RNA Splicing and Cellular Rejuvenation

In this article, I will first examine what what senescent cells are and a few of their causes (Section A). Thereafter, I will look at the possibility to rejuvenate these elderly cells (Section B) I will conclude by evaluating the significance of this discovery in terms of  organizing and optimizing longevity. (Section C)

Section A

What Causes Senescent Cells?

A variety of macromolecular damage can cause our cells to become senescent including toxins and radiation.  The passage of time is another cause of senescence. Our cells divide about 50 times, their telomeres shortening with each division. DNA damage is another cause of cellular senescence. When a cell becomes sufficiently damaged, it is programmed to self-destruct in a process called apoptosis, a form of cell death.

Unfortunately, some of these damaged cells refuse to commit suicide. The body’s immune system clears out many of these recalcitrant cells.  However,  with an age and an unholistic lifestyle, the immune system weakens, causing increasing numbers of these senescent cells to build up. These zombie cells can be found in most of our organs and tissues, up to 20 percent of cells, if not more. These cells release massive amounts of inflammatory chemicals that significantly contribute to the chronic conditions of aging

Section B

Rejuvenating Senescent cells with Red Wine ?

A team led by Professor Lorna Harries at the University of Exeter has discovered a new way to rejuvenate these worn-out human  senescent cells. The team published their findings in the journal, BMC Cell Biology. (1) (Source) The discovery builds on the research team’s earlier findings which showed that a class of cellular helpers called messenger RNA splicing factors become progressively switched off as we age.  The team found that they could use chemicals to switch the splicing factors back on, which in turn made the senescent cells look and behave like younger cells and start dividing again.

“This is a first step in trying to make people live normal lifespans, but with health for their entire life. Our data suggests that using chemicals to switch back on the major class of genes that are switched off as we age might provide a means to restore function” (Source)

The team of researchers rejuvenated the cells using novel resveratrol analogs. Resveratrol naturally occurs in foods like red wine, blueberries, dark chocolate or red grapes. The University of Exeter team discovered that the resveratrol analogs switched on the splicing factors in the aging cells. Within hours, the cells looked younger and began to rejuvenate and started dividing and acting like younger cells.

Mechanism of Action

It is established that senescent cells lose messenger RNA and splicing Factors. Senescent cells also lose their ability to correctly regulate their genes, making the host more susceptible to disease. Notably, senescent cells experience a decline in splicing factors that aid the process of decoding our DNA and manufacturing proteins.

Our genes provide the instructions for building cells using messenger RNA (mRNA), a single-stranded RNA molecule that is complementary to one of the DNA strands in a gene. Splicing factors are essential in ensuring that our genes perform their full range of functions and help to build mRNA.

Messenger RNA is a RNA version of the gene that leaves the nucleus of the cell and moves to the cytoplasm where proteins are made. In general, one gene can be transcribed into a mRNA molecule that will end up making one specific protein. During protein synthesis by the translation machinery, a tiny worker called a ribosome moves along the mRNA, reads its base sequence, and uses the genetic code to build proteins.

RNA Splicing Factors Decline With Age

As we grow older, our splicing factors tend to work less efficiently, or not at all, degrading our cell’s capabilities to make mRNA. Geroscientists have linked mRNA processing as a key determinant of lifespan and have observed that as we age, levels of splicing factors decline in both our blood and certain cells. A decline in splicing factor levels causes cells to become dysfunctional. Most notably, senescent cells have fewer mRNA splicing factors, degrading their abilities.

Resveratrol 

 Research has abundantly shown that resveratrol extends lifespan in various animals by activating the SIRT1 enzyme and increasing the levels of nicotinamide adenine dinucleotide (NAD). 

Encouraged by these findings, Professor Harries designed a panel of novel resveratrol analogs to see which ones could restore splicing factor expression to levels comparable with those seen in young cells.

The team identified and tested a total of six resveratrol analogs, including the original resveratrol compound, and documented the effects of the various compounds in their study. Because resveratrol is known to reduce markers of inflammation and inhibit SIRT1, the geroscientists engineered each of these novel resveratrol analogs to have differing effects on SIRT1 and pro-inflammatory chemicals. The researchers verified that the resveratrol analogs reversed aging in the cells by restoring splicing function and ruled out other potential reasons for resveratrol’s rejuvenating effects, such as senescent cell clearance. The team reported that of the analogs, resveratrol had the most significant impact reducing the levels of inflammatory compounds and markers of inflammation, including IL-2, IL-6, IL-8, TNF-α, and IFNγ.

Restoring telomere length can also help to rejuvenate senescent and other cells. Resveratrol can also help to do this as well as many other molecules and holistic techniques. (Source).

Section C

Discussion

One drawback that we see senolytics is that in their killing process, there is tissue atrophy. When cellular space gets empty, it is tempting for a weakened and aged body to fill it with more senescent cells.  

