Update on the Science of Aging : The latest avatar, The Retro-transposon Theory of Aging

Although not revolutionary in terms of making significant progress on the Optimal Longevity Science front, Brown University’s longevity experts have nonetheless confirmed a relevant correlation between the increase of retro-transposons within eukaryotic genomes and accelerated aging. In this blog-article, I will first look at the findings that led to this conclusion (Section A) and thereafter, follow up on its scientific validity  (Section B).

Section A

The Transposon or Retro-transposon Model of Aging

Transposons are DNA elements capable of moving around the genome. Contrarily to what the medical press has called these elements, the research experts have characterized these entropy-promoting agents as “transposable elements”.

“Transposable elements (TEs) are mobile genetic elements, highly enriched in heterochromatin, that constitute a large percentage of the DNA content of eukaryotic genomes”. (1)  (Source)

At the time of the publication of this research, published in the journal, Proceedings of the National Academy of Sciences last september 2016, (2) the experts were claiming that this finding could significantly help to develop life-extending treatments that would inhibit the mechanisms that produce these transposons or transposable elements (TEs).

Primary mechanisms

Previous studies have shown that the mechanisms which normally keep these transposons from migrating to other areas of the genome are centered around the firmly wound structure of heterochromatin. Longevity scientists have already known for decades the link between chromatin and aging,  (3) but with this new  2016 finding, we can better understand its mechanisms.

As human eukaryote cells age, these heterochromatin structures deteriorate. Therein, the DNA structure in key areas begins to loosen, transposons are then allowed to insert themselves into other genes, that which disrupts their function and affects health and longevity. In this perspective, the Brown university experts looked at fruit flies, who are also eukaryote creatures, to attempt to identify the exact mechanisms and genes that would be responsible for this molecular disarray.

Aging in Drosophila melanogaster is characterized by loss of repressive heterochromatin structure and loss of silencing of reporter genes in constitutive heterochromatin regions”. (4) (Source)

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Top: Activity with age. Fluorescence in the fat body of fruit flies tracks the activity of transposable elements of DNA. It increases markedly with age. Credit: Jason Wood/Brown University

The Validating  Experiments

Using green fluorescent protein (GFP) as a marker, (See top picture) the researchers were able to study the movement of transposons in the genome of Drosophila fruit flies. As the flies aged, Helfand and his colleagues noted an increase in transposon activity. Interestingly, the transposon activity did not increase linearly as the flies aged; transposon movement throughout the genome was at its peak as the flies began to die. The fruit flies reached a certain age and then the heterochromatic-based deterioration took off exponentially. (5)

Controlling Transposons with Holistic Medicine

In another experiment, the research team found that feeding the flies a low-caloric diet significantly delayed the point at which transposon activity began to increase. Dietary changes have already been shown to be successful interventions at prolonging lifespan, but here, we have even more solid evidence that dietary restriction, which is key in happiness and holistic medicine, is decisive insofar as a significant extension of Life is concerned. In particular, the genetic mechanism that was identified by the researchers are explained below:

A dietary restriction regimen, known to extend life span, repressed the age-related increased expression of genes located in heterochromatin, as well as TEs” (6)

Genetic Manipulation

In addition to experimenting with dietary retriction, Dr. Helfand and his team manipulated genes known to regulate DNA structure and organization into heterochromatin, which are conserved in both Drosophila and humans. The researchers found that the upregulation of the gene Su(var)3-9 – a gene which induces DNA to form a heterochromatic structure – extended the flies’ lifespan by 20 days. (7) Furthermore, the researchers found that manipulating genes known to affect heterochromatin structure, including overexpression of Sir2, Su(var)3–9, and Dicer-2, as well as decreased expression of Adar, mitigated age-related increases in expression of TEs. Increasing expression of either Su(var)3–9 or Dicer-2 also led to an increase in life span. (8)

“Together, these data support the retrotransposon theory of aging, which hypothesizes that epigenetically silenced TEs become deleteriously activated as cellular defense and surveillance mechanisms break down with age. Furthermore, interventions that maintain repressive heterochromatin and preserve TE silencing may prove key to preventing damage caused by TE activation and extending healthy life span” (9)

 Section B

Critical Appraisal: Cause or Consequence ?

Despite the evidence provided by the multiple experiments performed by the Brown Univeristy Lab, there is up to now no credible evidence that this undeniable correlation between transposons disarray and accelerated aging is causative.  In other words, whether  it is the aging process that causes transposons’ deletrious hyperactivity or transposons that cause accelerated againg in cellular biology is still up for debate. The work the Brown University Lab published confirms a few mechanisms, but nothing substantial appears to have been discovered. There are many correlations in the process of aging and this one may be either an epiphenomenon thereof, or something more significant. Hopefully, the 10 million dollars grant that the Brown University team received for this  research will eventually clarify this question. A pubmed search in December 2017 still shows nothing conclusive.

The Brown Lab team states that they will now study the  expression of transposable elements to see if that undermines health and lifespan. The Lab is also considering the use of the CRISPR gene editing technique to specifically disable the ability of transposable elements to mobilize within the genome. (Source)

However, even if significant findings are made, these would lead to either drugs that would inhibit heterochromatin pathways or promote genetic manipulation. While these interventions may lead to some age delaying in insects and animals, nothing compelling shows that these findings will significantly benefit human beings in their quest to achieve their designed healthy life span potential of 120 years and help them to mitigate today’s onslaught of chronic disease epidemics. 

