Resetting cells to a youthful regenerative state

Exciting work out of the Sinclair lab shows that winding back the hands of the epigenetic clock with Yamanaka factors resets the genome for cell regeneration – even restoring vision.

A recently-published paper in Nature has caused rather a stir; Lu, Sinclair et al. have shown that neurons in the eye can be reset to a youthful state in which their ability to regenerate is switched back on. As well as signposting a powerful potential therapeutic target for age-related neuronal diseases, the research is another step to unlocking the secrets of the mechanisms of aging.

Longevity.Technology: Age is one of the major risk factors for glaucoma, the most common cause of human blindness, as well as a risk factor for the progression of the disease. As well as having an impact on healthspan and quality of life, blindness hugely impacts on independent living ability.

Lead author Yuancheng Lu, PhD, a research fellow in genetics at Harvard Medical School and a former doctoral student in Sinclair’s lab summed up the research when he said it “could potentially revolutionize the treatment of the eye and many other organs affected by aging [1].”

Discovery of four transcription factors that can remove epigenetic markers on cells, reverting them back to their original pluripotent embryonic state, won their finder Shinya Yamanaka the Nobel Prize for Medicine 2012. However, using the powerful Yamanaka Factors is risky as they can trigger tumours and rewind cell states so far their identities are wiped.

Regeneration of a mouse optic nerve cell following treatment. Source: Sinclair Lab, Harvard Medical School

To avoid this, the research team left gene c-Myc out of the line-up, using the other Yamanaka genes, Oct4, Sox2, and Klf4. These were delivered into the retinal ganglion cells (RGCs) of adult mice with an optic nerve injury using an adeno-associated virus (AAV).

The researchers saw a significant reversal of the age-related vision deficits that the mice had. As well as reversing the glaucoma-like condition, the delivered factors stimulated the regrowth of optic nerve fibre. In short, the previously-lost vision was restored in mice with and without the glaucoma-like condition, with the number of RGCs surviving post-injury doubled, and a five-fold increase in nerve regrowth demonstrated.

“Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function,” said senior author David Sinclair, PhD, professor of genetics in the Blavatnik Institute at Harvard Medical School, co-director of the Paul F Glenn Center for Biology of Aging Research at HMS, and David Sinclair, PhD, and Co-Founder & Chairman of the Board at Life Biosciences [2].

“Our study demonstrates that it’s possible to safely reverse the age of complex tissues such as the retina and restore its youthful biological function.”

The team theorised that as methylation adds extra methyl groups onto DNA over time, the genetic instructions become degraded, with genes that should be switched on actually switched off and vice versa. Predictable DNA methylation changes are used in aging clocks to work out biological age, and the team thought that by using the Yamanaka factors to erase some of these methylation footprints, the biological age of the cells could be rewound – something that has been done in cells and tissue in the lab, but not in living organisms before.

Sinclair, Lu and the team are aware that findings need to be repeated in a range of different animal models, before human experiments can be considered. However. they are confident that the “results offer a proof of concept and a pathway to designing treatments for a range of age-related human disease [2].”

“If affirmed through further studies, these findings could be transformative for the care of age-related vision diseases like glaucoma and to the fields of biology and medical therapeutics for disease at large,” commented Sinclair [3].


Images courtesy of : Sinclair Lab, Harvard Medical School