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Joao Pedro de Magalhaes Interview

João Pedro de Magalhães on the Ethics of Longevity

João Pedro de Magalhães, professor at the University of Birmingham, is known as a prominent geroscientist who has been in the field forever, enriching it with top-tier research. He is also a skilled longevity advocate who has long taken interest in the ethics of longevity, first offering his perspective as far back as 2003. Prof. de Magalhães has been collaborating on this topic for years with Uehiro Institute at the University of Oxford.

A couple of weeks ago, de Magalhães and his co-author, Zhuang Zhuang Han from University of Cambridge, published a paper titled “The ethics case for longevity science” at the journal Aging Research Reviews. At the time when the debate around longevity is quickly moving into the mainstream, and public attitudes towards life extension can either accelerate or hamstring the progress of geroscience, a clear-eyed, well-argued overview of the ethics of longevity is a welcome addition to the discourse. As another pioneer of longevity advocacy, Lifespan News immediately jumped on the opportunity to discuss our favorite topic.

Why did you choose a scientific journal rather than mainstream media or podcasts? It seems a bit like preaching to the choir.

In the field of aging and longevity, we’ve always had this problem: if I give a public lecture and say I’m trying to cure Alzheimer’s, or cancer, or cardiovascular disease, people are delighted. But if I say I’m trying to cure aging – to cure all age-related diseases at once – there’s suddenly a lot of concern. It’s a fascinating and, I think, even disturbing phenomenon: the public wants to cure individual age-related diseases but doesn’t like the idea of curing all of them simultaneously. As researchers, I think we have an obligation to address that.

Some of these concerns are genuine. Overpopulation is a real issue, and if people aren’t dying as much, it’ll be worse. The equality question – what if longevity drugs are so expensive that only billionaires can access them – is also reasonable. These are not new questions; I’ve been encountering them for more than twenty years. I’ve actually had an essay addressing them on my website since 2003. I wrote a book chapter on the topic in 2013 with a colleague, and I’ve had an affiliation with the Uehiro Institute in Oxford, which focuses on philosophy and bioethics, where I gave a talk a couple of years ago.

More recently, in 2024, I participated in a debate in Cambridge on these very issues – that’s where I met my collaborator on this paper, a brilliant PhD student who is also interested in the ethics of aging research. So, it was a confluence of ideas over the past couple of years that made the time feel right to write this up. As for the choice of medium: the idea is that colleagues working on aging and longevity can use this paper as a reference. When ethical concerns come up – at conferences, on social media, in public talks – they can point to a piece in Ageing Research Reviews and say: here’s how we address these arguments. It provides the ammunition, so to speak.

Like you said, you’ve been in this discussion for more than 20 years. What has changed – in attitudes, in your own views, in the arguments being made?

Honestly, not that much. The concerns people had twenty years ago are still largely the same: equality, overpopulation, the ossification of society if people don’t die – something Elon Musk, for instance, has mentioned, and there is an argument to be made there. The “aging is natural and we shouldn’t intervene” position has also been around for a long time. If you think about it in terms of actual interventions, caloric restriction – first demonstrated in 1935 – is still the most robust longevity intervention we have. Life expectancy continues to increase, and there have been advances in statins, vaccines, and so on, but there hasn’t been a radical change in terms of dedicated longevity therapies. So no, I don’t think the landscape of arguments has changed dramatically.

Here is something I keep thinking about in this context: do we even need to engage the public on this now, when we’re still quite far from meaningful life extension, i.e., from the point where most ethical concerns about longevity even become relevant?

I think it’s about having clear goals. There’s a lovely paper from over a hundred years ago – from the turn of the twentieth century – openly discussing curing cancer. That was a goal. People have been talking about curing cancer for at least 120 years, and they still talk about it even if may not happen in their lifetimes. That’s what makes it attractive as a mission.

Contrast that with what some organizations in our field do. Altos Labs, for example, takes great pains not to sound like a longevity company. There’s still a reluctance, among both companies and academics, to say plainly that they’re working on aging, and I think we need to be honest about what the ultimate goal is: to completely abolish age-related diseases. Being healthy is good; being sick is bad. I cannot believe I still have to make that case.

What you’re saying, essentially, is that we need to own the aim of meaningfully extending the human lifespan rather than trying to hide or obfuscate it.

Yes, we shouldn’t be afraid of it. We have to be realistic – this isn’t happening anytime soon. But if a cancer charity said, “We don’t actually want to cure cancer; we just want cancer patients to be a bit healthier while they’re dying of it,” everyone would find it absurd. Nobody would support it. Yet, in aging, we effectively do the same thing – we say we want to improve health a little but not completely. That, I think, is a discussion we need to have openly.

One of the strongest points in your paper is the idea that people don’t apply the same ethical framework to longevity medicine that they apply to any other branch of medicine. Can you expand on that?

Curing cancer would be wonderful, but it wouldn’t radically extend life expectancy; the calculations suggest we’re talking about single-digit years of gain. It would improve health, but it wouldn’t fundamentally change the human condition. Curing aging would be a transformative shift in how human societies work, in everything. I’ve written about how longevity is depicted in science fiction, and the changes would be massive. I suspect that’s why some people are uncomfortable: it would be such a dramatic revolution in the fabric of society that they apply a different standard to aging research than to disease research.

I mostly agree with your paper, but let me play the devil’s advocate about two concrete problems. The first is eternal dictators – that hot-mic chat between Xi and Putin last year got a lot of attention. The second is the US Supreme Court: its justices hold lifelong appointments, and this is enshrined in the Constitution, which is virtually impossible to amend in today’s political climate. I think these are actually compelling examples of the problems meaningful life extension could create.

The Supreme Court is a good example I hadn’t thought about. I suppose many social and government structures would have to be adjusted – like what “life in prison” means if you’re living a thousand years. Twenty years in prison is a very significant portion of a normal adult’s life, but if you live a thousand years, it’s a rounding error. Legal structures would certainly need to be revised across the board, and the Supreme Court’s lifelong appointments would fall into that category.

On immortal dictators: yes, I think that’s a valid concern. A dictator with an enormous grip on power who never ages could remain entrenched indefinitely. North Korea is instructive here – dictators do die, and yet power simply passes to a family member, and the system carries on. We don’t have an easy solution to that even now. The silver lining is that the proportion of the world living under dictatorships is much lower than it was a hundred or two hundred years ago. But I do think immortal dictatorships are a genuine potential issue.

Combine this with the plausible idea that AI-powered surveillance and enforcement will enable dictators to rule eternally, nipping any opposition in the bud, and you get a rather grim picture.

It’s a concern, yes. The argument about the ossification of institutions applies broadly: if the CEO of a company never ages, they could remain in place essentially forever, which stifles progress. Scale that up to a state with AI-augmented control, and the concern is amplified. I don’t think there’s an easy solution.

Which brings me to a broader point: I feel our field should have a much more structured, “friendly-adversarial” discussion about these questions. We need to break out of our echo chamber and stress-test our arguments. Do you agree, and do you have ideas on how to achieve this?

I completely agree. I’ve done some of this – in Oxford, in Cambridge, in France, and now with colleagues in Birmingham on a project addressing future technological developments more broadly. But the key thing is to be honest: curing aging would not make everything magically wonderful. There are real issues. Overpopulation is already a problem, and reducing mortality will make it worse. I agree with that. The right response, though, is not to abandon the goal of keeping people healthy; it’s to engage with philosophers and bioethicists who have valid concerns, acknowledge what’s legitimate, and debate what isn’t.

Regarding overpopulation and similar concerns, you write about the moral priority of existing persons over abstract future populations, which I read as a pointed argument against long-termism – a camp that is well-represented within the longevity field as well.

The core moral argument is that the people alive today matter more than prospective future individuals who don’t yet exist. You can make all sorts of arguments premised on the interests of people who don’t actually exist – “it’s immoral not to have more children,” and so on – but it’s very difficult to make those claims with confidence. What we can say with confidence is that technological progress has, historically, expanded our capacity to support larger populations at higher living standards. We now have the largest human population in history and the highest life expectancy and the best quality of life in the history of civilization, simultaneously. The Malthusian doomsday predictions never materialized because human ingenuity adapted.

More practically: nobody in their right mind would argue we should kill people to solve overpopulation. So why would we let people die of disease for the same reason? Besides, the major driver of population growth is fertility rates, not life expectancy. The way societies that face genuine population pressure deal with it is by reducing fertility – not by allowing people to die.

Let’s move to the inequality argument, which says that anti-aging therapies will be available only to the privileged few. What I’m concerned about is whether we’re not accounting enough for the nature of longevity treatments. It begins to look like in order to reach any meaningful life extension, it will have to be a barrage of many interventions starting from a young age. That doesn’t fit our current healthcare model, which basically works by redistributing money from young people who rarely require healthcare to older ones. I understand that investing in longevity treatments for younger people will eventually reduce the cost of healthcare for old people, but I’m worried about a possible transition period.

You’re right that healthcare costs are heavily skewed toward older individuals, and there are real open questions – how early do interventions need to start? Does caloric restriction, which works better when initiated earlier in animal models, set the template? We don’t know yet whether rejuvenation technologies will be more applicable later in life, but the economic logic of intervening in aging is actually very strong. Even a drug that slows aging by ten percent – not radical life extension, just ten percent – would generate enormous medical and economic benefits. Andrew Scott and David Sinclair have a paper in Nature Aging on exactly this point, and we cite it in our paper.

On the accessibility question: yes, novel therapies start expensive and available only to the wealthy. That’s the pattern across the history of medicine. Antibiotics, when first available, were so scarce that urine from patients who had received a dose was collected and the antibiotic was purified from it to give to the next person. Today, antibiotics are widely available. The market for an effective anti-aging intervention would be enormous, and strong market demand has historically driven the democratization of technology. I would expect longevity interventions to follow the same trajectory.

Regarding the “naturalness” argument. I think it’s the easiest one to refute, and I’m actually wondering if people still use it.

Rarely, at this point. We’re so accustomed to technology – AI, global video calls, air travel – that the “nature knows best” argument has little traction with most people. There are specific groups, certain religious communities for instance, that refuse particular medical interventions. But they’re exceptional. The embrace of mobile phones, of medicine, of technology generally, is now a worldwide phenomenon – not confined to wealthy countries. So, I don’t think the “aging is natural” argument carries much weight anymore.

That said, there is one corner of the “naturalness” landscape that I do think deserves more serious engagement: genetic interventions. Curing a disease is one thing; changing someone’s genome to prevent a disease is another, and people instinctively feel the difference. Personally, I think that’s largely a technical safety issue rather than a philosophical one – if we could safely modify genes in embryos to eliminate, say, the APOE4 allele that dramatically raises Alzheimer’s risk, most people would consider that a straightforward medical intervention.

Your paper also addresses more individualist objections: boredom and loss of meaning. Personally, I find these almost too subjective to discuss seriously – some people are bored at thirty, some are never bored. People should simply have the choice. But walk me through how you engage with these arguments.

I never really found the boredom argument compelling, and frankly it wasn’t in the first draft of the paper. We added it after discussions at the Uehiro Institute in Oxford, where some people raised it. But, you’re right – boredom is an individual experience. It can happen at twenty, at fifty, or never. If someone with an extended lifespan reaches a point where they feel they’ve had enough, they retain individual agency to end their life on their own terms. It’s not an argument against offering the option of a longer life.

