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
Scientists have rolled back time for live mice through systemic cellular reprogramming, according to a study published December 15 in Cell. 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 study suggests that epigenetic changes drive the aging process, and that those changes may be malleable. “We did not correct the mutation that causes premature aging in these mice,” says lead investigator Juan Carlos Izpisua Belmonte, a professor in the Salk Institute of Biological Science’s Gene Expression Laboratory. “We altered aging by changing the epigenome, suggesting that aging is a plastic process.”
This is the first report in which cellular reprogramming extends lifespan in a live animal. Previous efforts resulted in mice that either died immediately or developed extensive tumors. The Salk team used a partial cellular reprogramming approach that did not cause tumors or death. “We were surprised and excited to see that we were able to prolong the lifespan by in vivo reprogramming,” says co-first author Pradeep Reddy.
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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 Salk team used partial reprogramming, which induced expression of Yamanaka factors for just 2 to 4 days. Cells do not reach pluripotency. Rather, a cell that starts off as a skin cell remains a skin cell. But signs of age-associated dysfunction in the cell diminish. In this study, partial reprogramming of cells in vitro reduced DNA damage accumulation and restored nuclear structure. “These changes are the result of epigenetic remodeling in the cell,” says Izpisua Belmonte.
Epigenetic marks, which change over a lifetime in response to environmental changes, regulate and protect the genome. Some marks turn on specialized functions, such as skin cell machinery in a skin cell, and turn off mechanisms that aren’t needed, such as liver cell machinery. “During aging, marks are added, removed, and modified,” says co-first author Alejandro Ocampo. “It’s clear that the epigenome is changing as we get older.”
Salk Institute researchers discover that partial cellular reprogramming reversed cellular signs of aging such as accumulation of DNA damage. (Left) Progeria mouse fibroblast cells; (right) progeria mouse fibroblast cells rejuvenated by partial reprogramming. Credit: Salk Institute
The team induced expression of Yamanaka factors in all cells of the organism using their partial reprogramming approach. Several organs improved. For instance, tissue from skin, spleen, kidney and stomach all had improved appearance when inspected under a microscope. The cardiovascular system, which often fails and causes early death in these prematurely aging mice, also showed improvements in structure and function. “It is difficult to say specifically why the animal lives longer,” says co-first author Paloma Martinez-Redondo. “But we know that the expression of these factors is inducing changes in the epigenome, and those are leading to benefits at the cellular and organismal level.”
The team also tested applications of partial reprogramming in models of injury in mice. In this study, partial reprogramming enhanced the regeneration of muscle tissue and beta cells in the pancreas following injury.
Next steps will involve learning more about how the epigenome changes during partial reprogramming. “We need to go back and explore which marks are changing and driving the aging process,” says Izpisua Belmonte.
Ocampo et al. In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 2016 DOI: 10.1016/j.cell.2016.11.052