×

The Blog

Building a Future Free of Age-Related Disease

DNA mutation

Targeting an Inflammatory Pathway Fights Alzheimer’s

Scientists have discovered that a rare mutation protects against Alzheimer’s disease by dampening a central inflammatory pathway. They recapitulated these results using a small molecule [1].

The woman who beat the odds

For the last 40 years, scientists have been studying a massive extended family of about 6,000 people in and around Medellín, Colombia. Many members of this family carry a rare genetic mutation, PSEN1 E280A (Paisa). Its carriers are virtually guaranteed to develop early-onset Alzheimer’s disease. Typically, they show signs of cognitive impairment in their mid-40s, develop dementia in their 50s, and die in their 60s.

One woman in this family, Aliria Rosa Piedrahita de Villegas, was a remarkable exception. Despite carrying the Paisa mutation, she remained cognitively healthy until her early 70s and died from cancer in 2020 at the age of 77.

Aliria’s post-mortem brain scans showed that her brain was full of amyloid plaques, one of the key pathological hallmarks of Alzheimer’s. However, she had very little of the second hallmark, neurofibrillary tangles of tau protein, especially in brain regions related to memory.

It turned out that, in addition to the harmful Paisa mutation, Aliria also had two copies of another, extremely rare mutation in the APOE3 gene. This variant is known as the R136S or Christchurch mutation, named after the city in New Zealand where it was first identified.

Since then, researchers have identified several dozen people with one copy of the mutated gene instead of two, making them heterozygous. In those people, the mutation was mildly protective, hinting at a dose-dependent relationship [2]. However, until now, little has been known about the mechanism behind the protective effect of the Christchurch mutation. A new study from Weill Cornell Medicine provides an interesting answer.

Numerous protective effects

The researchers used CRISPR/Cas9 to create a mouse model In which the native mouse APOE gene was replaced with either the normal human APOE3 gene or the protective APOE3 with the Christchurch mutation. These mice were then crossed with an established mouse model of tauopathy (P301S) to study the mutation’s effects in the presence of tau pathology independently of amyloid plaques. Mutation-carrying mice showed a marked decrease in the accumulation of aggregated tau in the hippocampus. The mutation also protected against the loss of synapses, preserving levels of synaptophysin and the post-synaptic protein PSD95.

One of tauopathy’s most insidious symptoms is myelin loss, which harms neuronal function. Mice with the mutation were protected, demonstrating upregulation of myelin basic protein (MBP) and other myelination markers in the hippocampus.

Functionally, the mutation prevented the tau-induced decline in theta and gamma power in the hippocampus. Theta and gamma waves are rhythms of synchronized electrical activity generated by large groups of neurons. They are fundamental to how the brain processes information, especially for memory. A decline in theta and gamma power indicates that the brain’s circuits are not effectively communicating and coordinating.

This circuit-level disruption is a direct underlying cause of the cognitive impairments seen in Alzheimer’s, such as difficulty forming new memories. The paper notes that these deficits can appear long before neurons die, making them an early indicator of disease.

“We are particularly encouraged that this mutation ameliorates disease at the level of brain function, which has not been shown before,” said Dr. Sarah Naguib, the study’s co-first author.

Interestingly, the researchers did not use the usual physical tests, such as the Morris water maze, to assess cognitive function. Theta and gamma waves may be more direct markers of brain activity than physical manifestations, which can be influenced by many external factors.

APOE3 Mice

Inflammation is the key

The researchers also ran in vitro experiments in mouse microglia, the brain’s resident immune cells, and in human microglia derived from induced pluripotent stem cells. In the brain, APOE genes are mostly expressed in microglia and astrocytes but much less so in neurons.

The experiments showed that microglia with the R136S mutation were more efficient in the uptake and clearance of tau. This could indicate that the mutated cells excel in preventing extracellular tau from entering neurons, where this protein is most dangerous.

A central finding was that the R136S mutation suppressed the cGAS-STING-interferon signaling pathway in microglia. This pathway, a central regulator of inflammation, is normally activated by tau pathology and is known to be a major driver of Alzheimer’s progression and symptoms.

Treating tauopathic mice that had the normal APOE3 gene with a cGAS inhibitor recapitulated many of the mutation’s benefits, reducing tau spread and protecting against synaptic loss. The treatment caused highly correlated gene expression changes in both microglia and excitatory neurons.

“This is an exciting study because it suggests that inhibiting this cGAS-STING pathway could make the brain more resistant to the Alzheimer’s process, even in the face of significant tau accumulation,” said the study’s senior author, Dr. Li Gan, director of the Helen and Robert Appel Alzheimer’s Disease Research Institute at Weill Cornell Medicine. “We can’t engineer the rare Christchurch mutation into people to prevent Alzheimer’s, but targeting the same pathway it modulates could offer a new therapeutic strategy for Alzheimer’s and potentially other neurodegenerative conditions.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

LIterature

[1] Naguib, S., Lopez-Lee, C., Torres, E. R., Lee, S.-I., Zhu, J., Zhu, D., Ye, P., Norman, K., Zhao, M., Wong, M. Y., Ambaw, Y. A., Muñoz-Castañeda, R., Wang, W., Patel, T., Bhagwat, M., Norinsky, R., Mok, S.-A., Walther, T. C., Farese, R. V., … Gan, L. (2025). The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway. Immunity.

[2] Quiroz, Y. T., Aguillon, D., Aguirre-Acevedo, D. C., Vasquez, D., Zuluaga, Y., Baena, A. Y., … & Arboleda-Velasquez, J. F. (2024). APOE3 Christchurch heterozygosity and autosomal dominant Alzheimer’s disease. New England Journal of Medicine, 390(23), 2156-2164.

Elderly muscle

Lipid Metabolite Rejuvenates Muscle Stem Cells in Mice

A recent study investigated the effect of a single treatment of prostaglandin E2 on improving muscle strength and rejuvenating muscle stem cells in mice. The researchers explored the molecular and epigenetic aspects underlying this rejuvenation [1].

Aging muscle stem cells

Sarcopenia, a loss of skeletal muscle mass and strength, is an age-related disorder that leads to increased risks of other conditions such as osteoporosis, heart failure, and cognitive decline.

Its sources include significant decreases in both the number and function of muscle stem cells, which are typically needed to regenerate skeletal muscles. Aging also causes changes in the microenvironment of muscle stem cells, leading to disrupted signaling that results in reduced self-renewal and increased senescence. Identifying ways to reverse these processes would be a promising avenue for both ameliorating sarcopenia and accelerating recovery after injury.

In a previous study, this study’s researchers reported that a lipid-derived metabolite, prostaglandin E2 (PGE2), which is located in membranes, responds to muscle injury [2], and a transient increase in PGE2 signaling is necessary for muscle stem cells to regenerate muscles.

Muscle repair is also delayed in mice that do not have either a functioning PGE2 receptor called EP4 or sufficient levels of PGE2, and PGE2 levels decrease in skeletal muscles with age. Increased levels of 15-hydroxylprostaglandin dehydrogenase (15-PGDH) cause this age-related in PGE2 levels.

Overcoming muscle loss with PGE2 and exercise

For their first experiment, the researchers used genetically engineered young and aged mice that lacked EP4 receptors in muscle stem cells. Those mice exhibited approximately 20% reduced muscle strength and muscle mass compared to control animals.

Aged, genetically engineered mice were treated for five days with a non-hydrolyzable PGE2 analog. This form of PGE2 is resistant to degradation by 15-PGDH, whose activity is increased in aged muscle. The same mice were subjected to daily downhill running. Two weeks from the start of the experiment, the researchers observed an increase in the mice’s muscle strength, suggesting that even such short treatment with PGE2, when combined with exercise, can partially overcome sarcopenia.

Lasting consequences

Next, they simulated muscle injury by injecting a toxin called notexin (NTX), which causes damage to muscles, into old mice. Two days later, these mice received a single, high dose of non-hydrolyzable PGE2 to simulate the PGE2 surge that happens after injury in young mice. Assessing the mice two weeks after the toxin and PGE2 treatment, the researchers noted a significant increase in muscle stem cells expressing Pax7, a transcription factor essential for muscle development and regeneration. A single PGE2 treatment helped to regenerate muscle, increase muscle mass, and enhance strength in aged mice.

This and subsequent experiments, in which aged PGE-2-treated cells are engrafted into young animals and then treated with toxin, suggest that PGE-2 has a positive long-term effect on the regenerative capacity of muscle stem cells that persist in the progeny of the treated cells.

Those observations were confirmed by cell culture experiments using isolated aged muscle stem cells treated with PGE2. Those cells showed a significant increase in cell proliferation compared to untreated aged muscle stem cells. The researchers observed that cell numbers increased by approximately 60%, which they believe “overcomes the deficit in proliferative capacity” of aged muscle stem cells. Apart from increased proliferation, PGE2-treated aged stem cells also showed a threefold reduction in cell death.

“What amazes me most is that a single dose of treatment is sufficient to restore muscle stem cell function, and that the benefit lasts far beyond the duration of the drug,” said Yu Xin (Will) Wang, Ph.D., an assistant professor at the Center for Cardiovascular and Muscle Diseases, Center for Data Sciences, and Cancer Metabolism and Microenvironment Program at Sanford Burnham Prebys. “In addition to making new muscle, the stem cells stay in the tissue, where they sustain the effect of the PGE2 and instill the muscle with further capacity to regenerate.”

Sleeping through regeneration

After observing the positive impact of PGE2 treatment, the researchers investigated age-related changes in PGE2-EP4 signaling. They isolated the myofibers (individual muscle cells) with their associated muscle stem cells from young (2-4 months) and aged (over 18 months) mice.

They observed a substantial reduction in the expression of the PGE2 receptor EP4 in the Pax7-positive muscle stem cells isolated from aged mice compared to those isolated from young mice (70% of aged cells expressed EP4 compared to nearly 100% of young cells). Even among the aged muscle stem cells that expressed this EP4 receptor, the levels of expression were lower by roughly 50% compared to cells from young animals.

“PGE2 levels in muscle also decline with age, so we see blunted signaling from reductions in both the messenger and receiver,” said Wang. “PGE2 is an alarm clock to wake up the stem cells and repair the damage. Aging essentially reduces the volume of the alarm and the stem cells have also put on ear plugs.”

Further analysis of single-cell levels in young and aged muscle stem cells and myogenic progenitors showed that diminished PGE2 signaling changes gene expression during regeneration in aged muscle stem cells. The results also suggested that PGE2 signaling starts in stem cells and is propagated to their cellular progeny.

The researchers identified that the transcription factor family known as AP1, which includes transcription factors such as JUN and FOS, was persistently activated in aged muscle stem cells. AP1 is involved in various processes including cell growth, differentiation, and apoptosis. Persistent activation of AP1 family members was also observed in human muscle biopsies, suggesting conservation across species.

PGE2 treatment of aged muscle stem cells suppressed age-dependent AP1 activation. It significantly impacted gene expression levels, leading to more rejuvenated gene expression patterns.

“The genes that are upregulated during the aging process are downregulated after treatment, and vice versa,” Wang said.

Molecular memory

The regenerative effects of PGE2 treatment are observed even weeks afterwards. The researchers hypothesized that some kind of “molecular memory” must be driving those changes. Most likely, this kind of memory is caused by epigenetic changes in the chromatin landscape that are propagated to the muscle stem cells’ progeny.

To test this hypothesis, the researchers analyzed chromatin accessibility and correlated it with a gene expression analysis. They found differences between chromatin regions that were more accessible (open) or less accessible (closed) in aged compared to young muscle stem cells. The distribution of those differences suggested that, with aging, the activity of genes involved in muscle stem cell expansion during injury is decreased. In contrast, the activity of other regions, including AP1, is increased.

PGE2 treatment rejuvenated the aged muscle stem cells, altering the accessibility pattern of chromatin.

Beyond muscle

Overall, the researchers demonstrated that a single injection of PGE2 into aged muscles has a long-term rejuvenating effect, and when combined with exercise, it increases muscle strength and mass. Such results are promising for patients suffering from sarcopenia, but whether those results translate to humans is still unexplored.

However, the authors believe in PGE2’s therapeutic potential, and they think it can extend beyond rejuvenating muscle cells.

“We’ve previously shown that PGE2 can also benefit the muscle fiber and neurons that innervate the muscle. PGE2 has been implicated in the regenerative process and signaling for the intestine, liver, and several other tissues, potentially opening up an approach that could restore the renewing capacity of other aged tissues,” elaborated Wang. “The ultimate goal is to improve people’s quality of life by reversing the effects of aging.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Wang, Y. X., Palla, A. R., Ho, A. T. V., Robinson, D. C. L., Ravichandran, M., Markov, G. J., Mai, T., Still, C., 2nd, Balsubramani, A., Nair, S., Holbrook, C. A., Yang, A. V., Kraft, P. E., Su, S., Burns, D. M., Yucel, N. D., Qi, L. S., Kundaje, A., & Blau, H. M. (2025). Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength. Cell stem cell, S1934-5909(25)00192-4. Advance online publication.

[2] Ho, A. T. V., Palla, A. R., Blake, M. R., Yucel, N. D., Wang, Y. X., Magnusson, K. E. G., Holbrook, C. A., Kraft, P. E., Delp, S. L., & Blau, H. M. (2017). Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength. Proceedings of the National Academy of Sciences of the United States of America, 114(26), 6675–6684.

Long-term lung disease

Senolytics May Treat Some Long-Term Viral Lung Damage

In Aging Cell, researchers have published their findings that mice exposed to influenza experience long-term consequences that can be partially ameliorated with senolytics.

Post-viral syndromes

Long before the spread of the SARS-CoV-2 virus that causes COVID-19, it had been well-established that viral lung diseases such as influenza lead to lasting damage [1, 2]. Increased risks of idiopathic pulmonary fibrosis (IPF), emphysema, chronic obstructive pulmonary disease (COPD), and further infection by bacteria have all been documented [3].

Cellular senescence has been previously found to be linked to chronic lung diseases [4]. Viral infection in the lungs has been found to drive cells senescent, including both influenza [5] and SARS-CoV-2 [6]. However, not every lung disease can be properly treated by removing senescent cells [7]. These researchers, therefore, investigated the links between senescence and viral infection and aimed to determine if senolytics would be harmful or helpful.

