“This film changed my life.”

It’s one of hundreds of messages we’ve received from people who’ve experienced Forever Young at a screening — and it’s responses like these that convinced us to start this Substack in the first place.

After years of research and countless conversations with dozens of the world’s leading longevity scientists, our award-winning documentary premieres on Apple TV on May 26th.

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Forever Young was financed independently, so the science could stay the star of the story — no studio notes, no sponsors or supplement companies shaping the narrative, no compromises. That independence is what made the film honest. It also means we don’t have a studio's marketing power. We have you.

Our mission with the film is to build a bridge between life-changing longevity science and the public, but in order to achieve this, we need your help.

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We all know someone who could use a boost of inspiration, a reminder that our genes are not our destiny, and the realization that this is the most exciting time to be alive in human history. Forever Young is essential viewing whether they’re new to longevity or deep in the science — and you and the people in your life are exactly who we made it for.

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The Forever Young Team

One in eight American men will be diagnosed with prostate cancer in his lifetime — and the actual number who carry cancer cells in the prostate at some point is far higher. Autopsy studies of men who died of unrelated causes have repeatedly found that by their seventies, more than a third already had cancer cells in their prostate. By 80, it is closer to six in ten. Most never knew, and most would never have needed to.

Almost no man is told this.

The biology explains why. Prostate cancer is unusual among cancers in that most cases are slow-growing. Pathologists grade prostate cancer on the Gleason score, a measure of how disorganized and aggressive the cells look under a microscope. High Gleason scores denote aggressiveness and lethality. Low-grade prostate cancers — the kind that turn up most often in autopsies of men who died of something else — can sit in place for decades without spreading and without causing symptoms. They are technically cancer, but they behave more like a mole than a tumor. The dangerous prostate cancers, the ones that kill 36,000 American men a year, are a different beast: high-grade, primitive, fast-dividing, prone to escape beyond the prostate and spread to bone. The biological gap between the two is enormous. The clinical tools to tell them apart, until very recently, were not.

That gap is the entire problem. For the last thirty years, telling a man he had cancer cells in his prostate would have caused more harm than good — because the medical system had no reliable way to tell a slow-growing tumor from a lethal one. The moment a man was told he had cancer, the system sprang into action. Surgery. Radiation. Incontinence. Impotence. By some estimates, between 42 and 66 percent of diagnosed prostate cancers would have caused no clinical harm if left alone. Hundreds of thousands of men were treated for cancers that were never going to kill them, and lived the rest of their lives with the consequences, which, for many men, were not mild.

For a decade, the system gave up. Men are dying for it.

Faced with this dilemma, the U.S. Preventive Services Task Force revised their guidance. In 2008 and again in 2012, USPSTF rated routine PSA screening at level “D,” recommending against routine use for most men, due to potential harms. Detection of prostate cancer collapsed, and prostate cancer incidence in the U.S., the number of new cases detected, dropped almost forty percent as a result. New prostate cancers still arose, but they were no longer being detected.

Then the bill came due. Distant-stage prostate cancer — the metastatic disease that actually kills men — has been climbing 4.6 to 4.8 percent per year. The sharpest increases are in men under 55. The American Cancer Society projects 36,320 American men will die of prostate cancer in 2026, more than the year before, and more than the year before that.

The medical system faced a binary choice - Option A was to screen for prostate cancer, treat everything that was found, and give some men, who were never under threat, impotence and incontinence. Option B was to omit screening and condemn some men to die from prostate cancer that would have been treatable, had it been found early enough. Until the system could more easily tell the difference between indolent and dangerous prostate cancer, there was no Option C.

But Option C has now arrived.

The cyclotron does what the PSA test never could.

A cyclotron — a particle accelerator about the size of a pickup truck, sitting in a hospital basement — produces radioactive isotopes with half-lives measured in hours. Chemists bind those isotopes to small molecules engineered to seek out a single protein: PSMA, prostate-specific membrane antigen, which prostate cancer cells display on their surface in vast quantities and almost no other cell type does.

Here’s how the test works: A man is injected with the cyclotron-generated tracer. An hour later, a PET scan lights up exactly where prostate cancer is — and, critically, how aggressive it looks. PSMA-PET (often combined with MRI) allows physicians to see in exquisite detail where prostate cancer resides. The same precision molecular targeting that picks out prostate cancer cells alone can be used to deliver a lethal payload exclusively to cells expressing PSMA - by linking the targeting molecule to a strong radioactive isotope, to a molecule of chemotherapy medicine, or to an antibody that will draw the attention of the body’s immune system to the cancer. All of these payloads are capable of killing prostate cancer cells while leaving neighboring normal tissue largely unaffected.

In March 2026, researchers at the European Association of Urology Congress in London presented a phase 3 trial showing that adding PSMA imaging to the diagnostic pathway reduced the number of prostate biopsies by roughly half, without missing clinically significant cancer. When the imaging finds something small and contained, focal therapies now exist that destroy only the lesion. The era of removing the entire gland to treat a few millimeters of disease is ending.

The question is no longer whether a man has cancer cells in his prostate. The question is the one that always mattered: Does he have cancer cells that threaten his life?

This is why screening is about to make sense again.

For a generation, an informed man had a defensible reason to avoid the PSA test - and, as we’ve seen, the U.S. government actively advised him to do so. The downstream consequences of a positive test result were often worse than the disease the test was designed to detect. But today, with precision imaging that can grade a lesion before anyone touches it, and treatments that can destroy the dangerous part of the prostate without destroying its function, the information from a regular screen is finally usable.

Evidence suggests that men in the high-risk window — particularly Black men, men with a family history, and men over 50 — should be having this conversation with their physicians now. Not in five years, when the guidelines catch up to the technology. Now.

The cells are already there in most aging men. For the first time, that fact is becoming useful information instead of a coin flip.

Picture the version of this that arrives within the decade. A man in his fifties walks into a clinic for an annual check. A blood draw, a brief scan, a conversation. If something is found, the imaging can inform his doctor about the probability that his disease is a slow lesion that requires surveillance or a life-threatening issue that merits treatment. If treatment is needed, it is targeted to a few millimeters of tissue, done in an outpatient visit, and he goes home the same day with his continence and sexual function intact. He repeats the screen at regular intervals. He never develops metastatic disease. He dies of something else, decades later.

That future is not theoretical. Every component of it exists in 2026, in working clinics, in published trials, in the hands of physicians treating real patients. What is missing is scale, awareness, and time. If even half of the 36,000 American men dying of prostate cancer each year were caught at this earlier window, the lives saved over a decade would exceed the population of a small city. Multiply that across the millions of men globally who never enter the screening conversation at all, and the number becomes one of the largest avoidable death tolls in modern medicine.

The prostate cancer oncology space is one of the fastest-moving areas of medicine today, with innovative diagnostic and therapeutic approaches proliferating like never before. The promise of these technologies is powerful, but the adversary they are directed against is complex and difficult to a degree that we should not underestimate. PSMA is an enormous advance, but up to 10% of prostate cancers don’t display PSMA at all, and so these cancers effectively disappear from the current PSMA radar. Once prostate cancer has embedded itself into bone, its favorite locations outside the prostate itself, treatment becomes enormously difficult, and the field still lacks viable treatments for the eradication of bony metastatic disease. As important an advance as PSMA is, there are still plenty of obstacles to overcome before we reach a future in which prostate cancer deaths are a thing of the past.

This Is Just the Beginning

The information gap between what longevity scientists know and what reaches the general public is the central problem of this revolution. Most men have spent the last decade being told screening is more trouble than it’s worth. The technology that made that true is being replaced — quietly, mostly out of public view.

Paid subscribers get new paradigm thinking, action protocols, deep dives, and exclusive scientist interviews — the full picture of what the longevity revolution actually means for your life. Science is moving fast. Don’t fall behind.

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Sources

American Cancer Society. Key Statistics for Prostate Cancer. Cancer Facts & Figures 2026. Atlanta: American Cancer Society; 2026.

Bell KJL, Del Mar C, Wright G, Dickinson J, Glasziou P. Prevalence of incidental prostate cancer: A systematic review of autopsy studies. International Journal of Cancer. 2015;137(7):1749–1757.

Jahn JL, Giovannucci EL, Stampfer MJ. The high prevalence of undiagnosed prostate cancer at autopsy: implications for epidemiology and treatment of prostate cancer in the prostate-specific antigen-era. International Journal of Cancer. 2015;137(12):2795–2802.

Buteau JB, et al. Impact of [68Ga]Ga-PSMA-11 PET/CT in the diagnosis of prostate cancer in men with equivocal or non-suspicious findings on multi-parametric MRI (PRIMARY2): A multi-centre, phase III, randomised trial. Presented at the 41st European Association of Urology Congress, London, March 13–16, 2026. Abstract GC26-006.

Loeb S, Bjurlin MA, Nicholson J, et al. Overdiagnosis and Overtreatment of Prostate Cancer. European Urology. 2014;65(6):1046–1055.

U.S. Preventive Services Task Force. Screening for Prostate Cancer: Recommendation Statement. Annals of Internal Medicine. 2012;157(2):120–134. (USPSTF Grade D recommendation, subsequently updated to Grade C in 2018 for men aged 55–69.)

Fenton JJ, Weyrich MS, Durbin S, et al. Prostate-Specific Antigen–Based Screening for Prostate Cancer: A Systematic Evidence Review for the U.S. Preventive Services Task Force. JAMA. 2018;319(18):1914–1931.

Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): A prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208–1216.

This article is for educational purposes only and is not medical advice. Discuss your individual screening and treatment decisions with your physician.

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Your spine is held upright right now by five biological systems firing in real time. None of them is under conscious control.

Most people think of posture as a habit. It isn’t. It’s a vital sign — a continuous readout of how those five systems are performing.

When the system ages, the spine bends forward. The shape most adults end up with by 70 isn’t bad luck. It’s the accumulated output of biological processes that begin in the third decade of life — and modern habits are accelerating the damage.

Posture Is the Real-Time Output of Five Biological Systems

Standing up is active work. The body delivers it through five integrated systems.

The paraspinal muscles — the erector spinae, multifidus, and deep spinal stabilizers — are slow-twitch fibers that fire constantly to hold the spine vertical. They function like guy-wires on a sailboat mast.

The intervertebral discs are pressurized, hydrated cushions that give the spine its curves: the inward sweep at the lower back, the outward arch through the chest, and the inward curve at the neck. As they lose water, the spine compresses and bends forward.

Proprioception, also called “joint position sense,” is an independent sensory system beyond sight, sound, smell, taste, and touch. Sensors in your muscles, tendons, and joints continually report the degree to which all of your joints are extended or contracted, telling your brain exactly where your limbs are located in space.

The vestibular system, in the inner ear, senses gravity and acceleration, telling the brain which way is up, which is down, and whether you are changing velocities in any direction.

Visual input provides constant orientation, showing your brain exactly where you are in space, your position, how fast you are moving, and where your limbs are. Research suggests vision plays a major role in postural control.

Lose any one of these systems and the spine begins to fold.

Good Posture Is a Vital Sign That Medicine Rarely Tracks

The simple act of standing up straight for ten seconds launches a cascade of biological changes.

The diaphragm drops further into the abdomen. The rib cage expands an extra inch in every direction. The amount of air the lungs can hold goes up. The heart, which had been pumping against a compressed chest cavity, suddenly has room to work. The vertebral arteries threading through the neck — the ones feeding the back of the brain — stop being slightly kinked. Half a dozen systems improve in the same instant.

Slump back into a forward-curved position, and all of it reverses.

Posture isn’t decorative. It’s the position the body holds for sixteen hours a day, and every system running through the torso is helped or hindered by it. Slow-twitch muscles along the spine fire more intensely when the body is upright, which helps keep them from being gradually replaced by fat — a process called spinal sarcopenia. Researchers studying embodied cognition have found that upright posture lowers cortisol and lifts mood within minutes. Even the gut moves food differently depending on how compressed the abdomen is.

A doctor will check blood pressure, pulse, temperature, and breathing rate at every visit. Nobody will look at how the patient is sitting in the chair.

Four Mechanisms Drive the Forward Curve

Four mechanisms pull the spine forward with age.

Spinal sarcopenia. The paraspinal muscles undergo accelerated atrophy beginning in midlife. A 2024 study found severe fatty infiltration of the multifidus, even in patients without generalized muscle loss elsewhere — meaning the spinal extensors can fail before the rest of the body shows signs of decline.

Disc dehydration. Intervertebral discs lose water beginning in the third decade. Anterior disc height shrinks faster than posterior, turning each disc into a wedge that tilts up the back end of each vertebral body — turning the thoracic spine into a forward curve known medically as kyphosis, and less glamorously as “dowager’s hump.”

Vertebral wedging. Even without overt fractures, vertebral bodies undergo subtle wedging with age. A 2017 narrative review found that 60 to 70 percent of severe kyphosis cases occur without vertebral compression fractures. The forward curve is primarily a soft-tissue and muscle problem, not a bone one.

Proprioceptive decline. With age, the brain receives degraded position signals. People lose track of where their body is in space, and postural compensations begin without their awareness.

Sitting and Screens Accelerate All Four Mechanisms

The modern workday combines two postures that compound the damage: long hours seated and long hours looking down at a screen.

Eight hours a day in a chair leaves the spinal extensors unloaded. The muscles receive the signal that they aren’t needed and atrophy more quickly. A January 2024 cohort study by Gao and colleagues followed 481,688 adults for nearly 13 years and found that those who predominantly sat at work had 16 percent higher all-cause mortality and 34 percent higher cardiovascular mortality.

Screen time piles on. The average US adult spends roughly 7 hours a day on screens; Gen Z averages closer to 9. Most of that time, the head is tilted forward, and the human head is essentially a 12-pound bowling ball perched on top of a narrow column of bone. Biomechanical modeling estimates that a 60-degree forward tilt — the angle most people use to scroll a phone — multiplies the load on the cervical spine roughly fivefold. An October 2025 radiographic study found measurable changes in cervical alignment among healthy young adults during active texting.

The 70-year-old spine is no longer a problem that only occurs at 70. So how do you know if yours is already on the way?

A Stack of Books Can Reveal Your Risk

Try this tonight. Lie flat on your back on a hardwood floor, arms at your sides, no pillow. Let your head fall where it wants.

If the back of your head touches the floor and your eyes look straight at the ceiling, your spine is in neutral. If your chin tilts up and the back of your head hovers above the floor, slide paperback books under your head one at a time until your gaze levels out. Count them.

Zero books = neutral. One or more = hyperkyphotic.

The protocol comes from Deborah Kado’s research at UCLA. In her 2004 cohort, 44 percent of men over 65 needed at least one book.

So why does this matter?

Hyperkyphotic Posture Predicts a 1.44× Higher Mortality Rate

People with hyperkyphotic posture die earlier than people without it.

Three separate Kado cohort studies have reached the same conclusion. The 2004 Rancho Bernardo study — the source of the blocks test — found a 1.44-fold higher mortality rate in adults with the forward curve, after adjustment for age and sex. A 2009 follow-up confirmed the finding held even after controlling for vertebral fractures and bone density. A 2022 replication in 2,931 older men found the same pattern.

The mechanism is mostly pulmonary. A folded thorax compresses the rib cage, the lungs can’t fully expand, and vital capacity drops. In severe cases, hyperkyphosis specifically predicts a pulmonary cause of death.

Forward head posture from screens shows up in young adults the same way: a 2024 systematic review found reductions in forced vital capacity of 0.25 to 0.81 liters compared with neutral controls. The same compression pathway, decades earlier.

The shape of your spine is, quite literally, the shape of your future lung function.

The Forward Curve Reverses

Here’s the good news: hyperkyphosis is one of the rare aging biomarkers that responds to exercise alone — no prescription, no surgery, no clinic visits.

Three randomized trials make the case. In 2009, Gail Greendale’s team at UCLA put 118 adults over 60 through six months of yoga, and their kyphosis measurably improved. In 2017, the SHEAF trial showed the same with targeted spine-strengthening: three sessions a week with a physical therapist for six months, with a measurable reversal.

The most remarkable finding comes from Mehrsheed Sinaki at the Mayo Clinic. Sinaki had postmenopausal women do one exercise — prone trunk extension — five times a week for a single year. Ten years later, those women had significantly fewer vertebral compression fractures, even though most had long since stopped exercising.

A year of work bought a decade of structural protection.