I’ve always found these arguments a little apologetic about aging. Aging and death are, for now, inevitable – and I think a lot of these “death gives life meaning” claims are coping mechanisms. We say, “maybe it’s not so bad after all,” because we have no alternative. The paper actually does address this: we note that the “death gives meaning” thesis mistakes a coping strategy for a normative truth. If boredom is a real concern for someone after several centuries, the solution is individual choice, not denying everyone the option.

I liked your autonomy argument – the idea that access to life extension is fundamentally a matter of individual freedom.

It’s about taking responsibility for our own lives. At the moment, aging is the binding constraint – a shackle on individual existence. If we can lift that constraint, people can live longer and, I would argue, happier lives. The argument for autonomy is also a counterweight to the paternalistic reasoning embedded in the anti-longevity position: the idea that some authority should decide how long a life ought to be, or what counts as sufficient years. That strikes me as deeply problematic.

You make an interesting analogy in the paper between geroscience and the Apollo program – the idea that a concerted effort on aging could actually accelerate progress across many fields.

The Apollo program generated technologies that impacted fields far beyond space exploration. Aging underpins most of the diseases and functional changes that accumulate in our bodies over a lifetime. A well-funded, systematic program with geroscience at its core – modulating aging itself rather than tackling each disease separately – would, in principle, cross-fertilize and benefit medicine and biology much more broadly. We’re not there yet; the field of aging is still relatively small compared to, say, cancer research. But, the aspiration of an Apollo program for aging is something that comes up in the field, and I think it’s worth articulating explicitly.

Another point you raise is that the anti-longevity discourse is often heavily ageist: it makes an implicit assumption that older people have had their run and are now disposable. Why does this attitude persist, and how do people not see themselves defending a fundamentally inhumane position?

It’s almost always implicit rather than explicit. There’s a general cultural tendency to view older individuals as having “lived their lives,” as if their remaining years are somehow worth less. You see it in some of these arguments: “Well, you’ve had a good run; a natural lifespan of about a hundred years is enough.” That is a form of ageism, even if the person making the argument doesn’t recognize it as such.

Should we be confronting this directly – trying to change attitudes not just toward longevity research, but toward older people and aging in general?

Probably, though the right framing is an open question. Should we talk about “healthspan,” “longevity,” “anti-aging,” or “aging research”? I’ve had many discussions about what language best advances the field. My instinct is that there’s no single answer – different framings work better for different audiences. If you’re addressing governments, medical doctors, or students, you’ll need to tailor the message. I don’t think there’s a one-size-fits-all approach to marketing the field.

Do you think public attitudes have become more favorable to longevity in recent years?

There’s certainly more awareness. People like Aubrey de Grey, David Sinclair, and Bryan Johnson have pushed the ideas toward a broader audience, and the internet and social media enable mass communication that simply didn’t exist thirty years ago. But, there’s still a lot of suspicion, and part of the reason is that we don’t yet have treatments that demonstrably work. Into that vacuum have stepped a lot of “longevity influencers” – some of whom come across as snake oil salesmen. The field has a long history of charlatans promising extended life.

The recent controversy around Peter Attia and the Epstein files generated criticism of the longevity field more broadly. That perception problem is real, and the way to address it is by doing rigorous science, not overhyping results, and – ultimately – producing something that actually works. If we develop an intervention that demonstrably slows aging in humans, people will take us much more seriously.

On the other hand, I wonder whether we should be less apologetic and more aggressive in making the ethical case – essentially shame people into supporting the longevity agenda and research, even if we still don’t have a lot to show for it.

It depends on context and audience. When we face ethical pushback, we should push back in return. We’re sometimes too cautious. We can make a strong case that this is an ethical endeavor: we have an aging population, aging is the primary driver of suffering, disease and death in modern societies, and we should be addressing it. We shouldn’t be ashamed of that. At the same time, we have to be realistic and not overpromise. Don’t claim we’re about to cure aging next year, but also don’t apologize for trying.

Last question: what is your “elevator pitch” for our cause?

The major killers – the major sources of suffering – in modern societies are age-related diseases: cardiovascular disease, dementia, Alzheimer’s, frailty, multimorbidity. These are horrible conditions with no effective treatments. Dementia is watching someone’s mind be destroyed. If we could understand the underlying processes that drive all of these diseases simultaneously, and slow those processes down, people would be healthier for longer. That would be a massive medical advance with enormous social and economic benefit. That is what we are trying to do, and we should be proud of it.

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Menopause

Menopausal Hormone Therapy Does Not Increase Mortality

An analysis of over 800,000 women found no association between menopausal hormone therapy and increased mortality [1].

A controversial therapy

One of the first major changes that women undergo as they age is menopause, which usually occurs between 45 and 55 years of age. Menopause not only marks the end of reproduction, the hormonal changes that accompany it are associated with declines in cognition, cardiovascular health, and other unpleasant symptoms that affect around 80% of women, such as hot flushes, night sweats, and decreased libido [2, 3]. Menopause also has a profound impact on the economy, with menopause-related unemployment having an estimated $2.1bn (£1.5bn; €1.7bn) impact annually in the United Kingdom alone [4].

Menopausal hormone therapy containing the sex hormone estrogen can reduce menopause-related symptoms; however, its use has recently decreased due to safety concerns [5, 6]. Those concerns were raised by the 2002 Women’s Health Initiative study, which linked hormone replacement therapy to a higher risk of breast cancer, heart attack, stroke, and blood clots [7]. However, this study had a major caveat: the participants were, on average, 63 years old at enrolment, well past menopause.

Other studies, investigating women who are just before menopause (perimenopausal) and are younger compared to the Women’s Health Initiative study, paint a different picture. For example, in a review that we have recently covered, the authors examined a broad range of studies assessing the risks and benefits of hormone replacement therapy. They suggested that, while the risk-benefit ratio should be evaluated on an individual basis, hormone replacement therapy could be used as a geroprotector to extend women’s healthspan.

Similarly, previous studies also suggest that menopausal hormone therapy use leads to either a reduction or no change in mortality [8-10]. However, as the authors of this study suggest, those studies have many shortcomings, such as data having unknown treatment durations or samples that are too small.

A robust dataset

To address this, the authors of this study used nationwide Danish registers to obtain data from over 800,000 women born between 1950 and 1977 and living in Denmark on their 45th birthdays. This study excluded women with any risk factors for menopausal hormone therapy (except for the primary analysis; however, this exclusion didn’t change the conclusions), women who started using menopausal hormone therapy before age 45, and women who underwent surgical removal of the ovaries (oophorectomy). Participants were followed up for 7 to 21 years. The authors used this data to determine whether menopausal hormone therapy increases the risk of all-cause mortality.

Among the participants, almost 12% were exposed to menopausal hormone therapy. The type of hormone used varied among participants; however, the most common were tablets containing estradiol and continuous norethisteronacetat. Median treatment duration, recorded at the end of the follow-up period, was short (1.7 years), and fewer than 1% of women reported 10 or more years of use.

There were some differences between groups of women who took and didn’t take hormone replacement therapy. Those who did take the therapy, on average, “had delivered slightly fewer children, were more often divorced, had hypertension, had three or more hospital contacts between age 44 and 45, and had previously undergone hysterectomy and/or bilateral oophorectomy” (removal of uterus or ovaries) compared to women who did not.

Neutral or beneficial?

The researchers did not find an association between menopausal hormone therapy use and increased mortality. When looking at specific causes of death, no significant difference was found for long-term (≥5 years) menopausal hormone therapy use for either cardiovascular or cancer mortality, and only a modest change for short-term (<5 years) use of menopausal hormone therapy.

The lack of association between menopausal hormone therapy and increased risk of mortality was also observed when the researchers compared data from siblings, where at least one sister used the therapy and one didn’t. This analysis minimized the impact of unmeasured confounding factors, as siblings are more likely to have similar lifestyles than the general population.

When analyzing a subgroup of women who underwent bilateral oophorectomy between 45 and 54 years, they observed 27-34% lower mortality risk, dependent on the duration of use, among women who used menopausal hormone therapy compared to those who didn’t. For women who underwent a hysterectomy, no significant increase in mortality was found.

Those findings are similar to other previous studies and agree with the guidelines from the Royal College of Obstetricians and Gynaecologists, which recommend “offering hormone therapy to all women who undergo bilateral oophorectomy before menopause, until the average age of natural menopause is reached (about 51 years), provided there are no contraindications” [11].

Hormone replacement therapy is not a uniform therapy, and its dosage and administration can vary. The authors, therefore, divided women who underwent therapy into categories and noted that lower mortality, as compared with never having used menopausal hormone therapy, was observed in groups who used transdermal menopausal hormone therapy formulations, such as plaster or gel; used estrogen monotherapy or estrogen with cyclic progesterone; or started menopausal hormone therapy at age 52 or older.

They also noted that the side effects of hormone replacement therapy do not necessarily occur after the use but during the therapy. To investigate this, the researchers completed a separate analysis by excluding women at menopausal hormone therapy cessation and found that, in this case, menopausal hormone therapy was associated with a significantly reduced mortality. While this might suggest hormone replacement benefits that cease after the therapy is discontinued, there is also a possibility of healthy user bias. Therefore, these results should be interpreted with caution.

Strengthening support for the current policy

The findings of this study add evidence in support of the Endocrine Society’s guidelines, which “recommend menopausal hormone therapy for women who have recently begun menopause who have moderate to severe symptoms and no contraindications” [12].

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

Literature

[1] Mikkelsen, A. P., Bergholt, T., Lidegaard, Ø., & Scheller, N. M. (2026). Menopausal hormone therapy and long term mortality: nationwide, register based cohort study. BMJ (Clinical research ed.), 392, e085998.

[2] El Khoudary, S. R., Greendale, G., Crawford, S. L., Avis, N. E., Brooks, M. M., Thurston, R. C., Karvonen-Gutierrez, C., Waetjen, L. E., & Matthews, K. (2019). The menopause transition and women’s health at midlife: a progress report from the Study of Women’s Health Across the Nation (SWAN). Menopause (New York, N.Y.), 26(10), 1213–1227.

[3] Avis, N. E., Crawford, S. L., Greendale, G., Bromberger, J. T., Everson-Rose, S. A., Gold, E. B., Hess, R., Joffe, H., Kravitz, H. M., Tepper, P. G., Thurston, R. C., & Study of Women’s Health Across the Nation (2015). Duration of menopausal vasomotor symptoms over the menopause transition. JAMA internal medicine, 175(4), 531–539.

[4] NHS Confederation. Women’s health economics: investing in the 51 per cent.

[5] Yang, L., & Toriola, A. T. (2024). Menopausal Hormone Therapy Use Among Postmenopausal Women. JAMA health forum, 5(9), e243128.

[6] Ameye, L., Antoine, C., Paesmans, M., de Azambuja, E., & Rozenberg, S. (2014). Menopausal hormone therapy use in 17 European countries during the last decade. Maturitas, 79(3), 287–291.

[7] Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., Kooperberg, C., Stefanick, M. L., Jackson, R. D., Beresford, S. A., Howard, B. V., Johnson, K. C., Kotchen, J. M., Ockene, J., & Writing Group for the Women’s Health Initiative Investigators (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA, 288(3), 321–333.

