NeuroAge wants to reprogram your brain back to a younger state

Startup seeks new biomarkers as it develops cellular reprogramming drugs designed to reverse brain aging and combat dementia. 

Last month, Californian cellular reprogramming startup NeuroAge Therapeutics revealed it had received $250,000 in funding from the Alzheimer’s Drug Discovery Foundation’s Diagnostics Accelerator – a $100 million global research initiative funded by philanthropists including Leonard A Lauder, Bill Gates, Jeff Bezos, MacKenzie Scott, the Dolby family, and The Charles and Helen Schwab Foundation, among others.

With the aim of developing and validating biomarkers for the early detection of Alzheimer’s disease and related dementias, the accelerator supports research initiatives and companies like NeuroAge, which is working to identify new biomarkers as part of its mission to design personalized reprogramming therapeutics capable of reversing brain aging.

Longevity.Technology: When it comes to the treatment of Alzheimer’s and dementia, the pharma industry has long been focused on the strategy of removing toxic proteins from brain cells. While this has yielded some success, it is based on a reactive, uniform approach that often happens after irreversible damage has already occurred. Berkeley-based NeuroAge was founded to pursue a new way: targeting brain aging itself. The company aims to leverage new biomarkers of brain aging to develop personalized treatments that can begin earlier, and before irreversible damage to the brain occurs. To find out more about the company’s approach, we spoke to co-founder and CEO Dr Christin Glorioso.

Reflecting on the recent progress in Alzheimer’s drug development, Glorioso, a trained neuroscientist who founded NeuroAge with Dr Priyanka Joshi, feels that the excitement over the FDA’s recent approval of lecanemab should be tempered a little.

NeuroAge wants to reprogram your brain back to a younger state
NeuroAge co-founders Priyanka Joshi and Christin Glorioso.

“It only improves cognition by about 30% and works better for people that are in early stages of the disease – plus there are bad side effects, including brain bleeding and swelling in about 20% of people,” she says. “So, families around the country, including my own [Glorioso has an aunt who’s currently suffering with Alzheimer’s] are wondering, is this worth it? And I think, for a lot of people, it isn’t.”

Targeting amyloid isn’t working

Much of the focus of Alzheimer’s drug development has been centered around targeting the buildup of toxic proteins like amyloid beta and tau, and Glorioso says that the drugs have been successful in achieving their objective… at least in part.

“They’ve created antibody drugs to try to get rid of those proteins, and they’ve been successful in getting rid of the proteins, but it hasn’t fully solved the problem,” she explains. “And, for me, that wasn’t unexpected. When I started medical school in 2003, I had a professor who created some of the first ways of imaging amyloid proteins in the brain and he told me this couldn’t possibly be the cause of Alzheimer’s, because there are people who have lots of amyloid in their brains and have perfectly normal cognition.”

“If amyloid was really the cause of Alzheimer’s, you would expect there to be a relationship between how much amyloid you had in your brain and how bad your cognition was. But we don’t see that. And that’s the first big red flag.”

Of course, Glorioso acknowledges that the fact that the amyloid-targeting drugs are having an effect means that there must be some relationship between the plaques and dementia.

“In my opinion, it’s likely that the disease is multifactorial, and amyloid plays some role, but it’s certainly not the whole story,” she says. “We need other approaches, and even big pharma companies think this as well.”

Reprogramming brain aging

Enter NeuroAge, which was founded two years ago to address dementia by targeting the aging process itself. And it wants to do that using a technology that has become synonymous with the longevity field: cellular reprogramming.

“What we’ve seen in our research is that there are these huge changes in about 10% of gene expression in the human brain, which looks like a program,” says Glorioso. “And it’s a program that pushes you towards diseases like Alzheimer’s and Parkinson’s, and the rate at which you’re on that trajectory determines whether you’ll get one of these diseases or not.”

According to Glorioso, this observation is consistent with what is seen in other areas of biology – a trajectory that leads towards bad outcomes and age-related disease.

“You start losing neurons in your 20s, and whether you get a neurodegenerative disease or not is just about the rate at which you get there – whether you lose enough neurons in certain areas of your brain before you die,” she says. “And so that opens up this whole other possibility of using reprogramming drugs to prevent those neurons from dying and to slow down that rate. And so that’s what our company focuses on.”

