Researchers treated mice with anti-aging regimen beginning in middle age and found no increase in cancer or other health problems later on
From: Salk Institute
March 7, 2022 -- Age
may be just a number, but it's a number that often carries unwanted side
effects, from brittle bones and weaker muscles to increased risks of
cardiovascular disease and cancer. Now, scientists have shown that they can
safely and effectively reverse the aging process in middle-aged and elderly
mice by partially resetting their cells to more youthful states.
"We are elated
that we can use this approach across the life span to slow down aging in normal
animals. The technique is both safe and effective in mice," says Juan
Carlos Izpisua Belmonte, co-corresponding author and a professor in Salk's Gene
Expression Laboratory. "In addition to tackling age-related diseases, this
approach may provide the biomedical community with a new tool to restore tissue
and organismal health by improving cell function and resilience in different
disease situations, such as neurodegenerative diseases."
As organisms age, it is
not just their outward appearances and health that change; every cell in their
bodies carries a molecular clock that records the passage of time. Cells
isolated from older people or animals have different patterns of chemicals
along their DNA -- called epigenetic markers -- compared to younger people or
animals. Scientists know that adding a mixture of four reprogramming molecules
-- Oct4, Sox2, Klf4 and cMyc, also known as "Yamanaka factors" -- to
cells can reset these epigenetic marks to their original patterns. This
approach is how researchers can dial back adult cells, developmentally
speaking, into stem cells.
In 2016, Izpisua
Belmonte's lab reported for the first time that they could use the Yamanaka
factors to counter the signs of aging and increase life span in mice with a
premature aging disease. More recently, the team found that, even in young
mice, the Yamanaka factors can accelerate muscle regeneration. Following these
initial observations, other scientists have used the same approach to improve
the function of other tissues like the heart, brain and optic nerve, which is
involved in vision.
In the new study,
Izpisua Belmonte and his colleagues tested variations of the cellular
rejuvenation approach in healthy animals as they aged. One group of mice
received regular doses of the Yamanaka factors from the time they were 15
months old until 22 months, approximately equivalent to age 50 through 70 in
humans. Another group was treated from 12 through 22 months, approximately age
35 to 70 in humans. And a third group was treated for just one month at age 25
months, similar to age 80 in humans.
"What we really
wanted to establish was that using this approach for a longer time span is
safe," says Pradeep Reddy, a Salk staff scientist and co-first author of
the new paper. "Indeed, we did not see any negative effects on the health,
behavior or body weight of these animals."
Compared to control
animals, there were no blood cell alterations or neurological changes in the
mice that had received the Yamanaka factors. Moreover, the team found no
cancers in any of the groups of animals.
When the researchers
looked at normal signs of aging in the animals that had undergone the
treatment, they found that the mice, in many ways, resembled younger animals.
In both the kidneys and skin, the epigenetics of treated animals more closely
resembled epigenetic patterns seen in younger animals. When injured, the skin
cells of treated animals had a greater ability to proliferate and were less
likely to form permanent scars -- older animals usually show less skin cell
proliferation and more scarring. Moreover, metabolic molecules in the blood of
treated animals did not show normal age-related changes.
This youthfulness was
observed in the animals treated for seven or 10 months with the Yamanaka
factors, but not the animals treated for just one month. What's more, when the
treated animals were analyzed midway through their treatment, the effects were
not yet as evident. This suggests that the treatment is not simply pausing
aging, but actively turning it backwards -- although more research is needed to
differentiate between the two.
The team is now
planning future research to analyze how specific molecules and genes are
changed by long-term treatment with the Yamanaka factors. They are also
developing new ways of delivering the factors.
"At the end of the
day, we want to bring resilience and function back to older cells so that they
are more resistant to stress, injury and disease," says Reddy. "This
study shows that, at least in mice, there's a path forward to achieving
that."
Belmonte is
currently an Institute
Director at Altos Labs, Inc., in addition to being a professor at the Salk
Institute.
Other authors included
Mako Yamamoto, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque,
Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida and Concepcion
Rodriguez Esteban of Salk; Kristen Browder, Zijuan Lai, Qingling Li, Feroza
Choudhury, Weng Wong, Yuxin Liang, Dewakar Sangaraju, Wendy Sandoval, Michal
Pawlak, Jason Vander Heiden and Heinrich Jasper of Genentech, Inc.; Amin
Haghani and Steve Horvath of UCLA; Estrella Nuñez Delicado of Universidad
Católica San Antonio de Murcia; and Pedro Guillen Garcia of Clínica CEMTRO.
https://www.sciencedaily.com/releases/2022/03/220307113027.htm
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