[8] Grodstein, F., Stampfer, M. J., Colditz, G. A., Willett, W. C., Manson, J. E., Joffe, M., Rosner, B., Fuchs, C., Hankinson, S. E., Hunter, D. J., Hennekens, C. H., & Speizer, F. E. (1997). Postmenopausal hormone therapy and mortality. The New England journal of medicine, 336(25), 1769–1775.

[9] Holm, M., Olsen, A., Au Yeung, S. L., Overvad, K., Lidegaard, Ø., Kroman, N., & Tjønneland, A. (2019). Pattern of mortality after menopausal hormone therapy: long-term follow up in a population-based cohort. BJOG : an international journal of obstetrics and gynaecology, 126(1), 55–63.

[10] Manson, J. E., Aragaki, A. K., Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., Chlebowski, R. T., Howard, B. V., Thomson, C. A., Margolis, K. L., Lewis, C. E., Stefanick, M. L., Jackson, R. D., Johnson, K. C., Martin, L. W., Shumaker, S. A., Espeland, M. A., Wactawski-Wende, J., & WHI Investigators (2017). Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality: The Women’s Health Initiative Randomized Trials. JAMA, 318(10), 927–938.

[11] Manchanda, R., Gaba, F., Talaulikar, V., Pundir, J., Gessler, S., Davies, M., Menon, U., & Royal College of Obstetricians and Gynaecologists (2022). Risk-Reducing Salpingo-Oophorectomy and the Use of Hormone Replacement Therapy Below the Age of Natural Menopause: Scientific Impact Paper No. 66 October 2021: Scientific Impact Paper No. 66. BJOG : an international journal of obstetrics and gynaecology, 129(1), e16–e34.

[12] Stuenkel, C. A., Davis, S. R., Gompel, A., Lumsden, M. A., Murad, M. H., Pinkerton, J. V., & Santen, R. J. (2015). Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism, 100(11), 3975–4011.

Fat cells

Thermogeneration by White Fat Could Be Used to Treat Obesity

Scientists have discovered that, like brown fat, white fat has a mechanism that burns fuel to produce heat. This effect could potentially be used to create weight loss drugs [1].

Central heating

Cells use energy to power various cellular processes, with heat being a byproduct. However, we might need additional heat to survive. Brown adipocytes are a type of fat cell specializing in heat production. They are critically important in infants and small mammals, helping them to stay warm, but in adult humans, they are relatively scarce.

In obese people, they are even more scarce: brown adipocytes are few and far between, overshadowed by white adipose tissue, which is much worse at producing heat [2]. However, a new study from Cornell University, published in Nature Metabolism, describes a novel mechanism of heat generation in white adipocytes. Enhancing this new mechanism could be a potential new avenue for treating obesity.

Fat cells store energy primarily as triglycerides, molecules that consist of three fatty acid chains linked to a glycerol backbone. When the body needs energy, one of the ways to get it is via lipolysis in fat cells, which cleaves those fatty acids from the backbone and thus creating free fatty acids (FFA). Most of those are then transported outside the cell and into the bloodstream for distribution in tissues in need of energy.

Some FFAs stay inside the cells and undergo either beta-oxidation, an energy-producing process that uses FFAs as fuel, or reattachment to glycerol backbones (re-esterification). Unlike beta-oxidation, re-esterification is an energy-consuming process, requiring lots of ATP, the energy currency of the cell. Hence, theoretically, re-esterification should be directly correlated with cellular respiration, the cell’s default energy-producing process. However, as scientists have previously noticed, the opposite is true: re-esterification is inversely correlated with cellular respiration. This study set out to understand why this is the case.

A distinct uncoupling mechanism

To undergo either beta-oxidation or re-esterification, FFAs must be activated. By tinkering with various stages of these processes, the researchers established that the factor driving respiration was free, unactivated fatty acids themselves.

For mitochondria to work properly, they must push protons into the space between their inner and outer membranes; those protons coming back via ATP synthase is what creates ATP molecules, the difference in the proton “pressure” being the membrane potential. The scientists found that when lipolysis was stimulated, this mitochondrial membrane potential collapsed. Another set of experiments confirmed that this was due to the abundance of FFAs in the cell.

This unusual situation, when oxygen consumption by the cell goes up even as the membrane potential decreases, is called uncoupling. Cells were consuming oxygen vigorously even when ATP synthase was completely blocked, which is only possible if protons are leaking back through something other than their normal route of ATP synthase. Something was making these mitochondria’s inner membranes permeable to protons, decreasing membrane potential and causing the “engine” to run without producing the normal amount of ATP.

In brown adipocytes, this is exactly how thermogenesis works via the uncoupling protein UCP1, making mitochondria produce heat instead of ATP, sort of like idling the car’s engine to keep the heater working [3]. However, UCP1 is not known to be expressed in white adipocytes, which is what the researchers saw in their experiments as well. Therefore, the white adipocytes were using an alternative uncoupling mechanism.

The researchers struck gold when they focused on the protein AAC, which sits inside the inner membrane and acts as an ADP/ATP carrier. Blocking AAC completely blocked the uncoupling function, confirming that FFAs create a proton leak via that protein. Apparently, FFAs compete with ADP/ATP for AAC’s “attention.” AAC’s interaction with FFAs both causes the proton leak and distracts AAC from its “day job” supporting ATP production.

White fat takes over thermoregulation in obese mice

Moving to experiments in vivo, the researchers created a strain of mice with increased re-esterification and less intracellular FFAs as a result. Otherwise, the mice were normal, including regular levels of lipolysis, meaning that any differences in thermogenesis could not be explained by reduced fuel supply to other tissues like muscle or brown fat.

On normal diet and/or at room temperature, the mutant mice showed largely normal cold responses. Suspecting that brown adipocytes were still working well enough to ensure thermoregulation, the researchers put the mice on a high-fat diet and in thermoneutral (30°C) housing. Combined, these conditions led to the inactivation of brown adipocytes and expansion of white fat mass. As a result, the mutant mice gained more weight, had more fat mass, could not maintain core temperature during cold exposure, and died at significantly higher rates than controls.

After a couple of alternative explanations were ruled out, it became clear that while in control mice, white adipocytes took over thermoregulation via FFA-mediated uncoupling after the inactivation of brown adipocytes, the same mechanism did not work in mice with less intracellular FFA, making them unable to resist cold by producing heat. The researchers suggest that reversing this logic – i.e., increasing heat production by white adipocytes, such as by ramping up intracellular FFAs – might pave the road to new obesity treatments, which could work especially well alongside popular GLP1 receptor agonists.

“There is still a lot of research to do, but in principle this approach to treating obesity might be very effective and safe,” said the study’s senior author, Shannon Reilly, an assistant professor of metabolic health in medicine and a member of the Joan and Sanford I. Weill Center for Metabolic Health at Weill Cornell Medicine. “Current weight-loss medications work by reducing hunger but sometimes have unpleasant digestive side effects. This new approach complements these existing therapies and thus could potentially be used in conjunction with lower doses to minimize unwanted side effects.”

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

Literature

[1] Ahmadian, M., Aksu, A.M., Dhillon, P. et al. (2026). Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes. Nat Metab.

[2] Becher, T., Palanisamy, S., Kramer, D. J., Eljalby, M., Marx, S. J., Wibmer, A. G., … & Cohen, P. (2021). Brown adipose tissue is associated with cardiometabolic health. Nature medicine, 27(1), 58-65.

[3] Cannon, B., & Nedergaard, J. (2004). Brown adipose tissue: function and physiological significance. Physiological reviews, 84(1), 277–359.

Neuron

How a Sirtuin Protects Against Brain Diseases

In Aging Cell, researchers have explained how the sirtuin SIRT6 protects against proteostasis-related brain disorders by maintaining the function of nucleoli and limiting protein production.

The nucleus and nucleoli

A cell’s nucleus has one or more nucleoli, where the cell does its critical work of synthesizing ribosomal RNA (rRNA), building the factories that are responsible for translating other DNA into RNA. With aging, nucleoli expand and increase in number [1], and this is found in progeric, premature aging as well [2].

One sirtuin, SIRT6, has been found to recruit the chromatin remodeler SNF2H to sites of DNA double breaks [3]. SNF2H is also part of the nuclear remodeling complex (NoRC), which regulates this transcription of rRNA. Unsurprisingly, SIRT6 has been found to be a necessary part of the brains of mammals; monkeys that do not express it are born with malformed brains and do not live long outside the womb [3], while overexpression extends and improves the lives of mice [4]. Mice that do not express it do not suffer the same immediate fate as monkeys, but they suffer from learning disabilities and their brains resemble those of Alzheimer’s disease patients, who also have decreased levels of SIRT6 [5].

SIRT6 controls protein production

With this evidence in hand, the researchers decided to home in on the proteostasis-related effects of SIRT6. They first took another look at their previous work on SIRT6 and mitochondrial function in neurons [6], and they noticed close relationships between the gene expression of Alzheimer’s patients and that of SIRT6-deficient mice. They also noted that some of the most downregulated genes in the absence of SIRT6 are related to ribosomal function.

Further experiments confirmed this relationship. Neurons taken from SIRT6-deficient mice were found to indeed lack SNF2H at chromatin sites, which also led to a decrease in recruitment of the NoRC component TIP5. The total levels of SNF2H and TIP5 did not decrease in the SIRT6-deficient cells; instead, the cells generated more TIP5 RNA. The lack of SIRT6 led to a similar increase in the number and size of nucleoli, increasing the rate of production of rRNA.

The researchers then created multiple varieties of SIRT6-deficient cells. In every case, unless a transcription inhibitor was introduced to stop it, the deficient cells consistently overproduced proteins. This was found to be accompanied by an overall increase in the amino acids used for building these proteins.

Too much production, not enough quality assurance

However, this increase in protein synthesis was not accompanied by an increase in protein chaperones. The researchers tested a line of immortalized human kidney cells’ ability to refold proteins after a heat shock. Cells that produced SIRT6 normally were able to properly refold roughly three-fifths of the damaged proteins; cells that lacked SIRT6 were only able to refold roughly a fifth. Inhibiting protein translation restored these cells’ maintenance abilities.

The researchers suspected that this overproduction without proper maintenance would lead to the accumulation of protein aggregates. They used a line of cells that are prone to forming aggregates, some of which were made incapable of producing SIRT6. These SIRT6-deficient cells, indeed, produced substantially more aggregates than their unmodified counterparts.

These findings were recapitulated in worms. Without SIRT6, C. elegans nematodes were much more prone to heat shock and had much more rapid declines in motility compared to unmodified worms. The researchers then combined this deficiency with a strain that expresses polyQ in their neurons, which leads to protein aggregates; slowing protein translation with 4PBA restored some of the related motility and lifespan decline in the polyQ worms, even if they expressed SIRT6.

This discovered relationship between SIRT6 deficiency, excessive protein production, and protein aggregation leads to different avenues for potential interventions. The researchers note that 4PBA has already been approved by the FDA and suggest that it might be useful against overproduction-related proteostasis disorders. Previous work has also found that caloric restriction increases SIRT6 [7], although implementing this consistently and safely requires careful monitoring.

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

Literature

[1] Kriukov, D., Eremenko, E., Smirnov, D., Stein, D., Tsitrina, A., Golova, A., … & Toiber, D. (2024). Nuclear expansion and chromatin structure remodeling in mouse aging neurons. NAR Molecular Medicine, 1(3), ugae011.