Paid subscribers get the full five-move protocol used in the Greendale, Katzman, and Sinaki trials, plus the desk-and-screen setup that cuts daily cervical load — and the equipment list that earns its place in a longevity-minded home.

The Five-Move Protocol

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Two curves are rising at the same time, and the world hasn’t yet caught up to the implications of their convergence.

The first is artificial intelligence. The Stanford HAI 2026 AI Index reports organizational adoption at 88 percent, with generative AI reaching 53 percent of the population within three years — faster than the personal computer or the internet at comparable points in their respective curves. The second is human longevity. Researchers at the Buck Institute, the Salk Institute, and a constellation of laboratories around the world are reframing aging as a modifiable biological process, redrawing the boundaries of how long and how well we are likely to live.

AI hit 53 percent of the population faster than the internet

The cognitive revolution is no longer a future to anticipate. It is the current infrastructure.

Stanford’s 2026 AI Index documents a deployment curve that outruns every prior general-purpose technology in the modern record. Organizational adoption stands at 88 percent. Four in five university students now use generative AI for coursework. The estimated value of generative AI tools to U.S. consumers reached $172 billion annually by early 2026, with the median per-user value tripling between 2025 and 2026.

In medicine, the change is concrete. CRISPR-GPT, an LLM agent system developed by researchers at Stanford, Princeton, and Google DeepMind and published in Nature Biomedical Engineering in 2025, enables novice researchers to design and execute gene-editing experiments that previously required deep expertise and weeks of iteration. A generative radiology system deployed at Northwestern Medicine produced an average 15.5 percent gain in radiologist efficiency, with some radiologists reaching 40 percent, all without loss of diagnostic accuracy. The pattern is consistent: cognitive work that used to be the province of long-trained specialists is becoming faster, more accessible, and more reliable in the hands of anyone with the right system at their side.

Aging is now treated as modifiable, not inherited

The longevity revolution is the less visible of the two, but no less consequential. A growing scientific consensus now treats aging as a modifiable process rather than a fixed biological inheritance. Lifestyle, environment, sleep, metabolic health, social connection, and the chemistry of inflammation are not merely incidental contributors to lifespan. They are levers — and the levers are within reach.

We are gaining cognitive capacity through AI. We are gaining biological durability through longevity science. Both converge on the same prior question: capacity for what? Durability for what?

Across 87 years, one factor predicts who stays healthy

The Harvard Study of Adult Development, ongoing since 1938 and the longest in-depth longitudinal study of human life ever conducted, has reached a singular and durable conclusion: the quality of our close relationships is the single best predictor of health and happiness across the lifespan. Better than wealth, IQ, or social class. Participants who reported strong, satisfying relationships at age 50 were the healthiest at age 80. Their relationships protected them, measurably, against heart disease, diabetes, and cognitive decline. The current director, Dr. Robert Waldinger, summarizes it bluntly: loneliness kills.

In A General Theory of Love, psychiatrists Thomas Lewis, Fari Amini, and Richard Lannon described what their research at UC San Francisco had revealed: human nervous systems are not self-contained. We co-regulate. The presence of trusted others measurably alters our heart rate, our cortisol levels, and the architecture of our emotional response. Connection is not a feeling we have; it is a physiological state that we are.

The World Health Organization has now formalized the finding. The June 2025 report of the WHO Commission on Social Connection attributes 871,000 deaths annually to the physiological effects of loneliness — roughly 100 every hour. The Commission ties loneliness directly to cardiovascular disease, type 2 diabetes, cognitive decline, and early mortality, with health effects that the report compares to — and in some cases finds exceeding — those of smoking and obesity. In May 2025, the World Health Assembly passed its first-ever resolution on social connection, urging Member States to develop evidence-based policies to address it.

Connection is the third pillar of health, alongside physical and mental well-being.

Therapy is now the #1 use of generative AI

Marc Zao-Sanders’ April 2025 analysis published in Harvard Business Review, “How People Are Really Using Gen AI in 2025,” found that “Therapy/Companionship” had become the #1 use case for generative AI globally, with the broader category of personal and professional support accounting for 31 percent of all use, nearly double its 17 percent share in 2024. Workday’s January 2025 study, Elevating Human Potential: The AI Skills Revolution, found that 82 percent of individual contributors believe employees will increasingly crave human connection as AI becomes more integrated into work. Only 65 percent of managers agreed.

People are turning to AI to fill a gap that their lives no longer reliably provide. We have a relational deficit at the civilizational scale, and given what the WHO has now told us, that deficit is also a public health crisis. It is showing up in our deployment data because, in too many lives, it has nowhere else to go.

Raise AI the way we raise children — by transmitting what we’ve learned

As AI systems become more capable and more deeply integrated into human decision-making, the clean line between biological and synthetic minds will become harder to draw. That isn’t a reason for fear, or for retreat into claims of permanent human uniqueness. It is a reason to pay close attention to what we transmit to these systems, and how.

This is the insight at the core of David Brin’s argument. In his 2023 Wired essay “Give Every AI a Soul, or Else,” and at greater length in his 2025 book Ailien Minds, Brin makes the case that the best path to AI alignment is not to constrain these systems with rules they will eventually find ways around, but to raise them as members of our civilization. We should extend to them the practices that, across human history, have actually produced beings capable of living well alongside one another: individuated identity, reciprocal accountability, values transmitted through cultivation rather than coercion, and the deliberate inheritance of what we have learned about flourishing.

The strength of Brin’s frame lies in its ability to dissolve a false binary. The values we should be teaching these systems — the centrality of connection, the discipline of attention, the priority of meaning over mere optimization, the orientation of the self toward something beyond itself — are not values we hold against AI. They are the values we have learned about ourselves, painfully, across millennia. And as longevity science is now confirming, they are also the values that produce the longest and healthiest human lives.

Relational infrastructure is now infrastructure

We are investing at unprecedented scale in cognitive infrastructure through AI and in biological infrastructure through longevity science. We need to invest at the same scale in relational infrastructure — in the conditions that make deep human connection possible, sustained, and honored. The Harvard Study, the WHO Commission, and the molecular biology of aging are converging on the same finding: relational health is health. That means protected time, renewed community institutions, and strengthened family and intergenerational bonds.

It also means being clear-eyed about what we are teaching the systems we build. Every model is a mirror of the values we transmit to it. If we want AI that supports human flourishing, we first have to know what human flourishing actually requires. The question of AI alignment and the question of human well-being turn out, at root, to be the same question.

Viktor Frankl observed in 1946 that meaning is found not by turning the self inward but by giving the self to something beyond itself. That insight is now inscribed in the data — in the Harvard Study, in the WHO Commission, in the Lewis neuroscience, in the deployment patterns of our most powerful new tools. His insight applies as fully to the systems we are building as to the lives we are extending.

The two curves are not threats. They are an inheritance. The years we add to human life will only matter if the connections that make life worth living are there to fill them. That is the work.

This is a guest contributor post:

Author

Dr. Dennis A. Trinkle is a technology executive, serial entrepreneur, and historian of innovation, science, technology, and medicine. He is President and CEO of TechIndiana, Indiana’s employer-led talent engine for the AI era, and Professor of Information and Communication Sciences at Ball State University. He writes about the convergence of synthetic intelligence, longevity science, and human connection, and can be found on LinkedIn here.

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Sources

Brin, David. “Give Every AI a Soul, or Else.” Wired, July 2023.

Brin, David. Ailien Minds: Advice about — and for — Our Natural, AI and Hybrid Heirs. San Diego: Self-published, 2025.

Frankl, Viktor E. Man’s Search for Meaning. Boston: Beacon Press, 1959. (Originally published in German, 1946.)

Huang, Jonathan, et al. “Efficiency and Quality of Generative AI–Assisted Radiograph Reporting.” JAMA Network Open, June 5, 2025. https://doi.org/10.1001/jamanetworkopen.2025.13921

Lewis, Thomas, Fari Amini, and Richard Lannon. A General Theory of Love. New York: Random House, 2000.

Qu, Yuanhao, Kaixuan Huang, et al. “CRISPR-GPT for agentic automation of gene-editing experiments.” Nature Biomedical Engineering, July 30, 2025. https://doi.org/10.1038/s41551-025-01463-z

Stanford Institute for Human-Centered Artificial Intelligence (HAI). 2026 AI Index Report. Stanford University, April 2026. https://hai.stanford.edu/ai-index/2026-ai-index-report

Waldinger, Robert, and Marc Schulz. The Good Life: Lessons from the World’s Longest Scientific Study of Happiness. New York: Simon & Schuster, 2023.

Workday, Inc. Elevating Human Potential: The AI Skills Revolution. Pleasanton, CA: Workday, January 14, 2025. https://newsroom.workday.com/2025-01-14-New-Global-Research-from-Workday-Reveals-AI-Will-Ignite-a-Human-Skills-Revolution

World Health Organization Commission on Social Connection. From Loneliness to Social Connection: Charting a Path to Healthier Societies. Geneva: WHO, June 30, 2025. https://www.who.int/groups/commission-on-social-connection/report

Zao-Sanders, Marc. “How People Are Really Using Gen AI in 2025.” Harvard Business Review, April 9, 2025. https://hbr.org/2025/04/how-people-are-really-using-gen-ai-in-2025

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Magnesium might be the most underrated mineral in the human body. It’s a cofactor in over 300 enzymatic reactions. Every time a cell produces energy — every muscle contraction, every nerve signal, every heartbeat — magnesium is part of the machinery. ATP, the molecule that fuels almost everything you do, only works when bound to a magnesium ion. The same mineral sits at the structural center of chlorophyll, which is why every green plant on earth is green.

Magnesium gets its name from a region in ancient Thessaly known as “Magnesia,” named after the tribe that inhabited it, the Magnetes. Minerals and ores from this region were known to the ancient Greeks as “Magnesian stones,” which included compounds such as magnesium carbonate and what we would recognize as magnetic iron ores. So while magnets do not contain magnesium at all, they share the same linguistic root.

Without enough magnesium in your body, you can’t sleep well. Your blood pressure drifts up. Your muscles cramp. Your stress response stays stuck in the on position. Over the years, low magnesium has been linked in large national datasets to a higher risk of cardiovascular disease, type 2 diabetes, metabolic syndrome, dementia, and stroke.

In the brain, magnesium plays a role in a variety of functions: magnesium supports synaptic plasticity, modulates NMDA receptors, reduces neuroinflammation, dampens oxidative stress, inhibits amyloid-beta accumulation, and helps maintain blood-brain barrier function.

And yet around half of American adults don’t get enough magnesium. The most recent national survey found 57% of men and 52% of women fell below the threshold of adequate intake.

Why We Run Short

Magnesium has been quietly leaving the food supply for decades. Industrial agriculture has stripped it from the soil. Refining whole grains into flour removes most of what’s left. Processed foods, which now make up the majority of American calories, contain little to begin with. Even people eating what seems like a reasonable diet often fall short, because so much magnesium has been removed from the food we eat.

The body also bleeds magnesium under stress. Cortisol increases urinary excretion. Caffeine and alcohol do the same. Common medications — proton pump inhibitors (PPIs) for acid reflux, diuretics for blood pressure, certain antibiotics — all reduce absorption or increase loss. PPIs are particularly problematic – a recent meta-analysis found that about 20% of patients on PPIs have magnesium levels that are below the lower limit of what’s considered normal.

Aging makes the problem worse on every front. Stomach acid levels decline, which weakens the absorption of inorganic forms of magnesium. Kidney conservation drops. Older adults are also more likely to be on multiple medications that deplete the mineral. By the time most people are in their seventies, the gap between what their bodies need and what they’re getting has widened considerably.

The Form Matters More Than the Dose

So millions of people supplement. Walk into any pharmacy, and you’ll find dozens of magnesium products in tablets, capsules, powders, and gummies. The trouble is that the form most of those bottles contain is the form the body absorbs the worst.

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The supplement aisle for joint pain is a graveyard of failed theories. Glucosamine, chondroitin, collagen, MSM, turmeric, fish oil, vitamin D—the list runs the length of an aisle. Almost none of those compounds help with osteoarthritis, and every major medical guideline worldwide says as much.

One compound may break the pattern. It does not appear in the joint-health section. It is a molecule produced by gut bacteria from polyphenols in pomegranates, walnuts, and berries, and most adults cannot make it efficiently on their own. In cartilage cells taken from human osteoarthritis patients, it does what every supplement before it has failed to do.

The supplements every major guideline recommends against

Osteoarthritis affects 595 million people worldwide, roughly 7.6 percent of the global population, and the number keeps rising. It is the leading cause of long-term joint pain in adults and a major driver of joint replacement surgery. No approved disease-modifying treatment exists.

Into that void has poured the joint-health supplement industry. The 2019 American College of Rheumatology and Arthritis Foundation guideline strongly recommends against glucosamine for hand, hip, and knee osteoarthritis, and strongly recommends against chondroitin for knee and hip osteoarthritis. The 2019 Osteoarthritis Research Society International guideline reached the same conclusion for knee osteoarthritis. A 2023 systematic review of all major osteoarthritis guidelines worldwide found that none recommended any nutraceutical.

The reason those supplements failed is the same reason the aisle is still full of them: they were built on a disease model that is no longer accurate.

Osteoarthritis is a mitochondrial disease

The traditional picture of osteoarthritis treats it as mechanical wear. Cartilage wears down, and the joint runs out of cushioning. The supplement logic followed: feed the joint the chemical building blocks of cartilage, and it will rebuild. Glucosamine and chondroitin are both components of the cartilage matrix.

Cartilage is not inert. It is maintained by cells called chondrocytes, which run on mitochondria—the cell’s powerhouses. As tissue ages, mitochondria accumulate damage. Healthy cells dispose of damaged mitochondria through a recycling process called mitophagy. When mitophagy fails, damaged mitochondria accumulate. Cells lose energy, stop producing cartilage matrix, leak inflammatory signals, and enter senescence.

Osteoarthritis is not a materials shortage. It is a cellular-energy failure.

Most adults cannot make Urolithin A from pomegranates

Urolithin A is a postbiotic—a small molecule produced by gut bacteria during the fermentation of ellagitannins, a class of plant compounds found in pomegranates, walnuts, strawberries, and raspberries. The molecule itself does not exist in the food.

In 2016, researchers at the École Polytechnique Fédérale de Lausanne identified Urolithin A as the first natural compound shown to induce mitophagy in a living animal. Worms given the compound accumulated fewer damaged mitochondria with age and lived longer. Mice given it recovered muscle function. Translating those results to humans proved problematic: most people do not produce enough Urolithin A from food to replicate the effect.

Adults fall into three urolithin metabotypes. About a third produce Urolithin A efficiently from dietary precursors. Another third produces a mixed pattern of related molecules with smaller amounts of Urolithin A. The remaining third—metabotype 0—produces no urolithins at all, no matter how many pomegranates they eat. The trait is determined by the composition of gut bacteria, and its capacity declines with age. A 2021 study of 100 healthy adults found that only 12 percent had detectable Urolithin A in their blood at baseline; even after a glass of pomegranate juice, only about 40 percent meaningfully converted the precursors.

Direct supplementation bypasses the gut entirely, delivering the finished molecule.

What happens when you give Urolithin A to human osteoarthritis cells

In 2022, a team led by Davide D’Amico took chondrocytes from the knee joints of patients with osteoarthritis—not healthy donors, not animal surrogates, but living cells from people with the disease. Treatment with Urolithin A restored mitochondrial respiration and reactivated mitophagy. In a parallel mouse model of post-traumatic osteoarthritis, the compound reduced cartilage degeneration, lowered synovial inflammation, and decreased pain-related behaviors.

Later studies built on that finding through different mechanisms. A 2024 paper used a targeted delivery system to deliver Urolithin A directly to chondrocytes in a rat osteoarthritis model and demonstrated protection against cartilage breakdown. A 2025 study traced the compound’s protective effect to suppression of ferroptosis, a form of iron-dependent cell death now linked to osteoarthritis. A separate 2025 paper using a lipid nanoparticle delivery in a mouse osteoarthritis model reported reduced inflammation and slowed disease progression.

Different delivery systems, different mechanisms, the same finding: the cells that maintain cartilage stay alive longer and function better in the presence of Urolithin A.

