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.
Nature Communications – Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells. By Tapash Jay Sarkar, Marco Quarta, Shravani Mukherjee, Alex Colville, Patrick Paine, Linda Doan, Christopher M. Tran, Constance R. Chu, Steve Horvath, Nidhi Bhutani, Thomas A. Rando, Vittorio Sebastiano. (Stanford University)
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
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