Models Suggest that Declining T Cell Production is the Primary Reason for Age-Related Increases in Cancer Risk

In the open access paper noted here, researchers use modeling to suggest that age-related decline of the thymus, and thus of the immune system, is more important than mutation as a determinant of cancer risk. Cancer is at root caused by mutational damage to DNA. While DNA repair and replication mechanisms are highly efficient, mutations nonetheless occur - and must occur at some rate in order for evolution to take place. It is a numbers game, in that the more time, the more cells, and the more cell activity, the greater the odds that a cancerous mutation will occur. Mutation rates are also affected by external factors such as radiation, toxic molecules in the cellular environment, and other forms of stress put upon cells. But this is just the primary cause, the trigger enables a cell to replicate without restraint.

After a mutation occurs, there are several classes of process that work to shut down or destroy potentially cancerous cells. We suffer countless potential cancers in our lives, but near all are suppressed before they start. The first line of defense is internal to cells: mechanisms such as those related to p53 that can respond to cancerous mutations and aberrant behavior by inducing immediate programmed cell death or inducing the state of cellular senescence. The latter shuts down replication, sets the cell on the path to self-destruction via apoptosis, and further issues signaling that calls in the immune system to destroy the errant cell. The immune system is the second, and perhaps more important line of defense. Immune cells of various types aggressively seek out and destroy cells that show signs of cancer or other undesirable behavior.

Unfortunately, the immune system declines in effectiveness with age. One of the reasons for this decline is a slowing of the rate at which new T cells are created. This is in part a question of the loss of stem cell activity that occurs throughout the body, reducing the generation of new cells of all sorts. Perhaps more important in the case of T cells is the age-related atrophy of the thymus, however. This organ is where T cells mature before taking up their assigned roles in the body. It is highly active in childhood, but the active tissue begins to be replaced by fat at the onset of maturity, a process called involution. This continues over a life span and into old age, and the pace at which new T cells mature falls along with it.

A slow rate of T cell replacement causes the existing specialized and active T cell populations to become ever more worn and ragged, lacking reinforcements that can respond effectively to new challenges. This affects most of the aspects of immune function, from the response to invading pathogens to the ability to catch and destroy cancerous cells before they start in earnest the process of generating a tumor. For this reason there is considerable interest in the research community in finding ways to rejuvenate the thymus, to restore the active tissue that acts as a nursery for T cell maturation. If successful, this should go some way towards regaining the lost capacity of the immune system.

Thymic involution and rising disease incidence with age

T cells develop from hematopoietic stem cells as part of the lymphoid lineage and have the ability to detect foreign antigens and neoantigens arising from cancer cells. In the thymus, lymphoid progenitors commit to a specific T cell receptor and undergo selection events that screen against self-reactivity. Cells that pass these selection gates then leave the thymus, clonally expanding to form the patrolling naive T cell pool.

The vast majority of vertebrates experience thymic involution (or atrophy) in which thymic epithelial tissue is replaced with adipose tissue, resulting in decreasing T cell export from the thymus. In humans, this is thought to begin as early as 1 year of age. The rate of thymic T cell production is estimated to decline exponentially over time with a half-life of ∼15.7 years. Declining production of new naive T cells is thought to be a significant component of immunosenescence, the age-related decline in immune system function. With the recent successes of T cell-based immunotherapies, it is timely to assess how thymic involution may affect cancer and infectious disease incidence.

It is clear from epidemiological data that incidence of infectious disease and cancer increases dramatically with age, and, specifically, that many cancer incidence curves follow an apparent power law. The simplest model to account for this assumes that cancer initiation is the result of a gradual accumulation of rare "driver" mutations in one single cell. Furthermore, the fitting of this power law model (PLM) can be used to estimate the number of such mutations. Exponential curves have also been used to fit cancer incidence data, resulting in worse fits than the PLM overall. Nevertheless, it is worth noting that exponential rates close to the declining curve for thymic T cell production can be seen to emerge from the incidence data, indicating the relevance of the thymic involution timescale. While the PLM fits well, it does not account for changes in the immune system with age. To better determine the processes underlying carcinogenesis, we asked whether an alternative model, based only on age-related changes in immune system function, might partly or entirely explain cancer incidence.

