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Building a Future Free of Age-Related Disease

Public Longevity Group

Lifespan Research Institute Launches Public Longevity Group

[Mountain View, September 17, 2025]Lifespan Research Institute (LRI) today announced the launch of the Public Longevity Group (PLG), a new initiative focused on bridging the cultural gap between scientific breakthroughs in aging and their public acceptance. To kickstart its work, PLG has opened a crowdfunding campaign to develop tools that measure and strengthen public trust in longevity science.

While the science of longevity biotechnology continues to advance, skepticism and cultural resistance limit progress, with some studies showing that more than half of Americans would reject a safe, proven therapy to extend life. This hesitation poses risks of raising costs, delaying health-promoting regulation, and slowing the delivery of treatments that could combat age-related diseases and extend healthy lifespan.

“The breakthrough that unlocks all other breakthroughs is public trust,” said Sho Joseph Ozaki Tan, Founder of PLG. “Without it, even the most promising therapies may never reach the people they’re meant to help. PLG exists to change that.”

“Persuasion is a science too,” said Keith Comito, CEO of Lifespan Research Institute. “To bring health-extending technologies to the public as quickly as possible, we must approach advocacy with the same rigor as our research. With PLG, we’ll be able to systematically measure and increase social receptivity, making the public’s appetite for credible longevity therapies unmistakable to policymakers, investors, and the public itself.”

PLG is developing the first data-driven cultural intelligence system for longevity—a platform designed to track real-time sentiment, test narratives, and identify which messages resonate and which backfire. Early tools include:

  • The Longevity Cultural Clock: a cultural barometer mapping readiness and resistance across demographics and regions.
  • Sentiment Dashboards: real-time monitoring of public, investor, and policymaker perceptions.
  • Narrative Testing Tools: data-driven analysis that will enable robust pathways to public support.

The crowdfunding campaign will provide the initial $100,000 needed to launch these tools, creating the cultural foundation required for healthier, longer lives.

With a lean, data-driven team, the group aims to provide open-access cultural insights for advocates and policymakers while offering advanced analytics to mission-aligned partners.

Campaign Timeline:

  • Campaign completion: November 2, 2025
  • Dashboard development: Dec 2025 – Feb 2026
  • First survey deployment: Feb – Apr 2026
  • Beta dashboard launch: May 2026
  • First public insight report: June 2026

Supporters can contribute directly at: https://lifespan.io/campaigns/public-longevity-group/

The PLG campaign is sponsored by the members of LRI’s Lifespan Alliance, a consortium of mission-aligned organizations that believe in the promise of extending healthy human lifespan. Newly-joined members include OpenCures, AgelessRx, and Lento Bio.

About Lifespan Research Institute

Lifespan Research Institute accelerates the science and systems needed for longer, healthier lives by uniting researchers, investors, and the public to drive lasting impact. LRI advances breakthrough science, builds high-impact ecosystems, and connects the global longevity community.

Media Contact:

Christie Sacco

Marketing Director

Lifespan Research Institute

christie.sacco@lifespan.io

(650) 336-1780

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 ethical journalism and sustains our future.
Lung inflammation

Lung Fibrosis Drug Lowers Biological Age Estimates

Six different aging clocks detected younger blood protein profiles in patients taking the experimental lung-fibrosis drug rentosertib. This suggests possible anti-aging effects, but separating those from the narrower benefits of treating fibrosis remains a challenge [1].

The AI-developed drug

Many drugs developed for particular diseases act on aging-related biological processes. That creates an opportunity: a clinical trial could investigate both whether a drug treats its intended disease and whether it has broader effects on aging. Ordinary clinical measurements cannot establish those broader effects, but we now have biological age clocks that closely track chronological age or predict mortality risk [2]. These clocks have been used in numerous trials as proxies to estimate the intervention’s effect on aging.

In a new study published in Nature Biotechnology, the researchers analyzed blood samples from a Phase 2a trial whose results were published last year [3]. That 12-week, randomized, double-blind, placebo-controlled trial tested rentosertib, an inhibitor of the kinase TNIK, which has been implicated in several aging-related processes [4].

Rentosertib was developed by the longevity biotech company Insilico, using a proprietary AI-based drug discovery platform, to treat idiopathic pulmonary fibrosis (IPF), a progressive disease in which excessive scar tissue compromises lung function. IPF is age-related, with a mean age of onset around 65 years, and aging processes such as cellular senescence and inflammation are heavily involved.

The new analysis included 42 of the trial’s 71 participants. Alongside placebo, the trial tested three regimens: 30 milligrams once daily, 30 milligrams twice daily, and 60 milligrams once daily.

Lower biological age readings

The researchers used six different proteomic clocks, which analyze protein levels in blood. The proteomic clocks’ appeal is partly interpretability: researchers can identify which proteins affect the readings and connect them to known biological processes more directly than is often possible with methylation-based clocks. The clocks were developed by different teams, using data from UK Biobank, including one clock developed by Insilico itself. Four of the clocks were trained on chronological age, and two on mortality.

All six clocks detected lower predicted biological ages in patients taking rentosertib, although not at every dose or visit. After four weeks, the four chronological age-based clocks rated patients taking 60 milligrams once daily (the single-dose regimen) roughly three years younger, on average, than at the start of treatment. These changes were statistically significant compared with placebo. However, the two clocks trained to predict mortality risk did not show a significant change at that dose at week four.

Patients taking 30 milligrams twice daily (the split-dose regimen) showed the most consistent decreases across both types of clocks. The largest reductions in predicted biological age appeared by week four, with little additional change over the remaining eight weeks.

These results essentially mean that patients’ blood protein profiles became more similar to those associated with younger people. They do not, however, establish that the treated patients regained years of youth or would live longer.

Is there a broad anti-aging effect?

Looking beyond the clock readings, the researchers found that treatment changed the levels of 326 blood proteins, including proteins involved in fibrosis, metabolism, and cellular stress responses. Most changes in the two higher-dose groups persisted throughout the trial or appeared later in treatment, suggesting that the drug continued affecting patients’ biology even after predicted ages plateaued.

The researchers then examined which proteins contributed most to the younger age estimates. A fibrosis-associated protein, LTBP2, stood out as a major contributor. It was used by all six clocks, which raises the question of whether their agreement mainly reflects the drug’s effect on fibrosis, rather than broader slowing of aging.

To explore whether the lower age estimates reflected more than improvement in fibrosis, the researchers compared changes in predicted age with changes in lung function. The two did not closely track each other. This suggests that improved lung function alone might not explain the clock changes, although lung function does not capture every aspect of IPF.

The team then compared the treatment-induced protein changes with differences between younger and older participants in UK Biobank. With the split dose, proteins associated with aging tended to move in the opposite direction: those found at higher levels in older people tended to decrease, and vice versa. This pattern was not statistically significant with the single daily dose.

Finally, the researchers examined proteins associated with cellular senescence. These proteins tended to increase in the placebo group but decrease with treatment, suggesting that rentosertib might reduce senescence-associated activity, although the researchers did not directly measure senescent cells in tissues.

These findings strengthen the case for investigating rentosertib as a potential geroprotector. However, because fibrosis, metabolism, and senescence are closely connected, they still cannot definitively establish whether the drug affects aging beyond its benefits for IPF.

“This study illustrates how biomarkers of aging can be incorporated into conventional clinical trials,” Vadim Gladyshev, a professor of medicine at Harvard Medical School and a coauthor of the study, told Lifespan News. “If validated more broadly, such approaches could allow us to learn not only whether a treatment affects a particular disease, but also whether it influences some aspects of aging biology.”

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 ethical journalism and sustains our future.

Literature

[1] Zhavoronkov, A., Galkin, F., Chen, S., Ren, F., Aliper, A., Durymanov, M., … & Gladyshev, V. N. (2026). Integration of proteomic aging clocks in a phase 2a clinical trial supports simultaneous geroprotective assessment. Nature Biotechnology, 1-13.

[2] Argentieri, M. A., Xiao, S., Bennett, D., Winchester, L., Nevado-Holgado, A. J., Ghose, U., … & van Duijn, C. M. (2024). Proteomic aging clock predicts mortality and risk of common age-related diseases in diverse populations. Nature medicine, 30(9), 2450-2460.

[3] Xu, Z., Ren, F., Wang, P., Cao, J., Tan, C., Ma, D., … & Zhavoronkov, A. (2025). A generative AI-discovered TNIK inhibitor for idiopathic pulmonary fibrosis: a randomized phase 2a trial. Nature medicine, 31(8), 2602-2610.

[4] Ewald, C. Y., Pulous, F. E., Lok, S. W. Y., Pun, F. W., Aliper, A., Ren, F., & Zhavoronkov, A. (2024). TNIK’s emerging role in cancer, metabolism, and age-related diseases. Trends in pharmacological sciences, 45(6), 478-489.

Grok Bot

Your Personal Longevity Assistant: Evipedia Grok Bot

With Grok Bot, SpaceXAi has created something really special and helpful. And the Evipedia Grok Bot turns this gem into something even more precious. A specialized AI assistant offering an evidence-based 2nd opinion on health and longevity interventions. It integrates Grok, the AI4L persona, the Evipedia MCP server, and Evipedia-hosted search into one super-useful companion.

What Evipedia Grok Bot will do for you

The bot will allow you to have interactive conversations about a wide range of health and longevity interventions. It delivers helpful 2nd opinions on these topics, and all its answers are grounded in the same principles and behavior used by Evipedia and AI4L:
  • Tailored for the Longevity Community — answers are framed for risk-aware adults actively optimizing their health, not for the general population
  • Evidence First — conclusions rest on human clinical trials and meta-analyses; conflicting, thin, or absent evidence is named as such rather than smoothed over
  • Graded Findings — each benefit and risk carries an explicit High, Medium, Low, or Speculative grade and, where the literature supports one, a magnitude
  • The Full Picture — interventions are looked at across mechanism, benefits, risks, interactions, protocol, monitoring, and open research
  • Commercial Interests — when the evidence comes from parties with a financial stake in the intervention, or from an organization whose members profit from the position it endorses, conflicts are named on every side of the debate
  • Evipedia Lookup — health and longevity questions are checked against the evidence reviews on evipedia.ai before the model answers from memory
  • Plain Language — acronyms and jargon get a short explanation at first use, and scientific nomenclature follows field convention
  • Verified Links — every PMID, NCT ID, and DOI is retrieved and checked before it is shown; a URL that cannot be verified is omitted rather than guessed
  • Review Suggestions — when an intervention under sustained discussion has no Evipedia review, the model offers to suggest it to the Evipedia editorial team or points to generating an evidence review using the AI4L prompt

What’s in Evipedia

Evipedia is a comprehensive, continuously updated online encyclopedia that provides much-needed, accurate, and up-to-date information on a wide range of health and longevity-related interventions.
  • Free to Use — Evipedia is completely free to use and open to everyone. We built Evipedia as a backbone tool for the whole longevity and rejuvenation community. Our goal is to empower individuals with knowledge to make informed decisions about their health and longevity.
  • 770+ Evidence Reviews — Including whole-body therapies, brain health, skin rejuvenation, hormone optimization, peptides, psychedelics, medications, blood and plasma therapies, complementary cancer approaches, foundational habits, diets, foods, probiotics, botanicals, isolates, and many more.
  • A Dual Structure for Every Entry — Each intervention has a one-page Quick Reference Sheet for an at-a-glance protocol, benefits, risks, contraindications, and monitoring, plus a Full Evidence Review for in-depth analysis.
  • Continuous Updates — Entries are continuously updated to reflect the latest developments in health and longevity. On average, reviews are refreshed every 4-6 weeks, ensuring access to the most current information available.
  • Full Audit and Quality Transparency — Every “Quick Reference Sheet” and “Evidence Review” on Evipedia includes an Audit Report that outlines the detailed audit criteria and the history of audits and fixes applied to the documents.
  • Stable Permalinks – Beautiful Sharing Cards — Every intervention has a fixed, short URL and a purpose-designed social sharing card — ideal for citing a compound in a supplement stack or anchoring a claim in an online discussion.
  • AI & Agent-friendly, Extensive Integration Support — Built as a backbone service for the longevity and rejuvenation community, Evipedia features a wide variety of AI integration tools and an easily accessible API. All are free to use, under an AI- and agent-friendly site policy and the Creative Commons 4.0 license.
  • Built on AI4L — Evipedia is built on top of our open-source AI4L framework, which enables anyone to create high-quality, evidence-based reviews of health and longevity interventions. At the core of AI4L is our novel “Audit-Driven Prompting” approach to generate hallucination-free, accurate, and well-structured reviews using frontier AI models.

About Forever Healthy

Forever Healthy Foundation is a private, humanitarian initiative with the mission of enabling people to vastly extend their healthy lifespan. More at forever-healthy.org
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 ethical journalism and sustains our future.
LSM 1

From World Cup Champions to Longevity Champions

Fresh from Spain’s spectacular victory in the 2026 FIFA World Cup, Madrid is preparing for another kind of world-class gathering: one focused not on winning more years of sporting glory, but on winning more healthy years of life.

On September 30 and October 1, 2026, the International Longevity Summit Madrid 2026 will bring together leading scientists, physicians, entrepreneurs, investors and futurists to explore one of humanity’s greatest challenges—and potentially greatest opportunities: extending healthy human life.

Organized by the International Longevity Alliance, the Summit comes to a city uniquely positioned to lead the global conversation on longevity. Spain has the highest life expectancy in the European Union, while the Comunidad de Madrid has recorded the highest life expectancy of any EU region, reaching the remarkable landmark of 85.7 years according to Eurostat. Madrid may therefore be more than simply a great European capital; it could increasingly be considered a “Blue Zone 2.0”: a modern, dynamic metropolis where exceptional longevity meets cutting-edge science, biotechnology and innovation.

LSM 2

And now, after Spain’s national team, La Roja, captured the 2026 FIFA World Cup, Spain can proudly claim another world-leading achievement. In July, Spain defeated Argentina 1–0 after extra time to win its second men’s World Cup title, adding a new chapter to a country already renowned for its health, lifestyle and longevity.

