1. Thymus Regrowth with FOXN1
The thymus gland is a time bomb that would kill us at a certain age, if nothing else got us first. It shrinks (the medical word is “involution”) gradually through life, beginning in childhood and culminating in disastrous results in old age.
The thymus is a small gland located just behind the top of the breastbone. Among your white blood cells, your first-defense cells are the T-cells, named for their association with the thymus. The thymus is training ground for the T-cells, where they learn to distinguish friend from foe. The body has many types of cells, and the T-cells must not attack any of them; but they also must reliably identify invading microbes.
These immune functions are related to many aspects of health, and not just attacking invasive microbes. The immune system is continually eliminating errant, pre-cancerous cells before they can become cancers, as well as cells in the body that have been taken over by a viral infection. Rampant inflammation and auto-immune disorders are the consequence when the immune system begins to turn against self late in life.
As the thymus shrinks year by year, the immune system breaks down. A 90-year-old thymus may be one tenth the size it was in the bloom of childhood, and this goes a long way toward explaining the vulnerability of older people to viral infections that would not be serious for a young person. Arthritis is well-characterized as an auto-immune disease, but there are auto-immune aspects of other diseases including Alzheimer’s
There is good reason to think that if we can preserve or even regrow the shrinking thymus, then there will be benefits that echo through many or all the diseases of old age. Human growth hormone has been used with some success, but reactions to HGH vary, and there is reason to worry about its long-term effects. There is a recent breakthrough in treatment for the thymus that looks very promising. A transcription factor is a coded chemical signal capable of switching the expression of many genes at once, turning some on and others off in one sweep. FOXN1 is a transcription factor that has been isolated from the thymus of young mice, and by re-introducing it to old mice, a Scottish research team succeeded in consistently stimulating the thymus to regrow [ref]. The larger thymus looked and functioned much like the thymus of a young mouse.
The most glaring absence in the blood as we age is naive T-cells, cells that are not pre-trained to fight any specific infection from the past, but are primed to look out for new invaders. So it is most promising that the thymus glands regenerated with FOXN1 produced copious naive T cells.
In the Scottish experiments, mice were genetically engineered with extra copies of the FOXN1 gene that could be turned on with a drug as trigger. You and I don’t have these extra copies, so we need another means to get FOXN1 into our aging thymi. FOXN1 is not something we can take in a pill, because it is a large protein molecule that is routinely chopped up for recycling during digestion. A research group at University of Texas is injecting little snippets of DNA (called plasmids) containing the FOXN1 gene directly into the thymus with some success [ref]. Turning on the cell’s own FOXN1 gene would be ideal, and there are already candidates that can do this. There is no reason to doubt the feasibility of FOXN1 drugs, but for now we have only rumors that they are under development.
2. New Anti-Inflammatory Drugs based on ARF6 Inhibitors
Inflammation has been a recurring theme in this blog, because inflammation is the most obvious and ubiquitous mode by which the body destroys itself.
The fact that simple, “dumb” NSAIDs lower mortality in older people and increase life expectancy is very promising, but the promise is limited because inflammation has an important positive function as well as its self-destructive role. That’s why the more powerful NSAIDs have side-effects that limit their use. To make real progress in this area, we will need smart anti-inflammatories that go selectively after the destructive role, and leave the protective function intact.
Dean Li and his research group at University of Utah have been addressing just this challenge. Their breakthrough paper came in 2012, when they announced the discovery of a signaling pathway that controls just the destructive inflammation, and is not involved in the good kind. In petri dishes, they identified a target signal called ARF6, and for therapy they constructed a protein that contained the last 12 units at the tail end of ARF6.
Have you ever broken off half a key inside a doorknob? Not only can’t you turn the knob, you can’t pull the key out, and you can’t get another key in there either. You may have to give up on the lock and get a new doorknob. The tail end of ARF6 works like half a key. It fits neatly into the same receptor as the full ARF6 molecule, but once inside it doesn’t change the conformation of the receptor the way that the full molecule does. It won’t open the lock, and it stays stuck in the keyhole, blocking access to the real, working key.
