Aging is one of the most complex biological processes and the prime driver for many human diseases. For a long time, it was considered to be a unidirectional process. However, in the year 2006, Nobel Prize winning scientist Yamanaka proved that mature differentiated cells of the body, such as skin cells, can be converted to undifferentiated embryonic-like cells by the process of cellular reprogramming. This can be achieved by the expression of Yamanaka factors, which include four genes namely Oct4, Sox2, Klf4 and c-Myc (OSKM). These factors result in epigenetic changes in the cells, i.e. heritable changes in the cellular gene expression without any change in the DNA sequence. The reprogrammed cells are termed as induced pluripotent stem cell (iPSCs). iPSCs have unlimited self-renewal ability and under suitable conditions, they can give rise to all the differentiated cell types found in the body.
Interestingly, the process of cellular reprogramming has been shown to improve various age-related phenotypes in cells under in vitro or laboratory culture conditions. However, an important question that remains to be answered is whether we can use the reprogramming method to slow or reverse the process of aging without converting the cells to iPSCs. Also, one of the major concerns is that when the process of cellular reprogramming is performed in vivo i.e. at the organismal level, it results in tumor development and high mortality rates. Addressing these issues, scientists (Ocampo et al.), at the Salk Institute for Biological Sciences, recently published their findings in the journal Cell, where they developed an in vivo partial reprogramming method that can reverse the signs of aging without the risk of tumor formation.
The researchers initially tested their method under in vitro conditions. For this purpose, they used skin cells isolated from the mouse model of premature aging and induced short-term expression of Yamanaka factors for 2-4 days. It is important to note that for the complete reprogramming of mature cells to generate iPSCs, these factors are typically expressed for 2-3 weeks. Partial reprogramming, induced by short-term expression of Yamanaka factors, did not alter the identity of skin cells. However, researchers made the interesting observation that this method reduced the generation of double-strand breaks in DNA and production of reactive oxygen species and also lowered the expression of various genes involved in ageing-associated pathways. Further experiments revealed that epigenetic remodeling of the cells, during the process of partial reprogramming, is the main driver for improving these hallmarks of aging.
When applied in the aging mouse model, in vivo partial reprogramming resulted in an increase in the average lifespan of animals from 18 weeks to 24 weeks. These mice rescued the development of cardiovascular alterations and showed normal proliferation rates in multiple organs. The researchers also tested the applicability of this method in physiologically aged mice. Partial induction of OSKM in 12-month-old mice resulted in better pancreatic function and enhanced muscle regeneration.
In vivo partial reprogramming might not be possible in humans because of the requirement of genetic engineering technique for the expression of Yamanaka factors. However, researchers showed that partial reprogramming of aged human cells under in vitro conditions resulted in improvement in a few of the hallmarks associated with aging. Although further experiments are necessary for its validation, if successful, this technique will provide a unique platform to tackle age-related disorders, such as Alzheimer’s and diabetes, in humans. Epigenetic-modifying drugs, that can mimic the process of partial reprogramming, can be developed to ameliorate various effects of aging.
In conclusion, while the results from this study are very encouraging, it is important to keep in mind that we have not discovered the Philosopher’s stone and it might not be possible to stop the process of aging completely. However, in the future, various strategies can be developed to control age-associated diseases, resulting in healthier living and increased longevity. Until then, we can be hopeful to turn back the hands of time at least at the cellular level!
Journal reference:
Ocampo A, Reddy P, Martinez-Redondo P, Platero-Luengo A, Hatanaka F, Hishida T, Li M, Lam D, Kurita M, Beyret E, Araoka T, Vazquez-Ferrer E, Donoso D, Roman JL, Xu J, Rodriguez Esteban C, Nuñez G, Nuñez Delicado E, Campistol JM, Guillen I, Guillen P and Izpisua Belmonte JC. In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming. Cell. 2016 Dec 15; 167(7):1719-1733.e12. doi: 10.1016/j.cell.2016.11.052.
Other references:
http://www.cell.com/cell/fulltext/S0092-8674(16)31662-2
http://www.sciencedirect.com/science/article/pii/S1471491416300533
https://www.sciencedaily.com/releases/2016/12/161215143541.htm
http://www.salk.edu/news-release/turning-back-time-salk-scientists-reverse-signs-aging/
https://www.sciencenews.org/article/proteins-reprogram-cells-can-turn-back-mices-aging-clock
About the authors:
Isha Verma is currently pursuing her PhD in Stem cell research from the Indian Institute of Science, Bangalore. She loves reading and traveling.
Radhika Raheja completed her PhD from Cornell University and is currently a Postdoctoral fellow at the Brigham and Women’s Hospital. Her research interests have centered around oncology and neuroimmunology. Among other things, she is striving to effectively communicate scientific discoveries to the community.
About the illustrator:
Ipsa Jain is a Ph.D. student at IISc. She wants to gather and spread interestingness. She prefers painting and drawing over writing.
