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This episode of Longevity by Design discusses groundbreaking research on the use of gene therapies to target common diseases of aging. Dr. Noah Davidsohn leverages genes associated with aging as targets for de-aging cells and reducing the burden of age-related diseases. The research appears promising—Dr. Davidsohn is confident that these findings will eventually improve human lifespan and healthspan. Tune in for conversations that dissect the latest research in the field of longevity.
About Dr. Noah Davidsohn
Dr. Noah Davidsohn is Co-Founder & Chief Scientific Officer at Rejuvenate Bio, a gene therapy company pioneering novel therapies for chronic age-related diseases. He is an expert in translating age-reversal research and technologies that utilize recombinant DNA, genetic therapies, viral vector production, and advanced models of disease and aging. Dr. Davidsohn received his PhD in Biological Engineering at MIT and joined Dr. George Church's lab as a postdoctoral fellow where he focused on breakthrough genetic therapies for age-related diseases. He has over ten years of experience designing and conducting laboratory studies with numerous publications.
What is epigenetics?
Dr. Davidsohn begins the episode by describing epigenetics. “Epigenetics is the layer that controls what parts of your DNA are turned on or off. For example, DNA is in your neurons, skin cells, and liver. Different parts of that genetic program are turned on in those different cell types. Epigenetics controls which genes are on and off.”
Can you reverse epigenetics?
A person’s genetic code generally doesn't change with age, while epigenetic changes are reversible without changing your DNA. Chemical markers can turn on or off on the histones (which control DNA) or DNA methylation itself, which can alter how the DNA is expressed.
Epigenetics controls how we grow and develop from infancy to adulthood by turning on various genetic programs. So, intervening at the epigenetic level can change a process that naturally evolves as we age.
How do Yamanaka factors reverse epigenetic aging?
Dr. Davidsohn walks the audience through recent publications that investigate Yamanaka factors and the aging reversal of cells. First, he defines Yamanaka factors. Yamanaka factors are a minimum set of four genes that are able to take a differentiated adult cell and turn it into a pluripotent stem cell (a cell that continues to renew and divide).
Although convoluted, Dr. Davidsohn describes how Yamanaka factors reflect the aging process. “There are a lot of convolutions between aging and stem cell likeness. So, if you turn an adult cell into a stem cell, new tools that measure age show that being a stem cell is basically like being zero years old. So, a key goal right now is to learn how to deconvolute cell identity from a cell's age.”
Epigenetic reprogramming in the research
Epigenetics and vision
Dr. Noah Davidsohn describes his supporting role in a 2020 publication that used genetic reprogramming to restore vision.  "At the time, I was already working with AAV gene therapies and helped them develop the OSK gene therapy. We wanted to reverse damage from the optic nerve. We were able to show that if you make the cells younger, they can heal from that optic nerve damage and still continue to function. The gene therapy temporarily turns on O, S, and K, three Yamanaka factors that de-age cells. Yamanaka factors act as this control system that allows us to turn on OSK temporarily, obviating that safety factor for only a temporary period of time. So, you can benefit from de-aging the cell without losing the cell's identity. And so, you keep a neuron, a neuron, but it's a younger neuron now."
Epigenetics and life extension
In January 2023, Dr. David Sinclair and a team of experts published a landmark paper about the relationship between epigenetic information and the aging process in wild-type mice.  “The key thing here is that nobody had previously shown that normal, old wild-type mice could be rejuvenated, de-aged, and age reversed using these factors. For example, we were able to reverse damage in a damaged optic nerve model. The important thing that we were able to show is that normal, healthy, old mice can have increased lifespan and healthspan using this therapy.”
Dr. Davidsohn quantifies this age reversal's impact on lifespan in wild-type mice: "In fact, the remaining lifespan doubled. So, if you theoretically were going to live ten additional years, you'd instead live another 20 years. Here, we're able to give a therapeutic treatment at the end of your life and extend those disease-free, healthy years."
Yamanaka factors in future research
Yamanaka factors’ promising effect on aging begs the question, ‘How can we optimize Yamanaka factors in research to reap aging benefits?’
- Should Yamanaka factors be kept on longer? “The way we induce the Yamanaka factors is we turn them on for a week, and then we've had them off for a week and cycled for the rest of their life.” Yamanaka factors cannot be kept on for too long because they become stem cells that may turn into cancer cells.
- Can Yamanaka factors be turned on earlier in the aging process? “Data in the aging field suggests that the earlier you intervene, the bigger the effect you have at the end of life. However, in practice, this becomes a much longer experiment.” Dr. Davidsohn wanted this proof of concept study to be as short as possible and as applicable as possible in an effort to target the most vulnerable populations to quantify their potential therapeutic benefit efficiently. “The older population are the people who have the most age-related diseases. Applying therapies to our eldest, most sick population is the best possible scenario.”
- Get Yamanka factors into more cells, and turn them on in more cells. Dr. Noah Davidsohn believes that the two ways to get an increased benefit from Yamanaka cells are to get them into more cells and make sure that they’re turned on in all cells.
Does epigenetic modification apply to human health?
The impact of epigenetic reprogramming at the cellular level and in animal models is encouraging. But is gene therapy ready to be researched and applied to humans?
"In the next three to five years we'll translate epigenetic modification therapy to human studies for specific age-related diseases. The goal is to be disease free, not necessarily to live forever. If we can get rid of all age-related diseases, people may consequently live a lot longer, but to me, the disease-free years are the important part."
Gene therapy targets for age-related diseases
Dr. Davidsohn continues the conversation on using gene therapy to target age-related disorders. Certain disorders are monogenic, meaning a single gene defines the attribute. But age-related diseases are often polygenic—meaning a complex set of genes leads to the expression of a trait. "The diseases of aging have more far-reaching effects than one particular gene. Most age-related problems do not have a defined ideology of what genes are causing the problem. It's usually a myriad of genes or damage to the cells, for example."
"Dysregulated gene expression over time is thought to be the core driver of age-related diseases, and in our work, we're trying to reregulate these two genes back to an earlier state. The paradigm here is that we're reregulating gene expression starting with two proteins that can have wide-ranging effects across numerous age-related diseases. In the next generation of Yamanaka factor-based therapeutics for epigenetic modification, we'll actually modify thousands of genes at the same time."
Dr. Davidsohn’s previous research showed that these two genes can treat heart failure, kidney failure, diabetes, and obesity. “If you target genes from an aging perspective, you're holistically treating a number of different things.”
Is aging a disease?
One question that is up for debate among many scientists in the field of aging is, ‘Is aging a disease?’ Longevity experts like Dr. David Sinclair have weighed in. In Dr. Davidsohn’s opinion, “to classify aging as a disease, we need to define really good biomarkers of aging.” And from Dr. Davidsohn’s perspective, targeting age-related diseases can have downstream effects on how we age. “I’m coming at aging from a disease perspective: how can we get rid of a lot of different diseases in a lot of different people? For example, heart disease, obesity, and diabetes impact many Americans, so targeting these diseases can help reduce their burden on the population.”
Top tip for healthspan
When asked about his top tip for improving healthspan, Dr. Davidsohn notes, “The best thing to do is to exercise and eat right to reduce the risk of developing age-related diseases. That way, people are alive long enough to benefit from promising age-reversal therapeutics.”
 https://pubmed.ncbi.nlm.nih.gov/33268865/ https://www.cell.com/cell/fulltext/S0092-8674(22)01570-7