Année : 2024

The nights are the longest of the year, the holidays are drawing near, and we are back with a festive edition of the Lifespan.io editorial. This time, we bring you some of this year’s highlights and talk about what the future holds for our content.

Lifespan.io and SENS Research Foundation merge

Regulars will recall that Lifespan Extension Advocacy Foundation and SENS Research Foundation merged in October. We are now the Longevity Research Institute (LRI), an organization focused on rejuvenation biotechnology research and news.

The two organizations have combined to pursue the goal of healthier and longer lives for all. Keith Comito, President of the Board, had this to say about the merge:

“Lifespan.io and SRF have shared a rich legacy in the battle against age-related diseases, driven by passion and purpose in both advocacy and research. Today, we unite these powerful forces to forge an organization uniquely equipped to identify and advance the most transformative projects in our field. Together with you, the Lifespan Research Institute will work to create a future where vitality and long-lasting health are within reach for everyone.”

Lifespan.io will continue to bring you the latest longevity news from the same website, so there’s no need to change your bookmarks!

Celebrating a decade of independent non-profit journalism

Lifespan.io has been one of the top sources for non-profit aging research news for the last decade. Here are some of the things we have achieved:

10 years of independent journalism.
270 news articles published this year so far!
160 longevity topics and growing.
147 leading researchers interviewed since 2014.

Not bad for a small non-profit organization that started with a handful of people, right? We think so, and it has been an awesome experience supporting the aging research field over this last decade.

This field is a very unique one, and it is both a challenge and privilege to focus our journalism on it. Since we started 10 years ago, there has been a significant change in the field. This field of research, which a significant part of the public had considered to be fringe, is steadily growing in credibility and respect.

Hucksters peddling unscientific nonsense continue to harm our field’s reputation, but things are starting to improve. In recent years, real science has started to take the spotlight.

Many rejuvenation treatments are in or near human trials, and the science is gaining traction as its credibility increases. While there is still much work to be done, there is reason for optimism and hope that longer, healthier lives are something that we can achieve in the near future.

Independent journalism is at risk

Dear readers, I am Steve Hill, Editor-in-Chief of Lifespan.io, and I need to tell you about the crisis happening right now in journalism.

The anti-competitive practices of big tech firms are an existential threat to independent journalism. Companies like Google and Meta are effectively gatekeepers of online content, deciding what internet users see. While this has long been the case, the level of control they have is now extreme.

Facebook, Linkedin, X, and other social media are increasingly trying to keep users on their platforms. They have made social media into a walled garden: a place where external content is consumed without any benefits for its creators, such as independent journalists.

The emphasis on paying to be seen on social media, even by your own followers, has gotten completely out of hand. This hurts content creators who are struggling to be seen, doubly so for non-profit organizations like us.

Non-profit content makers like us are increasingly being pushed out of internet search results. This is in part thanks to sweeping changes that Google has made to its search algorithm.

The risks from AI-generated content are greater than ever before, too. Often, such AI content is filled with misinformation and cannot be a trusted source. On top of that, Google’s clumsy attempts to stem the tide of low-quality AI content with changes to its search algorithm has damaged many legit content creators too.

Finally, the use of AI search overlays means that content creators like us are effectively having our content stolen, repackaged, and served up by Google as their own work. All of this is done without any acknowledgement or reward for content creators’ efforts!

All of this means that it’s become harder to reach people and tell them about the amazing work happening in our field. It is absolutely vital, now more than ever before, for independent voices to be heard.

Why independent longevity journalism is important

We are an important voice for the aging and rejuvenation research field. Our ethics code of longevity journalism is what makes us stand out from our competitors and makes us a source of information you can trust.

Our non-profit status means thaat our news remains free from government and commercial influence and will always be free. This is because we believe in sharing knowledge and a world where science is not locked behind paywalls.

But, it’s like the old saying goes: “Use it or lose it!” Put simply, without the support of the community, we cannot continue to be your trusted source for longevity news. If you value independent journalism that isn’t motivated by profit, please consider supporting us this holiday season!

How you can support independent longevity journalism

If you like what we do and you want to help us to keep doing it, I would like to ask you to support us in one or more ways:

Donate: No matter how big or small, every little bit helps us to keep creating content for you. Help us by making a donation today.
Be a Hero: The most important way you can support our work is by becoming one of our monthly patrons: the Lifespan Heroes.
Stay informed: Keep up to speed about what is happening in the exciting world of rejuvenation research by joining our monthly newsletter.
Follow us: We are on Facebook, Instagram, Linkedin, and X.

With your support, independent journalism can continue to thrive, and we can keep bringing you the best in independent journalism covering aging, longevity, and rejuvenation.

Best wishes to you and your family for the holidays and a happy new year.

Now, on to more positive things as we take a look at this year’s top stories and future plans for content here on the news outlet.

