Aging blood behaves like an orchestra whose conductor is gradually going deaf. At first the musicians still hold their tuning, but each year the brass plays louder and louder, while the strings are barely audible. In the same way, blood-forming stem cells (HSCs) with age produce too many innate immune cells and too few adaptive immune cells. This skew is called myeloid, and it makes the elderly body vulnerable to infections and chronic inflammation.
But what if the conductor were given a short course of exercises in time, one that would preserve his hearing for decades? That is exactly what the researchers did: they took young mice and for 16 days switched on four proteins known as Yamanaka factors. These proteins are usually used to return a mature cell to a state close to embryonic, that is, to completely erase its specialization. Here, however, they were switched on only briefly, without pushing the cells all the way to transformation.
Aging blood behaves like an orchestra whose conductor is gradually going deaf. At first the musicians still hold their tuning, but each year the brass plays louder and louder, while the strings are barely audible. In the same way, blood-forming stem cells (HSCs) with age produce too many innate immune cells and too few adaptive immune cells. This skew is called myeloid, and it makes the elderly body vulnerable to infections and chronic inflammation.
But what if the conductor were given a short course of exercises in time, one that would preserve his hearing for decades? That is exactly what the researchers did: they took young mice and for 16 days switched on four proteins known as Yamanaka factors. These proteins are usually used to return a mature cell to a state close to embryonic, that is, to completely erase its specialization. Here, however, they were switched on only briefly, without pushing the cells all the way to transformation.
The result was astonishing. Mice that received such a course at the age of two to three months retained a blood cell balance like that of young mice into old age (20-24 months). They did not accumulate DNA damage, and their stem cells engrafted upon transplantation just as well as those of young donors. At the same time, the Yamanaka factors themselves stopped working just a month after the course ended. So the cells were not simply "supported" by these proteins; they remembered something important.
The memory turned out to be written not in the genes but in their packaging. DNA in the nucleus is wound around proteins like thread around spools. Regions that need to be used lie loose, while unneeded ones are tightly wound and covered with chemical marks. With age this packaging loosens: silenced DNA regions, including mobile elements (repetitive pieces capable of jumping around the genome), begin to activate and introduce chaos. Reprogramming restored the tight packaging and silenced these elements.
Another layer of protection is the AP-1 protein, which responds to stress and inflammation. In old cells it is too active and makes them behave incorrectly. After reprogramming its influence weakened. When researchers gave old mice an AP-1 inhibitor, their stem cells also worked better. This confirms that the issue is not only mobile elements but also the inflammatory background.
Such an approach resembles vaccination: a short exposure in youth creates long-term protection. So far this is only about mice, but if the effect can be reproduced in humans, for example with small molecules, it could change the strategy for combating blood aging. Instead of treating already aged cells, it will be possible to teach them in advance not to age.
A single 16-day course of doxycycline in youth protected mice from the age-related decline in blood formation for almost their entire lives, even though the Yamanaka factors themselves stopped being expressed after just a month.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.