Epigenetic Reprogramming of Aging
Aging is the main risk for pathologies like arthritis, hypertension, and diabetes. Classical medicine treats the symptoms of age related degeneration. Germ cell biology can be used to combat aging.
It is Dr. Sebastiano’s belief that epigenetics are the fundamental root of aging. Methylation changes, chromatin organization, and histone modifications and positioning are some of the possible epigenetic modifications. By controlling epigenetics we can target multiple pathologies at once. Germ cells undergo massive epigenetic remodeling after fertilization and during germline differentiation.
Cloning and induced pluripotent stem cell methodologies support the idea that epigenetic renewal can lead to complete rejuvenation of a cell. iPSC cells often utilize full de-differentiation to revert the cell back to an embryonic state. However, it’s possible to use the yamanaka factors in short bursts to only partially revert a cells epigenetic state. Plasmids and viral vectors cannot carry out this task – but mRNA can. It’s safer and the duration of expression can be tuned, unlike plasmid or viral expression.
Partial reprogramming appears to affect every hallmark of aging with the exception of telomeres. It has been demonstrated to work in a variety of naturally aged human cells. The current method uses 4 days of reprogramming to reverse aging, measured via a litany of biomarker data. In cooperation with Steve Horvath, methylation patterns were also measured and determined to reverse in age.
This principle can be applied to stem cells, such as muscle stem cells, to create long term regenerative effects. Marco Quarta and Tom Rando collaborated in an experiment to partially deprogram mouse muscle stem cells. Muscle growth was increased while no tumor formation was observed. The same experiment was done on human muscle stem cells and similar outcomes were observed.
In vivo delivery. If we effectively deliver to specific cell types, it will be a dramatic shift in the way we think about regenerative medicine. RNA technology, broadly speaking, will be a game changer. For us and for other fields – it was dramatic what it could do in the context of vaccines and the same will be true for us.