Long-term damage is visible in mice

This study began with a population of pathogen-free Black 6 male mice that were 8-10 weeks old when exposed to a sublethal dose of H1N1 influenza. Without treatment, these mice developed lesions in their lungs four days after infection, which grew in the first two weeks, including inflammatory infiltrates and abrasion of the epithelial tissue in the airway. Four weeks after infection, much of this damage had been healed, but the epithelium was still abraded and there were visible signs of emphysema development and fibrosis. Three months after infection, the epithelium had partially healed but the emphysema and fibrosis were still around: the mice had developed chronic lung disease.

This infection was linked to cellular senescence: the senescence biomarkers p16 and p21 spiked strongly within the first two weeks of infection and were decreased but still at four weeks, even though the virus had been cleared out of the mice’s systems. These biomarkers were not significantly elevated at three months, even though lung disease had been firmly established. This rise and fall of senescence were linked to an increase in one DNA damage marker, γH2AX, but a decrease in another, 53BP1.

Despite this lack of overall senescence, however, it still persisted in some specific areas, showing different levels of damage in the same animal. Some lung bronchi had no signs of cellular senescence and were completely restored to normal three months after infection. Other bronchi had visible damage, which coincided with p16-expressing senescent cells still in the area. This finding was confirmed with an examination of lungs derived from monkeys.

Removing senescent cells has a significant benefit

Intrigued by these findings, the researchers used a genetically engineered mouse model whose senescent cells are very easy to remove. Doing this as the mice were infected, and continuing for four weeks, led to better healing: the mice whose senescent cells were removed had less emphysema, less fibrosis, and faster epithelial repair. As expected, it had no effects on the overall inflammation that occurred as a reaction to infection.

Some of these findings were recapitulated in wild-type mice given the powerful senolytic compound ABT-263s (navitoclax) one day after infection, continuing for 4 weeks. Like with the genetically engineered mice, there was no significant effect on overall inflammation; however, the senescent cell population was significantly reduced, and viral load was decreased slightly as well.

Unfortunately, navitoclax was unable to affect emphysema or fibrosis 28 days after infection, although it did lead to significantly better epithelial repair. The researchers suggest that these mixed results may be due to the negative effects of cellular death by apoptosis and note that some previous work has suggested that apoptosis may actually promote fibrosis [8].

Even with these mixed results, however, the existence of a clear benefit in the form of epithelial repair leads these researchers to believe that senolytics with different mechanisms of action, such as the well-known combination of dasatinib and quercetin, may be instrumental in treating the long-term effects of viral lung diseases. If this approach is able to remove lasting harm from the lungs, people suffering from emphysema, IPF, and COPD may be able to breathe a lot easier.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Herold, S., Becker, C., Ridge, K. M., & Budinger, G. S. (2015). Influenza virus-induced lung injury: pathogenesis and implications for treatment. European Respiratory Journal, 45(5), 1463-1478.

[2] Umeda, Y., Morikawa, M., Anzai, M., Sumida, Y., Kadowaki, M., Ameshima, S., & Ishizaki, T. (2010). Acute exacerbation of idiopathic pulmonary fibrosis after pandemic influenza A (H1N1) vaccination. Internal Medicine, 49(21), 2333-2336.

[3] Sheng, G., Chen, P., Wei, Y., Yue, H., Chu, J., Zhao, J., … & Zhang, H. L. (2020). Viral infection increases the risk of idiopathic pulmonary fibrosis: a meta-analysis. Chest, 157(5), 1175-1187.

[4] Barnes, P. J., Baker, J., & Donnelly, L. E. (2019). Cellular senescence as a mechanism and target in chronic lung diseases. American journal of respiratory and critical care medicine, 200(5), 556-564.

[5] Schulz, L., Hornung, F., Häder, A., Radosa, L., Brakhage, A. A., Löffler, B., & Deinhardt-Emmer, S. (2023). Influenza virus-induced paracrine cellular senescence of the lung contributes to enhanced viral load. Aging and Disease, 14(4), 1331.

[6] Lee, S., Yu, Y., Trimpert, J., Benthani, F., Mairhofer, M., Richter-Pechanska, P., … & Schmitt, C. A. (2021). Virus-induced senescence is a driver and therapeutic target in COVID-19. Nature, 599(7884), 283-289.

[7] Born, E., Lipskaia, L., Breau, M., Houssaini, A., Beaulieu, D., Marcos, E., … & Abid, S. (2023). Eliminating senescent cells can promote pulmonary hypertension development and progression. Circulation, 147(8), 650-666.

[8] Victorelli, S., Salmonowicz, H., Chapman, J., Martini, H., Vizioli, M. G., Riley, J. S., … & Passos, J. F. (2023). Apoptotic stress causes mtDNA release during senescence and drives the SASP. Nature, 622(7983), 627-636.

Vitalist Bay

Longevity Policy, Advocacy in the Spotlight at Vitalist Bay

Just several years ago, longevity conferences were few and far between. Today, there’s no shortage of them. Happening regularly around the globe, they foster scientific debate and showcase geroscience advances to the world while energetically discussing longevity biotech and regulations.

However, one important subfield, working with public opinion and politicians, has been all but excluded from these events. Only recently, conferences have begun to offer stage time to a handful of speakers on these subjects, despite the almost universal agreement that the field’s success depends in large part on public sentiment being on our side.

The organizers of Vitalist Bay, a longevity-themed “pop-up village” which was active during April and May this year in Berkeley, California, made the next logical step. The last of the eight weekly conferences, called Longevity Policy and Media, was dedicated solely to influencing public opinion and politics in order to promote a longevist worldview.

While the conference did not turn up huge crowds, it was an important first attempt to kick-start a discussion about how the longevity movement can take over the global agenda. We are bringing you a selection of talks from the event.

Longevity as a human right

I took part in the conference in my personal capacity to deliver the opening talk, which proposed to recognize longevity as a human right. My previous journalistic career revolved around societal and political issues, including the question of human rights. Transitioning to the longevity field made me realize that we can use this extremely powerful concept to supercharge our efforts to increase healthy longevity for everyone.

Many people mistakenly think of human rights as a partisan category associated with a particular sector of the political spectrum. Nothing could be farther from the truth. Human rights are the bedrock of modern Western society. This includes the US, where the language of human rights appears already in the Declaration of Independence with its mention of “inalienable rights,” specifically to life, liberty, and the pursuit of happiness. While for a long time, large swathes of society were deprived of those rights, today, we are much closer to them being properly inclusive.

Human rights are fundamentally human, in the sense that they are not derived from any external origin, be it a deity, as the Declaration suggests, or any other moral authority lying outside our civilization. Instead, human rights have emerged from a process of cultural evolution, which has roots in biological evolution since, as social species, we’re endowed with basic empathy and a sense of fairness. Fundamentally, the concept of human rights strives to reduce human suffering. This is just one of its features that resonates with longevity, since aging is probably the biggest source of suffering in the world.

The right to longevity only partially overlaps with the right to healthcare. The latter currently does not cover or utterly neglects several aspects of longevity, such as early diagnostics or environmental factors, and in general, is not well-suited to deliver maximum longevity to everyone. The right to longevity can be seen as a direct extension of ‘The Big Three’ from the Declaration of Independence: the right to life (aging is what ends life), the right to liberty (from death and suffering), and the right to pursuit of happiness (because you need to be alive to pursue anything).

If longevity is recognized as a right, society will be expected to mount an effort to fulfill this right that would dwarf any moonshot project, such as the Apollo program, similarly to how giant sums are poured into fulfilling the right to education. Importantly, the longevity movement would not have to demonstrate scientific breakthroughs as a prerequisite for receiving society’s support. Instead, we would be able to demand funding as a prerequisite for the breakthroughs.

Taking up the language of human rights would silence many of the critics and vastly improve the longevity movement’s public image, which today suffers from many misconceptions, such as presumably being elitist and aiming at prolonging life for billionaires. Human rights are the instantly recognizable language of the mainstream. Turning to it would enable the longevity movement to attract attention, command respect, and form much broader coalitions.

Finally, longevity still has a strong economic argument behind it. In the end, it is more akin to a smart investment than spending, similar to public education and healthcare. However, by leading with the moral argument and sealing the deal with the economic one, we can achieve a much bigger impact.

A+ for communication, D- for theory of change

Adam Gries, co-founder of the Vitalism movement and one of Vitalist Bay’s organizers, talked about how effective communication hinges on the underlying theory of change: the idea of how exactly we can bring the desired outcome, in our case, meaningful life extension. “A communication strategy comes from a theory of change, which is your perspective on how the thing you want to happen will end up happening, how that change will occur,” he explained.

Some longevity activists believe we should start with a massive change in public opinion, others hold that we should free the markets, such as by doubling down on decentralized science or moving research to friendly jurisdictions. Some believe that a particular breakthrough, such as achieving life extension in pets or doubling a mouse’s lifespan, would spark a longevity revolution. Yet others think we should just wait for AI to solve aging.

Sometimes, when people in our field accuse each other of ineffective communication, they mean that they disagree with their opponent’s theory of change. However, it is normal and often beneficial when different actors are guided by different theories of change, provided they communicate effectively based on them.

Still, there is a place for discussion on several key issues, such as whether death should be mentioned in our communications. How should we as a movement self-identify? Should we really be demanding that aging be considered a disease, given that this might stigmatize the elderly, who are already disenfranchised? How optimistically should we sound, as both optimistic and pessimistic tones have their strengths and weaknesses. How strong should our language be?

Adam mentioned that marginalized communities tend to “punch back” and radicalize, alienating the mainstream even more. The longevity field should tread a fine line between being too disruptive and being too compliant; of course, various groups see that line differently. The fact that “our society is strangely bipolar about aging and death,” Adam said, does not make this task any easier.

Like several other speakers, Adam was open and almost enthusiastic about working with the new Presidential administration. Despite legitimate political disagreements that some longevity community members might have with it, “the current administration is arguably the most pro-longevity in history in terms of its staffing choices,” Adam contended, which gives our movement a window of opportunity if we can communicate our vision effectively.

Legislating longevity

In his talk, Dylan Livingston, founder of the only longevity-oriented lobbying non-profit in the US, the Alliance for Longevity Initiatives (A4LI), made the case that lobbying offers the best return on investment (ROI) for the field.

A4LI has been around for three years, pursuing its mission “to advance legislation and policy that increase healthy human lifespan with a focus on equitable access [to longevity therapies].” Dylan particularly emphasized that last point, which doesn’t get brought up enough in our field. “If we want to get broad, grassroots support from people, we need to make sure that they know that this is for everyone,” he said.

Another thing Dylan emphasized was bipartisanship. He came to longevity “from deep democratic ties,” but started working with figures on the political right, such as former House speaker Newt Gingrich, early on.

Accordingly, A4LI formed a bipartisan congressional Longevity Science Caucus, on which Dylan gave an update: some of the caucus members have retired, but some new ones joined, including Rep. Peters from San-Diego, a major biotech hub. “House is where the appropriation process starts,” said Dylan, explaining A4LI’s decision to engage first with this branch of government.

We reported on A4LI’s first DC Fly-In, a unique gathering of longevity leaders in the US capital, early last year, where the organizers had a chance to mingle with policymakers, educating them in geroscience and advancing the longevity agenda. This year, the event returned, bigger and better, with more attendees and days of activity. Governmental officials joined in, including Dr. Mehmet Oz, who was recently appointed as the administrator of the Centers for Medicare and Medicaid Services (CMS). Dylan praised Mehmet for bringing up specific longevity-related topics such as senolytics and mitochondrial dysfunction.

A4LI managed to arrange numerous meetings with congressional offices and expects 20-30 new members to join the caucus as a result. “When caucuses get to this size, they start having the ability to actually influence legislation and policy,” Dylan explained.

A4LI was actively involved in passing Montana’s bill expanding ‘right to try’ from terminally ill patients to everyone. This year, another bill was passed, laying the groundwork for the law’s practical implementation, such as licensing requirements. This should “lead to a new world where drugs and therapeutics rooted in the biology of aging can be administered,” Dylan said.

Lobbying pays dividends, Dylan argued, bringing examples from other lobbying efforts, such as by the Alzheimer’s Foundation and military contractors. He finished by recounting the organization’s plans: to continue to grow the caucus, introduce a longevity-related bill based on their white papers in 2027, and get a White House Council on Longevity Policy established.

He also mentioned some challenges, including those coming from the new administration. “NIH is under deep scrutiny, and NIA seems to be on its way out,” he said. While this is deeply worrying, the possible demise of NIA also provides an opportunity to build something new.

The political right’s embrace of longevity

Dylan’s talk served as a nice segue to the next one, given by Breanna Deutsch, a former political operative who has been working in conservative politics since 2014, first in Congress and then at a conservative think tank. Today, Breanna is in the tech industry, but “still immersed in this world, including Trump’s world,” she said. Breanna is also the author of the 2020 book Finding the Fountain: Why Government Must Unlock Biotech’s Potential to Maximize Longevity.

She started by analyzing how Republicans’ attitudes towards health and wellness have evolved in the last 10-15 years. Back then, Breanna said, these topics were largely off Republicans’ radar, the overall attitude being, “Give me my McDonald’s and my big soda and don’t lecture me about it.” Eating healthy food was considered a very un-masculine thing to do.

Today, Breanna noted, the rhetoric has flipped: “Now conservatives say that we’re being poisoned by those big companies, our food is laced with chemicals, and the government needs to get involved to fix it.” Conservatives are also more open to looking beyond the traditional healthcare system, which they now distrust due to the opioid epidemic and the COVID-era mandates. While this can increase the popularity of “snake oil” cures, it also makes the political right less skeptical about the longevity message. Of course, the healthy lifestyle has become masculine, promoted by people like Joe Rogan.

In part, this shift has been brought about by Trump’s populist message, Breanna said. The party that was associated with the establishment, including medical and business establishments, has become imbued with a strong disdain for consensus. This and the conspiratorial touch led to the rage against Big Pharma that once was reserved for the political left.

All this led to the rise of Robert F. Kennedy Junior with his mixed message that has at least some longevity-aligned elements, such as eating healthy. RFK brought many longevity advocates with him to Washington, such as Jim O’Neill, former CEO of SENS Research Foundation. Some policy actions that are already underway include creating a commission to investigate chronic diseases, most of which are age-related.

Breanna acknowledged the serious challenges that Trump’s administration has created, such as the deep cuts to the NIH budget and the cancellation of research grants. This should be fought with lobbying, she suggested, because Congress has control of the purse. Yet, having high-level officials who understand and are aligned with the longevity movement could also pose an opportunity to refocus the funds.

The ‘wise view’ defends the indefensible

Philosopher Patrick Linden is the author of The Case Against Death, probably the best book that deals (quite convincingly) with various ethical and practical arguments against life extension, or, as he puts it, “goes through all the most important defenses people have made on behalf of death.”