On the other hand, by restoring the immune system and the vigor of senescent cells with products like resveratrol analogs, there is much less loss of vital tissue. Furthermore, senescent cell have their role in wound healing, embryogenesis and even cancer prevention. In effect, emerging findings suggest that programmed induction of cell senescence may be important for regulating reproductive and wound healing processes, partly facilitated by immune clearance. (Source)

Another drawback is that there is not much human clinical research with resveratrol because this natural wine molecule cannot be patented. To overcome the patent limitations, a company called Sirtris formulated a resveratrol analog called SRT501. In 2008, GlaxoSmithKline (GSK) purchased Sirtris. However, there is still a lack of clinical trials that can test the effectiveness of resveratrol analogs in humans.

Research on both living human cohorts and isolated cells have looked at the types of genes which change in expression levels (the process by which information from a gene is used to make the tens of thousands of proteins needed by a cell during aging). This has revealed that the largest changes occur in genes which regulate how “messenger RNAs” are made. These transfer the information stored in DNA to the cellular machinery which turns it into proteins.

In the human cell, proteins known as “RNA splicing factors” determine which messenger RNA can be made from RNA building blocks in a process known as RNA splicing. The ability of our cells to do this is restricted with aging. But it was unclear whether this loss is a result of senescent cells accumulating in aging tissue or something new, occurring in parallel with senescence until now as I’ve shown above.

In the study mentioned above and published in BMC Cell Biology, it was shown that one of wine’s natural substance, resveratrol can rejuvenate senescent cells by targeting RNA splicing.

In the study’s experiments, senescent cells were treated with Resveratrol like compounds that where synthesized in the lab.

https://www.ncbi.nlm.nih.gov/pubmed/29041897

This compound was shown to alter RNA splicing in cancer cells. Resveratol affects multiple cellular pathways. The synthetic variants  were chosen in terms of their ability to modulate RNA splicing. RNA splicing patterns were rapidly reset to that seen in young cells and then the senescent cultures began to grow again. Variations of this basic experiment showed that splicing factor restriction is separate from senescence but interacts with it.

Restoring RNA splicing rejuvenates senescent cells in part because our cells are normally rendered senescent through telomere shortening, the gradual loss of the DNA at the ends of chromosomes that occurs with repeated cell division. Some RNA splicing factors that decline with age are capable of helping to repair telomeres and so, if you restore them, they lengthen telomeres back up and stop the cell being senescent.

It would be interesting to test natural resveratrol in red wine holistically, with other natural molecules and techniques. There is already a good amount of litterature that shows the beneficial effects of diets containing these foods – altered splicing may be one. And contrarily to what the experts have claimed, we may not need to to drink 30 liters of wine a day to this RNA splicing affect. Resveratrol, like many natural products, has a whole range of activities.

Restricted splicing has serious implications beyond the capacity of cells to divide and how tissues deal with stress. It limits cell responses, potentially contributing to the increased frailty that is a hallmark of aging in many organisms including humans. Cells from old individuals that have not yet become senescent still have compromised splicing. RNA splicing is upstream. That is where we need to go.

Conclusion

By the middle of this century the over 60s will outnumber the under 18s for the first time in human history. This should be good news, but growing old today also means becoming frail, sick and dependent. Improving the overall health of older Americans however could save the US alone enough money to pay for clean drinking water for everyone on Earth for the next 30 years.

There has been significant progress made over the last decade. In 2009, it was shown that the drug rapamcyin extended the lifespans of mice by 10-15%. Two years later a landmark study showed that experimental clearance of “senescent” cells – dysfunctional cells which build up as we age and cause damage to tissue – improved healthy lifespan in laboratory mice. These senescent cells are therefore being therapeutic targets for the Industry.

In dealing with the challenge of senescent cells, senolytics that kill senescent cells is one way to approach  aging. However, targeting upstream the splicing factors with natural molecules like resveratrol or even resveratrol analogs can be beneficial as well as restoring the immune system and other bodily functions. More experimentation and in particular human clinical trials would be warranted. Senescent cells are evolutionary strong. So before targeting and killing them, it may be wiser to better understand  Nature’s rationale for these “zombie” cells and focus more upstream. While resveratrol holds promise as a fountain of youth, caution is warranted. More often than not, promising compounds have shown spectacular results in cell cultures only to be a flop in human trials.

References

Splicing Factor 

Eva Latorre, Vishal C. Birar, Angela N. Sheerin, J. Charles C. Jeynes, Amy Hooper, Helen R. Dawe, David Melzer, Lynne S. Cox, Richard G. A. Faragher, Elizabeth L. Ostler, Lorna W. Harries. Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence. BMC Cell Biology, 2017; 18 (1) DOI: 10.1186/s12860-017-0147-7.

University of Exeter. “Old human cells rejuvenated in breakthrough discovery on aging.” [Press Release] ScienceDaily, 7 November 2017. Link to press release.

