Inside the World’s First Age Reversal Trial
In a Nutshell
The world's first age-reversal trial (ER-100) has begun, testing epigenetic reprogramming via OSK genes to restore vision in glaucoma and optic nerve stroke patients, with the first participant dosed and early results promising. The eye serves as both a window to brain aging—via AI retinal scans that predict mortality risk—and an ideal entry point for whole-body rejuvenation therapies. Daily interventions include caloric restriction, violet light exposure, lutein/omega-3 supplementation, and avoiding smoking/alcohol to slow age-related vision loss.
These notes were generated by AI and may contain inaccuracies.
The eyes are not just a separate sensory organ. They are part of the brain. Reversal of aging isn't just for the eye. It seems to work across the entire body of animals too.
David Sinclair is a scientist and professor working on understanding why we age and discovering new ways to slow and even reverse the aging process. He shares an insider look at the latest from his lab, the field, and what's just around the corner.
The world of vision science is moving really fast with exciting developments. Matthew Lelant is a professor of journalism at Utah State University and recently earned a PhD in climate science. He is also co-author on the book Lifespan.
Today's conversation focuses on the eye, how the retina and optic nerve function, and how problems like glaucoma, cataracts, and age-related macular degeneration develop. The episode also covers daily choices, lifestyle habits, and preventative strategies to protect sight in the long run.
David Sinclair is 57 years old. Many people experience vision problems starting in childhood with nearsightedness, or around age 40 when reading gets harder, screens get blurrier, or night driving becomes more difficult.
David Sinclair recently co-authored a review on oculomics and AI looking at how artificial intelligence can scan the micro-architecture of the back of the eye. By using advanced AI to read subtle, hidden patterns in the retina, a simple non-invasive eye scan can estimate true biological age, track brain health, and predict risk for future diseases.
Aging is in part a loss of biological information, and restoring that information could help cells remember how to function like they're young again. This is the idea behind ER-100, the first cellular rejuvenation therapy using epigenetic reprogramming to receive FDA clearance to enter human clinical trials.
ER-100 or epigenetic reprogramming 100 uses controlled expression of OSK, three of the Yamanaka genes, to try and help damaged retinal nerve cells recover more youthful function. The Life Biosciences trial is testing the safety and tolerability of ER-100 in people with blindness caused either by glaucoma (due to eye pressure) or by NAION (a stroke in the back of the eye).
Earlier this year, the first participant received their first dose of ER-100. The trial is going well.
David Sinclair gives a special shout-out to Wanglu Orion and to Shiaochan, both who pioneered the work in his lab. He also mentions Dr. Sharon Rosen Gibson who's running the ER-100 trial at Life Biosciences.
Today's episode focuses on understanding how eyes age, how to catch problems before they cause permanent damage, and how to have the best chance of slowing age-related decline in vision for decades.
The eye is one of the parts of the body that will definitely get a disease and will be dysfunctional at least. Everyone experiences this. It starts even in the 30s. By the time people are in their 50s, about half have issues.
When people are asked what symptom of aging they would want to reverse first, the overwhelming answer is they want their vision back because people want to see their grandkids. Without vision, it's not just lonely, but it actually accelerates other diseases as well.
Aging is like falling off a cliff. It all happens at once. Lifestyle changes can delay and even reverse the effects of aging in the eye.
The outside part is called the cornea. These are epithelial cells that protect the eye. The iris is the colored part of the eye. The pupil is actually just the absence of tissue that lets the light in. The lens is that transparent, flexible, literally a lens that becomes opaque as people get older.
One of the most important and actually the most complex part of the eye by far is the retina, which is the place at the back of the eye. This curved receptor region with the rods and the cones. The retina has multiple layers and it starts with nerves and then there's blood vessels and then there's the rods, the cones, and some what are called RPE (retinal pigment epithelial) cells behind that that support those rods and cones.
The rods don't help with color vision. They're the ones that are very sensitive to low light. Basically black and white ones. Rhodopsin is the chemical in there that detects those very small amounts of photons. The cones are the ones that have the red, green, or blue detection. They have different proteins in there that detect those different wavelengths.
There are nine proteins called opsins. They detect different wavelengths. Some species have a lot more. Humans only detect three colors. The mantis shrimp has 16 different color detection in the ultraviolet and infrared spectrum.
Even insects see often in four colors and see ultraviolet as well. Dogs can see things at distances and detect movement very well, much better than humans, but they really only can see in the blue and the yellow and are red-green colorblind.