According to Patrick, the main idea of his book is quite elementary: life is good, death is bad. “It seems like a simple message,” he said. “Why, as a philosopher, do I have to defend this thesis? Because people would argue against it.”

The view that death should be embraced (not when it’s “untimely,” however, which is an interesting cultural paradox) has permeated human culture since Socrates and Plato. While it often has religious underpinnings, non-religious thinkers, starting with Epicurus, have been normalizing or hallowing death too, for instance, as a pillar of the “natural order of things.”

Today, you can still hear it from people like the bioethicist Leon Kass, who said, “Death is a blessing for every human individual whether he knows it or not,” or Elon Musk, who once said, “I don’t think we should try to have people live for a really long time.” Patrick mockingly calls this the ‘wise view’ since it is deemed to be intellectually and morally superior to the “foolish” and “egoistic” fear of death.

The situation is no better in popular culture. Patrick mentioned Yoda, who “sounds like a stoic” when he says that death is a natural part of life. He also recounted a fascinating anecdote about asking an AI model to think up a title for a popular philosophy book about longevity and death. The model’s first suggestion was “Eternal Reflections: Embracing Mortality.”

Polls show that many people who would not want to live past the “natural” lifespan of about 85 years are convinced that their brethren would. “They’re basically saying, longevity is not for me, but those other people probably can’t resist it,” Patrick quipped, “because they think they’re wiser than most. Not wanting to be sick is socially acceptable, but not wanting to age or die is taboo.”

Even today’s fascination with healthspan, the part of life lived in good health, amounts to normalizing death, according to Patrick. In a recent poll, 65% would want to only live to 85 if they are guaranteed both mental and physical youthfulness. “Why do we have to talk about more than health?” Patrick said. “Because it’s too modest a goal to live healthy until 85 and then drop dead. Health is good, but existence, not being dead, is first.”

Patrick argued that not just our intelligence and physical health, but our consciousness itself is precious, even if we are experiencing decline. He told the audience about his father, who recently passed away. Being severely disabled, he hoped until his last day to enjoy the view of the blooming tree growing outside his window. For Patrick, this was a powerful reminder of how strong our will to live remains till the very end, and how often people underestimate this urge when asked about it earlier in life.

Vitalist Bay Art

Part of the longevist art exhibition at Vitalist Bay

Advocacy with a single-issue political party

Felix Werth, who came to Vitalist Bay all the way from Germany, is the founder and chairman of this country’s Party for Rejuvenation Research (Partei für Verjüngungsforschung). Germany has a well-developed multi-party system that gives a fair chance to single-issue parties, provided they can sweep enough votes.

The party was founded a decade ago and has participated in 24 elections, including two European, three federal, and 17 state elections. The best result it has achieved was 0.5% of the vote in three state elections, ten times less than the electoral threshold required to get your representatives in.

However, it’s not just about the result. Participating in an election gives you a voice and visibility, especially in countries like Germany, where the state facilitates election propaganda for parties.

To participate in an election, a party needs to collect signatures. “This is already very good public outreach that gives you a reason to approach strangers on the street and educate them about longevity,” Felix said.

When the required number of signatures is collected and the party is admitted to the election, the real outreach starts. In many countries, including Germany, parties get free airtime on TV and radio, often at prime time. As a result, millions of people watched Felix’s party’s TV ads aired on Saturday evening.

Naturally, TV ads are also shared on social media. The two ads produced by the party were viewed hundreds of thousands of times on online platforms. Reach is often a function of creativity and can be immense.

Parties are also allowed to hang up election posters for free, 6-8 weeks prior to the election. The idea is to choose prime locations, such as pedestrian shopping streets. Passersby take photos of the posters and distribute them on their social media.

The media also shows interest in covering quirky parties that advocate for a single issue, even if as entertainment. Felix was proud about his party getting on a top German satirical show; after all, there’s no bad publicity. The one-minute-long segment was watched by five million viewers and later amassed almost two million YouTube views.

The party was also widely covered by newspapers with headlines such as “The Party That Fights Against Aging.” Finally, election participation drives people to the party’s website, where they can get a more thorough view of its agenda.

While the electoral barrier looks out of reach for now, if you get more votes, you can lobby bigger parties to include your agenda in their program, Felix said. He also invited US-based longevity activists to come to Germany and participate in signature collection, which he touted as a great experience.

Transhumanism and vitalism

The next speaker was also presenting a party he had founded: an extremely unusual combination for a longevity conference. Gennady Stolyarov II, chairman of the US Transhumanist Party, said his aim was to persuade the audience that “openly transhumanist politics are necessary for vitalism to succeed.”

“The core message of transhumanism,” he said, “is that through science, technology, and reason, we can overcome the obstacles that have historically plagued the human condition, the most important one being involuntary death, but also diseases, poverty, scarcity, war, pollution, tribalism, etc.” According to Gennady, transhumanism seeks not to replace humans but to enable them to lead their best lives and fully realize their potential.

Significant life extension is one of the party’s core values, along with fostering “a cultural, societal, and political atmosphere informed and animated by reason, science, and secular values,” and using science and technology to reduce or eliminate the existential risks to the human species.

A bit oxymoronically, the Transhumanist Party is non-partisan relatively to the two big American parties, with a focus “on policy rather than politics.” It is careful not to alienate anybody from the conventional political spectrum, but also happy to disagree with them, Gennady said.

The party is unabashedly “radical” in its approach to life extension and does not shy away from talking about immortality. Here, however, the message is also very inclusive. Transhumanists are fine with talking about healthspan, they just don’t think that we should stop there.

An ambitious goal, Gennady said, is inspiring and motivating. “How many of you would have attended if it were called The Healthy Aging Bay?” he asked rhetorically, adding that “we need a far-reaching vision to inspire a civilizational shift.”

The longevity movement needs transhumanists, Gennady argued, because transhumanism expands the Overton window of possibilities. “The current Overton window doesn’t encompass the reforms that we want,” he said, “but if transhumanism shifts that window, then those reforms would be well within it.” He cautioned against the approach of “strategic conservatism” that’s recently become popular in the longevity field.

Gennady quoted the 19th-century abolitionist William Lloyd Garrison: “Urge immediate abolition as earnestly as we may, it will alas be gradual abolition in the end. We have never said that slavery would be overthrown by a single blow. That it ought to be, we shall always contend.”

“We should always contend that innocent human death should be abolished immediately,” Gennady explained. “Without advocating for immediate abolition, it will be even more gradual.”

Like with Felix’s party, the electoral successes of the Transhumanist Party over its ten years of existence are few. This predicament is exacerbated by the country’s two-party system that severely limits horizons for any new player. Yet, Gennady said that even participating in elections and political process in general brings visibility and opportunities for advocacy.

Patients as catalysts: the hidden force behind healthcare policy reform

Melissa King presented another interesting organization: Healthspan Action Coalition, which she co-founded with Bernard Siegel, also an experienced patient advocate, about three years ago.

Melissa and Siegel met in 2004 while working on a ballot initiative campaign in California that founded the California Institute for Regenerative Medicine (CIRM). CIRM is focused on stem cell and gene therapies and funded with billions of state dollars.

Today, according to Melissa, it is still a unique state-level agency, and its projects are driving actual cures. CIRM’s connection to the longevity field may be best illustrated by the fact that it funded research by Shinya Yamanaka, the father of cellular reprogramming.

In 2020, as the original CIRM funding was running out, Melissa spearheaded another advocacy effort, and a new ballot initiative was passed to fund CIRM with another 5.5 billion dollars with the help of patients turned advocates. “By getting this funding, we provided great competitiveness for California, and we’re a true leader in regenerative medicine,” Melissa said. She argued that we need more public funding for science because “private funding doesn’t come in as early.”

The Healthspan Action Coalition (HAC) has been rapidly growing and now includes 216 members from the fields of longevity research, biotech, venture capital, and advocacy. Any organization that shares the coalition’s values is free to join, Melissa said, adding that she wants the movement to become global.

Decades of patient advocacy have shown the power of this approach, with diseases such as diabetes, cancer, and HIV. When patients and their families have to become activists to get the funding, the chances of them succeeding are high.

With aging, of course, everyone is a patient, which makes patient advocacy a particularly powerful tool, if we can engage enough people and change their mindset about longevity. This, in turn, requires ramping up efforts to provide information on longevity and geroscience. “Come out and talk to people, because you’re informed,” Melissa urged the audience.

Today, HAC is working on leveraging its impressive membership to change minds and policies. Work is ongoing on the Therapeutic Healthspan Research, Innovation, and Validation Enhancement (THRIVE) Act, which HAC hopes to promote with legislators. “We invite everyone to be part of this conversation,” Melissa said. She closed with two powerful quotes. The first one comes from Abraham Lincoln: “Public sentiment is everything. With public sentiment, nothing can fail. Without it, nothing can succeed.”

The second one is by the famous anthropologist Margaret Mead: “Never doubt that a small group of thoughtful, committed citizens can change the world, indeed, it’s the only thing that ever has.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Glial cell

Engineering Microglia to Deliver an Anti-Alzheimer’s Drug

In Cell Stem Cell, researchers have described how genetically engineered microglia can be used to deliver therapeutic proteins to the brain.

The blood-brain barrier

Delivering therapeutic compounds to the brain has a concern that is absent for other organs: the blood-brain barrier (BBB), which retains strict controls over the kinds of compounds that can reach the brain and thus protects it from contamination. Deterioration of the BBB can lead to significant neurological problems [1]. However, the BBB can also prevent therapeutic compounds from entering it, which has represented a significant problem in drug delivery [2].

Getting around the BBB may involve invasive methods, such as directly injecting compounds or neural stem cells (NSCs) into brain tissue, or virus-based gene therapy. However, all of these methods have their own limitations and concerns; NSCs may form tumors [3], and virus-based approaches may cause inflammation [4]. If the goal is simply to deliver a protein into the brain, these sorts of methods may do more harm than necessary.

These researchers, therefore, have chosen mature microglia, helper cells in the brain, as their therapeutic vector. These cells do not form tumors [5], and previous work has found that they can properly engraft into models [6].

Responsive to plaques

The researchers developed a mouse model that does not create its own microglia and accumulates amyloid plaque. They also engineered induced pluripotent stem cells (iPSCs) to create microglia (iMG) that generate neprilysin, an enzyme that degrades amyloid beta, upon sensing these plaques through the receptor CD9.

Initial analysis suggested that this approach worked. These iMG only expressed CD9 alongside plaques rather than throughout the brain. Further work found that this extended to neprilysin as well; the researchers also noted that a secreted-neprilysin (sNEP) approach, as opposed to simply generating neprilysin on the membrane (NEP), led to more distribution of this therapeutic compound.

This secretion approach also improved the microglia’s ability to clear these plaques through phagocytosis in vitro. Compared to ordinary human microglia, NEP microglia consumed amyloids at 1.5 times the speed, and sNEP microglia consumed amyloids twice as fast. These benefits were found in the mouse model as well; these microglia were often able to penetrate and degrade amyloid beta, decreasing amyloid burden in general and reducing the sizes of amyloid plaques in the brain.

There were benefits for synapses, which disintegrate rapidly in these model mice [7], as measured by the crucial synaptic protein synaptophysin (SYP). NEP microglia had no statistically significant effect on SYP; however, sNEP microglia restored levels of this protein approximately to those of a control group. These levels were found to be significantly correlated with the expression of neprilysin.

Like human Alzheimer’s patients, these model mice develop astrogliosis [8], an inflammatory increase in the prevalence of astrocytes. In the hippocampus, mice given sNEP microglia enjoyed a significant reduction in GFAP, a protein related to astrogliosis; however, this reduction was not to the level of the control group.

Fortunately, other proteins that are known to be targets of neprilysin were not affected in unrelated regions of the brain, showing that the localization was effective in this model. The researchers also found that “widespread engraftment of sNEP-microglia is not necessary to achieve brain-wide reductions in amyloid species”; targeting the hippocampus and cortex with precise injections of iMG were enough.

The reduction in amyloid was also accompanied by a tremendous reduction in inflammation. Key inflammatory proteins, including interleukins, had levels indistinguishable from those of a control group, despite these proteins normally being highly elevated in this Alzheimer’s model.

This is extremely early-stage research, and the authors describe their study as a proof of principle. Nearly every element of this study was carefully controlled at the genetic level; wild-type mice were not involved. Whether or not iPSC microglia can be made suitable for human use is still an open question, but if successful, this approach may open the door for the delivery of otherwise unfeasible drugs.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Profaci, C. P., Munji, R. N., Pulido, R. S., & Daneman, R. (2020). The blood–brain barrier in health and disease: Important unanswered questions. Journal of Experimental Medicine, 217(4), e20190062.

[2] Terstappen, G. C., Meyer, A. H., Bell, R. D., & Zhang, W. (2021). Strategies for delivering therapeutics across the blood–brain barrier. Nature Reviews Drug Discovery, 20(5), 362-383.

[3] Amariglio, N., Hirshberg, A., Scheithauer, B. W., Cohen, Y., Loewenthal, R., Trakhtenbrot, L., … & Rechavi, G. (2009). Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS medicine, 6(2), e1000029.

[4] Prasad, S., Dimmock, D. P., Greenberg, B., Walia, J. S., Sadhu, C., Tavakkoli, F., & Lipshutz, G. S. (2022). Immune responses and immunosuppressive strategies for adeno-associated virus-based gene therapy for treatment of central nervous system disorders: current knowledge and approaches. Human gene therapy, 33(23-24), 1228-1245.

[5] Zong, H., Parada, L. F., & Baker, S. J. (2015). Cell of origin for malignant gliomas and its implication in therapeutic development. Cold Spring Harbor perspectives in biology, 7(5), a020610.

[6] Chadarevian, J. P., Hasselmann, J., Lahian, A., Capocchi, J. K., Escobar, A., Lim, T. E., … & Blurton-Jones, M. (2024). Therapeutic potential of human microglia transplantation in a chimeric model of CSF1R-related leukoencephalopathy. Neuron, 112(16), 2686-2707.

[7] Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., … & Vassar, R. (2006). Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. Journal of Neuroscience, 26(40), 10129-10140.

[8] Oakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., … & Vassar, R. (2006). Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. Journal of Neuroscience, 26(40), 10129-10140.

Older woman's brain

Longer Reproductive Spans Linked to Younger Brains in Women

Analysis of over a thousand postmenopausal women suggests that women with longer reproductive spans, earlier first period (menarche), and later menopause experience slower brain aging [1].