[2] Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 1-13.

[3] Zhang, W., Wan, H., Feng, G., Qu, J., Wang, J., Jing, Y., … & Hu, B. (2018). SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature, 560(7720), 661-665.

[4] Roichman, A., Kanfi, Y., Glazz, R., Naiman, S., Amit, U., Landa, N., … & Cohen, H. Y. (2017). SIRT6 overexpression improves various aspects of mouse healthspan. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(5), 603-615.

[5] Kaluski, S., Portillo, M., Besnard, A., Stein, D., Einav, M., Zhong, L., … & Toiber, D. (2017). Neuroprotective functions for the histone deacetylase SIRT6. Cell reports, 18(13), 3052-3062.

[6] Smirnov, D., Eremenko, E., Stein, D., Kaluski, S., Jasinska, W., Cosentino, C., … & Toiber, D. (2023). SIRT6 is a key regulator of mitochondrial function in the brain. Cell Death & Disease, 14(1), 35.

[7] Zhang, N., Li, Z., Mu, W., Li, L., Liang, Y., Lu, M., … & Wang, Z. (2016). Calorie restriction-induced SIRT6 activation delays aging by suppressing NF-κB signaling. Cell cycle, 15(7), 1009-1018.

Robot diagnostics

AI Tool Sets New Standard in Diagnosing Rare Diseases

A new system, which consists of a large LLM and a network of agentic tools, outperformed several other models and human physicians [1].

Too rare to easily diagnose

Rare diseases can be notoriously hard to diagnose. Patients average over 5 years to receive a correct diagnosis, enduring repeated referrals, misdiagnoses, and unnecessary interventions in what is known in rare disease medicine as ‘the diagnostic odyssey’ [2]. These rare diseases, defined as conditions affecting fewer than 1 in 2,000 people, collectively impact over 300 million people worldwide. About 7,000 distinct disorders of this type have been identified, with 80% of them being genetic in origin [3].

While AI assistants have shown great promise in diagnostics, diagnosing rare diseases remains a daunting task even for them. Rare diseases are often multisystemic and require cross-disciplinary knowledge; individual diseases have very few cases, making supervised learning hard; and hundreds of new rare genetic diseases are discovered per year, so knowledge is constantly shifting. On top of that, clinical deployment of such models demands transparent reasoning rather than black-box predictions.

In a new study published in Nature, an international team of scientists has presented DeepRare, a multi-agent system for differential diagnosis of rare diseases. While based on the large language model DeepSeek-V3, the system is different from a basic LLM in that it integrates more than 40 specialized agentic tools for various tasks.

Not your usual LLM

DeepRare uses a three-tier design. Tier 1 is the Central Host, a large LLM with a memory bank. It orchestrates the entire workflow: decomposes the diagnostic task, decides which agents to invoke, synthesizes evidence, makes tentative diagnoses, and runs self-reflection loops. Tier 2 is the Agent Servers layer. It consists of six specialized modules, each managing its own tools, such as the Phenotype Extractor, which converts free-text clinical narratives into standardized terms, and the Knowledge Searcher, which retrieves data in real time from web search engines and medical-specific sources. Retrieved documents are then summarized and relevance-filtered by a lightweight LLM (GPT-4o-mini). The external data sources the agents use, such as Google, PubMed, and Wikipedia, constitute Tier 3.

AI Diagnostic Setup

The system operates in two stages. The first one is information collection, where phenotype and genotype branches run in parallel. The phenotype branch standardizes HPO (Human Phenotype Ontology) terms, retrieves relevant literature and cases, and runs phenotype analysis tools. The genotype branch annotates variants and ranks them by clinical significance. The central host then performs synthetic analysis and generates a tentative diagnosis list.

The second stage is self-reflective, where the central host critically re-evaluates each hypothesis against all collected evidence. If all candidates are ruled out during self-reflection, the system goes back, increases the search depth, collects more evidence, and repeats as needed. Once candidates survive self-reflection, the system generates a final ranked list of diseases with reasoning chains (free-text rationales with clickable reference links).

DeepRare’s crucial advantage is that it does not have to be pre-trained on cases of rare diseases, as training LLMs requires a lot of data which simply does not exist for rare diseases, some of which are only known from a handful of cases. Instead, a generally trained LLM orchestrates specialized tools for data retrieval and analysis, synthesizes their outputs through reasoning, and iteratively validates its own conclusions.

Best in class

DeepRare was evaluated across nine datasets, spanning 6,401 total cases, 2,919 distinct rare diseases, and 14 medical specialties. The metrics used were Recall@1, @3, and @5 (whether the correct diagnosis appears in the top 1, 3, or 5 predictions).

The first evaluation was against 15 other digital tools, including general LLMs, reasoning LLMs, medical LLMs, and agentic systems. All the models received standardized Human Phenotype Ontology (HPO) descriptions as input.

DeepRare achieved an average Recall@1 of 57.18% and Recall@3 of 65.25% across all benchmarks, outperforming the second-best method (Claude-3.7-Sonnet-thinking) by 23.79% and 18.65% margins, respectively. However, given the pace of LLM development, several models released after the study’s design period were not included in the comparison; for instance, the top ChatGPT version the study used was 4o.

The model then went head-to-head with human expert physicians. 163 clinical cases were presented identically to DeepRare and five rare disease physicians with at least 10 years of experience, who were allowed to use search engines but not AI tools. DeepRare achieved Recall@1 of 64.4% vs. physicians’ 54.6% and Recall@5 of 78.5% vs. 65.6%. According to the authors, this is one of the first demonstrations of a computational model surpassing expert physicians on rare disease phenotype-based diagnosis.

To validate DeepRare’s reasoning, the researchers then turned to ten associate chief physicians, who evaluated 180 randomly sampled cases. They assessed whether each cited reference was both reliable and directly relevant to the diagnostic conclusion and found reference accuracy to be 95.4%.

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

Literature

[1] Zhao, W., Wu, C., Fan, Y., Qiu, P., Zhang, X., Sun, Y., Zhou, X., Zhang, S., Peng, Y., Wang, Y., Sun, X., Zhang, Y., Yu, Y., Sun, K., & Xie, W. (2026). An agentic system for rare disease diagnosis with traceable reasoning. Nature, 10.1038/s41586-025-10097-9. Advance online publication.

[2] Glaubitz, R., Heinrich, L., Tesch, F., Seifert, M., Reber, K. C., Marschall, U., … & Müller, G. (2025). The cost of the diagnostic odyssey of patients with suspected rare diseases. Orphanet Journal of Rare Diseases, 20(1), 222.

[3] Nguengang Wakap, S., Lambert, D. M., Olry, A., Rodwell, C., Gueydan, C., Lanneau, V., … & Rath, A. (2020). Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. European journal of human genetics, 28(2), 165-173.

Doctor holding heart model

A Circulating Inflammation Suppressor Decreases Mortality

Researchers publishing in Aging have used Mendelian randomization to conclude that the inflammatory factor IL6 causes increased mortality and that its circulating receptor, IL6R, decreases it.

Looking for a proof of danger

Chronic, age-related inflammation (inflammaging) is very well-known to be closely connected to negative age-related outcomes, to the point that it has been addressed by the Hallmarks of Aging authors [1]. However, as these researchers note, proving causation in this case is particularly difficult; inflammation often comes with a large variety of confounding factors, and reverse causation must also be ruled out [2].

To accomplish that, the researchers turned to Mendelian randomization, a technique that uses large genomic datasets derived from very large groups of people, to discover the effects of various conditions in a way that is far less prone to confounding and reverse causation. They chose the well-studied inflammatory factor IL6, along with its soluble receptor IL6R, which leads this inflammatory factor down a different and possibly contradictory pathway [3].

Ruling out other factors

This study found that increases in IL6R cause increased longevity and protected against a variety of conditions. While Alzheimer’s and kidney diseases were unaffected, increases in IL6R were found to be protective against lung cancer, diabetes, stroke, and coronary artery disease. People with more circulating IL6R had less all-cause mortality.

Similarly, increases in IL6 were found to cause more overall mortality, and genetic propensities for the various conditions that cause mortality, such as heart disease, were not connected to this increase in IL6, meaning that reverse causality was not a factor. C-reactive protein and GDF15, two other inflammation-related compounds frequently studied in aging, were not found to have any effects.

The researchers noted that, because very few genes are associated with increased inflammation, they had to use only those genes that were very significantly and strongly associated in order to avoid creating data from weak instruments. Additionally, by using repeated leave-one-out analyses, the researchers made sure that the associations that they discovered stood on their own. None of the individual genes responsible for the IL6 increase was found to be the cause; instead, the cause was, indeed, the increased IL6.

A cardiovascular focus

The researchers noted that most of the causes of increased mortality linked to IL6 were cardiovascular in nature. They note that IL6R is not abundant in the walls of blood vessels or heart tissue, and therefore, increases in this anti-inflammatory factor throughout the bloodstream bring it to where it is needed. By binding to and taking away IL6, the researchers reason, IL6R prevents this inflammatory compound from worsening various cardiovascular conditions, such as thrombosis and dysfunction of the endothelium, providing a “clear mechanistic pathway” for its beneficial effects.

The researchers sum up their findings simply: “Taken together, the results of the current mendelian randomization study strengthen the rationale for IL6R antagonism as a potential strategy to reduce cardiovascular disease and associated mortality.” Fortunately, an IL6R antagonist already exists in the clinic: tocilizumab is already approved by the FDA and has been found to reduce mortality in both the contexts of COVID-19 [4] and giant cell arteritis [5].

However, this approach still needs to be examined carefully. Experiments will need to be performed in animals and people to determine if artificially increasing circulating IL6R through tocilizumab or other methods is a viable method of reducing overall cardiovascular disease risk.

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

Literature

[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243-278.

[2] Emerging Risk Factors Collaboration. (2010). C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. The Lancet, 375(9709), 132-140.

[3] Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. The Lancet, 379(9822), 1214-1224.

[4] Rosas, I. O., Bräu, N., Waters, M., Go, R. C., Hunter, B. D., Bhagani, S., … & Malhotra, A. (2021). Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. New England Journal of Medicine, 384(16), 1503-1516.

[5] Stone, J. H., Tuckwell, K., Dimonaco, S., Klearman, M., Aringer, M., Blockmans, D., … & Collinson, N. (2017). Trial of tocilizumab in giant-cell arteritis. New England Journal of Medicine, 377(4), 317-328.

Lifetime Cognitive Enrichment Associated With Less Dementia

A recent study suggests that cognitive enrichment throughout life is associated with reduced dementia risk, and it has the potential to delay the onset of dementia and mild cognitive impairment by five to seven years [1].

Cognitive stimulation

Engagement in cognitively stimulating activities has been linked to lower dementia incidence, better cognitive function, and a slower rate of cognitive decline [2-4]. However, previous studies have some limitations. First, they often examine engagement in cognitive activities at a single life stage. Second, they frequently focus on a single activity, such as solving crossword puzzles.

While it’s important to identify which activities and at what life stages contribute to maintaining cognitive function in older age, it’s also essential to recognize that these activities are part of broader lifestyles that individuals engage in throughout their lives, collectively affecting cognition.

To gain a more comprehensive picture, the current study examined the relationships between lifetime cognitive enrichment, access to various resources throughout life, Alzheimer’s disease-related dementia, and cognitive decline.