Beyond Yamanaka

While many of the cellular reprogramming strategies in longevity are gene therapies focused on Yamanka factors, NeuroAge is taking a somewhat different approach.

“I think of the Yamanaka factors as the ‘big bosses’ of the cells – they control everything, they can turn your cells all the way back to a stem cell,” says Glorioso. “But there are other factors that are less powerful – ‘middle managers’ that control the rate of these changes that happen within your neurons in your brain. And if you can restore levels or function of those proteins back to the way they were when you were 25, then you can reprogram the brain aging trajectory. And that’s what our drugs are aimed at doing.”

In addition to targeting different reprogramming factors, Glorioso says NeuroAge is not a gene therapy company.

“The Yamanaka factors are hard to drug with anything other than a gene therapy and most of the companies trying to target them are starting with less invasive, easier to control parts of the body, like skin,” says Glorioso. “But we’re going after the brain, and we have other targets that aren’t transcription factors, so we can use small molecules.”

While there are currently only a limited number of targets that can be targeted with small molecules, NeuroAge is leveraging recent developments in AI to predict new kinds of small molecules with different structures that are better at crossing the blood brain barrier. This essentially means that, if the company is successful, its reprogramming drug could potentially be taken in pill form – which means its effects should be reversible, unlike those of a gene therapy.

Biomarkers of brain aging needed

However, in order to develop and commercialize its brain-age reversing drugs, NeuroAge also has to face the fact that the biomarkers needed to identify the people in need of them have not yet been validated. And this leads to the other part of the company’s mission: to validate key biomarkers of brain aging – a key area of Glorioso’s research focus in recent years.

This summer, NeuroAge will roll out a brain aging test to consumers, comprising a blood test to assess genetic and epigenetic risk factors, a brain MRI, and cognitive testing.

“The NeuroAge test is a diagnostic for brain age, so we can tell you how old your brain is, but it’s also prognostic for your future risk of dementia more than 30 years ahead of time,” says Glorioso. “The goal of the test is to inform people about their brain aging – what their future risk is, both from a genetic standpoint, but also from blood biomarkers, brain MRI and cognitive testing. And really to empower people to change their lifestyle and be able to decrease their risk.”

“We’re talking with several longevity clinics about partnering with them because there isn’t a test like this on the market.”

Using machine learning approaches, NeuroAge also hopes to gain insight into what proteins may be driving brain aging on a personalized level.

“By taking the test, people will also be contributing to drug discovery, and the creation of new drugs that are going to work for them down the line,” says Glorioso. “If we’re tracking your protein levels of these factors, which we’re designing drugs for, then we’re going to find out which of those drugs will work best for you. And that’s really the other piece with this NeuroAge test – we going to need to develop the biomarkers at the same time as developing the drugs for them.”

The road to the clinic

Based at Berkeley Skydeck, one of the most prestigious accelerators in the US, NeuroAge is in the middle of raising its seed funding round, which will be used to support the launch of its brain age test.

“On the drug discovery side, we’re in the preclinical phase – we have lab space, we have collaborations with AI companies and with some academic partners, and we’re also in discussions with various Big Pharma partners about codeveloping some of our targets,” says Glorioso.

One of the challenges with validating aging targets is waiting for cells or animals to age, which can be a time-consuming process for longevity biotechs. NeuroAge is taking an innovative approach to this challenge. 

“Our collaborators at UCSD and the Salk Institute have created a system where you can take your own skin cells and turn them into neurons without going through the stem cell stage – so they retain the age of the person that they came from,” explains Glorioso. “This means we can create neurons from the skin cells from a 70-year-old, give our drugs to those 70-year-old neurons and show that we’ve turned back the clocks without having to age them. That’s our first step towards validating and screening our drugs.”

“Over the next couple of years, we aim to have substantial data from the NeuroAge test, while also having preclinical validation in cells from this neuron system and to have identified our lead drug candidates. We’re hoping to have our first drugs to market in about eight years. That’s ambitious, but we think we can do it.”