Linking sex hormones to brain health

The female reproductive system fails to work properly much earlier than other systems in the human body. The aging of the reproductive system not only prevents females from bearing children relatively early in life, it also impacts the aging process of other organs. The brain is a prominent example, as the risk of developing dementia increases around menopause [2].

The aging of the reproductive system is tightly linked to the levels of female sex hormones, including estrogen. The most prevalent form of estrogen in the female body is estradiol.

Changes in estradiol levels are linked to milestones in a woman’s reproductive life. Estradiol levels start to increase before menarche and remain elevated until the first age-related missed period (perimenopause). At perimenopause, estradiol levels begin to decrease. This decrease in estradiol levels persists through menopause and postmenopause, resulting in low estradiol levels.

The researchers suggest that a decrease in estradiol might be an essential factor in developing dementia and other age-related neuropathologies in the female population.

Such a link is supported by animal studies that demonstrate estradiol’s role in brain health-promoting processes, including the promotion of synaptic plasticity, enhancement of neurogenesis, and protection against oxidative stress and neuroinflammation [3-5]. In human studies, although some research suggests that the timing of menarche and menopause is an essential risk factor for dementia, the link between brain health and estradiol is not as definitive.

The authors of this study aimed to better understand of the relationship between brain aging and the female reproductive span (the period between menarche and menopause), which is characterized by high levels of estradiol.

The age of the brain

To assess brain age, 1,006 postmenopausal women underwent structural magnetic resonance imaging (MRI) scans: one initial brain scan and one follow-up brain scan approximately 2 years later.

The researchers used these images to estimate each brain’s age and then calculate BrainAGE, the difference between this estimate and the participant’s chronological age. BrainAGE combines complex changes in different areas of brain structure into a single biomarker that can be used as a predictor of dementia and age-related cognitive decline. The difference in BrainAGE between the two time points was used in the longitudinal analysis.

Longer reproductive span, younger brain

The researchers conducted two types of analysis: a cross-sectional analysis that examined a specific section of the population at a particular time point and a longitudinal analysis that tracked changes over time.

They analyzed the relationship between reproductive span, age at menarche, age at menopause, and BrainAGE for the cross-sectional analysis or the change in BrainAGE for the longitudinal study.

Both types of analysis revealed similar results. First, the researchers reported a significant negative association between BrainAGE and change in BrainAGE (depending on the analysis) and reproductive span, indicating that females with longer reproductive spans had younger brains compared to those with shorter reproductive spans. However, the effects are relatively small in both types of analyses.

There was also a negative association between BrainAGE, the change in BrainAGE, and age at menopause: each year older at menopause corresponded to 0.1 years younger in brain age in the cross-sectional analysis and 0.06 years younger in the longitudinal study.

The researchers observed a significant positive association between BrainAGE, the change in BrainAGE, and age at menarche. Their estimation shows that each year younger at menarche corresponded to a brain that is 0.32 years younger in the cross-sectional analysis and 0.08 years younger in the longitudinal study.

Even when the researchers accounted for many variables, such as the number of live births, hormone replacement therapy, removal of uterus or ovaries, body mass index, blood pressure, diabetes, education, income, and a composite lifestyle factor, the results were similar and statistically significant except for age of menarche in the longitudinal analyses.

While both menarche and menopause appear to contribute to brain aging, the strength of the association and the rate of change with age vary. The researchers suggest that different underlying biological mechanisms can cause it.

They suggest that during menopause, there are more biological mechanisms at play than just a decrease in estradiol levels, such as increasing levels of follicle-stimulating hormones, which might lead to an increased deposition of amyloid-β and tau [6]. Apart from hormonal changes, menopause is also associated with inflammation, which can play a role in brain health [7].

They also suggest that older women are less likely to accurately remember age at menarche, making those estimations less reliable.

The window of opportunity

The researchers discuss how the results of their study align with previous findings, which all point towards the positive impact of estradiol on brain health and its neuroprotective properties.

“These findings support the idea that estradiol, the most potent and prevalent form of estrogen during a woman’s reproductive years, may help protect the brain as it ages,” said lead researcher Associate Professor Eileen Lueders from the University of Auckland’s School of Psychology.

The study’s authors also believe their findings align with the concept of a ‘window of opportunity’ (which we discussed before). This concept suggests that hormonal interventions such as hormone replacement therapy, to be effective against dementia, should be started around the menopausal transition.

“It’s encouraging to see research shedding light on how a woman’s reproductive years may shape brain health later in life,” says Alicja Nowacka, a Ph.D. student at the University of Auckland who was not involved in the study.

“As more women weigh the benefits of hormone therapy during menopause, findings like these spark important conversations and open the door to more inclusive, focused research in women’s brain health.”

Expanding the research

While the study’s results were interesting and contributed to a better understanding of women’s health, the authors call for future expansion of the study, as this analysis had several limitations. First, the study sample was relatively small and lacked diversity in ethnicity and socioeconomic status, which restricts the generalizability of the results.

Additionally, while menarche and menopause correlate with changes in female sex hormones, including estradiol, those were not directly measured. Future studies should address this, as the interplay between brain health and estradiol levels may be complex and sensitive to subtle changes in estradiol levels. There may also be other factors that can impact brain health, such as lifestyle choices and genetic makeup, which should be taken into consideration in the analysis.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Luders, E., Poromaa, I. S., Barth, C., & Gaser, C. (2025). A Case for estradiol: younger brains in women with earlier menarche and later menopause. GigaScience, 14, giaf060.

[2] Mosconi, L., Rahman, A., Diaz, I., Wu, X., Scheyer, O., Hristov, H. W., Vallabhajosula, S., Isaacson, R. S., de Leon, M. J., & Brinton, R. D. (2018). Increased Alzheimer’s risk during the menopause transition: A 3-year longitudinal brain imaging study. PloS one, 13(12), e0207885.

[3] Vegeto, E., Benedusi, V., & Maggi, A. (2008). Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases. Frontiers in neuroendocrinology, 29(4), 507–519.

[4] Behl, C., Widmann, M., Trapp, T., & Holsboer, F. (1995). 17-beta estradiol protects neurons from oxidative stress-induced cell death in vitro. Biochemical and biophysical research communications, 216(2), 473–482.

[5] Tanapat, P., Hastings, N. B., Reeves, A. J., & Gould, E. (1999). Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. The Journal of neuroscience : the official journal of the Society for Neuroscience, 19(14), 5792–5801.

[6] Xiong, J., Kang, S. S., Wang, Z., Liu, X., Kuo, T. C., Korkmaz, F., Padilla, A., Miyashita, S., Chan, P., Zhang, Z., Katsel, P., Burgess, J., Gumerova, A., Ievleva, K., Sant, D., Yu, S. P., Muradova, V., Frolinger, T., Lizneva, D., Iqbal, J., … Ye, K. (2022). FSH blockade improves cognition in mice with Alzheimer’s disease. Nature, 603(7901), 470–476.

[7] Mishra, A., & Brinton, R. D. (2018). Inflammation: Bridging Age, Menopause and APOEε4 Genotype to Alzheimer’s Disease. Frontiers in aging neuroscience, 10, 312.

Older people with financial problems

Financial Behavior Might Help Diagnose Dementia Early

By analyzing a large UK dataset, scientists have identified various financial behaviors that might point to dementia years before it leads to loss of financial capacity [1].

The money trail

Alzheimer’s disease and related dementias remain a particularly hard nut for scientists to crack. One commonly mentioned problem is that dementia is usually diagnosed relatively late, when current treatments are already ineffective. Preclinical studies have shown promising results when given at the early stages of such diseases, but in the real world, early detection in humans is a challenging task.

This creates a need for non-clinical early dementia markers, which might be hidden in behavioral patterns. However, such behaviors must leave a detectable footprint. Wearable devices are becoming more prevalent, creating a wealth of personal health data that can be used for disease diagnostics, but what if we go for something seemingly unrelated to health, like financial transactions?

Financial behavior leaves a detailed digital trail, and several recent studies have linked it to cognitive decline [2]. However, this hardly needs studies to verify, as it is well known that elderly people become less financially organized and begin falling prey to scams.

Clear signs years before loss of capacity

In a new study, published in JAMA Network Open, researchers from the University of Nottingham in the UK used banking data to investigate whether financial behaviors could serve as early indicators of a decline in financial capacity, which supposedly correlates with dementia.

This case-control study analyzed the anonymized banking records of 16,742 people who had a “loss of financial capacity” (LFC) marker noted when a power of attorney (PoA) was registered with a major UK bank. This LFC group was compared to a control group of about 50,000 people with no reported loss of financial capacity.

The LFC group had a mean age of 72.8 years and was 61.4% female. The control group was closely matched for demographic and socioeconomic characteristics, with a mean age of 72.7 years and 61.0% being female. The study examined 344 financial measures over a 10-year period leading up to the PoA registration. To account for multiple comparisons, the researchers used a particularly robust permutation approach with 1000 iterations.

The results revealed significant differences in the financial behaviors of the two groups. Five years before the PoA registration, the LFC group, compared to the control group, showed decreased average spending on clothing by 9.1 percentage points, travel by 9.6 percentage points, and hobbies by 7.9 percentage points. Conversely, the LFC group was more likely to spend more on items associated with increased time at home, such as household gas and electricity bills, by 5.1 percentage points.

Spending habits change

The LFC group also showed signs of heightened financial vulnerability, including more frequent PIN reset requests, an increase in reported fraud cases, more frequent reports of lost or stolen credit or debit cards, and slightly increased spending on charity. People in the LFC group demonstrated reduced attention to their finances, with a lower number of monthly online banking logins.

“These patterns provide the first large-scale evidence that behavioral data held by financial institutions can reveal the early emergence of cognitive decline,” said Professor John Gathergood, of the University of Nottingham School of Economics. “It is a powerful demonstration of how anonymized banking data can be used responsibly to protect the most vulnerable members of society.”

The data that’s already there

The study had significant limitations, the most obvious being a lack of formal diagnoses in the LFC group. While tying LFC status to dementia is a valid assumption, analyzing a sample of people with proven dementia is a more robust approach that will hopefully be explored in future studies.

Many experts think that “liberating the data” that already exists and is being gathered by various institutions can accelerate progress in biology and geroscience in particular. This, however, requires interlinked changes in regulation and public opinion. “In contrast to biomarkers,” the paper says, “cognitive and functional measures, such as behavioral financial data, are already stored in large volumes by financial institutions, which have a direct interest in protecting vulnerable customers.”

“As a society, we need to better support people at risk of losing financial capacity long before the signs become obvious to friends or family,” Professor Gathergood added. “Early detection through financial behavior may be a key part of that solution. By better understanding behavioral markers of declining capacity, banks can explore how to strengthen safeguards for customers.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Trendl, A., Anwyl-Irvine, A., Vomfell, L., Abbey, E., Stewart, N., Atkins, D., … & Leake, D. (2025). Early Behavioral Markers of Loss of Financial Capacity. JAMA Network Open, 8(6), e2515894-e2515894.

[2] Cloutier, S., Chertkow, H., Kergoat, M. J., Gélinas, I., Gauthier, S., & Belleville, S. (2021). Trajectories of decline on instrumental activities of daily living prior to dementia in persons with mild cognitive impairment. International Journal of Geriatric Psychiatry, 36(2), 314-323.

Liposome

A New Method of Modifying Stem Cells

Researchers have investigated a never-before-used method of transfecting senescent mesenchymal stem cells (MSCs) and published their results In the Cell journal Molecular Therapy Nucleic Acids.

Detergents for gene therapy

Altering the genetics of a living person is much trickier than altering them in cells in a dish, and it requires entirely different approaches. One of the most obvious concerns is the reliability of the intervention itself; cells in a dish can be simply thrown away if they are found to be unsuitable, but a flawed gene therapy in a person may lead to cancer.

The most well-known method of delivering gene therapy is with a viral vector; however, such an approach carries its own risks, including both cancer and an inflammatory immune reaction that may accelerate aging [1]. Liposomes, particles made out of fat molecules, are the most commonly investigated replacements [2]; however, they carry their own risks of toxicity, and they are not as effective as viruses in delivering genes [3].

Niosomes are similar to liposomes, except that they replace phospholipids with non-toxic polysorbate compounds that are found in commercial detergents [4]. Previous work has investigated niosomes in such contexts as bone regeneration [5] and retinal therapy [6]. The best formulation for niosomes for any particular use is still in question, and these researchers have investigated how such additions as squalene [7], cholesterol, and even simple sucrose [8] might increase transfection.

To the researchers’ knowledge, using niosomes to alter the genes of senescent MSCs has never been previously attempted, and so they investigated multiple formulations to determine which is the most effective.

Testing multiple formulations

This work used two separate populations of umbilical cord-derived MSCs that were driven senescent through the application of Palbociclib, which disrupts the normal cell cycle. These cells were confirmed to be senescent by both morphology and by SASP factors such as interleukins and CDKN1A.

The researchers complexed together their niosomes with reporter DNA (nioplexes) at different ratios, using either squalene or cholesterol in the presence or absence of sucrose. At specific DNA ratios, sucrose appeared to greatly increase particle size with squalene, although there was no linear relationship between particle size and DNA ratio. Sucrose seemed to suppress particle size with cholesterol at certain ratios, although there was still no linear relationship. Previous work has noted that cells find smaller particles easier to uptake [9].

There was a significant and noticeable relationship between sucrose and the ability of cholesterol-containing niosomes to properly complex, and thus protect, DNA, especially at the lowest ratios that contained more DNA. These results were not seen with squalene.

The differences between squalene and cholesterol when applied to cells, however, were stark when made in the absence of sucrose. Nioplexes made with squalene, particularly at a 10-to-1 niosome-to-DNA ratio, were excellent at transfecting non-senescent cells in both populations. However, these nioplexes, similar to the commonly used lipofectamine, were far worse at transfecting senescent cells than nioplexes made with cholesterol. The effectiveness of all nioplexes slightly dwindled between 24 hours and 72 hours.

Sucrose increased the effectiveness of both squalene and cholesterol-based formulations on senescent cells. At most ratios, the effect at 72 hours was even stronger than at 24, demonstrating an increase in lasting effectiveness.

With or without sucrose, however, nioplexes were far safer for cells than lipofectamine. This work showed that lipofectamine is highly toxic, killing large proportions of MSCs exposed to it, in both senescent and non-senescent groups. Neither squalene nor cholesterol formulations without sucrose led to an increase in mortality over controls, and adding sucrose only led to a very slight increase.

Interestingly, senescent and non-senescent cells were found to uptake the nioplexes through different methods of endocytosis, as confirmed by treatments that blocked these forms. Additionally, all of the tested therapies slightly increased SASP expression from cells that were already senescent.

