In vivo amelioration of age-associated hallmarks by partial reprogramming

Developers

Alejandro Ocampo, Pradeep Reddy, Pedro Guillen, Juan Carlos Izpisua Belmonte, etc

Description of the technology

Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo.

In process of the technology development, the experiments in mouse model in vivo were carried out, which showed that partial reprogramming could slow or reverse the aging process and extend organismal lifespan. The partial reprogramming by short-term cyclic expression of Yamanaka factors − Oct4, Sox2, Klf4, and c-Myc (OSKM) genes − ameliorated cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature ageing. Similarly, expression of OSKM in vivo improved recovery from metabolic disease and muscle injury in older wild-type mice. Partial reprogramming erased cellular markers of aging in mouse and human cells (culture of human inducible pluripotent stem cells were used). In vivo reprogramming improves regeneration in 12-monthold wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.

Practical application

The technology is highly valuable for both future experimental investigations of ageing and medical practice, because it was the first attempt of ageing process reversal in vivo by cell reprogramming.

The developed approaches and in vivo platform for the reprogramming of epigenetic marks may be used to better understand physiological ageing, as well as the role of epigenetics during mammalian aging.

The results of the study can allow to develop future effective therapies for ageing diseases (e.g. progeria, degenerative diseases, etc) and the methods of lifespan extending.

Laboratories

• Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla (USA)
• Universidad Cato´ lica San Antonio de Murcia (UCAM) Campus de los Jero´ nimos, 30107 Guadalupe, Murcia (Spain)
• Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor (USA)
• Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona (Spain)

Links

Publications

• Ocampo, A. et al. «In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming." 176.7 Cell (2016): 1719–1733.
• Zhang, W. et al. «Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging." 348 Science(2015): 1160–1163.
• Ruiz, S. et al. «Generation of a drug-inducible reporter system to study cell reprogramming in human cells." 287 J. Biol. Chem. (2012): 40767–40778.