Turning Back Time
Wish you could still be YOU…only younger? Learn how science is turning back time
Part 3 of a series on the mission to defy aging
There it was…in large, bold letters…Turn Back Time.
Right there…on the home page of Turn Biotechnologies’s website.
Almost immediately, I thought of Cher…circa 1989…and started singing “If I Could Turn Back Time.”
Methuselah Foundation — the founding investor — had just introduced me to Turn Bio.
My curiosity was piqued.
And it wasn’t long before I discovered that Turn Bio’s approach to reversing aging has more facets than… dare I say it?…Cher has talents.
But, before we talk about reversing aging, let’s talk about aging, itself.
Aging is a multi-dimensional process
Currently, there are nine well-accepted hallmarks of aging. They are:
While other start-up companies may be trying to tackle aging by focusing on a single hallmark, Turn Bio is focusing on all except telomere attrition — with good reason.
But Turn Bio’s approach is founded on technology developed at Stanford University. And Stanford University scientists are at the heart of Turn Bio’s research and development…and on their scientific advisory board.
As for results? Well, they have already demonstrated youthful reversion for all eight hallmarks. And, thus far, their technology has proved to rejuvenate five different tissue types. Current targets are osteoarthritis, skin damage, and sarcopenia/dystrophy.
Turning back time the Turn Bio way
Turn Bio’s platform technology was developed by Vittorio Sebastiano (co-founder; chairman of scientific advisory board) and Jay Sarkar (co-founder; chief technology officer (CTO)). Sebastiano is an assistant professor at Stanford. He has a background in developmental biology, stem cell biology, nuclear reprogramming, and regenerative medicine. Sarkar is a recent graduate student of his, and has a background in mathematics, applied physics, and electrical engineering. Their work was supported by the National Institutes of Health, the Department of Veterans Affairs, and CalPoly. And patent protection is being pursued (see, e.g., Int’l Pat. App. Pub. No. WO 2019/178296).
So…I asked Sebastiano and Sarkar a few Q’s to gain a basic understanding of their platform technology — “reversing cell aging by transient reprogramming.” Starting with…
♦What is a “reprogramming factor”?
“A reprogramming factor is a protein that promotes the conversion of one cell type into another cell type,” answered Sebastiano. “In other words, these are single factors — or sets of different factors — that can profoundly reorganize the epigenetic information [see text box] of the cells and convert it into a different kind of information. Although this applies to any type of conversion, reprogramming is often used in the context of embryonic reprogramming.”
♦How are reprogramming factors introduced into cells?
By non-integrating messenger RNA (mRNAs). As Sebastiano explains, “mRNAs are copies of the information that is encoded in the DNA that is needed to make proteins. mRNAs, by their nature and chemical properties, cannot integrate into the DNA. So, they cannot alter the sequence of the DNA in the cells. They provide a very safe and effective way to promote the expression of a gene, or set of genes, in cells. Another advantage for our application is that the mRNAs have a half-life of about 16–24 hrs. What this means is, unless you continue to provide mRNAs to the cells, eventually the mRNAs that you introduced are depleted — and the proteins that they encoded are no longer expressed.”
♦Why only transiently express the mRNAs?
Transient expression is key. “If expressed for too long,” says Sebastiano, “the reprogramming factors can erase completely not only the age of the cells but also the identity of the cells.”
The erasure of cell identity is undesirable and problematic for the development of rejuvenation therapies. The goal is to rejuvenate without destroying the structure, function and cell type distribution in tissues and organs. And that’s what Turn Bio’s platform technology does — it rejuvenates cells while avoiding dedifferentiation and loss of cell identity.
Tackling eight of the nine hallmarks of aging
After covering the basics of the platform technology with Sebastiano and Sarkar, I followed up with another co-founder — Marco Quarta, who further developed Turn Bio’s platform for the applications in regenerative medicine. As Turn Bio’s chief scientific officer (CSO), Quarta has over 15 years of research experience — in aging, stem cell biology, regenerative medicine, and bioengineering. He is also the founder and director of multiple academic labs — including labs at Stanford — and a founder of several biotech companies.