This study was specifically on niosomes and nioplexes, focusing on targeting rather than a treatment’s potential effectiveness. The cells were not being modified to do anything other than report that they had been transfected, and there were no animals involved. Creating appropriate gene therapies to load into these niosomes, and determining that they are safe in living organisms, is the domain of future research.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Fafián-Labora, J. A., & O’Loghlen, A. (2020). Classical and nonclassical intercellular communication in senescence and ageing. Trends in Cell Biology, 30(8), 628-639.

[2] Mitchell, M. J., Billingsley, M. M., Haley, R. M., Wechsler, M. E., Peppas, N. A., & Langer, R. (2021). Engineering precision nanoparticles for drug delivery. Nature reviews drug discovery, 20(2), 101-124.

[3] Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014). Non-viral vectors for gene-based therapy. Nature reviews genetics, 15(8), 541-555.

[4] Villate-Beitia, I., Gallego, I., Martínez-Navarrete, G., Zárate, J., López-Méndez, T., Soto-Sánchez, C., … & Pedraz, J. L. (2018). Polysorbate 20 non-ionic surfactant enhances retinal gene delivery efficiency of cationic niosomes after intravitreal and subretinal administration. International Journal of Pharmaceutics, 550(1-2), 388-397.

[5] Attia, N., Mashal, M., Grijalvo, S., Eritja, R., Zárate, J., Puras, G., & Pedraz, J. L. (2018). Stem cell-based gene delivery mediated by cationic niosomes for bone regeneration. Nanomedicine: Nanotechnology, Biology and Medicine, 14(2), 521-531.

[6] Puras, G., Martínez-Navarrete, G., Mashal, M., Zarate, J., Agirre, M., Ojeda, E., … & Pedraz, J. L. (2015). Protamine/DNA/niosome ternary nonviral vectors for gene delivery to the retina: the role of protamine. Molecular pharmaceutics, 12(10), 3658-3671.

[7] Carballo-Pedrares, N., Sanjurjo-Rodriguez, C., Señarís, J., Díaz-Prado, S., & Rey-Rico, A. (2022). Chondrogenic differentiation of human mesenchymal stem cells via SOX9 delivery in cationic niosomes. Pharmaceutics, 14(11), 2327.

[8] Carballo-Pedrares, N., Kattar, A., Concheiro, A., Alvarez-Lorenzo, C., & Rey-Rico, A. (2021). Niosomes-based gene delivery systems for effective transfection of human mesenchymal stem cells. Materials Science and Engineering: C, 128, 112307.

[9] Singh, J., Michel, D., Chitanda, J. M., Verrall, R. E., & Badea, I. (2012). Evaluation of cellular uptake and intracellular trafficking as determining factors of gene expression for amino acid-substituted gemini surfactant-based DNA nanoparticles. Journal of nanobiotechnology, 10, 1-14.

Blood vessel cells

A Popular Sweetener Adversely Affects Blood Vessels

A new study has lent more support to previous epidemiological data that ties the popular sugar substitute erythritol to elevated cardiovascular risk [1].

Deceptively sweet

Sugar substitutes have been around for decades, and while some people have reported decreases in weight and blood glucose, a growing body of research suggests there might be some downsides to guiltless sweetness.

Recent epidemiological studies have found a link between the popular sweetener erythritol and increased cardiovascular and cerebrovascular risk. A study from 2023 showed that elevated erythritol levels were positively associated with non-fatal and fatal heart disease and stroke, both in males and females, across several population subgroups in the United States and Europe [2].

Populational studies can neither establish a causal relationship nor provide a mechanistic explanation. However, in this case, the researchers also conducted a small prospective trial showing that exposure to an equivalent of 30 grams of erythritol, the usual dose found in one standard-size artificially sweetened drink, significantly increases clot-forming (thrombogenic) potential both in vitro and in vivo. A new study from the University of Colorado Boulder, published in the Journal of Applied Physiology, went even further, revealing a possible mechanism behind this association.

Multiple signs of cardiovascular dysfunction

The researchers worked on an in vitro model based on brain microvascular endothelial cells. These cells line capillaries in the brain and are important for maintaining healthy blood flow, blood-brain barrier integrity, and low inflammation levels. “Endothelial cell dysfunction is a major antecedent to heart disease and stroke,” the authors wrote, “however, the effects of erythritol on endothelial cell function are not well understood.”

After subjecting the cells to the same dose of erythritol as in the earlier 2023 study for 24 hours, the researchers found that the levels of reactive oxygen species (ROS), harmful molecules that can oxidize and damage DNA, proteins, and lipids, accelerating aging and disease processes, was 75% higher than in control cells.

Expression of catalase and SOD-1 was 25% and 45% higher, respectively. Catalase is an antioxidant enzyme that breaks hydrogen peroxide down into water and oxygen, and SOD-1 converts superoxide radicals into less-reactive hydrogen peroxide. Together, they form a frontline enzymatic shield against oxidative stress, which the cells apparently used with limited success, to mitigate the increased levels of ROS.

According to the paper, these results suggest that, at minimum, erythritol does not negatively affect cells’ antioxidant machinery. “However,” the authors note, “we cannot rule out the possibility that longer exposure or repeated chronic exposure to erythritol would result in diminished SOD-1 and catalase bioavailability and in further exacerbation of ROS production.”

The researchers then assessed the production of nitric oxide (NO), a compound that relaxes blood vessel walls, curbs platelet sticking, and dampens inflammation to preserve healthy vascular tone and endothelial function. They found changes in phosphorylation, a type of post-translational modification, of eNOS, an enzyme central to NO production, which ultimately resulted in a 20% decrease in NO production. Diminished NO bioavailability is a hallmark of endothelial dysfunction and is linked to elevated cardiovascular risk [3].

Another worrying sign was that erythritol treatment caused a 30% increase in endothelin-1, a peptide that constricts blood vessels, elevates blood pressure, and fosters vascular inflammation. Along with lower NO availability, this can eventually lead to disrupted blood flow and increased risk of stroke.

Lastly, the researchers assessed the levels of t-PA, the enzyme that transforms plasminogen, an inactive blood protein, into plasmin, the active form that chews through fibrin and melts clots. Baseline t-PA levels were identical in the treated and control cells. However, erythritol blunted the increase in t-PA in response to thrombin, which is how an endothelial cell reacts to clotting risk.

Approach with caution

The researchers admit that in vivo studies are needed to confirm their findings. However, this is already an important addition to the current epidemiological data that points to potential cardiovascular risks from artificial sweeteners.

“While erythritol is widely used in sugar-free products marketed as healthier alternatives, more research is needed to fully understand its impact on vascular health,” said Auburn Berry, a graduate student at the University of Colorado Boulder and first author of the study. “In general, people should be conscious of the amount of erythritol they are consuming on a daily basis.”

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Berry, A. R., Ruzzene, S. T., Ostrander, E. I., Wegerson, K. N., Fersiva, N. O., Stone, M. F., … & DeSouza, C. A. (2025). The Non-Nutritive Sweetner Erythritol Adversely Affects Brain Microvascular Endothelial Cell Function. Journal of Applied Physiology.

[2] Witkowski, M., Nemet, I., Alamri, H., Wilcox, J., Gupta, N., Nimer, N., … & Hazen, S. L. (2023). The artificial sweetener erythritol and cardiovascular event risk. Nature medicine, 29(3), 710-718.

[3] Yetik-Anacak, G., & Catravas, J. D. (2006). Nitric oxide and the endothelium: history and impact on cardiovascular disease. Vascular pharmacology, 45(5), 268-276.

Touching DNA

Preventing CRISPR From Causing Senescence

Researchers publishing in Cell Reports Medicine have taken a look at what causes CRISPR/Cas9 gene-editing technology to drive cells senescent and investigated a potential method of preventing it.

Breaking and repairing DNA

Genetic engineering of living cells through CRISPR/Cas9 technology requires three things to occur. The DNA must be disconnected in a double-strand break, new DNA must be inserted, and the cell must then close the DNA with the inserted gene inside [1].

Beyond any concerns with the DNA being inserted, the very process of breakage and repair raises issues. Breaking apart DNA leads to a DNA damage response, part of which involves p53, a factor that encourages cellular senescence [2]. The viral vectors that insert DNA, such as lentiviruses and the commonly used AAV6, lead to increased p53 as well [3]. Previous work has found that temporarily inhibiting p53 may allow these cells to proliferate long enough to be effective [2].

Successful engineering leads to increased senescence

For their first experiment, the researchers electroporated and targeted human hematopoietic stem and progenitor cells (HSPCs) with a variety of edits: a guide RNA, a single-strand oligodeoxynucleotide, and AAV6-driven gene modifications adding green fluorescent protein (GFP) at two separate loci, AAVS1 and IL-2RG. There was also an electroporation-only control group.

Compared to the other groups, the two AAV6 gene modifications had much stronger inflammatory reactions, including upregulation of interleukins, p16, CDKN1A, and the crucial senescence biomarker SA-β-gal. AAV6 was found to be more effective in genetically engineering cells when targeting the IL-2RG locus compared to the AAVS1 locus; however, targeting this locus led to more inflammation in most metrics as well. Even four days after the modification, the engineered cells were still showing persistent signs of DNA damage and inflammation.

Higher doses of AAV6 led to more efficient engineering, as measured by comparisons of homology-directed repair (HDR) versus non-homologous end joining (NHEJ). The former is less prone to genetic errors than the latter.

However, cells that were successfully engineered, as measured by the presence of GFP, were much more likely to become senescent than control groups. These effects continued even as the cells clonally expanded, with some effects being seen even in cells that were exposed to AAV6 but did not express GFP.

These findings were recapitulated in mice. These human cells were grafted into immunodeficient animals and allowed to proliferate. Cells that were exposed to higher doses of AAV6 grew more slowly than cells exposed to lower doses, which were statistically no different from the control group. These effects were directly related to cellular senescence, and cells that had successfully expressed the GFP protein were more likely to become senescent. These altered stem cells also produced different results: engineered HSPCs produced more B cells and fewer T cells than the control group.

The researchers made sure that these results were not due to GFP in particular; similar results were found when an entirely different nerve growth factor reporter was used.

A potential solution

The researchers decided to combat this inflammatory and senescence-promoting effect by administering anakinra, a direct antagonist of the IL-1 cytokine, alongside AAV6. This significantly reduced the number of successfully engineered cells that exhibited signs of senescence. Targeting NF-κB, another inflammatory factor, with SC514 yielded similar results, as did targeting p53 with GSE56. Critically, none of these treatments, administered separately or in combination, seemed to affect the efficiency of the genetic engineering.

These findings, too, were recapitulated in mice. Directly targeting these sources of inflammation and senescence led to more cellular proliferation without affecting engineering efficiency, thus leading to significantly more GFP cells being found in the mice when the graft was placed in the spleen. There was a trend in this direction in the bone marrow, with treated engineered cells being able to form significantly more colonies in this area than untreated engineered cells.

Interestingly, however, these treatments had different effects on the mutation rate. SC514 and GSE56 both increased mutation rate, raising the possibility of genotoxicity; Anakinra, on the other hand, lowered it, decreasing both unwanted deletions and the number of micronuclei in addition to less mutational burden overall, including mutations of cancer-related genes.

While clinical trials involving genetically engineered cells pretreated with anakinra are required to ensure the efficacy of this approach in people, these findings strongly suggest that such pretreatment may quickly become standard procedure in generating modified cells destined for engraftment. The DNA damage response and related senescence are unwanted side effects of genetic engineering, but this study demonstrates that they are side effects that can be mitigated.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Salsman, J., & Dellaire, G. (2017). Precision genome editing in the CRISPR era. Biochemistry and cell biology, 95(2), 187-201.

[2] Schiroli, G., Conti, A., Ferrari, S., Della Volpe, L., Jacob, A., Albano, L., … & Di Micco, R. (2019). Precise gene editing preserves hematopoietic stem cell function following transient p53-mediated DNA damage response. Cell stem cell, 24(4), 551-565.

[3] Piras, F., Riba, M., Petrillo, C., Lazarevic, D., Cuccovillo, I., Bartolaccini, S., … & Kajaste‐Rudnitski, A. (2017). Lentiviral vectors escape innate sensing but trigger p53 in human hematopoietic stem and progenitor cells. EMBO molecular medicine, 9(9), 1198-1211.

Viva Frontier Tower PR

Longevity Manhattan Project Launches: San Francisco, June 20

Viva.city and BerlinHouse are opening Viva Frontier Tower, a 6-week popup village in the newly purchased 16-floor Frontier Tower in downtown San Francisco. From June 20 to August 4, this space will bring together people building the future in AI, Crypto, and Longevity.

One Tower. Three Tracks. Endless Ideas.

For 6 weeks, the tower will host three tracks:

LONGEVITY BIOTECH: June 20 – July 3

  • SUMMIT: June 22-23

AI: July 4 – July 17

  • SUMMIT: July 12-13

CRYPTO: July 18 – August 4

  • SUMMIT: July 19-20

There will also be some parallel themes on Robotics, Arts & Music, Human Flourishing, as well as an incubator program, culminating with a Demo day Aug 2.

Founders, researchers, and creators will co-work, share ideas, and build projects together.

Think: rooftop debates about methylation clocks, roundtable sessions on partial reprogramming, and pitch days for longevity-focused startups. Between events, participants will hang out, co-work, and co-create in the same building, with a focus on daily habits that promote health: Blueprint-style breakfasts, group fitness, biohacking sessions, and sleep optimization practices while accelerating medical innovation.

This isn’t a conference. It’s a prototype for the future of living aligned around health, agency, and bold science.

Why This Matters

Innovation is too slow, too scattered, and often lonely. Viva Frontier Tower brings the right people into one place, at the right time.

Previous “pop-up city” experiments in Montenegro and in Honduras brought together around 200 residents each, for two months, designed to experience what it might feel like to live in a city full of aligned individuals, and how a new regulatory framework could allow “warp-speed” drug development.

We’ve previously welcomed leaders like Bryan Johnson, Ethereum founder Vitalik Buterin, Skype founder Jaan Tallin, Harvard professor George Church, AngelList founder Naval Ravikant, Coinbase CEO Brian Armstrong and musician Grimes, among others.

Who’s Coming

This pop-up follows the success of other popup cities including Zuzalu and Vitalia. For the first summit, on Longevity Biotech, speakers include Aubrey de Grey, Irina Conboy, and Karl Pfleger.

