A new pharmacological therapy achieves reprogramming aging in mice and human cells
July 27, 2015
Researchers have optimized cell reprogramming strategies to achieve rejuvenation of cells with normal and pathological aging
Oviedo, July 27, 2015. A team of researchers of the University of Oviedo led by Professor of Molecular Biology Carlos López-Otín, in collaboration with the Josep Carreras Institute and the Universities of Barcelona and Harvard, have identified a new mechanism altered during the aging process. This discovery, published today in Nature Cell Biology, has allowed them to develop a new treatment that doubles the lifespan of mice suffering from accelerated aging. Moreover, this paper has been chosen to be the front cover of this prestigious journal in August.
The group of researchers focused on the study of the cell reprogramming process which allows experts to convert adult cells into induced stem cells (iPS), capable of generating any cell type in the organism. The reprogramming process implies cell rejuvenation and requires the elimination of molecular and cellular alterations associated with aging.
However, reprogramming cells from patients with accelerated aging or very old individuals is inefficient due to the multiple alterations accumulated in their cells. Therefore, the initial objective of this work was aimed at identifying the alterations present in cells from patients with Néstor-Guillermo or Hutchinson-Gilford progeria syndrome, who gather many of the mutations associated with normal aging. "The study of these pathologies is of great biological interest due to the keys it may provide concerning normal aging and the possibility to test therapeutic approaches aimed at alleviating or delaying its effects", Carlos López-Otín points out.
This work, published today in Nature Cell Biology, proves the relevance of mechanisms involved in cell plasticity to find new strategies to fight aging
Researchers found that the cells from those patients or elderly individuals presented hyperactivation of cellular inflammatory processes. Surprisingly, "treatment with anti-inflammatory drugs increased the efficiency of cellular reprogramming up to levels comparable to cells from younger individuals", explains José María Pérez Freije, co-director of this work. "It is the first time we can relate hyperactivation of inflammation biochemical processes with cellular reprogramming routes", explains Fernando G. Osorio.
In order to translate results into potential clinical applications, researchers identified a key component, essential in inflammatory response involved in this process that is the protein DOT1L. This protein has the ability to regulate numerous genes involved in the cellular reprogramming process and blocks the generation of stem cells iPSCs. After treating human and mice with accelerated aging, with DOT1L inhibitors, researchers observe a remarkable improvement of all the symptoms associated with aging, and actually increased life expectancy of these mice in more than 65%. These results "far exceed those obtained in previously developed therapeutic strategies for the treatment of accelerated aging syndromes without showing apparent side effects", says Clara Soria-Valles, main author of the work.
This Discovery has its roots in previous works of this research group published in Nature, Nature Medicine, Cell and Science Translational Medicine, in which they described various mechanisms involved in accelerated aging and the development of the first therapies for these treatments. Some of these therapies are currently in clinical trials for the treatment of patients with accelerated aging. Since DOT1L inhibitors are being used for the treatment of some types of leukemia, "they might be tested in patients with progeria in the near future, either alone or combined with other therapeutic agents", says José María P. Freije. This work "shows the usefulness of the study of the mechanisms involved in cellular plasticity loss that results from aging, to identify new therapeutic targets that allow intervention in this natural process", concluded López-Otín.
The researchers involved in this project are: Clara Soria-Valles, Fernando G. Osorio, Ana Gutiérrez-Fernández, Alejandro De Los Ángeles, Clara Bueno, Pablo Menéndez, José I. Martín-Subero, George Q. Daley, José María P. Freije and Carlos López-Otín.