Success in the lab for the Longevity Research Institute

2024 was a year to celebrate our organization’s success in the lab. Researchers at the Longevity Research Institute (LRI) published results in December showing they had achieved the expression of an essential mitochondrial gene in the nucleus and proper functioning of the protein.

This important research builds on years of work towards finding a solution to age-related mitochondrial dysfunction. The mitochondria are the power stations of our cells. Unfortunately, as we age, they get increasingly damaged and unable to function.

To combat this, LRI aims to make copies of the mitochondrial genes inside the safety of the cell nucleus. This research brings us another step closer to that final goal. If we can keep our mitochondria healthy and functional as we age, it could have big implications for our health and longevity.

“This work represents the culmination of more than a decade’s worth of effort to provide a genetic backup system for mitochondrial DNA in mammals, for which inherited mutations cause disease in nearly 1 in 200 people,” said Dr. E. Lillian Fishman, Director of Research and Education at LRI.

This line of research could help combat diseases such as age-related muscle loss, Parkinson’s, and Alzheimer’s. It might also be used to potentially treat mitochondrial diseases that cause seizures and blindness.

Top stories of 2024

It’s been a busy year packed with great stories, but as is customary for this time of year, here are some of the best ones from 2024.

I Dined with Bryan Johnson and Didn’t Die

Journalist Arkadi Mazin was invited to Bryan Johnson’s home for one of his famous “Don’t Die Dinners”.

Johnson has been hosting these dinners for a few years. His guests often include celebrities and key figures in longevity research and important figures in the longevity research field.

Johnson is a somewhat controversial figure in the longevity community. His efforts to improve his health and extend his life have sparked much discussion. In this interview, Arkadi delves into what drives him to do the things he does for longevity.

Whether his approach is right or wrong is a subjective opinion, and you may or may not agree with his methods. However, we believe you will enjoy this interview either way.

Have We Maxed Out on Life Expectancy Gains?

One research paper that seems to have ruffled quite a few feathers in the community suggested that radical life extension was all but impossible in this century.

Often, predictions like these are followed by a demonstration that the said impossible thing is in fact possible. The Wright Brothers are an example of that: they demonstrated that heavier-than-air flight was perfectly possible despite experts at the time saying it was not.

However, what seems to have escaped quite a few people about this paper was that Jay Olshanky and the other authors did not discount the possibility that radical life extension may be achieved if breakthroughs in rejuvenation biotechnology were to occur.

It really is the case that nature is not going to solve aging and that life expectancies are no longer rising as they have in previous decades. It says everything about what nature will do, but puts no limits on what we might achieve through science.

Mehmood Khan on Aging Policy and Collaboration

Recently, Arkadi did an interview with Dr. Mehmood Khan about aging policy and how reframing the goal of rejuvenation biotechnology might help to drive progress forward faster. Longevity apparently means something quite different to high-level policy makers than it might for most people.

To these policymakers, it isn’t about people living longer for the sake of living longer but about productivity. This is why we need people like Khan advocating for our field and being able to speak the language policymakers want to hear to unlock funding for longevity research.

As sad as it is that we need to argue for the right to live longer and healthier lives through science, this is the reality of things. We think this interview might be an interesting read and help you understand what we are up against when it comes to advocacy and making policy work for us, not against us.

AI in Longevity: The Reality Today

Lifespan.io journalist Maria Isabella brought us an overview of the role of AI in longevity research and how it is being used in healthcare today.

Patient data analysis is a currently popular use case for AI, and a number of companies are involved in this. AI isn’t without its potential issues though, and we take a look at some of these in this article.

We are planning to delve deeper into the emerging use of AI in relation to aging and rejuvenation research in the future, but for now, we think you should enjoy this high-level summary of the technology.

Peter Diamandis: “Stay Healthy, Anti-Aging Tech is Coming”

In August, Peter Diamandis shared his thoughts on the aging and rejuvenation field with Arkadi.

Diamandis is an influential figure in the aging and rejuvenation world. He is an entrepreneur and investor in several fields, including commercial space flight and rejuvenation biotechnology.

During this fascinating interview, he shares his insights into how to encourage high-net-worth investors to get into the longevity space and why it is such a challenge to do so.

While there are a number of challenges our field faces in both progressing the research and funding for that research, Diamandis offers an overall message of hope and positivity for the future that we think you will enjoy.

These are just some of the great articles Lifespan.io has published this year, and we hope you continue to enjoy reading more in 2025.

Future improvements to our content

Our commitment to bring you the best in independent journalism will continue in 2025. In fact, we are scaling up what we plan to offer in the new year in order to bring you even more quality content.

Earlier this year, we did an audience survey, and the results were amazing! We asked you what you wanted to see us focusing on, you told us, and we listened. So, for 2025, we are going to be exploring new and exciting content and bringing you more of the things you asked for.

Based on your feedback, we are going to be publishing more interviews, op-eds (opinion pieces by leading external researchers), special reports, feature pieces, and more!