The optic nerve consists of the bundles at the back of the eyes, the retinal ganglion cells, which project out the back of these rods and cones and gather into a large cord that comes out the back of the eye. It's about a centimeter to the back of the brain. It's actually an extension of the brain. The eye is literally a piece of the brain.
The vitreous humor is the liquid inside the eye. The problem with it with aging is that it doesn't drain well, and so the eye can swell up. This is the disease called glaucoma. It's very serious and affects millions of people just in the US.
The sclera is the white opaque outer layer of the eye. The current theory is that it helps humans see where the person is looking and it's very helpful to be able to judge people's emotions. There are at least 25 species of mammals that have whites around their pupils so that other members of the species can see where they're looking. Even gorillas and some other primates have whites around their eyes. Bonobos have light brown sclera.
The macula is the central area in the retina that is important for very detailed vision. What can happen is the blood vessels grow too much around that region and people can also accumulate junk. This leads to age-related macular degeneration.
Even smaller than the macula is the very tiny little pit in the center of it that provides the sharpest vision. That is the fovea.
Opsins, these proteins that detect light, do not only occur in the eye. They also occur everywhere. There are photoreceptors in the skin and even in the brain. This is why photobiomodulation works. This is how people know it's daylight. Even some people who are blind know that it's daylight. Their bodies can keep a rhythm and even can detect bright light even though they can't see anything.
A paper in Science in 2002 titled "Phototransduction by Retinal Ganglion Cells That Set the Circadian Clock" showed these ganglion cells are not detecting light for vision, but they detect it so that other things can happen. They regulate organs, metabolism, making people hungry, and setting the ability to sleep at the right time.
Circadian rhythms are important for aging. As people get older, they don't sleep as well. A lot of people struggle to even go to sleep and stay asleep. One of the main reasons is the circadian rhythm is controlled by longevity genes, the sirtuins. The sirtuin 1 that needs NAD struggles to work in the elderly because people don't make enough NAD as they get older.
David Sinclair is working on whether NAD can be replaced or enhanced to get people to wake up nice and early, nice and chirpy, and then sleep well at night. So far, it looks good in mice, and clinical trials are being done now in people.
When looking at someone's eyes, you're looking straight into a part of their brain. The eyes are an exposed part of the brain.
Different physiological systems experience aging at different rates. The heart experiences aging different than the liver, different than the skin, different than the eyes. The brain is very well protected and so it's a little harder to non-invasively measure aging in the brain. But the eyes are exposed to the world, so aging in the eyes can be measured.
There have been a number of studies that use different aspects of the eye to measure how fast people are aging. One study pulls liquid out of the eye and looks at the proteins to develop a clock that could predict age.
Another study used 80,000 images of the back of the eye from the UK Biobank. They could use AI to look at the differences over time and very accurately, within about 3 years, predict how old somebody actually was just by looking at the eye. This helped predict all causes of mortality. A person whose eyes are more like 60 when they're actually 50 would be predisposed to diseases that would eventually kill them.
A team of researchers from Australia demonstrated in 2022 that the biological age of the cells in the retinas are also a predictor of mortality. This is called the retinal age gap, which is the difference between the actual biological health of an eye and the person's chronological age since birth.
A 2% increase in the risk of death from any cause for each year of difference between a person's actual age and the older biological age identified by the eye. If the eye is 6 years older than the rest of the body, that translates into a 12% increase in risk.
Retinal cell thickness shows a strong association with biomarkers for Alzheimer's disease, based on 2021 research from Seoul National University. The eye and brain share common mechanisms of aging and disease, with the information theory of aging demonstrating this connection. Correlations between retinal diseases and Alzheimer's disease or mild cognitive impairments have been observed. Recent studies from the last couple of years show that changes happening to the retina can predict Alzheimer's disease well before any symptoms appear.
The decision to examine the eye was driven by student Wanchen Lu's interest rather than convenience. David Sinclair initially wanted to study the liver, believing it would be easier, but Lu recognized the eye's advantages for human translation. The eye already has an approved AAV (adeno-associated virus) treatment on the market for retinitis pigmentosa, a genetic disease. If reprogramming works in the eye, there's already an established delivery mechanism available. The assumption underlying this work is that if aging can be understood at a fundamental level, it will apply to every cell type in the body.