The tail stub of ARF6 worked like a broken key to interfere with the real ARF6, preventing it from doing its job. The Li lab was able to block the inflammatory reaction that responds to ARF6 without affecting the course of inflammation that is beneficial and protective.
They went on to inject their tail stub molecule intravenously in mice. They report exciting initial successes, treating mouse arthritis without gumming up the other important functions of inflammation.
Some bacteria kill the host not directly but by inducing such a violent inflammatory reaction that the patient dies of his own inflammation. Dr Li’s team challenged mice with LPS, which is the chemical that induces this fatal inflammation. Mice protected with their ARF6 tail stub had reduced inflammatory responses, and mostly survived, while those without the tail stub mostly died after being poisoned with LPS. [ref]
This is a discovery that has yet to make front page headlines, but Dr Li’s team is fully aware of the potential for changing the way we treat the inflammatory basis of arthritis and other diseases of old age, especially coronary artery disease.
3. Telomere Length Directly Affects Gene Expression
Short telomeres cause cell senescence, which pulls a stem cell out of circulation and, worse, causes the cell to emit signals that damage neighboring tissues and the body as a whole. This has been the basis of the theory that telomeres act as a kind of fuse for an epigenetic time bomb. This month, a paper came out of Woody Wright’s Univ of Texas lab that adds a mechanism by which telomeres can affect aging even before cells become senescent. Telomeres affect gene expression, which is the epigenetic state of a cell. The same chromosome tends to express and repress different sets of genes depending on length of its telomeres.
It has long been suspected that telomere length affects gene expression. As far back as 1990, Telomere Position Effect (TPE) was noted as affecting gene regulation. But until this month’s study, there was no coherent idea how this occurs. In order to study the effect systematically, the Wright team had to create a culture of cells all with the same telomere length. They were both able to image the conformation of the chromosomes and also measure the genes they expressed as a function of telomere length. Wright introduces the acronym TPE-OLD, for Telomere Position Effect Over Long Distances. What they found was that
- Telomere length affects the folding and conformation of the DNA
- Telomeres wrap back over coding DNA and have effects extending at least 10MB from the end
- Telomere length affects the transcription of at least hundreds, perhaps thousands of genes.
(To have a sense of the scale, keep in mind that a human chromosome is hundreds of millions of base pairs long (108), that the length of a telomere is only about 10 thousand BP (104), and that there are about 25,000 genes in the human genome. So, even though telomeres are 0.01% of the length of the chromosome, they may affect the transcription of 3% of all genes.)
Gene expression changes with age in some ways that are regular and others that are random. I would say that as we age, our epigenetic state changes toward a self-destructive, inflammatory mode, and also drifts randomly out of tight regulation.
Telomere length varies greatly from one tissue to another, from one cell to another within a tissue, and from chromosome to chromosome within a cell. It is difficult to make sense of this within a picture of a tightly-regulated aging program. But the idea that the random portion of telomere length contributes to epigenetic drift seems plausible to me.
In any case, the present study opens a door to a new science, and gives added credibility to the idea that telomere length plays a fundamental role in human aging.
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I think that with regard to thymus and inflammation, we may end up getting stuck between a rock and a hard place. What if the thymus although now artificially enlarged lacks the ability to “teach” T-cells about self/non-self? The extra naive cells would go on to attack self and inflammation would increase. Did the researchers verify the priming of the T-cells against non-self only? I guess what I’m trying to say is that the artificial enlargement of an organ is not necessarily correlated with normal functioning.
I was intrigued by your last entry on telomeres. Especially the part that said there was length variability within the chromosomes of a single cell. Will one chromosome with a “zero” length telomere get copied? Got to research this!
The thymus not only regrew, but functioned like a young thymus.
Concerning zero-length telomeres, I believe that the chromosome becomes unstable long before this, triggering either a repair mode or a senescence mode in the cell.
Hi Josh,
This is an excellent synopsis. Rarely can you find objective summarizing of longevity research.