From world champions on the football field to potential champions of healthy longevity, Spain is demonstrating that the future may belong to those who know how to live—and perhaps someday live much longer.

LSM 3

A new royal home at Spain’s most prestigious medical institution

After the success of previous editions held at the Ilustre Colegio Oficial de Médicos de Madrid (ICOMEM), where the Summit was inaugurated with the participation of the Mayor of Madrid, José Luis Martínez-Almeida, the 2026 edition takes a major institutional step forward.

This year, the Summit will be held at the magnificent Real Academia Nacional de Medicina de España (RANME), the Royal National Academy of Medicine of Spain, the country’s most prestigious medical institution. Founded in 1734, the Academy occupies a unique place in Spanish scientific history. The Academy is under the High Patronage of His Majesty King Felipe VI, underlining the exceptional institutional importance of the venue. The Academy is also historically associated with some of the greatest names in medicine, including Spain’s Nobel laureates Santiago Ramón y Cajal and Severo Ochoa.

Located in the historic heart of Madrid, between the Royal Palace and the Teatro Real, the RANME will provide an extraordinary setting for a conversation that could reshape the future of medicine itself.

From George Church and Ray Kurzweil to Eric Topol and Peter Diamandis

The International Longevity Summit has rapidly become a meeting point for some of the world’s most influential thinkers in longevity, biotechnology, medicine and the future of humanity.

Previous editions of the International Longevity Summit in Madrid have featured an exceptional roster of speakers, including George Church, pioneering geneticist; Ray Kurzweil, futurist and inventor; Steve Horvath, creator of the epigenetic clock; Andrea Maier, longevity physician and researcher; Mehmood Khan, global health and life sciences leader; Liz Parrish, biotechnology entrepreneur; Aubrey de Grey, biomedical gerontologist; Bryan Johnson, entrepreneur and longevity pioneer; María Blasco, molecular biologist and telomere researcher; João Pedro de Magalhães, biogerontologist and aging researcher; and Michael Ringel, biotechnology and pharmaceutical executive—along with many other leading scientists, physicians, entrepreneurs, and innovators from around the world.

The 2026 edition continues and expands this tradition of quality. Among the distinguished participants and speakers announced for 2026 are Eric Topol, cardiologist and digital medicine pioneer; Peter Diamandis, entrepreneur and futurist; Brian Kennedy, aging researcher; Valentin Fuster, cardiologist and cardiovascular scientist; Bashayer Almubarak, longevity and health innovation leader; Guido Kroemer, cell biologist and aging researcher; Steven Austad, biogerontologist; Michel Poulain, demographer and Blue Zones researcher; Michael West, stem cell pioneer; Mike Chan, longevity expert and entrepreneur; Wei-Wu He, biotechnology entrepreneur; Patrick E. Sewell, longevity physician; Ronald Bonilla, dentist and longevity innovator; Tina Woods, health and longevity leader; Daniel Wallerstorfer, geneticist and biotech entrepreneur; David Wood, futurist and longevity advocate; and Kenneth Scott, entrepreneur and longevity advocate—along with many other leading international and Spanish scientists, physicians, entrepreneurs, and innovators.

The program will span the biology of aging, rejuvenation biotechnology, preventive and regenerative medicine, artificial intelligence, health data, biomarkers, the longevity economy and the profound social consequences of potentially dramatic increases in human healthspan.

From conference to scientific marketplace: posters and startup pitches debut in 2026

For the first time, the International Longevity Summit will introduce scientific poster sessions and startup pitches, opening the stage to a new generation of researchers, entrepreneurs and innovators. Through an international Open Call, selected participants will have the opportunity to present research projects, scientific posters, short talks and startup initiatives to an audience of experts, investors, physicians and longevity enthusiasts. The goal is to make the Summit not only a place where established leaders discuss the future, but also a platform where the next generation of breakthroughs, companies and scientific careers can begin.

A distinguished group of prestigious Spanish and international institutions is supporting this historic event, organized by International Longevity Alliance (ILA) at the Royal National Academy of Medicine of Spain (RANME), in collaboration with the Official College of Physicians of Madrid (ICOMEM) and Madrid Innovation. International supporters include European Wellness and Triple Helix Science at the Gold level, as well as Novogenia and Nesa World at the Silver level. The event is also endorsed by leading foundations and organizations, including HealthGevity Nation, Hevolution Foundation, Human Longevity Inc., HumanityPlus, Immortalis, KHL Foundation, Life Extension Foundation, Lifeboat Foundation, Longevity Escape Velocity Foundation, Millennium Project, XPRIZE Foundation, together with innovative companies such as Cenegenics, GERO, and OXANA. This year, the Summit will also welcome a new generation of startups working in healthtech, healthcare innovation and longevity, with the logistical support of CRRATE and StartUp Olé Salamanca.

The 2026 edition aims to further strengthen Madrid’s role as a bridge between Europe, Latin America, North America and the rapidly expanding global longevity economy.

LSM 4

Two days of UNESCO history before exploring the future

The Summit will begin even before the scientific program officially opens. On September 28 and 29, participants will be able to join two special pre-conference excursions to some of the most remarkable UNESCO World Heritage sites surrounding Madrid. The first day will travel south-east to Alcalá de Henares, Aranjuez and Toledo. The second will head north-west to Ávila, Segovia and El Escorial.

The contrast is intentional: participants will explore centuries of Spanish and European history before returning to Madrid to discuss technologies that may transform the future of human life itself. From ancient cathedrals and royal palaces to cellular rejuvenation, artificial intelligence and longevity escape velocity, the International Longevity Summit 2026 promises a journey through both humanity’s past and its possible future.

This summer, Spain has shown the world how to win on the football field. This autumn, Madrid will invite the world to explore how humanity might also win the greatest matches of all: the race against aging!

International Longevity Summit 2026

Dates: September 30 – October 1, 2026

UNESCO World Heritage Tours: September 28–29, 2026

Free registration for the Madrid Longevity March

Venue: Real Academia Nacional de Medicina de España (RANME)

Organizer: International Longevity Alliance

Information and registration: www.LongevitySummit.Madrid

Videos: Teaser · UNESCO Tours · Full 12-minute Promo

Media kit: Images and Clips

General inquiries: info@longevitysummit.madrid

About José Cordeiro

LSM 5

José Cordeiro, PhD, is an engineer from MIT and MBA from INSEAD. He is director of the International Longevity Alliance, vicechair of HumanityPlus, fellow of the World Academy of Art & Science, senior fellow of The Millennium Project, founder of the International Longevity Summit in Madrid, founding faculty of Singularity University in Silicon Valley, former Spanish candidate to the European EurParliament and coauthor of the international bestseller The Death of Death.

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 ethical journalism and sustains our future.
Weak muscles

Calcium Mishandling Contributes to Muscle Loss

Researchers have discovered and explained how calcium mishandling in muscle cells leads to long-term muscle weakness in older people.

Calcium is not just for bones

Skeletal muscle cells use calcium ions to control how and when they contract. This activity is modulated by CaMKII, a protein kinase that also regulates muscle adaptations in response to exercise [1] and serves a great many unrelated functions throughout multiple other tissues.

In young tissues, this system works well, with exercise producing reactive oxygen species (ROS) that are used to stimulate muscle growth [1]. However, with aging, this falls apart in multiple ways: calcium ions leak out of where they are supposed to be [2], mitochondria and calcium become uncoupled [3], and, as has been well-known for decades, ROS and oxidative damage are no longer properly mitigated [4]. The authors hypothesized that CaMKII signaling is involved in this dysregulation.

Constant expression weakens muscles

In their first experiment, the researchers examined the muscles of 3.7-month-old mice and compared them to those of 33-month-old mice; 33 months is exceptionally old for a mouse, and mice of that age were provided by the gerontologist Dr. Rafael deCabo. These elderly mice had significantly smaller muscles than the younger group, substantially more CaMKII in muscle tissue, and more evidence of CaMKII activity while at rest. However, the researchers noted that the biomarker they used to detect activity, pT287-CaMKII, is not entirely consistent in various muscle tissues and CaMKII can be modified in many other ways [5].

To determine the effects of constant CAMKII activity in muscle, this team developed a adeno-associated virus (AAV) that caused it to become active only in that tissue. This AAV had local effects, meaning that the researchers were able to inject it onto only one tibialis anterior muscle of each individual mouse; the identical muscle on the other side was injected with a simple fluorescent reporter protein with no significant effects. Interestingly, feedback mechanisms caused natural CAMKII to be suppressed in the muscles that were given this artificial CAMKII increase.

Within less than two months, this increase in constant CaMKII caused the targeted muscles to shrink and become pound-for-pound weaker than the unmodified muscles in the same mice; direct stimulation at multiple frequencies found that the targeted muscles were unable to exert nearly as much force. While it did not impact total mitochondrial number, it had significant negative effects on mitochondrial organization. A similar experiment with a different cohort of mice found that, after nine months, the loss of muscle mass became even more significant.

Some of this muscle loss was found to be driven by inflammation. Blocking the inflammatory signal NF-κB while activating CaMKII blunted some of the effects; the muscles in this group did not become pound-for-pound weaker, but they still lost mass.

Age-related gene expression changes

Gene expression was also significantly impacted. While there were some differences, the impact of constant CaMKII expression was broadly similar to that of natural aging in muscle, and the researchers identified many biochemical pathways that are increased both by natural aging and by increased CaMKII. Most notably, iron-handling pathways were significantly disrupted by CaMKII.

The researchers also injected naturally aged mice with CN19o, which inhibits CaMKII; while individual genes were not significantly affected, the sum total of gene expression was found to move towards a more youthful phenotype. While it did not increase muscle size in 21-month-old mice, suppressing CaMKII in these mice increased their ability to contract.

The researchers hold that age-related constant CaMKII signaling is a significant contributor to sarcopenia. In youth, this signaling is beneficial, but in an aged environment, it is apparently doing more harm than good. However, the researchers did not experimentally validate why constant CaMKII activation has the mitochondrial effects it does, nor did they fully elucidate the connection between calcium and iron signaling. Further work will need to be done to determine if CaMKII is a useful target in people.

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 ethical journalism and sustains our future.

Literature

[1] Wang, Q., Hernández-Ochoa, E. O., Viswanathan, M. C., Blum, I. D., Do, D. C., Granger, J. M., … & Anderson, M. E. (2021). CaMKII oxidation is a critical performance/disease trade-off acquired at the dawn of vertebrate evolution. Nature communications, 12(1), 3175.

[2] Lamboley, C. R., Wyckelsma, V. L., McKenna, M. J., Murphy, R. M., & Lamb, G. D. (2016). Ca2+ leakage out of the sarcoplasmic reticulum is increased in type I skeletal muscle fibres in aged humans. The Journal of physiology, 594(2), 469-481.

[3] Pietrangelo, L., D’Incecco, A., Ainbinder, A., Michelucci, A., Kern, H., Dirksen, R. T., … & Protasi, F. (2015). Age-dependent uncoupling of mitochondria from Ca2+ release units in skeletal muscle. Oncotarget, 6(34), 35358.

[4] Mecocci, P., Fano, G., Fulle, S., MacGarvey, U., Shinobu, L., Polidori, M. C., … & Beal, M. F. (1999). Age-dependent increases in oxidative damage to DNA, lipids, and proteins in human skeletal muscle. Free Radical Biology and Medicine, 26(3-4), 303-308.

[5] Brown, C. N., & Bayer, K. U. (2024). Studying CaMKII: tools and standards. Cell reports, 43(4).

DNA clock

Comparing the Responsiveness of Epigenetic Aging Biomarkers

In a recent study, researchers have evaluated how responsive several DNA methylation (DNAm) biomarkers are to a range of longevity interventions [1].

Waiting too long

Testing lifespan-extending interventions in humans has a major problem: it can take many years, or even decades, to see results. Nobody wants to wait that long. Therefore, it is essential to find proxies, such as biomarkers, that accurately reflect whether an intervention is working. Some of the most popular biomarkers in the aging field are epigenetic aging clocks, DNAm biomarkers that are intended to reflect a person’s biological age or rate of aging.

While these clocks are becoming increasingly popular, they are still not sufficiently validated to serve as surrogate endpoints for human longevity clinical trials, and there isn’t enough data on their responsiveness to longevity-promoting interventions.

“If these new biomarkers are eventually validated to predict long-term health, scientists will be able to evaluate anti-aging therapies much faster,” said Raghav Sehgal, the lead author of this study. “Instead of waiting decades for evidence from clinical trials, we’ll be able to see which interventions are effective and in which people in a few years or even months.”

Multiple comparisons

To analyze how epigenetic aging clocks and other biomarkers respond to various aging interventions, the researchers used data from 51 existing longitudinal interventional studies. The researchers grouped the interventions in their dataset into four groups: “lifestyle (including diet and exercise), pharmacological (for example, metformin, rapamycin, semaglutide, ketamine and anti-TNF therapy), supplements (for example, omega-3 fatty acids and folate) and medical procedures (for example, hyperbaric oxygen therapy, organ transplants and gene therapy).”

Then, they calculated the effect of each intervention using 16 epigenetic clocks and 94 other DNA methylation biomarkers; they used ‘DNAm biomarkers’ as an umbrella term for both of those tools.

Using multiple biomarkers can serve two functions. First, surrogate biomarkers can help predict long-term outcomes. Second, discovery biomarkers can help explain which molecular mechanisms an intervention affects [2, 3].

“What we did was pretty unique,” Sehgal said. “We already know that certain things might prolong healthspan and lifespan. There are data from retrospective analyses as well as animal models. We took all that knowledge along with the real-world clinical studies to identify which interventions in humans were slowing down aging across the board in these known biomarkers.”