What’s Included

  • 16 floors of co-working, lounges, and event spaces
  • Healthy lunch every weekday
  • Track-specific programming and salons
  • Community of aligned builders
  • Longevity lifestyle: movement, sunlight, biomarker tracking, and health tools

Participation starts at $475 for a two-day summit or $1,900 for the full six-week experience. But to many in the longevity space, the draw isn’t the programming—it’s the people. Scientists, founders, funders, and philosophers all under one roof, sharing meals, workouts, and whiteboard sessions.

Great ideas die in isolation. This pop-up is your amplifier.

Applicationhttps://vivafrontier.com/


About Viva.city

Viva.city builds spaces for people working on health, technology, and the future of humanity.

About BerlinHouse

BerlinHouse creates spaces where bold communities come to life.

Press Contact

J.P. Medved

jp@viva.city

719-351-2605

Gut bacteria close up

How Gut Microbiota Impact Endothelial Cell Senescence

In a recent study that included data from humans, mice, and cell culture experiments, researchers demonstrated that gut microbes and their metabolites can profoundly influence the senescence of endothelial cells. They also explored the molecular processes underlying these changes [1].

Senescence in the blood vessels

Endothelial cells line the inner surfaces of blood vessels, and their proper functioning is essential for cardiovascular health [2]. However, aging leads to the senescence of endothelial cells and is accompanied by numerous cellular changes, which, in turn, cause endothelial cell dysfunction and contribute to the development of cardiovascular diseases associated with aging [3].

In a recent study, the researchers sought to understand the mechanisms driving endothelial cell senescence. They decided to focus on the potential impact of microbiota-derived metabolites and oxidative stress, as previous research had suggested a possible link between these processes.

The host-microbial connection

The researchers started their study by analyzing plasma metabolites in 24-month-old (aged) and 3-month-old (young) mice. Aged mice had higher plasma concentrations of phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), compared to young mice.

Those two metabolites are interconnected in the metabolic pathway that is shared between the host and microbiome. In this pathway, dietary phenylalanine is converted into PAA by the microbiome, then the host metabolizes PAA into PAGIn.

The researchers observed that both the products and components of this metabolic pathway are elevated in aged mice. Specifically, their analysis of microbial genes indicated that the homologs of two genes essential in converting phenylalanine into PAA, ppfor and vor genes, were more abundant among the microbes in the aged mice, which correlated with an increase in plasma PAA levels. Plasma PAGln levels showed weaker associations.

This pathway plays a crucial role in cardiovascular diseases, as previous research has identified links between PPFOR and atherosclerotic cardiovascular diseases [4]. PAGIn has been associated with heart failure [5] and cellular senescence [6], and PAA has been linked to major adverse cardiovascular events in cardiac patients [7].

Additionally, the researchers identified a bacterium, Clostridium sp. ASF356 MGG37314, which was “the only PPFOR-positive bacterium positively associated with plasma PAA levels in aged mice.” There was also an association between plasma PAGln but not PAA, among five other taxa from the class Clostridia, in aged mice.

To compare whether similar processes occur in humans, they analyzed the data from the TwinsUK cohort. As in murine studies, they observed age-associated increases in PAA and PAGln, as well as enrichment of bacteria belonging to the Clostridium genus harboring the ppfor gene, in older participants of the TwinsUK study. Enrichment in Clostridium correlated more prominently with PAA levels than with PAGIn.

This age-related elevation in the PAA levels and Clostridium was associated with significant endothelial dysfunction, increased cellular senescence biomarkers, and the senescence-associated secretory phenotype (SASP) in the aortic endothelial cells of aged mice. The researchers suggested that the gut microbiome and PAA play key roles in the vascular decline associated with aging.

Aging-promoting processes

To test the effect of Clostridium sp. ASF356 and its metabolite PAA on aortic endothelial senescence and dysfunction, the researchers wiped out the mice’s microbiome with antibiotics and then colonized it with Clostridium sp. ASF356. They observed an increase in both PAA and PAGIn in the Clostridium sp. ASF356-colonized mice.

Analysis of tissues taken from mouse aortic endothelial cells showed multiple signs and markers of endothelial cell senescence and dysfunction. Treating mice with a senolytic cocktail of dasatinib and quercetin reversed major markers of senescence, which correlated with improved vascular function. All of this suggested a direct involvement of Clostridium sp. ASF356 in endothelial senescence in vivo.

To establish the role of PAA in this process, the researchers used a different approach. They treated proliferating human aortic endothelial cells with PAA. This treatment resulted in cellular senescence, as observed by multiple biomarkers. Dasatinib and quercetin treatment of PAA-treated cells reduced the viability of senescent endothelial cells but not proliferating cells. It also reduced some senescence biomarkers and improved the process of new blood vessel formation (angiogenesis).

When PAA was administered to young mice, the researchers observed increased plasma levels of PAA and PAGIn as well as increased levels of senescence markers in aortic cells and worsening markers of vascular health, similar to observations made in young mice colonized with Clostridium sp. ASF356. This suggested “a causal role for PAA in driving endothelial cell senescence.”

Stressing the cells

After establishing a causal link between microbiota and endothelial cell dysfunction, the researchers sought to gain a deeper understanding of this relationship at the molecular level. Previous research has suggested that excessive reactive oxygen species (ROS) trigger endothelial cell senescence [8]. Other studies suggest that gut microbiota regulate oxidative stress-responsive host genes [9].

Combining information from those studies with their results, the researchers investigated whether PAA can increase the levels of H2O2, one of the reactive oxygen species.

When proliferating endothelial cells were exposed to PAA, the researchers observed an increase in ROS levels, specifically mitochondrial H2O2. They also noted that treating proliferating endothelial cells with PAA led to changes in metabolism, and some measures of metabolic activity resembled those seen in senescent endothelial cells.

Further experiments uncovered how the signals are transmitted. They learned that PAA induces mitochondrial H₂O₂ overproduction, leading to increased levels of IL-6, one of the SASP factors. These molecular changes lead to a cascade of further molecular alterations, resulting in the upregulation of the SASP, reduced angiogenesis, epigenetic modifications, energy imbalance, and vascular dysfunction.

Fighting microbes with microbes

Aging changes to the microbiome also include a reduction in the health-promoting short-chain fatty acids (SCFAs), such as acetate, a key anti-inflammatory SCFA, due to the depletion of acetate-producing bacteria. Reduced levels of acetate-producing bacteria are associated with the severity of cardiovascular diseases [10].

Treating PAA-exposed proliferating endothelial cells with sodium acetate exhibited senomorphic effects, including the rescue of proliferation and suppression of the SASP. The researchers also observed reduced levels of senescence markers and DNA damage as well as mitigation of PAA-induced telomere shortening.

Sodium acetate treatment also prevented mitochondrial oxidative stress, improved mitochondrial function, and restored energy balance in PAA-exposed endothelial cells.

On the molecular level, sodium acetate has been previously reported to positively impact nuclear factor erythroid 2-related factor 2 (Nrf2), a molecule regulated by Sirt1 and a master regulator of many antioxidant enzymes [8].

The researchers observed that PAA treatment suppressed Sirt1 and Nrf2, promoting the cytosolic localization of Nrf2 and impairing its antioxidant functions. Acetate treatment restored nuclear Nrf2 expression, which promoted the expression of ROS-neutralizing enzymes.

Sirt1 played a role in this process, as the experiments suggested that acetate-mediated Nrf2 nuclear retention depends on Sirt1. Additionally, the upregulation of Sirt1 by sodium acetate led to the suppression of NF-κB signaling, which, in turn, suppresses the expression of genes encoding SASP components.

Sodium acetate also had a positive impact on PAA-induced angiogenic incompetence. The researchers demonstrated that acetate’s senomorphic properties facilitated the restoration of endothelial function and exerted a pro-angiogenic effect in PAA-induced senescent endothelial cells.

Potential biomarkers and therapeutic approaches

This study broadly suggests that, as the lead author of the study, Seyed Soheil Saeedi Saravi, said, “The aging process of the cardiovascular system can therefore be regulated via the microbiome,” specifically Clostridium sp. ASF356 and its metabolite PAA.

The study suggests a mechanism by which senescence is triggered by PAA-induced mitochondrial H2O2 production, leading to an exacerbated SASP, DNA damage, and proliferative arrest.

The authors suggest using the abundance of Clostridium sp. ASF356 in the microbiome or PAA as potential vascular aging biomarkers.

Beyond explaining the mechanism behind the connection between microbiota and vascular aging, they also identified the role of sodium acetate as a senomorphic agent with pro-angiogenic potential, which could be therapeutically used to promote improvements in endothelial function.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Saeedi Saravi, S. S., Pugin, B., Constancias, F., Shabanian, K., Spalinger, M., Thomas, A., Le Gludic, S., Shabanian, T., Karsai, G., Colucci, M., Menni, C., Attaye, I., Zhang, X., Allemann, M. S., Lee, P., Visconti, A., Falchi, M., Alimonti, A., Ruschitzka, F., Paneni, F., … Beer, J. H. (2025). Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging. Nature aging, 10.1038/s43587-025-00864-8. Advance online publication.

[2] Donato, A. J., Machin, D. R., & Lesniewski, L. A. (2018). Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circulation research, 123(7), 825–848.

[3] Han, Y., & Kim, S. Y. (2023). Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics. Experimental & molecular medicine, 55(1), 1–12.

[4] Zhu, Y., Dwidar, M., Nemet, I., Buffa, J. A., Sangwan, N., Li, X. S., Anderson, J. T., Romano, K. A., Fu, X., Funabashi, M., Wang, Z., Keranahalli, P., Battle, S., Tittle, A. N., Hajjar, A. M., Gogonea, V., Fischbach, M. A., DiDonato, J. A., & Hazen, S. L. (2023). Two distinct gut microbial pathways contribute to meta-organismal production of phenylacetylglutamine with links to cardiovascular disease. Cell host & microbe, 31(1), 18–32.e9.

[5] Poesen, R., Claes, K., Evenepoel, P., de Loor, H., Augustijns, P., Kuypers, D., & Meijers, B. (2016). Microbiota-Derived Phenylacetylglutamine Associates with Overall Mortality and Cardiovascular Disease in Patients with CKD. Journal of the American Society of Nephrology : JASN, 27(11), 3479–3487.

[6] Yang, H., Wang, T., Qian, C., Wang, H., Yu, D., Shi, M., Fu, M., Liu, X., Pan, M., Rong, X., Xiao, Z., Chen, X., Yeerken, A., Wu, Y., Zheng, Y., Yang, H., Zhang, M., Liu, T., Qiao, P., Qu, Y., … Zhao, C. (2025). Gut microbial-derived phenylacetylglutamine accelerates host cellular senescence. Nature aging, 5(3), 401–418.

[7] Nemet, I., Li, X. S., Haghikia, A., Li, L., Wilcox, J., Romano, K. A., Buffa, J. A., Witkowski, M., Demuth, I., König, M., Steinhagen-Thiessen, E., Bäckhed, F., Fischbach, M. A., Tang, W. H. W., Landmesser, U., & Hazen, S. L. (2023). Atlas of gut microbe-derived products from aromatic amino acids and risk of cardiovascular morbidity and mortality. European heart journal, 44(32), 3085–3096.

[8] Allemann, M. S., Lee, P., Beer, J. H., & Saeedi Saravi, S. S. (2023). Targeting the redox system for cardiovascular regeneration in aging. Aging cell, 22(12), e14020.

[9] Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020). Gut Microbiota and Cardiovascular Disease. Circulation research, 127(4), 553–570.

[10] Marques, F. Z., Nelson, E., Chu, P. Y., Horlock, D., Fiedler, A., Ziemann, M., Tan, J. K., Kuruppu, S., Rajapakse, N. W., El-Osta, A., Mackay, C. R., & Kaye, D. M. (2017). High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice. Circulation, 135(10), 964–977.

Cancer vaccine

New Study Could Pave the Way for Better Cancer Vaccines

Scientists have found that only about 1% of presented tumor antigens come from oncogenic mutations. The remaining 99%, previously overlooked, may offer better treatment targets [1].

Going after mutations

Cancer arises from a series of mutations that drive abnormal cellular behaviors, such as runaway proliferation. Cancerous cells also normally present abnormal peptides on their surfaces that the immune system detects and targets. This presentation is carried out by major histocompatibility complex (MHC) class I proteins, which are not to be confused with MHC class II proteins that present external peptides ingested by the cell, such as from bacteria or viruses.

Targeting these mutated tumor-specific antigens (mTSAs) has become a strategy behind many experimental treatments, most notably anti-cancer vaccines, which prime the immune system to go after cells that express a particular mTSA. However, since mutations are often tumor-specific, those vaccines must be tailored to each patient, which makes them finicky and prohibitively expensive. Despite all the effort, mTSA-targeting vaccines often do not produce the expected result.

To create a vaccine, scientists sequence the tumor’s genome, identify tumor-specific mutations, and then use algorithms to predict what an antigen derived from the mutated gene would look like. The vaccine is then built based on that predicted sequence.

Looking for what’s actually there

Novel techniques have made it easier to look for antigens that are actually present on the cell’s surface rather than rely on predictions. In a new study published in Nature Cancer, scientists from the Institute for Research in Immunology and Cancer (IRIC) at the University of Montreal catalogued tumor antigens in 505 melanoma and 90 lung cancer samples by using a state-of-the-art multi-omic approach, and they arrived at striking results.

They found that only about 1% of the tumor antigens came from mutations. The remaining 99% came from non-mutated parts of the genome, often from sequences that are normally silent or minimally active in healthy tissues.

These fell into three groups. First were aberrantly expressed tumor-specific antigens (aeTSAs), peptides from unmutated genomic regions that are normally silent in healthy adult tissues but activated in cancer. Their origins varied and often included “non-canonical regions,” such as gene parts that are usually spliced out of the final RNA used to make the protein (introns), intergenic regions, and non-coding RNAs.

The second group consisted of tumor-associated antigens (TAAs): unmutated proteins that are overproduced in cancer but also found in some healthy tissues. Finally, the third group included lineage-specific antigens (LSAs): proteins that are typical of the tissue the cancer came from, such as melanocyte markers in melanoma.

The researchers found that mutated antigens are rare because many mutations don’t get transcribed into RNA, which means the corresponding proteins don’t get made. If there’s no protein, there’s nothing for the immune system to see. Plus, the few mutations that are transcribed often occur in genomic regions that don’t generate peptides that are well suited for presentation to immune cells.

Meanwhile, many aeTSAs are made into proteins, get presented on the cell surface, and can trigger immune responses. The study showed that immune cells from healthy donors can recognize and kill cancer cells presenting these aeTSAs. This suggests that they could be powerful targets for cancer immunotherapy.