NSAIDs harm 13 to 15 percent of users

The current standard of care for osteoarthritis pain short of surgery is non-steroidal anti-inflammatory drugs (NSAIDs)—ibuprofen, naproxen, celecoxib, diclofenac. They reduce pain effectively, and they carry a long tail of harm. Roughly 13 to 15 percent of NSAID users develop upper gastrointestinal adverse effects. NSAIDs account for about 30 percent of hospital admissions for adverse drug reactions. All prescription versions carry an FDA black-box warning for cardiovascular risk. A 2024 study tracking more than 4,000 people with knee osteoarthritis found that long-term NSAID users were roughly twice as likely to experience worsening pain and disability over four to five years as non-users.

Urolithin A shows a different pattern. The first-in-human trial established it as safe and bioavailable in healthy older adults at daily doses up to 1,000 milligrams. The compound has an FDA Generally Recognized as Safe status. A 2022 randomized trial in 88 middle-aged adults reported roughly 12 percent improvement in leg muscle strength with no serious adverse events. A 2022 randomized trial in 66 older adults aged 65 to 90 reported improved muscle endurance and lower inflammatory markers. A November 2025 Nature Aging trial reported improvements in immune cell function in 50 middle-aged adults.

For a compound a person might take for years, the safety profile is the argument.

The clinical trial that has not been done

No published randomized controlled trial has tested Urolithin A specifically for osteoarthritis pain or joint function in humans. The available evidence is mechanistic in human osteoarthritic cells, efficacious in multiple animal models, and safe across human trials of other endpoints.

That gap cuts both ways. Nobody can yet claim Urolithin A has been proven to treat osteoarthritis in people. Nobody can reasonably group it with the failed supplements either. The biological, human cell, and animal outcome data are of a different kind from anything else sold for joint health. What remains is for a randomized trial to settle it.

Get in the Game

Urolithin A is one of many compounds in a growing list that are reshaping longevity medicine. Rapamycin. Metformin. Bisphosphonates. Each was developed for something else. Each turns out to target the biology of aging itself. Forever Young is tracking these drugs one by one in our ongoing series on the compounds changing the landscape of longevity medicine. The list keeps growing.

The longevity revolution is moving fast. Don’t fall behind.

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Medical disclaimer: This article is for informational purposes only and is not medical advice. The evidence on Urolithin A and osteoarthritis is mechanistic and preclinical; no published clinical trial has yet tested it for osteoarthritis outcomes in humans. Anyone considering adding a supplement to manage joint pain or any other condition should discuss it with their physician, particularly if they take prescription medication or have a chronic illness.

Sources

Kolasinski SL, Neogi T, Hochberg MC, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee. Arthritis & Rheumatology. 2020;72(2):220–233.

Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis and Cartilage. 2019;27(11):1578–1589.

Steinmetz JD, Culbreth GT, Haile LM, et al. Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet Rheumatology. 2023;5(9):e508–e522.

Ryu D, Mouchiroud L, Andreux PA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nature Medicine. 2016;22(8):879–888.

D’Amico D, Olmer M, Fouassier AM, et al. Urolithin A improves mitochondrial health, reduces cartilage degeneration, and alleviates pain in osteoarthritis. Aging Cell. 2022;21(8):e13662.

Andreux PA, Blanco-Bose W, Ryu D, et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nature Metabolism. 2019;1(6):595–603.

Singh A, D’Amico D, Andreux PA, et al. Urolithin A improves muscle strength, exercise performance, and biomarkers of mitochondrial health in a randomized trial in middle-aged adults. Cell Reports Medicine. 2022;3(5):100633.

Liu S, D’Amico D, Shankland E, et al. Effect of Urolithin A Supplementation on Muscle Endurance and Mitochondrial Health in Older Adults: A Randomized Clinical Trial. JAMA Network Open. 2022;5(1):e2144279.

Singh A, D’Amico D, Andreux PA, et al. Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population. European Journal of Clinical Nutrition. 2022;76(2):297–308.

Denk D, Singh A, Kasler HG, et al. Effect of the mitophagy inducer urolithin A on age-related immune decline: a randomized, placebo-controlled trial. Nature Aging. 2025;5(11):2309–2322.

Chen L, Yang J, Cai Z, et al. Mitochondrial-Oriented Injectable Hydrogel Microspheres Maintain Homeostasis of Chondrocyte Metabolism to Promote Subcellular Therapy in Osteoarthritis. Research. 2024;7:0306.

Wang X, Xu Q, Huang J, et al. Urolithin A protects mice against osteoarthritis by inhibiting chondrocyte ferroptosis through activating AMPK/mTOR/HIF-1α signaling pathway. Journal of Nutritional Biochemistry. 2025;147:110111.

Yi G, Li M, Zhou J, et al. Novel pH-responsive lipid nanoparticles deliver UA-mediated mitophagy and ferroptosis for osteoarthritis treatment. Materials Today Bio. 2025;32:101697.

Mehta P, Dhapte-Pawar V, Sykes K, et al. Association of long-term use of non-steroidal anti-inflammatory drugs with knee osteoarthritis: a prospective multi-cohort study over 4-to-5 years. Scientific Reports. 2024;14:6440.

Cortés-Martín A, Selma MV, Tomás-Barberán FA, González-Sarrías A, Espín JC. Where to Look into the Puzzle of Polyphenols and Health? The Postbiotics and Gut Microbiota Associated with Human Metabotypes. Molecular Nutrition & Food Research. 2020;64(9):1900952.

A strange silence is spreading across the developed world. It is the silence of the unborn children who are not coming, the families that are not forming, the cradles that remain empty by choice. Fertility rates have fallen below replacement level not just in Europe and America but in South Korea, Brazil, Iran, and China, countries with vastly different economies, politics, and cultures. In his Foreign Affairs essay “The Age of Depopulation” (2024), Nicholas Eberstadt, the demographer and Henry Wendt Chair in Political Economy at the American Enterprise Institute, documents what he calls a near-universal march toward below-replacement fertility, and asks the question that most policymakers are too timid to confront: why, in an era of unprecedented prosperity and freedom, are women choosing not to have children?

Now that we are living longer lives, these questions are even more pressing.

Various answers have been put forth, i.e., the cost of housing, the burden of student debt, and the absence of affordable childcare. They are not wrong, but they are insufficient. In his National Affairs essay “The Future of Global Population,” Eberstadt examines income, education, urbanization, and the status of women as candidate explanations and finds them all wanting as standalone accounts. They treat fertility decline as a logistical problem awaiting a logistical solution, when in fact something far deeper is at work. The crisis is a cultural one, rather than a financial one. It is that the cultural conditions that once made motherhood genuinely meaningful, enjoyable, and dignified have been systematically dismantled, and replaced with a social environment that is, in almost every way, hostile to the quiet, unhurried, demanding work of raising children.

This is, at its root, a crisis of hierarchy. Every civilization operates with an implicit answer to the question: what matters most? For most of human history, across wildly different cultures and creeds, that answer placed love, family, and human connection at the apex of human existence. This is not because people were unambitious, but because these were understood as the arena in which life’s deepest experiences occurred: sacrifice, loyalty, unconditional love, legacy, and belonging. The modern West has quietly but decisively inverted that hierarchy. At the top now sit career achievement, personal branding, self-optimization, and the ceaseless pursuit of individual experience. Children, who demand exactly the opposite of all those things, requiring the surrender of optionality, the subordination of self, and the patient investment of love that yields no monetizable return, have become almost irrational within this new ordering of goods. Until we name that inversion honestly, no legislation will reverse the trend.

The Pressure on the Modern Woman

Begin with the woman herself, because the cultural pressures converging on her are extraordinary in their cumulative weight. She is asked, simultaneously, to be a serious professional whose career reflects her intelligence and ambition; an emotionally present, developmentally attentive mother whose children are thriving by every measurable metric; a physically vital and attractive partner; and, increasingly, a curated public persona whose life looks aspirational from the outside. These demands do not merely compete for her time. They compete for her identity. And they have created a double bind from which there is no clean exit: pursue career aggressively and feel the guilt of the absent mother; lean into family and feel the anxiety of the underachieving professional.

Social media has made this bind nearly unbearable. The Instagram mother is always present, always patient, always creative; her children’s lunches are artful, her family vacations are luminous, her postpartum body is recovered. She is, of course, a fiction, but one real mothers measure themselves against daily. The result is that the actual texture of motherhood, the tedium, the mess, the grinding exhaustion punctuated by moments of piercing joy, feels like failure by comparison. In The Anxious Generation (2024), social psychologist Jonathan Haidt documents how platforms redesigned in the early 2010s shifted from tools for connection into engines of social comparison and public performance, reshaping self-perception among young women with particular force. Women absorb this message from an early age, and many conclude, not unreasonably, that they are not equipped for a task whose bar has been set at an inhuman height. It is the perfect trap.

The Colonization of Family Life

Even for women who want children and have them, the conditions necessary to find deep satisfaction in motherhood have been eroded. The family’s domestic life, its time, attention, and interior space, has been colonized by forces that present themselves as enrichment but function as fragmentation.

Consider youth sports, which have undergone a transformation so gradual that few have stopped to name what has been lost. What began as wholesome recreation has become, in one generation, a semi-professional, year-round, enormously expensive industry that consumes families rather than building them. Weekends that might have been lazy and unstructured, the kind of time when children and parents actually talk, when family identity forms, and when creativity percolates, are now scheduled to the hour with travel tournaments and training sessions. And this is, crucially, framed as good parenting, as an investment in the child’s development and future. To opt out is to risk your child falling behind. The logic is airtight, and the cost is invisible. It is the slow disappearance of unhurried family life that, in fact, most people remember with love.

The entertainment and attention economy compounds this. The family home, which once functioned as a protected sanctuary, a space with its own rhythms, rituals, and culture, is now a site of constant commercial competition. Streaming services, social media platforms, and gaming ecosystems are designed by some of the world’s most sophisticated engineers and psychologists to capture and hold attention. They compete directly with the unmediated experience of family presence, and they are very good at winning. A father and son in the same room but on separate screens are not, in any meaningful sense, together.

Here, the displacement of intimacy by digital life enters the picture not just as a family problem but as a demographic one. According to the General Social Survey, the share of young adults ages 18 to 29 who reported no sexual activity in the past year doubled from 12% in 2010 to 24% in 2024, a pattern the Institute for Family Studies links directly to the rise of digital substitutes and declining rates of committed relationships. This sits uncomfortably alongside cultural assumptions about liberated modern sexuality. The young men and women most likely to seek genuine connection are also among the most susceptible to the anesthetic pleasures of digital worlds that deliver stimulation without vulnerability, excitement without risk, and the simulation of intimacy without its cost. The result is a generation in which genuine erotic and romantic encounters, the precondition for family formation, are happening less often.

The Loss of Sacred Time

The decline in religion deserves particular attention, because the Sabbath, in whatever tradition it took, was historically the one institution powerful enough to impose protected family time and invest it with cosmic significance. The Sabbath said, in effect, this time is not yours to optimize or monetize. It belongs to something larger. In How the West Really Lost God (Templeton Press, 2013), Mary Eberstadt argues that religious decline and family decline are not merely correlated; they operate as what she calls “the double helix of society,” each dependent on the strength of the other for successful reproduction, and each accelerating the other’s collapse. When the Sabbath goes, the last structural defense against the colonization of family time goes with it. What remains is a set of private preferences competing against billion-dollar industries, and private preferences lose.

Into this vacuum has rushed what Abigail Schrier documents with uncomfortable precision in Bad Therapy: Why the Kids Aren’t Growing Up (Sentinel, 2024): the displacement of maternal authority by a vast apparatus of professional expertise. A generation of parents, Schrier shows, has come to view the exercise of authority as an outmoded power move, turning instead to therapists, school counselors, pediatricians, parenting coaches, and social media commentators who now occupy the space once held by mothers and grandmothers as the unquestioned authorities on child-rearing. The mother’s instinct, her felt sense of what her child needs, is now subject to constant second-guessing by credentials she does not hold and frameworks she did not choose. When a mother’s judgment is systematically treated as insufficient, the dignity of motherhood erodes. A vocation that society treats as requiring constant external supervision and correction cannot maintain societal respect. Dignity and respect are essential for meaning.

What Has Happened to Men

No account of falling fertility is complete without an honest reckoning with what has happened to men, because women do not form families alone, and the conditions under which they might feel safe and willing to do so depend partly on what men are able and willing to offer.

Two forces have converged to undermine male partnership in family formation. The first is structural and economic. In Men Without Work (Templeton Press, 2016, updated 2022), Eberstadt documents what he calls an invisible national crisis. Between 1965 and 2015, work rates for American men of prime working age spiraled relentlessly downward, reaching levels lower than those of 1940, at the tail end of the Great Depression. The Milken Institute Review adds that median male income, measured in inflation-adjusted dollars, in 2018 was just 2% higher than in 1973, with less-educated men experiencing outright real declines. The provider role, never the whole of fatherhood, but historically one of its anchoring functions, has become genuinely harder to fulfill. Men are operating in an economy that has made the traditional markers of male readiness for family life increasingly unattainable.

The second force is cultural. The framework of toxic masculinity, whatever its legitimate applications, has had the broader effect of rendering male protectiveness and provision culturally suspect. The instinct to provide, to protect, to take responsibility for a family’s security, instincts that for most of human history were understood as virtues, are now refracted through a lens of suspicion. Young men absorb this, and some respond by withdrawing from the very roles that family formation requires. Young women absorb it too, and some respond by viewing the offer of male protection not as reassurance but as a red flag. The result is a cultural atmosphere in which one of the foundational conditions for confident family formation, a woman feeling genuinely safe, partnered, and provided for, has become harder to achieve from both directions at once.

The Paradox of Modern Misery

There is a paradox at the heart of modern misery that our culture has not yet found the courage to name. We are, by material measures, the most comfortable human beings who have ever lived, and we are also among the most restless, the most medicated, the most rootless. The self-help industry, which generates billions of dollars annually, is premised on the assumption that the path to fulfillment runs through the self: through its optimization, its healing, its expression, its liberation. And yet the more assiduously we tend the self, the more elusive satisfaction becomes.

Viktor Frankl, who had seen human beings at their most stripped and suffering, understood why. In Man’s Search for Meaning (Beacon Press, 1959), he argued that meaning cannot be pursued directly; it can only be found as a byproduct of giving the self to something beyond itself. Self-transcendence, in Frankl’s framework, is the psychological oxygen without which the human person slowly suffocates. Through this lens, it is clear that a culture that turns the self perpetually back toward itself, that makes self-care its highest ethic and personal fulfillment its ultimate goal, is a culture of imprisonment rather than liberation.

Motherhood has always been the quintessential practice of self-transcendence. Not in a sentimental sense, but in a rigorous one: it requires the daily, hourly reorientation of the self’s attention, energy, and love toward another being whose needs are not your own, whose timeline is not your own, whose existence makes claims on you that you did not negotiate and cannot exit. This is exactly what makes it hard. And it is exactly what makes it meaningful. The mother who rises at three in the morning for a feverish child is not failing to take care of herself. Rather, she is transcending herself. And in that transcendence, repeated ten thousand times across the years of a child’s growth, she is becoming something that a life of self-cultivation alone could never produce.

A culture that praises this, that holds it up as one of the highest things a human being can do, will have more mothers, and more flourishing ones. A culture that subtly demotes it, that treats the desire to mother as a limitation rather than a calling, as a retreat from ambition rather than its deepest expression, is not only getting its demographics wrong. It is getting its anthropology wrong. It has forgotten what human beings are for.

None of this is to say that motherhood is the only arena in which self-transcendence is possible, or that every woman’s path to meaning runs through the nursery. Human beings have always found ways to apply themselves to religious devotion, care for the sick and elderly, artistic creation, civic life, and friendship of the deepest kind. What all of these have in common is the fundamental movement away from the self and toward something that makes a claim on us larger than our own comfort or advancement.

But motherhood has always been the most universal, the most immediate, and the most unambiguous expression of that movement. It requires no special talent or vocation, only the willingness to be radically present to another human being who cannot survive without you. And it is precisely for this reason that its demotion is so revealing. When a culture can no longer honor the woman who gives herself to the raising of children, when it treats her desire to do so as a limitation rather than a calling, as a retreat from ambition rather than its deepest expression, it has not simply failed mothers. It has been revealed that it no longer understands what human beings are for.