The ethics of launching a supplement based on your research (op-ed) – We’ll invite a leading expert to speak about the perils and positives of researchers who opt to launch supplements following their initial research. Is it ethical or harmful to perception and progress in the field?
The hype and reality of the field (op-ed) – While we should be committed to the defeat of aging, it is important to ensure we remain grounded and realistic. A leading expert (probably Matt K) will discuss the field in a sober and realistic manner.
The reality of AI in research (op-ed) – We’ll invite a leading expert to talk about how exactly AI is being used in the research setting, its potential, and its limitations. There is a lot of misconception around what AI is likely to achieve in the context of aging research, so it’s important to have a grounded discussion about it.
Reviewing progress in the field (review) – We’ll publish a high-level report on where we are in the context of achieving damage repair. We used to do a yearly report called “SENS – Where are we now?” This will be similar but with a wider Hallmarks of Aging focus to match our excellent Rejuvenation Roadmap.

We will be exploring the world of longevity investment and business and taking deep dives into the things investors want to know about the field:

Lifespan prediction – We’ll look at capabilities of AI in this area, companies working in this field, actual technology, and why finance companies may be interested (spoiler: it’s medical and pension costs).
AI and Longevity – We’ll take a look at the reality of solutions and perspectives, including external expert commentary.
DeSci and longevity – How much funding has DeSci/crypto really generated? We’ll analyze the impact of DeSci on the field and asking the question: Has DeSci been a success or failure in driving progress? We’ll look at the biggest funding of the year, research, what has been learned, and what could be ahead in 2025 for DeSci.
Thinking of doing research? – We’ll discuss funding, including crypto, along with the reality of application procedures, including commentary from internal and external experts.
Economics of living longer – Are we ready? We’ll discuss infrastructure, finance, health and planning.

Expanding the Rejuvenation Roadmap –  We aim to continue to grow the Rejuvenation Roadmap. We are currently tracking 224 rejuvenation biotech interventions and biomarkers, and we want to increase that to 300+ in the next year.

There is plenty to look forward to in the new year, and we hope you will continue to visit us for your aging research news. Finally, we wish you Happy Holidays from the Lifespan.io team!

Stay up to date, join the newsletter!

If you want to keep up with the latest research news, then feel free to join our newsletter. We will see you in the next editorial with more updates and news on what our new organization has been doing to defeat age-related diseases.

Earlier this month, for the third year in a row, the famed Buck Institute for Research on Aging hosted the Longevity Summit. This two-day event was organized by Longevity Global, a community of longevity researchers, investors, and enthusiasts, and its founder Dr. Christin Glorioso. While not the biggest or the longest conference in the field, Longevity Summit has consistently attracted top-tier speakers and audience members. We are happy to bring you a selection of talks from the event. As is our custom, we apologize to the equally worthy speakers whose talks we were unable to include.

Calico wants to compute aging away

Calico was founded more than a decade ago by Alphabet, Google’s parent company. Well-funded and well-positioned to move the longevity field forward, it ignited a lot of hopes that have since faded somewhat due to a perceived lack of tangible results. While we’ve seen some quality research from Calico, such as Synthia Kenyon’s groundbreaking work, the anxiety is still there, and every appearance by a Calico scientist is an event.

Dr. Madeleine Cule talked about using large human cohorts to study changes in aging and how they are related to disease. Her talk hinted at Calico leveraging its Google roots in its fight against aging. “For a computational scientist,” Cule said, “it’s an exciting time with advances in AI and machine learning, plus interesting datasets to ask and hopefully answer questions.”

Cule started by stating the obvious: that the closest model organisms to humans are humans. However, human clinical trials are complicated and costly, and for the purposes of studying aging, also prohibitively long due to our species’ longevity.

Thankfully, more and more human data is now collected and stored in repositories such as UK Biobank. Analyzing this data does not replace clinical trials, but it can greatly help scientists in understanding aging. UK Biobank, Cule said, is “perfect for an aging company because we can look at changes during aging that affect multiple disease outcomes simultaneously, potentially making new connections.” Biobank data, she added, provides us a window into changes occurring before disease onset and an unbiased, often longitudinal, look at health across the body and its various systems.

Combining this data with the latest machine learning techniques to extract new measurements might help us understand disease outcomes. “In our framework for advancing drug discovery,” Cule explained, “we can use these human measurements to identify new age-related traits with heritable components, then use rapidly accumulating molecular data to interrogate causal relationships. This becomes a platform for developing new therapeutic hypotheses we can test in independent cohorts, experimental medicine approaches, mouse experiments, or in vitro systems.”

Cule then shared a specific example of her team’s work that uses deep learning to extract information from abdominal imaging stored in the UK Biobank database. This dataset contains rich information about body composition and organ health linked to multiple aging-related diseases, such as cardiovascular disease and cancer.

