Insight Into the Cause of Thymic Involution

Researchers here investigate the mechanisms involved in thymic involution, the atrophy of the thymus that occurs early in adulthood. The scientists propose that this atrophy occurs because thymus tissue is deficient in natural antioxidant compounds, and is thus unable to resist even normal levels of oxidative stress in the body.

The thymus plays an essential role in the process of generating new immune cells to tackle threats such as viruses, bacteria, and rogue cells. In childhood this organ is very active, but in adult life the flow of new immune cells slows to a trickle as a result of atrophy of the thymus. This is one of the factors contributing to the age-related decline of the immune system, and a number of research groups are investigating ways to rejuvenate or replace the thymus so as to provide a larger supply of active, useful immune cells to adults. This research on the cause of thymic involution is probably less relevant to rejuvenation, as the damage is already done in those of us needing a new thymus, but it may be useful when it comes to the ongoing protection and maintenance of a rejuvenated or replaced thymus.

The development of interventions to slow the progression of thymus atrophy has been limited by the lack of knowledge about the underlying mechanisms. The prevailing theory suggests that sex hormones play a key role, but this explanation does not account for the accelerated speed at which the thymus diminishes in size in comparison to other tissues. Researchers developed a computational approach for analyzing the activity of genes in two major thymic cell types - stromal cells and lymphoid cells - in mouse tissues, which are very similar to human thymic tissues in terms of function and the properties of atrophy. They found that stromal cells were deficient in an antioxidant enzyme called catalase, resulting in the accumulation of free radical and metabolic damage.

To test whether catalase deficiency plays a causal role in thymus atrophy, the researchers performed genetic experiments to enhance catalase levels in mice. By 6 months of age, the size of the thymus of the genetically engineered mice was more than double that of normal mice. Moreover, mice that were treated with two common antioxidants from the time of weaning achieved nearly normal thymus size by 10 weeks of age. "Our studies show that, rather than an idiosyncratic relationship to sex steroids, thymic atrophy represents the widely recognized process of accumulated cellular damage resulting from lifelong exposure to the oxidative byproducts of aerobic metabolism."

Taken together, the findings provide support for the free-radical theory of aging, which proposes that reactive oxygen species such as hydrogen peroxide cause cellular damage that contributes to aging and a variety of age-related diseases. These toxic molecules, which form in cells as a natural byproduct of the metabolism of oxygen, have been linked to progressive atrophy in many organs and tissues as part of the normal aging process. However, these are generally slow, progressive processes that do not become apparent until late in life and often go mostly unnoticed.

Link: http://www.sciencedaily.com/releases/2015/08/150806133043.htm

Comments

"Taken together, the findings provide support for the free-radical theory of aging, which proposes that reactive oxygen species such as hydrogen peroxide cause cellular damage that contributes to aging and a variety of age-related diseases. These toxic molecules, which form in cells as a natural byproduct of the metabolism of oxygen, have been linked to progressive atrophy in many organs and tissues as part of the normal aging process. However, these are generally slow, progressive processes that do not become apparent until late in life and often go mostly unnoticed."

Isn't evidence for the free-radical theory of aging evidence against the SENS Research Foundations approach to reversing aging? Surely it is much harder to fix damage to a very wide variety of molecules throughout the body vs seven somewhat narrow classes of damage?

Posted by: Jim at August 7th, 2015 3:20 PM

Hi Jim,

Three things:

First, of course, one of those seven categories of damage is the accumulation of cells bearing mitochondria with deletion mutations; by rendering mitochondrial mutations harmless, the age-related rise in oxidative stress can be abrogated or very significantly reduced.

Second: there are far more than seven dynamic metabolic processes (and, indeed, far more than seven sources of free radical generation) that contribute or may contribute to degenerative aging. And while abrogating rise in oxidative stress with age via allotopic expression of the necessary proteins can be confidently presumed to be entirely benign (since it restores the normal structure and function of the electron transport present in young, healthy people), the same cannot be said for interventions that would interfere with the many sources of free radical generation or interdict those free radicals before they hit their targets, since many of those free radicals are either the necessary products or the needed regulators of physiological processes (such as their use by the immune system; in cell survival, growth, proliferation, and differentiation; and in apoptosis, a necessary bulwark against cancer). One does not have the option of "only" quenching the "bad" free radicals.

And, third: you may be thinking on the wrong scale here. We have no intention of digging in to prevent the death of individual thymic epithelial cells: we are going to either grow up engineered thymic tissue to engraft to maintain or restore the original thymus, or engineer a new thymus and replace it wholesale.

Overarachingly: remember, we do not care and it does not matter what causes a particular form of aging damage: irrespective of its cause, removal, repair, replacement, or rendering harmless such damage will restore youthful cellular and tissue structure and function, and thereby youthful health.

Posted by: Michael at August 7th, 2015 5:17 PM

Thanks for clarifying that Michael.

So I'm guessing that this experiment, if repeated, shows that lack of an anti-oxidant molecule in thymic cells leads to higher rates of damage in that organ and cell loss.

I wonder if this is just protein and DNA damage induced apotosis and then lack of replacement of the lost cells by stem cells.. but then in a youthful environmental milieu surely stem cell division should not be impaired... although the thymus may be like the heart or brain in that it naturally has more limited stem cell renewal for some reason.

It would also be interesting to see if thymic tissue has higher rates of some of the other classes of damage such as mitochondrial hotspots, intra cellular garabage, and senescent cells.

Posted by: Jim at August 7th, 2015 9:06 PM

Michael, how do you explain the lifespan increase caused by mitochondria targeted antioxidants such as IAC, SkQ1, MitoQ, C60-oo. I very much get the impression that a certain degree of ROS quenching is a net positive. It also seems to be a positive in cancer care with metastatic suppression.

I am deeply sympathetic to rejuvenation treatments and wish that moree efforts would be made. But I am also looking for wharever can be done at this moment in time. SOD/Catalase mimetics might be a good bet.

Who knows how long until the brains peroxidation issues can be fixed...

Posted by: arren at August 8th, 2015 3:03 PM

@arren - It is pretty easy to increase lifespan in shorter lived species. Do any of those chemicals pass the "But So Does Aspirin" test?

"It helps greatly to realize that life span and health are much more plastic in short-lived species than in comparatively long-lived species such as we humans. All sorts of things extend life in lower animals by a large amount yet have no such result in humans. Consider calorie restriction for example, which extends life by 40% in mice, but certainly doesn't do as much in humans. Did you know that ibuprofen use meaningfully extends life in a number of species to a an equal or greater level than metformin, a currently hyped drug candidate to slow aging? Or that aspirin has sizable effects on life span in short-lived species as well? Yet clearly neither of those extends human life span to anywhere near the same degree, despite decades of use and a great deal of data on its effects."

Posted by: Jim at August 8th, 2015 9:33 PM

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