Summary: Regenerative reprogramming of the body with injections could turn back the clock in our organs, say scientists in a Jan 2018 report. Prematurely aged mice lived 30% longer after Salk Institute researchers genetically reprogrammed their cells while still in the body. [This article first appeared on the website LongevityFacts.com. Author: Brady Hartman. ]
Imagine a time in the future when the doctor gives you the bad news: you need a heart transplant. In the past, this would be an expensive and drastic procedure. Instead, the doctor gives you an injection that rejuvenates your heart. In time, your heart eventually mends itself, reverting to the strength and vigor of your youth.
The dream is closer to reality than you think, thanks to a novel technique developed by a team researchers headed by Juan Carlos Izpisua Belmonte at the Salk Institute in La Jolla.
The Salk scientists borrowed a page from stem cell technology to boost the lifespan of mice and rejuvenate some of their tissues.
However, their novel technique does not use stem cells.
Instead, the scientists employ a simple injection of molecules that turn back the clock in aged cells, while they are still in the body. The technique hasn’t been tested on humans, yet. However, it could lead to ways to rejuvenate our organs and keep our bodies vigorous as we get older.
In a review provocatively titled “Elixir of Life: Thwarting Aging With Regenerative Reprogramming,” a team of scientists at the Salk Institute reveals a novel technique that restores aged cells to a more youthful state, as the authors say
“Recent advances in the field of regenerative medicine have shown that aging is not an irreversible process.”
The Salk researchers believe that they could rejuvenate humans using chemicals to reverse epigenetic changes, as they put it in the new review,
“Given the recent progress in identifying chemicals that can boost or even replace in vitro, we envisage that findings related to 4F [four Yamanaka factors] will also eventually lead to safe chemical-based therapeutic strategies in regenerative medicine that will shift the focus from invasive replacement therapies to regeneration-oriented self-healing.”
The study was published in January 2018 in the American Heart Association journal called Circulation Research.
Juan Carlos Izpisua Belmonte headed up the study which includes the co-authors Ergin Beyret, Paloma Martinez Redondo, and Aida Platero Luengo – a group of scientists in Belmonte’s lab at the Salk Institute for Biological Studies in La Jolla, California.
In the new study, Belmonte’s team reviews the progress they have made on the regenerative reprogramming technique, and discuss its potential use in regenerating human organs and tissues.
The review reinforces the idea that scientists can reverse the aging process, by reprogramming the epigenetic clock in our cells to rejuvenate organs and tissues.
How It Started
The excitement began in December of 2016 when the Salk team announced they could induce mouse skin cells to look and behave young again. The group reported they rejuvenated mice with a premature aging disease, countering the signs of aging and increasing the rodent’s lifespan by 30 percent. The early-stage work gave rise to the promise of turning it into a rejuvenation therapy for humans.
“Our study shows that aging may not have to proceed in one single direction,” announced Belmonte, in a December press release announcing the finding, adding “It has plasticity and, with careful modulation, aging might be reversed.”
Keeping Identity Intact
The technique pioneered by Belmonte and colleagues borrows from stem cell technology. In creating stem cells, technicians use particular chemicals called Yamanaka factors that induce a matured adult cell to return to its earliest stage of development. Yamanaka factors are used to create induced pluripotent stem cells (iPSCs) – cells in an embryonic state that can be then turned into any other type of tissue in the body.
However, Belmonte’s novel technique doesn’t return cells to an embryonic state. Instead, the technology turns back the clock only a handful of decades. Unlike a stem cell, which doesn’t know yet whether it is a heart, muscle or liver cell, Belmonte’s reprogrammed cells retain their identity. A heart cell remains a heart cell, just decades younger.
To work this magic, Belmonte’s team relied on four proteins, called Yamanaka Factors, which instruct a cell to revert to an embryonic state. However, instead of giving the adult cells a full dose of these Yamanaka Factors, the Salk researchers gave smaller amounts in carefully timed doses. The four Yamanaka factors are also called transcription factors because they turn DNA into RNA and are the proteins OCT4, KLF4, SOX2, and c-Myc.
The technique involves tweaking part of the human genetic code called the epigenome. Like the rest of our body, our chromosomes show signs of aging. Our genome does not only contain DNA, but it also contains another set of instructions called epigenetic marks, that controls how active our genes are. As we get older, these marks change, fouling up the gene activity that keeps our cells working. In fact, these marks are so predictable; they form the basis of an epigenetic clock. Researchers have used them as a biomarker of aging which can tell a person’s age, with an accuracy of 4 years.
These epigenetic alterations aren’t permanent, however. Researchers can reprogram these cells to more youthful settings and rejuvenate old cells, as Belmonte and team announce in the Jan 2018 review
“Pursuing this line of thought, can we improve the healthspan by resetting the old epigenome to a younger state so that the cells regain their young phenotype?”
Pitfalls of Regenerative Reprogramming
The technique had undesirable results in the past. Infusing Yamanaka factors as a whole-body treatment produced disastrous effects in laboratory animals. Experiments in 2013 and 2014 resulted in the deaths of all of the animals, either because of cancers or because the induced cells lost their identities.