The group started working on it about five years ago by annotating individual organs. Even with Calico’s considerable resources, the process was painstaking and time-consuming, but it eventually paid off. “Thanks to linkage with health outcomes,” Cule said, “we can look across the whole disease spectrum to understand connections.”

She provided an example involving the cardiovascular system. Using body scans, Cule’s team segmented and analyzed blood vessel diameters at different anatomical locations. “This gives us a way to study aneurysm or aging of large blood vessels that isn’t accessible using just clinical information,” she said.

In the future, the team plans to expand beyond using machine learning to replicate what humans would do. “Latest machine learning models don’t need to anchor to what a radiologist might see or think interesting,” Cule noted. “We’re working with machine learning engineers on representation learning approaches that summarize whole images or particular organs into vectors that aren’t necessarily human-interpretable.”

In 2020, Calico teamed up with the UK Biobank to add a longitudinal component by inviting tens of thousands of individuals to repeat the imaging process. “This is exciting for aging research,” Cule said, “because it allows us to study aging-related decline across many imaging phenotypes, identify traits where change predicts disease outcomes, characterize genes involved in the aging process, and identify biomarkers of disease progression – crucial for future clinical trials.”

The hierarchy of clocks

David Fuhrman, Associate Professor at the Buck, gave a talk on creative approaches to building novel biological age clocks. Since we need tools to measure aging in vitro, in animal models, and in humans, this field has been booming, with researchers using epigenetic, transcriptomic, proteomic, lipidomic, and other techniques.

Fuhrman started by showing the audience a slide where different types of biological age clocks were compared side by side. “My favorite is the inflammatory clock,” he then said. “It can give you really good intervention guidance, as opposed to more standard first-generation clocks.”

Fuhrman’s complaint about epigenetic clocks is that “we don’t really know how to actuate them very well,” unlike cellular and proteomic clocks. When we understand the proteins involved and the organs we want to target, he explained, it gives clinicians and consumers a much more focused way of intervening.

Fuhrman also heads the Thousand Immunomes project at the School of Medicine at Stanford to identify chronic inflammation biomarkers and build a clock based on them. This clock, he noted, tracks with several clinical endpoints such as multi-morbidity and frailty, even years before they occur, and serves as a surrogate of immune aging and heart health.

“The higher the inflammatory age, the worse the phenotypes overall, both in our Thousand Immunomes cohort and in an independent cohort of exceptional longevity individuals,” Fuhrman said. “We can also predict mortality. We’re now commercializing this through companies, mostly through longevity clinics, wellness centers, and functional medicine practices.”

At his Buck lab, Fuhrman’s team is using baseline multi-omics measurements to predict different functional outcomes with aging. This clock is proxy-methylation-based, that is, it uses methylation data as a proxy for underlying biological processes associated with aging. The clock predicts intrinsic capacity, which according to Fuhrman, is one of the most important measures of aging. Interestingly, few methylation sites (CpGs) selected by this new clock overlap with first and second-generation clocks.

“Using gene sets based on LLMs associated with different hallmarks of aging, we asked if our intrinsic capacity clock relates to hallmarks of aging,” Fuhrman said. “The answer is yes, mostly for chronic inflammation and cellular senescence. We can also associate high intrinsic capacity with overall health, exposome, and lifestyle choices.”

As an example, certain foods drive higher or lower intrinsic capacity as measured by the clock, with all flavonoids, as well as omega-3 fatty acids from animal sources, showing positive correlations. Conversely, omega-6 fatty acids are negatively correlated with intrinsic capacity.

Switching gears, Fuhrman reported on a new study that uses data from UK Biobank and Health and Retirement Study. The idea is to build what Fuhrman calls a third-generation clock: “We’re trying to predict UK ICD-10 chapters – different diseases people die from – using clinical lab measurements first, then creating a metric we can predict using multi-omics: proteomics, metabolomics, DNA methylation patterns, and transcriptomics.”

First-generation clocks were trained to predict chronological age, while most second-generation clocks were trained to predict all-cause mortality. “But if you have a clock that tells you about brain acceleration or heart acceleration, clinicians and consumers can better guide interventions,” Fuhrman noted. “Taking the massive amount of data collected in the UK Biobank and Health and Retirement Study, we’re now creating what I believe is the largest disease-omics mapping that exists today.”

Paying attention to the hypothalamus

Another Buck representative, Dr. Ashley Webb, gave a talk on an area of the brain that is apparently getting too little attention. Cognitive science has long focused on the hippocampus, which makes sense since this part of our brain is crucial for learning. “While our lab studies this area too,” Webb said, “we felt there was another region that has been hugely neglected in the context of aging and neurodegeneration. A number of years back, we started thinking about the hypothalamus, which has numerous functions that are critical for healthy aging.”

Hypothalamus is involved in controlling appetite, hormone production, and circadian rhythms. Some research in animal models shows that manipulating neurons within the hypothalamus affects lifespan. “What makes the hypothalamus very interesting to study, but also very complex, is that this is a highly diverse region,” Webb said. “There are many different subregions and neural subtypes with diverse functions.”

