{"id":308,"date":"2014-11-24T14:56:51","date_gmt":"2014-11-24T14:56:51","guid":{"rendered":"http:\/\/joshmitteldorf.peachpuff-wolverine-566518.hostingersite.com\/?p=308"},"modified":"2014-11-24T14:56:51","modified_gmt":"2014-11-24T14:56:51","slug":"three-technologies-to-watch","status":"publish","type":"post","link":"https:\/\/scienceblog.com\/joshmitteldorf\/2014\/11\/24\/three-technologies-to-watch\/","title":{"rendered":"Three Technologies to Watch"},"content":{"rendered":"

1. Thymus Regrowth with FOXN1<\/b><\/p>\n

The thymus gland is a time bomb that would kill us at a certain age, if nothing else got us first. \u00a0It shrinks (the medical word is “involution”) gradually through life, beginning in childhood and culminating in disastrous results in old age.<\/p>\n

The thymus is a small gland located just behind the top of the breastbone. \u00a0Among your white blood cells, your first-defense cells are the T-cells, named for their association with the thymus. \u00a0The thymus is training ground for the T-cells, where they learn to distinguish friend from foe. \u00a0The body has many types of cells, and the T-cells\u00a0must not attack any of them; but they also must reliably identify invading microbes.<\/p>\n

These immune functions\u00a0are\u00a0related to many aspects of health, and not just attacking invasive microbes. \u00a0The 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. \u00a0Rampant inflammation and auto-immune disorders are the consequence when the immune system begins to turn against self late in life.<\/p>\n

As the thymus shrinks year by year, the immune system breaks down. \u00a0A 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. \u00a0Arthritis is well-characterized as an auto-immune disease, but there are auto-immune aspects of other diseases including Alzheimer’s<\/a><\/p>\n

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. \u00a0Human growth hormone has been used with some success, but reactions to HGH vary, and there is reason to worry about its long-term effects. \u00a0There is a recent breakthrough in treatment for the thymus that looks very promising. \u00a0A transcription factor<\/a> is a coded chemical signal capable of switching the expression of many genes at once, turning some on and others off in one sweep. \u00a0FOXN1<\/a> 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<\/a>]. \u00a0The larger thymus looked and functioned much like the thymus of a young mouse.<\/p>\n

The most glaring absence in the blood as we age is naive T-cells<\/a>, cells that are not pre-trained to fight any specific infection from the past, but are primed to look out for new invaders. \u00a0So it is most promising that the thymus glands regenerated with FOXN1 produced copious naive T cells.<\/p>\n

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. \u00a0You and I don\u2019t have these extra copies, so we need another means to get FOXN1 into our aging thymi. \u00a0FOXN1 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. \u00a0A 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<\/a>]. \u00a0Turning on the cell\u2019s own FOXN1 gene would be ideal, and there are already candidates that can do this. \u00a0There is no reason to doubt the feasibility of FOXN1 drugs, but for now we have only rumors that they are under development.<\/p>\n

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2. New Anti-Inflammatory Drugs based on ARF6 Inhibitors<\/strong><\/p>\n

Inflammation has been a recurring theme in this blog, because inflammation is the most obvious and ubiquitous mode by which the body destroys itself.<\/p>\n

The fact that simple, \u201cdumb\u201d 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. \u00a0That\u2019s why the more powerful NSAIDs have side-effects that limit their use. \u00a0To 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.<\/p>\n

Dean Li and his research group at University of Utah have been addressing just this challenge. \u00a0Their breakthrough paper came in 2012<\/a>, when they announced the discovery of a signaling pathway that controls just the destructive inflammation, and is not involved in the good kind. \u00a0In 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.<\/p>\n

Have you ever broken off half a key inside a doorknob? \u00a0Not only can\u2019t you turn the knob, you can\u2019t pull the key out, and you can\u2019t get another key in there either. \u00a0You may have to give up on the lock and get a new doorknob. \u00a0The tail end of ARF6 works like half a key. \u00a0It fits neatly into the same receptor as the full ARF6 molecule, but once inside it doesn\u2019t change the conformation of the receptor the way that the full molecule does. \u00a0It won\u2019t open the lock, and it stays stuck in the keyhole, blocking access to the real, working key.<\/p>\n

The tail stub of ARF6 worked like a broken key to interfere with the real ARF6, preventing it from doing its job. \u00a0The Li lab was able to block the inflammatory reaction that responds to ARF6 without affecting the course of inflammation that is beneficial and protective.<\/p>\n

They went on to inject their tail stub molecule intravenously in mice. \u00a0They report exciting initial successes, treating mouse arthritis without gumming up the other important functions of inflammation.<\/p>\n

Some bacteria kill the host not directly but by inducing such a violent inflammatory reaction that the patient dies of his own inflammation. \u00a0Dr Li\u2019s team challenged mice with LPS, which is the chemical that induces this fatal inflammation. \u00a0Mice 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.\u00a0[ref<\/a>]<\/p>\n

This is a discovery that has yet to make front page headlines, but Dr Li\u2019s 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.<\/p>\n

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3.\u00a0Telomere Length Directly Affects Gene Expression<\/strong><\/p>\n

Short telomeres cause cell senescence, which pulls a stem cell out of circulation and, worse,\u00a0causes the cell to emit signals that damage neighboring tissues and the body as a whole. \u00a0This has been the basis of the theory\u00a0that telomeres act as a kind of fuse for an epigenetic time bomb. \u00a0This 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. \u00a0Telomeres affect gene expression, which is the epigenetic state of a cell. \u00a0The same chromosome tends to express and repress different sets of genes depending on length of its telomeres.<\/p>\n

It has long been suspected that telomere length affects gene expression. \u00a0As far back as 1990<\/a>, Telomere Position Effect (TPE) was noted as affecting gene regulation. \u00a0But\u00a0until this month’s study, there was no coherent idea how this occurs. \u00a0In order to study the effect systematically, the Wright team had to create a culture of cells all with the same telomere length. \u00a0They were both able to image the conformation of the chromosomes and also measure the genes they expressed as a function of\u00a0telomere length. \u00a0Wright introduces the acronym TPE-OLD, for Telomere Position Effect Over Long Distances. \u00a0What they found was that<\/p>\n