Regeneration of the Atrophied Thymus is a Growing Field Once Again
The thymus plays host to thymocyte cells originally generated in the bone marrow, guiding their maturation into T cells of the adaptive immune system. The aged thymus steadily loses active tissue, however, and the supply of new T cells dwindles as a result. Most people in their 50s have very little thymic function, and without a supply of reinforcements the adaptive immune system becomes ever more dysfunctional over time. Back in the 2010s there was considerable academic interest in approaches to the regeneration of the thymus based on upregulation of FOXN1 expression, but that proved challenging enough for those efforts to die out (aside from one persistent academic group that may have recently found a solution). Absence of a suitable delivery system for FOXN1 gene therapy targeted to the thymus was one major issue. That FOXN1, like many transcription factors, downregulates its own expression was another. Now, however, there are a fair number of companies in the growing longevity industry working on various possible approaches to the problem.
Tolerance Bio is developing an allogeneic cell therapy platform based on induced pluripotent stem cells (iPSCs) as well as pharmacological treatments aimed at immune diseases. Thymic dysfunction is linked to various immune diseases due to age-related decline, congenital defects, or damage from medical interventions like surgery, chemotherapy, and infection. Tolerance Bio aims to reverse these effects by developing artificial thymuses from stem cells, targeting disease-specific treatments such as thymic organoids. The company also seeks to delay thymic involution with drugs to prevent both natural and accelerated thymic decline. Restoring thymic function could not only combat immune diseases but also extend healthy lifespan by improving the body's immune response.
Tolerance Bio joins a number of companies seeking to harness the power of the thymus against aging and disease, including ARPA-backed Thymmune, Vidaregen and Thymox. In 2015, Dr Greg Fahy, renowned aging researcher and CSO of Intervene Immune, commenced the first clinical trial to explore if thymus regeneration could reverse aspects of human aging, with results showing participants' epigenetic age was "significantly decreased" by the treatment.
Link: https://longevity.technology/news/tolerance-bio-launches-to-boost-human-healthspan-via-the-thymus/
'Black hole' formed by aging cells hobbles key immune organ's function, regeneration
https://www.fredhutch.org/en/news/center-news/2024/08/dudakov-aging-thymic-epithelial-cells.html
"The cells that "mentor" developing T cells are called thymic epithelial cells, or TECs. We know that TECs get replaced by adipose cells as we age, but there's a lot left to learn about other age-related changes in the thymus.
"We found that with age there seems to be kind of this alternate-lineage differentiation of thymic epithelial cells," Dudakov said. "They kind of look like TECs, but they're not TECs."
He and Kousa dubbed these cells age-associated TECs, or aaTECs. Not yet replaced by fat, aaTECs have apparently decided to "retire" early. No longer do they help educate T cells or help repair damage. They appear to be undergoing an identity crisis, showing lower expression of certain genes that are TEC hallmarks.
Zhao, on Gray's team, used innovative thick-slice microscopy on mouse thymus tissue to enable the collaborators to see non-functional regions that appear to correspond to the aaTECs Kousa and Dudakov had described. Though still rich in epithelial cells, these areas lack T cells.
Age-associated TECS "exist in very tight clusters - so tight that they barely allow any other cells to enter that space," Kousa said. "This prompted us to characterize these areas as thymocyte [developing T-cell] 'deserts.' In order for the thymus to function properly, it heavily relies on different cell types (the majority of which are thymocytes) interacting with and contacting each other."
The tight clusters of aaTECs "creates these nonproductive niches within the thymus - we call them scars, essentially - that are not supportive of T cell development," Dudakov said.
With time, the islands where T cells can find the guidance they need grow smaller and smaller."
Off topic, but a cure for CMV might also be in the works:
https://www.fredhutch.org/en/news/center-news/2024/10/jerome-walter-hsv-gene-drive.html
Thanks Reason, you'd think rejuvenation of the thymus would be a huge game changer.
Also thanks Jim for the article. Surprised there hasn't been much progress ( until now?) for this low priority issue. I noticed news of progress in the HIV treatment ( cure?).
Also, be great to see advancement for foot fungus and skin disease ( I somehow got eczema), that would be great too.
Lygenesis also in the mix. Officially has thymus as one of their programs, even if liver is far ahead in practical roadmap terms.