Embryonic cells are primed for rapid growth, and too much of a good thing has bad consequences. Rapid cell division is essential for a growing embryo. However, it causes cancer in adults. Another problem with having large numbers of cells reverting to the embryonic state is it could result in organ failure, leading to death.
However, Belmonte’s team has refined the process as of late, carefully timing and measuring out the dose to avoid these side effects. The Salk team avoided cancer by introducing the Yamanaka factors for a shorter period, as the authors say in the new review
“Remarkably, we have recently observed that transient expression of 4F [four Yamanaka factors] is sufficient to reset the cell’s aging clock without loss of its identity or cellular divisions, indicating that rejuvenation of the cell occurs much early during its conversion to iPSCs.”
Testing the Regenerative Reprogramming Idea
To test out their theory back in 2016, the team turned to a rare genetic disease called progeria. Mice and humans with progeria show many signs of aging including organ dysfunction, DNA damage, and a dramatically shortened lifespan. Moreover, the epigenetic marks on the chromosomes of progeroid mice and humans are prematurely dysfunctional.
Skin in the Game
Using skin cells obtained from mice with progeria, the Salk team exposed the cells to the four Yamanaka factors for a short duration. When examined, the cells showed a reversal of multiple aging hallmarks without losing their skin-cell identity. Exposure to the four Yamanaka factors reset the cell’s aging clock without the loss of its identity, reports Belmonte.
Reprogramming Progeroid Mice
Encouraged by this result, Belmonte’s team used the same reprogramming method in live mice with progeria. The results were striking: Compared to the untreated mice, the reprogrammed mice looked younger; their cardiovascular and other organ function improved and, notably, they lived 30 percent longer and did not develop cancer. When examined, the rodent’s cells showed a rejuvenation of the hallmarks of aging, as the Salk scientists say in the new review,
“Moreover, we have observed that ubiquitous induction of 4F extends the life expectancy of a mouse model of accelerated aging (Hutchinson–Gilford progeria syndrome) in correlation with an increase in the epigenetic marks associated with youth, whereas a decrease in those associated with old age.”
Reprogramming Healthy Mice
Lastly, the researchers turned their efforts to normal, aged mice and those with injuries. In these rodents, a course of treatment with the Yamanaka factors improved the regenerative capacity of their pancreas and muscle. Injured pancreas and muscle tissue healed faster in the reprogrammed mice, indicating a definite improvement in their quality of life.
In the current review, Belmonte put their findings in a nutshell, saying
“Altogether, the key concept raised by this work is that aging is a manifestation of progressive epigenetic dysregulation that can be reset by transient in vivo reprogramming induced by 4F expression.”
Belmonte and colleagues dispel the notion that there is a master clock in the epigenome, and this epigenetic clock controls our fate. Instead, while the epigenetic clock plays a substantial role, the authors are careful to state that aging could be caused by the interplay of a variety of factors, adding
Better than Stem Cells
Stem cells have been heralded as a panacea for many diseases and conditions, including heart disease and stroke, AMD, type 1 diabetes, and respiratory diseases. Moreover, some propose using them to treat Alzheimer’s, Parkinson’s disease and other forms of dementia.
Despite their immense promise, physicians have been slow to adopt iPSCs for stem cell therapies. Doctors have been held back by concerns about safety and functionality.
And rightly so. As Belmonte points out
“cells derived from iPSCs frequently display heterogeneity and immature functionality, making them unsuitable for transplantation.”
Moreover, adds Belmonte, manipulating cells in a test tube runs the risk of contamination and accumulation of genetic mutations, potentially leading to cancer.
The Salk technique bypasses these issues. Cells never leave the body, and so can’t become contaminated, and run a lower risk of genetic mutations. Moreover, the reprogramming technique is far less invasive, requires less specialized labor and should be less expensive.
Bottom Line on Regenerative Reprogramming
The Salk scientists have developed tools that give them the ability to change the human epigenome with greater precision than ever before. Belmonte’s finding dovetails nicely with new reports that researchers are developing a better understanding of the epigenetic changes that occur in cancer and aging.
Belmonte and colleagues are quick to point out that they haven’t found the fountain of youth, yet. As the researchers put it in the new review,
“Although the therapeutic effect of 4F [four Yamanaka factors] on the progeria mice and acute injuries discussed here is remarkable, we have not seen the best of it yet. We do not know yet whether 4F or similar reprogramming factors can extend the life span of wild-type animals.”
While it could take a decade or more, to bear fruit, the Salk researchers believe that they could rejuvenate humans using the regenerative programming technique to reset aging in diseased organs and tissues.
Related: Researchers crack a secret code to the epigenetic changes produced by cancer.
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Cover photo credit: Getty Images(iStock).
Ergin Beyret, Paloma Martinez Redondo, Aida Platero Luengo and Juan Carlos Izpisua Belmonte. “Elixir of Life: Thwarting Aging With Regenerative Reprogramming.” Circulation Research. 2018;122:128-141, originally published January 4, 2018. [paywall]
Ocampo, Alejandro et al. “In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming.” Cell , Volume 167 , Issue 7 , 1719 – 1733.e12
Turning back time: Salk scientists reverse signs of aging. [press release] SALK NEWS. December 15, 2016
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