My question relates to Points Nos. 1 & 3: wouldn’t activating telomerase (or extending the telomere in some other way) have an the effect of making the thymus more youthful? I.e., can you kill two birds with one stone by just activating telomerase? Obviously this is a question that cannot be answered at this time, nonetheless I wonder what telomerase cannot do.
We don’t know all the ways in which telomerase operates as an aging clock. There are advocates like Andrews and Fossel and West who think that telomeres are the primary source of aging, and the epigenetic state and everything else will follow. I think we don’t know how well this will work, but it’s the “low hanging fruit” and should be the subject of intense research.
As you say,Josh, we can’t play around with the thymus by sticking in extra copies of a transcription factor – but the real question is, why is that transcription factor produced by young thymus cells and not by old ones? Song, G already showed that aged involuted thymuses could be restored to youthful functionality so we know that the apparent aging and turning to fat (involution) is reversible – so that it’s not any intrinsic change in the organ and you don’t have to insert extra genes into the organ, but make it use the ones it has.
Chronic inflammation is behind most if not all of the diseases of aging, including cancers – so that is a big problem and any solution such as you describe would be great. Of course knowing the ‘why’ of the chronic inflammation of old age would perhaps eliminate trying to dupe the body – it seems clear that inflammatory factors, particularly TNF stimulate cells to become senescent cells (they were already non-cycling) – since TNF stimulates the transcription factor NF-kB which causes senescent cells to spend large amounts of energy (they are very active) producing inflammatory cytokines and tissue-matrix destroying enzymes. Problem is that the same NF-kB that causes them to produce inflammatory (and cancer-promoting), factors also prevents them from suiciding (apoptosis) so if you want to see the cellular equivalent of a zombie that’s the senescent cell. So what I’m trying to say is that senescent cells are born of inflammation and give rise to inflammation as well as converting other cells to senescence – breaking that positive feedback cycle is what is needed (I think).
Finally, telomere length is a complex function of stress and cellular generations, not just marking cell divisions. Experiments (Lapasset, L. in Quebec) have shown that telomeres can be regrown under the proper circumstances. I think that telomere length is one of the aging clocks – telomerase has been used to extended life in mice – but certainly hasn’t given them immortality. I think death and aging are too important to Nature to allow but a single pathway, though I do think that telomeres are important determinants of cell aging – and when telomeres reach critical length, that has an effect on the entire body through blood borne signals. Now really the only cells were you really care about their long term survival are the stem and progenitor cells, the other cells are made by them – but the question is why do these stem cells have shortening telomeres when they are supposed to have active telomerase? Finding and solving that problem – inducing telomerase in cells, especially stem cells during aging would be the way to go, but there are risks. We know that acquiring an active telomerase is usually the ‘immortalization’ step for would-be cancers. Learning how to make the cell use its telomerase seems to be needed – unlike (how unlikely it now sounds) ‘wear and tear’ theorists (like ‘ancient astronaut theorists’) would have you believe, the telomerase genes are not corrupted beyond redemption, they are just turned off. Why?
I did a bit of digging on the ARF6 inhibitor. Unless I read it wrong on the internet after searching for small molecule suppliers, the inhibitor protein, SecinH3, seems to have the side effect of enhancing insulin resistance.
Thanks, Dan – this is an important side effect, and may be a deal-breaker.
Hi Josh
This is excellent reporting from the cutting edge of anti-aging research. However I am also interested in what works at the moment. I note your comment “There is good reason to think that if we can preserve or even regrow the shrinking thymus, then there will be benefits that echo through many or all the diseases of old age. Human growth hormone has been used with some success”
I think I read in your blog some time back of one person regenerating his thymus by taking HGH for a year & then stopping taking HGH at that point. Is there any news of what happened to the regenerated thymus after he stopped the HGH ? Did it involute again or had the clock been reset completely ?
To my knowledge, he hasn’t had an MRI measurement of his thymus since he did the experiment more than 10 years ago.