I asked Quarta about the impact of the technology on the hallmarks of aging. Starting with…
♦How does the transient expression of non-integrating mRNAs encoding reprogramming factors tackle the nine hallmarks of aging?
“The nine hallmarks of aging all depend on cellular functions that are regulated by the epigenome,” Quarta says.
Okay, time to hit the “pause” button and talk about the “epigenome.”
The epigenome is more than DNA and “stuff” — like methyl groups — that are on it. It also includes proteins that help keep things tidy.
To put things into perspective, consider the fact that the genome is around 6.4 billion base pairs (A+T’s and G+C’s). Geneticsalive.com reports that the entire human genome is about 6.5 feet long (check out geneticsalive.com/howbig.html for a fun, interactive illustration).
The proteins, which help keep things tidy — the “histones” — are like spools, around which the DNA gets wrapped like thread
And, just like the “stuff” that gets added on to the DNA, histones also impact gene expression. Genes that are wrapped around histones are inaccessible — they can’t be expressed. Genes that are not wrapped around histones — the loose “thread” between “spools” — are accessible and can be expressed.
Now, back to Quarta…
“When the epigenome is fine-tuned, all cellular functions work in concert. With aging, the epigenome gets loose and cellular functions slowly deteriorate. Eventually, they become dysfunctional and aged cells stop working. Transient expression of non-integrated mRNAs encoding reprogramming factors (also called Epigenetic Reprogramming of Aging or ERA) acts on the epigenome by fine-tuning it again — restoring cellular functions back to more youthful states,” he says.
♦What is stem cell exhaustion, and how does ERA reverse it?
“Stem cells have the capacity to regenerate themselves and tissue. The process is called ‘self-renewal’. As stem cells age, they lose their self-renewal function. Eventually, the pool of available stems cells is depleted, along with the capacity to regenerate tissue. The process is called ‘stem cell exhaustion’,” explains Quarta.
Turn Bio treated aged stem cells and transplanted them into the muscles of healthy and diseased (dystrophic/sarcopenic) hosts. They demonstrated restored self-renewal and tissue regeneration, not to mention striking increases in muscle function.
“ERA allows stem cells to repair their self-renewal function. The stem cells make more copies of themselves, which, in turn, repair and regenerate more effectively aged tissue,” he says.
♦And how does ERA impact intercellular communication?
“With aging, communication between cells becomes ‘noisy,’ and so, too, the functions that the cells are trying to regulate. By fine-tuning the epigenome, ERA enables cells to re-establish clear communication, thereby restoring proper cellular function,” explains Quarta. Indeed, Turn Bio has shown a reduction in pro-inflammatory signaling in normally aged cells and diseased cells in the context of osteoarthritis.
♦And what about nutrient sensing?
“Similar to intercellular communication, the ability of cells to sense substrates becomes noisy with age. Cells end up producing too much or not enough nutrients and become sick. ERA reduces the noise, resets the baseline, and restores balance between substrates and nutrient production,” Quarta explains. Turn Bio has demonstrated the effectiveness of ERA in counteracting extracellular matrix metabolism in osteoarthritis.
♦And mitochondrial dysfunction?
“Mitochondria produce energy for cell functions. They also produce damaging free radicals. When mitochondria are functioning properly, there is enough energy being produced for cells to carry out all their functions. Free radicals are effectively managed. When cells age, mitochondria become progressively less efficient at producing energy, and free radicals accumulate. The accumulation of free radicals causes even more damage. ERA restores younger, healthier, more energetic mitochondria, while clearing out those that are damaged/degraded,” says Quarta.
We’re talking about zombie cells — like we did in Part 1 of this series on the mission to defy aging, when we talked to Matthew Scholz of Oisín Biotechnologies. While Oisín’s approach is to use targeted DNA to kill senescent cells, Turn Bio’s approach is to prevent senescence by restoring normal functioning to aged cells. Turn Bio has demonstrated a reduction in senescent and pre-senescent features of aged cells and diseased stem cells in osteoarthritis and connective tissue, which is relevant to skin aging.