Measuring cognitive enrichment

This longitudinal study examined 1,939 older adults with a mean baseline age of 80 years, mostly female, from Northeastern Illinois who participated in the Rush Memory and Aging Project. The cohort consisted mostly of highly educated, non-Hispanic White people of European descent, which could limit generalizability. Participants were free of dementia at the beginning of the study and underwent annual clinical evaluations for almost 8 years. During that time, 551 persons developed Alzheimer’s disease-related dementia.

Based on lifetime-enrichment data collected through surveys, the researchers developed a composite measure of enrichment that captures each individual’s living environment.

“Our study looked at cognitive enrichment from childhood to later life, focusing on activities and resources that stimulate the mind,” said study author Andrea Zammit, Ph.D., of Rush University Medical Center in Chicago.

For early-life enrichment, the researchers took into account such factors as parental education; number of siblings; access to various cognitive resources at age 12, such as a newspaper subscription, encyclopedia, globe, or atlas; frequency of cognitively stimulating activities at age 6, for example, being read to; similar activities at age 12, such as reading books; and foreign language instruction before age 18.

For midlife and late life, the researchers considered income and frequency of engagement in cognitive activities; additionally, at the midlife time point, they assessed access to cognitive resources such as magazines, a dictionary, or a library card.

A lifetime enrichment composite score was computed as the average of the three composite scores and was moderately correlated with education and global cognition.

Higher enrichment, lower dementia risk

The analysis of the data showed that every point higher in lifetime enrichment was associated with a 38% reduced risk of dementia and a 36% reduced risk of mild cognitive impairment.

When scores were analyzed separately, the benefits of cognitive enrichment were evident as well, with the risk of Alzheimer’s disease-related dementia reduced by 20%, 21%, and 29%, and the risk of cognitive impairment lower by 17%, 20%, and 24% for early-, mid-, and late-life cognitive enrichment, respectively.

The researchers also calculated that for people at the 90th percentile of lifetime cognitive enrichment, compared with people at the 10th percentile, dementia onset was delayed by almost 5.5 years, with a mean age of 93.8 years (compared to 88.4 years); and for mild cognitive impairment by 7 years, with a mean age of 84.5 years (compared to 77.5 years). The delay was also present when each stage was analyzed separately, but it was smaller for early and mid-life enrichment.

Dementia onset cognitive enrichment

The authors noted differences among study participants at baseline that they attributed to lifetime cognitive enrichment. The cognitive abilities of people at the 10th percentile declined 14% faster than those at the 50th percentile, and those at the 90th percentile declined 10% more slowly.

Among people who died during the follow-up period, the researchers didn’t observe meaningful associations between cognitive enrichment scores and neuropathological changes in the brain. However, they observed associations between higher cognitive enrichment scores and better cognitive function near death and slower cognitive decline.

Individual factors

While composite scores of cognitive enrichment are important for showing global trends, the researchers also conducted separate analyses of individual indicators, which showed a positive association with late-life cognition for all tested indicators except the availability of childhood resources.

The greatest effects were observed for midlife participation in cognitive activities and foreign language instruction, even after adjusting for socioeconomic status. It’s not the first time that learning a foreign language has appeared as a protective factor against cognitive decline or aging. We recently discussed a study linking multilingualism to delayed aging, which further supports the beneficial effects of speaking more than one language.

Lifelong consistency

The researchers conclude that “results suggest that cognitive health in late life is in part the product of lifetime exposure to cognitive enrichment,” and higher lifelong cognitive enrichment has the potential to reduce the risk of Alzheimer’s disease by nearly 40%. While the effect seems to be the strongest for mid- and late-life engagement, the researchers make an argument about the importance of creating intellectually stimulating environments in early life, as this helps to instill the love of lifelong learning in young individuals, which will help them to reap the benefits of intellectual engagement later in life. They also recommend public investment in creating spaces that provide free access to cognitively stimulating activities, such as libraries and other free services, so that these resources are readily available to those with limited financial resources.

“Our findings are encouraging, suggesting that consistently engaging in a variety of mentally stimulating activities throughout life may make a difference in cognition,” said Zammit. “Public investments that expand access to enriching environments, like libraries and early education programs designed to spark a lifelong love of learning, may help reduce the incidence of dementia.”

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

Literature

[1] Zammit, A. R., Yu, L., Poole, V. N., Kapasi, A., Wilson, R. S., & Bennett, D. A. (2026). Associations of Lifetime Cognitive Enrichment With Incident Alzheimer Disease Dementia, Cognitive Aging, and Cognitive Resilience. Neurology, 106(5), e214677.

[2] Wang, H. X., Karp, A., Winblad, B., & Fratiglioni, L. (2002). Late-life engagement in social and leisure activities is associated with a decreased risk of dementia: a longitudinal study from the Kungsholmen project. American journal of epidemiology, 155(12), 1081–1087.

[3] Gow, A. J., Pattie, A., & Deary, I. J. (2017). Lifecourse Activity Participation From Early, Mid, and Later Adulthood as Determinants of Cognitive Aging: The Lothian Birth Cohort 1921. The journals of gerontology. Series B, Psychological sciences and social sciences, 72(1), 25–37.

[4] Stern, C., & Munn, Z. (2010). Cognitive leisure activities and their role in preventing dementia: a systematic review. International journal of evidence-based healthcare, 8(1), 2–17.

NUS Healthy Longevity Conference

Global Conference to Tackle Longevity Clinical Translation

The NUS Academy for Healthy Longevity invites you to the Geromedicine Conference, set to take place from February 26-27, 2026, at the National University of Singapore. This premier event will gather global experts in geroscience, researchers, clinicians and industry leaders to explore the translation of geroscience into real-world interventions aimed at optimizing health and extending healthspan. Healthy Longevity Speaker

Key Themes:

Clinical Translation: Focused on implementing practical, evidence-based interventions in personalized care, discussions will center around individual molecules like NAD+ precursors, bioactive compounds such as urolithin A and ergothioneine, and the gerotherapeutic potential of repurposed drugs. Clinical Pathways: Sessions will delve into the growing interest in personalized care, foundational to precision geromedicine. Hear from healthcare professionals about how longevity clinics implement gerotherapeutic strategies into patient care. Innovation and Collaboration: Experience the forefront of innovation with over 10 startup pitches, 50 scientific abstracts, industry showcases, and panels on uniting key players, reflecting the interdisciplinary nature of the geroscience. Join us at this pivotal event to gain exclusive insights into the latest advancements in nutraceuticals and repurposed drugs. Register now to secure your place and connect with pioneers driving the future of precision geromedicine. Check out the programme for more information: Agenda

Venue Details:

Location: Shaw Foundation Alumni House, 11 Kent Ridge Drive, Singapore 119244 Time: Registration begins at 8:00 AM on Day 1, and 8:30 AM on Day 2. The conference will be accessible to a virtual audience, ensuring that the discussions reach a global audience beyond the confines of the venue.
We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future.
Healthy Foods

New Study Calculates Lifespan Gains From Five Popular Diets

Scientists have pitted five diets against each other to see which one is associated with more years of life gained [1].

The clash of the diets

Unhealthy eating is recognized as a globally leading cause of death [2]. Surprisingly, few studies have actually evaluated the gains in life expectancy associated with adherence to a healthy diet. In a new study published in Science Advances, an international group of scientists pitted five leading dietary practices against each other using data from UK Biobank, a huge repository of health-related information on hundreds of thousands of British citizens.

The sample was comprised of 103,649 participants (mean age 58.3 years, 56.4% female) who had completed two or more web-based 24-hour dietary assessments and were free of cardiovascular disease (CVD) and cancer at baseline. Each participant was scored on five dietary pattern indices based on what they reported eating: Alternate Healthy Eating Index (AHEI-2010), Alternate Mediterranean Diet (AMED), healthful Plant-based Diet Index (hPDI), Dietary Approaches to Stop Hypertension (DASH), and Diabetes Risk Reduction Diet (DRRD).

Each score was divided into quintiles. The five scores were moderately-to-highly intercorrelated, meaning that the dietary patterns they capture are often overlapping (which is expected), but not identical. The model was adjusted for race, education, socioeconomic deprivation, smoking status, physical activity, BMI, total energy intake, baseline dyslipidemia, hypertension, diabetes, and, for hPDI, DASH, and DRRD, alcohol consumption.

The researchers also wanted to see how dietary patterns interact with known longevity gene variants. They calculated a longevity polygenic risk score (PRS) from 19 single nucleotide polymorphisms (SNPs) which were significantly associated with longevity in a genome-wide association study (GWAS). This model was additionally adjusted for ten genetic principal components.

The winners and the losers

DRRD showed the strongest association with longevity, as the top quintile had 24% lower mortality than the bottom quintile. The authors attribute this to the fact that DRRD’s scoring algorithm directly includes dietary fiber and glycemic index, the two components that individually showed the strongest associations with mortality: fiber was protective, while high glycemic index was detrimental. Product-wise, sugar-sweetened beverages turned out to be the most harmful, in line with previous research [3].

Other scores followed DRRD closely, with 20% reductions in mortality for the top quintiles of AHEI and AMED compared to the bottom ones, 19% for DASH, and 18% for hPDI. Interestingly, noticeable sex-related differences were observed. When the researchers looked at life expectancy, the top performer for men was DRRD, with 3 years gained between the lowest and the highest quintiles, while for women, it was AMED, with 2.3 years. For both sexes, the least effective diet was hPDI (1.9 and 1.5 years, respectively).

How do “longevity genes” factor in?

The team then analyzed PRS’ association with remaining life expectancy, and it turned out to be slightly lower: 1.4 years for men and 1.7 years for women. However, the PRS was split into tertiles, so the researchers compared the top and bottom tertiles. Importantly, the effects of diet and genetics were roughly additive, with DRRD showing the largest combined gains in both sexes. Being both in the top DRRD quintile and in the top PRS tertile was associated with 3.2 years of additional life expectancy for men and 5.5 years for women.

However, the combined estimates are peculiarly noisy, especially for men. For instance, having a top AMED score and a top PRS gives only 1 year for men, which is actually less than either diet alone (2.2) or PRS alone (1.4). This is probably because the combined estimates come from much smaller slices of the cohort, resulting in noise, rather than due to any negative interaction. The women’s combined numbers behave more sensibly and are roughly additive.

Crucially, these estimates are for a 45-year-old person. The life expectancy benefits of switching to a better diet, naturally, diminish with age, as fewer years remain for the risk reduction to play out, while the risk of dying from something unrelated to diet increases.

While this is a well-executed and carefully sensitivity-tested observational study, a few caveats apply. The effect sizes are modest, and the confidence intervals are wide enough for the true benefit to be as small as about 0.5 years in some comparisons. These are also best-case comparisons that compare top and bottom quintiles, while most people usually do not switch their diets from the worst to the best. Finally, the PRS interaction story is intriguing but might not be statistically robust, leaving room for further research.

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

Literature

[1] Lv, Y., Song, J., Ding, D., Luo, M., He, F. J., Yuan, C., MacGregor, G. A., Liu, L., & Chen, L. (2026). Healthy dietary patterns, longevity genes, and life expectancy: A prospective cohort study. Science advances, 12(7), eads7559.

[2] Afshin, A., Sur, P. J., Fay, K. A., Cornaby, L., Ferrara, G., Salama, J. S., … & Murray, C. J. (2019). Health effects of dietary risks in 195 countries, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The lancet, 393(10184), 1958-1972.

