Turning Back the Clock on Aging Cells - The New York Times 25.03.

2020, 14:12

Turning Back the Clock on Aging

Cells
By Nicholas Wade March 24, 2020

Researchers report that they can rejuvenate human cells by

reprogramming them to a youthful state.

A scanning electron micrograph of a human embryonic stem cell.David Scharf/Science Source

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Researchers at Stanford University report that they can rejuvenate

human cells by reprogramming them back to a youthful state. They hope
that the technique will help in the treatment of diseases, such as
osteoarthritis and muscle wasting, that are caused by the aging of tissue
cells.

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A major cause of aging is thought to be the errors that accumulate in the

epigenome, the system of proteins that packages the DNA and controls
access to its genes. The Stanford team, led by Tapash Jay Sarkar, Dr.
Thomas A. Rando and Vittorio Sebastiano, say their method, designed to
reverse these errors and walk back the cells to their youthful state, does
indeed restore the cells’ vigor and eliminate signs of aging.

In their report, published on Tuesday in Nature Communications, they

described their technique as “a significant step toward the goal of
reversing cellular aging” and could produce therapies “for aging and
aging-related diseases.”

Leonard P. Guarente, an expert on aging at M.I.T., said the method was

“one of the most promising areas of aging research” but that it would
take a long time to develop drugs based on RNA, the required chemical.

The Stanford approach utilizes powerful agents known as Yamanaka

factors, which reprogram a cell’s epigenome to its time zero, or
embryonic state.

Embryonic cells, derived from the fertilized egg, can develop into any of
the specialized cell types of the body. Their fate, whether to become a
skin or eye or liver cell, is determined by chemical groups, or marks, that
are tagged on to their epigenome.

In each type of cell, these marks make accessible only the genes that the
cell type needs, while locking down all other genes in the DNAs. The
pattern of marks thus establishes each cell’s identity.

As the cell ages, it accumulates errors in the marking system, which

degrade the cell’s efficiency at switching on and off the genes needed for
its operations.

In 2006 Dr. Shinya Yamanaka, a stem-cell researcher at Kyoto University,

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amazed biologists by showing that a cell’s fate could be reversed with a

set of four transcription factors — agents that activate genes — that he
had identified. A cell dosed with the Yamanaka factors erases the marks
on the epigenome, so the cell loses its identity and reverts to the
embryonic state. Erroneous marks gathered during aging are also lost in
the process, restoring the cell to its state of youth. Dr. Yamanaka shared
the 2012 Nobel Prize in medicine for the work.

But the Yamanaka factors are no simple panacea. Applied to whole mice,
the factors made cells lose their functions and primed them for rapid
growth, usually cancerous; the mice all died.

In 2016, Juan Carlos Izpisua Belmonte, of the Salk Institute for Biological
Studies in San Diego, found that the two effects of the Yamanaka factors
— erasing cell identity and reversing aging — could be separated, with a
lower dose securing just age reversal. But he achieved this by genetically
engineering mice, a technique not usable in people.

In their paper on Tuesday, the Stanford team described a feasible way to

deliver Yamanaka factors to cells taken from patients, by dosing cells
kept in cultures with small amounts of the factors.

If dosed for a short enough time, the team reported, the cells retained
their identity but returned to a youthful state, as judged by several
measures of cell vigor.

Dr. Sebastiano said the Yamanaka factors appeared to operate in two

stages, as if they were raising the epigenome’s energy to one level, at
which the marks of aging were lost, and then to a higher level at which
cell identity was erased.

The Stanford team extracted aged cartilage cells from patients with
osteoarthritis and found that after a low dosage of Yamanaka factors the
cells no longer secreted the inflammatory factors that provoke the

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disease. The team also found that human muscle stem cells, which are
impaired in a muscle-wasting disease, could be restored to youth.
Members of the Stanford team have formed a company, Turn
Biotechnologies, to develop therapies for osteoarthritis and other
diseases.

The study is “definitively a step forward in the goal of reversing cellular

aging,” Dr. Izpisua Belmonte said.

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