The lab is now reversing the age of the brain in mice using the same technologies that restored blindness. A seminal 2020 paper demonstrated that genetic reprogramming using three of the four Yamanaka factors could recover youthful epigenetic information and restore vision in mice. The paper was published in December 2020 after extensive peer review. Initial findings showed vision improvement in old mice, mice with glaucoma, and mice with damaged optic nerves. Questions remained about long-term safety, duration of effect, and whether treatment could be repeated.
A follow-up paper titled "Sustained vision recovery by OSK gene therapy in a mouse model of glaucoma" demonstrated that turning on the therapy for a long time had no negative side effects. The 2020 paper showed effects lasting 6 to 8 weeks, but the sustained study showed the effect lasting for many months after switching it off—specifically 11 months. For a lab mouse with a 2-3 year lifespan, this represents approximately one-third of the animal's life, translating to decades in human equivalent terms.
Concerns about cancer risk from reversing aging in cells were addressed. The treatment does not cause tumors in the eye and appears perfectly safe in mice. The effect is described as a "true reset" or "semi-permanent reset" rather than requiring continuous treatment like most drugs. Aging continues after the reset, but an inducible system allows the treatment to be turned back on by giving an antibiotic. The plan is that patients would receive vision restoration for glaucoma, aging, or macular degeneration, with effects lasting several years before requiring another course of antibiotics to regain vision.
The research supports the belief that every cell contains a backup copy of the software of youth. This has been demonstrated across multiple cell types including kidneys, muscle, brain, spleen, and other tissues. The location of this software encoding is unknown but suspected to be attached to DNA as some chemical marker. The information is thought to be laid down when eyes are very young and stays until triggered to reset. Age reversal stops at about 80% of youth rather than going to zero, which would risk cancer. A barrier prevents cells from becoming too young, though the mechanism is not understood.
Bruce Ksander, co-director of the Ocular Oncology Center of Excellence at Harvard Medical School, is leading studies bridging mice and humans. An April 2023 abstract presentation at the Association for Research in Vision and Ophthalmology conference in New Orleans revealed that the vision restoration process works in monkeys. Monkey eyes are structurally identical to human eyes, unlike mouse eyes which have a membrane and lack the white. Mice with bad vision had vision returned after 28 days of treatment. Additional studies are examining how long treatment can be left on and whether longer duration produces better results.
Vision improvement in monkeys was measured using pattern electroretinography (PERG), similar to ECG for hearts but applied to the eye. The PERG measures electrical activity in the optic nerve in response to changing patterns. Monkeys were shown a checkerboard pattern, and electrical activity changes were measured. Treatment restored electrical activity within 28 days.
Age-related macular degeneration (AMD) involves two types: one with growing blood vessels treatable by injection, and another involving untreatable lipofuscin accumulation. Lipofuscin consists of protein aggregates containing damaged proteins and oxidized lipids that block nerve function. Research with Bruce Ksander examined what happens when the retina is age-reversed. The lipofuscin "junk boxes" disappeared when the eye was made young again, with cells clearing the protein and fat accumulations. Retinal layers that appeared damaged and disorganized returned to being perfectly layered and youthful.
Retinal pigment epithelial (RPE) cells can be grown in the lab and aged using sodium iodate to induce oxidative stress. Aged cells show poor growth and abnormal appearance. Age reversal treatment allows these cells to grow beautifully again. The goal is to use these cells as a screening platform to find new chemicals that reverse aging, eventually moving from cell screens to mouse studies and then human trials.
Vision loss represents a continuum rather than a binary disease state. Everyone experiences macular degeneration at different rates, not just those diagnosed with the disease. Medical cutoffs for treatment create artificial distinctions, but aging processes occur throughout adult life. The approach advocates preventing illness before it strikes rather than waiting for disease thresholds. Being natural and common does not mean aging should be accepted as inevitable.
The American Optometric Association states that adults aged 40-60 will experience symptoms of age-related vision changes. By age 50, approximately 60% of the population needs glasses, contacts, or surgery. This increases to 94% by age 75. By 2050, an estimated half the world will need glasses for myopia. Myopia prevalence has increased sevenfold in recent decades, possibly related to computer screens or lack of sunlight exposure, with new evidence suggesting violet light absence causes eye malformation and nerve dysfunction.
