Epigenetic reprogramming used to reverse signs of aging in animal model.

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Greying hair, crow’s feet, an injury that’s taking longer to heal now one is older, faced with the unmistakable signs of aging, most people have had a least one fantasy of turning back time.  Now, a study from researchers at the Salk Institute rolls back time for live mice through systemic cellular reprogramming.  The team state that in mice carrying a mutation leading to premature aging, reprogramming of chemical marks in the genome, known as epigenetic marks, reduced many signs of aging in the mice and extended their lifespan on average from 18 weeks to 24.  The opensource study is published in the journal Cell.

Previous studies show that cellular reprogramming turns an adult cell, such as a skin cell, into an induced pluripotent stem (iPS) cell. IPS cells have high proliferation rates and are not yet specialized to perform functions, such as being part of the skin. Reprogramming involves inducing the expression of four factors, called Yamanaka factors, in cells. The factors must be expressed for 2 to 3 weeks for cells to reach pluripotency.  The current study uses partial reprogramming to alter aging in live animals by changing the epigenome, suggesting that aging is a plastic process.

The current study utilises skin cells from mice with progeria to induce the Yamanaka factors for a short duration. The lab explain that both mice and humans with progeria, a rare genetic disease, show many signs of aging including DNA damage, organ dysfunction and dramatically shortened lifespan. Moreover, epigenetic marks are prematurely dysregulated in progeria mice and humans. They note that, importantly, epigenetic marks are modified during cellular reprogramming.

The group state that when they examined the skin cells using standard laboratory methods, the cells showed reversal of multiple aging hallmarks without losing their skin-cell identity.  Encouraged by this result, the team used the same short reprogramming method during cyclic periods in live mice with progeria.  Results show that compared to untreated mice, the reprogrammed mice looked younger; their cardiovascular and other organ function improved, and they lived 30% longer, yet did not develop cancer. Data findings show that on a cellular level, the animals showed the recovery of molecular aging hallmarks that are affected in normal aging and progeria.

Lastly, the researchers turned their efforts to normal, aged mice. In these animals, the lab observed the cyclic induction of the Yamanaka factors led to improvement in the regeneration capacity of the pancreas and muscle.  Data showed that the injured pancreas and muscle healed faster in aged mice that were reprogrammed, indicating a clear improvement in the quality of life by cellular reprogramming.

The team surmise their work shows that partial reprogramming erases cellular markers of aging in mouse & human cells, and that epigenetic changes are at least partially driving aging. For the future, the researchers state they believe that induction of epigenetic changes via chemicals or small molecules may be the most promising approach to achieve rejuvenation in humans. However, they caution that, due to the complexity of aging, these therapies may take up to 10 years to reach clinical trials.

Source: Salk Institute

This image shows the discovery by researchers that induction of partial cellular reprogramming improved muscle regeneration in aged mice. (Left) Impaired muscle repair in aged mice; (Right) Improved muscle regeneration in aged mice subjected to reprogramming.  Credit: Courtesy of Juan Carlos Izpisua Belmonte Lab /Salk Institute.

This image shows the discovery by researchers that induction of partial cellular reprogramming improved muscle regeneration in aged mice. (Left) Impaired muscle repair in aged mice; (Right) Improved muscle regeneration in aged mice subjected to reprogramming. Credit: Courtesy of Juan Carlos Izpisua Belmonte Lab /Salk Institute.

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