Comparing multiple interventions using multiple biomarkers allowed the authors to identify patterns in how different intervention types affect health and aging. For example, they noted that pharmacological interventions produced stronger DNAm biomarker responses than any other category and were the only ones with significantly larger effect sizes. They were also one of two categories, along with a lifestyle intervention, to show significantly reduced epigenetic age. The authors hypothesize that pharmacological interventions’ robust effects may stem from their ability to target inflammation and metabolic pathways such as TNF, AMPK, and mTOR.

Replications matter

The authors note that their compiled studies include replicated studies of the same intervention and use multiple clocks to measure similar outcomes, which allows them to test whether certain interventions have consistent effects.

To identify intervention types with a strong, consistent effect on biomarkers, the authors propose two requirements: “the intervention should modify DNAm biomarkers of a given generation to the same magnitude and direction in a particular study” and “a second study of the same intervention should modify the same biomarkers.”

Both requirements were met by therapies that reduce tumor necrosis factor (TNF) and are used to treat conditions such as inflammatory arthritis and inflammatory bowel disease, suggesting that such therapies may prevent pathological aging in patients with autoimmune disorders. The requirements were also met by two different types of Mediterranean diets in healthy populations.

Not all DNAm biomarkers are created equal

Tests of responsiveness and concordance of the DNAm biomarkers, defined as ”the likelihood that if a DNAm biomarker detected a significant effect, then others would agree on the effect”, showed the superiority of generation 2+ biomarkers.

Similarly, biomarkers differed in sensitivity. Focusing on lifestyle and pharmacological interventions, the researchers noted intervention-type-specific sensitivity across multiple biomarkers and differences in effect-size magnitude between categories: DunedinPACE was highly responsive in the lifestyle category, but in the pharmacological category, it was affected by fewer interventions than other second-generation biomarkers.

Study population health status also affected DNAm biomarker responses, with several biomarkers significantly more responsive in disease groups than in healthy populations, similar to previous studies suggesting that people with health problems may have more room for improvement than healthy people [4, 5]. Only DunedinPACE showed similar response levels in both populations, suggesting that it can be applied in both contexts.

The authors suggest that the training population on which those biomarkers were developed partly explains these observations, since biomarkers trained on populations with more diverse health statuses are more sensitive to changes in populations with disease, while those trained on healthier groups have higher sensitivity in healthier cohorts.

Understanding biology

Those researchers also went a step further, using Generation X (GenX) DNAm biomarkers to gain mechanistic insights into biological aging, which can later support more precise, targeted aging therapies. With this technique, the authors observed which organs are affected by different interventions, such as a reduction in lung system scores upon smoking cessation or the impact of metformin on inflammatory, brain-related, and metabolic pathways, as well as the effect of different diets on various biomarkers and scores, which can aid in measuring diet-specific impacts on different aspects of aging.

Such analyses let researchers focus on biomarkers specific to certain pathways, capturing earlier changes in those systems and organs that composite biomarkers can miss by “averaging out” effects across components.

Narrowing down the choices

In summary, understanding which DNAm biomarkers work best and provide the most useful information across different interventions helps researchers choose the best tools for future clinical trials, minimizing time and cost while maximizing meaningful results.

This analysis of DNAm biomarkers suggests that clinical trials should prioritize generation 2+ clocks, mainly DunedinPACE and PCGrimAge, since their responses were the strongest and the most consistent. However, they still need validation as surrogate endpoints in human clinical trials.

“As researchers, we have a long way to go in understanding the aging process and whether the steps we take to manage it really work,” said Sehgal.

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 ethical journalism and sustains our future.

Literature

[1] Sehgal, R., Borrus, D., Armstrong, J. F., Gonzalez, J., Kasamoto, J., Markov, Y., Priyanka, A., Smith, R., Carreras-Gallo, N., Lasky-Su, J., Dwaraka, V. B., Corley, M. J., & Higgins-Chen, A. (2026). Responsiveness of epigenetic aging biomarkers to longevity interventions in humans. Nature medicine, 10.1038/s41591-026-04562-9. Advance online publication.

[2] Moqri, M., Herzog, C., Poganik, J. R., Biomarkers of Aging Consortium, Justice, J., Belsky, D. W., Higgins-Chen, A., Moskalev, A., Fuellen, G., Cohen, A. A., Bautmans, I., Widschwendter, M., Ding, J., Fleming, A., Mannick, J., Han, J. J., Zhavoronkov, A., Barzilai, N., Kaeberlein, M., Cummings, S., … Gladyshev, V. N. (2023). Biomarkers of aging for the identification and evaluation of longevity interventions. Cell, 186(18), 3758–3775.

[3] Fleming, T. R., & Powers, J. H. (2012). Biomarkers and surrogate endpoints in clinical trials. Statistics in medicine, 31(25), 2973–2984.

[4] Yao, A., Gao, L., Zhang, J., Cheng, J. M., & Kim, D. H. (2024). Frailty as an Effect Modifier in Randomized Controlled Trials: A Systematic Review. Journal of general internal medicine, 39(8), 1452–1473.

[5] Pandey, A., Kitzman, D. W., Nelson, M. B., Pastva, A. M., Duncan, P., Whellan, D. J., Mentz, R. J., Chen, H., Upadhya, B., & Reeves, G. R. (2023). Frailty and Effects of a Multidomain Physical Rehabilitation Intervention Among Older Patients Hospitalized for Acute Heart Failure: A Secondary Analysis of a Randomized Clinical Trial. JAMA cardiology, 8(2), 167–176.

Food-Ignoring Mouse

Late-Life GLP-1 Treatment Increases Lifespan in Female Mice

In a new study, semaglutide given late in life increased median lifespan in female mice by more than 12% and improved various health markers. Semaglutide’s effect possibly went beyond caloric restriction [1].

Old mice, new drugs

GLP-1 receptor agonists, which act on a hormone that regulates insulin secretion and appetite, have revolutionized obesity treatment, showing benefits across several seemingly unrelated diseases. This raised the question whether the drugs’ effect goes beyond caloric restriction, which itself is a potent anti-aging intervention that has produced robust healthspan and lifespan extensions in animal models [2]. So far, human studies have not yielded conclusive results [3], so there is value in going back to animal studies, where interventions can be investigated across the model’s entire lifespan.

A new study, led by scientists from UC Berkeley and published in Nature, features a fairly straightforward design: take female mice, start giving them GLP-1 receptor agonists late in life, and see what happens. The researchers began daily semaglutide treatment in 20-month-old, non-obese, non-diabetic, female mice that ate standard lab chow, and continued it for the rest of their lives. Forty mice received semaglutide, and 39 received saline injections.

Median lifespan extended

Semaglutide reduced food intake by approximately 24% and lowered body weight. Body composition shifted toward a lower fat percentage and a higher lean-mass percentage. This, however, does not mean that overall lean mass increased – just that the animals lost more fat than muscle. There was no significant change in energy expenditure, suggesting that weight loss was mainly due to reduced calorie intake.

In the central result, median lifespan increased from 742 to 834 days: a gain of 92 days, or approximately 12.4%. The controls’ median lifespan amounted to 24.4 months, which means that although the treatment period was fairly short, it nevertheless produced a significant increase in lifespan. 742 days is also on the lower end of female C57BL/6 mice’s lifespan in previous studies, so replicating the results in longer-lived cohorts would be valuable. Mortality was delayed across several non-tumor categories, which is consistent with benefits extending beyond one particular terminal condition.

Live long – but how about prospering?

To determine if the longer-lived animals were also functioning better, the researchers treated old mice in a separate cohort for three months, testing movement, exploration, memory, physical performance, and glucose regulation. Most functional comparisons involved ten mice per group.

Semaglutide-treated mice moved more and explored exposed areas more readily in unfamiliar environments. They also performed better in a spatial memory test. Motor coordination, hanging performance, and treadmill endurance all improved, as did glucose tolerance.

The researchers then analyzed various aging-related cellular processes. Hematopoietic stem cells (HSCs) age somewhat paradoxically: they can become more numerous even as their regenerative performance deteriorates. They also increasingly favor the myeloid lineage, which includes monocytes and granulocytes, over the lymphoid lineage, which includes B and T cells. Semaglutide treatment partially reversed these aspects of HSC aging.

In the dentate gyrus, a region of the hippocampus involved in learning and memory, semaglutide increased the number of both dividing cells and immature neurons, suggesting improved neurogenesis and providing a plausible biological link to the uptick in memory performance.

Inflammation is a major hallmark of aging. Semaglutide reduced inflammatory gene expression in liver and muscle tissues and reduced inflammatory immune-cell signals in the liver. This included fewer macrophages expressing high levels of the inflammatory cytokine IL-6.

Several markers associated with cellular senescence also decreased after treatment, including expression of p16 and p21 in the liver, visceral fat, and spleen along with senescence-associated β-galactosidase staining in the kidney and spleen. However, this does not establish that semaglutide has a senolytic effect.

In the liver and spleen, semaglutide reduced the proportion of cells that bear γ-H2AX, a marker associated with DNA damage. It also increased mitochondrial gene expression and ATP content in muscle and reduced mitochondrial oxidant signaling in blood stem cells. On top of that, the treatment seemed to improve some markers of cellular stress triggered by misfolded proteins.

More than eating less?

To understand how much of the effect could be explained simply by mice eating less, the team compared semaglutide directly with a 24% reduction in food intake in another cohort of old female mice. In an experiment that lasted for five months, ten animals per group received saline, semaglutide, or caloric restriction.

The two interventions resulted in similar total food intake and comparable weight and fat loss, but the mice exhibited different eating patterns: mice under caloric restriction finished their daily rations quickly and then fasted for a prolonged period. Semaglutide-treated mice ate more gradually throughout the day, consistent with a suppressed appetite rather than enforced restriction.

Both treatments broadly preserved physical function, while untreated animals declined. The similarities spanned movement in unfamiliar evironments, rotarod and hanging performance, and treadmill endurance.

However, semaglutide-fed mice fared better than calorically restricted ones in spatial memory and glucose tolerance. Here, semaglutide improved performance above baseline, while caloric restriction generally maintained it near baseline. However, there was no caloric-restricted lifespan group, so this study did not answer the question of whether semaglutide extended life more than an equivalent reduction in food intake would have done.

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 ethical journalism and sustains our future.

Literature

[1] Feng, Y., Barthez, M., Wang, Y., Chen, Y., Qiu, H., Wang, C. L., … & Chen, D. (2026). Late-life semaglutide treatment slows ageing and extends lifespan in female mice Nature, 1-8.

[2] Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., … & Anderson, R. M. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nature communications, 8(1), 14063.

[3] Newsome, P., Francque, S., Harrison, S., Ratziu, V., Van Gaal, L., Calanna, S., … & Sanyal, A. (2019). Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity. Alimentary pharmacology & therapeutics, 50(2), 193-203.

Running mouse

Mice With Growth Hormone Halted in Middle Age Live Longer

Researchers publishing in Aging Cell have described how stopping growth hormone receptor production in midlife significantly lengthens the lives of mice.

Growth but diabetes

Growth hormone affects the metabolism of fats (lipids), increasing the levels of circulating fatty acids while increasing insulin-like growth factor 1 (IGF-1) and impairing the function of insulin itself [1]. Growth hormone has been associated with tissue-specific forms of aging [2], and people who are congenitally insensitive to growth hormone (Laron syndrome) exhibit increased resistance to multiple aspects of aging, including diabetes, cognitive decline, and cardiovascular problems [3].

This relationship between growth hormone and aging is similar in mice and people [4]. Mice with reduced levels of growth hormone live longer than their unaltered counterparts [5], and such mice also have significant reductions in debilitating age-related conditions, such as osteoarthritis [6].

Those mouse models, however, are genetically modified, with effects from birth. Bringing this into the clinic requires affecting growth hormone in adulthood in order to avoid interfering with growth and development. This team has previously developed a mouse model in which growth hormone is disrupted in young adulthood, finding that such mice live longer than wild-type mice [7].

In this study, the researchers built on their previous findings by using a mouse model that ceases production (knockout) of the growth hormone receptor (GHR) at 12 months of age, which roughly corresponds to midlife in humans: a time during which many people would presumably begin to seek treatment for age-related disorders.

The longest-lived mice live even longer

The very first result that the researchers discuss is lifespan, which was markedly improved in both males and females. While they were shorter and smaller than their unaltered counterparts later in life, GHR knockout males had an improved survival curve compared to the male control group. Females with GHR knocked out had no changes in body weight or size but also an improved survival curve.

Interestingly, this lifespan increase was found predominantly in the longest-lived animals, particularly in females; while the shortest-lived members of both the control and GHR knockout groups died at roughly the same ages, the longest-lived female GHR knockout mice lived for four months longer than the longest-lived female control mice. This increase in lifespan occurred alongside significant reductions in IGF-1, particularly in males.

Under normal circumstances, an increase in fat mass and a decrease in lean mass is a cause for concern, and treatments that improve healthspan metrics in mice often do the exact opposite. With a GHR knockout, however, both sexes had increased fat mass and decreased lean mass in later life compared to the control group. Despite this induced obesity and reduction in muscle mass, inflammatory biomarkers were largely unaffected, the mice were not weaker overall according to physical performance tests, and males in the GHR knockout group had improved insulin responses and less fasting glucose; females were unaffected in this area.

Tissue-specific effects

The porous parts of the spinal bones (vertebral trabecular bone) were significantly preserved in male mice, with porosity and bone mineral density being more like that of younger mice. Females were unaffected in this area.

The liver responds strongly to growth hormone signaling, so it is unsurprising that its gene expression was significantly changed when GHR was knocked out, with males being more strongly affected than females. Interestingly, the livers of male mice began exhibiting gene expression that was more associated with that of female mice, and even female mice with GHR knocked out had reduced expressions of genes that are more strongly expressed in males.

Near the end of this paper, the researchers express the opinion that “these findings reinforce the central role of the GH/IGF-1 axis in aging biology and support the concept that pharmacological inhibition of GH signaling during adulthood may represent a feasible strategy for promoting healthy aging.” They reaffirm their findings in a short communication sent to Aging Cell, in which they note the multiple potential problems with completely restricting growth hormone and focus on growth hormone antagonism as a potential treatment avenue.

