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Flip this epigenome: Making old mice good as new

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Scientists at the Salk Institute for Biological Studies knew it could be done in principle–all you had to do to erase the telltale signs of aging in mammalian cells was slip in a virus containing four genes, a gang collectively known as OSKM, or the “Yamanaka factors”. Once inside, these transcription factors waited for you to flip them on with the antibiotic doxycycline, and then they’d get to work remodeling the cell’s gene expression in the image of its younger, undifferentiated self, in the process restoring the repair mechanisms that keep young cells healthy. But that was just a few isolated cells in a petri dish. So much could go wrong when you tried it on an entire organism.

Cancer, for one thing. Previous studies had demonstrated that reverting cells to an embryonic-like state also produced teratomas, tumors composed of tissues from multiple germ layers. These cells were pluripotent, able to take on the identities of multiple different tissue types, but lacking the normal mechanisms to halt growth before it got out of control. The Salk researchers chose to stop short of pluripotency by using mice with only one copy of the gene cassette that they hoped would help them stem the tide of aging.

But runaway growth wasn’t the only trouble newly youthful cells could cause. The researchers first laced the mice’s drinking water with doxycycline for eight days, killing over half their subjects. Because they were inducing OSKM continuously, cells in vital organs lost their identities as members of those organs, which caused them to fail. So the researchers tried again, partially reprogramming by administering the doxycycline in cycles of a just a couple days with breaks in between. This time, it worked: the mice looked healthier outside and in, with straighter spines, thicker skin, and improved heart function. They ended up living 30% longer than their untreated cohorts.

Quick results with the help of a convenient disease

These were, of course, progeroid mice. For years we’ve been studying aging with the help of a collection of rare genetic conditions called progeroid syndromes, chief among them Hutchinson-Gilford progeria. The disease causes a host of symptoms that mimic normal aging at an extremely young age, and leaves molecular markers similar to those of normal aging as well. Previous work had shown cells from individuals with HGPS could be rejuvenated through cellular reprogramming, and working with mouse models containing the mutation responsible for human HGPS would mean that results could be observed within a fraction of the time necessary with normal mice.

Because no progeroid conditions are perfect models for normal aging, however, the question of whether the treatment’s benefits were transferable to healthy mice remained. Using non-progeroid, wild type mice, the researchers investigated the effects on two cell types that commonly cause malfunctions in aging bodies by failing to regenerate after injury: pancreatic beta cells, responsible for glucose homeostasis and diabetes, and satellite cells, muscle stem cells that are required to maintain the skeletal muscle essential for mobility. They administered toxins affecting each cell type, and confirmed that the treated mice replaced the damaged tissue in a manner closer to younger mice.

The researchers noted that all cellular improvements were preceded by the restoration of two histones involved in maintaining heterochromatin, parts of the epigenetic code which are often dysregulated during aging. Reinforcing its important role in the causing some of the ailments of aging, the results the Salk researchers obtained by modulating the epigenome could be a ray of hope for scientists striving to end those ailments.

http://www.sciencedirect.com/science/article/pii/S0092867416316646

Tegan McCaslin

Tegan is Geroscience's lead editor, and writes on a variety of topics--mainly science, medicine, and humans--here and elsewhere on the web.