Mimetic Desire and the Models We Inherit

Pull all of this together, and what emerges is not a list of discrete problems but a single, underlying disorder: the demotion of human connection from its rightful place at the summit of human existence. Aristotle understood that human flourishing, eudaimonia, was never a solitary achievement. It was relational, civic, embedded in bonds of loyalty and love that gave individual life its depth and context. Frankl placed love first among the sources of meaning, before work, before suffering borne with dignity, before everything. Robert Bellah and his colleagues saw it coming in Habits of the Heart (University of California Press, 1985), documenting how Americans were drifting, as though on autopilot, toward increasingly narrow and self-centered notions of success, dissolving the communities of memory, family, religion, and civic association that anchor a self in something larger than its own preferences. These thinkers, from vastly different traditions, converged on the same insight: that a life organized around the self, however successful by external measures, is a life impoverished at its core.

René Girard, the French academic, helps us understand not just what has gone wrong but how the inversion propagates. Girard argued that human desire is not self-originating. He argued that we learn to want by watching others want, by taking on the desires of models we admire, envy, or wish to resemble. Most of the time, we do not come to our wants independently, through some inner consultation with our authentic selves. This insight, which Girard called mimetic desire, is usually applied to the dynamics of rivalry and conflict. But it illuminates the fertility crisis with equal precision.

Consider what the dominant culture has offered young women as its models of the admirable life. The woman who is celebrated, followed, emulated, and envied is typically the one who has built a career of consequence, maintained her independence, curated a life of visible richness, and remained, if not childless, then certainly unencumbered or unfazed by her children’s needs. She is not anti-child; she is simply focused elsewhere, and what she is focused on looks compelling. Her desires are transmitted to those who watch her, not as propaganda but as the subtler and more powerful thing: as aspiration. Young women do not decide to want their lives. They simply find, after long exposure, that they do. This is why the fertility crisis resists policy solutions. You cannot solve a mimetic problem with a financial incentive. The desire not to have children, or to have very few, is a mimetically acquired orientation toward a particular kind of life, absorbed from models that the culture has placed before women as worthy of desire and imitation.

What has the modern West offered in place of the older wisdom? A hierarchy that places at its apex the maximally free, maximally productive, maximally self-expressive individual, unencumbered by obligation, optimized for personal achievement, curating an identity rather than building a life. Children fit poorly into this vision. They are, by their nature, an interruption of the self’s project. They arrive without invitation and leave without permission. They demand love that is not contingent on their performance, time that cannot be reclaimed, and attention that the attention economy will not compensate. In the old hierarchy, these demands were understood as the conditions under which the deepest human growth occurs. In the new one, they look like liabilities.

Women are not failing to have children because they are selfish or confused. They are responding, with considerable rationality, to a cultural environment that has told them, in a thousand ways, through a thousand channels, that the sacrifices of motherhood are not worth making, that the respect once accorded to mothers is no longer on offer, and that the conditions under which raising children might be genuinely joyful have been quietly removed.

The empty cradles, then, are not only a demographic warning. They are a symptom of a civilization that has forgotten how to transcend itself, and is suffering, in its comfort and its restlessness, the predictable consequences of that forgetting.

Toward a Cultural Renaissance

The fertility crisis will not be solved by making motherhood more convenient. While subsidized childcare and extended parental leave may be helpful, they address the logistics of a problem whose roots are philosophical. What is required is something more difficult and more necessary: a cultural renaissance, a conscious, collective recovery of the conviction that human connection is not one priority among many but the supreme human project, the context within which everything else finds its meaning.

This means recovering protected space, time genuinely set apart from the claims of commerce, productivity, and performance, in which family life can breathe and accumulate the texture of shared experience. It means recovering respect for maternal authority and instinct, against the infantilizing pressure of expert culture. It means an honest reckoning with what has happened to men and what it costs women and children when men are economically marginalized and culturally delegitimized. It means, above all, a fundamental reordering of what we praise and what we honor, a culture that greets the desire to mother not with ambivalence or condescension, but with the recognition that this desire points toward something ancient, essential, and true about what it means to live well.

Here again Girard points the way, and this time toward hope. If desire is mimetic, then cultural renewal is also mimetic. The woman who inhabits motherhood with evident depth and joy, who is seen to be flourishing rather than merely sacrificing, who commands genuine respect rather than quiet condescension, becomes a mimetic force in her own right. She makes a certain kind of life newly desirable, not through persuasion, but through the oldest and most powerful of human mechanisms, the contagion of admiration. What our culture most needs is better models of what a life ordered around love and connection actually looks like, lived fully, visibly, and without apology.

That reordering cannot be legislated. It must be lived, modeled, and spoken aloud, by writers and teachers and religious communities and parents who are willing to say, clearly and without apology, that the person who gives herself to the raising of children is not settling for less. She is reaching for more. She is doing what Frankl said all meaning requires: she is turning away from herself and toward another, and in that turning, she is finding what the self-referential culture has promised but cannot deliver.

It means, perhaps above all, recovering some version of the ancient, cross-civilizational intuition, expressed in the Sabbath, in Aristotle, in Frankl, in every wisdom tradition that has survived long enough to be worth inheriting, that we are not here primarily to produce or perform or optimize, but to love and be loved, to belong to one another, to bring new life into the world and tend it with our whole attention.

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Author Bio

Dr. Sarah Centeno is a board-certified psychiatrist who trained at Stanford University, where she served as chief resident in the Department of Psychiatry, and has practiced in Marin, California, since 2006. She appears in Forever Young, where she introduces human connection as “the fifth vital sign,” and can be found at sarahcentenomd.com.

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Sources

Aristotle. Nicomachean Ethics. (Various translations; Book I for eudaimonia as relational flourishing.)

Bellah, Robert N., Richard Madsen, William M. Sullivan, Ann Swidler, and Steven M. Tipton. Habits of the Heart: Individualism and Commitment in American Life. University of California Press, 1985.

Eberstadt, Mary. How the West Really Lost God: A New Theory of Secularization. Templeton Press, 2013.

Eberstadt, Nicholas. “The Age of Depopulation.” Foreign Affairs, 2024.

Eberstadt, Nicholas. “The Future of Global Population.” National Affairs.

Eberstadt, Nicholas. Men Without Work: America’s Invisible Crisis. Templeton Press, 2016. Updated edition, 2022.

Frankl, Viktor E. Man’s Search for Meaning. Beacon Press, 1959.

General Social Survey (GSS). Sexual activity data, 2010–2024. Cited in: Bailey, Grant, and Brad Wilcox. “The Sex Recession.” Institute for Family Studies, 2025.

Girard, René. Deceit, Desire, and the Novel. Johns Hopkins University Press, 1966.

Girard, René. Things Hidden Since the Foundation of the World. Stanford University Press, 1987.

Haidt, Jonathan. The Anxious Generation: How the Great Rewiring of Childhood Is Causing an Epidemic of Mental Illness. Penguin Press, 2024.

Shrier, Abigail. Bad Therapy: Why the Kids Aren’t Growing Up. Sentinel, 2024.

Stelzner, Peter, and others. “The Male Non-Working Class.” Milken Institute Review, 2020.

Before your first heartbeat, a nerve began forming in the developing embryo — winding its way from the brain to the throat, heart, and gut, becoming the body’s most intimate internal messenger. It has been running quietly ever since: calming, regulating, connecting, and protecting. When this nerve weakens, the heart ages faster. When it thrives, so do you. It is called the vagus nerve.

The Thread of Life

The vagus nerve is not a single strand but a vast, branching network, making up one of the longest nerves in the human body. The vagus begins at the brainstem and then runs down through the neck, into the heart and lungs, and deep into the abdomen. Its name comes from the Latin verb vagari (to wander, stroll, or roam), which also gives rise to words like vagrant and vagabond. The vagus nerve, the wanderer of the nervous system, meanders its way through most of the important organs of the chest and abdomen, finally running out of steam by the more distal parts of the colon. It is a two-way nerve highway, carrying information about the organs to the brain and relaying instructions from the brain on how the organs should function.

Most people encounter the vagus nerve in the context of the “rest and digest” response — the parasympathetic counterpart to the adrenaline-driven fight-or-flight state. In response to vagal nerve stimulation, heart rate slows, digestion proceeds, and inflammation is suppressed. When vagal input diminishes, the body tilts toward a state of low-grade physiological alarm — one that, sustained over years, drives the biology of aging.

The Cardio Connection

In December 2025, a study published in Science Translational Medicine reported that maintaining vagal nerve connections to the heart on both sides acts as a powerful defense against cardiac aging, with the right branch in particular protecting heart muscle cells and preserving the heart’s structural integrity independently of heart rate.

“When the integrity of the connection to the vagus nerve is lost, the heart ages more rapidly.”

— Prof. Vincenzo Lionetti, Sant’Anna School of Advanced Studies · Science Translational Medicine, 2025

What made the finding especially significant was the corollary — even partial restoration of that connection is sufficient to counteract cardiac remodeling and preserve effective contractility. The team developed bioabsorbable nerve conduits designed to guide vagal nerve regeneration back to the heart. The implications for cardiac and transplant surgery are considerable.

The Quiet Extinguisher

The term “inflamm-aging” describes the low-grade chronic inflammation that quietly accumulates with age and underlies virtually every major age-related disease: cardiovascular disease, cancer, neurodegeneration, diabetes, and osteoporosis.

The vagus nerve is one of the body’s primary mechanisms for controlling inflammation. The principal neurotransmitter of the vagus is acetylcholine, and when the vagus nerve fires, the delivery of acetylcholine to the spleen signals macrophages to reduce their output of inflammatory cytokines, including TNF-alpha, IL-6, and IL-1β, while boosting anti-inflammatory signaling molecules like IL-10. Researchers call this the cholinergic anti-inflammatory pathway. It functions like a biological brake on runaway inflammation. As vagal tone declines with age, that brake weakens. The smoldering fire of inflammaging begins to spread.

This connects directly to how Dr. Eric Verdin, president and CEO of the Buck Institute for Research on Aging, characterizes aging: “the subtle accumulation of unrepaired damage” — a process that accelerates once it begins, outpacing the body’s capacity to repair. The cholinergic anti-inflammatory pathway is one of those repair systems. And it runs through the vagus nerve.

The Gut/Brain Connection

Perhaps the most striking recent discovery about the vagus nerve was published in Nature in March 2026 by researchers at Stanford and the University of Pennsylvania.

As mice aged, the researchers found an accumulation of gut bacteria, particularly Parabacteroides goldsteinii, that produce medium-chain fatty acids (MCFAs). These MCFAs, in turn, activate pro-inflammatory immune cells in the gut, prompting them to produce inflammatory cytokines such as TNF-alpha and IL-1B. These cytokines then impair the function of sensory neurons in the vagus nerve, weakening the vagal signal reaching the brain. And when vagal input to the brain is reduced, this results in decreased production of vital neurotrophic factors, such as brain-derived neurotrophic factor (BDNF). Without BDNF, neurons in the hippocampus become dramatically less able to form new synaptic connections – and without new connections, there can be no new memories. The wholly surprising outcome of this lengthy chain of events is that an aging gut microbiome can, through the vagus nerve, reach the brain and dampen memory function.

Just to make sure the causal loop was correctly elucidated, the researchers then stimulated the vagus nerve directly in the aging mice, and found that they were able to completely reverse the cognitive deficits that aging had established – proving that aging-related cognitive impairment is not necessarily hard-wired and is, at least theoretically, reversible in certain specific situations. This is a dramatically different conceptualization of age-induced learning impairment, which has traditionally been viewed as a downstream consequence of neuronal damage and cellular loss in the brain, rather than as a process that can be modulated from the gut.

“The degree of reversibility of age-related cognitive decline in the animals just by altering gut-brain communication was a surprise. We tend to think of memory decline as a brain-intrinsic process.”

— Christoph Thaiss, Ph.D., Stanford University · Nature, March 2026

This is animal research, and translating findings from mice to humans is never automatic. But the mechanistic clarity of the pathway (gut bacteria → immune inflammation → inflammatory cytokine signaling → vagal suppression → hippocampal decline), and the successful reversal of this process, deserve more attention. Multiple research groups are now investigating whether the same sequence occurs in people.

How To Measure Vagal Tone

Since the activity level of the vagus nerve is turning out to be critical, how do we measure that in the living human body? Heart rate variability — HRV — is the beat-to-beat variation in the interval between heartbeats. If sympathetic (i.e., fight-or-flight) activity dominates, the heart rhythm tends to be regular, like a metronome. But when vagal activity strengthens, heart rhythm gets measurably less regular, and more variation is found in the inter-beat time intervals. Heart rate variability (HRV) is one of the most reliable non-invasive proxies for vagal tone. High HRV indicates a responsive, well-regulated autonomic nervous system with ample parasympathetic (i.e., vagal) activity. Low HRV indicates the opposite, and evidence increasingly suggests it matters for how long and how well we live.

Research published in 2024 proposed that an imbalance in the autonomic nervous system — measurable through HRV — should be considered a biomarker of aging itself, offering a tangible link between physiological disruption and age-related health outcomes. Studies of centenarians have found that the lifestyle behaviors most associated with maintaining higher HRV — regular physical activity, dietary discipline, limited alcohol, and not smoking — map closely onto the behaviors that characterize the world’s longest-lived populations.

If you are wondering about the status of your own HRV, you don’t have to wonder for long. Modern wearables now make HRV tracking accessible to anyone. Keep in mind that when tracking your data, morning resting HRV, measured the same way every day, produces meaningful trend data. A single reading in isolation tells you very little.

How Can You Improve Your Vagal Tone?

Vagal tone appears to be malleable across the lifespan, and several approaches to maintaining it are supported by evidence. Slow nasal breathing with an extended exhale — inhaling for approximately four counts, exhaling for six or more — has been shown to acutely increase HRV. Brief cold exposure activates the mammalian dive reflex, producing a rapid parasympathetic response. Regular aerobic exercise is among the most studied interventions for long-term vagal tone. Singing, humming, and gargling activate the laryngeal branches of the vagus nerve. And some intriguing research suggests that sustained, meaningful social connections may also increase HRV.

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A full protocol for our paid subscribers is coming next. Meanwhile, a simple hack to stimulate your vagal nerve in 30 seconds can be found in our article below:

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SOURCES

Thaiss CA, Levy M, et al. Gut microbiota-derived medium-chain fatty acids suppress vagal sensory neurons via GPR84 and CCKAR-mediated pathways, impairing hippocampal memory formation. Nature. March 2026.

Dushpanova A, et al. Autonomic nervous system imbalance as a quantitative biomarker of cardiovascular aging and all-cause mortality risk. Science Translational Medicine. December 2025. (Sant’Anna School / Lionetti group)

Tegegne BS, et al. Reference values of heart rate variability from 10-second resting ECGs: the Lifelines Cohort Study. European Heart Journal: Digital Health. 2020. Umetani K, Singer DH, McCraty R, Atkinson M. Twenty-four hour time domain heart rate variability and heart rate: relations to age and gender over nine decades. Journal of the American College of Cardiology. 1998;31(3):593–601. Nunan D, Sandercock GR, Brodie DA. Normal values for short-term heart rate variability in healthy adults. Pacing and Clinical Electrophysiology. 2010;33(11):1407–1417.

Borovikova LV, Tracey KJ, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–462. (Seminal) Koopman FA, Tracey KJ, Tak PP, et al. Vagus nerve stimulation inhibits cytokine production in rheumatoid arthritis. PNAS. 2016;113(29):8284–8289. Bonaz B, Sinniger V, Pellissier S. Anti-inflammatory properties of the vagus nerve. Journal of Physiology. 2016;594(20):5781–5790. Thayer JF, Yamamoto SS, Brosschot JF. Autonomic imbalance, HRV and cardiovascular disease risk. International Journal of Cardiology. 2010;141(2):122–131.

Franceschi C, Campisi J. Chronic inflammation (inflammaging). Journals of Gerontology Series A. 2014;69 Suppl 1:S4–9. Ferrucci L, Fabbri E. Inflammageing in ageing, cardiovascular disease, and frailty. Nature Reviews Cardiology. 2018;15(9):505–522.

Porges SW. The polyvagal perspective. Biological Psychology. 2007;74(2):116–143. Lewis T, Amini F, Lannon R. A General Theory of Love. Random House. 2000.

DISCLAIMER

The information in this article is for educational purposes only and does not constitute medical advice. Consult a qualified healthcare provider before making any changes to your health regimen. Some links in this article are affiliate links. If you purchase through them, we may earn a small commission at no additional cost to you.

