Fight Aging!

Startup biotech companies have started to use the publication of preprint scientific papers as a way to enhance their standing with investors; putting out a preprint is considerably faster than formal publication, and requires no review process. Many startups undertake programs of research and development that are novel enough to have little in the way of a foundation of prior scientific literature, and thus this is one area of scientific publication in which more weight than usual should be given to the peer review process. In particular, one should be skeptical regarding claims of very large extension of life span in animal models in preprint papers.

Yes, someone will turn up at some point with a surprising, novel approach to rejuvenation that is impressive in comparison to the past scope of slowed aging and extended life in mice, and perhaps that program will be wrapped in a biotech company, and perhaps they will want the benefits of publishing as soon as possible rather than waiting on review. That future seems inevitable, given the pace of progress in aging research and the trend towards opening and democratizing the peer review process. Nonetheless, extraordinary claims still require extraordinary evidence. The history of claimed extension of life span in mice is littered with failed replication, and particularly so for studies that used small numbers of mice and claimed a large extension of life.

The startup biotech program reported in today's preprint paper is conducted by Sentcell. It is interesting and novel enough for the rest of the world to be skeptical until much more work on the topic is published. The size of the reported extension of life in mice resulting from their novel therapy is very large relative to the best that can be achieved via established approaches; large enough to reduce the credibility of the work, especially given the small numbers of mice used per study group. The researchers claim to have isolated a particular subset of cell communications that induces rejuvenation, which in and of itself is reasonable. Many companies and research groups are indeed exploring how cells might change one another's behavior for the better. Consider that stem cell therapies produce benefits via the signaling of transplanted cells as one example among many. It is the size of gain in mouse life span reported here that calls for a far greater body of supporting evidence in order to be taken at face value, given how very much larger it is than the effects of, e.g. stem cell therapies, exosome therapies, senolytics, and so forth.

CD4+ T cells confer transplantable rejuvenation via Rivers of telomeres

One theory attributes ageing to the accumulation of terminally differentiated or senescent cells in multiple tissues, disrupting homeostasis. A true fountain of youth would need to target senescent cells across organs, be tightly regulated, and transfer youth-promoting activity from a young organism to an old one - as in the original parabiosis studies. One rejuvenation candidate arises from telomere transfer between immune cells. We previously showed that antigen-presenting cells (APCs) donate telomere-containing vesicles to CD4+ T cells during immune synapse formation, extending their telomeres, preventing senescence, and generating long-lived, stem-like memory T cells.

Here we show that, after telomere acquisition, recipient CD4+ T cells undergoing fatty acid oxidation, assemble and release "Rivers" of telomeres into the circulation. These Rivers recycle surplus APC telomeres unused by the T cells and rejuvenate tissues throughout the body, extending lifespan - an unprecedented programme in which CD4+ T cells transmit youth-promoting signals between organisms. While analysing antigen-specific T cell memory responses, we observed that APC telomere transfer was accompanied by abundant extracellular telomeric material. Histology revealed that these extracellular telomeres were not merely tethered to T cells but arranged in vessel-like networks, suggesting release into circulation. The elongated, punctate structures appeared to flow along these networks, evoking miniature streams of genetic material - henceforth referred to as telomere Rivers.

In aged mice, adoptive transfer of young or metabolically reprogrammed CD4+ T cells triggered River production in vivo, and Rivers isolated from these animals could be transplanted into other aged mice to propagate the rejuvenation phenotype independently of T cells. River therapy extended median lifespan by ∼17 months, with several mice surviving to nearly five years. This immune-driven telomere transfer pathway is conserved across kingdoms, including plants, defining the first systemic, transplantable programme of youth.