Great post. I visit Post Secret regularly and found this, in regards to the GDF11 clinical trials:
http://postsecret.com/2014/11/23/sunday-secrets-53/blood/#main
Could lead to nothing or be a fake, but it certainly is interesting.
I assume the link is a joke.
It definitely could be. Are you familiar with Post Secret? It’s a fairly popular site and there have been a few books released under its name. Basically, people send the website anonymous postcards that contain personal secrets. In this case, it could be a truthful confession, or someone trolling the life extension community. I suppose debating over the legitimacy of the secrets is a part of the fun.
Of all the web site, blogs and so on, this one explains the best me personal thoughts regarding aging and anti-aging technologies and ideas (have to mention Vince Giuliano as well). Which, having in mind my knowledge of the topic, might not be a compliment for Mr. Mitteldorf…:)
Having said this, I couldn’t agree more with all the things mentioned here. Immune system (and Thymus in particular) does seem like one of the internal aging clocks. I would just add that immune based therapies for fighting cancer (to complex topic to open it here) are big news lately, so it looks like our immune system can be, not just rejuvenated, but upgraded as well.
I just have one question, which is not related to this:
How do you comment latest presentation from Dr David Sinclair? He was talking about some latest experiments they did on mice – manipulating epigenes which allowed them to turn young mice into old and old into young (to explain it as short as possible). He said that paper will be published very soon, but he just gave some basic information which he found very exciting.
This seems to fit your ideas?
I haven’t seen this, but if you can send me a link, I will take a look. Otherwise, we’ll just have to wait until it comes out in print. Making old mice young with epigenetics would be a big step from where we are now in just the right direction.
-JJM
Sure.
Here is the news link: http://medicalxpress.com/news/2014-11-age-reversal-real.html
And here is the link to Deans lecture: https://www.youtube.com/watch?v=x0-Jt7az-54
Interesting part starts around 56:00 and he starts talking about experiment around 1:00:00.
He is saying here that they turned young mouse into old and he is saying that process is reversible.
In the interview (first link) it is mentioned that they can do it the other way around.
What I am not sure about is if this last part (rejuvenating old mice) is interpretation of journalist. Also, it is not clear if they restored youthfulness in truly old mice or in mice that was originally young (or middle aged) and turned into old one – two very different things I believe.
However, it is interesting that science is starting to address this in such a way.
Hello there..
Before the gene defective in progeria became known as a Lamin A protein gene, Mike Fossel used to make the case that progeria was caused by shortened telomeres because the progeria kids all had abnormally short telomeres. I debated with him at the time and bet him that it was something else and the shortened telomeres were just a side effect…..at the time many guessed progeia was caused by a defective DNA helicase which is altered in Werner’s syndrome..but it turned out to be a defective lamin A protein which is involved in silencing various genes in order to maintain a cells pattern of differentiation…
And how does the lamin A defect cause short telomeres?
Its been observed that the malformed Lamin A protein is absent in normal young people but can be identified in ever greater quantities in the plasma of progressively older normal individuals; this seems to add support to the telomere position hypothesis.
Mike
Researchers are calling a new class of drugs that selectively kill senescent cells senolytics.
It appears that the nutraceutical quercetin can selectively terminate some senescent cells. Exciting field to begin watching.
http://onlinelibrary.wiley.com/doi/10.1111/acel.12344/abstract
My first take on this is that it is exciting that the idea discovered by van Deursen is being moved quickly toward a pharmaceutical product, but I don’t think we’re there yet. Quercetin has been tested and doesn’t extend lifespan in mice, though van Deursen saw very solid life extension. And Dasatinib is $3,000/gm and untested for safety.
I’ll write more about this soon.
Pills do not grow on trees.
The human body is a collective group of organic life which require natural nutrititional foods and clean drinking water.
The old adage, “… you are what you eat”.
I have argued in this space and elsewhere that there is no such thing as “natural” anti-aging medicine. If this idea is new to you, please follow the link for the full explanation.
Hello
Any thoughts on the latest study touting quercetin and Dasatinib for life extension?
Study seems to suggest a periodic treatment for best effectiveness…