Right now, as you read this, your DNA is accumulating damage – a truly incredible amount of damage, if you look at the numbers. Each active cell in your body sustains somewhere between 10,000 and 100,000 DNA damage events per day. Much of this damage occurs as a direct consequence of the cell carrying out its normal daily activities. Cellular metabolism generates highly damaging reactive oxygen species that rip into DNA. Radiation from the sun and the cosmos slams into the DNA double helices and breaks them – sometimes one strand, sometimes both strands. DNA damage is the price of being alive and awake. Every hour awake, you run a biological tab.

Sleep is when the bill comes due. If we don’t pay that bill, our body punishes us.

In 2007, the World Health Organization classified night-shift work as a probable human carcinogen — not the chemicals, not the stress, but the schedule itself. For many, this might seem hard to believe – just the act of being awake when your brain thinks you should be asleep causes cancer? But the answer is unequivocally yes. Once you understand what is actually happening during the hours you are not sleeping, that finding makes complete sense.

In the years since the WHO labeled shiftwork a carcinogen, the mechanisms have come into focus with a precision that surprised even the researchers studying them. A 2025 analysis of CDC data from more than 3,000 U.S. counties found that insufficient sleep ranked higher than diet and exercise as a predictor of shorter life expectancy, second only to smoking.

What researchers now understand is not just that sleep repairs, but how precisely timed that repair is, and how completely the system breaks down when the timing goes wrong.

The Repair Window

Your body closely tracks DNA damage. A protein called PARP-1 functions as a damage sensor, and when it detects DNA breaks accumulating during wakefulness, it actively makes you sleepy. The urge to sleep is, in part, your genome’s way of insisting on repair time. Sleep is not something that happens when consciousness runs out — it is something your biology actively demands because it’s keeping you alive.

During sleep, the repair machinery runs on a precise schedule. Circadian clock proteins regulate DNA repair pathways — specific processes peak during specific sleep stages. In animal models, markers of DNA double-strand breaks peak just before sleep and decline by roughly 70 percent during subsequent sleep.

“Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans.”— Koritala et al., Journal of Pineal Research

Night-shift work does not simply mean sleeping at the wrong time. Circadian misalignment severs the relationship between damage accumulation and repair. When circadian rhythms are disrupted, DNA repair genes lose their rhythmicity — they stop oscillating in the patterns that enable repair. Research published in the Journal of Pineal Research found that after simulated night-shift conditions, workers showed both elevated DNA damage and a reduced capacity to repair that damage. Other analyses find that circadian disruption impairs double-strand break repair capacity by 40-60%.

The cancer risk follows directly. The accumulation of unrepaired DNA damage leads to cells malfunctioning, mutations rising, and ultimately the most catastrophic of all possible cellular abnormalities – the unchecked growth and multiplication of cells that we call cancer.

Your Brain After Dark

Wakefulness is expensive for the brain in a specific way. Neurons fire continuously, generating toxic byproducts that accumulate in the spaces between cells. For decades, no one understood how the brain cleared this waste — unlike every other organ, it has no conventional lymphatic drainage system.

In 2012, neuroscientist Maiken Nedergaard and her team at the University of Rochester found the answer. They named it the glymphatic system. During sleep, the interstitial space between brain cells expands by approximately 60 percent, allowing cerebrospinal fluid to flush through brain tissue and carry away the metabolic waste that has been building all day. But this cleaning crew only comes at night.

Amyloid beta — the protein most associated with Alzheimer’s pathology — clears at twice the rate during sleep as during wakefulness.

Animal models of Alzheimer’s show impaired glymphatic function. The hypothesis that chronic sleep disruption accelerates disease progression by preventing nightly clearance is now one of the more intensively studied questions in neurodegenerative research.

The cognitive exhaustion that follows poor sleep is not simply tiredness; it represents the dysfunction inherent in a brain that was not adequately cleaned. A 2025 study of 27,500 adults found that poor sleep is associated with measurably older brain age, driven in part by chronic systemic inflammation — the same pathway that links sleep loss to cardiovascular disease and metabolic decline.

The glymphatic system is most active during slow-wave sleep — the deepest stage — and its activity declines naturally with age. Studies of centenarians find that those who retain more slow-wave sleep have significantly better cognitive outcomes than those who do not. What researchers call successful aging is partly a story about how consistently the overnight cleaning process runs.

Why Weekends Are Costing You

Both findings above might seem like arguments for sleeping more hours. Duration matters — but when those hours arrive may matter just as much.

Sleep regularity — the consistency of bedtime and wake time from day to day — has become one of the more active areas of sleep research. A 2025 systematic review of 59 studies found consistent evidence linking irregular sleep timing to elevated rates of cardiovascular disease, metabolic disease, and all-cause mortality, often regardless of total hours slept.

The mechanism is the same one at work in the night shift data, just slower. Your circadian system not only regulates sleep but also schedules the repair processes that require sleep to operate. DNA repair peaks are timed. Glymphatic flow is timed. Hormone secretion, immune function, metabolic regulation — all timed. When sleep arrives unpredictably, these processes cannot coordinate as they normally do in the impressive orchestra of a well-run brain. Instead, repair processes may run at the wrong moment, impairing their optimal function, or they may miss the window entirely.

The most common time people introduce this irregularity is on weekends, when they sleep two to three hours later than on weekdays. Researchers call this social jet lag. The physiological consequences are measurable and compound across years.

Your wake time should be the same every day of the week. Not roughly the same. The same. Before any other intervention, this single change addresses the scheduling problem at its root.

Sleep looks like passive rest from the outside, and the truth is that it’s anything but that. Sleep involves your body running a host of maintenance routines that strive to undo the damage that’s been accumulating in your body since the moment you woke up this morning – DNA damage, toxic waste buildup, imbalances between the pro-inflammatory and the anti-inflammatory arms of the immune system. And that’s not all that sleep is doing; not by a long shot. Sleep also traffics in raw information duties - it tunes the brain toward peak operating efficiency by pruning neuronal connections that have become irrelevant, and it categorizes and files your daily memories into long-term storage. If you’re interested in the information-management function of sleep, we may cover that topic in a future piece.

For now, just keep in mind that sleep is absolutely vital to your health, in ways that scientists are only beginning to discover. It’s a fair bet that as the research proceeds, even more beneficial effects of sleep will be discovered. But the evidence thus far is compelling enough to indicate that sleep should be a vital priority for anyone interested in their health and longevity.

TAKE ACTION

Now that you understand what sleep is actually doing, the next question is what to do about it. In our next article for paid subscribers, we break down five research-backed protocols — ranked by longevity impact — covering everything from the one schedule change that may matter more than hours slept, to what the data says about deep sleep, insomnia, and your metabolism after dark.

Read the Protocol →

SOURCES

Koritala BSC, et al. Night shift schedule causes circadian dysregulation of DNA repair genes and elevated DNA damage in humans. Journal of Pineal Research. 2021.

Xie L, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-377

Yang JH, et al. Loss of epigenetic information as a cause of mammalian aging. Cell. 2023;186(2):305-326.e27.

Lunsford-Avery JR, et al. Adolescent sleep regularity and health outcomes. Sleep. 2020.

Cappuccio FP, et al. Sleep duration and all-cause mortality: a systematic review and meta-analysis. Sleep. 2010;33(5):585-592.

Bloomberg M, et al. Joint associations of physical activity and sleep duration with cognitive ageing. Lancet Healthy Longev. 2023;4(7):e345-e353.

World Health Organization / IARC. Night shift work. IARC Monographs, Volume 98. 2010.

Slide lecture: Lewis TB, MD. Sleep, Aging, and Longevity. Unpublished academic presentation, 2025.

The information in this article is for educational purposes only and does not constitute medical advice. Consult a qualified healthcare provider before making changes to any health regimen.

In our last article, we established the why: sleep is not rest; it is active biological repair. Your genome is being edited. Your brain is being cleansed. Your circadian clock is either being honored or disrupted, with consequences that compound over decades.

This article is the what and the how— a structured protocol built directly from the research, organized by impact, with the statistics attached so you can evaluate the evidence yourself.

Five protocols. Ranked in order of longevity relevance. Evidence suggests that working through them systematically and discussing any pharmacological considerations with your physician is one of the highest-return interventions for anyone serious about healthspan.

Establishing a Baseline

Before initiating protocols, it is important to establish a baseline, as most people dramatically overestimate how well they sleep.

Only 26% of adults regularly get 8 or more hours of sleep per night.

53% report sleeping 6 to 7 hours — a range that carries measurably elevated health risk.

20% report sleeping 5 hours or less — the highest-risk category in the data.

These numbers matter because the research on sleep duration and mortality follows a U-shaped curve: the lowest risk sits at 7 to 8 hours, with risk rising on both sides. Short sleepers — defined as less than 6 to 7 hours per night — carry a 10 to 16 percent higher all-cause mortality risk compared to those in the optimal range. That is before accounting for the compounding effects on cardiovascular disease, metabolic health, cognitive decline, and cancer risk, each of which has its own independent dose-response relationship with sleep quality and duration.

The good news is that the research also shows something encouraging: having all five favorable sleep habits is associated with an additional 4.7 years of life expectancy for men and 2.4 years for women, compared to individuals with zero or one favorable habit. These are not marginal gains. They are measurable, meaningful, and — critically — achievable without a prescription.

Here is what those habits look like in practice.

Read more

Dr. Thomas Lewis wants to correct that framing entirely.

In this video, Dr. Thomas Lewis breaks down the neuroscience of meditation — and why it reaches further into your biology than most peo…

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Tap water is not just H2O. Depending on where you live, water carries dissolved elemental minerals picked up as it moves through bedrock and soil — calcium, magnesium, potassium, sodium, fluoride. Most people are vaguely aware of this. Hard water leaves mineral deposits on faucets. Fluoride has been added to municipal supplies since the 1940s. The rest is largely invisible.

One of the minerals in tap water is lithium. In trace amounts — parts per billion — it occurs in groundwater almost everywhere, leaching from surrounding rocks into aquifers and reservoirs. The lithium in water is a completely natural occurrence, and it has been in humanity’s drinking water for the entire duration of our existence as a species – until recently.

Lithium appears right above sodium on the periodic table of the elements, and it shares many properties with sodium. Consequently, lithium was used as a substitute for table salt – which is sodium chloride – for a brief time in the late 1940s and early 1950s. This lithium-for-sodium switch was based on the idea that lithium salt would be healthier than sodium salt for blood pressure and kidney function. Unfortunately, lithium has what is called a “narrow therapeutic window” – in other words, the dose that harms people is not very much larger than the dose that may help them. And the doses in lithium table salt were large. A number of people were sickened by lithium table salt, and some died. The FDA pulled lithium from the market shortly thereafter.

Ironically, at about the same time in Australia, Australian psychiatrist John Cade published his findings on lithium’s extraordinary effectiveness for treating manic episodes in bipolar disorder, launching its use as a psychiatric medication, and saving countless lives in the process, when the dose was closely titrated and monitored. But in the US, the FDA was slow to retract its original finding that lithium was too dangerous for any use. Australian physicians used lithium to treat bipolar disorder from 1950 on, but twenty long years would elapse before lithium was approved by the FDA in 1970, when the US became the 50th country to approve lithium as a medicine that doctors could prescribe.

Most people, if they have heard of lithium at all, are familiar with its use as a psychiatric medicine, not as a micronutrient. Researchers studying the effects of lithium at trace concentrations have been working in the shadow of its psychiatric reputation ever since.

In August 2025, a team at Harvard published findings in Nature suggesting that the brain’s relationship with lithium may be more fundamental than previously understood — that lithium depletion may have a role in Alzheimer’s disease, and that the shift away from tap water toward purified bottled water may be reducing our exposure to natural trace lithium without anyone noticing.

The Pattern in the Population Data

Epidemiologists comparing dementia rates across regions kept finding the same anomaly: in areas where tap water naturally contains more lithium, fewer people develop dementia. The pattern holds in Denmark, Japan, Texas, and the UK — independently, across different populations and water sources. A 2024 systematic review in the International Journal of Bipolar Disorders examined all available data and concluded that evidence across four studies on three continents supports a link between trace lithium exposure and lower risk of, and mortality from, dementia.

The natural lithium concentrations in groundwater are vanishingly small: 0.002 to 0.056 milligrams per liter. These are not pharmaceutical amounts. They are closer to what you would find in food grown in lithium-containing soil — the kind of background exposure that was, until recently, simply part of how humans lived. But now that food is extensively washed and commercially processed, we’re no longer getting much trace lithium exposure in what we eat. Trace amounts of lithium have been slowly removed from the water and the food we consume.

Note: For anyone curious about their own exposure: municipal water utilities are required by the EPA to publish an annual Water Quality Report — sometimes called a Consumer Confidence Report — which can include trace mineral data for your specific water district, including lithium. Search yours at EPA.gov using your zip code.

A Question About Your Water Bottle

Before the mechanism: how many people are actually getting any lithium at all?

About 72 percent of Americans drink both tap and bottled water; roughly 19 percent drink bottled exclusively. Only about 8 percent rely on tap or filtered tap water. And bottled water consumption has climbed steadily — 16.2 billion gallons in 2024, up sharply from two decades ago.

The problem lies in how corporations manufacture bottled water. Most commercially bottled water undergoes reverse osmosis, distillation, or multi-stage filtration before packaging. These processes strip the water of contaminants but also remove trace minerals, including lithium. Drinking purified bottled water, regardless of its source, likely delivers little to no lithium.

People spend more time in contact with tap water while bathing than while drinking. But human skin does not absorb any lithium at all. Studies of people bathing in spa water with lithium chloride at concentrations far above anything in tap water found no meaningful uptake into the bloodstream. If you want to get lithium into your body, you must ingest it.

The population-level shift toward purified bottled water has likely reduced trace lithium intake over the same decades during which dementia rates have climbed. Researchers are beginning to ask whether those two trends are related. The answer is not yet fully known, but scientists have made some fascinating and suggestive discoveries.

What the Brain Tissue Showed

Researchers at Harvard Medical School measured 27 minerals in post-mortem brain tissue from hundreds of older adults, after classifying them into 3 groups: cognitively healthy, mildly impaired, and Alzheimer’s-diagnosed. Of all 27 minerals, lithium was the only one significantly reduced in people with mild cognitive impairment, the condition that often precedes Alzheimer’s. As disease severity increased, lithium levels dropped further. Amyloid plaques — the protein deposits central to Alzheimer’s pathology — were actively sequestering lithium, pulling it out of the surrounding tissue.

To test whether lithium depletion is driving the cognitive decline rather than merely accompanying it, the researchers reduced cortical lithium levels by about 50 percent in mouse models. Amyloid-beta deposits, of the sort seen in the brains of Alzheimer’s patients, increased. Phosphorylated tau – another toxic protein frequently seen in neurodegenerative conditions – accumulated. Synapses evaporated, axons degraded, and cognitive decline accelerated.

The underlying mechanism linking lithium depletion to adverse brain environments involves GSK3-beta, an enzyme that lithium inhibits. Without sufficient lithium, GSK3-beta ramps up the molecular processes — amyloid processing, tau phosphorylation — that define Alzheimer’s progression.

When the researchers gave lithium orotate to the lithium-depleted mice, their memory nearly recovered. Lead author Bruce Yankner described the implication carefully: “The idea that lithium deficiency could be a cause of Alzheimer’s disease is new and suggests a different therapeutic approach. Before recommending lithium orotate, we need to determine the effective and safe dose range in people.” His lab has announced plans for a human trial.

The Human Trials

The most cited clinical result is a 2013 Brazilian trial by Nunes et al. Alzheimer’s patients receiving 300 micrograms of lithium daily — a true microdose — showed no cognitive decline over 15 months on the Mini-Mental State Examination (MMSE), while the placebo group continued to deteriorate. A 13-year follow-up published in 2023 found the gap had widened: lithium patients scored 25.5 on the MMSE versus 18.3 for placebo; verbal fluency was 34.7 versus 11.6. These differences are large and clinically significant. They are also from a single small pilot study, which limits what conclusion we can reasonably draw from them.

The most methodologically rigorous recent test is the LATTICE trial, published in JAMA Neurology in March 2026. The study ran at the University of Pittsburgh from 2018 to 2024, enrolling 80 adults aged 60 and older with mild cognitive impairment and randomizing them to two years of low-dose lithium (150 mg/d or 300 mg/d) vs. placebo, tracking cognition, brain imaging, and Alzheimer’s biomarkers throughout.