Importantly, these aeTSAs were often shared across patients, unlike mutated antigens, which tend to be unique to each person. Therefore, aeTSAs could be used to develop generalized, off-the-shelf cancer vaccines or T cell therapies.

The upshot of this study is that while mutations often initiate cancer, that doesn’t mean the mutated proteins are abundant or relevant as immune targets once the tumor is established. Other aberrant proteins, not derived from the initiating mutations but essential for maintaining cancerous behavior, might be better targets for immunotherapies due to their relative abundance or widespread presentation.

“This is an intriguing study that explores a novel approach to cancer immunotherapy,” said Dr. Anna Barkovskaya, a researcher at Lifespan Research Institute who was not involved in this study. “Previous developments in the field, most notably immune checkpoint blockade in mutation-heavy melanoma and non-small cell lung cancer, were dramatic but were only successful for a subset of patients and not applicable to cancers where mutational load is smaller. Multiple studies that followed focused on trying to identify new mutated tumor-specific antigens, but by their nature, those are patient-specific, rare, and are expressed at a low level.”

“By contrast,” she explained, “the authors of this study used genome-wide sequencing that isn’t limited only to protein-coding regions, to identify non-mutated tumor antigens that were either aberrantly expressed or specific to the lineage of origin of the cancer cells. They found that such antigens are much more common than the mutant ones, tend to be more abundant, and are highly immunogenic, inducing a potent and specific cytotoxic CD8+ T cell-mediated response.”

More evidence from a different study

A complementary study, published almost simultaneously in Science, reinforces these insights by showing that most tumor-presented antigens in human pancreatic cancer arise not from mutations but from noncanonical sources, such as long non-coding RNAs and untranslated regions (UTR) [2]. As in the IRIC study, the team found that these aberrantly expressed peptides, which are absent from normal tissues, can elicit T cell responses and serve as potent immunotherapy targets.

Just like in the first study, some of the cancer-derived peptides were shared by multiple patients, which means they can be used to create off-the-shelf treatments. Some were highly immunogenic and enabled the creation of genetically modified T cells that “could exert robust killing of patient-derived pancreatic cancer organoids both ex vivo and in vivo.” Pancreatic cancer remains one of the most treatment-resistant cancers, making this research particularly important.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Apavaloaei, A., Zhao, Q., Hesnard, L., Cahuzac, M., Durette, C., Larouche, J. D., … & Perreault, C. (2025). Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer. Nature Cancer, 1-19.

[2] Ely, Z. A., Kulstad, Z. J., Gunaydin, G., Addepalli, S., Verzani, E. K., Casarrubios, M., … & Freed-Pastor, W. A. (2025). Pancreatic cancer–restricted cryptic antigens are targets for T cell recognition. Science, 388(6747), eadk3487.

Boyang Wang Interview

Boyang Wang on Targeting Underfunded Longevity Projects

In this interview, Boyang Wang of Immortal Dragons discusses the kinds of projects he wants to fund, ways in which the industry can be encouraged to develop, relationships between the East and West in longevity research and development, and what got him involved in longevity.

Hello, and welcome to this Lifespan interview, where today, I have the pleasure of interviewing Boyang Wang, who is the founder of Immortal Dragons, a fund operating in the longevity research space in Singapore. Can you start, Boyang, by describing yourself a bit? How did you get into this field, and what led you into founding Immortal Dragons?

Thanks for having me, Keith. This is Boyang, I’m the founder of Immortal Dragons, a purpose-driven longevity fund. We invest in longevity biotech, life extension projects beyond conventional capital investments; we also do advocacy work like translating and publishing books. We do podcasts in Chinese for the Chinese longevity community. We do sponsorship and grants for organizations and events, all to further the research and advancement of the sector.

What got me into longevity? This is actually a recurring theme; it’s not only that I’ve been thinking about why we must age and die, I never figured out the puzzle of existence or consciousness, so I feel like we need more time to think this through. It’s fundamental to extend lifespan and healthspan so that we have more time to figure out the meaning of life, to do whatever you want, to achieve our goals. Also, there is a theme of survival. I’ve had interesting encounters with the healthcare system. I’ve had interesting medical conditions since I was young, so I’ve always witnessed firsthand the limitations and, of course, the marvels of our modern healthcare system, so it’s very natural for me to work on longevity.

It definitely sounds like you have a lot of reasons for entering this field and a lot of passion. Picking up on that point, Immortal Dragons is described as a purpose-driven fund focused on life extension, prioritizing impact over economic returns. How is this different from other funds?

We say we are a purpose-driven fund, and the key implication is that Immortal Dragons values impact over economic returns. This is a more rational, more concrete concept than it sounds; when we say we do not prioritize economic returns, it is pretty practical. I’m coming from a tech entrepreneur background, so I’m not from a biomedical background. If I wanted to maximize economic return, I should have been investing in technology or things that I’m more familiar with, the computer science-related tech sector.

I’m investing in the field of longevity because I want to see things happening: I want to see progress and breakthroughs in the sector. When we make investments, we are less focused on the potential economic returns. For example, if we wanted to invest in a pharma company that could make the most money for us, we might not do a good job, because this is the game that big pharma companies are playing, and they know their games. Rather, we invest in companies that might be working on cutting-edge, moonshot, high-risk technologies that are probably very meaningful for the sector but might not bring the most economic returns.

How do you measure this? Is there a formal, codified investment thesis, where you quantify impact versus economic returns and weigh those things when you’re looking at an investment? Is it more of a feeling based on your due diligence, or are there specific impact metrics that you look at?

Quantifying impact is not easy, but we do have some working themes that we are focused on, such as replacement. We feel like replacement, not repair, is an interesting direction as an anti-aging strategy. There are recent papers on it that we draw this analogy from. One comparison is electrical engineering, where it’s hard to fix a smartphone; if you smash it, even the best engineers might have a hard time fixing the chips and the screen LED, but what the engineers would do is replace the screen, the motherboard, and so on.

In terms of biology, we see replacement as a very promising direction for intervention, so we look at xenotransplant companies. We look at companies that work on cryopreservation, which is related to transplantation. We look at companies that work on 3D bioprinting for tissues and human organs ex vivo, and we even look at companies that work on whole-body replacement. This is one of the working themes, and we then measure the rarity, the importance of the work, to hopefully partially quantify the impact of the investment.

Are there other factors that determine what you might fund? For example, if there was a therapy that was more repair than replacement, are there other elements of a potential project that would bring it into the sphere of things that you might fund? Is anybody else focusing on rarity? You mentioned evangelism in the past; is the ability for a project to inspire the public something that you might factor into potential impact?

Indeed, if there’s a deal that is highly sought after, then we will probably not be so keen to make an investment, because there will be plenty of capital and resources flowing into the project. Rather, if we see a project that’s unique and important, a puzzzle piece that is not getting the required funding, we’ll be more interested in it. If there’s a project that can hopefully inspire the public or at least inspire a few mission-aligned groups of people, that is also interesting for us.

Is this affected by the different kinds of systems in the body? For example, replacement might be a more challenging strategy to pursue in terms of neuroscience. Do you have neuroscience projects that you’re looking to fund as well, or is that something that’s deprioritized? Are you looking at other modalities involved in the neuroscience side of things, because I imagine it’s a little bit more difficult to replace your brain?

Yes, absolutely. The brain is tied to the very existence of our being, so it’s more tricky. When it comes to the brain and neuroscience, we look at other modalities. We look at companies that are working on nurturing brain tissue and then transplanting that created tissue into your brain and integrating it into your existing systems. Hopefully, that will enhance and rejuvenate your brain tissue and your nervous system rather than replacing it. In this area, we look at other modalities more of a gradual enhancement, but when it comes to other body parts, we are more interested in the replacement strategy.

That intersects with some work that the ARPA-H is doing with Jean Hébert’s project. Do you look at any other programs like ARPA-H for inspiration or guidance to see what other funds or other governmental agencies are looking to fund, and is that something that gives you an indication of what you would like to explore or is that something that you would rather deprioritize, because you feel like they are taking care of that side of things?

We are certainly interested in what public sector or other organizations might be sponsoring, ARPA-H being one. Of course, there’s XPRIZE. There are the Middle East, MENA countries, where sovereign funds are looking to fund such efforts as well. We are based in Singapore, so we also see that there have been some initiatives from the Singaporean government and universities. We have the first longevity research center set up in Singapore by the National University of Singapore headed by Professor Brian Kennedy, which has been around for a few years. These are great initiatives.

We have communications with them, but government agencies often have the mission of advancing public health, so they really look at things that improve lifespan on average and impact a large proportion of the population, such as diabetes, metabolic diseases, and neurodegenerative cardiovascular diseases.

I feel like nimble and independent organizations like ours have the responsibility to work on the cutting edge. Instead of improving the average life expectancy, we want to set an example and inspire the sector by making a few people live to 120 or 150. One example would be Larry Ellison. He’s apparently pretty successful, at least seemingly in his anti-aging and longevity effort, in inspiring high-net-worth individuals by showing his achievements and so putting resources to work on this sector.

You’re saying that if you could succeed in having a few significant outliers, that will serve as a powerful signal to the world to say “Hey, we can actually get gains here”, and that would catalyze more funding.

Yes, absolutely. We believe in the power of role models. After the Wright Brothers, there are so many who succeeded in creating powered aircraft; after Tesla, there are so many companies who successfully built very good electric vehicles. The power of role models is invaluable.

Have you received any kind of challenges on that sort of thesis, by people saying “Hey, you should really be working on doing that sort of blanket minimum median raising as opposed to this”? Or, does everyone that you’ve interacted with understand the points that you’ve just made?

The field of longevity can be controversial at times. There are actually criticisms coming from different perspectives, one being that everything that we’re talking about is pretty far-fetched if not pseudoscience. When you talk about creating organs or organoids that will be usable for humans, or you talk about therapeutic plasma exchange, which is also a replacement strategy, many coming from a more traditional background would totally oppose it.

There are other times when it’s criticized for being unrealistic or unhelpful for the general public, who might benefit more from statin dosage for their cardiovascular health or less sugar intake. There’s criticism from all different perspectives, but to work on something that’s controversial will be meaningful. If there’s an aligned interest, if there’s already consensus, then it’s more suitable for bigger organizations than a small fund like us.

Given that you’re approaching this from the perspective of moonshots like this, can you speak more about the thesis of being focused on impact more than economic returns, and how does that inform your team? Does everybody feel the same? What is the structure of the fund. What’s your team size, and how many investments have you made?

We are a 40 million AUM fund. Our structure is a bit special in that we are more of a CVC, a corporate VC structure. We only have one external LP, and the majority of our fund is coming from our previous businesses, so we have total flexibility in terms of making investments. We don’t have a stringent LP mandate; we don’t need to call capital, we have our capital ready.

We have five or six teammates who are working full time on our fund. There’s also departments like finance, legal, and human resources, that we share with our larger group of companies. We’ve been investing as an organization for almost two years by now. We have funded more than 10 investment projects so far, and we deployed a few million US dollars. We plan to continue or accelerate as we see more breakthroughs and progress in the sector.

What are your thoughts on the current funding landscape in general? Instead of simply being an LP for other funds, why did you choose to do this yourself? What are the biggest gaps or unmet needs in the field that you hope Immortal Dragons will address?

We do also invest in other funds as an LP, but the reason why I have to work on it myself is because this mission is very important to me, and I have to work on it full time rather than just sit on the sideline and watch others work on it.

We feel like there’s definitely not enough attention, resources, or talent. Everything in this direction is so fundamental, so important, and yet it’s not getting the kind of attention that it deserves. Partially, we feel that he reason is complicated. There’s a mentality shift required, where people have internalized the idea of aging and death. There is an economic flywheel that’s not there yet.

For the past many decades, investing in anti-aging has been a not-so-fruitful endeavor, but we believe it’s now at an inflection point. There is also a moral implication in that the argument for longevity and anti-aging is not established, especially not for the general public, and thought leaders have been working on this as well. Notably, Nick Bostrom is a philosopher influential in this area, and he has famously written The Fable of the Dragon Tyrant to address many of the moral arguments around anti-aging, longevity, and longer lifespans.

We also translated the book The Case Against Death by Patrick Linden into Chinese and published it in the Chinese market. It’s also a pretty compelling and comprehensive discussion on the morality of longevity. So many of these need to be addressed, and investors need to see returns, and we need to make our voice heard to move the needle and turn the tide.

On that subject, there’s obviously a lot of different steps in the pipeline of realizing healthspan-extending technologies. There’s the research itself, there’s government issues and funding, there’s the ecosystem of investment, and there’s public sentiment. Are any of these a critical bottleneck that needs addressing, or is it an all-of-the-above strategy?

It’s not easy to find the one key factor that’s the most important, and that’s why, from Immortal Dragons’ perspective, we try to work on a few of these factors. We look at the economic flywheel. Currently, it’s not very attractive to fund longevity projects or work on them because there’s fewer success stories, for founders, for large investors, and for the general public to invest in. We are looking to help; we’re really looking forward for a wave of longevity and anti-aging companies to reach a turning point where they get publicly listed, they will generate returns for retail investors in the public market, and that will be a powerful motivational incentive for more people to invest in and to turn the tide.

We don’t emphasize economic return as a fund, but as a mechanism, it’s really one of the most powerful: capitalist, free market return on investment is the most important motivational incentive structures that we have discovered to push the sector further. We have seen this kind of hyper growth in the tech sector in the last few decades. If this can happen in longevity, in anti-aging, that will really accelerate its development.

Is there any room in the fund to support or invest in projects that aren’t strictly biotechnology? For example, there’s a movie project to make Fable of the Dragon Tyrant; that went through our Longevity Investor Network by Protostellar Media, for example. There’s also a Dragon Tyrant blockchain game that’s being built by SkillCap that is working with the Lifespan Research Institute. Would you ever consider funding projects like this that are not biotechnology but related to the overall goal of potential economic return and inspiring the public?

These are very interesting projects, and this kind of effort will be a perfect candidate for sponsorship or grants by Immortal Dragons. We are one of the early major sponsors of Vitalist Bay, and we’re happy to see the team pulled off a pop-up city/conference that attracted the best minds in the sector and individuals from all over the world, and some of them might be new to longevity. That would be a better candidate for sponsorship or grants instead of equity investment.

Can you explain a little bit more about what that looks like operationally? Is there like a separate tranche of funding within the fund that’s allocated for grants, or is it like a separate granting mechanism that functions somehow alongside the primary fund?