The team’s initial experiment involved single-nucleus RNA sequencing on 3-month-old and 20-month-old mice and produced a high-quality dataset. It showed that some neuronal subtypes remain stable and are more resilient to aging.

The experiment involved only female mice. This limitation actually led to an interesting discovery – the gene most upregulated with age across various subtypes of hypothalamic neurons was a long non-coding RNA known as Xist (pronounced “exist”). “It’s involved in X chromosome inactivation early in life,” Webb explained. “Males are XY, females are XX, and the way we deal with having two X chromosomes in females is through dosage compensation.”

Early during development, Xist is expressed from one of the X chromosomes and silences it throughout life. The researchers were surprised to find that Xist was also the most altered with age. Eventually, they learned to predict a cell’s age from changes in Xist.

Webb told the audience about another interesting finding: while glial cells seemed to age similarly in males and females in terms of gene expression, neurons showed marked differences. “When we looked at neurons – both excitatory and inhibitory – we saw a lack of coordination in how the neurons were changing with age in males versus females,” she said.

Webb concluded her talk by presenting the new machine learning pipeline that her team created to analyze cell-type specific aging in the brain, specifically in the hypothalamus. Transcriptomic clocks are notoriously noisy. Comparing them to methylation clocks, the researchers realized that the latter were binary (a site is either methylated or demethylated), while transcriptomic data is continuous.

“Drawing inspiration from these clocks, we decided to binarize our matrix,” Webb said. “When we did that, it denoised the data. We ran this binary dataset through the same pipeline, and to our surprise, our performance shot up to about 95%. We call this new method Cell-By-Age.”

Cell-By-Age is essentially a transcriptomics-based machine learning method used to predict single-cell age using single-cell RNA-seq datasets. “It’s useful because it can discover cell-type specific aging signatures and evaluate interventions,” Webb explained. “We’ve already tested this by taking a dataset from Andrew Dao’s lab at Stanford, where they exercised mice, and Cell-By-Age could predict rejuvenation of cell types in the brain.”

Reprogramming selected cell types

Vittorio Sebastiano, Stanford professor and CSO of Turn Biotechnologies, is one of the leading authorities on partial cellular reprogramming. Under his guidance, Turn is holding its own in this competitive niche against giants like Altos Labs, producing exciting results.

Sebastiano began with an overview of epigenetics’ role in aging, echoing David Sinclair’s information theory of aging. “Aging,” he said, “is fundamentally an epigenetic problem – something that happens in the epigenome. Because of this deterioration of epigenetic information, we see the manifestation of aging at cellular, tissue, and organismal levels.” Since the epigenome dictates cellular behavior, changes in it result in changes across the whole spectrum of aging markers.

Sebastiano suggested that nature already solved aging on a cellular level via epigenetic reset that occurs early in embryogenesis. Without that, continuation of life would have been impossible. Understanding this epigenetic reset “requires understanding female reproductive biology and gives us tremendous opportunities to develop anti-aging interventions,” he noted.

Sebastiano then proceeded to describe Turn’s proprietary platform called Epigenetic Reprogramming of Aging (ERA). “We started this work in late 2014, published in 2020, and eleven years later, I can tell you – it works,” he said.

ERA uses mRNA technology to deliver six reprogramming factors. As of now, ERA’s effectiveness has been demonstrated in 12 different human cell types. The team primarily works with human cells to shorten the way to clinical use. Turn is actively working with several cell types and indications in parallel, and Sebastiano provided two concrete examples.

In collaboration with Marco Quarta and his company Rubedo, Turn rejuvenated aged stem cells from muscle and transplanted them into age-matched hosts. Compared to untreated stem cells, age-matched stem cells treated with ERA restored muscle strength to young muscle levels – about a 40% increase.

Sebastiano is convinced that treating all cells in the body with reprogramming factors is a mistake, although this approach has produced some positive results in animal models. Instead, reprogramming should be targeted to cell types where it would be most beneficial, such as stem cells and immune cells, and tailored for specific indications.

In this spirit, Turn is working on reprogramming aged T cells. “We saw increased expression of two markers associated with T cell functionality – the higher their expression, the more likely the cells can kill tumor cells in the body,” Sebastiano said. “With the ERA treatment, we can restore or enhance the population of stem cell-like cells in the T cell population, which has potential therapeutic implications.” Importantly, the cells also showed a higher proliferative capacity when challenged with cancer cells and were much better at killing those.

The company is now extending this work to blood stem cells. The day of the talk, Turn announced a partnership with the Children’s Hospital of Philadelphia.

Sebastiano’s team was able to compare epigenetic changes caused by the treatment to those caused by other interventions. Interestingly, cellular reprogramming seems to be more aligned in this regard with caloric restriction, while rapamycin alters methylation in different regions.