Verbal memory declined at about half the rate in the lithium group — an encouraging numerical finding, but the trial missed achieving statistical significance on all six of its prespecified primary endpoints, including hippocampal volume, cortical gray matter, and BDNF levels. The investigators designed LATTICE as a pilot feasibility study, not a definitive efficacy test. The purpose of the study was to confirm safety and produce the effect size estimates needed for a properly powered trial. The lead investigator called it the third independent study to suggest lithium may slow cognitive decline in people with MCI — and noted that any future trial should specifically enroll participants with confirmed Alzheimer’s pathology via blood-based biomarkers.

A January 2026 meta-analysis in Neuroscience and Biobehavioral Reviews (Kishi et al.) reviewed the available clinical evidence and found a consistent positive direction, while acknowledging the limitations of the trial data. A large, adequately powered confirmatory trial has not been run.

The Nutrient Hypothesis

What researchers are cautiously arguing is that lithium’s role in this story is less pharmacological than nutritional. Before industrial water treatment and food processing, humans ingested trace lithium continuously — through groundwater and food grown in lithium-containing soil. Some researchers now propose that lithium belongs in the same category as iodine, selenium, and zinc: trace minerals that the body requires in small amounts, and which we used to obtain through ordinary environmental exposure.

The iodine comparison is the clearest precedent. In regions of the United States where iodine was absent from the soil, goiter and thyroid disease were widespread because affected patients lacked something the body needed. Fortifying table salt with iodine is now considered one of the more consequential public health interventions of the 20th century. Whether lithium belongs in a similar conversation is a question the Harvard findings have made harder to dismiss.

What Is and Isn’t Established

The ecological studies are correlational. The Nature findings draw primarily from animal models and post-mortem tissue data. The most rigorous human trial failed to meet its primary endpoints. No large randomized controlled trial has established that lithium supplementation slows or prevents Alzheimer’s disease in people.

What the accumulated evidence does support is a biologically coherent pattern: lithium is clearly present in the brain, lithium is depleted early in Alzheimer’s pathology, the absence of lithium in animal models accelerates the disease’s hallmark processes, and populations with more lithium in their water develop dementia at lower rates. Whether that pattern translates into a clinical intervention — and at what dose, in what form, for whom — is what the next generation of trials is being designed to answer.

If we look back across the history of lithium administration, we can see the truth of the dictum of the 16th-century Swiss physician and alchemist Paracelsus: the difference between a medicine and a poison often comes down to the dose. Lithium in large doses was deadly as a salt substitute; lithium in much lower doses is indisputably therapeutic in bipolar disorder, and, at very low doses indeed, lithium might be helpful in preventing cognitive decline.

The most pro-lithium stance is likely that expressed by a group of Italian researchers, writing in Neuroscience & Biobehavioral Reviews: “[W]ith caution, we dare to express that we cannot discard that, in the near future, we see low-dose lithium added to our diet to prevent cognitive decline.”

For anyone interested in pursuing lithium, a conversation with a physician is the right starting point. Lithium in supplement form is available, but dosing, form, and individual health circumstances all matter, and the evidence base for any specific recommendation in humans remains thin.

Some people, having reviewed the research, have begun taking over-the-counter lithium orotate supplements — typically at doses of 1 to 5 milligrams of elemental lithium per day, well below the psychiatric range. This is not a recommendation. The evidence base for any specific supplementation protocol in humans remains preliminary, and lithium at any dose can interact with medications and is contraindicated in certain health conditions. Anyone considering it should have that conversation with a physician first.

This Is Just The Beginning

Dementia has surpassed cancer as the number one fear for aging Americans. Our understanding of how it works has radically shifted in the last few years. And yet, much of the science has still not made it to the public. We’re changing that with our Rethinking Dementia series, where we explore root causes, reveal existing medicines to treat and prevent it, and share essential protocols to reduce risk.

Paid subscribers get a fundamentally different way of thinking about aging — one grounded in the new science, not the old assumptions. That means action protocols, deep dives into the drugs, biology, and breakthroughs reshaping human health, and exclusive video interviews with the world’s top longevity scientists. All with a healthy dose of humanism.

More than 100 articles and videos. Q&As with the rock stars of the field. And much more. New content drops multiple times each week.

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Key Studies Referenced

Aron L. et al. (2025). Lithium deficiency and the onset of Alzheimer’s disease. Nature, 645, 712–721.

Gildengers A.G. et al. (2026). Low-Dose Lithium for Mild Cognitive Impairment: A Pilot Randomized Clinical Trial. JAMA Neurology.

Kishi T. et al. (2026). Lithium for Alzheimer’s disease: Insights from a meta-analysis. Neuroscience & Biobehavioral Reviews, 180, 106458.

Nunes M.A. et al. (2013). Microdose lithium treatment stabilized cognitive impairment in patients with Alzheimer’s disease. Current Alzheimer Research, 10, 104–107.

Damiano R.F. et al. (2023). Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment. Brazilian Journal of Psychiatry, 45, 46–49.

Duthie S.J. et al. (2024). Trace lithium levels in drinking water and risk of dementia: a systematic review. International Journal of Bipolar Disorders.

Guilliot S. et al. (2023). Lithium, a Treatment Option for Alzheimer’s Disease? Journal of Alzheimer’s Disease.

Pereira A.A.R. et al. (2024). Microdose lithium improves behavioral deficits and modulates molecular mechanisms of memory formation in SAMP-8. PLoS ONE, 19(4): e0299534.

Shen et al. Frontiers in Pharmacology (2024). Molecular mechanisms and therapeutic potential of lithium in Alzheimer’s disease.

Pacchiarott et al. (2023) Should we consider adding low-dose lithium to our diet to prevent cognitive decline and suicidality? Neurosci Biobehav Rev. doi: 10.1016/j.neubiorev.2023.105329.

MEDICAL DISCLAIMER

This article is for informational purposes only and does not constitute medical advice. The research discussed is preliminary and ongoing. Nothing here should be interpreted as a recommendation to begin, change, or stop any supplement or medical treatment. Lithium in pharmaceutical doses requires close medical supervision. Any interest in trace lithium supplementation should be discussed with a licensed physician who can evaluate individual health circumstances.

We don’t plan it. Our diaphragms contract spasmodically. Abdominal muscles engage. Air forces its way out in short, rhythmic bursts. Then our faces contort in a way we would never arrange intentionally. For a few seconds, we lose control of our own bodies.

That involuntary quality is the first clue that laughter is something stranger and more ancient than it looks. Brain imaging studies show that its neural signature bears almost no resemblance to language — different size, different location, an entirely different pattern. It is not a learned behavior: infants laugh competently at two months, a full twenty-two months before they can string three words together, which tells us that laughter cannot be a form of language. And laughter cannot be convincingly faked.

The sound itself is oddly constrained and stereotyped. Laughter is always the same syllable repeated — ha-ha-ha, he-he-he, ho-ho-ho — never a mixed sequence, never arbitrary. On an acoustic spectrum, it looks most similar not to any other human vocalization, but to a bird call, like a duck’s quack. An involuntary, rhythmic, repetitive, social signal. Which raises the question: a signal for what?

Laughter Isn’t Limited to Humans

When researchers began tickling rats, the animals emitted ultrasonic vocalizations at around 50 kilohertz — far beyond human hearing. When those sounds were converted to an audible frequency, they were unmistakably similar to laughter. More striking: when the tickling stopped, the rats did not turn away. They looked for the hand. They chased it. They wanted more.

Bonobos and chimpanzees laugh during rough-and-tumble play, producing a breathy, rhythmic sound that is acoustically distinct from anything else they vocalize — and instantly recognizable to human ears. Even the grumpy-looking great apes laugh when they play and wrestle.

As primatologist Frans de Waal wrote, “Tickling a juvenile chimpanzee is a lot like tickling a child. The ape has the same sensitive spots: under the armpits, on the side, in the belly. He opens his mouth wide, lips relaxed, panting audibly in the same ‘huh-huh-huh’ rhythm of inhalation and exhalation as human laughter. The similarity makes it hard not to giggle.”

This is not a coincidence. It tells us that laughter is not a human invention or a cultural artifact. It is an ancient biological signal, conserved across species over millions of years of evolution, that emerges from one specific context: play. The breathy, rhythmic sound is simply the exhalation of physical exertion, repeated — what our ancestors sounded like when they were safe enough and connected enough to rough-house with each other. We inherited it from them. And the body still treats it accordingly.

What Evolution Was Actually Trying to Do With It

If laughter is a signal, what is it signaling? The evidence points to two things at once: safety and belonging. When animals engage in rough-and-tumble play — behaviors that could easily be misread as aggression — laughter is the continuous broadcast that says this is not a fight. I am not a threat. We are playing.

For social species whose survival depends on group cohesion, that signal is enormously valuable. It lowers defenses. It synchronizes nervous systems. It creates the conditions for trust, cooperation, and mutual protection — all of the things that kept our ancestors alive long enough to become our ancestors.

“Laughter is almost entirely a social phenomenon. When researchers tracked laugh frequency, laughter in social settings was more than 30 times higher than when people were alone.” — Dr. Thomas Lewis, psychiatrist and neuroscientist

That 30-fold number is not incidental. It is the whole point. Laughter did not evolve to make you feel good in a room by yourself. It evolved as a signal between creatures. And that origin — social, ancient, wired into the nervous system long before language arrived — turns out to explain a great deal about what it does to the body when it fires.

There is also a distinction worth making between what researchers call Laughter 1.0 and Laughter 2.0. Laughter 1.0 is the real thing: ancient, involuntary, enormously contagious, physically overwhelming. It replaces speech rather than punctuating it — you genuinely cannot do both at once. Laughter 2.0 is its more strategic descendant: the polite chuckle, the social lubricant, the acknowledgment of someone’s joke. It is, essentially, a performance of the real thing. The body, as we’ll see, knows the difference.

The Longevity Connection

Three large population studies have examined what happens over time to people who laugh a lot versus those who don’t. Their findings point in the same direction and are difficult to dismiss.

The largest tracked 53,000 Norwegians for fifteen years. Women with the highest humor scores showed a 48% lower risk of death from all causes, a 73% lower risk of death from heart disease, and an 83% lower risk of death from infection. Men showed a 74% reduced risk of dying from infection. A separate Norwegian study found that adults in the top quarter for humor appreciation were 35% more likely to be alive at the seven-year follow-up. A Japanese cohort study found that those who laughed least had significantly higher rates of death and cardiovascular events — independent of smoking, drinking, hypertension, and diabetes.

These associations held after controlling for every other risk factor researchers could think of to include. Laughter was not a proxy for being healthy in other ways. It contributed something distinct:

Evidence suggests that how often you genuinely laugh is a real predictor of how long you live.

It’s About How Often, Not How Hard

The Japanese cohort study did not track how intensely people laughed or for how long. It asked a simpler question: how often? The mortality difference appeared between people who laughed at least once a week and those who rarely did.

What this suggests is that the key variable is regularity, not intensity. A daily low-grade dose of genuine amusement appears to do more than an occasional evening of helpless laughter once a month. The body seems to benefit from laughter the way it benefits from movement — not in heroic, infrequent episodes, but as a quiet, consistent feature of daily life.

That reframes the question. Not “How do I laugh more?” but “Have I laughed today?” Those are meaningfully different inquiries.

Who You Laugh With Changes the Biology Entirely

The 30-fold difference in laugh frequency between social and solitary settings is striking enough on its own. But research by Oxford evolutionary psychologist Robin Dunbar reveals that social and solo laughter are not just quantitatively different — they are qualitatively different at the physiological level.

Laughing with another person raises pain thresholds measurably more than laughing alone — a direct marker of stronger endorphin release. The mechanism appears to involve mirror neurons and oxytocin pathways that simply are not activated when you are watching something funny by yourself. The full biological cascade — endorphins, oxytocin, and cortisol reduction — appears to require another person in the room. Laughing alone produces the cortisol drop. The rest is blunted or absent.

This connects to something Dr. Thomas Lewis argues throughout our award-winning documentary Forever Young: love and relationships are not soft variables in human health. They are biological imperatives. The laughter data support that at the cellular level. Shared laughter is not a pleasant byproduct of good relationships. It is part of the mechanism by which good relationships protect the body and regulate physiology.

The broad patterns in longevity research also suggest that the interventions with the strongest evidence tend not to be solitary pursuits. Eating together, moving together, belonging to something — all confer measurably greater biological benefit than the solo version. Laughter follows the same logic.

It’s a Biological Event

When genuine laughter fires, it is a multi-system biological event. The cascade goes like this.

Endorphins are released — the body’s natural opioids. Cortisol, the body’s primary stress hormone and a well-documented driver of biological aging, drops by roughly 31% per session of genuine laughter, according to a pooled analysis of multiple trials. More surprising: that drop begins before the laughing does. Researchers found that simply anticipating something funny — knowing a comedy was coming — reduced cortisol by 39% and adrenaline by 70% before a single laugh had occurred. The body responds to the expectation of humor, not just the experience of it.

Natural killer cells — the immune cells that hunt and destroy cancerous and virally infected cells without needing prior exposure — are also activated. Studies have found measurable increases in NK cell activity following a comedy film, with corresponding changes in gene expression in the cells responsible for that activity. These are not self-reported feelings. They are observable, measurable biological events downstream of something as seemingly simple as laughing at something funny.

The vagus nerve is involved too — the long cranial nerve governing the body’s parasympathetic “rest and digest” response. Sustained laughter stimulates vagal tone, lowering heart rate and blood pressure, and shifting the body away from the stress state. Vagal tone has emerged as a meaningful predictor of cardiovascular health and resilience. Every genuine laugh, held long enough, is physiological training for a system most people never think about.

Taken together, we can see that laughter is not merely a pleasant side effect of feeling good, but rather constitutes an intervention—one that simultaneously touches inflammation, immunity, stress hormones, cardiovascular function, and gene expression, at no cost and with no side effects, in as little as one sitting.

The Gender Gap in Laughter May Be Partly Explaining the Gender Gap in Longevity

Women outlive men by five to seven years on average in most developed countries. The reasons are complex and still debated. But one finding from the Norwegian humor-and-mortality research adds an intriguing thread.

In the 15-year cohort, the protective association between humor and longevity was substantially larger for women than for men. One possible explanation the researchers offered: men’s humor scores declined as they aged, while women’s did not. Men, on average, appear to become less receptive to humor over time. Women, on average, do not.

Does aging reduce men’s capacity for humor, or do men with lower humor engagement age faster? Does this contribute to the mortality gap, or is it a marker of something else? The honest answer is that we do not know. What we can say is that the group that scores lower on humor as it ages is the same group that dies younger, and that longevity science has not yet taken that overlap seriously enough to explain it.

So is laughter truly the best medicine? This is an area that needs more research, but it is certainly one of the most promising miracle drugs we know of.

This is Just the Beginning

Dr. Thomas Lewis — the neuroscientist whose research anchors this piece — delivers a 20-minute lecture on the science of laughter that goes considerably further than we could here. It's now available to paid subscribers.

Laughter turns out to be doing something real at the cellular level. So do some drugs your doctor has probably never mentioned. We go deep into the miracle drugs already being used off-label by top aging researchers. The evidence is more interesting than the headlines suggest. Paid subscribers get full access to our deep dives exploring the drugs, treatments, and new approaches that are changing what we know about aging. More than 100 articles and insider access, for less than the cost of dinner.

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Key Sources

Svebak S, et al. Trøndelag Health Study cohort (~54,000 participants, 7-year follow-up). Sense of humor and survival. American Psychosomatic Society.

Romundstad S, et al. Sense of humor and mortality: 15-year follow-up of 53,556 Norwegians. Int J Psychiatry Med.

Sakurada K, et al. Associations of frequency of laughter with risk of all-cause mortality and cardiovascular disease: Yamagata Study. J Epidemiol. 2020;30:188–193.

Kramer CK, Leitao CB. Laughter as medicine: systematic review and meta-analysis of spontaneous laughter on cortisol. PLOS ONE. 2023.

Berk LS, et al. Cortisol and catecholamine stress hormone decrease associated with anticipation of mirthful laughter. Exp Biol 2008. American Physiological Society.

Berk LS, Tan SA, et al. Neuroendocrine and stress hormone changes during mirthful laughter. Am J Med Sci. 1989;298(6):390–396.

de Waal F. What I Learned From Tickling Apes. New York Times, 2016 Apr 08.