Discussion

While providing substantial new evidence that health becomes endangered when aging cells lose control of rogue elements of DNA called transposon is useful and helps us to better understand the mystery of senescence and aging, Dr  Stephen L. Helfand, who recently received honors from the American Advancement of Science Academy for this work, (10) has still not shown whether this relationship between rogue DNA elements and heterochromatin loosening is causal. A review of the scientific literature showed that only one other more recent study in this field exists, one connecting these transposons with Amyotrophic lateral sclerosis (ALS)  (11). (Source) But there too, the study showed more correlation than causation.

The aging field is replete with theories, including with one of my favorite ones based on the microbiome’s composition. (Source). But mainstream Science is still unable to propose a coherent Aging Model that can be actionable in terms of significantly extending human Life Span to at least 120 years old for most humans.

Over the past years, many distinct, yet overlapping mechanisms have been proposed to explain organismal aging. These include free radicals, loss of heterochromatin, genetically programmed senescence, telomere shortening, genomic instability, nutritional intake and growth signaling, to name a few. This transposon study highlights the relationship between loss of heterochromatin integrity, transposons going berserk and accelerated aging. Which is good to know, but there is nothing we as humans can do to control this process, except by going into caloric restriction.

Indeed, if anything, this study confirmed the relevance of simply eating fewer calories to live longer and healthier. Under 1000 calories a day for at least a few days each month. Thanks to which the body can upregulate longevity genes, including considerably slowing down this transposons phenomenon as the Brown Univeristy experts noted.  I will be writing another post on this later.

Conclusion

This study does provide some evidence that a breakdown in TE silencing and repression may be a contributing factor to aging. And by preventing TE activation, diseases of aging may be delayed. But this study does not show conclusive evidence that drugs or genetic manipulation can significantly prolong a healthy lifespan.

In our understanding of optimal longevity, we must not forget the big picture regarding the two central modern biological theories of aging, namely: programmed theories and damage or error theories. The programmed theories are driven by biological timetables (changes in gene expression, physiological maintenance, repair and defense). In this perspective, we need to ask why do aging tissues lose their capacity to regenerate, why do stem cells fail to function as one gets older, and how do tissues change during aging such that they no longer support normal regenerative processes and repair mechanisms.

On the other hand, damage or error theories highlight environmental assaults, such as exposure to carcinogens, confounded by lifestyle choices (diet, exercise, etc.) and, inter alia, chronic stress.

If we are to guarantee People their alleged 120 years old healthy life span “birth right”, then more time, efforts and funds should be invested in those who research credible healthy longevity approaches which will both promote significant cellular repair mechanisms and minimize incoming damages that accelerate the biologically driven aging process.

As we know or should know, whether it be in cancer research, modern cardiology, geriatric or gerontology, gene editing and-or synthetic drugs are usually very expensive and tend to lead to complications and serious side effects. Even if these high-tech modalities can delay the ultimate rendez-vous with death by a few months. It’s still challenging to try to fool “Mother Nature” or Evolution’s billions of years of adaption with synthetic drugs or gene manipulation. Trying will help to better understand theory, may produce delaying techniques, but why not invest in happiness medicine and holistic interventions, both of which have proven beyond any reasonable doubt that living to at least 120 years of healthy lifespan is possible ?

Christian Joubert (Happiness Medicine Institute and Longevity Gazette Director)

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Reference and Precision Notes

(1). Jason G. Wood, Brian C. Jones, Nan Jiang, Chengyi Chang, Suzanne Hosier, Priyan Wickremesinghe, Meyrolin Garcia, Davis A. Hartnett, Lucas Burhenn, Nicola Neretti, Stephen L. Helfand. Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span inDrosophila. Proceedings of the National Academy of Sciences, 2016.(Source), http://www.pnas.org/content/113/40/11277
(2). http://www.pnas.org/content/early/2016/09/07/1604621113. Most eukaryotic genomes contain abundant transposable elements (TEs), mobile DNA elements that can replicate and move within the genome. Because of the deleterious nature of active TEs, cells have mechanisms to suppress and prevent TE activation, including formation of repressive heterochromatin.
(3). Epigenetics. 2012 Jul;7(7):680-8. doi: 10.4161/epi.20540. Epub 2012 Jul 1. Global heterochromatin loss: a unifying theory of aging https://www.ncbi.nlm.nih.gov/pubmed/22647267
(4).  Op. cit. footnote 1.
(5).  Ibid.
(6). Ibid.
(7). Ibid.
(8). Ibid.
(9).  Ibid. Ibid. In addition, ….??? Mutation of Dicer-2 led to an increase in DNA double-strand breaks. Treatment with the reverse transcriptase inhibitor 3TC resulted in decreased TE transposition as well as increased life span in TE-sensitized Dicer-2 mutants.
(10). Helfand, MD, a professor of biology, earned his honor “for distinguished contributions to the field of molecular and translational aging research, particularly for identifying molecular genetic pathways underlying aging and human disease, the AAAS said in the announcement. In 2016, for example, he was the senior author of a study in the Proceedings of the National Academy of Sciences in which his team provided substantial new evidence that health becomes endangered when aging cells lose control of rogue elements of DNA called transposons. (Source)
(11). Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS, http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006635
(12). Lik Sprava. 2007 Jan-Mar;(1-2):10-7. Role of microorganisms in etiology and pathogenesis of aginghttps://www.ncbi.nlm.nih.gov/pubmed/17682510. Latent and chronic infections may initiate and support processes of senescence, stimulating signs of aging and age-related diseases.

Exhibit A

Review of Aging Fundamentals

Exhibit B

Review of the Transposon Theory of Aging

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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.

Professor Joubert teaches how to extend a healthy cancer-free Lifespan to 122 years thanks to safe, efficient and cost friendly breakthrough protocols. 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-or irrational mainstream “standards of care” in order to genuinely serve their patients, evidence-strong Science and internationally recognized human rights. For details, see the links called “Contact” and “Mission” (under the “About” link).

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

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