Third time’s the charm?

A lot of eyes have been on UNITY Biotechnology, a company that aims to bring senolytic treatments to the clinic. In 2020, UNITY’s Phase 2 clinical trial, one of the first in longevity biotech, failed, sending ripples through the entire field. Another one failed in 2023. Undaunted, UNITY’s team has since then continued to hone their approach. The company’s Chief Scientist Mike Sapieha was at the Buck to give an update.

Sapieha talked about the direction stemming from his academic research: vision loss. Some types of vision loss are age-related (most people who lose their sight are above age 50, Sapieha said). Vision loss not only causes depression but also reduces mobility, accelerates dementia, and contributes to other age-related morbidities.

Something that many vision loss disorders have in common is a failure of vascularization. “This starts as a dropout in healthy blood vessels,” Sapieha said, “then growth of blood vessels into areas of the eye that are physiologically avascular, meaning in a healthy eye, blood vessels typically don’t grow there.”

Around 2004-2006, treatment of many of those diseases was revolutionized with the first anti-vascular endothelial growth factor (VEGF) treatments. Today, it is a lucrative market of around 14 billion dollars.

The problem, according to Sapieha, is that those drugs target all vasculature growth. UNITY, on the other hand, wants to selectively target only “the bad blood vessels.”

“The anti-VEGFs hit all blood vessels,” Sapieha said, “so we asked: is there a way to molecularly identify these abnormal structures and develop a tool to selectively eliminate them? Much like gardening, where you cut out dead branches and the healthy ones regenerate.”

Sapieha’s team found that pathological angiogenesis causes retinal neurons to go into a hibernation-like state, triggering endoplasmic reticulum stress pathways. If this ER stress is not resolved, cells in the retina enter senescence.

After those senescent cells start producing inflammatory factors, neutrophils arrive at the scene to mark the senescent cells for destruction. However, with age, this immune-mediated elimination of senescent cells becomes compromised. “We spent years identifying susceptibility nodes in senescent blood vessel cells and landed on a protein called BCL-XL, which lives inside mitochondria and sequesters death effectors,” Sapieha said.

The scientists decided to go specifically after senescent endothelial cells. After proving that the drug was safe, the team focused on diabetic macular edema, a complication of diabetic retinopathy, which affects around 1.7 million people in the U.S.

“We found senescent cells were highly enriched in areas of disease activity, right next to the leaking blood vessels,” Sapieha said. “Single-cell RNA sequencing in mouse models showed about 5-10% of endothelial cells expressing these senescence markers.”

One of the main roles of endothelial cells is to maintain the blood barrier via proteins called adherens junctions. The researchers discovered that in senescent cells, these proteins do not form properly, compromising the barrier function. “In efficacy models, we saw inflammatory factors like IL-6, IL-1β, and TNF-α increased, then significantly reduced with UBX treatment,” Sapieha said.

UNITY’s Phase 2 clinical trial enrolled patients who had received anti-VEGF standard of care for about six months and plateaued in improvement, despite continuing to receive injections every six weeks. Sapieha’s team hypothesized that, with their senolytic approach, one injection would be enough to eliminate senescent cells and allow healthy neighboring cells to regenerate.

A year after the single injection, 53% of patients improved to the point where they needed no other treatments. “Most striking, patients with BCVA Best Corrected Visual Acuity, a measurement of how well a person can see with corrective lenses) under 60 gained an average of 10 letters after one year with that single injection – potentially enough improvement to restore driving ability,” Sapieha said. More results are expected at the end of Q1, 2025.

Measuring brain aging

The debate around amyloid’s role in Alzheimer’s disease has dominated the field for decades. However, according to Dr. Christin Glorioso, who, this time, was wearing her NeuroAge Therapeutics founder hat, we might need to think about it differently. “Amyloid is a risk factor, like cholesterol,” she said. “We should think about it not as the single cause of Alzheimer’s disease, but one cause among many.”

Alzheimer’s is multifactorial and doesn’t look the same in all people, Glorioso noted. This means that we need better biomarkers and segmentation to predict who anti-Alzheimer’s drugs will work for. It is also important to diagnose the disease and identify responders and non-responders earlier, since current drugs have been shown to work better at an early stage.

Glorioso’s company is focusing on aging itself as a key risk factor. Her research shows that pathological processes in brain cells start surprisingly early. “Even in your 20s,” she explained, “you have calcium dysregulation, mitochondrial dysfunction, DNA damage, changes in neurotransmitters, and brain-specific hallmarks like loss of synapses between neurons and inflammatory processes in glia.”

By studying donated brain tissue, Glorioso’s team discovered many genes that show pro-Alzheimer’s age-related changes, such as calbindin and GFAP. This allowed the researchers to create an algorithm that predicts brain age from 52 blood RNA transcripts. “This is an organ-specific aging clock, similar to Tony Wyss-Corey’s work with proteomics, but using RNA-seq as a more accessible approach,” Glorioso said. “You go to your doctor yearly to check cholesterol for heart disease risk and glucose for diabetes risk, but no one checks brain aging – we didn’t have a way to assess neurodegeneration risk.”