There is already such an antagonist that has been approved by the FDA, Pegvisomant, which has never been clinically tested for any potential anti-aging effects, despite proposals having been made to do so [8]. While this research provides evidence for the potential of such a trial, it may also be the case that treatments that impact growth hormone at a tissue-specific level can provide tangible lifespan and healthspan increases in people, although substantial work needs to be done in development and trials in order to confirm this.

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 ethical journalism and sustains our future.

Literature

[1] Vijayakumar, A., Novosyadlyy, R., Wu, Y., Yakar, S., & LeRoith, D. (2010). Biological effects of growth hormone on carbohydrate and lipid metabolism. Growth Hormone & IGF Research, 20(1), 1-7.

[2] Chesnokova, V., Zonis, S., Ainsworth, R., Apaydin, T., Valencia, C. W., Greiner, E. C., … & Melmed, S. (2025). Local Growth Hormone Facilitates Aging of the Colon Epithelial Microenvironment. Aging Cell, 24(10), e70187.

[3] Guevara-Aguirre, J., Mishra, A., Canepa, M., Guevara, C., Villacres, Á., Guevara, A., … & Longo, V. D. (2024). Normal or improved cardiovascular risk factors in IGF-I-deficient adults with growth hormone receptor deficiency. Med, 5(7), 816-825.

[4] Qian, Y., Berryman, D. E., Basu, R., List, E. O., Okada, S., Young, J. A., … & Kopchick, J. J. (2022). Mice with gene alterations in the GH and IGF family. Pituitary, 25(1), 1-51.

[5] Bartke, A., & Darcy, J. (2017). GH and ageing: Pitfalls and new insights. Best Practice & Research Clinical Endocrinology & Metabolism, 31(1), 113-125.

[6] Liu, H., Davis, T., Duran-Ortiz, S., Martino, T., Erdely, A., Profio, S., … & Zhu, S. (2024). Growth hormone-receptor disruption in mice reduces osteoarthritis and chondrocyte hypertrophy. Geroscience, 46(5), 4895-4908.

[7] Duran‐Ortiz, S., List, E. O., Ikeno, Y., Young, J., Basu, R., Bell, S., … & Kopchick, J. J. (2021). Growth hormone receptor gene disruption in mature‐adult mice improves male insulin sensitivity and extends female lifespan. Aging cell, 20(12), e13506.

[8] Longo, V. D., Antebi, A., Bartke, A., Barzilai, N., Brown‐Borg, H. M., Caruso, C., … & Fontana, L. (2015). Interventions to slow aging in humans: are we ready?. Aging cell, 14(4), 497-510.

Last Generation to Die

The Last Generation to Die: Interview With Tim Maupin

Filmmaker Tim Maupin has spent a number of years developing The Last Generation to Die, a near-future film about what happens when the first true rejuvenation technologies arrive and who gets left behind. The project has now reached the top 65 of the Future Vision XPrize, a global contest seeking optimistic visions of humanity’s future. We talked to him about the personal stakes behind the story, the challenge of creating future positive stories, and why the film’s central dilemma feels increasingly urgent.

Thanks for joining us, Tim. So, the exciting news is that one of your films was nominated for the Future Vision XPrize. The brief for the contest is to create a 3-minute sci-fi trailer depicting an optimistic, abundant future for humanity. The grand prize winner gets $2.6M+ to turn their vision into a feature film, plus over $1M in prizes for runners-up. Can you tell us a little bit about that, Tim?

Yes, it’s a longevity-focused film that I’ve been working on for quite a while called The Last Generation to Die. It is in the top 65 of over 2500 entries in the X Prize Future Vision contest, which is definitely exciting news.

That’s great, I remember watching the preview some years ago, and I always thought it was a really interesting idea, so I’m really glad to see that it has been nominated. Making it into the top 65 films is a real achievement, so what happens next?

The next step is they choose the top ten, and then that goes down to the top five. The top five get to go to the moonshots event, which is a pretty big deal. The judges are Neil deGrasse Tyson, Mira Lane, Neil Stevenson, and Rod Roddenberry. So, there are some important names involved with this. From there you pitch live, and they show the trailers, and then they actually choose the winner live that night in the room.

It’s a really important event, so fingers crossed, and we’ll see where it goes from there. I think the top ten also get invited to the event too, so even getting into the top ten would be pretty great as well.

Sounds good, so can you tell us a little more about the film itself?

I made it as a short film a few years ago that was played at some film festivals. I’d always envisioned it as a feature, but I really got back into that process after my father passed away in 2019. That was when I went back to the script, and, in some ways, I became a lot more able to write it, because I was living the material in a way that I hadn’t before. After that, it became a lot more real and still is. My mom is also aging, and I’m seeing that very directly, so it’s a very personal and real film.

It’s set in the near future where a female scientist named Lily is at the forefront of a new technology that’s going to slow and even reverse aging. Her father Oliver has a major heart issue, and she’s able to get him on the trial for this technology as a last-ditch effort to save him. And it works and I mean it works really well, he actually starts de-aging and gets much healthier at the same time.

During the film, Lily’s mother falls ill with a rare neurodegenerative disease. But, she doesn’t fit the inclusion criteria of the trial, and they are too afraid to risk trying the technology on her, so her mother’s health ends up failing while her father’s health actually improves because his age is reversing.

So, you have this interesting dynamic between her parents as the film goes on. From a longevity standpoint, I think it is a great thought experiment to consider what would happen in terms of our current form of aging and what could happen with some kind of new rejuvenation technology. I hope that it pulls on the heartstrings of folks in a very direct way as events play out like that.

Then, there’s a whole extra plot that covers how some people in the company are trying to maximize profits with this technology, and she’s fighting that as well. Ultimately, I’d say it’s a bittersweet film, it’s very positive in one way but also very real and nuanced in another.

From my perspective, I think setting a film at the gulf between these two worlds, situations like this will happen. There’ll be a point where some people unfortunately don’t make it and some people get age-reversal technologies. I just think that’s a great point to set the film because it’s got inherent conflict from that standpoint, and you get to see those two dynamics in one spot in time.

That’s basically what the film’s about. I hope by seeing that it encourages people to want to bring this technology on faster and do what they can to support it.

That’s a good synopsis. I saw the original trailer, and I always thought it was an intriguing idea. So glad to see it’s reached this stage, and, obviously, I’ve got my fingers crossed that it makes the top five because it’s exploring some very important near-future possibilities.

The dynamic in the film between the parent who qualifies for the trial and the one who doesn’t feels especially timely. With the first biomedical repair therapies now entering human trials, questions about access and how we regulate multi-disease approaches are becoming real rather than theoretical.

So, let’s talk about how the film originally got started. I understand that it has roots with our organization, Lifespan.io, as it was called back then when the film started. Can you tell us a little bit about how that came about and how it helped to get the film underway?

Yes, absolutely. I started working for Lifespan.io around the same time that I got back into the film, which was great timing because I was surrounded by folks who are working on the same goal and seeing the actual reporting on the research helped to inform the film. So, being involved with Lifespan.io at the time was informative for the film but also energizing on a personal level.

Not only that, but Keith Comito and Oliver Medvedik from Lifespan.io actually served as advisors for the film too. Lifespan.io also helped get the film off the ground by acting as a fiscal sponsor in those early days.

Talking about actually keeping the film going and getting it to where it is, specifically, let’s talk about the jellyfish connection. Can you tell us a little bit about jellyfish and how it has helped you to get the film to where it is?

Jellyfish is a related organization to Lifespan in some ways and includes Keith Comito. The idea behind it was to build a community of filmmakers and artists focused on longevity-related film and media. Films that were a little bit more of the positive future side of things. The goal for the past couple of years has been to try to support that community and find ways to help fund these projects. Funding for films, especially independent films, is always challenging, and so the Jellyfish DAO was started as a crypto model.

But, we are looking at ways to expand that beyond just crypto funding and looking for unique and innovative funding models that might help to grow and support longevity-related films. It’s also a good test case for decentralized science to do things that public funding probably wouldn’t support.

To speak more broadly about the concept of the prize itself, all the films in the competition appear to have a future-positive focus, this is the opposite of what a lot of films set in the future have, which instead often have dystopian storylines. What are your thoughts on that?

The dystopian versus positive storytelling is always an interesting thing to consider, and I agree that dystopian tales do have their place. I think it’s a good simulation, as it were, to imagine how things could go.

But, I strongly agree with the premise of the contest. We do have a lot of dystopian tales, arguably too many, and I think it’s time to balance things in the other direction a bit. Because some might argue that we are living in a bit of a dark time right now and I think we do need to be projecting positive visions to counter that. It’s also very clear that movies and culture do actually shape how things happen to a certain degree in the future.

So, I think by continuing to project positive things, we’re continuing to push forward towards a better future. Even if it may seem like it’s just a movie, I honestly believe that it filters through people’s psyche and does actually change how things can go. I’m honestly very grateful that they’ve put this contest out because I think it’s a much needed counterbalance.

But, I will admit it’s not easy to make future positive films. Dystopian films are easier to write and make because there’s a clear villain and there’s more obvious conflict. It is a challenge to come up with something that still has conflict, still engages people, but ultimately ends in a positive place. It’s been really interesting to see the other creators in the contest try to figure that out as well.

I definitely think it’s a worthy challenge and something worth pushing for. Future positive framing is also important for the biomedical repair field too, because the field does have a tendency to overpromise and underdeliver, which has given it a somewhat tarnished image. There’s a lot of misinformation, hype, and also misunderstanding about what the field is really doing – treating age-related diseases by treating the reasons we age and get sick in the first place. Do you think films like this can probably help with that image?

I think so, and I would say that my film takes a fairly nuanced approach that isn’t as grandiose as immortality or anything like that. It’s taking a more realistic look at some of the more commonly overlooked things about the field. Concepts that make a ton of sense, like if you target aging, you’re simultaneously combating many diseases at once. A film like this can put that in a way that makes sense in a story fashion where it’s not just didactic information that you’re sort of preaching to people.

So yes, I would agree, and there’s also other narratives like the concern that only the billionaires are going to get this tech, which I’m not saying isn’t worth thinking about as a potential risk, but it’s also pushing towards the idea that this really should be for everyone as a counterpoint and that’s actually possible if we decide to make it so. So, I think having the vision to move in a positive direction is important, especially in a movie form.

What sort of impact do you think the film might have if it gets nominated in the top five?

Great question! If it reaches that point, from what I’ve heard, being in the top five gives you more exposure, because you’re on the stage and Range Media Partners and others are right there. So I think it would stand a good chance of getting a lot more attention and potentially some funding.

The other thing to mention is that we have an amazing cast. We have Ed Harris, Lily Rabe and Mamoudou Athie on board now. That’s quite something for an independent film, it’s an achievement to have such great actors interested and I think they could also help to potentially speed that up.

Ideally, we’d be moving a lot closer to getting it into production if we got into the top five. The ideal production window would be next year in spring or summer. So, being in the top five in the contest would absolutely help speed that up.

Wow, that’s quite an upgrade from the original trailer I watched a few years ago, then. Where can people watch the contest version?

People can watch The Last Generation to Die contest video over at the FutureVision XPrize and also vote for it and any of the other films in the contest. They have a pretty cool voting platform where it’s not just a social media-based contest. They give you two trailers, and you vote for one and you cycle through. It’s a little cooler than what you usually see for these things, so I would encourage people to go check those out and vote.

Jellyfish has another film in there called Senti. I would encourage everyone to go take a look at the films there and support this prize because I think we need more of it, and it sounds like they’re gonna continue to do it.

That sounds great. Do we know exactly when they’ll announce the finalists?

I think next week, we will find out the top 10, so it’s very soon. Then I think the top five may come the week after that. So within the next two weeks, we’ll probably find out the top five.

Thank you for taking the time to speak with us today, Tim, and we wish you the best of luck with your film.

As The Last Generation to Die makes clear, the arrival of the first biomedical repair therapies in human trials brings questions of access and equity into sharp focus. Ensuring these technologies benefit society broadly, rather than becoming another driver of inequality, is not only a moral issue but an economic one, something we explore in more detail in our recent white paper – Why Democratizing Rejuvenation Is an Economic Imperative.

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 ethical journalism and sustains our future.

Longevity Science Foundation

Invested in Her Campaign Extends Fundraising Deadline

Driven by ongoing support from their community, The Longevity Science Foundation is extending the deadline for the Invested in Her campaign to October 1, 2026, as they work toward a $250,000 fundraising target to support early-stage research into ovarian aging and menopause.

Hundreds of millions of women live longer than men yet spend more years in poor health. The biology driving this disparity is rooted in ovarian aging and the menopausal transition, and it remains one of the most underfunded areas in medicine. Invested in Her is raising $250,000 to fund the science that closes that gap, for mothers, daughters, and women everywhere.

Only 8.8% of NIH funding is directed to women’s health research, and only a fraction of that studies ovarian aging and the menopausal transition. The result is that a critical biological transition remains insufficiently studied, limiting prevention, early intervention, and targeted treatment.

The implications extend across women’s long-term health. Women live longer than men on average but spend more years in poor health, while the hormonal cascade associated with ovarian decline and menopause reverberates across major systems, including cardiometabolic, brain, and skeletal health. Closing the research gap is how we begin to close the health gap.

Funding the Full Picture

Through its scientific review process, the LSF has identified a portfolio of high-impact projects ready for immediate funding. Rather than funding isolated therapies alone, the LSF is targeting the full arc of women’s reproductive aging through three coordinated pillars: measurement, biological understanding, and early-stage intervention.

The work will support:

  • Measurement: developing better ways to measure ovarian aging and the menopausal transition, because better measurement is the first step to better medicine.
  • Biology: answering why women’s aging unfolds the way it does and improving our understanding of the mechanisms connecting reproductive aging to broader systemic decline.
  • Intervention: advancing early-stage approaches that treat reproductive aging as modifiable, not inevitable.