Takahashi K, et al. The elevation of natural killer cell activity induced by laughter in a crossover-designed study. Int J Mol Med. 2001;8(6):645–650.

Bennett MP, et al. The effect of mirthful laughter on stress and natural killer cell activity. Altern Ther Health Med. 2003;9(2):38–45.

Hayashi T, et al. Laughter regulates gene expression in patients with type 2 diabetes. Psychother Psychosom. 2006;75:62–65.

Dunbar RIM, et al. Social laughter is correlated with an elevated pain threshold. Proc Biol Sci. 2012;279(1731):1161–1167.

Toti A, et al. The role of humor and self-care in longevity: a systematic review. Cureus. 2026;18(1):e101820.

Gonot-Schoupinsky FN, Garip G. From positive psychology to positive biology: laughter and longevity. Explor Med. 2023;4:1109–1115.

Lewis T. Lecture on the science of humor.

Laughter is not a form of speech. It predates language by years. It happens 30 times more often around other people. Rats do it. Bonobos do it. And on an a…

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Most people think of stress as a psychological problem. Something to manage, breathe through, or power past. Neuroscience has reached a different conclusion — one that matters to anyone who cares about how well they age.

Around 75 percent of American adults report experiencing stress. At least two-thirds say their stress manifests as physical symptoms — stomachaches, backaches, and persistent headaches. In 2024, 43 percent of adults said they felt more anxious than the year before, up from 37 percent the year prior and 32 percent the year before that. Stress is not just common – it’s rising.

What most people have not been told is what that stress is doing — structurally, measurably — to the architecture of their brain.

Cortisol is a key hormonal mediator of stress, so when stress hits, the adrenal glands release cortisol into the bloodstream. The brain’s primary memory center, the hippocampus, is lined with cortisol receptors. When cortisol floods the system chronically, those hippocampal receptors don’t just signal distress – they initiate a neurotoxic cascade that physically damages hippocampal neurons…and sometimes kills them.

The higher the sustained cortisol, the worse the memory function. And the damage accumulates over time.

Understanding the mechanism is the first step to interrupting it.

A Response Built for Seconds, Not Years

Our response to stress is not a design flaw.

For hundreds of thousands of years, the human survival toolkit included one of the most effective emergency systems in biology: the fight-or-flight response. You see a threat – the hypothalamus fires up the pituitary, which in turn signals the adrenal glands. Within seconds, cortisol and adrenaline flood the bloodstream. Heart rate spikes. Blood diverts from the digestive system to large muscle groups. The body prepares to confront or escape a threat.

As immunologist Firdaus Dhabhar has put it, evolution did not select for the biological stress response to sicken or kill us, but rather to enable our survival. Without a fight-or-flight response, a lion has no chance of catching its prey, and the prey has no chance of escape.

Most stressful events in the natural world last only seconds to minutes. A lion lunges out of cover, you respond, and you either get away, or you don’t – but in either case, it’s all over swiftly. This is acute stress — short, sharp, resolution-oriented. Cortisol spikes, the threat resolves, cortisol drops; the body recovers. Homeostasis is restored. Brief, resolvable stress actually improves the body’s regulatory systems; exercise is one example.

The problem is not stress itself.

The problem is stress without resolution.

The System Was Never Meant to Run All Day

Acute stress has a short half-life – it is adaptive, often immune-enhancing, and evolutionarily useful. The kind of stress that modern life runs on, however, is chronic, repetitive, and unrelenting. Traffic jams. Incessant dings and notifications. The unread email count that never reaches zero. This kind of stress stretches on day after day, week after week, month after month, year after year.

Research at Cambridge describing the evolutionary mismatch puts it plainly: “Our body reacts as though all these stressors were lions. Whether it’s a difficult discussion with your boss or traffic noise, your stress response system is still the same as if you were facing lion after lion. As a result, you have a very powerful response from your nervous system, but no recovery.”

Our stress response system was never calibrated for a world in which perceived threats simply persist without resolution. And the biological machinery designed to handle short-burst survival threats, when run continuously instead of in brief spurts, has measurable consequences.

Human physiology was shaped in conditions that included frequent movement, short bursts of intense stress, and immersion in natural environments. With the advent of agriculture and then industrialization, we moved from living in nature to living in human-made cities. Instead of living in the natural world that we were adapted to, we now live in manufactured environments of our own making, and for which we are most definitely not designed – environments with constant noise, little exposure to the sun or sky, continuous sensory input, artificial lighting, processed foods, and long periods of sedentary activity.

Chronic psychological stress in industrialized populations has been characterized in the research literature as an immune-altering factor associated with inflammatory, autoimmune, and chronic diseases. The mechanism is not separate from the modern disease burden. It is one of its drivers.

The scale is measurable. According to the American Psychological Association’s (APA) 2024 Stress in America survey, 53 percent of U.S. adults cite stress as the factor with the biggest impact on their mental health. Workplace hassles, financial anxiety, relational strain, and the persistent background pressure of modern life together constitute a continuous load of stressors that our stress response system is ill-equipped to handle.

Where Cortisol Goes First

The hippocampus is a curved structure in the medial temporal lobe of the brain. The hippocampus makes new memories, consolidates them into long-term storage, and enables spatial navigation. When someone remembers the name of the person they just met, recalls a conversation from three days ago, or navigates back to a parking spot in an unfamiliar city, that’s the hippocampus in action. In effect, the hippocampus is responsible for giving each of us a past.

Rodent studies established early that the hippocampus contains among the highest concentrations of glucocorticoid receptors in the brain — the specific receptors that cortisol binds to. Human and primate data suggest a similarly dense distribution of receptors in the hippocampus, though the picture is more complex in primates than in rodents. The role of the hippocampus in providing negative feedback to the hypothalamic-pituitary-adrenal (HPA) axis — signaling the body to reduce cortisol production once a stressor has passed — requires it to be highly sensitive to cortisol signals. That sensitivity is also the source of its vulnerability.

Under acute stress, cortisol binds to glucocorticoid receptors in the hippocampus. In the short term, this serves a purpose: it sharpens the memory encoding of threatening events, an adaptive function. The system was designed to be used briefly, then released.

The research literature describes the core paradox: basal levels of glucocorticoids are essential for neuronal development, plasticity, and survival, whereas sustained stress-induced glucocorticoid levels produce neuronal damage and loss.

If you look at a classical diagram of a neuron, you can see that at one end, the neuron sprouts an arborizing, root-like array of tendrils, which are called dendrites. Incoming neuronal signals contact the dendrites first, and then propagate across the neuron to the other end. Part of learning involves neurons sprouting new dendrites and making new connections. And sometimes, new neurons are created in the hippocampus, a process called neurogenesis, which is necessary to keep the neuronal population in the hippocampus vigorous and enriched with younger neurons.

Sustained cortisol exposure impairs a neuron’s ability to make new dendrites and shuts down neurogenesis. The mechanism involves cortisol disrupting cellular energy metabolism, leaving neurons resource-depleted. Cortisol also amplifies extracellular concentrations of excitatory amino acids that are toxic to neurons at elevated levels. The end result is impaired memory function, as stunted neurons do their best to limp on in a toxic environment - but if the cortisol bombardment is long and relenting enough, some neurons inevitably succumb and die.

The damage is detectable on imaging. Research consistently shows that chronic cortisol elevation is associated with hippocampal shrinkage and impaired neurogenesis. Researcher Yvette Sheline studied major depression — a condition characterized by sustained HPA-axis dysregulation and elevated cortisol — and found hippocampal volume in depressed patients was 10 to 15 percent smaller than in non-depressed controls. Remarkably, the evidence of damage was so firm that hippocampal shrinkage in these patients correlated with the number of days of untreated depression they had endured. When you’re depressed, and your hippocampus is under siege from excess cortisol, every day counts, it would seem.

The clearest human evidence comes from patients with Cushing’s syndrome, a condition in which the pituitary or the adrenals escape the normal operating parameters and produce chronically excessive cortisol levels. These patients show hippocampal atrophy on MRI and significant cognitive impairment. When their cortisol levels are normalized through treatment, hippocampal volume partially recovers, supporting the argument from both directions. Elevated cortisol damages hippocampal structure; reducing it allows partial recovery.

The memory consequences track the structural findings. Research consistently associates elevated cortisol with impaired performance on verbal recall, spatial memory, and other hippocampus-dependent tasks. In healthy aging populations, cortisol levels measured over several years have been shown to predict subsequent hippocampal atrophy and memory decline. The relationship is dose-related and directional: higher sustained cortisol, worse memory outcomes.

The Age Accelerator

The hippocampus is also one of the regions most affected by normal aging. After age 50, cortisol levels frequently rise in a gradual, age-associated pattern as the feedback mechanisms that keep cortisol in check fail. Rising glucocorticoid levels in later life are associated with age-related memory impairment and hippocampal cell loss. Chronic stress does not create an entirely separate aging process — it appears to accentuate a cortisol problem that, for many, is already in motion by the time of later life. By that measure, unmanaged chronic cortisol load is a significant and underappreciated contributor to cognitive aging.

The hippocampus does not just receive cortisol’s signal – the hippocampus itself participates in regulating cortisol production. A healthy hippocampus sends inhibitory signals back up the HPA axis — telling the hypothalamus and pituitary to reduce cortisol output, once a stressor has resolved. This is one of the brain’s primary mechanisms for turning off its own stress response.

However, there’s a catch here. Chronic cortisol elevation damages the hippocampus, and a damaged hippocampus loses some of its capacity to rein in elevated cortisol, which means cortisol production continues with less effective feedback control. This, in turn, produces more hippocampal damage, further weakening the feedback loop.

This is the Glucocorticoid Cascade Hypothesis, first proposed by Sapolsky, Krey, and McEwen in 1986 and extensively supported since.

The same mechanism is thought to operate in normal aging. A lifetime of elevated glucocorticoid exposure gradually impairs the hippocampus’s ability to regulate the HPA axis, which is part of why older adults tend to have higher baseline cortisol and a slower return to baseline after stress. This is not exclusive to clinical conditions. It is the background consequence of chronic unmanaged stress running through a lifetime.

So, what can we do about it?

The Alzheimer’s connection, the reversibility window, and the limbic resonance solution are exclusive to paid subscribers. Join the readers who want the full picture.

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A SURPRISING DISCOVERY

A Stanford scientist is staring at data from Wales that should not exist.

The data compared two groups of 79-year-olds, whose dates of birth were separated by a single week, but who were comparable on every other metric — education level, income, rates of diabetes, heart disease, and cancer. One group had received a shingles vaccine, and the other had not, due to a bureaucratic eligibility cutoff. Seven years later, the vaccinated group was 20 percent less likely to have been diagnosed with dementia.

The difference was so striking that when Dr. Pascal Geldsetzer, the Stanford physician leading the research, first saw it, he ran the analysis again. Then again. He searched for any confounding variable that might explain it away and found none. “This huge protective signal was there, any which way you looked at the data,” he said.

The study, published in Nature in April 2025, made headlines — briefly. Then the science moved even faster. In December 2025, a follow-up study published in Cell revealed something more startling: the shingles vaccine not only appears to prevent dementia – it also appears to slow dementia in people who already have it. Among patients living with dementia who had received the vaccine, the risk of dying from the disease dropped meaningfully. “That means that the vaccine doesn’t just have a preventive potential, but actually a therapeutic potential,” Geldsetzer said.

In the two years since the original Wales study, Geldsetzer’s team has replicated the dementia-protective signal in health records from England, Australia, New Zealand, and Canada. “We just keep seeing this strong protective signal for dementia in dataset after dataset,” he said.

A vaccine against a painful rash may turn out to be one of the most significant brain health interventions ever identified.

THE DATA CONVERGING FROM ALL DIRECTIONS

Most Americans over 50 have heard of the shingles vaccine; they think of it as protection against a painful rash. They are not wrong — but they are dramatically underestimating what this intervention now appears to do.

At IDWeek 2025, researchers presented findings from an analysis of more than 174,000 adults across 107 U.S. health systems (presented at conference; pending peer review). Compared to patients who received the pneumococcal pneumonia vaccine, those who received the shingles vaccine showed a 50 percent lower risk of vascular dementia, a 27 percent lower risk of blood clots, a 25 percent lower risk of heart attack or stroke, and a 21 percent lower risk of death from any cause.

Those cardiovascular findings align with a larger peer-reviewed study published in the European Heart Journal in May 2025. Analyzing more than 1.27 million people aged 50 and older in South Korea over up to twelve years, researchers found that shingles vaccination was associated with a 23 percent lower risk of cardiovascular events overall — including a 26 percent lower risk of major events such as stroke, heart attack, and cardiac death — with protective effects lasting up to eight years. The authors noted that the study does not establish a causal relationship and that results from an Asian cohort may not generalize to all populations.

On dementia specifically, a 2024 study in Nature Medicine, using a natural experiment with more than 200,000 people, compared the newer recombinant vaccine (Shingrix) with the older formulation and found that the recombinant vaccine added an average of 164 additional dementia-free days among those who later developed dementia. A study published in Nature Communications in early 2026 found that completing the full two-dose recombinant vaccine series was associated with a 51 percent reduction in dementia risk among adults aged 65 and older, with the protective effect appearing stronger in women than in men.

“Shingles is more than just a rash — it can raise the risk of serious problems for the heart and brain.” — Dr. Ali Dehghani, Case Western Reserve University, IDWeek 2025

THE BIGGER QUESTION

Why would a vaccine against shingles protect the brain? Why would it reduce heart attacks, blood clots, and all-cause mortality? Why would it appear to slow a disease that has resisted every pharmaceutical intervention thrown at it for decades?

The answer forces a question medicine has been reluctant to confront directly: what if a significant portion of what we call aging — what we call dementia, what we call vascular disease — is being silently driven by a virus most people have been carrying since childhood?

The virus is called varicella-zoster virus, or VZV. It is the same virus that causes chickenpox. And virtually everyone over 50 still has this virus, lying dormant in the body’s nerve cells. After a childhood case of chickenpox, the virus remains in the body. It retreats into the ganglia of the sensory nerves, where it can reside quietly for decades. For most of the nerves in your body, the sensory ganglia are located in chains along the spinal cord. For sensory nerves of the head and neck – the cranial nerves – the sensory ganglia are clinging to the undersurface of the brain.

With age, as immune surveillance declines, the virus escapes suppression and resumes replication, spreading from the sensory ganglia along the sensory nerves toward the skin. If the virus reaches the skin, the result is shingles, a painful rash that can appear on almost any part of the body. Often, VZV reactivates without producing a rash at all — no outward sign reaches the skin, but inflammation is traveling along the nerves nonetheless. And when VZV reactivates from a cranial nerve ganglion, the ganglia's close proximity to the brain can allow it to enter the brain itself.

Researchers are now finding evidence that these silent reactivations — repeated over years, over decades — may be quietly causing cumulative damage. The kind of damage that, by the time a neurologist names it, is called Alzheimer’s disease.

THE STEALTH MECHANISM

VZV reactivation can produce neuroinflammation within the brain, contribute to the deposition of amyloid proteins, promote tau aggregation, and produce patterns of cerebrovascular injury strikingly similar to those pathologists find in Alzheimer’s disease.

VZV is not the only virus capable of producing neuroinflammation in the brain. Herpes simplex virus 1 (HSV1) is the virus responsible for cold sores. Like VZV, HSV also establishes lifelong latency in the nervous system and engages in periodic reactivation. Intriguingly, HSV1 has been found inside the amyloid plaques of Alzheimer’s patients. Research published in the Journal of Neuroinflammation in 2024 found that HSV-1 infection in animal models accelerated amyloid deposition, triggered widespread inflammation, and produced measurable cognitive decline.

While amyloid beta proteins are found in large amounts in the brains of Alzheimer’s patients, it’s becoming increasingly clear that amyloid is likely to be a marker for the presence of an underlying neurodegenerative process, not the cause of that process. One emerging theory holds that amyloid beta is a defense response the brain deploys against invasion: a biological trap designed to surround and neutralize pathogens. In this view, the reason why HSV1 DNA has been found inside amyloid plaques in the brains of Alzheimer’s patients is that the virus elicits neuroinflammation, which is the real driver of neurodegeneration, and amyloid is part of the brain’s defense against the virus. Years later, the virus may be gone from the field of battle, but the amyloid remains, just as we can still see today the remnants of the WWI trenches dug in France more than a century ago.