Our model outperforms the power law model with the same number of fitting parameters in describing cancer incidence data across a wide spectrum of different cancers, and provides excellent fits to infectious disease data. Our hypothesis and results add to the understanding of infectious disease and cancer incidence, suggesting in the latter case that immunosenescence, rather than gradual accumulation of mutations, serves as the predominant reason for an increase in cancer incidence with age for many cancers. For future therapies, including preventative therapies, strengthening the functionality of the aging immune system appears to be more feasible than limiting genetic mutations, which raises hope for effective new treatments.


Janko Nikolich-Zugich, who presented at the SENS 5 conference, recently got a 10 million grant to rejuvenate the Thymus, however he thinks it will also be necessary to rejuvenate the lymph nodes:

"Although T-cells still enter the lymph system in older people, the scant T-cells that are produced can't readily enter the lymph nodes. "The reason for that is the lymph nodes are undergoing profound changes with aging," Nikolich-Zugich says.

In fact, researchers see a lot of fibrosis in the lymph node, meaning the connective bundles are starting to get thicker, less organized and less flexible.

"Lymph nodes aren't able to effectively call in the cells from the outside, so fewer cells arrive," he says. "Moreover, when the cells arrive, they don't move inside like they should. Inside the lymph node is a superhighway meshwork, and we have found that this really gets messed up in aging."

Scientists have tried rejuvenating only the thymus by blocking the body's androgen production to increase its T-cell production, but increased, long-lasting immunity has proved elusive for the very reason that T-cells can't gain entrance to the lymph nodes.

So, Nikolich-Zugich and his collaborators are formulating a novel plan of attack.

"There is one important part of this grant that is different from the approaches that people have been taking from the past," Nikolich-Zugich says. "The novel idea here is that we want to rejuvenate both the thymus and the peripheral lymph organs, so both the factory that makes the cells and sites where the T-cells go to do the real work of defense against infection can once again work together.

"We feel like we will never get to rejuvenation if we work only on the thymus."

In fact, the grant, sponsored by the National Institutes of Health, is a program project grant, which by design includes several interrelated individual projects, each run by Nikolich-Zugich and his collaborators. Some of the projects look at the thymus, others at the lymph nodes."

Posted by: Jim at February 8th, 2018 3:59 AM

The obvious escapes mention. The lack of zinc is the primary reason for thymic involution (shrinkage). This starts early. Mother's milk provides just enough zinc up to 6 months of age and then the infant grows to a point where it needs more zinc and breast milk is insufficient and the thymus gland shrinks. Due to lack of adequate intake and poor absorption and over-binding by metallothionein, zinc's binding protein, the aged suffer thymic atrophy. Zinc absorption is enhanced with vitamin B6 and is released by selenium. The thymus hormone thymulin essentially is a peptide which can be purchased a thymus glandulars from most health shops. Modern medicine simply watches the human immune system wither and treats the sequelae (pneumonia, lymphoma, poor vaccination antibody response, cancer, etc.) In old animals, zinc produced a full recovery of thymus gland functions and re-activation of natural killer cells. See below.

Int J Immunopharmacol. 1995 Sep;17(9):703-18.
Reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice.

Mocchegiani E1, Santarelli L, Muzzioli M, Fabris N.
Author information

With advanced ageing the zinc pool undergoes progressive reduction as shown by the low zinc plasma levels and the negative crude zinc balance, both in humans and in rodents. It has been suggested that such zinc deficiency might be involved in many age-related immunological dysfunctions, including thymic failure. The relevance of zinc for good functioning of the entire immune system is, at present, well documented. In particular, zinc is required to confer biological activity to one of the best-known thymic peptides, thymulin, which is responsible for cell-mediated immunity. In deep zinc deficiencies, in humans and other animals, the low thymulin levels are due not to a primary failure of the thymus, but to a reduced peripheral saturation of thymic hormones by zinc ions. In aged mice both a reduced peripheral saturation of the hormone and a decreased production by the thymus were present. Oral zinc supplementation in old mice (22 months old) for 1 month induced a complete recovery of crude zinc balance from negative (-1.82) to positive values (+1.47), similar to those of young animals (+1.67). A full recovery of thymic functions with a regrowth of the organ and a partial restoration of the peripheral immune efficiency, as measured by mitogen responsiveness (PHA and ConA) and natural killer cell (NK) activity, were observed after zinc supplementation. These findings clearly pin-point for relevance of zinc for immune efficiency and suggest that the age-related thymic involution and peripheral immunological dysfunctions are not intrinsic and irreversible events but are largely dependent on the altered zinc pool. PMID: 8582782

Posted by: Bill Sardi at February 11th, 2018 5:46 AM

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