While genetic reprogramming approaches are not yet ready for human use, maintaining overall body health helps preserve eye health. Vitamin C decreases glaucoma risk, protects against oxidative and UV damage, and helps prevent cataracts. However, vitamin C supplements might be associated with increased risk of age-related cataracts in women. David Sinclair takes a middle dose of 1,000 milligrams daily (within the 2-gram upper safe limit), partly for epigenetic aging benefits shown in published lab results.
Vitamin A from beta carotene in carrots converts to retinal, which is essential for opsin proteins in rods and cones. Retinyl undergoes conformational change when hit by photons, triggering G-protein coupled cascades for optic nerve signaling. Vitamin E serves as an antioxidant protecting against oxidative stress. Zinc interacts with taurine and vitamin A, supporting plasma membranes, retinal reactions, and neuronal signaling. Vitamin B1 (thiamine) decreases inflammation and supports healthy nerves. Sinclair takes a B vitamin blend including B1, B6, B9, and B12, particularly important for those with low meat consumption.
Omega-3 fatty acids reduce inflammation throughout the body and promote retinal function development. Studies show omega-3 supplementation improves high intraocular pressure associated with glaucoma. David Sinclair primarily takes omega-3s for cardiovascular disease prevention but notes their eye health benefits as well.
Omega-3 fatty acids help treat dry eye symptoms, which affect many people even when young, causing scratchy, painful blinking particularly in dry winter air. NAD boosters have been shown in a Japanese study to help with dry eye, and low-dose rapamycin in eye drops can prevent dry eye by suppressing the immune system. These longevity genes protect and rejuvenate the eye similarly to how they protect the liver and kidney.
Lutein is taken daily as a red capsule and has been shown in clinical trials to slow eye aging, particularly macular degeneration. Lycopene comes from reddish vegetables and fruits, with tomatoes containing significant amounts - one large raw tomato provides 5 mg, while a quarter cup of tomato paste provides 19 mg. High doses of lycopene during pregnancy are associated with low birth weight in children, so pregnant women should avoid high doses, though it's beneficial for adult eyesight. Tomatoes also provide vitamin C.
Astaxanthin is a carotenoid found in trout, algae, yeast, and shrimp that gives fish their pink color. It protects the eye from oxidative stress, macular degeneration, and aging. The best way to get nutrients is through food when possible, though supplements may provide necessary doses.
Colored vegetables provide the most benefit through xeno-hormesis - plants that have been stressed produce protective chemicals and vibrant colors. Dark green, bright orange, and red vegetables are particularly beneficial. Metformin has been shown to slow down macular degeneration, and a father's AMD was completely stopped and possibly improved with dietary changes and lutein supplementation.
Keto diet increases optic nerve mitochondrial biogenesis, which helps with cell survival in glaucoma in mice. Calorie restriction decreases retinal ganglion cell death in mice, delays age-related cataracts in rodents, and is neuroprotective against ischemia. Plant-based diets and Mediterranean diets slow down eye aging. A 2012 study showed that eating greens, kale, carrots, and peaches reduced glaucoma risk in women, likely due to vitamin A, vitamin C, and xenobiotic compounds.
Caloric restriction slows aging across the entire body, including the eyes, by turning on cellular defenses. A major cause of aging is loss of epigenetic information - the ability of cells to read the right genes at the right time. During aging, nerve cells in the eye lose their ability to maintain their identity, leading to dysfunction. Caloric restriction induces hormesis, tricking cells into thinking times are tough and activating sirtuin genes that help wrap DNA and maintain epigenetic information.
Caloric restriction doesn't require constant hunger. Skipping breakfast, having a late lunch, or eating dinner early and fasting until 11:00 AM the next day puts the body in a state of perceived adversity part of the day. After a few weeks, the body adapts and morning hunger decreases. This approach provides long-term benefits without starvation.
Violet light (distinct from ultraviolet light) is essential for maintaining eye shape and activity. Kazuo Tsubota discovered that without adequate violet light exposure, myopia develops. The sevenfold increase in short-sightedness globally may result from reduced sunlight exposure and LED screens that don't produce sufficient violet light. Studies showed mice responded well to violet light, and children with glasses blocking violet light had greater incidence of short-sightedness. A USB violet light device is used during winter months when outdoor exposure is limited.
UV radiation modifies lens proteins causing cataracts and blurry vision, increases eyelid cancers, and damages DNA by linking thymine bases together to form dimers. When cells detect DNA damage from sunburn, they mount an inflammatory response to protect cells while killing off heavily damaged cells that might cause cancer. Lasers should be avoided as they damage eyesight.
