River Of Youth: What Are ‘Telomere Rivers’, And Could They Really Reverse Ageing?

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Earlier this year, researchers reported an entirely new and intriguing behaviour of a specific type of T cell known as a CD4+ T cell. Under certain circumstances, these cells can release telomeres (segments of non-coding DNA that usually cap the ends of chromosomes to protect them) into the bloodstream. These ‘telomere rivers’, so-named after their appearance under the microscope, seem to have a rejuvenating effect. Mice treated with river-producing T cells showed a quite stunning increase in lifespan, with some animals living33(for) up to 58 months – around 20 months longer than the longest-living untreated mice. Despite the fact that these findings have neither been peer-reviewed or33[nor] replicated, the biotech startup behind this research (Sentcell) has already secured funding for phase I human clinical trials to see if their approach can affect immune ageing in humans. While we should be cautious about such early evidence, the phenomenon of ‘telomere rivers’ described is very interesting and worth talking about.

Telomere Shortening: The Ticking Clock

The33[delete the] DNA is the instruction book containing the information necessary to produce all of the proteins a cell needs to function. Every time the cell divides, that entire book needs to be replicated so that each new cell can receive a copy. However, the molecular machinery responsible for replicating the DNA has a quirk: when it reaches the very end of a strand of DNA, it is unable to copy the very last part. This would result in the loss of vital genetic information each time the cell divides, which is not acceptable. To avoid this, cells add segments of non-coding DNA to the ends of each chromosome33[.These are the telomeres.]called telomeres. Each time the cell divides, the telomeres get a little shorter, but the important DNA that contains genetic information is protected.

Once the cell has divided a certain number of times (50-70 times for human cells)33[,] there is not enough telomere material left to safely divide again. Once this happens, rather than lose coding DNA, cell division shuts down permanently, resulting in a state called senescence. This is actually a good thing in young organisms, as it means that rapidly dividing cancer cells will quickly have their division halted if they can’t acquire a mutation that allows them to bypass senescence. However, as an increasing number of normal cells begin to turn senescent in old age, they start to become a problem. Senescent cells are a kind of ‘dead weight’ within the organs they occupy, as they don’t don’t function as well as normal cells. They also release a cocktail of inflammatory and signalling molecules known as the SASP (senescence-associated secretory phenotype) which is now thought to contribute to many age related diseases, including promoting and sustaining nearby cancers.

There is now a lot of interest in targeting senescent cells in various ways. One approach is to use drugs that selectively kill senescent cells (senolytics) or at least suppress the SASP (senostatics). Another is to try to regrow telomeres to prevent senescence from occurring – a capability that is inherent to some of our cells, but that is lost over time.

The Discovery of Telomere Rivers

This brings us to the discovery of ‘telomere rivers’. It started with an observation featuring two types of immune cell: APCs and CD4+ T cells. APCs are antigen-presenting cells – they take antigens from pathogens (molecules that are specific to a given type of pathogen) and present them to other immune cells like CD4+ T cells. CD4+ T cells are like ‘conductors’ of the immune system, helping to boost the activity of other immune cells and direct the immune response as a whole to target the antigen in question.

T cells are among those cell types that have some ability to resist senescence, which is thought to be due at least partly to the elongation of telomeres by an enzyme called telomerase. However, in 2022, researchers found that when APCs present T cells with antigens, they also transfer telomere material to the T cell. These donated telomeres then fused33[tense? re previous sentense] with the ends of the T cell’s chromosomes, effectively granting it an new lease of life by delaying senescence.

Then, in November of last year, the same authors published a preprint study detailing some new findings about this telomere transfer. They describe how, after acquiring telomeres from APCs, CD4+ T cells 33packaged excess unused telomeres into vesicles that they then released as ‘telomere rivers’. In mice, 33there rivers appeared to be taken up by other tissues, which finally brings us to the most eye-catching finding concerning lifespan.

The Mouse Study

In a series of experiments, researchers gave mice either APCs that had been exposed to antigen in order to trigger the APC-CD4+ cell interaction, then harvested the resulting telomere rivers and injected them into five 20 month-old mice (roughly ‘equivalent’ to a human in their 60s). 33(where is the “or” part of this sentence? – “…gave mice either APCs…. or…”)They found that a year later, the treated mice had significantly fewer markers of cellular senescence in multiple organs (brain, liver, heart, kidneys, lungs) when compared to the equally sized control group. Treated mice also had fewer markers of inflammation.

However, the most impressive finding came from an experiment in which 5 groups33[,each containing 20 old mice,] of around 20 old mice each were given one33[of] either isolated telomere rivers, river-producing T cells, or three control treatments (empty vesicles, ‘aged’ T cells or serum). They found that treatment with isolated rivers or river-producing T cells was associated with a large, statistically significant increase in median lifespan (the age by which 50% of mice are dead) as well as a large increase in maximum lifespan (the age reached by the very oldest mice). For the mice treated with isolated rivers, median lifespan increased by 17 months – a roughly 70% increase over controls. The oldest mice in either of the three control groups lived 37 months, which is expected for the specific strain of mice studied, while oldest treated mouse survived 56 months.

The graph above shows the percentage of surviving mice over time in each group. Notice how survival in the treated groups (green and yellow) looks like a delayed version of the control groups. The first deaths occur over two years later in the treated groups, and the last deaths also occur over two years later – treated mice do not appear to die off faster towards the end of the experiment (allowing control mice to ‘catch up’). This graph shows exactly what we would expect a true delaying of the ageing process to look like.

Too Good To Be True?

If confirmed, these results would be a significant breakthrough in terms of mouse lifespan extension, but it’s important to put the magnitude of the claims into perspective. The graph shows that by the time 50% of mice in the control groups are dead, not a single death has yet occurred in the treatment groups. By the time every single mouse in the control groups are dead, around three quarters of mice in the treated groups are still alive. In human terms, this would be like a treatment that allowed three quarters of recipients to make it past 100.

To put the reported findings into context of other lifespan-extending treatments, the largest increase in median lifespan shown in the ITP (which conducts some of the most rigorous mouse lifespan experiments) was 33%, achieved with a combination of rapamycin (a drug that mimics some of the effects of calorie restriction, among other things) and acarbose (a blood sugar-lowering drug). This is less than half of the effect reported in the present study. Experiments targeting telomerase in order to extend telomere length in mice have generally achieved increases in median lifespan of up to 25%.

As the saying goes, extraordinary claims need extraordinary evidence, and there are a few reasons to remain cautious about these findings. As already mentioned, these results haven’t been peer-reviewed or replicated. 20 mice per group also isn’t a very large sample size for a lifespan extension study, as by the time you are comparing median lifespans, you are only comparing groups of 10 mice, while the 10% longest-living mice only number 2 animals.

Clinical Trials

Despite the early stage of this research, SentCell is planning human clinical trials to explore whether telomere rivers might be able to improve immune function in those with immune deficiencies, such as in HIV infection and in old age. Based on available information, it seems like these trials will be using ‘rejuvenated’ CD4+ T cells that will produce telomere rivers and hopefully restore function to the rest of the immune system. If these trials are successful33[,] it will lend credence to the idea that telomere rivers can have a rejuvenating effect, even if lifespan extension remains a long way away.