Building Momentum Around Women’s Health

The campaign recently brought its community together at 7 World Trade Center in New York City for the Invested in Her event, uniting investors, clinicians, researchers, founders, philanthropists, advocates, and other leaders across healthcare and industry. Through personal stories, presentations, panel discussions, and networking, participants explored the challenges facing women’s health and the opportunities to create meaningful change.

Attendee feedback reinforced the need for action. When asked about the biggest barriers to progress in women’s health, healthcare system design and lack of research funding led the room. For the LSF, the answer is clear: it needs to continue doing its part in funding holistic women’s health research to create equitable solutions for every woman.

Invested in Her will continue building on this momentum through October 1, directing attention and funding toward research that can improve how women’s reproductive aging is measured, understood, and ultimately addressed. 100% of donations go directly to research, with no overhead deducted, and all eligible gifts are tax-deductible. Support Invested in Her and help fund the science that closes the gap in women’s health, menopause, and ovarian aging 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 ethical journalism and sustains our future.
Rejuvenation Roundup August 2026

Rejuvenation Roundup August 2026

Properly untangling aging means untangling its various counterbalances, sometimes on the individual level. Here’s what’s been investigated this month.

Interviews

Wei-Wu HeWei-Wu He: People Should Become the CEOs of Their Own Health: Wei-Wu He is an unusual combination of scientist and businessman, and his current company focuses on using precision medicine to lengthen people’s lives.

Michael Snyder: We Need to Track Health, Not Disease: Michael Snyder, Director of the Center for Genomics and Personalized Medicine at Stanford University, is convinced that wearables will help drive the transition from “sickcare” to healthcare.

Advocacy and Analysis

Ships togetherWhy Democratizing Rejuvenation Is an Economic Imperative: Worldwide healthcare faces an unsustainable situation. We spend trillions managing the late-stage effects of biological aging, yet routinely overlook the underlying causes that drive them. Driven by an aging society, the financial burdens of treating diabetes, dementia, and heart disease are pushing Social Security and Medicare towards increasing and potentially catastrophic budget deficits.

Research Roundup

Valine Restriction Increases Male Mouse Lifespan by 23%: A new study has found that restricting dietary valine extends both median and maximum lifespan in male mice while improving healthspan in both sexes.

PastaA New Transcriptomic Clock for Intervention Analysis: A team of researchers has developed Pasta, a transcriptomic clock that accurately predicts the age-related effects of various compounds and gene expressions.

A New Target Against High Blood Pressure: Researchers have discovered why the protein AGGF1 has significant effects on blood pressure and published their findings in Aging Cell.

Organism complexityWhy Affecting Aging in Complex Organisms Is So Hard: A new study proposes a theoretical framework that explains why the more complex an animal is, the harder it is to move the needle on its rate of aging.

A Drug Combination Fights Both Senescence and Cancer: In Aging, the Conboys and their team have described how a combination treatment kills both senescent and cancer cells and lengthens the lives of old mice.

No getting fatA Million-Person Study Finds a Protective Metabolic Gene: A massive human genetics study identified rare folliculin-interacting protein 1 (FNIP1) mutations associated with favorable metabolism and much lower cardiometabolic disease risk. Experiments in human liver cells and mice suggest a therapeutic route.

How Senescence Spreads Between Brain Cells: Researchers have gone into deep detail regarding how each of five senescent brain cell types expresses and receives factors that encourage other cells to become senescent.

Fat cellsHow Old Fat Cells Trigger Inflammation and Raise Risks: Using cohort studies and a mouse model, researchers have found that the circulating factor ANGPTL8, which is produced by senescent fat cells, is related to age-related diseases and mortality in mice and people.

In ALS, Microglia Eat Living Neurons, Mistaking Them for Dead: This study suggests that in amyotrophic lateral sclerosis – and possibly other neurodegenerative diseases – the brain’s immune cells devour stressed but still living neurons due to altered signaling.

Rat tendonsA Tougher Extracellular Matrix Strengthens Tendons in Rats: Researchers have found that an upstream promoter of two extracellular matrix proteins increases healing and strength capabilities in the tendons of rats.

Short, Intense Exercise Elicits Beneficial Metabolic Changes: Compared to moderate-intensity exercise, high-intensity sprint-interval exercise produced larger changes in circulating protein and metabolite levels and stimulated proteins associated with cardiometabolic health benefits.

Aggressive cancerWhy Turning Off Cancer Genes Doesn’t Always Work: A recent study has examined whether senescence might allow cancer cells to survive oncogene withdrawal and become even more dangerous.

A Mechanistic Explanation for SIRT1’s Effects: Researchers have found that the sirtuin SIRT1 stabilizes the human genome by suppressing retrotransposition, which occurs when parts of the genome transcribe themselves onto other parts.

Impact of N-PEP-12 Supplementation on Attentional Performance and Mental Wellbeing in Healthy Adults with Subjective Cognitive Complaints: These findings support further investigation of N-PEP-12 as a nutritional intervention for early subjective cognitive changes associated with aging.

Diet-dependent, beneficial and adverse effects of rapamycin on life span of Drosophila melanogaster: These results confirm the adverse effects of rapamycin during development and demonstrate its potential to switch between beneficial and harmful effects on adult life span depending on other components of the diet.

Natural Bioactive Compounds Targeting Key Hallmarks of Aging: Functional Food Potential of Spermidine, Fisetin, Berberine, and Urolithin A: Together, the four compounds primarily target distinct but complementary aging-associated pathways (autophagy, senolysis, metabolic regulation, mitophagy), suggesting rational potential for combined functional food formulations.

A Systems Pharmacology Model of Aging Identifies Optimal Combination Therapies With Secondary Benefits on Weight Loss and Metabolic Health: Metabolic optimization and aging optimisation are distinct objectives that do not converge on the same drug combination.

A machine learning-derived dietary pattern for aging: The MYTH Diet may offer a biologically informed, scalable framework for developing personalized nutrition strategies aimed at supporting healthy aging and longevity.

Social media use duration and epigenetic aging among U.S. adults in the MIDUS refresher study: These findings provide preliminary evidence that social media use duration is associated with the pace of biological aging as measured by DunedinPACE.

Living Beyond Our Evolutionary Warranty: Why Non-Communicable Diseases May Be The Inevitable Costs of an Extended Lifespan: Accepting NCDs as partially intrinsic to extended lifespan while pursuing interventions delaying onset may yield more realistic health goals than assuming complete preventability.

Intrasplenic Thymus Organogenesis from Injectable Tissue Fragments Restores Functional T-Cell Immunity: These results identify the spleen as an optimal ectopic niche for thymus regeneration and provide a promising strategy for clinical immune reconstitution and regenerative immunology.

Beyond Diabetes: Continuous Glucose Monitoring as a Candidate Precision Tool for Cardiovascular Prevention and Healthy Longevity: The shared longevity genes identified in this work offer potential targets to promote healthy aging and decrease age-onset disease.

News Nuggets

Forever Healthy FoundationForever Healthy Launches the Evipedia Browser Extension: The extension currently recognizes 3,700+ terms across 630+ evidence reviews. It is free to use and available for Chrome, Firefox & Safari. Installing the extension is a simple one-click process from Evipedia’s extension page.

GenBio Launches a “Virtual Cell” AI Model: This AI startup, which lists Nobel laureate David Baker among its co-founders, has announced a “world model” of a cell that can simulate both its natural state and responses to successive perturbations, potentially transforming biological 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 ethical journalism and sustains our future.
Chromatin

A Mechanistic Explanation for SIRT1’s Effects

Researchers have found that the sirtuin SIRT1 stabilizes the human genome by suppressing retrotransposition, which occurs when parts of the genome transcribe themselves onto other parts.

When DNA modifies itself

Long interspersed elements-1 (LINE-1) have existed in organisms’ genomes, including our own, for well over a billion years [1]. They are the only autonomous elements that transpose themselves within the human genome, and they occupy a full sixth of it [2]. Two proteins generated by LINE-1 elements, ORF1 and ORF2, are responsible for a third of the human genome [1].

As catalysts of genomic instability, LINE-1 elements have aided in human evolution, and they are directly responsible for the complexity of the human brain [3]. However, this comes at a high cost: the same instability that allowed us to evolve is itself an aspect of aging, and it is directly responsible for multiple other aspects, including senescence [4] and cancer [5].

Heterochromatin is the packed non-coding DNA that functions as a transcriptional regulator. While it is well-known in aging research as a key part of epigenetic alterations [6], newer research has found that its age-related diminishment allows LINE-1 elements to proliferate [7]. H3K9me3, a fundamental marker of heterochromatin, has been found to be directly responsible for keeping LINE-1 elements in check [8].

A possible explanation for sirtuins’ effects

Sirtuins have been heavily researched in the context of aging. SIRT6 has been specifically identified as a suppressor of LINE-1 activity [9], and SIRT1 is known to have benefits against age-related disorders in several organisms, including in the lungs of mice [10]. However, before this study, no one had yet investigated whether or not SIRT1 suppresses LINE-1 as well.

In their first experiment, the researchers used HeLa cells, an established line of human cancer cells. Using fluorescent reporter proteins to identify LINE-1 activity, the researchers found that the overexpression of SIRT1 in these cells minimized this activity, and silencing SIRT1 increased it. Similar results were found in IMR90 human cells and mouse embryonic fibroblasts.

These results were due to direct effects on a LINE-1 internal promoter. Silencing SIRT1 increased the activity of this promoter, increasing the production of ORF2, which led to increased DNA damage within cells. Similarly, overexpressing SIRT1 decreased this damage. These results were confirmed with the DNA damage marker γH2AX.

Protection on multiple fronts

LINE-1 is also known to trigger the cGAS-STING inflammatory pathway [11], which often leads to cellular senescence. After a high dose of radiation exposure, the researchers found that 30% of a control group of HeLa cells became senescent; however, this dose was only sufficient to drive 13% of a SIRT1-overexpressing group into senescence. In HCA2-hTERT, another cell line, SIRT1 overexpression dropped senescence from 38% to 20% after a high radiation dose. Similarly, SIRT1 overexpression reduced the SASP factors secreted by senescent cells, while silencing SIRT1 increased them.

Quiescence is a state in which cells do not divide; however, unlike senescence, these cells are not incapable of division but are simply waiting for a trigger. SIRT1 was found to have exceptionally strong effects on LINE-1 in quiescent cells, being enriched at its loci and preventing it from harming these reserve cells.

The team then investigated how SIRT1 interacts with two well-known regulators of genomic stability, Lamin B1 and KAP1. Interestingly, while SIRT1 did not have any effects on the levels of these proteins, it improved their ability to interact, aiding in heterochromatin stability. SIRT1 was also found to be positively associated with H3K9me3 in chromatin.

While this research only involved cells and not mice or people, it offers plausible explanations for why SIRT1 has the effects reported in other studies. The researchers state that their “findings establish a new mechanistic framework for SIRT1-mediated senescence intervention, with profound implications for delaying aging and mitigating age-related diseases.” Further work will need to be done to confirm if this framework is correct and that these results hold true in vivo.

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 ethical journalism and sustains our future.

Literature

[1] Baldwin, E. T., van Eeuwen, T., Hoyos, D., Zalevsky, A., Tchesnokov, E. P., Sánchez, R., … & Taylor, M. S. (2024). Structures, functions and adaptations of the human LINE-1 ORF2 protein. Nature, 626(7997), 194-206.

[2] Beck, C. R., Collier, P., Macfarlane, C., Malig, M., Kidd, J. M., Eichler, E. E., … & Moran, J. V. (2010). LINE-1 retrotransposition activity in human genomes. Cell, 141(7), 1159-1170.

[3] Garza, R., Atacho, D. A., Adami, A., Gerdes, P., Vinod, M., Hsieh, P., … & Jakobsson, J. (2023). LINE-1 retrotransposons drive human neuronal transcriptome complexity and functional diversification. Science Advances, 9(44), eadh9543.

[4] De Cecco, M., Criscione, S. W., Peckham, E. J., Hillenmeyer, S., Hamm, E. A., Manivannan, J., … & Sedivy, J. M. (2013). Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements. Aging cell, 12(2), 247-256.

[5] Rodić, N., & Burns, K. H. (2013). Long interspersed element–1 (LINE-1): passenger or driver in human neoplasms?. PLoS genetics, 9(3), e1003402.

[6] Lee, J. H., Kim, E. W., Croteau, D. L., & Bohr, V. A. (2020). Heterochromatin: an epigenetic point of view in aging. Experimental & molecular medicine, 52(9), 1466-1474.

[7] Li, X., Yu, H., Li, D., & Liu, N. (2024). LINE-1 transposable element renaissance in aging and age-related diseases. Ageing Research Reviews, 100, 102440.

[8] Guerra, M. V., Cáceres, M. I., Herrera-Soto, A., Arredondo, S. B., Varas-Godoy, M., van Zundert, B., & Varela-Nallar, L. (2022). H3K9 methyltransferases Suv39h1 and Suv39h2 control the differentiation of neural progenitor cells in the adult hippocampus. Frontiers in Cell and Developmental Biology, 9, 778345.

[9] Van Meter, M., Kashyap, M., Rezazadeh, S., Geneva, A. J., Morello, T. D., Seluanov, A., & Gorbunova, V. (2014). SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nature communications, 5(1), 5011.

[10] Zhou, J., Chen, H., Wang, Q., Chen, S., Wang, R., Wang, Z., … & Jin, J. (2022). Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription. Aging Cell, 21(8), e13680.

[11] Mathavarajah, S., & Dellaire, G. (2023). LINE-1: an emerging initiator of cGAS-STING signalling and inflammation that is dysregulated in disease. Biochemistry and Cell Biology, 102(1), 38-46.

Michael Snyder Interview

Michael Snyder: We Need to Track Health, Not Disease

Michael Snyder, Director of the Center for Genomics and Personalized Medicine at Stanford University, is obsessed with health-tracking wearables. During our interview, he wore four wrist-worn devices – watches and bands – and two rings. He is convinced that these small but powerful gadgets will help drive the transition from today’s “sickcare” to true healthcare, which, as its name suggests, should start with proactively monitoring health rather than waiting for disease to develop. They can also provide the longitudinal health data we need for personalized medicine – and to feed data-hungry AI models.