Genomic instability results from gradual damage to DNA in ways that are not naturally repaired. Genetic mutations can result. There also is an increased risk of cancer. Turn Bio is tackling this hallmark of aging by increasing levels of DNA structural support proteins and reducing levels of DNA damaging molecules — like reactive oxygen species.
As discussed above, DNA methylation and how the DNA is wound around histones impact which genes are expressed. Turn Bio is tackling epigenetic alterations by re-establishing youthful characteristics in terms of DNA methylation…levels of histones…and levels of heterochromatin (i.e., tightly packed DNA).
♦Loss of proteostasis?
“Proteostasis” refers to the homeostasis of proteins. There are various pathways involved in the synthesis, folding, trafficking and degradation of proteins. These pathways affect proteins inside and outside of cells. Turn Bio is looking to tackle this hallmark by elevating protein clearance and increasing activity in two pathways — namely the autophagosome-lysosome pathway and the ubiquitin-proteasome pathway. The autophagosome-lysosome pathway digests long-lived proteins and protein aggregates, among others. The majority of intracellular proteins are degraded by the ubiquitin-proteasome pathway.
A telomere is a region of repetitive nucleotide sequences at the ends of chromosomes. The telomeres serve to protect the ends of the chromosomes from sticking to each other. Telomeres also protect against the loss of genetic information during cell division. As cells divide, the telomeres get shorter. This process is referred to as “telomere attrition.” While there is an enzyme — telomerase — that adds repetitive nucleotide sequences to the telomeres, eventually the enzyme is silenced. When that happens, the telomeres are too short for cells to divide.
Turn Bio is not focusing on restoring the length of telomeres. Why? Because a change in length of telomeres could impact cell identity. Turn Bio doesn’t want to change the identity of cells — only reprogram them to a more youthful state. As Quarta explains, “Changing the identity of differentiated cells can be dangerous because they can become cancerous. Avoiding a change in telomere length during ERA is a safety step to avoid the risk of cancer.”
What’s next for Turn Bio, and when?
As for what’s next…Quarta says, “The technology and approach developed by Turn Bio targets the most profound and effective, rejuvenative, cellular mechanism. We already have demonstrated how ERA can be used ex vivo in cell-based therapies, such as for rejuvenating aged stem cells in regenerative medicine. We are now advancing our program for direct in vivo ERA. We want to bring ERA from a petri dish to inside the body — in multiple tissues and organs. In vivo ERA will be a new epigenetic intervention that is safe, simple and effective.”
As for when…Quarta says, “It is happening in our laboratories as we speak.” Programs for indications in the areas of osteoarthritis, muscle weakness, and skin rejuvenation are being advanced.
Indeed, Turn Bio has successfully achieved in situ delivery in multiple tissues, including the muscle, the eye, and the brain. They are also in the process of testing systemic delivery. Currently, their most promising approach is based on nanotechnology developed to deliver a mRNA cocktail to tissues — accurately and without invoking an adverse immune response.
And Turn Bio is working with multiple partners in clinical stage to advance cell-based therapy for different regenerative medicine applications across different clinical applications. Examples include joint and muscle dysfunctions.
The current projection is that Turn Bio could have a product in the cell-based regenerative market within 4–5 years. The expectation for market entry of products designed for in vivo cellular reprogramming is 5–7 years.
With Turn Bio continuing its current trajectory, Cher will have to change the lyrics of “If I Could Turn Back Time” to “When I Turn Back Time.” When she was in her 40’s, Cher belted out “If I Could Turn Back Time” on a naval ship in a costume deemed too risqué for the music video to appear on MTV before 9 p.m. — that was in 1989 (the official video — with 19M views — still plays on YouTube). Now, in her 70’s, Cher maintains a plank position for five minutes every single day. Age-defying.