[3] Imamura, F., O’Connor, L., Ye, Z., Mursu, J., Hayashino, Y., Bhupathiraju, S. N., & Forouhi, N. G. (2015). Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. Bmj, 351.

Maze mouse

Silencing Growth Hormone Has Strong Effects in Mouse Brains

Researchers have found that altering a growth hormone receptor in the brain adipose tissue of aged male mice slows their mental aging and allows them to perform far better on cognitive tests.

Growth signaling is not necessarily good

The axis of growth hormone and insulin-like growth factor 1 (IGF-1) is well-known in aging, and the relationship between this regulator and brain aging has been previously documented [1]. Interestingly, while circulating growth hormone and IGF-1 levels decline with aging [2], suppressing this signaling extends lifespan [3], and mice with reduced levels of this signaling perform better on cognitive tests [4]; this also occurs when the mice express an agonist that suppresses it [5].

The researchers of this study focused on its effects on fatty (adipose) tissue, which is metabolically active and secretes factors that affect other systems [6], including the brain [7]. While previous work has discovered that adipose-specific growth hormone knockout (Ad-GHRKO) mice have better insulin sensitivity and longer lives [8], how well these mice perform on cognitive tests had not been previously measured.

Benefits for neural function and inflammation

The researchers first directly examined the brains of these mice, comparing 18- to 24-month-old Ad-GHRKO mice to controls. The modified mice were more neurally active overall and had less neuronal loss in the dentate gyrus, the part of the hippocampus responsible for forming new memories. This was accompanied by an increase in synapse formation and a decrease in neuroinflammation: there were decreases in the inflammatory factors IL-6 and TNF-α along with an increase in the anti-inflammatory factor IL-10.

There was also a reduction in cellular senescence. The modified mice had significantly less of the senescence marker SA-β-gal throughout their brains, including the amyglada, the dentate gyrus, and the cortex. They also had significantly less tau phosphorylation, an age-related protein alteration that contributes to cognitive decline and, in humans, is a sign of Alzheimer’s disease.

The excitability of neurons declines with age, and here, too, knocking out growth hormone in the adipose tissue proved beneficial; the aged modified mice fired their neurons much more like younger mice did, while aged controls had stark reductions in neural firing frequency.

Adipose growth hormone KO frequency

Stark benefits on cognitive tests

The researchers then turned to four standard cognitive tests: the novel object recognition test, which shows that the mice can discriminate between familiar and unfamiliar things; the Y-maze tests, which tests for exploration ability; the Morris water maze test, which tests memory and navigation behavior; and a floor shock test, which tests memory in adversive conditioning. On all four of these tests, the aged modified mice performed almost exactly like their younger counterparts, while the aged controls performed far worse; this was in spite of the modification not noticeably affecting the older mice’s physical ability.

Adipose growth hormone KO brain

According to the authors, “this study provides evidence that adipose tissue acts as a key peripheral regulator of brain aging.” While the number and power of cognitive and biochemical benefits that arose from this modification are striking, these experiments were performed on a single-sex group of genetically altered mice. Aapplying these findings to wild-type animals, and then human beings, is a challenge of its own.

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

Literature

[1] Ashpole, N. M., Sanders, J. E., Hodges, E. L., Yan, H., & Sonntag, W. E. (2015). Growth hormone, insulin-like growth factor-1 and the aging brain. Experimental gerontology, 68, 76-81.

[2] Liu, H., Bravata, D. M., Olkin, I., Nayak, S., Roberts, B., Garber, A. M., & Hoffman, A. R. (2007). Systematic review: the safety and efficacy of growth hormone in the healthy elderly. Annals of internal medicine, 146(2), 104-115.

[3] Bartke, A. (2008). Growth hormone and aging: a challenging controversy. Clinical interventions in aging, 3(4), 659-665.

[4] Kinney-Forshee, B. A., Kinney, N. E., Steger, R. W., & Bartke, A. (2004). Could a deficiency in growth hormone signaling be beneficial to the aging brain?. Physiology & behavior, 80(5), 589-594.

[5] Basu, A., McFarlane, H. G., & Kopchick, J. J. (2017). Spatial learning and memory in male mice with altered growth hormone action. Hormones and Behavior, 93, 18-30.

[6] Booth, A., Magnuson, A., Fouts, J., & Foster, M. T. (2016). Adipose tissue: an endocrine organ playing a role in metabolic regulation. Hormone molecular biology and clinical investigation, 26(1), 25-42.

[7] Letra, L., & Santana, I. (2017). The influence of adipose tissue on brain development, cognition, and risk of neurodegenerative disorders. Obesity and Brain Function, 151-161.

[8] List, E. O., Berryman, D. E., Slyby, J., Duran-Ortiz, S., Funk, K., Bisset, E. S., … & Kopchick, J. J. (2022). Disruption of growth hormone receptor in adipocytes improves insulin sensitivity and lifespan in mice. Endocrinology, 163(10), bqac129.

Longevity Innovation Forum 2026

Longevity Innovation Forum in San Diego

San Diego, CA – March 11–12, 2026 – Longevity Global will host the inaugural Longevity Innovation Forum, a two-day gathering bringing together leading scientists, clinicians, biotech founders, investors, and longevity enthusiasts advancing the science and translation of healthy aging. Held in San Diego’s thriving biotech hub, the Forum will spotlight Southern California’s growing longevity ecosystem while fostering collaboration across academia, industry, and the broader community interested in extending healthspan.

The program will feature an exceptional lineup of speakers, including Mike Snyder (Stanford University), Eric Verdin (Buck Institute for Research on Aging), Steve Horvath (Altos Labs), Jeanne Loring (Scripps Research & Aspen Neuroscience), Irina Conboy (Generation Lab), and other leaders at the forefront of aging biology and translational medicine. Sessions will explore biomarkers of exceptional longevity, women’s health and aging, epigenetic clocks, cellular rejuvenation, translational and clinical approaches to age-related disease, and emerging strategies to modulate the biological drivers of aging.

Designed as a high-signal yet accessible forum, the Longevity Innovation Forum aims to bridge cutting-edge research with real-world application. By convening researchers, founders, clinicians, investors, and engaged members of the longevity community, the event seeks to create a shared space for dialogue, partnership, and forward-thinking ideas. Building on the momentum of Longevity Global’s established programming, the San Diego Forum extends that vision to one of the world’s most dynamic biotech clusters.

“Our goal is to create an environment where scientific breakthroughs, entrepreneurship, and community can intersect,” said Salah Mahmoudi, organizer of the Longevity Innovation Forum. “Longevity research is progressing rapidly, and advancing the field will require collaboration across disciplines – from laboratory science to clinical practice to informed public engagement. We’re excited to bring that energy to San Diego.”

Event Details

Dates: March 11–12, 2026

Location: Pacific Center, San Diego, California

Format: Two-day summit featuring keynote presentations, panel discussions, startup pitches, and curated networking opportunities

Registration: https://luma.com/ib3870so

Confirmed Speakers

Mike Snyder (Stanford, Personalis, january AI, Mirvie) • Eric Verdin (Buck Institute) • Steve Horvath (Altos Labs) • Jeanne Loring (Scripps Research & Aspen Neuroscience), Irina Conboy (Generation Lab) • Sonia Setayesh (Civilization Ventures) • Pinchas Cohen (USC, CohBar) • Lauren Booth (Calico) • Aladdin H. Shadyab (UCSD) • Manish Chamoli (LongGame Ventures) • Peter (Højer) Mathiesen (Iduna Capital) • Christin Glorioso (NeuroAge) • Hanadie (Juvena Tx) • Ben Blue (Ora Biomedical) • Daniel Sollinger (Jellyfish DAO) • Alan Alexander (CoreViva) • Bérénice Benayoun (USC) • Heather Koshinsky (Berkeley SkyDeck) • Christopher Shen (Aleutian Tx) • Carter Palmer (Third Element Bio) • Karl Pfeleger (AGINGBIOTECH.INFO) • Vittorio Sebastiano (UC Irvine, TurnBio) • Shasha Jumbe (LEVEL 42 AI) • David Scieszka (Vertical Longevity Pharma) • Chris Patil (BioAge) • Amir Kiani (Genexgen) • Salah Mahmoudi (ReneuBio) • Ashley Webb (Buck Institute, Bolden Tx) • Brenda Eap (A4LI) • Lauren Carnevale (Torrion) • Sunjya Schweig (California Center for Functional Medicine) • Matthew Shtrahman (UCSD) • Erin Gibson (Stanford) • Amit Sharma (Lifespan Research Institute) • Anthony Molina (UCSD) • Frederick Beddingfield (Rubedo Life Sciences) • Tom Zuber (Zuber Law) • Dorothea Portius (Nutrition Scientist) • Irit Rappley, PhD (NNP Laboratories) • Aimee Schoof (Jellyfish DAO) • Joshua Johnson (University of Colorodo, Llifeahead) • Julio de Unamuno IV (SDVC) • Alison Moore (Chief of Geriatrics, UCSD) • Thomas Butler (BioRevolution) • Krista Ramonas (LabXMD) • Ronjon Nag (R42, Stanford)

Sponsors

Vibrome • Generation Lab • Zero Gravity • HomeLab • Zuber Law • Sterling Bay • ReneuBio • Chen Institute • AthenaDAO • Juvena Tx • GROWISE

Media Partners

Lifespan.io • Nucleate • Berkeley SkyDeck • Connect • LaunchBio • A4LI • NeuroAge

About Longevity Global

Longevity Global, a branch of nonprofit Academics for the Future of Science (AFS), connects longevity researchers, entrepreneurs, and investors through curated summits and community-driven programming. Its flagship Longevity Summit at the Buck Institute has become a leading annual convening in the field. Through events in California and beyond, Longevity Global works to accelerate collaboration and the translation of aging science into clinical and commercial impact.

Media Contact

Salah Mahmoudi, Director Longevity Global San Diego

Organizer, Longevity Innovation Forum

Email: salah@longevitygl.org

Phone: (650) 714-1244

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

Cellular Reprogramming Rescues Memory-Encoding Neurons

Scientists have applied partial reprogramming to memory-encoding neurons (engrams) and achieved memory improvements in Alzheimer’s models and wild-type mice [1].

Rejuvenating neurons

Partial cellular reprogramming, which uses certain factors to rejuvenate cells while maintaining their identity) has shown promise across various conditions and cell types, including neurons [2]. Rejuvenating these long-lived brain cells is imperative for achieving meaningful life extension, since, unlike most organs, the brain cannot be simply replaced.

In a new study published in Neuron, a team of researchers from the Swiss Federal Technology Institute of Lausanne (EPFL) achieved targeted reprogramming of engram cells, the specific neurons that encode memories. The team used three of the four Yamanaka factors, Oct4, Sox2, and Klf4, to create the reprogramming cocktail OSK; cMyc was left out. This “abridged” formula supposedly allows for safer reprogramming without de-differentiation and is analogous to the one used in the upcoming very first clinical trial of cellular reprogramming in humans.

The team built a clever dual-AAV system, with one virus carrying a transcriptional activator that turns on during learning and the other encoding the OSK factors. The entire system is gated by doxycycline: removing it from drinking water opens a labeling window around the learning event so that only neurons active during learning get tagged and reprogrammed. Doxycycline is then reintroduced to shut off expression.