However, Snyder’s scope of interests is much wider than that. He made waves with a study that reported two distinct periods of pronounced age-related change in people’s 40s and 60s. He also studies the deeply individual patterns of aging, which he calls “ageotypes,” and is developing the concept of intrinsic capacity as a quantitative measure of health to be used in longevity research and drug trials.

I just saw you wearing all those wearables, and I think that’s a great place to start: how do we work with all the data from these devices?

In my case, I’m collecting a lot of data, but that’s more on the research side. The average person will normally wear just one, possibly two of these things – not six or seven or eight like I do.

Wearables are powerful because they measure 24/7, as long as you keep them charged. That means they’re tracking your health, they know your healthy baseline, and you can look for shifts from it. We got involved when they first came out as fitness trackers and thought they could be powerful health monitors because they measured resting heart rate and a few other things. Now they measure even more – heart rate variability, which is super important for health monitoring, blood oxygen. There’s medical value in that information.

We have strong circadian patterns throughout the day. Heart rate goes up during the day, blood pressure shifts – but if you track all that, you can look for shifts from the norm.

We started putting wearables on our cohort and discovered pretty much right away that we could tell when someone was getting ill. In my case, it started with Lyme disease. I picked it up presymptomatically because my blood oxygen dropped.

Then we showed that we could detect respiratory viral infections. It really hit home when the pandemic arrived in 2020. We partnered with Fitbit and showed that you could tell when people were getting COVID in advance of symptoms.

It works particularly well for COVID because it has a long presymptomatic period. Influenza and some other respiratory viruses have more like a 36- to 48-hour incubation before symptoms appear. We can still pick those up before symptoms, but with COVID you have more time.

Especially with COVID, I guess that’s important in two ways: preventing transmission and starting treatment as early as possible, such as with Paxlovid.

Yes, definitely. Paxlovid is thought to be especially effective when you use it right away. We’re running studies where family members of transplant patients have devices. If a family member gets ill, they’re alerted and can self-isolate so the transplant patient doesn’t get infected, which could be very serious.

We’ve had family members get red alerts. They quickly test for COVID or influenza, and often we can tell it’s one or the other. Sometimes, we know they’re ill but aren’t quite sure with what. The treatment differs depending on what they have, as you point out, and they can self-isolate. They’ve been pretty grateful for the alerting system. I think that’s the first sort of clinically actionable demonstration.

You’ve been working with wearables for years, and both their capabilities and the accuracy of the measurements have been increasing. Are they really coming of age now? Can they meaningfully change how we do research? There’s a distinction to be made here between tracking an individual trajectory and getting population-level insights.

They’re definitely embedded in research now. Everybody uses them to track activity and basic physiological parameters. They’re not yet embedded in the clinic. Some concierge services are bringing in these data – but not most standard health plans – partly because the existing system hasn’t been set up for it and isn’t incentivized that way.

We tend to practice sick care rather than healthcare because the financial incentives aren’t aligned. We need to fix that. If we actually practice healthcare, people will routinely wear these devices because tracking is so integral to keeping people healthy.

Other groups have shown that you can pick up atrial fibrillation with a smartwatch, and it works reasonably well – in the 30-50 percent range, I think. None of these devices is perfect, although they keep getting better.

Interestingly, for our alerting system, the number one trigger of red alerts is workplace stress, not a respiratory viral infection. That makes sense because it’s mostly built around heart rate and related measures. Now that we have other data types, I’m quite confident we can distinguish respiratory infections from mental stress. That’s something we’re working on.

Knowing when people are mentally stressed is a big deal. If something is mentally or physically stressing you, you should take care of yourself. We don’t have good biomarkers for mental health. There’s a lot more to do, but I think wearables will be excellent indicators of both mental and physical stress.

We haven’t published this yet, but we had a case of someone who died of a heart attack, and his wife shared his data. He had an Apple Watch and an Oura Ring, and it’s pretty clear he had a step-function change about four and a half months before the event – resting heart rate and a lot of other parameters shifted.

We need real-time systems that pull in the data, track people, and alert them when something is off. It comes back to the car-dashboard analogy. If a light goes on, you may not know exactly what it is, and it may be a false alarm in terms of something serious. But usually if an alert goes off, something is happening, and then you can follow up.

On the population side, wearable companies are sitting on these huge mountains of data. Do you think it will ever be possible to anonymize and use it? Are there efforts in that direction?

I don’t think companies are incentivized to share their data, and I expect they generally won’t. Some are forced to share if they want to publish. So a lot of this is going to come from academic researchers.

Many of us share our smartwatch data, but continuous glucose monitoring is a good example of the problem. There are many CGM studies, but it’s very hard, if not impossible, to get the underlying data. With smartwatches, some big biobanks are now putting wearables on people. All of Us has Fitbits on many participants. UK Biobank has done more with ActiGraph, but they’re discussing wearables as well.

I’d like to think the cohort we’ve followed pioneered some of this too. It’s relatively small, but we did deep -omics profiling, put wearables on people early, and learned that these things are powerful.

One of the more important things we learned was with continuous glucose monitoring. CGMs were being used a lot for insulin-dependent type 1 and type 2 diabetics. When we got involved, they weren’t really being used in so-called normal people and prediabetics. We put them on those groups and discovered right away that a lot of people thought to be normal weren’t so normal. They were spiking pretty badly – sometimes as badly as diabetics.

That was actually one of my questions. I’ve worn a CGM a few times for a few weeks.

Very powerful, right? You’ll never eat the same again. I mean that in a good way. You see what spikes you, and that’s very personal. What spikes your glucose can be very different from what spikes mine. We’re all very different.

Do you think the question about the importance of glucose spikes is settled? Are they really that crucial for health?

I think it’s settled in certain ways. There are at least two obvious lines of evidence. Time in range is strongly related to diabetes, and many studies show that diabetes strongly affects health, especially cardiovascular disease. There are also studies showing that postprandial spikes – spikes after meals – are associated with cardiovascular disease independently of diabetes. So, in my mind, the data on spiking are pretty clear. There are nuances, of course. If you lift weights, for example, you can break down glycogen into glucose, so not every rise has the same meaning.

Constant monitoring obviously is amazing: it gives you important insights into your health and can flag many things early on. But what about overdiagnosis, overtreatment, false positives, or just the constant background anxiety you can get when you measure yourself all the time?

I think it’s an education issue. You’re right that some people get overly anxious, and you want to be careful about how information is returned. It’s up to the person to decide how they want that information, in my opinion, but most people are quite capable of handling it.

When people first get these devices, everybody gets very absorbed in them – what foods spike you and all that. Then you settle into a pattern where they’re fairly useful. They can alert you to some pretty serious health issues, so I think it’s better to know. I like the car analogy. Your car has lots of sensors. You wouldn’t dream of driving it without a dashboard.

I could even argue that things like whole-body MRI can reduce anxiety in some cases. I know someone who was very worried because their family had a history of ovarian cancer. They got a whole-body MRI and were very pleased that everything looked good.

The mismatch with whole-body MRI is that people assume, ‘If you have nodules, you may have cancer.’ That’s the wrong way to think about it. You want to know what nodules you have, but the real issue is whether any are growing. Everybody has nodules. We need longitudinal data.

I have nine nodules. I get whole-body MRIs every three months. That may be overkill – I’m trying to see how often we really should measure people. If you have an aggressive cancer, it can take off pretty quickly.

Yes, we’re believers in whole-body MRI. You’re going to have nodules, and the key is knowing where they are so that if you ever get cancer, have it operated on, and then get follow-up imaging, you know what your background looked like. Without that baseline, you may be in a difficult position.

In my opinion, everybody should get a whole-body MRI so they know their baseline. I think you should get a discount on your health plan if you do these sorts of things – whole-body MRI, wearables, genome sequencing – because you’ll be better able to manage your health.

Hopefully we’ll eventually see some involvement from insurance companies. But for that, we need hard evidence that continuous monitoring actually works. Do we have it now? Are we close?

For wearables, I’d argue there are plenty of cases where they’ve been useful, but have the proper trials the medical establishment wants to see been done? Not really. It would be nice to have them so we can show that this keeps people healthier and maybe saves lives in some cases. They’ll have to be large because we’re doing health tracking, not disease tracking, and that’s a big difference.

Let’s move to your ARPA-H project, which I think is the biggest recent news. It studies intrinsic capacity. What is intrinsic capacity, why is it important, and how could it affect the way we do longevity research?

Intrinsic capacity is sort of a wellness score – a functional health state, if you will. We have lots of measurements for disease, and that’s what’s embedded in our health system. We have ICD codes: if you have a disease, it can be coded, with reimbursement mechanisms for the diagnostic tests and therapeutics associated with it. We don’t have comparable measures for wellness. That’s where intrinsic capacity comes in.

It’s built around functional areas. The WHO came up with five categories: cognition, locomotion, psychological well-being (things like depression and anxiety), sensory function (such as hearing and vision), and vitality. Vitality is kind of a giant bucket and probably should be broken into subtypes because it involves heart aging, blood, and many other things.

There are validated tests already, many of them surveys, and other measurements are coming from wearables. You can measure gait, heart rate, heart rate variability. Grip strength is a good one. Locomotion in general relates to mobility and strength. We’re funded to do two things. One is to build an intrinsic-capacity score that gets FDA approved – that’s the mission – and, if possible, divide it into subdomains. I like that because we’re big on something called ageotypes, which we can come back to. The idea is to have a quantitative score for someone’s health, not their disease.

That could also be a big deal for drug trials. Imagine you have a good drug – the GLP-1s, for instance, are now thought to have many important health benefits. How do you know whether someone’s health is actually improving? Or, you discover a new drug and think, ‘This is the solution.’ How do you prove it? You need a quantitative measurement that tracks improvement. That’s what intrinsic capacity is about.

The other part of this ARPA-H PROSPR grant is to build a home test. We think the final score will probably combine blood, wearables, and surveys. The idea is to make something simple that you can do frequently to see your health state. We’re supposed to get the home test down to around $100.

We’ve invented microsampling in the lab, where you collect small drops of blood, mail them in, and we can measure thousands of analytes from that tiny sample.

Is it fair to say that you basically did what Theranos tried to do?

In a sense, yes, but they could have done what we did, and they didn’t. They tried to reproduce a lot of conventional clinical tests. Some of our measurements are clinical-grade, but we don’t try to do every standard clinical assay – we don’t do LDL, for example – because that’s not how the technology is set up. What we do are scientifically validated measurements that are in the literature and are valuable markers.

You collect these small blood samples – from a fingertip, or there are methods that collect them from the upper arm – mail them in, and we make all these measurements. We spun out a company called Iollo that does this. You send in the sample, they make about 650 measurements, combine your data with information from the literature, and use AI to make very specific recommendations.

Most people improve their markers. We think this is the future: health tracking through wearables, facial and voice recognition, and biochemical measurements you can make at home. Instead of going to a physician every two years and waiting until you’re sick, you could do this routinely while you’re healthy.

If it’s easy, people will do it often. Going to a doctor’s office is inconvenient – you have to take time off work. It’s a pain. The key is making this easy and convenient so people get measured often and keep themselves healthy. That’s the mission.

We’re not doing every biochemical measurement you’d do in a physician’s office. We do quite a few, but some are surrogates, and they may even be better for certain purposes.

Physiology measured in a physician’s office can also be quite off. There’s white-coat syndrome: people get nervous, their heart rate and blood pressure may be high. If you pull someone’s resting heart rate from a smartwatch first thing in the morning, that’s often a much better reflection of what’s going on.

That’s a good point. When I go to the doctor, my blood pressure is always high for no apparent reason. It’s also one measurement a year or a few months, so unless it’s extremely off, it doesn’t reveal very much.

Exactly. What do you do with a measurement you know is flawed? Same with heart rate. Longitudinal measurements can be useful for infectious disease, mental health, and, we believe, heart issues and other things as well.

Another area we’re getting involved in is supplements. Supplements have a bad reputation, somewhat deservedly. You walk into CVS and there’s a whole row of them, and for most, the data aren’t very strong.

The data around foods containing many of those compounds are often better. Diets rich in antioxidant-containing foods, for example, are generally associated with better health outcomes, fewer events, and lower all-cause mortality.

But, critics will say, ‘You haven’t shown that the same thing works as a supplement.’ And that’s fair. We need more studies. There are some supplements, such as vitamin D in particular settings, where there’s evidence of benefit, but broadly, we need much better data.

So we launched a website called MySuppleHub. It’s a community-driven supplement encyclopedia. You can look up supplements you use or are curious about, get information about them, and share your experiences.

That actually sounds like it could be a game changer.

I hope so. We’ll see if it works. We just launched it and several thousand people have already signed up. We’d love to get millions. Then we want to take the supplements that are most widely used or look most interesting and run studies around them to see how they really affect health. I think that could be super cool.

I can see how an intrinsic-capacity score works for health monitoring and early detection. But, if we’re talking about aging biomarkers for use in aging research, what are its advantages over something like an epigenetic clock, which may be less explainable but perhaps easier to measure?

I think the epigenetic clocks from Steve Horvath and others are the prototype for all of this. They work. The data are pretty strong that they’re associated with all-cause mortality and other outcomes when the clock is accelerated. The limitation is that they don’t give you as much actionable information. What do you do with a methylation clock per se? There are methylation markers that are surrogates for particular things, but the overall number doesn’t necessarily tell you what to act on.

Through our deep profiling – metabolomics, proteomics, transcriptomics, and other measurements – we track people over time and see how they change. Everybody changes differently. Some are cardiovascular agers, some metabolic agers, some show more oxidative-stress aging. Some are all of the above; you can have combinations of things going off. Back to the car analogy: your car ages as a whole, but certain parts may age faster.

The entire car doesn’t break at the same time.

