Old human cells return to a more youthful and vigorous state after being
induced to briefly express a panel of proteins involved in embryonic
development, according to a new study by researchers at the Stanford University
School of Medicine.
The researchers
also found that 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 an adult cell into
what are known as 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.
The study found
that inducing old human cells in a lab dish to briefly express these proteins
rewinds many of the molecular hallmarks of aging and renders the treated cells
nearly indistinguishable from their younger counterparts.
“When iPS cells
are made from adult cells, they become both youthful and pluripotent,” said
Vittorio Sebastiano, PhD, assistant professor of obstetrics and gynecology and
the Woods Family Faculty Scholar in Pediatric Translational Medicine. “We’ve
wondered for some time if it might be possible to simply rewind the aging clock
without inducing pluripotency. Now we’ve found that, by tightly controlling the
duration of the exposure to these protein factors, we can promote rejuvenation
in multiple human cell types.”
Sebastiano is the senior author of the study, which will be published
online March 24 in Nature Communications. Former graduate student Tapash
Sarkar, PhD, is the lead author of the article.
“We are very
excited about these findings,” said study co-author Thomas Rando, MD, PhD,
professor of neurology and neurological sciences and the director of Stanford’s
Glenn Center for the Biology of Aging. “My colleagues and I have been pursuing
the rejuvenation of tissues since our studies in the early 2000s revealed that
systemic factors can make old tissues younger. In 2012, Howard Chang and I
proposed the concept of using reprogramming factors to rejuvenate cells and
tissues, and it is gratifying to see evidence of success with this approach.”
Chang, MD, PhD, is a professor of dermatology and of genetics at Stanford.
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. The RNA
messages encode the instructions for making the Yamanaka proteins. Over time,
these proteins rewind the cells’ fate — pushing them backward along the
developmental timeline until they resemble the young, embryonic-like
pluripotent cells from which they originated.
During this
process the cells not only shed any memories of their previous identities, but
they revert to a younger state. They accomplish this transformation by wiping
their DNA clean of the molecular tags that not only differentiate, say, a skin
cell from a heart muscle cell, but of other tags that accumulate as a cell
ages.
Recently
researchers have begun to wonder whether exposing the adult cells to Yamanaka
proteins for days rather than weeks could trigger this youthful reversion
without inducing full-on pluripotency. In fact, researchers at the Salk
Institute for Biological Studies found in 2016 that briefly expressing the four
Yamanaka factors in mice with a form of premature aging extended the animals’
life span by about 20%. But it wasn’t clear whether this approach would work in
humans.
Sarkar and
Sebastiano wondered whether old human cells would respond in a similar fashion,
and whether the response would be limited to just a few cell types or
generalizable for many tissues. They devised a way to use genetic material
called messenger RNA to temporarily express six reprogramming factors — the
four Yamanaka factors plus two additional proteins — in human skin and blood
vessel cells. Messenger RNA rapidly degrades in cells, allowing the researchers
to tightly control the duration of the signal.
The researchers
then compared the gene-expression patterns of treated cells and control cells,
both obtained from elderly adults, with those of untreated cells from younger
people. They found that cells from elderly people exhibited signs of aging
reversal after just four days of exposure to the reprogramming factors. Whereas
untreated elderly cells expressed higher levels of genes associated with known
aging pathways, treated elderly cells more closely resembled younger cells in
their patterns of gene expression.
When the
researchers studied the patterns of aging-associated chemical tags called
methyl groups, which serve as an indicator of a cell’s chronological age, they
found that 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.
The researchers
are now optimizing the panel of reprogramming proteins needed to rejuvenate
human cells and are exploring the possibility of treating cells or tissues
without removing them from the body.
“Although much
more work needs to be done, we are hopeful that we may one day have the
opportunity to reboot entire tissues,” Sebastiano said. “But first we want to
make sure that this is rigorously tested in the lab and found to be safe.”
Journal article: https://www.nature.com/articles/s41467-020-15174-3
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