Transient reprogramming, mediated by transient expression of mRNAs, promotes a rapid reversal of both cellular aging and of epigenetic clock in human fibroblasts and endothelial cells, reduces the inflammatory profile in human chondrocytes, and restores youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.
Old human cells can become more youthful by coaxing them to briefly express proteins used to make induced pluripotent cells, Stanford researchers and their colleagues have found. The finding may have implications for aging research. Elderly mice regained youthful strength after their existing muscle stem cells were subjected to the rejuvenating protein treatment and transplanted back into their bodies.
The proteins, known as Yamanaka factors, are commonly used to transform adult cells into induced pluripotent stem cells, or iPS cells. Induced pluripotent stem cells can become nearly any type of cell in the body, regardless of the cell from which they originated. They’ve become important in regenerative medicine and drug discovery.
By making old human cells in a lab dish to briefly express Yamanak proteins rewinds many of the molecular hallmarks of aging and renders the treated cells nearly indistinguishable from their younger counterparts.
Exposure to proteins
Researchers in Sebastiano’s laboratory make iPS cells from adult cells, such as those that compose skin, by repeatedly exposing them over a period of about two weeks to a panel of proteins important to early embryonic development. They do so by introducing daily, short-lived RNA messages into the adult cells.
They used genetic material called messenger RNA to get cells to temporarily express six reprogramming factors — the four Yamanaka factors plus two additional proteins — in human skin and blood vessel cells.
Cells from old people showed signs of aging reversal after just four days of exposure to the reprogramming factors.
The treated cells appeared to be about 1½ to 3½ years younger on average than untreated cells from elderly people, with peaks of 3½ years (in skin cells) and 7½ years (in cells that line blood vessels).
Comparing hallmarks of aging
Next they compared several hallmarks of aging — including how cells sense nutrients, metabolize compounds to create energy and dispose of cellular trash — among cells from young people, treated cells from old people and untreated cells from old people.
“We saw a dramatic rejuvenation across all hallmarks but one in all the cell types tested,” Sebastiano said. “But our last and most important experiment was done on muscle stem cells. Although they are naturally endowed with the ability to self-renew, this capacity wanes with age. We wondered, Can we also rejuvenate stem cells and have a long-term effect?”
When the researchers transplanted old mouse muscle stem cells that had been treated back into elderly mice, the animals regained the muscle strength of younger mice, they found.
Finally, the researchers isolated cells from the cartilage of people with and without osteoarthritis. They found that the temporary exposure of the osteoarthritic cells to the reprogramming factors reduced the secretion of inflammatory molecules and improved the cells’ ability to divide and function.
They hope to reboot entire tissues after rigorous testing and perfecting the procedure.
Abstract
Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.
SOURCES- Stanford, Nature Communications, Biorxiv
Written By Brian Wang, Nextbigfuture.com
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
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Why does mRNA cause inflammation? Isn’t it a natural part of cellular activity?
Delivery of mRNA rather than DNA plasmids could be sufficient as mRNA is rapidly degraded in cells, and does not run the risk of integration into chromosomal DNA next to oncogenes. You’d need a better delivery method than Viral vectors, maybe something like Oisin Biotechnologies fusogenix lipid nanoparticles. Modifying one of the RNA bases is enough to prevent the inflammation normally caused via toll like receptors.
The transplant here was just for convenience of applying the treatment in vitro, and then testing it in vivo. This isn’t a treatment that can easily be applied systematically. As I say, you’d probably have to do some viral reprograming of the cells to enable it to be done in a whole organism. Think of it more as a demonstration of principle, than a viable treatment.
Now, some tissues can be completely rejuvinated by transplant, bone marrow, for instance.
I’m encouraged that there’s continual progress on multiple fronts. I’m not at all confident that it will add up to enough, fast enough, to be much help for me. (I’m 61, and not from long lived stock.) Maybe. But it sure looks like they’ll have this thing licked before my son has to worry about getting elderly.
And that’s some consolation, anyway.
It’s hard to see muscle transplants becoming a cure for aging. Perhaps parabiosys offers the idea of rejuvenated old blood replacing current old blood: https://www.scientificamerican.com/article/fountain-of-youth-young-blood-infusions-ldquo-rejuvenate-rdquo-old-mice/
but this is still an unproven treatment in humans.
Doing this in a controlable way across the entire organism might be challenging. Maybe using a virus to deliver a genetic circuit, that triggers the cycle in response to the presence of some short lived signal chemical?
Aging is not a defence against cancer, natural again reduces cells of certain molecule strains, and also stores certain molecules for the good, (for example your skin tan color is a defense as well). Its not possible to detect good from bad cells, because of the enormous amount of differences between good and bad cells and each of us has different genetics. The best we can do is fix certain things that obviously go wrong and who eventually result in broken cell. We might be able to fix some genetic errors, though at the same time could introduce new errors as well.
Some cells that do go wrong, might eventually reproduce and create a cancer.
Personally i think the best way to deal with cancer is to check for molecules who indicate its a strong feeder and multiplyer, those are typical cancer signs, cell membrame differences could point to that, but then again there are so many types of cells, and so many cancers that this is a currently acctive fore front of cancer research topics.
You could be right, If acting like young cells include them living longer and having lots of “kids”. Hopefully. acting like young also includes them repairing themselves more effectively.
Would getting old cells to act as young cells be likely to cause cancers, as old cells, which are likely to have accumulated damage, would no longer be senescent and would instead multiply.
That is to say, could aging be a defense mechanism against cancer?
If so, perhaps we could select cells without damage (somehow?) and then we could induce only those cells to express pluripotent stem cell factors.