The team began with 9- to 10-month-old mice, which, like humans, exhibit age-related declines in cognitive abilities. Aged animals showed decreased freezing (representing worse memorization of danger) compared to young mice, confirming age-related memory impairment. OSK-injected aged mice were rescued to young-like freezing levels. Importantly, reprogrammed hippocampal engrams were preferentially reactivated upon recall compared to non-reprogrammed ones, suggesting specific enhancement of the functional cells.

The reprogramming also reversed age-related cellular hallmarks while preserving neuronal fate. “These results suggest that OSK induction does not lead to a loss in cell identity but rather strengthens it,” the paper says.

Memory improvements

To test whether the effect extends to remote memory, which depends on the medial prefrontal cortex (mPFC) rather than the hippocampus [3], the team targeted mPFC engrams in a separate cohort of aged mice using the same system. Again, aged controls showed impaired freezing, while OSK-injected aged mice did not. The researchers detected restoration of identity and functional markers, demonstrating that the effect is not region-specific.

Next, they moved to APP/PS1 mice, which develop amyloid pathology and memory deficits and are often used as an Alzheimer’s disease model. In a five-day water maze test, control APP/PS1 mice showed reduced use of spatial search strategies and took longer paths compared to wild type controls, indicating cognitive and memory impairment. OSK-injected APP/PS1 animals showed significantly increased use of spatial strategies and took shorter paths. Basically, while wild-type Alzheimer’s mice got stuck using random-like strategies, OSK-treated Alzheimer’s mice regained normal learning progression. Here too, the experiments targeted both hippocampal and mPFC engrams, with comparable results.

“This paper directly addresses a big fear of brain reprogramming – ‘won’t it scramble memories?’ They target learning-activated engram neurons, test recall two days later, and see the opposite of memory erasure: memory is rescued,” said Yuri Deigin, CEO of YouthBio, which is gearing up for its own clinical trials of partial reprogramming in Alzheimer’s. “Moreover, they explicitly ask whether OSK causes dedifferentiation, and the identity readouts move the other way, suggesting identity is being reinforced, not lost. And they don’t just show a short-term bump: they restore remote memory at two weeks via mPFC engrams.” Deigin and YouthBio were not involved in this study.

Reduced biological age

Finally, the team built a regression model using learning metrics from the water maze to predict chronological age in mice. This model achieved moderate power (R = 0.57), predicting age with a median error of 10 weeks. When applied to OSK-injected aged wild-type mice, it showed a significant reduction in predicted cognitive age. For Alzheimer’s mice (two different models – APP/PS1 and 5xFAD), non-treated animals showed accelerated cognitive aging, while OSK-injected mice returned to chronological age levels.

One important nuance is that in the OSK system the researchers used, the reprogramming and learning events are necessarily simultaneous; the labeling strategy can only identify engram neurons at the moment they fire during encoding, so there is no way to target OSK to those cells in advance. Therefore, the cognitive benefits likely arise less from improved encoding of memories and more from better recall, as engram neurons undergo rejuvenation during the days to weeks after learning. In principle, if engram neurons could be identified while quiescent, pre-treating them with OSK before a learning challenge might yield even stronger effects.

“On a personal note, it’s validating,” said Deigin. “I proposed back in 2019 that partial reprogramming could counteract Alzheimer’s and age-related cognitive decline, and we built YouthBio Therapeutics around that hypothesis. There are now multiple independent mouse studies pointing in the same direction. Biology R&D moves slowly, but the implications are profound: partial reprogramming may be disease-modifying well beyond Alzheimer’s.”

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

Literature

[1] Berdugo-Vega, G., Sierra, C., Astori, S., Calati, V., Orsat, J., Scoglio, M. J., Sandi, C., & Gräff, J. (2026). Cognitive rejuvenation through partial reprogramming of engram cells. Neuron. Advance online publication.

[2] Antón-Fernández, A., Roldán-Lázaro, M., Vallés-Saiz, L., Ávila, J., & Hernández, F. (2024). In vivo cyclic overexpression of Yamanaka factors restricted to neurons reverses age-associated phenotypes and enhances memory performance. Communications Biology, 7(1), 631.

[3] Frankland, P. W., & Bontempi, B. (2005). The organization of recent and remote memories. Nature reviews neuroscience, 6(2), 119-130.

T cwlls

Creating CAR-T Cells Using Current Alzheimer’s Antibodies

A team of researchers has biologically engineered T cells with currently available Alzheimer’s drugs in order to directly attack the characteristic amyloid plaques of Alzheimer’s disease.

Building on the current paradigm

Most Alzheimer’s treatments used in the clinic are -mabs, monoclonal antibodies that are designed to attack the amyloid beta plaques that accumulate in the brains of people with Alzheimer’s. However, while they have been found to have enough meaningful benefits in clinical trials to be approved by the FDA, they are not a cure, and some analyses question their effectiveness [1].

The immune system has been documented to play various roles in neurodegenerative diseases, although those roles can be both beneficial [2] and harmful [3]. CD4+ T cells, which were engineered in this study, naturally have beneficial effects against Alzheimer’s [4] and protect injured neurons [5].

The chimeric antigen receptor (CAR) approach also uses antibodies; however, these antibodies are attached to immune cells in an effort to encourage them to destroy pathologies. Most research in this area has focused on cancer; particularly leukemia [6], and we have written about this technology being used against a broad variety of cancers and senescent cells in the gut.

Instead of destroying cells, however, these researchers want their engineered cells to destroy the Alzheimer’s plaques themselves and to home in on damaged sites in the hope that their presence might protect the damaged area [5]. The CARs they used were built with two of the same -mabs currently used in the clinic: aducanumab and lecanemab.

Tentatively positive initial results

Testing against various forms of amyloid beta peptides, they found that the lecanemab-derived CAR (Lec28z) was significantly more responsive than the aducanumab-derived one (Adu28z). Only assembled fibrils were targeted; neither of the CARs was responsive to the monomer or oligomer forms of this amyloid. Lec28z was also more responsive to brain extracts derived from mice modified to get Alzheimer’s; therefore, the researchers continued using this version throughout the rest of their experiments.

The researchers injected a key vein of Alzheimer’s model mice with Lec28z-modified T cells derived from wild-type mice, and then delivered another injection three weeks later. After three more weeks, the brains of the injected mice were examined.

Compared to control groups injected with saline or unmodified T cells, the CAR-T-injected mice had significant increases of both CAR T cells and regular T cells at the sites of amyloid beta plaques. The overall amount of amyloid beta was reduced, both near the injection site and throughout the brain’s dura.

However, there was no decrease in amyloidosis throughout the bulk of the brain. While these cells were in fact dispersed throughout the brain and homing in on plaque sites, they also activated the local T cells and microglia, “raising concerns about prolonged T cell activation and the potential emergence of detrimental phenotypes including cytotoxicity.”

Transience is highly beneficial

Therefore, the researchers attempted a more transient approach. Three doses of CAR-T cells transfected with Lec28z mRNA were given ten days apart, with a brain examination conducted 10 days after the final dose. This approach was found to be more effective; the treated animals had less microglial activation and amyloid throughout the brain along with less overall pathology.

These findings, while positive and potentially groundbreaking, are very preliminary. The researchers did not conduct behavioral tests, and mice do not naturally get Alzheimer’s disease. Substantial further work, including a trial involving human beings, needs to be done to determine if -mab drugs can be replaced in the clinic with CAR-T versions.

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

Literature

[1] Knopman, D. S., Jones, D. T., & Greicius, M. D. (2021). Failure to demonstrate efficacy of aducanumab: An analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimer’s & Dementia, 17(4), 696-701.

[2] Marsh, S. E., Abud, E. M., Lakatos, A., Karimzadeh, A., Yeung, S. T., Davtyan, H., … & Blurton-Jones, M. (2016). The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proceedings of the National Academy of Sciences, 113(9), E1316-E1325.

[3] Chen, X., Firulyova, M., Manis, M., Herz, J., Smirnov, I., Aladyeva, E., … & Holtzman, D. M. (2023). Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature, 615(7953), 668-677.

[4] Mittal, K., Eremenko, E., Berner, O., Elyahu, Y., Strominger, I., Apelblat, D., … & Monsonego, A. (2019). CD4 T cells induce a subset of MHCII-expressing microglia that attenuates Alzheimer pathology. Iscience, 16, 298-311.

[5] Walsh, J. T., Hendrix, S., Boato, F., Smirnov, I., Zheng, J., Lukens, J. R., … & Kipnis, J. (2015). MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4. The Journal of clinical investigation, 125(2), 699-714.

[6] Grupp, S. A., Kalos, M., Barrett, D., Aplenc, R., Porter, D. L., Rheingold, S. R., … & June, C. H. (2013). Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. New England Journal of Medicine, 368(16), 1509-1518.

Intestinal bacteria

Young Microbes Rejuvenate Intestinal Function in Mice

Transferring microbiota from young to aged mice helped to restore molecular signaling necessary for proper intestinal function and improved the regenerative capacity of intestinal stem cells [1].

Everyday companions

Bacteria, viruses, and other microbes are well-known as agents that cause disease and should be avoided. However, the microbes that make us sick, while more noticeable, are in the minority. The majority of microbes are either harmless or beneficial, and we all coexist with millions of them every day. Moreover, we cannot function properly without their assistance. Researchers refer to these microbes as microbiota: microbes that reside both inside and outside the human body and are especially abundant in the intestine.

Microbiota affect multiple aspects of health, including digestion and immune modulation, along with aging processes; aging-related changes in microbiotal composition are associated with age-related conditions such as obesity [2], inflammatory bowel disease [3], and irritable bowel syndrome [4].

The microbiome matters

The authors of this study focused on the aging processes in the intestinal epithelium. Aging is associated with reduced intestinal epithelial turnover and a decline in the self-renewal and differentiation abilities of its stem cells. At the molecular level, previous studies have linked this functional decline in intestinal stem cells to reduced canonical Wnt signaling [5].

The researchers began by assessing Wnt gene expression in the intestinal crypts of mice, which are home to these stem cells. Microbiotal abundance was found to affect Wnt signaling, and its removal reduces regenerative capacity after irradiation.

Transferring microbiota

One approach that has the potential to restore age-related changes in microbiotal composition is fecal microbiota transfer. Those researchers performed heterochronic fecal microbial transfers (FMTs), transferring young microbiota to aged animals and aged microbiota to young animals, along with control groups of homochronic control transfers (young microbiota to young animals and aged microbiota to aged animals).

Seven days after this transfer, an analysis suggested that it impacted the composition of the microbiome of the recipient, “with the age clock of the microbiota in the intestine of the recipient animal set to the clock of the FMT donor.”

An analysis of Wnt gene expression found that the control group of young animals that received young microbiota had more expression of Wnt3 and of the canonical Wnt signaling genes Ascl2 and Lgr5, as well as the intestinal stem cell marker gene Olmf4 in crypts, compared to aged animals that received aged microbiota.

When aged animals received young fecal samples, the expression levels of central canonical Wnt signaling genes in aged crypts and intestinal stem cells increased compared to aged animals that received an aged microbiome. Transferring young microbiota to aged animals also improved the function of aged intestinal stem cells, specifically the regeneration of intestinal epithelial tissue.