Exactly. You want to know what the weak link is. We call these aging patterns ageotypes. I like that name because it covers organ-specific aging – heart age, kidney age – but also more systemic things like oxidative stress and inflammation. So we can track how you’re aging.

Iollo, the company I mentioned, uses microsampling to measure your metabolic profile. They estimate biological age and your ageotype. You can see things like heart age and oxidative stress. Then AI can see what’s off and make very specific recommendations – not just ‘exercise more’ or ‘eat better,’ but specific dietary and lifestyle changes. People who follow the recommendations improve their markers about 95% of the time.

I think this is the future. Between wearables and microsampling for biochemical measurements, we’ll be able to measure people much more often, track their trajectories, and follow how they progress.

That brings up an important concept. The healthcare system focuses on population averages: are you inside the normal range or outside it? We think the individual trajectory is much more important. You can sit at the low end of normal as your healthy baseline, then double a value – a liver enzyme, for example – and still technically be within the normal range. Your physician may say nothing. But if a marker suddenly doubles, something may be off.

We’ve seen this in our research. In one case, a person reached out after a liver marker shifted and said, ‘Mike, what’s going on here?’ I said, ‘I don’t know – why don’t you get another measurement?’ He did, and the next measurement was outside the normal range. Under the traditional system, he might not have gone back until a routine checkup two years later, if at all. Who knows what damage could have occurred by then?

So, we think the individual trajectory is much more important than comparing one measurement with a population reference range.

That’s a paradigm shift that could eventually require redoing our entire healthcare system.

It is a paradigm shift, but I don’t think it’s that hard, technologically. You can have algorithms tracking you. We’re all going to have agents tracking our health in the future. There’s going to be a lot of information around you, and the system can alert you when things are off.

What about the incentives in the US healthcare system? Are they likely to help or impede this transition, especially compared with other countries?

The US is at a huge disadvantage because the financial incentives aren’t aligned. Our health system is fragmented. The average time someone stays in a health plan is about 18 months. Why would an insurer put a lot of money into prevention if, 18 months from now, you’re probably going to move to another plan?

Other countries often have single-payer systems. Once you get your genome sequenced, for example, that information stays in the system and can be used over time to help manage your health.

I think health plans should give people incentives for having a smartwatch, getting their genome sequenced, getting checkups – things that help people keep themselves healthy. Ideally, those people will have less chronic disease and cost the healthcare system less, although you could argue that maybe you’re just delaying some costs until the last year of life.

Do you think we’re too obsessed as a society with keeping our health data private?

Way too obsessed, in my view, because almost nothing is private anymore. There are cameras on every street corner. We all use credit cards, which generate a lot of personal data, and nobody panics about that because nobody wants to walk around with bags of cash.

With health data, what people are really worried about is abuse. I believe that in a wealthy society there should be some minimum level of healthcare, and you shouldn’t be discriminated against because of your health information. If you can protect people from misuse, everybody should be able to benefit from health tracking. To me, the privacy issue is overemphasized relative to the potential value.

Healthcare organizations have vast troves of data that we can barely touch because of all kinds of restrictions.

And they haven’t figured out the analytics. That will change with AI. The physician of the future is going to be an AI agent. In the immediate future, there’ll still be a human in the loop, and humans will remain very important for a while. Down the road, we’ll see.

But, we all need AI agents because there’s simply too much information. An agent can pull together all the information collected about you and make recommendations. And you can interface with it 24/7, which is kind of nice.

If people are shown clear benefits from sharing their data, you think they’ll become more open to it?

I hope so, because not sharing is a disaster. We have eight billion people on the planet. Even detailed information from just 0.1% of them is about eight million people. That would be an enormous amount of data. We need detailed data if we want to track all the elements of health.

Can we touch on your famous paper about the transitions around ages 44 and 60 and nonlinear aging? It became very widely discussed and probably misunderstood in some places. It also wasn’t a huge study, so I’d like you to explain what it actually showed.

It was a small number of people, but they were densely tracked, and that’s the key. The main point is that aging is nonlinear – certain things change more at certain times.

Some of what happens in the 60s was already well known before our study. Your immune system declines, you lose muscle mass, and so on. But we saw other things too. Oxidative stress changes throughout life and tends to increase sharply as you hit your 60s. We also saw a lot of changes in the 40s.

Some of the statistical methods we used have since been questioned, and those criticisms are correct – we did make a mistake there. But the broader conclusion that aging is nonlinear is correct, and we still see waves of change in the 40s and 60s.

Then the question is what underlies those changes. For the wave in the 40s, we think lifestyle is probably part of it. In your teens and 20s, you’re often very active – at least I was. In your 30s, you’re developing your career, you may have a family, and however hard you try, you’re probably not quite as active. I think some of that catches up with you.

We also shift our preferences as we go through life. But, if you look at people who live long, healthy lives, there are some basic ingredients. They’re very active. They tend to avoid ultra-processed foods. They generally have good social and community networks, and many have strong family networks. That’s understudied and underappreciated. My prediction – also not studied nearly enough – is that they probably have good sleep patterns too. Most people don’t sleep enough. Sleep is my weak point, by the way. I’m pretty good on the other things, but not sleep. I’ve been working on it.

It’s hard to maintain all these things throughout your lifespan. In fact, we train people improperly from the start. We put kids in school where they sit all day, and prolonged uninterrupted sitting is bad. Studies show that getting people to move every half hour is beneficial. That’s hard in many settings, but at least moving once an hour would help. We need to ingrain healthy habits earlier, and maybe then we can make aging a little more linear.

Circling back to wearables, if young people start adopting them en masse, maybe that will help move them toward the idea that they need to adopt a healthy lifestyle earlier, while they still feel fine, or to continue being active in their 30s, just like you said.

Exactly. Don’t wait and try to fix a broken system. Keep people healthy rather than fixing something after it breaks.

One more question about that study. It included a little over a hundred participants, if I remember correctly. Did you see people who didn’t show that two-wave pattern or didn’t show it nearly as clearly? There’s probably something to be learned from such outliers.

That’s a good question. We’ve tended to look more at people aging unusually rapidly than at the straight-liners you’re talking about. In our earlier work on ageotypes, we see people with very different aging patterns. Some are metabolic agers, for example, and some are quite obese.

But your question about people with relatively straight trajectories is a great one. We should go back and look more carefully. We’ve enlarged the study somewhat and are almost finished collecting about 12 years of data. What’s powerful is that the dataset is both dense and long.

But the follow-up in the original study was pretty short.

It was – around three and a half years for that analysis. Now, for some data types, we have much longer follow-up. That means we can correlate very specific lifestyle patterns with aging phenotypes and biochemical and physiological changes. I think that’s going to make a huge difference.

We run all kinds of studies – fiber supplementation, for example – and people in the cohort also go on and off things like statins or GLP-1 drugs as part of their normal lives. A lot of that is embedded in the longitudinal data. The number of people is still small, but the information is extremely dense. It may not generalize to a million people, but it can give us strong hints.

We already know that GLP-1 drugs have many effects, but I predict we’ll find some new ones that aren’t as well known because of how densely we sample and follow people. We’ve seen the same thing when people become sedentary or, on the flip side, start exercising – dramatic changes.

Correlating those changes with lifestyle will be very valuable. At the end of the day, we want actionable information that lets people improve their ageotype and their metabolic and other health phenotypes.

I want to end with AI. Like many researchers in aging and longevity, you seem to see AI as essential for deciphering the extraordinary complexity of aging – especially once we start collecting huge amounts of wearable, biochemical, and other data on each person. But AI has also become very controversial in society. How do you think about its advance? Should people in our field be ambassadors for the beneficial side of AI?

Some people feel threatened about job security and things like that, I guess. But to me, AI is the future. It’s going to be integrated into our lives and we’ll use it. Smartphones are integrated into our lives now. There are downsides – as a society, we probably have too much screen time – but it’s still an enormously useful tool.

Information is incredibly valuable for managing health. Medicine and health are information sciences, and there’s more information than any human can handle. We need AI agents that can collect the information about you, pull it together, and help determine what’s best for your health.

The caution is that AI builds on existing information. You need data to make these recommendations. AI doesn’t inherently know where the blank spots are. It can try to project into them, but that’s not the same as actually having the information. We need to fill those gaps – first so everyone is represented and can benefit, and second so we can give the best medical and health advice possible.

AI is already capable of a lot more than many people realize. In some circumstances, it clearly outperforms physicians.

I don’t think that message is out there enough. What people keep hearing is, ‘AI will help us develop new drugs.’ That’s important, but it’s not the whole story.

Not at all. The health-management side is already emerging. For certain tasks, like diagnosis from images, AI can be much more powerful than a human. We’re going to use things like retinal scans for health in the future, and much of that will be AI-driven.

Aggressive cancer

Why Turning Off Cancer Genes Doesn’t Always Work

A recent study has examined whether senescence might allow cancer cells to survive oncogene withdrawal and become even more dangerous [1].

Some blocking techniques are temporary

Many cancers depend heavily on a particular oncogenic signal to maintain their growth. Drugs that block these drivers can, therefore, produce dramatic tumor shrinkage. A major clinical problem, however, is that a small population of cancer cells may survive treatment and eventually regenerate the tumor, which no longer responds to the same treatment and often grows in a more aggressive, invasive manner. The biological changes that allow these surviving cells to persist during prolonged suppression of the oncogene are not fully understood.

Therefore, these investigators used a genetically controllable system in which cancer cell growth is driven by the SV40 large T antigen (Tag). Expression of this oncogenic protein could be switched on or off by adding or removing doxycycline, respectively.

Doxycycline can be used either by directly adding it to a cell culture or by adding it to the drinking water given to animals who carry such modified cells. This provides a way to reproduce, experimentally, the situation in which a tumor suddenly loses the oncogenic signal on which it has become dependent. The researchers followed the cells after oncogene withdrawal both in culture and in tumors grown in mice.

They also examined whether similar phenomena occur in a human cancer model. For this purpose, they used A375 melanoma cells carrying the common BRAFV600E mutation and treated them with vemurafenib, a drug that inhibits mutant BRAF. This second model tested whether the observations from the engineered mouse system might also apply to a clinically relevant form of targeted therapy.

Oncogene loss drives cellular senescence

When the oncogenic driver was removed, tumor cells rapidly stopped dividing and developed morphological and molecular characteristics associated with senescence. They became larger and flatter and accumulated senescence-associated β-galactosidase, a well-known biomarker. At the same time, cell-cycle regulator expression changed in a way that signified durable proliferation arrest: the cells were no longer able to divide.

Interestingly, this process did not follow the classic pattern in which p16 is strongly induced. Instead, senescence induction relied largely on a p21-associated mechanism. The authors explained this unusual pattern in terms of the interaction between SV40 Tag and the tumor-suppressor proteins p53 and Rb. Once Tag was removed, the regulatory relationship between these proteins changed, producing a form of senescence that differs from the canonical pathway.

Senescent cells remain biologically active

Although the cells stopped proliferating, they did not become metabolically or functionally inert. They altered their gene-expression programs and began producing a range of secreted molecules associated with inflammatory signaling and tissue remodeling.

These cells also underwent substantial metabolic adaptation. Rather than simply reducing energy production, they increased activity in both glycolysis and mitochondrial respiration. This suggests that the surviving population enters an energetically demanding state in which multiple metabolic pathways are running simultaneously. Such flexibility may help cells remain viable while they are unable to divide.

This finding changes our understanding of residual senescent cancer cells. They may appear dormant because they are no longer proliferating, but they remain metabolically active and capable of substantially influencing their surroundings.

Senescence can be followed by tumor regrowth

The most important observation of the study was that tumor cells that experienced oncogene withdrawal were more capable of producing recurrent tumors than cells that had not undergone this state. Tumors initially regressed when the oncogenic driver was switched off, but a subset subsequently began growing again.

In some animals, tumors eventually emerged even though the original oncogene remained suppressed. Nine of twelve animals in one experimental group developed tumors after a long delay despite continued inhibition of Tag. This demonstrates that recurrence did not necessarily require restoration of the original oncogenic stimulus. Instead, some cells acquired new ways of sustaining proliferation.

Thus, this study suggests a two-stage process: oncogene removal initially forces cancer cells into a non-proliferative state, but the prolonged survival of these cells creates an opportunity for genetic and functional adaptations that can eventually restore tumor growth.

Genetic changes accompany this escape from senescence

The cells isolated from recurrent tumors were substantially different from the original tumor population. They displayed extensive chromosomal abnormalities and increases in chromosome number, indicating that genome instability had developed during or after the senescent period. Such abnormalities can generate genetic diversity, potentially allowing a subset of cells to find alternative routes around the growth restriction imposed by oncogene loss.

The recurrent cells also displayed altered metabolic programs. Pathways involved in nucleotide production, amino-acid metabolism, and folate metabolism became more active, consistent with the increased biosynthetic requirements of cells that had returned to proliferation.

One of the most notable molecular changes was the increased expression of Mdm2, a protein that suppresses p53 activity. This provided a plausible mechanism for overcoming the growth arrest that had followed loss of SV40 Tag. Importantly, cells from recurrent tumors were particularly sensitive to an Mdm2 inhibitor, whereas the original tumor cells were not. This suggests that Mdm2 became a new dependency during the transition from oncogene dependence to oncogene-independent growth.

Changes in the tumor microenvironment

This study also indicates that recurrence cannot be explained entirely by alterations within the cancer cells. The investigators compared the immune and stromal composition of tumors before oncogene withdrawal, during tumor regression, and after recurrence.

The composition of the tumor environment changed substantially during this process. Recurrent tumors contained more endothelial cells, consistent with renewed blood-vessel formation. They also had fewer conventional dendritic cells and more regulatory macrophages. Together, these changes suggest that the environment surrounding the recurrent tumor becomes less favorable for effective immune surveillance and more supportive of tumor growth.

The secretory activity of senescent cells may contribute to this remodeling. Molecules released by these cells can affect neighboring immune, stromal, and vascular cells. Consequently, a population that initially suppresses tumor expansion by ceasing to divide may simultaneously create conditions that make later tumor growth easier.