We are pretty flexible, so we make decisions as they come. There’s no strict division of the fund into a sponsorship tranche and an equity investment tranche. In general, the ticket size for sponsorship will be less than then an investment check. 50,000-ish is the maximum we go to for sponsorship grants so far, but we are flexible, and we will evaluate projects as they come. Interested parties can approach us: our website is ID.life, and contact@ID.life is the email address where proposals can be sent.

Got it, and speaking of your website, I noticed that there’s you have a project focused on visualizing digital twins on the website. Is the aim of this type of work evangelism-related as well or purely scientific in nature?

This is another demonstration of how our fund is slightly different. We do such a collaborative project with researchers and other companies when we feel that there’s a value proposition and when we feel that there’s an area where we can contribute. Our team is pretty strong in computer graphics, in 3D modeling, so we created this digital twin project where the functionality is to visualize organs, different systems that vessels, neurons, muscle, skeletal structures, especially it will highlight any issue that there might be in the body.

The purpose of this system is multifold; for many who are not coming from biomedical backgrounds, they probably have not seen such a model of themselves, so it’s interesting for them to explore and enhance their understanding of their bodies. According to some clinics that we talk to, this is a valuable tool to keep clients compliant with doctors’ prescriptions, because the moment they step out from the clinic, the connection between patients and doctors can become pretty weak. We are still exploring the possible collaborations and use cases for this system. We probably will open source this soon, when it reaches a certain maturity level. Right now, it’s just our research project.

If patients can see what a healthier version of themselves will look like if they comply with the specific therapy, that will induce them to be more compliant?

We want this to serve as a motivational tool for clients, so they can see a healthier version of themselves already in the system,  which drives the patients to work towards that goal.

That kind of technology can intersect with the notion of digital biomarkers, technologies that might be able to non-invasively scan your face, your walking gait, your voice. Are you invested or interested in any such projects? You mentioned the NUS earlier, and I believe some of these technologies and approaches might be of interest to the groups working there.

We have seen a few products that are already out in the market that non-invasively detect biomarkers with pretty high precision and accuracy. So far, we have not invested in this direction. We feel like this is probably more of a improvement over the technology we already have. It’s good to have, but it’s not screaming for investment, and it’s less of a moonshot, but we find it to be meaningful. There are other funds out there interested in such projects.

Just an observation, the traditional blood drawing process has been improved a lot. There are currently gadgets that can draw your blood pretty painlessly. There is also continuous glucose monitoring that is pretty much painless. The progress in this direction seems to be pretty good.

In the past, you’ve spoken about connecting Eastern and Western longevity communities. What do you see as the most significant benefits of East-West collaboration, and what practical steps is Immortal Dragons taking to bridge these ecosystems?

There are many areas where collaborations can happen between the East and the West. I can at least think of four possible directions, one being capital. There’s an enormous amount of wealth generated in the East with economic development and progress in the past few decades.

In bioscience, we’ve already seen plenty of progress made by Eastern researchers and scientists. Without naming a comprehensive list, there’s Professor Yamanaka, who received a Nobel Prize for his iPSC research. There is one Chinese-American scientist, Zhang Feng, who is a pioneer in CRISPR and gene editing. In terms of cloning for mammals and primates, Eastern researchers and scientists are also pretty advanced and have been doing interesting work in the past years. In xenotransplants, both China and the US are leaders in this area. These researchers write in English, they publish in Cell and Nature, but there’s still gaps at times.

Clinical trials and research efforts are pretty expensive and sometimes are hard to organize in some developed countries due to strict regulations and probably bureaucracy and red tape, and that is one area where some Asian countries are more flexible.

With a huge population in the East, there comes market size and market potential. These are all areas where the East and West can collaborate. We feel like such collaboration is not as much as we want it to be, especially in the current geopolitical climate with more bridges getting burnt down. For some organizations and individuals, making that connection is even more important than before.

You’ve also noted in the past that Eastern cultures may be more conceptually open to life extension. How do you see such potential differences in cultural attitudes influencing things like regulatory environments, patient adoption, or investment trends in Asia versus the West?

That’s an interesting topic. Of course, there is criticism, there are people arguing against the idea of longevity, both in the West and the East. These concerns are coming from different angles. In the West, there is a strong religious influence such that there’s worry about playing God and “We probably shouldn’t linger too much on this life but rather live the best life and then go to heaven.” I’m not an expert on theology or these theories, but that’s the cultural connotation that I felt.

Whereas in the East, there’s less of a religious concern but a more practical concern that it might only be for the rich and about the problems that can come from longer lifespan, like limited resources. Societal classes might freeze once you give longer lifespans and healthspans to those who already have resources.

There are different issues to be addressed, but I feel like Eastern cultures are more receptive to the idea of longevity. There is a tradition in Taoism, from emperors in history that have pursued longer lives, of course failed attempts, but such an idea has been there all the time. I would say that they’re at least more open to the idea that it’s not unfathomable to think of a future of our civilization where people can live and work for up to a few hundred years and that we’ll be able to achieve great things with our longer lifespans, like traveling to other planets.

I’m assuming that you haven’t imbibed mercury like certain Chinese emperors of legend, but you have personally undergone procedures such as follistatin gene therapy and tissue banking. Would you say that these experiences relate in any way to your investment thesis in terms of risk tolerance, for example?

These are personal attempts, not exactly tied to the fund, but this does reflect on some ideas of risk profile, things that we feel are promising and the actions we think need to be taken. Prototype gene therapy, for example, is experimental. To say that a gene therapy is traditional is a bit weird, because this is a new field, but gene therapies are generally used for very serious medical conditions and are carried by a virus factor, a lentivirus or AAV, and this is often irreversible. The kind of gene therapy that I received is more for general health or anti-aging purposes instead of treating an immediate condition. It is carried by a nanolipid, or in my case, a PEI polymer, which is not as transmittable: it will not go to all my cells and will not be inherited. It’s a one-off shot that will gradually die out.

Many experts in the field are pretty against such a gene therapy, criticizing its efficacy, but they also agree that the possibility for an adverse event is also low because of its low dosage and low efficacy. From my perspective, I feel like this is definitely an early mover in creating gene therapy that’s more transient and more for a larger audience. I want to support the cause. I want to make the pioneers of longevity biotech make money, so that with their role model, there will be more companies that work on this.

If you feel like this gene therapy is not efficacious or you feel like this technology isn’t good enough, why not build a company and develop a better therapy? After all, they’re charging a high price, but they also already see some traction.

There are people such as Brian Johnson, who publicly stated that he received a gene therapy, so there’s definitely a market for it. Why not iterate and produce a better product? We want to see such an economic flywheel to attract more resources and talent, so my follistatin gene therapy is also a signal. I don’t believe it had much of a noticeable effect on me, but fortunately, there’s also no side effect or adverse event.

You’ve expressed both enthusiasm and caution about AI’s role in longevity. What specific intersections between those two areas are you most excited about, and what do you think are the greatest risks?

AI is a big trend and is influencing everything that we do; there are a few interesting directions, and there are companies already exploring those. There’s AI drug discovery for smaller molecules as well as biologics. There’s a idea of an AI doctor that can commoditize diagnosis and medical advice to an unprecedented level. There are also worries about hallucination and accountability that an AI doctor really cannot provide at the moment.

There are ideas about a clinical intelligence system where AI could really assist a doctor to make a diagnosis and medical decisions, and we can imagine how AI might be more comprehensively knowledgeable than our imperfect but marvelous biological brain, so they can work hand in hand.

These are all very interesting directions, and we feel like funds both from the tech sector and from the pharma or biotech sector are interested in such projects. I would say there’s no better time to start a company, to work on longevity. You have AI at your disposal, you have biotech and longevity research at an inflection point, and more capital, talents, attention, and resources will be drawn into the field.

On your LinkedIn, I noticed that you are a gamer and a dev, and your background is in computer science and being a tech entrepreneur. How do you think that background in other fields has shaped your approach to investing in longevity? Would you say this is a challenge, an advantage, or both?

I’ve been a hardcore gamer growing up, and I do feel that such experiences shaped my work and my perspective in many things. When I was very young, I got my first Game Boy, and then I started to play games like Pokemon. In the first few generations of Pokemon, there are glitches that you can exploit to catch a very rare Pokemon and so on. At first, I didn’t believe in such wild rumors, like you first need to smash your game cassette a few times and blow on it, then you can catch Mew or Mewtwo.

These glitches are real, because at that time, developers had limited RAM space to cram in the data. You can make the game behave unexpectedly to catch the Pokemon you want or duplicate important items in game, and that was a big shock to the young version of myself. I didn’t believe it could be real, but understanding that it is real gave me a sense of believing that we can achieve things.

The world that we live in, a simulation or not, is just another very realistic, very complicated game. It is not without glitches; it all works by code or by some law that we shall discover and conquer in order to make great things happen. We can make advanced science happen that is indistinguishable from magic. That probably gave me the idea that both the game world and the real world are malleable places.

What drives you personally for this mission? You mentioned earlier the various ways in which you’re passionate for this, but is there anything specific that you attribute this passion to? What’s your ‘why’?

Other things are limited: if you have a goal in life, you achieve the goal, and then the prince and the princess live happily ever after. However, at the end of the day, life extension is an infinite game that we might not win immediately. There’s a possibility that we do not win the game in this generation, but we will pass on this torch, and you either win the game and stay in the game or die trying. This gives me motivation to work on this every day. I just want to see how much we can push the boundary. This makes the work that we are working on pretty unique.

Great. Thank you for sharing, Boyang, and thanks for joining us in this Lifespan interview.

Thank you so much.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
DNA Pasta Clock

Researchers Find Age-Modulatory Perturbations at Scale

Scientists have developed a new open source transcriptomic aging clock and published their work as a pre-print [1]. The newly identified rejuvenating drugs and gene perturbations could be applied in regenerative medicine and longevity therapies, and the aging perturbations could find use for anti-cancer therapies.

Age-shift learning—one model for every platform

Pasta (Predicting age-shift from transcriptomic analyses) was trained on 17,212 healthy profiles from 21 bulk-RNA-seq or microarray studies. A ridge-regularized classifier learned from rank-difference vectors of same-tissue sample pairs ≥40 years apart, capturing the ordering of age-responsive genes rather than their absolute counts. In leave-one-dataset-out (LODO) tests this 40-year age-shift model outperformed the regression baseline and surpassed the previous multi-tissue benchmark, MultiTIMER [2], in 6 / 8 LODO datasets and 5 / 6 independent datasets.

Pasta clock 1

When single-cell data were aggregated into pseudobulks, Pasta retained the highest Pearson correlations, illustrating true cross-platform portability. Because ranks are platform-agnostic, the same coefficients apply, without re-alignment or batch-correction, to raw or normalized bulk, scRNA-seq and L1000 count matrices.

p53-anchored biology linked to senescence, stemness and cancer

Gene-set enrichment placed p53-mediated DNA-damage response at the core of the model: positive weights were dominated by CDKN2A/p16, ZMAT3 and other p53 targets, while miR-29 targets with anti-p53 activity carried the strongest negative weights. Functionally, Pasta separated senescent from proliferative or quiescent cells in 24 / 30 RNA-seq datasets and tracked a 450-day fibroblast passage toward replicative arrest almost linearly (PCC ≈ 0.90). At the opposite extreme it assigned exceptionally “young” scores to embryonic stem cells and to fibroblasts during OSKM reprogramming, while scores rose during directed hepatocyte differentiation, capturing both directions of the stemness-senescence continuum.

Pasta clock 2

Applied to TCGA cancer patient samples, Pasta’s age scores correlated more strongly than chronological age with histological tumor grade and stratified overall survival in adrenal, sarcoma, thymoma and other cancers, underscoring clinical relevance.

Chemical and genetic modulators of cellular age

Screening ~3 million CMAP L1000 profiles [3], the authors flagged 259 Aging and 59 Rejuvenating compounds. Pro-aging hits were highly enriched in FDA-approved chemotherapeutics (e.g., mitoxantrone, gemcitabine, doxorubicin), whereas rejuvenating compounds contained HDAC, MEK and GSK-3 inhibitors, compound classes often used in chemical reprogramming cocktails.

Pasta clock 3

Two predictions were taken to the bench: the antifolate pralatrexate (4th Aging hit) triggered SA-β-gal staining, p21 induction and irreversible arrest in A375 melanoma cells, while the natural product piperlongumine (20th Rejuvenating hit) up-regulated OCT4, SOX2 and NANOG in PC3 prostate cells, confirming a stemness-promoting, age-reversing profile. Extending the same pipeline to CRISPR, shRNA and over-expression constructs uncovered 841 Aging and 54 Rejuvenating gene perturbations. Aging drivers included CCNA2 knockout and KRAS/BRAF over-expression, mirroring cell-cycle arrest and oncogene-induced senescence; while youthful scores included MYC over-expression and TP53 loss, echoing known reprogramming and tumour-suppressor pathways.

Molecular traits that prime cells to respond to aging or rejuvenating cues

To pinpoint intrinsic features that dictate how a cell responds to age-regulatory cues, the authors computed aging- and rejuvenation-propensity scores, which corresponds to the average response of a given cell line to all identified age-modulatory chemical and genetic perturbations. They then correlated these scores to omics measurements for 19 cell lines in DepMap. Mutation analysis singled out TP53: lines bearing two inactive alleles almost never aged, those with one allele aged moderately, and wild-type lines aged readily (PCC = 0.88). Aging-prone lines were wired for oxidative stress: their proteomes were enriched for mitochondrial-translation and respiratory-chain factors, their transcriptomes echoed the same signature, and their genomes often carried extra copies of TRAF6-IRF7 and IFNA loci—configurations that amplify ROS and interferon-driven SASP signalling. Rejuvenation-prone lines, by contrast, over-expressed spliceosome, histone-acetyltransferase and other chromatin-remodelling proteins and frequently lost PRC2 and HDAC copies, genetic changes known to lower epigenetic barriers to induced pluripotency. These results may help design more personalized and effective rejuvenation and anti-cancer therapies.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.

Literature

[1] Salignon, J. et al. Pasta, an age-shift transcriptomic clock, maps the chemical and genetic determinants of aging and rejuvenation. 2025.06.04.657785 Preprint at https://doi.org/10.1101/2025.06.04.657785 (2025).

[2] Jung, S., Arcos Hodar, J. & del Sol, A. Measuring biological age using a functionally interpretable multi-tissue RNA clock. Aging Cell 22, e13799 (2023).

[2] Subramanian, A. et al. A Next Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles. Cell 171, 1437-1452.e17 (2017).