Halting Thymic Involution

 

The thymus is a thumb-sized organ just above the sternum where our immune cells are trained to recognize self from other. It is fully developed by the time we are 10 years old, but after that it begins gradually to shrink. By age 25, it has already lost 30% of its mass, and by age 60 it is less than half its peak size. There is evidence that this is related to the immune decline that contributes so much to growing mortality risk with age, and that reversing that decline might lead to longer, healthier lives.

 As we get older, the white blood cells that protect our bodies from cancer and infection become less effective. They make two kinds of mistakes, for which statisticians apply the creative terminology “Type 1” and “Type 2”. Type 1 mistakes are a failure to recognize the invader, and it is the reason that, for example, older people frequently die of influenza and pneumonia, while younger people seldom do. Type 2 mistakes are false positives – inadvertently attacking the body’s good, healthy cells as if they were an invader, with consequences that are even worse for us than Type 1. It is the root cause of auto-immune diseases and inflammation that are hallmarks of old age in mammals.  Decline of the thymus is intimately related to both types of errors.  There is indirect evidence that thymic involution exacerbates other aspects of aging as well, and there is lots of evidence correlating immune decline with mortality, independent of age.

T-cells are a kind of white blood cell that responds to new infections, and then remembers for many years (“memory T-cells”) the disease to which you were exposed, so that if it ever appears again, your immune response is jump-started. The “T” in “T-cell” stands forthymus, and it is in the thymus that these cells are trained to recognize all the 30,000 or so proteins that the body produces internally, and to attack any protein that’s not on its “white list”.

Once an invader is recognized and an immune attack is mounted, the particular cell that successfully identified the invader is rewarded with profuse replication, flooding the bloodstream with copies of itself until the infection is successfully repelled. After that, most of the clones die away, but a few remain circulating in the blood for many years afterward, just in case the same pathogen should appear in the future.

T-cells, then, are either “naive” or “memory” cells. It is the naïve cells – newly manufactured and trained in the thymus – that enable you to launch a defense against new (to you) diseases. The number of naïve cells declines with age, and the decline has been linked directly to shrinking of the thymus gland

Thirty years ago, a research lab in Tokyo tried grafting thymus glands from young mice into old mice. They repeated the operation every few months throughout the the lives of the older mice, and the mice lived half again as long as controls that didn’t receive transplants, despite the periodic trauma of the surgeries. (Of course, the donor mice had to be genetically very close to the host mice, because the immune system is ultra-specific to individual genotype; but that was easy to arrange, because lines of laboratory mice are routinely inbred so that they are genetically homogeneous.) Thymic involution is common to all vertebrates, and it is a good bet that it contributes substantially to aging in most if not all species, including humans.

There is no known benefit to humans or any animal from having a smaller thymus, so thymic involution is a good candidate for a mechanism of programmed aging, an aging clock like those described in this space two weeks ago.

 

What to Do About It

There are many studies with humans and animals reporting that thymic involution can be reversed and immune function restored with growth hormone (GH).  I hasten to add that I don’t recommend growth hormone for other reasons: it can lead to diabetes and cancer. Growth hormone has also been associated with increased mortality when administered to critically ill patients, (even though they were deficient in GH). A friend and colleague of mine experimented on himself in a controlled, medically-supervised trial, and succeeded within one month in regrowing his thymus and increasing immune function, – after which he was wise and knowledgeable enough to discontinue his own treatment (written up here).

Besides GH and thymus transplants, other interventions have measurable but less dramatic benefit for regrowing the thymus. These include thyroxine, interleukin-7 (IL-7) and luteinizing hormone (LH), supplementation with melatonin, arginine or zinc, and castration. (ref).  I realize that some of these interventions may be more appealing than others.

The hormone ghrelin has also been found to stimulate thymus growth in mice. The mechanism seems to be related to GH, since ghrelin binds to a class of receptors called Growth Hormone Secretagogues, stimulating endemic production of GH. Ghrelin also make you hungry, and there was some hope a few years back of manipulating ghrelin levels as a diet aid. This is one more suggestion that the same signals that make the body hungry contribute to life extension from calorie restriction (ref).

Thyroxine actually has other anti-aging properties as well – a topic for another day. LH may be a mild alternative on the castration axis: it tends to suppress production of testosterone. Leuprorelin (trade name “Lupron”) has been prescribed to prostate cancer patients because it cuts off testosterone very effectively, and presumably for that reason it would be a non-surgical substitute for castration.

IL-7 has been studied as therapy for cancer and some other illnesses where increasing immune response is desirable . In mice as in people, IL-7 has been shown to increase T-cell production and to stimulate re-growth of the thymus. Is it safe to use for a general population, not in extremis? The reason we’re not likely to find out soon is that IL-7 is priced like a cancer drug, at $10 million per gram

 

Neglected Opportunities

Research on reversal of thymic regrowth is a backwater of medical science. If this is an opportunity for major gains in life expectancy, then it is a neglected opportunity that has attracted little interest or funding. Based on evolutionary arguments, the general attitude seems to be that if the thymus shrinks over a lifetime, then it must not be much needed; or, conversely, that a Law of Nature assures us that any therapy to maintain its function must necessarily have dangerous side-effects that outweigh the benefits. Wikipedia calls it an “evolutionary mystery”:

Since it is not induced by senescence, many scientists have hypothesized that there may have been evolutionary pressures for the organ to involute…the best time to have a prodigiously functional thymus is prior to birth. In turn, it is well known from Williams’.theory of the evolution of senescence that strong selection for enhanced early function readily accommodates, through antagonistic pleiotropy, deleterious later occurring effects, thus potentially accounting for the especially early demise of the thymus.    (Wikipedia)

But this is ideology, a misplaced faith in general theory over explicit experimental results. Reality in the lab appears to be that

Thymic involution, adrenal involution, and somatic involution seem to provide no obvious benefits in humans that would outweigh the benefits of their elimination once the hazards associated with such issues as insulin-like signaling can be set aside. Fortunately, methods of eliminating or at least blunting thymic, adrenal, and somatic involution or their effects are already known…and will surely be improved in the future. (Fahy, 2010)

I remain hopeful that

An understandin of the causal mechanism of thymic involution could lead to the design of a rational therapy to reverse the loss of thymic tissue, renew thymic function, increase thymic output, and potentially improve immune function in aged individuals. (Aspinall and Andrew, 2000)

Much of the material in this article was derived and elaborated from a book chapter by Greg Fahy, who also edited the volume The Future of Aging.  Chapter 15 by Richard Aspinall and Wayne Mitchell in the same book offers more details.

3 Comments

  1. Have there been any studies comparing thymic size and/or function among centagenarians compared with, for example, population cross-sections at a younger age? ie. Is there any evidence that people who live longer have bigger thymus?

    Such evidence would support the idea of regenerating the thymus. Lack of such evidence would not necessarily refute it, but might douse it with a bit of cold water.

  2. 1. Glucocorticoids (cortisol, cortisone) cause thymic involution. Hence high stress, which causes high corticoid levels, would accelerate same, and drugs and nutrients that modify stress responses, and cortisol levels, would be helpful.

    2. A little-known peptide, gamma-glutamyltaurine, has pro-thymic activity, protecting against glucocorticoid-induced involution. It is synergistic with vitamin A in this. Note that vitamin A itself, alone, opposes many of the negative effects of corticoids.

  3. This article led me searching for information about antagonistic pleiotropy. Fascinating stuff.

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