Relevance to BRAF-targeted therapy

The experiments with human A375 melanoma cells provide evidence that the phenomenon is not restricted to the engineered mouse model. Inhibition of BRAFV600E with vemurafenib generated cells with several features of senescence, including prolonged growth arrest and changes in cellular morphology and secretory activity. The authors therefore suggest that a similar response could occur when human tumors are treated with drugs that remove a major oncogenic growth signal.

However, the authors also emphasize that the molecular mechanism is likely to depend on the genetic background of the cancer. For example, Mdm2-based escape may be particularly relevant to tumors in which p53 remains functional. Tumors carrying TP53 mutations would be expected to use different mechanisms to bypass senescence, so the therapeutic implications cannot simply be generalized to all cancers.

These findings have potentially important implications for targeted therapy. A treatment that efficiently suppresses an oncogenic driver may nevertheless leave behind a population of viable cells with a capacity to adapt. Consequently, preventing relapse may require strategies that eliminate these surviving cells or block the mechanisms they use to escape growth arrest.

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 ethical journalism and sustains our future.

Literature

[1] Schmitt, P., Hönig, K., Norcia, M. T., Nogueira, M. F., Flore, V., Vesperinas, I. S., … & Blankenstein, T. (2026). Oncogene inactivation-induced senescence facilitates tumor relapse. Nature Communications, 17(1), 6244.

Bicycle racers

Short, Intense Exercise Elicits Beneficial Metabolic Changes

A new study compared high-intensity sprint-interval exercise with moderate-intensity exercise. The former produced larger changes in circulating protein and metabolite levels than the latter and stimulated proteins associated with cardiometabolic health benefits [1].

Short and intense vs. long and moderate

Exercise is a well-known lifestyle factor that can positively impact health. Exercise benefits multiple cells, tissues, and organs through factors that are secreted by various cells and circulate in the body [2]. However, the particular type of exercise that offers the greatest return on investment remains debated. Similarly, the circulating factors that mediate exercise benefits are still not fully defined.

Since intensity affects the composition of secreted molecules, the researchers employed “young, active, metabolically healthy males” in order to understand how exercise intensity affects these molcules and their crosstalk between organs. One group performed sprint-interval exercise (SIE), a routine that consists of short bursts of physical activity: here, it was 6 sets of 30-second all-out cycling with 4-minute rests between sets. The other group did 90 minutes of continuous cycling as moderate-intensity exercise (MIE), with individually adjusted intensity.

Intensity-dependent changes

Initial analysis of all proteins (the proteome) in plasma showed intensity-dependent changes, encompassing almost a quarter of the total detected proteins, including factors involved in the formation of new blood vessels (angiogenesis), extracellular matrix remodeling, gut signaling, and potential neuroregulation, immediately after SIE. Most of these proteins returned to resting levels three hours after exercise, showing that SIE drives rapid changes in the plasma proteome. MIE shows only modest time-dependent changes.

The researchers also noted intensity-dependent and time-dependent changes in secreted metabolites following both SIE and MIE. For SIE, significant changes were observed immediately after exercise and again three hours later, while MIE showed a delayed response: only a few molecules changed immediately after exercise, but that number increased three hours later. The metabolites that changed following SIE are associated with high energetic demands, while those that changed following MIE reflect the sustained energetic demands that are characteristic of continuous exercise.

The researchers repeated the experiment on a subset of participants who underwent 8 weeks of training; similar results emerged. Similar observations also emerged when the researchers tested runners, suggesting these changes are specific to exercise intensity rather than training level or exercise modality.

“What’s exciting here is that just a few minutes of intense exercise can trigger a significant molecular response,” says Paul Cohen, Associate Professor at The Rockefeller University and the corresponding author of the study. “And we still see it after eight weeks of training, which tells us this response isn’t simply a product of the body struggling to keep up with unfamiliar stress. It may be that the responses we observed are intrinsic to intense exercise.”

Multi-organ crosstalk

Because those exercise-responsive proteins and metabolites were in plasma, the question is which organs released them and which organs they affect. Investigating this question suggested crosstalk among many organs and the systemic effects of the studied metabolites.

First, experiments suggested that multiple organs can be a potential source for plasma proteins released following both SIE and MIE, with immune-system proteins most represented. However, later experiments focused on skeletal muscle, a tissue known to be affected by physical exercise. Experiments using human and mouse skeletal muscle cell cultures and skeletal muscle samples collected from study participants before and three hours after SIE and MIE suggested a role for skeletal muscle in intensity-dependent release of organ-specific proteins, specifically muscle fiber-derived proteins, which was greater following SIE.

Next, the researchers focused on the tissues affected by those circulating proteins, since secreted proteins can affect organs if they bind to receptors on their surfaces. There were multiple ligand-receptor pairs that were differentially regulated following SIE but not MIE.

Using primary human adipocyte cell cultures as an example, the authors showed that exercise intensity can impact gene expression in these tissues, with significant changes following SIE and modest changes following MIE. While only adipose tissue was investigated, it is likely not the only tissue affected by exercise-intensity-dependent protein release, but further research needs to assess the extent of cross-talk between organs following exercise.

Cardiometabolic health benefits

The experimental data suggested that exercise intensity affects protein release, which impacts interorgan communication. Those processes, in turn, affect systemic metabolism. The observed changes in protein levels, while transient, might have long-term effects if repeated in regular bouts of physical activity. Previous studies proposed a link between repeated exposure to such “transient increases in beneficial circulating proteins” and cardiometabolic health [3]. This study’s authors asked whether the proteins identified as being regulated by SIE and MIE are associated with health outcomes.

Using UK Biobank data and their own data, they identified protein-disease associations. Among the identified associations, they focused on plausible links to cardiometabolic benefits. This allowed them to identify 143 proteins associated with multiple disease groups, most of which were regulated solely following SIE. Narrowing their search to proteins associated with a lower risk of metabolic disorders, obesity, and type 2 diabetes identified 33 proteins. All but one of those proteins were differentially regulated following SIE, which is a stark contrast to only 3 proteins that were regulated by MIE.

The intensity-dependent systemic benefits of exercise also appear to have long-term effects, as more than a quarter of the 33 identified proteins had previously been inversely associated with age.

Exercise Secretome

Mediators of health-promoting effects

Overall, this study shows exercise intensity-dependent changes in the plasma proteome and their systemic impact, and it provides understanding as to how short bursts of intense exercise can elicit whole-body health benefits.

As Luke Olsen, the postdoctoral fellow who conducted the studies, summarizes, “It’s well appreciated that different intensities of exercise stimulate distinct body-wide adaptations.” “However, the molecular mechanisms linking these intensity-dependent adaptations have remained largely elusive. Our work suggests that exerkines—proteins and metabolites released into the bloodstream following exercise—are highly sensitive to exercise intensity and may be the key mediators of the health-promoting effects of short bursts of vigorous exercise.”

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 ethical journalism and sustains our future.

Literature

[1] Olsen, L., Botella, J., Barrows, D., Romero, E., Baird, K., Katayama, M., Kilic, E., Peralta, C., Zanou, N., Sanford, H., Farrell, L., Axelrod, C. L., Plucińska, K., Walker, J., Yan, L., Fredrickson, K., Pourquie, O., Robbins, J. M., Vinogradova, E. V., Molina, H., … Cohen, P. (2026). Exercise intensity modulates interorgan communication and is associated with cardiometabolic health outcomes in humans. Cell reports. Medicine, 102988. Advance online publication.

[2] Chow, L. S., Gerszten, R. E., Taylor, J. M., Pedersen, B. K., van Praag, H., Trappe, S., Febbraio, M. A., Galis, Z. S., Gao, Y., Haus, J. M., Lanza, I. R., Lavie, C. J., Lee, C. H., Lucia, A., Moro, C., Pandey, A., Robbins, J. M., Stanford, K. I., Thackray, A. E., Villeda, S., … Snyder, M. P. (2022). Exerkines in health, resilience and disease. Nature reviews. Endocrinology, 18(5), 273–289.

[3] Robbins, J. M., Katz, D. H., Many, G. M., Rao, P., Smith, G. R., Tiwari, G., Jin, C., Spielmann, G., Montalvo, S., Iyer, G., Amar, D., Leach, D., Coyne, B. J., Lindholm, M. E., Goodpaster, B., Walsh, M. J., Clish, C. B., Burant, C. F., Gerszten, R. E., & MoTrPAC Study Group (2026). Blood Biochemical Responses to Acute Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC). bioRxiv : the preprint server for biology, 2026.03.02.704798.

Rat tendons

A Tougher Extracellular Matrix Strengthens Tendons in Rats

Researchers have found that an upstream promoter of two extracellular matrix proteins increases healing and strength capabilities in the tendons of rats.

Tendon injuries in older people

Previous research has found that, like with many other injuries, tendon injuries have an age-related component. The tendons of the biceps and rotator cuffs are more commonly injured in older people than in younger people [1], and older people heal slower after forearm injuries and have less range of motion in the fingers for a longer time [2].

Previous work has investigated this issue using explanted murine models, taking mouse tendons from the animals and investigating their functional abilities. Tendons from aged mice don’t handle stress deprivation as well [3], nor do they respond properly to added strain [4]. An aged tendon can often support the same amount of force as a young tendon; it simply heals slower [5].

In humans, tendon stem progrenitor cells (TSPCs) change with aging in their gene expression, including genes related to basic functions such as motility and the cellular skeleton [6], and these cells often lack self-renewal abilities [7]. Animal studies have confirmed that cell numbers along with the organization of elastin, a foundational protein in tendon function, decline as well [8].

This study began with a statistical, population-based analysis of trends in tendon injury. This analysis found that, unsurprisingly, tendon injuries, which are often caused by heavy lifting at work, decreased between 1990 and 2021. A country’s development index corroborated this idea; countries undergoing industrial development may have more than less-developed countries, but after a certain level of development, this decreases. However, despite not being under such stressful conditions, older people even today remain at a high risk of such injuries.

Male and female rat tendons age differently

The researchers then turned to rats, taking tendons from eight-week-old (young) and 18-month-old (old) groups of males and females, then stretching them a hundred times to simulate normal mechanical load. They found that in male but not female rats, tendon weight and, surprisingly, tensile strength significantly increased between the two groups; in female but not male rats, the tensile strength, force required to cause a 2-millimeter gap, and stiffness were all weakened with aging.

These changes occurred alongside cell type changes. In female rats, there were proportionaly more epithelial and immune cells with aging, and the numbers of fibroblasts and stromal cells decreased. In male rats, immune cells rose as well, but the proportion of fibroblasts increased rather than decreased; stromal cells also declined, but so did epithelial cells.

More extracellular matrix expression helps rat tendons

In both sexes, however, the researchers noted significant declines in the expression of two genes related to the extracellular matrix: Col1a1 and Sparc. This was also accompanied by a decrease in the transcription factor Creb3l1, which these researchers found to be a regulator of these genes, binding directly to their promoters. Transfecting rat tendon cells with a lentivirus that increases Creb3l1 was also found to increase both Col1a1 and Sparc; silencing Creb3l1 led to a substantial increase in cellular senescence.

The researchers then injected this lentivirus into living animals in order to determine its effects on tendon tissue. In males, tendon elasticity and strength was significantly increased after three weeks, and in both sexes, tendons appeared to heal better as well, with the treatment groups having tendinous tissue at the sites of injury while the control groups had granulous tissue instead.

Rats have different biomechanical stresses than people, and rat tendons taken outside the body are no substitute for human results. However, this study shines significant light on sex differences that should be examined for their relevance to humans, and it suggests a potential path forward for a treatment that encourages proper tendon repair by affecting proteins related to the extracellular matrix. Future work is required to determine how such a treatment can be developed and whether it could reduce strains and sprains in older people.

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 ethical journalism and sustains our future.

Literature

[1] Clayton, R. A., & Court-Brown, C. M. (2008). The epidemiology of musculoskeletal tendinous and ligamentous injuries. Injury, 39(12), 1338-1344.

[2] Edsfeldt, S., Eklund, M., & Wiig, M. (2019). Prognostic factors for digital range of motion after intrasynovial flexor tendon injury and repair: long-term follow-up on 273 patients treated with active extension-passive flexion with rubber bands. Journal of Hand Therapy, 32(3), 328-333.

[3] Connizzo, B. K., Piet, J. M., Shefelbine, S. J., & Grodzinsky, A. J. (2020). Age-associated changes in the response of tendon explants to stress deprivation is sex-dependent. Connective tissue research, 61(1), 48-62.

[4] Aggouras, A. N., Stowe, E. J., Mlawer, S. J., & Connizzo, B. K. (2024). Aged tendons exhibit altered mechanisms of strain-dependent extracellular matrix remodeling. Journal of Biomechanical Engineering, 146(7), 071009.

[5] Ackerman, J. E., Bah, I., Jonason, J. H., Buckley, M. R., & Loiselle, A. E. (2017). Aging does not alter tendon mechanical properties during homeostasis, but does impair flexor tendon healing. Journal of Orthopaedic Research, 35(12), 2716-2724.

[6] Kohler, J., Popov, C., Klotz, B., Alberton, P., Prall, W. C., Haasters, F., … & Docheva, D. (2013). Uncovering the cellular and molecular changes in tendon stem/progenitor cells attributed to tendon aging and degeneration. Aging cell, 12(6), 988-999.

[7] Zhou, Z., Akinbiyi, T., Xu, L., Ramcharan, M., Leong, D. J., Ros, S. J., … & Sun, H. B. (2010). Tendon‐derived stem/progenitor cell aging: defective self‐renewal and altered fate. Aging cell, 9(5), 911-915.

[8] Godinho, M. S., Thorpe, C. T., Greenwald, S. E., & Screen, H. R. (2017). Elastin is localised to the interfascicular matrix of energy storing tendons and becomes increasingly disorganised with ageing. Scientific reports, 7(1), 9713.