Doctors May Soon be able to Turn Back Time

Scientists from Children’s Medical Center Research Institute at UT Southwestern (CRI) have made ground-breaking discoveries that could help to reverse the ageing process.

Methods to reverse the aging process are widely sought after, not just to satisfy the desires of our image-conscious society, but primarily to address the variety of chronic and degenerative diseases which afflict the elderly and are a major cause of deaths. As we grow older, there is a gradual deterioration in our physiological functions which increases the risk of contracting age-related diseases such as cancer, diabetes and cardiovascular and neurodegenerative disorders. In an attempt to reverse this process, scientists are trying to isolate the genetic factors which influence aging, and there have been some major scientific breakthroughs in this area of late.

Earlier this year, important results were released by Prof. Fritz Müller, Dr. Chantal Wicky and their research team, who had determined the importance of the gene let-418/Mi2 in ageing, stress resistance, and development and reproduction. It was discovered that as soon as the gene’s role in growth, development and reproduction is over, its effects become potentially damaging and can lead to the onset of degenerative diseases. The gene was identified in a species of the Caenorhabditis elegans worm, and scientists discovered that when the gene was deactivated in adult worms under laboratory conditions, it extended their lives and their ability to cope with stress.

The team collaborated with Prof. Simon Sprecher’s team at the University of Fribourg, who have been investigating how the same gene functions in flies and plants, and were able to confirm that it has a similar effect in these species so it is hoped that its mechanism of action is the same in humans. If so, and if the gene could be deactivated after it has served its purpose for reproduction, there could be the potential for a major increase in human life expectancy.

The most recent advances have been made by a team led by Dr. Sean Morrison, Director of CRI and Professor of Pediatrics at UT Southwestern Medical Center, who have identified an RNA-binding protein called IMP1 that promotes stem cell self-renewal during fetal development. Self-renewal is the process by which stem cells divide to make more stem cells, which is important for the growth of tissues during fetal development and the regeneration of tissues throughout adult life.

At the same time, researchers including Dr. Hao Zhu, who also directs a lab at CRI and is Assistant Professor of Pediatrics and Internal Medicine at UT Southwestern, have shown that another RNA-binding protein, Lin28a, also promotes tissue repair by reactivating a metabolic state reminiscent of the juvenile developmental stage.

Dr. Zhu’s research, published in Cell, showed that reactivation of Lin28a — a gene that is normally turned on in fetal but not adult tissues — substantially improved hair re-growth and accelerated tissue repair after ear and digit injuries.

“Our work found that Lin28a promotes regeneration through a metabolic mechanism,” said Dr. Zhu. “This finding opens up an exciting possibility that metabolism could be modulated to improve tissue repair, whereby metabolic drugs could be employed to promote regeneration.”

Dr. Morrison’s investigation, published in the online journal Life, identified a set of genes including IMP1 that are turned on only within time-limited windows, and control developmental switches in stem cell properties between fetal development and adulthood. IMP1 is turned off during late fetal development, partly as a consequence of increasing expression of a third family of RNA-binding molecules called let-7 microRNAs. Importantly, let-7 microRNAs are turned on during late fetal development in part due to declining expression of Lin28a.

Drs. Morrison and Zhu’s laboratories both studied molecules at different ends of the same pathway — one that regulates stem cell self-renewal and tissue regeneration by modulating the expression of a network of RNA-binding proteins.

“These results are interesting because let-7-regulated networks were first discovered based on their ability to regulate the timing of developmental transitions in worms,” said Dr. Morrison. “This earlier finding suggests that the mechanisms employed by mammalian tissue stem cells to regulate changes in their properties over time are at least partly conserved and depend upon mechanisms inherited from invertebrates.”

A previous study from the Morrison laboratory found that expression of let-7 increases throughout adulthood, reducing the activity of stem cells in older animals. The current findings show that IMP1 inhibits the expression of genes that trigger stem cells to commit to specific fates, while promoting the expression of genes related to self-renewal. Further studies are likely to identify many more genetic targets that enable stem cells to adapt their properties to the changing growth and regeneration demands of tissues over an organism’s life span.

Together, these studies demonstrate that a network of RNA-binding proteins that are turned on specifically during fetal development promote stem cell function and tissue growth by regulating cellular proliferation and metabolism. The loss of Lin28a and IMP1 expression from adult tissues partly explains why adult tissues no longer grow and have less stem cell function than fetal tissues. Thus, by modulating the function of these pathways in adult stem cells, it may be possible to enhance tissue regeneration.

This area of research has been identified as such a key priority in health care that a conference dedicated solely to anti-aging research is being held in the US in December of this year. The A4M’s World Congress on Anti-Aging Medicine is being held on 12-15 December 2013 at The Venetian Resort & Exposition Center (Las Vegas, NV USA), and will be attended by the world’s leading medical professionals and researchers to discuss the latest advances in anti-aging and regenerative biomedical technologies. Government officials and politicians will also be present, with representatives from 65 different countries.

Governor Arnold Schwarzenegger has been selected to receive a special award, The Infinity Award, to recognise his involvement in the procurement of $3billion funding for stem cell research, and for his many other philanthropic endeavours including the foundation of the non-profit organization R20: Regions of Climate Action and the USC Schwarzenegger Institute for State and Global Policy. Other ‘celebrity’ attendees will include ER physician and host of the Emmy award-winning talk show, “The Doctors,” Travis Stork, MD, Gynecologist Judith Reichman, MD , host of tv series "Straight Talk on Menopause, and Suzanne Somers, who discuss natural bio-identical hormone replacement therapy (BHRT).

Eminent physicians will be presenting at the event on the following topics:
• Massimo Dominici, MD, Professor in Oncology & Hematology at the University of Modena (Italy), will review “Stem Cells: Understanding Aging as a Platform to Enhance Tissue Regeneration”

• Christoph Westphal, MD, PhD, Board of Fellows for Harvard Medical School, will share “Pharmaceutical Approaches to Treating Aging: The Sirtris Story”
• Michael Murphy, PhD, Group leader at the MRC Dunn Human Nutrition Unit (United Kingdom), will present “The Development of Mitochondria-Targeted Therapies for Age-Associated Diseases”

• Abraham Morgentaler, MD, FACS, Clinical Professor at Harvard Medical School, will present the latest evidence for “Testosterone Therapy in Men.”

Our potential to live longer is increasing by the day: the U.S. Census Bureau predict that life expectancy in the United States will be in the mid-80s by 2050. The oldest living person ever recorded was French woman, Jeanne Calment, who died aged 122 years and 164 days in 1997, though there are claims that from an Ethiopian man, Dhaqabo Ebba, that he is an incredible 160 years of age! It has not been possible to confirm Ebba’s age due to the lack of recorded evidence, but humans are definitely living longer and that has to be good news. All we need to do now is to try and ensure that we have a planet left on which to live.

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