New cellular reprogramming technique counters hallmarks of aging

Scientists from Salk Institute for Biological Studies showed that One clue to halting or reversing aging lies in the study of cellular reprogramming, a process in which the expression of four genes known as the Yamanaka factors allows scientists to convert any cell into induced pluripotent stem cells (iPSCs) Like embryonic stem calls, iPSCs are capable of dividing indefinitely and becoming any cell type present in our body. Dr. Juan Carlos Izpisúa Belmonte, professor in Salk’s Gene Expression Laboratory, is the senior author of the paper, published in Cell, in which also participated Dr. Josep Maria Campistol, CEO and nephrologist in Hospital Clínic, and researcher in IDIBAPS. Scientists from Universidad Católica de Murcia, among others, have also been involved.

Graying hair, crow’s feet, an injury that’s taking longer to heal than when we were 20—faced with the unmistakable signs of aging, most of us have had a least one fantasy of turning back time. Now, as Dr. Izpisúa says, the study shows that "aging may not have to proceed in one single direction, it has plasticity and, with careful modulation, aging might be reversed". This approach, which not only prompted human skin cells in a dish to look and behave young again, also resulted in the rejuvenation of mice with a premature aging disease, countering signs of aging and increasing the animals’ lifespan by 30 percent. The early-stage work provides insight both into the cellular drivers of aging and possible therapeutic approaches for improving human health and longevity.

As people in modern societies live longer, their risk of developing age-related diseases goes up. In fact, data shows that the biggest risk factor for heart disease, cancer and neurodegenerative disorders is simply age. Dr. Campistol says that "the study provides information on possible therapeutic options previously unsuspected to increase longevity." However, he says, "more studies will be needed to use this technique in humans."

While cellular rejuvenation certainly sounds desirable, a process that works for laboratory cells is not necessarily a good idea for an entire organism. For one thing, although rapid cell division is critical in growing embryos, in adults such growth is one of the hallmarks of cancer. For another, having large numbers of cells revert back to embryonic status in an adult could result in organ failure, ultimately leading to death. For these reasons, the Salk team wondered whether they could avoid cancer and improve aging characteristics by inducing the Yamanaka factors for a short period of time.

“In other studies scientists have completely reprogrammed cells all the way back to a stem-cell-like state,” says co-first author Pradeep Reddy, also a Salk research associate. “But we show, for the first time, that by expressing these factors for a short duration you can maintain the cell’s identity while reversing age-associated hallmarks.”

To find out, the team turned to a rare genetic disease called progeria. Both mice and humans with progeria show many signs of aging including DNA damage, organ dysfunction and dramatically shortened lifespan. Using skin cells from mice with progeria, the team induced the Yamanaka factors for a short duration. When they examined the 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. The results were striking: Compared to untreated mice, the reprogrammed mice looked younger; their cardiovascular and other organ function improved and—most surprising of all—they lived 30 percent longer, yet did not develop cancer. On a cellular level, the animals showed the recovery of molecular aging hallmarks that are affected not only in progeria, but also in normal aging.

“This work shows that epigenetic changes are at least partially driving aging,” says co-first author Paloma Martinez-Redondo, another Salk research associate. “It gives us exciting insights into which pathways could be targeted to delay cellular aging.”

“Obviously, mice are not humans and we know it will be much more complex to rejuvenate a person,” says Dr. Izpisúa, “but this study shows that aging is a very dynamic and plastic process, and therefore will be more amenable to therapeutic interventions than what we previously thought.”

Source: Salk Institute for Biological Studies

Article Reference

In vivo amelioration of age-associated hallmarks by partial reprogramming

Alejandro Ocampo, Pradeep Reddy, Paloma Martinez-Redondo, Aida Platero-Luengo, Fumiyuki Hatanaka, Tomoaki Hishida, Mo Li, David Lam, Masakazu Kurita, Ergin Beyret, Toshikazu Araoka, Eric Vazquez-Ferrer, David Donoso, Jose Luis Roman, Jinna Xu, Concepcion Rodriguez, Gabriel Núñez, Estrella Núñez-Delicado, Josep M. Campistol, Isabel Guillén, Pedro Guillén i Juan Carlos Izpisua Belmonte.

Cell. DOI: http://dx.doi.org/10.1016/j.cell.2016.11.052

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