Adaptive Immune System Aging

by johnswentworth2 min read13th Mar 20206 comments

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AgingGears-LevelWorld Modeling
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The human adaptive immune system is the “smart” part of the human immune system, the part which learns to recognize specific pathogens, allowing for immunity to e.g. chicken pox. For our current purposes, the key players are T-cells. T-cells start out “naive” and eventually learn to recognize specific antigens, becoming “memory” T-cells. The aged immune system is characterized by a larger fraction of memory relative to naive T-cells (without dramatic change in overall counts). This makes the elderly immune system slower to adapt to new pathogens.

This post is mainly about why the naive:memory T-cell ratio shifts with age, how to undo that shift, and some speculation about implications and applications.

A natural hypothesis (frequently asserted in the literature): the shift toward memory T-cells is driven by slower production of new (naive) T-cells. The T-cells themselves maintain overall cell count by living longer, resulting in a larger proportion of older (memory) cells.

The interesting part: why would the production of new T-cells fall with age?

Turns out there’s an obvious culprit: the thymus. The thymus is the last stop in the production line for new T-cells. It provides a sort of boot camp, training the T-cells to distinguish “self” (your own cells) from “other” (pathogens) using a whole battery of tricks. T-cells which make it through become full-time members of the naive T-cell reserve, and go on to police the body.

With age, the thymus does this:

(source: PhysAging). This is called “involution” of the thymus.

Many organs shrink with age, but the thymus is among the most dramatic. Unlike most age-related loss, it starts even before development is complete - the thymus shrinks measurably between day zero and a child’s first birthday. And it keeps on shrinking, at a steady rate, throughout childhood and adult life. The extremely early start of thymic involution suggests it’s more a developmental phenomenon than an age-related phenomenon - perhaps an appropriate hormonal mix could undo thymic involution?

Turns out, castration of aged mice (18-24 mo) leads to complete restoration of the thymus in about 2 weeks. The entire organ completely regrows, and the balance of naive to memory T-cells returns to the level seen in young mice. (Replicated here.) This is pretty dramatic evidence that:

  • The thymus only generates/regenerates in the absence of sex hormones
  • The age-related shift in naive:memory T-cell ratio is driven primarily by thymic involution

Particularly intriguing: we already have chemical castration methods, which are generally considered reversible. And it only took two weeks for the mice to regrow the whole thymus. At this point we’re speculating, but assuming chemical castration also works and it translates to humans and the thymus doesn’t rapidly re-involute after ceasing the chemical castration… that sounds pretty promising as an avenue to fixing age-related adaptive immune system decline in humans.

As long as we’re speculating, let’s speculate hard. Immunotherapy is the hot new thing in cancer these days - apparently T-cells in young people remove precancerous cells and attack tumors, but in old people that doesn’t happen as reliably. So… have there been any studies on how castration effects cancer? For starters, chemical castration is already a widely-used treatment for both prostate and breast cancer. It works. But that’s prostate and breast; they’re sex organs, which we’d expect to atrophy in the absence of sex hormones. I don’t know of any studies on the effects of chemical castration on other types of cancer, in humans.

In rats, however, at least one century-old study finds that castration prevents age-related cancer - and quite dramatically so. Castrated mice’ rate of resistance to an implanted tumor was ~50%, vs ~5% for controls. (This study finds a similar result in rabbits.) That old rat study cites a few others with mutually-conflicting results, and proposes that the age of the rats used explains it all: investigators who use young rats find that castration has little-to-no effect on resistance to an implanted tumor. Exactly what we’d expect if it’s all mediated by thymic involution & regrowth.

There’s a lot of questions here. Does chemical castration have similar effects to surgical castration on thymic regrowth in mice? Does chemical castration result in regrowth of the thymus in humans? (Several states/countries require chemical castration as a condition of parole for certain sex offenders, and it’s also used for prostate and breast cancer, so it should be possible to find a few old people using it and see whether their thymus has regrown.) Does the thymus rapidly re-involute after administration of chemical castration ceases? Does chemical castration work as a treatment for cancers besides prostate and breast? Is the effectiveness of chemical castration against cancer age-dependent? Can temporary administration of chemical castration prevent cancer for a long period of time?

Turning away from applications and back to gears, there's also some key questions around thymic involution itself. The individual cells of the thymus don't have unusually slow turnover; if the thymic cell count is decreasing over time, then either the rate of production is decreasing or the breakdown rate is increasing. There has to be some upstream cause. Whatever that cause is, it probably isn't the same upstream cause as most age-related problems - thymic involution doesn't follow the usual pattern of no noticeable problems during development, slow loss of performance in middle age, then accelerating failure in old age.

I’d be excited to see more work along these lines and/or references to relevant studies.

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