What if the plaques we have been targeting in Alzheimer’s research for thirty years are not the disease, but the aftermath of a battle the brain has been silently losing since middle age?

THE FLU VACCINE CLUE — AND THE SURPRISE INSIDE THE SHOT

The shingles vaccine is not the only common vaccine that has produced unexpected signals in dementia research. The flu vaccine — which targets an entirely different virus — also appears to reduce the risk of Alzheimer’s disease.

A study of nearly one million matched patients found that flu-vaccinated older adults had a 40 percent lower incidence of Alzheimer’s over four years compared to unvaccinated patients. A 2025 meta-analysis in Age and Ageing, examining 21 studies covering more than 100 million participants, found that influenza vaccination was linked to reduced dementia risk overall, and pneumococcal vaccination was associated with a 36 percent reduction in Alzheimer’s disease risk. Signals have also appeared for diphtheria, typhoid, and hepatitis A vaccines.

One explanation is systemic inflammation. Influenza and pneumonia generate a massive systemic inflammatory response that can and does reach into the brain. Vaccines drastically reduce the inflammatory burden of those infections, thus protecting the brain from neuroinflammation-induced degeneration.

Fundamentally, vaccines work by presenting pathogen-specific antigens to the immune system. These antigens train the immune system to attack that specific pathogen, much like giving an attack dog a sniff from clothing belonging to the person you want the dog to hunt and bring down. Less widely recognized is the fact that vaccines often contain other ingredients as well (often called “adjuvants”), including non-specific immune modulators that up-regulate immune system attack functions in general.

A 2025 study published in npj Vaccines analyzed 436,788 individuals and compared the dementia-protective effects of two different vaccines – RSV and shingles – that shared the same adjuvant. Both vaccines produced nearly identical reductions in dementia risk. In other words, the shingles-specific vaccine ingredients may not be the only active components of the vaccine. The adjuvant itself — a compound that trains the aging immune system to be more alert — may be doing significant independent work.

This finding is still early. But its implication is striking: the benefit of the shingles vaccine may be partly about shingles, and partly about giving the waning immune system a bit of a recalibrating boost in older patients.

WHAT THIS MEANS — AND WHAT WE STILL DON’T KNOW

The science in this sector is moving faster than medical guidelines typically do. Researchers are careful to emphasize that proof of causation has not been fully established. The dementia-protective signals emerged from studies of adults vaccinated in their late 70s and older, so how much of the benefit applies to those vaccinated at age 50 or 60 remains unknown. No randomized controlled trial has been conducted specifically to test vaccination as a dementia prevention strategy. Geldsetzer is currently seeking funding for exactly that trial.

One pattern has appeared consistently across multiple studies and is worth naming directly: the protective signal has been stronger in women than in men — in some analyses, substantially so. The reasons remain unclear, though researchers suspect differences in immune response and in the biology of VZV reactivation between sexes. Women also carry a higher baseline risk for dementia, which may partly explain the larger observed effect.

A further note on the evidence: the strongest causal findings — the near-randomized Wales natural experiment — were based on the older, live-attenuated-virus vaccine (Zostavax), which is no longer available in the United States. The newer recombinant vaccine, Shingrix (which contains no live virus) is supported by large observational studies showing a similar or stronger protective signal. The greater efficacy of Shingrix against shingles itself gives researchers reason to expect at least comparable protection in the brain against dementia. But direct causal evidence for Shingrix specifically is still accumulating.

What is not in dispute: Shingrix is the only shingles vaccine currently available in the U.S., the CDC recommends it for all adults 50 and older, and it has one of the strongest efficacy and safety profiles of any vaccine in routine adult use. For adults aged 19 and older who are immunocompromised — including those with rheumatoid arthritis, inflammatory bowel disease, cancer, or conditions requiring immunosuppressive medications — vaccination is recommended earlier, though timing relative to specific treatments is best discussed with a physician.

For healthy adults under 50, no recommendation currently exists. The shingles risk is low in this group, and the dementia data does not yet extend to this population.

The larger story is about a paradigm shift happening beneath the surface of mainstream medicine. We have spent decades treating aging as a purely metabolic and genetic phenomenon. The emerging evidence suggests we also need to account for what pathogens do to us over a lifetime — and how viruses that never truly leave us can silently shape the trajectory of the brain and body as we age.

WHAT TO KNOW BEFORE YOU GO

Who it is for. The CDC recommends two doses of Shingrix for all adults 50 and older with healthy immune systems, regardless of whether they recall having chickenpox. For adults 19 and older who are immunocompromised — due to conditions such as rheumatoid arthritis, cancer, or medications that suppress the immune system — vaccination is recommended starting at age 19. For healthy adults under 50, there is no current recommendation.

Efficacy. In adults 50 to 69 with healthy immune systems, Shingrix is 97% effective against shingles. In adults 70 and older, 91% effective. Protection is estimated to remain high for at least 7 years, with roughly 80% efficacy at 10 years, according to long-term follow-up data.

Common side effects. Shingrix produces a strong immune response — which is the point. In clinical trials, roughly 17% of recipients experienced reactions strong enough to temporarily interfere with normal activities. The most common symptoms are pain, redness, and swelling at the injection site, muscle aches, fatigue, headache, shivering, low-grade fever, and upset stomach. Most resolve within two to three days. Side effects are more pronounced after the second dose and more common in younger recipients. Over-the-counter pain relievers may help manage symptoms, per CDC guidance.

Rare but serious. The FDA added a formal warning to Shingrix prescribing information after post-marketing data identified a signal for Guillain-Barré syndrome (GBS), a rare neurological disorder. The estimated risk is approximately 3 excess cases per million doses administered within 42 days of vaccination. Causality has not been definitively proven. Both the FDA and CDC state that the benefits of vaccination continue to outweigh this risk, and that shingles infection itself also raises the risk of GBS. Severe allergic reactions are possible but rare. Those who have had a severe reaction to a prior Shingrix dose or to any of its ingredients are advised not to receive it.

Timing. The two doses are given two to six months apart. Both doses matter — one dose provides partial protection, but the full series is what delivers durable immunity. If more than six months have passed since dose one, it is recommended not to restart; getting dose two as soon as possible is advised.

THIS IS JUST THE BEGINNING

The shingles vaccine story opens a door into one of the most radical ideas in modern biology: that chronic diseases we have blamed on genes, diet, and lifestyle may have a hidden viral collaborator. It is one piece of a larger revolution.

Paid subscribers have access to our ongoing Rethinking and Miracle Drug series — deep dives on the new approaches and pharmaceutical breakthroughs reshaping what is possible in human longevity. Metformin, originally a diabetes drug, is showing up in cancer prevention and aging research. Rapamycin — discovered in the soil of Easter Island — is extending healthy lifespan in animal models in ways that even its researchers were surprised by. Retatrutide is redefining what we thought was possible in metabolic medicine. Inflammaging, dementia, and atherosclerosis are all now being radically rethought.

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MEDICAL DISCLAIMER

This article is for informational and educational purposes only and does not constitute medical advice. The content reflects current scientific research and emerging evidence as interpreted by the editorial team of Forever Young. It is not intended to diagnose, treat, cure, or prevent any disease or health condition. Vaccination decisions — including timing and appropriateness — should be made in consultation with a qualified healthcare provider who can evaluate your individual medical history, current medications, and risk factors. References to specific vaccines, drugs, or interventions are not endorsements. The authors are not physicians providing medical guidance. Always discuss any health decisions with your doctor before taking action.

SOURCES

1. Eyting M, Xie M, Michalik F, et al. “A natural experiment on the effect of herpes zoster vaccination on dementia.” Nature. 2025;641(8062):438–446. Published April 2, 2025.

2. Xie M, Eyting M, Bommer C, et al. “The effect of shingles vaccination at different stages of the dementia disease course.” Cell. 2025;188(25):7049–7064. Published December 2, 2025.

3. Dehghani A, Yendewa G. Shingles vaccine and risk of vascular dementia, cardiovascular events, and all-cause mortality. Presented at IDWeek 2025, Atlanta, GA. Conference presentation; pending peer-reviewed publication.

4. Lee S, Lee K, Oh J, et al. “Live zoster vaccination and cardiovascular outcomes: a nationwide, South Korean study.” European Heart Journal. Published May 6, 2025.

5. Taquet M, Dercon Q, Todd JA, Harrison PJ. “The recombinant shingles vaccine is associated with lower risk of dementia.” Nature Medicine. 2024;30:2777–2781.

6. Rayens E, et al. “Recombinant zoster vaccine is associated with a reduced risk of dementia.” Nature Communications. Published February 9, 2026.

7. Zhang Y, et al. “Herpes simplex virus 1 accelerates the progression of Alzheimer’s disease by modulating microglial phagocytosis and activating NLRP3 pathway.” Journal of Neuroinflammation. 2024;21:175.

8. Wainberg M, et al. “The viral hypothesis: how herpesviruses may contribute to Alzheimer’s disease.” Molecular Psychiatry. 2021;26:5476–5480.

9. Levine KS, Leonard HL, Blauwendraat C, et al. “Virus exposure and neurodegenerative disease risk across national biobanks.” Neuron. 2023;111(7):1086–1093.

10. Moir RD, Lathe R, Tanzi RE. “The antimicrobial protection hypothesis of Alzheimer’s disease.” Alzheimer’s & Dementia. 2018;14:1602–1614.

11. Bukhbinder A, Ling Y, Hasan O, et al. “Risk of Alzheimer’s disease following influenza vaccination: a claims-based cohort study using propensity score matching.” Journal of Alzheimer’s Disease. 2022;95(2):703–718.

12. Veronese N, et al. “Association between vaccinations and risk of dementia: a systematic review and meta-analysis.” Age and Ageing. 2025;54(11):afaf331.

13. Taquet M, Dercon Q, Todd JA, Harrison PJ. “Lower risk of dementia with AS01-adjuvanted vaccination against shingles and respiratory syncytial virus infections.” npj Vaccines.

14. U.S. Centers for Disease Control and Prevention. Shingles Vaccination: Who Should Get Vaccinated. Updated August 2025.

15. U.S. Food and Drug Administration. FDA Requires a Warning about Guillain-Barré Syndrome (GBS) be Included in the Prescribing Information for Shingrix. Safety Communication, March 2021.

Imagine a condition that strikes virtually every woman in her early fifties. Overnight, the risk of heart disease quadruples. Cognitive decline accelerates. Bones begin losing density at a quickening pace. A hormonal communication network built over thirty years — signaling between the brain, heart, immune system, and bones — goes quiet.

This condition is not classified as a disease. Medicine has labeled it as a natural part of aging. For most of the last century, hormone therapy was a standard part of how doctors treated it. Then, in 2002, that option was largely taken off the table, for the next twenty-three years, until now.

The condition we’ve been describing is called menopause. According to Dr. Jennifer Garrison, neuroscientist and Co-Director of the Center for Healthy Aging in Women at the Buck Institute for Research on Aging, classifying menopause as simply “natural aging” may be one of the most consequential medical decisions of the modern era. Speaking to TODAY, she put it plainly: “Menopause is the worst thing that can happen to a healthy woman’s body.”

In February 2026, the FDA quietly confirmed what researchers like Dr. Garrison had been arguing for years. On February 12, it formally approved label changes for the first batch of six hormone therapy medications — removing warnings about cardiovascular disease, breast cancer, and probable dementia that had been embedded in the prescribing information since 2003. The six medications span all four categories of HRT (Hormone Replacement Therapy): combination estrogen-progestogen therapy (Bijuva), estrogen-alone therapies (Divigel, Cenestin, Enjuvia), progestogen-alone therapy (Prometrium), and topical vaginal estrogen (Estring). Twenty-three additional companies have submitted proposed label changes; more approvals are expected to follow. The warnings and admonitions that caused doctors to stop prescribing HRT for menopause and women to stop asking about HRT appear to be dissolving.

The period from 2002 to 2026 is one of the most revealing chapters in modern women’s health.

THE STUDY THAT TURNED THE TIDE

For much of the late twentieth century, hormone replacement therapy was standard menopause care. Then in 2002, the Women’s Health Initiative — one of the largest women’s health studies in U.S. history — published interim findings suggesting that combined estrogen and synthetic progestin elevated the risk of breast cancer, heart disease, stroke, and blood clots. The headlines were immediate and overly dramatic. The FDA applied a black-box warning to all estrogen-containing hormone therapies where the anticipated use was for the prevention or treatment of menopausal symptoms. Doctors became substantially less willing to prescribe HRT. Overall, HRT prescriptions fell by 38% in the first year after the WHI publication, with prescriptions for estrogen + progestin medications falling by 66% in the same time period. In the end, the WHI study and the fear-mongering headlines trumpeted by the media appear to have led to tens of millions of women not taking HRT, who ordinarily would have done so.

What followed was two decades of accumulating evidence that the original findings had been profoundly misapplied. One problem is that the average participant in the trial was 63, more than a decade older than women who typically seek treatment at menopause. Many had pre-existing conditions that skewed any risk calculation. Additionally, the hormonal treatments studied in the WHI were predominantly synthetic hormones administered at doses that are now thought to be excessive. It’s quite possible that giving women higher doses of synthetic hormones and giving them physiologic doses of the hormones actually found in a woman’s body are two entirely different enterprises that might yield very different results. And the trial was designed to assess disease prevention in older women, not symptom management in newly menopausal women in their early fifties. Despite these methodologic weaknesses in the WHI data, the FDA warnings applied to every woman, regardless.

“The first WHI paper had a lot of misinformation in it. The problem wasn’t the research — it was the communication, and the fear narrative it spawned.”
— Dr. Jennifer Garrison, RTÉ, December 2025

Dr. Garrison has described the fallout as a generation-long failure: a whole generation of women was scared away from a treatment that could have protected their bones, brains, and hearts — while doctors were left practicing defensive medicine under the shadow of a warning the FDA has now acknowledged was inaccurate.

The scale is measurable. In 2020, approximately 41 million American women were between the ages of 45 and 64 — the primary window for menopausal hormone therapy. Only around 2 million received a prescription for systemic treatment. A gap that size, sustained across two decades, carries a health cost researchers are only beginning to quantify.

THE REVERSAL — WHAT THE FDA JUST DID

On November 10, 2025, the HHS and FDA jointly announced they were initiating the removal of black box warnings from HRT products for menopause — the beginning of a regulatory process that had been debated for years. At the FDA’s request, 29 drug companies submitted proposed labeling changes. Then, on February 12, 2026, the FDA formally approved the first batch: six specific medications spanning all four HRT categories. In the HHS press release accompanying the November announcement, FDA Commissioner Marty Makary stated that the old warnings had denied tens of millions of women access to treatments with “life-changing and long-term health benefits,” and characterized the prior medical consensus as “rooted in a distortion of risk.”

The FDA removed warnings linking HRT to cardiovascular disease, breast cancer, and dementia, while retaining the warning linking estrogen-only treatments to endometrial cancer, for which the evidence remains robust. The FDA also removed the longstanding directive to prescribe hormone therapy at the lowest dose for the shortest possible duration. As the FDA reviews the remaining companies’ submissions, additional approvals for label changes are likely.

WHAT THE EVIDENCE ACTUALLY SAYS

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After a private screening of the film, director David Donnelly sat down with Verdin for a live virtual Q&A with the audience. No talking points. Just an hour of unfiltered conversation with one of the most respected minds in longevity science.

In this conversation, Verdin reveals:

• The longevity variable most people completely overlook — and why he’s building an entire research center around it

• Why your outlook on life isn’t just a mood issue — and what the science says it’s actually doing to your body

• On the realities of GLP-1 agonists, V02 max, and other topics that have captivated popular culture

• The booming wellness trend he calls a total scam — and why it makes him furious every time he walks past one

Plus: what’s actually coming in anti-aging medicine, the real science on fasting, and what an approved longevity drug could look like within five years.

This is just the beginning.

Dr. Verdin mentioned something in passing that most people don’t fully register: the biology of aging can be modulated. One of the most extraordinary examples of that happening right now is at his own institution — the Buck Institute’s work on senescent cells, the so-called “zombie cells” that accumulate in your body as you age, quietly driving inflammation, accelerating disease, and shortening your life. Scientists now have drugs that can selectively eliminate them. In animal models, the results are extraordinary.

Paid subscribers get access to that interview as well as our full archive of 100+ videos and articles that give insider access to the drugs, treatments, science, and philosophy driving the most exciting revolution of our lifetime.

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