a positive reputation within the scientific community and beyond. Maintaining a good reputation is an ongoing commitment that requires ethical conduct and adherence to the principles of responsible research.
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Having said that, I can't speak for FBS contributors, but in my not-so-limited exposure to other researchers, there are a great many scientists who are not scammers and are very honest and diligent researchers. They usually don't have financial conflicts, have signed NDAs, and don't write books or publish insanely exaggerated claims on social media/popular press. Their experiments may fail or show insignificant or inconclusive results. They don't fake data to publish a paper or promote a spun-off business. I work with quite a few in diagnostics. They simply do their job and very rarely are mentioned by name. They are the unsung heroes of science. Every now and then even FBS mentions one of them in a in a subordinate clause.
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Now, working in academic's 'publish or perish' culture is a completely different beast.
D.Sinclair ... and the show goes on ...
Loss of epigenetic information as a cause of mammalian aging
https://pubpeer.com/publications/10C9F18A2F3AFCB48914A77F43B6EF
@Jones:
As a social scientist (outside academia as I am not back-stabbing enough to thrive there) I don't understand microscopy images and how to spot manipulation, but I abide by the guiding principles that you listed above, principles wildly disregarded by the scientists called out by FBS.
I also agree that Ivy League Universities are no guarantee of honesty (check out Francesca Gino, Harvard dishonesty researcher suspended for fabricating papers on dishonesty) and I agree that the vast majority of scientific endeavours aren't groundbreaking or life-changing, but boring and often failed experiments that are scarcely relevant to the clinic.
But can there be a middle ground between "immortality pill is 5 years away" and "all aging scientists are lying crooks"? The chasm leads to things like Ivermectin, anti-vaxxism, high school kids steering away from science... or going into it for all the wrong reasons.
The problem is that to be at the top of any profession, including science, one needs a great deal of narcissism (and machiavellianism, psychopathy), which means that as long as there is a media machine headed by individuals with the same personality traits the circus will go on.
FBS is more "fun" to read than Fightaging! (which is partial to its cause but also moderate IMO), but if Leonid & Co could intersperse their admittedly great whistleblowing and witty writing with some examples of good research and profiles of unsung heroes, they could foster cautious optimism towards science rather than disenchantment and hopelessness.
@Barbara T.
Actually, there should be only "middle ground". In the olden days, this "middle ground" was usually referred to as "the truth." At some point along the way "the truth" became boring. Now, in "attention-centered" societies, truth can't survive in the minds of the population. Getting attention is now more important than earning respect.
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Anyways, if a group of fraudsters poisons the knowledge pool of society through research misconduct for financial gains, it is essential for society to take swift and decisive action to address the issue and mitigate its consequences.
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Some steps that a society can consider taking:
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Investigate and expose the fraud: First and foremost, there should be a thorough investigation to identify and expose the fraudulent research and the individuals or groups involved. This may involve collaborating with independent researchers, experts, or regulatory bodies to ensure an impartial and unbiased examination.
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Retract fraudulent research: Once fraudulent research is identified, it should be immediately retracted from scientific journals and other publications. Retraction is a formal acknowledgment that the research was flawed or fraudulent, and it helps prevent the further spread of misinformation.
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Strengthen research integrity: Societies should invest in promoting research integrity and ethical conduct among researchers. This can be achieved through education, training, and implementing clear guidelines and codes of conduct in research institutions.
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Enforce penalties and legal actions: Fraudulent research is a serious offense and should be met with appropriate penalties and legal actions. This may include sanctions, fines, or criminal charges depending on the severity of the misconduct.
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Support whistleblowers: Encourage and protect whistleblowers who come forward with information about research misconduct. Whistleblower protection ensures that individuals who report fraudulent activities are shielded from retaliation and encourages a culture of accountability.
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Improve peer review and validation processes: Strengthen the peer review process to identify and prevent fraudulent research from being published in reputable journals. Additionally, support replication studies and independent verification of research findings to enhance the credibility of scientific knowledge.
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Promote transparency and data sharing: Encourage researchers to share their data openly, allowing others to verify and validate their findings. Transparency and data sharing can help identify inconsistencies or potential fraudulent practices.
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Collaborate with regulatory bodies: Engage with relevant regulatory authorities to establish protocols for handling research misconduct cases and coordinate efforts to address fraudulent research at a broader scale.
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Educate the public: Increase public awareness about research misconduct and its potential consequences. Educating the public can help individuals become more discerning consumers of information and reduce the impact of fraudulent research on society.
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Support ethical research practices: Provide incentives and support for researchers who prioritize ethical and responsible research practices. Recognition and funding should be allocated to those who demonstrate a commitment to maintaining the integrity of the knowledge pool.
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Addressing research misconduct is essential to maintain the trust and credibility of the scientific community and the knowledge that drives societal progress. By taking proactive measures and holding fraudulent actors accountable, society can work towards a more reliable and trustworthy knowledge pool.
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This is the value of FBS. Even if we don't like it when someone takes away the promise of eternal life.
I will leave this without further comment.
Medicine is plagued by untrustworthy clinical trials.
How many studies are faked or flawed?
Investigations suggest that, in some fields, at least one-quarter of clinical trials might be problematic or even entirely made up, warn some researchers. They urge stronger scrutiny.
https://www.nature.com/articles/d41586-023-02299-w
@Jones
I agree with your recommendations and I don't disagree with the whistleblowing value of FBS. But the solutions you listed lie within - or at least require the support of - the very institutions that benefit from the status quo.
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It's all good and dandy to say that So and So falsified X and Y study, but the way the problem is presented by FBS implies that all top academics are corrupt (which I don't necessarily disagree with) and whatcha gonna do about it but cover them in ridicule on an obscure blog while they laugh all the way to the bank.
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I think the mass media are the critical amplifiers here.
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Maybe what we need to do is to stop treating scientists like pill pusher Sinclair or God Impersonator (that's a good one) Church like superstars. If the quacks are denied the spotlight they crave - and here I am not blaming tabloids but "reputable" outlets like the Guardian, El Pais, the New Yorker etc - then the quacks won't get the millions they need to falsify their research and launch their start ups. At that point, all they'll be left to do is peddle their snake oil to the village crowds of yesteryear while the wider world hears of the 21st century equivalent of penicillin when people who were previously dying of Z condition stop dying of Z condition.
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As for eternal life, I personally believe that aging will be "solved" at some point in the future if we don't self-destruct in the meanwhile, but I can't see this happening for anyone who is not an infant today. And given the integrity of our top anti-aging researchers, with regard to timelines I am gonna go out on a limb and say that my guess is as good as theirs.
@Barbara T.
I have little hope for the 'sensationalist' press, but if you believe some predictions that claim that there will be dozens of trillions of $$$ flowing into longevity startups in the next couple of years, there's some hope. Markets will somewhat self-correct. 90+% of the startups will fail. Money will go 'poof'. Names will be burned. One investor generation will learn a thing or two. Like they did from the .com bubble, also a technology they didn't understand very well. Most stem cell startups already turned 'tits up'. Unity front-runs for senolytics. Some never tire to mention that Thiel & Bezos have invested in 'longevity' (Unity), they don't mention the ROI they've (not) made, though.