The final product is an “AI-based super predictor” that combines blood biomarkers, genetics, brain MRI, and cognitive testing to predict brain age. This information is actionable, Glorioso said, “because about 40% of your brain aging rate is due to lifestyle, with 60% genetic. There’s this huge modifiable component you can work on right now to reduce your brain aging.”

Glorioso cited recent research that supports this approach. A new study showed that just 25 extra minutes of exercise per week increased brain volume on MRI – “literally growing their brains back,” as Glorioso put it. In another case, an entrepreneur with high genetic risk for Alzheimer’s managed to reverse his amyloid accumulation through intensive lifestyle changes.

Glorioso’s company provides its clients with a comprehensive dashboard that includes measurements of their brain age and lifestyle recommendations. The “big six” are exercise, healthy eating, getting eight hours of sleep, community engagement, stress reduction, and staying mentally active. “There’s also good evidence for Omega-3s from fish, walnuts, and flaxseed,” Glorioso said. “Coffee and tea are very good for brain aging due to their polyphenols and other antioxidants, not the caffeine itself. We curate many other studies and provide information through both our dashboard and newsletter.”

The company is also moving beyond diagnostics. Using their multi-omic dataset, they are developing therapeutics targeting the pathways that drive brain aging. This includes a small molecule and an antibody for Alzheimer’s and mild cognitive impairment.

Make splicing great again

Lorna Harries, a professor of molecular genetics at the University of Exeter Medical School and founder of Senisca, focused her talk on splicing – the process of creating different mRNAs from a single pre-mRNA transcript by removing non-coding sequences (introns) and joining coding sequences (exons). “98 percent of your transcriptome is alternatively spliced,” Harries said, “so most genes can make a number of isoforms that are expressed at different times, in different places, in response to different stimuli. This is a fundamental underpinning of our molecular response to stress.”

Splicing, which is regulated by about 150 splicing factors, becomes dysregulated with age. Understanding those proteins makes it possible to restore the splicing ability, which Harries likened to partially reprogramming the cell. She called splicing dysregulation “a new and druggable hallmark of aging.”

However, to declare something a hallmark of aging, she said, you first have to show that it happens during normal aging in populations – which Senisca did in collaboration with Luigi Ferruci at the NIA. “Six of the seven most age-affected pathways were directly related to RNA processing, particularly splicing,” Harries said. The team validated these findings in multiple populations.

Working with human cells, the researchers found that replicative senescence is accompanied by downregulation of splicing-related genes. Vice versa, disrupting even a single splicing factor could trigger cellular senescence. More importantly, in the longitudinal cohort InCHIANTI, people with lower splicing factor expression showed faster decline in cognitive and physical function over time.

“Splicing factors are actually pretty good candidate aging genes,” Harries said. “They regulate splicing patterns globally, but they also do many other things – regulate telomeres, SASP (senescence-associated secretory phenotype) proteins and molecular stress resilience, play a role in DNA repair, and are essential for RNA quality control.”

“The million-dollar question was: what happens if we switch them back on?” she continued. When her team restored splicing factor levels in old cells, they saw a dramatic “reprogramming effect”: a 60 percent reduction in senescent cells. The formerly senescent cells re-entered the cell cycle, and their telomere length was restored to near-youthful levels.

This led to the development of two therapeutic approaches. The first uses small molecules for skin health applications, developed through a partnership with a major skincare company. The second, more ambitious approach uses oligonucleotides, small pieces of DNA or RNA that can precisely target specific genes.

Senisca is initially testing its oligonucleotide therapy on idiopathic pulmonary fibrosis (IPF), a devastating age-related lung disease where cellular senescence plays a major role. In laboratory tests using lung tissue from IPF patients, its treatment reduced senescent cells by 75-80 percent and decreased markers of tissue scarring. “We see drops in MMP7, a marker of pathological lung remodeling that we can track from laboratory studies all the way to the clinic,” Harries noted.

However, splicing factors are finicky, as they are highly auto-regulated and cross-regulated. Rather than completely blocking or activating these genes, Senisca’s treatment pushes them back toward their normal working range, restoring the equilibrium. “These genes exist in a Goldilocks zone – you don’t want too much or too little,” Harries said. “We just give them a little nudge, and the cell does the work for us.”

Creating induced pluripotent stem cells (iPSCs) causes mutant mitochondrial populations to change, and researchers have investigated this phenomenon more thoroughly.

