Three Longevity Technologies to Watch
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 as1990, 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.
This post previously appeared on Josh’s blog Aging Matters here.