“This reduced signaling causes a decline in the regenerative potential of aged intestinal stem cells,” said co-author Yi Zheng, PhD, director of the Division of Experimental Hematology and Cancer Biology at Cincinnati Children’s. “However, when older microbiota were replaced with younger microbiota, the stem cells resumed producing new intestine tissue as if the cells were younger. This further demonstrates how human health can be affected by the other life forms living inside us.”

Complex interactions

The microbiome contains many species of microbes, and the researchers investigated which of them affect Wnt signaling and intestinal stem cells. To narrow their search, they identified 7 microbial groups whose abundance was affected by both aging and the transfer of young microbiota to aged animals. One of those microbial species was Akkermansia muciniphila, whose abundance was higher in the aged animals that received aged microbiota and young animals that received aged microbiota compared to the young animals that received young microbiota and the aged animals that received young microbiota.

Akkermansia muciniphila’s role in the biology of aging appears complex and ambiguous. On one hand, elevated levels of this bacterium are generally considered beneficial for the intestine [6], and it has been shown to extend the lifespan of progeroid animals, which suffer from accelerated aging [7]. Several studies have also shown enrichment of Akkermansia muciniphila in the guts of healthy, long-lived older adults [8]. However, on the other hand, different reports show that centenarians, who are considered to be ‘successful agers’, have reduced levels of Akkermansia muciniphila [9], suggesting that its impact on aging processes might be negative.

In this study, orally providing more Akkermansia muciniphila to young and aged mice increased its levels in the the first and shortest segment of the small intestine (the duodenum) of aged mice, while levels in young mice were unchanged. The researchers suggest that this is due to insufficient mucin levels in the young intestinal epithelium. Mucin serves as a food source for Akkermansia muciniphila, and mucin levels in young animals may be insufficient to support its abundance; however, this was not tested.

Akkermansia muciniphila negatively impacted the expression levels of canonical Wnt signaling genes in aged animals. In aged mice, following the administration of this bacterium, the researchers observed a further reduction in Ascl2 and Lgr5 gene levels compared to untreated age-matched controls, but only a small change in young mice that received Akkermansia muciniphila. Further experiments also indicated a “reduced regenerative potential of aged intestinal stem cells exposed to A. muciniphila.”

The increased levels of Akkermansia muciniphila in the intestines of aged mice following treatment were accompanied by changes in the levels of other microbes. Researchers hypothesized that it is possible that these other microbes may be partially responsible for the observed changes in intestinal function and gene expression following its administration. However, the changes of other microbiome components and their impact on Wnt signaling and the regenerative capacity of intestinal stem cells were not evaluated in this study.

Despite the lack of mechanistic understanding, this study contributed to the growing body of scientific evidence demonstrating the microbiome’s impact on intestinal aging. As concluded by the corresponding author, Hartmut Geiger, PhD, director of the Institute of Molecular Medicine at Ulm University and former member of the Division of Experimental Hematology and Cancer Biology at Cincinnati Children’s, “Our findings show that younger microbiota can prompt older intestine to heal faster and function more like younger intestine.”

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

Literature

[1] Nalapareddy, K., Haslam, D. B., Kissmann, A. K., Alenghat, T., Stahl, S., Rosenau, F., Zheng, Y., & Geiger, H. (2026). Microbiota from young mice restore the function of aged ISCs. Stem cell reports, 102788. Advance online publication.

[2] Sun, L., Ma, L., Ma, Y., Zhang, F., Zhao, C., & Nie, Y. (2018). Insights into the role of gut microbiota in obesity: pathogenesis, mechanisms, and therapeutic perspectives. Protein & cell, 9(5), 397–403.

[3] Zuo, T., & Ng, S. C. (2018). The Gut Microbiota in the Pathogenesis and Therapeutics of Inflammatory Bowel Disease. Frontiers in microbiology, 9, 2247.

[4] Theodorou, V., Ait Belgnaoui, A., Agostini, S., & Eutamene, H. (2014). Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome. Gut microbes, 5(3), 430–436.

[5] Nalapareddy, K., Nattamai, K. J., Kumar, R. S., Karns, R., Wikenheiser-Brokamp, K. A., Sampson, L. L., Mahe, M. M., Sundaram, N., Yacyshyn, M. B., Yacyshyn, B., Helmrath, M. A., Zheng, Y., & Geiger, H. (2017). Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells. Cell reports, 18(11), 2608–2621.

[6] Naito, Y., Uchiyama, K., & Takagi, T. (2018). A next-generation beneficial microbe: Akkermansia muciniphila. Journal of clinical biochemistry and nutrition, 63(1), 33–35.

[7] Bárcena, C., Valdés-Mas, R., Mayoral, P., Garabaya, C., Durand, S., Rodríguez, F., Fernández-García, M. T., Salazar, N., Nogacka, A. M., Garatachea, N., Bossut, N., Aprahamian, F., Lucia, A., Kroemer, G., Freije, J. M. P., Quirós, P. M., & López-Otín, C. (2019). Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nature medicine, 25(8), 1234–1242.

[8] Zeng, S. Y., Liu, Y. F., Liu, J. H., Zeng, Z. L., Xie, H., & Liu, J. H. (2023). Potential Effects of Akkermansia Muciniphila in Aging and Aging-Related Diseases: Current Evidence and Perspectives. Aging and disease, 14(6), 2015–2027.

[9] Wang, F., Yu, T., Huang, G., Cai, D., Liang, X., Su, H., Zhu, Z., Li, D., Yang, Y., Shen, P., Mao, R., Yu, L., Zhao, M., & Li, Q. (2015). Gut Microbiota Community and Its Assembly Associated with Age and Diet in Chinese Centenarians. Journal of microbiology and biotechnology, 25(8), 1195–1204.

Sleep problems

Sleep Deprivation Affects Cognition via Myelin Loss

A new study links sleep loss to the thinning of the myelin layer, which slows signal transmission in axons. Restoring cholesterol homeostasis reverses the damage [1].

Sleep loss hurts myelin

Sleep quality is a strong extrinsic determinant of longevity [2]. Not only does sleep loss affect cognitive function [3], it has also been linked to a plethora of health problems, including increased dementia risk, cardiovascular disease, and immune dysfunction [4]. However, the underlying mechanisms are still being investigated. In a new study, published in the Proceedings of the National Academy of Sciences, a team of researchers from Italy and Spain has shed new light on this question.

The team started with scouring through the Human Connectome Project database for correlations between sleep loss and structural problems in the brain. They found a significant negative correlation between sleep quality and MRI-measured white matter microstructural integrity. In other words, poor sleep was linked to worse white matter, and this effect was brain-wide.

Oligodendrocytes are the cells that build myelin sheaths around axons; this myelin layer insulates axons, ensuring swift and faithful signal transmission. The researchers subjected rats to 10 days of sleep restriction and found widespread reductions in white matter integrity, reduced myelin basic protein (MBP) staining in the corpus callosum, thinner myelin sheaths, and fewer oligodendrocyte precursor cells (OPCs), all of which point to myelin deficiency.

Importantly, the team then ran a separate chronic mild stress cohort to rule out stress as the driver. Cortico-cortical evoked responses and corticosterone levels were unchanged with stress alone, suggesting that the effects are specific to sleep loss.

Sleep-restricted rats showed approximately 33% increased latency in transcallosal conduction; essentially, signals traveling between hemispheres were substantially slower. Sleep loss also affected cognitive function, causing worse novel object recognition and motor performance on rotarod, and impaired interhemispheric synchronization of neuronal activity, particularly during NREM sleep.

It’s all about cholesterol

Using transcriptomic data from oligodendrocyte-specific datasets, the researchers found that sleep loss massively dysregulated cholesterol-related pathways: biosynthesis and transport genes were downregulated, while endoplasmic reticulum (ER) stress and lipid degradation genes were upregulated. “In summary, the analysis of gene expression in oligodendrocytes revealed that sleep loss significantly impaired ER and lipid homeostasis, particularly affecting cholesterol metabolism,” the paper says.

Direct measurements confirmed markedly reduced cholesterol in purified myelin fractions from sleep-deprived mice. This cholesterol loss increased membrane fluidity in the inner leaflet of the myelin membrane, which would weaken the insulating properties of myelin. “Optimal membrane fluidity and curvature in myelin necessitate high cholesterol levels,” the authors explain. “This ensures membrane stability, minimizes ion leakage, and reinforces the insulating properties of myelin membranes.”

The researchers link the observed reduction in myelin cholesterol to deficits in intracellular trafficking and transport mechanisms. Sleep loss caused minimal changes in other lipids. “The impact of sleep loss on major cholesterol-related transcripts was more pronounced in oligodendrocytes than in other brain cell types,” the paper clarifies.

An almost complete rescue

The team reasoned that by boosting cholesterol redistribution during sleep loss, it would be possible to minimize or prevent myelin dysfunctions and restore optimal conduction velocity in rats. They performed a rescue experiment, administering 2-hydroxypropyl-β-cyclodextrin (cyclodextrin), a drug that promotes cholesterol redistribution to myelin membranes, via three subcutaneous injections during the 10-day sleep restriction.

When they measured cholesterol in purified myelin fractions afterward, the sleep-loss-plus-cyclodextrin group was statistically indistinguishable from normally sleeping controls: the drug completely prevented the myelin cholesterol depletion that sleep restriction would otherwise cause. Cyclodextrin partially fixed myelin ultrastructure, although it did not reduce the proportion of unmyelinated axons back to control levels, and it didn’t fully restore OPC density in the corpus callosum. The treated animals showed no significant change from baseline, meaning that the conduction delay was fully prevented.

Sleep loss cyclodextrin results

Importantly, the treatment also achieved behavioral rescue. For novel object recognition, sleep-restricted rats had a significantly reduced discrimination index (couldn’t distinguish new from familiar objects), but cyclodextrin-treated sleep-restricted rats performed comparably to controls. On the rotarod, where untreated sleep-restricted rats showed lower motor performance scores, the cyclodextrin group again performed at control levels. The authors note that since animals were given 24 hours of recovery before behavioral testing, residual physical fatigue is unlikely to explain the motor deficits.

Cyclodextrin, however, is not a precision tool. It facilitates broad cholesterol redistribution. While recent work suggests its effects are predominantly on oligodendrocytes, the authors admit that it also might be helping other cell types. While the rescue demonstrates that restoring cholesterol homeostasis is sufficient to prevent the behavioral deficits, further research is required to prove oligodendrocytes are the only cell population that matters.

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Literature

[1] Simayi, R., Ficiarà, E., Faniyan, O., Cerdán Cerdá, A., Aboufares El Alaoui, A., Fiorini, R., … & Bellesi, M. (2026). Sleep loss induces cholesterol-associated myelin dysfunction. Proceedings of the National Academy of Sciences, 123(4), e2523438123.

[2] Cappuccio, F. P., D’Elia, L., Strazzullo, P., & Miller, M. A. (2010). Sleep duration and all-cause mortality: a systematic review and meta-analysis of prospective studies. Sleep, 33(5), 585-592.

[3] Killgore, W. D. (2010). Effects of sleep deprivation on cognition. Progress in brain research, 185, 105-129.

[4] Shi, L., Chen, S. J., Ma, M. Y., Bao, Y. P., Han, Y., Wang, Y. M., … & Lu, L. (2018). Sleep disturbances increase the risk of dementia: a systematic review and meta-analysis Sleep medicine reviews, 40, 4-16.