Easy to mutate

Being outside of the protection of the nucleus, mitochondria DNA (mtDNA) mutates at anywhere from 10 to 100 times the rate of nuclear DNA [1]. At only 16,569 base pairs, mtDNA is very compact and does not contain the extra, non-coding introns that nuclear DNA has; therefore, any mutation may have a signficant effect. If a mutation occurs to all the mitochondria in a cell, it is homoplasmy, but if it only occurs to some of them, it is heteroplasmy, and its effects vary between cell types [2]. Heteroplasmy can have severe downstream consequences, including heart problems [3].

It is well-known that within certain cell types, mitochondria with harmful mtDNA deletions outcompete mitochondria that are more beneficial for the cell [4]. However, it remains unknown precisely why this is the case. Furthermore, while mitochondrial dysfunction has plenty of age-related consequences, it has not been proven if this DNA deletion is behind some or all of them. There are also few effective ways to directly alter mitochondria in living organisms.

However, previous work has found that cellular reprogramming can change the heteroplasmy of mitochondria. Interestingly, it can go one of two ways: either the heteroplasmy becomes dominant or becomes erased entirely [5]. This has a substantial effect on stem cells, which are greatly influenced by the quality of their mitochondria [6].

All or nothing

To start their experiment, the researchers used OSKM to reprogram three distinct cell lines, one with a well-known point mutation called A3243G and the others with a frequently discussed deletion called Δ4977, although the A3243G cells had 89% of their mitochondria affected while both of the Δ4977 lines had very low percentages of this deletion. As expected, the A3243G cells had substantial problems with respiration, while the Δ4977 cells were not significantly affected.

In all cases, the cells quickly became very strongly biased for or against these mitochondrial alterations. Some of the iPSCs generated from A3243G had similar percentages to that of the original cells, while others had none whatsoever. Similarly, while the stem cell generation process initially increased the amount of Δ4977 deletions, this amount dropped very quickly in nearly all of the generated cells after only four divisions; only cells with extremely high amounts of Δ4977 retained this mutation. Cells with approximately 50% of mitochondria containing the mutation either quickly lost it or gained more of it after four divisions.

While the stem cells with large percentages of mutations did not change how they differentiated into somatic cells, there were significant effects later on. The cells with large amounts of Δ4977 grew larger but divided less than the cells without it. While these mitochondrial mutants were able to slowly differentiate into fat cells and bone cells without any visible problems, they failed to beat properly when they were differentiated into heart tissue, and critical compounds necessary for cardiac function were not found in these cells.

As expected, these Δ4977 mutants also had significant alterations in nuclear gene expression as well: genes related to fundamental metabolism, oxidative stress, small molecule transport, and the management of cholesterol were all affected. There were also trends involving such aspects of metabolism as ADP to ATP translation and the usage of NAD+.

While A3243G mutants did not have a significant difference in epigenetic age, Δ4977 mutants did. These are freshly reprogrammed cells, which should have a minimum of difference, but this difference was greater than that of iPSCs taken from 20-year-olds and iPSCs taken from 100-year-olds, according to the Horvath epigenetic clock.

These findings are of interest to some researchers looking for a supply of mitochondrially mutated cells for use in the study of mitochondrial diseases, but others may simply feel relieved. While it is not clear if these results hold true for every mitochondrial mutation, the simple process of iPSC creation appears to create either significantly affected cells that can be discarded at the clinical level or cells whose gradually accruing mitochondrial mutations have been removed with no additional intervention required. This bodes well for iPSC-based therapies, particularly those that create cardiac and similar functional tissues.

Literature

[1] Allio, R., Donega, S., Galtier, N., & Nabholz, B. (2017). Large variation in the ratio of mitochondrial to nuclear mutation rate across animals: implications for genetic diversity and the use of mitochondrial DNA as a molecular marker. Molecular biology and evolution, 34(11), 2762-2772.

[2] Picard, M., Zhang, J., Hancock, S., Derbeneva, O., Golhar, R., Golik, P., … & Wallace, D. C. (2014). Progressive increase in mtDNA 3243A> G heteroplasmy causes abrupt transcriptional reprogramming. Proceedings of the National Academy of Sciences, 111(38), E4033-E4042.

[3] Baris, O. R., Ederer, S., Neuhaus, J. F., von Kleist-Retzow, J. C., Wunderlich, C. M., Pal, M., … & Wiesner, R. J. (2015). Mosaic deficiency in mitochondrial oxidative metabolism promotes cardiac arrhythmia during aging. Cell metabolism, 21(5), 667-677.

[4] Khrapko, K., Bodyak, N., Thilly, W. G., Van Orsouw, N. J., Zhang, X., Coller, H. A., … & Wei, J. Y. (1999). Cell-by-cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions. Nucleic acids research, 27(11), 2434-2441.

[5] Wei, W., Gaffney, D. J., & Chinnery, P. F. (2021). Cell reprogramming shapes the mitochondrial DNA landscape. Nature Communications, 12(1), 5241.

[6] Chakrabarty, R. P., & Chandel, N. S. (2021). Mitochondria as signaling organelles control mammalian stem cell fate. Cell stem cell, 28(3), 394-408.