Resveratrol 

Liu Y, Ma W, Zhang P, He S, Huang D; Ma; Zhang; He; Huang. “Effect of resveratrol on blood pressure: A meta-analysis of randomized controlled trials.” March 2014. Clinical Nutrition. 34 (1): 27–34. PMID 24731650. doi:10.1016/j.clnu.2014.03.009.  Link to Article.

U.S. National Library of Medicine. Clinical trial number NCT00920556. “A Clinical Study to Assess the Safety and Activity of SRT501 Alone or in Combination With Bortezomib in Patients With Multiple Myeloma.”

Hausenblas HA, Schoulda JA, Smoliga JM, “Resveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus-systematic review and meta-analysis”.  August 2014. Molecular nutrition & food research. 59 (1): 147–59. PMID 25138371. doi:10.1002/mnfr.201400173. Link to Article.

Turner RS, Thomas RG, Craft S, van Dyck CH, Mintzer J, Reynolds BA, Brewer JB, Rissman RA, Raman R, Aisen PS; Alzheimer’s Disease Cooperative Study “A randomized, double-blind, placebo-controlled trial of resveratrol for Alzheimer disease.” (2015). Neurology. 85 (16): 1383–91. PMC 4626244. PMID 26362286. doi:10.1212/WNL.0000000000002035. Link to Article.

Abstract

Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.

Results

Treatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists.

Conclusions

This is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.

https://bmccellbiol.biomedcentral.com/articles/10.1186/s12860-017-0147-7

Advanced immunotherapy

Senescence immunotherapy strategies as an alternative to senolytics for the removal of senescent cell

Even more upstream from splicing factors is the immune system. New findings have show that the immune system may be more  “anti-senescent cells” than senolytic drugs.

https://www.sciencedirect.com/science/article/pii/S1568163718300114  publication 

This more holistic approach is a logical idea given that during normal, healthy operation, the immune system does indeed detect and remove senescent cells. It is only as we age that this system breaks down and fails, leading to the accumulation of senescent cells, which are partially responsible for aging.

In effect, when the immune system works well, it removes senescent cells. In response to persistent DNA damage for example, induction into cell senescence promotes an immunogenic program which facilitates immune clearance of these damaged cells. Under physiological conditions, senescent cells can activate both innate and adaptive immune responses. Thereafter, the immune system removes these zombie cells thereby restoring tissue homeostasis. (Source) 

Senescent cells can also destroy themselves via a programmed process called apoptosis. (Source)

However, owing to the aging of the immune system and a un-holistic lifestyle, a failure to eliminate senescent cells can contribute to their persistence in tissues, leading to the development and progression of age-related diseases and accelerated aging and all the more so that these senescent cells have been shown to escape both the apoptosis and immune marcrophage-driven phagocytosis processes.

By rejuvenating the immune system with different techniques, including via regeneration of the thymus we would respect Nature’s senescent cells production for wound healing and cancer mitigation while promoting their elimination via the immune system, in particular the macrophages. However, just like with cancer cells whose innate intelligence tricks the immune system into not attacking them, senescent cells can also promote immune suppression, a response that may reflect differences between an acute versus chronic senescent phenotype. More research would be warranted. 

Literature

[1] Burton, D. Stolzing, A. (2018). Cellular senescence: Immunosurveillance and future immunotherapy. Science direct doi.org/10.1016/j.arr.2018.02.001

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DISCLAIMER. Nothing in this blog-webstie should be construed as medical or legal advise, including, but not limited to replies, comments and posts, all of which should not be deemed to constitute either a therapist-patient nor an attorney-client relationship. Securing informed consent with a holistically trained  competent health-care practitioner is highly recommended.

“death-resistant” cells

https://www.youtube.com/watch?v=1rJfrF_JoPE

K;uhk;hkh. Senescent cells are dysfunctional cells that build up as we age  Studies have shown that health improves if the senescent cells are cleared leading to a lifespan extension of up to 15% Resveratrol, a natural compound found in red wine and berries, reportedly can alter RNA splicing in cancer cells and have an impact on senescent cells. Cells treated with resveratrol reset to look like much younger cells.

Professor Joubert teaches in different parts of the world how to extend a healthy Lifespan to 120 years and beyond. Working on a Documentary and book that redefines Medicine in light of new discoveries, ancient wisdoms, innovative research and holistic science, he can be nonetheless available to coach patients back to homeostasis, wellbeing & Joie de Vivre. On occasion, Pr. Joubert can also coach health professionals to better protect their holistic practice when they must deviate from outdated and irrational mainstream “standards of care”. See links on “Contact” and “Mission” (under the “About” link) for details.

Posted in Longevity Medicine, Anti-Aging, Gerontology, Telmomeres, Telomerase, Caloric Restriction, mTOR, Sirtuins, Protein Misfoldment, Uncategorized

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