After eye damage from lasers or other stresses, NAD or NAD boosters protect the retina. Raj Apte at Washington University showed that raising NAD levels protects against retinal damage. This is particularly relevant for military pilots who may face laser attacks.
Smoking damages retinal cells and increases AMD risk. Alcohol consumption increases age-related macular degeneration risk. One episode of binge drinking (more than five drinks) was associated with a month and a half acceleration of biological aging. Even moderate daily drinking damages tissues including the eye and brain. Total alcohol consumption accelerates aging measurable in blood and eye markers.
Animal fats containing omega-6 fatty acids, red and processed meat should be consumed in moderation as they contribute to age-related vision loss over time. While ketogenic diets may provide initial benefits like muscle gain and weight loss, long-term evidence doesn't support meat-heavy diets for overall health including eye health.
Glaucoma involves naturally occurring changes in eye pressure. Sleeping face down or on certain sides can increase eye pressure, as shown in a South Korean study of 20 people. Increased pressure ages nerve cells in the eye consistent with the information theory of aging. Swimming goggles that create face pressure have been shown to increase glaucoma risk.
Mice on the International Space Station showed decelerated retinal epigenetic clocks with less methylation in their retinas after space flight. This suggests that reduced pressure on eyeballs may affect aging, though practical applications are limited. The broader principle is protecting eyes from radiation, pressure, and chemicals to slow aging.
Genetic sequencing can identify susceptibility to retinal damage, AMD, or retinitis pigmentosa. Those with genetic predisposition should be especially diligent about protective measures. Luxturna, approved in 2017, is a gene therapy from Spark Therapeutics that cures the RP65 mutation causing retinitis pigmentosa by delivering the healthy gene variant.
Stage one gene therapy replaces missing or defective genes, as with Luxturna. Stage two involves gene editing using CRISPR technology, approved for sickle cell anemia treatment. Stage three, currently in development, changes cell behavior through reprogramming rather than fixing individual genes. Chemical reprogramming using pills rather than gene therapy is being developed to restore eyesight by reprogramming cells.
Eyes represent an ideal starting point for aging reversal therapies as a contained liquid environment safe for gene therapy injection. The same reprogramming technology that works for eyes is expected to eventually work for brain, liver, kidney, and whole body. A study showed age reversal technology extended remaining lifespan by 109% in 25-month-old mice, demonstrating whole-body effects beyond just eye treatment.
Matt was thanked for his contributions to the conversation on aging of the eye. The hosts reflected on how their initial plan to discuss the topic evolved into a comprehensive discussion with substantial take-home value. They noted that the episode provided practical recommendations for protecting eye health at any age, emphasizing that it's never too early to begin implementing protective measures.
The hosts stressed that even individuals in their 70s or 80s should start taking action immediately. Key recommendations included protecting the eyes, activating longevity genes, consuming appropriate foods, and taking supplements believed to offer long-term eye protection.
The program was described as one where science and evidence take precedence, with the team dedicating hundreds of hours to presenting only verified facts. Listeners were directed to lifespan.com to access early episode releases, the Lifespan magazine, detailed show notes, transcripts, and links to referenced research papers.
Membership was positioned as a means to support medical research aimed at extending healthy lifespans for everyone. The hosts encouraged subscriptions and notification activation to stay updated on new content, noting that audience engagement helps improve the show's quality.
The audience was invited to share the episode with family and friends who might benefit from the information. For updates on longevity science discoveries, followers were directed to Instagram at lifespan and X (formerly Twitter) at join lifespan.
The production team was credited, including Andrew the Wonderman, Ying, Rajie, Geek Me Out, Romesh, Marissa, Vulgore, Kathleen, TLDDR, Fitzgerald, researchers Shivani Sethi and Adiv Johnson, and new producer Daniel Salazar. Serena was acknowledged with the nickname "honeypoon."
Additional thanks were extended to Inspirro Studio and Create Ape for their contributions to making the show possible, as well as to partners supporting longevity research.
The show was specified as being for informational purposes only and not constituting medical advice. Listeners were advised to consult qualified healthcare providers, as individual results may vary. The views expressed were noted as belonging to the host personally and not representing Harvard University or Harvard Medical School, with a full disclaimer available in the show notes.
Keep David Sinclair in your library
Save the videos and channels worth coming back to, and find them again in one place.
