Teasing apart the intricacies of human longevity is complicated. Diet, exercise, and other habits can change the trajectory of a person’s health as they grow older. Genetics also plays a role—especially during the twilight years. But experiments to test these ideas are difficult, in part because of our relatively long lifespan. Following a large population of people as they age is prohibitively expensive, and results could take decades. So, most studies have turned to animal aging models—including flies, rodents, and dogs—with far shorter lives.

But what if we could model human “aging in a dish” using cells derived from people with exceptionally long lives?

A new study, published in Aging Cell, did just that. Leveraging blood draws from the New England Centenarian Study—the largest and most comprehensive database of centenarians—they transformed blood cells into induced-pluripotent stem cells (iPSCs).

These cells contain their donor’s genetic blueprint. In essence, the team created a biobank of cells that could aid researchers in their search for longevity-related genes.

“Models of human aging, longevity, and resistance to and/or resilience against disease that allow for the functional testing of potential interventions are virtually non-existent,” wrote the team.

They’ve already shared these “super-aging” stem cells with the rest of the longevity community to advance understanding of the genes and other factors contributing to a healthier, longer life.

“This bank is really exciting,” Chiara Herzog, a longevity researcher at Kings College London, who was not involved in the study, told Nature.

Precious Resource

Centenarians are rare. According to the Pew Research Center, based on data from the US Census Bureau, they make up only 0.03 percent of the country’s population. Across the globe, roughly 722,000 people have celebrated their 100th birthday—a tiny fraction of the over eight billion people currently on Earth.

Centenarians don’t just live longer. They’re also healthier, even in extreme old age, and less likely to suffer age-related diseases, such as dementia, Type 2 diabetes, cancer, or stroke. Some evade these dangerous health problems altogether until the very end.

What makes them special? In the last decade, several studies have begun digging into their genes to see which are active (or not) and how this relates to healthy aging. Others have developed aging clocks, which use myriad biomarkers to determine a person’s biological age—that is, how well their bodies are working. Centenarians frequently stood out, with a genetic landscape and bodily functions resembling people far younger than expected for their chronological age.

Realizing the potential for studying human aging, the New England Centenarian Study launched in 1995. Now based at Boston University and led by Tom Perls and Stacy Andersen, both authors of the new study, the project has recruited centenarians through a variety of methods—voter registries, news articles, or mail to elderly care facilities.

Because longevity may have a genetic basis, their children were also invited to join, with spouses serving as controls. All participants reported on their socioeconomic status and medical history. Researchers assessed their cognition on video calls and screened for potential mental health problems. Finally, some participants had blood samples taken. Despite their age, many centenarians remained sharp and could take care of themselves.

Super-Ager Stem Cells

The team first tested participants with a variety of aging clocks. These measured methylation, which shuts genes down without changing their DNA sequences. Matching previous results, centenarians were, on average, six and a half years younger than their chronological age.

The anti-aging boost wasn’t as prominent in their children. Some had higher biological ages and others lower. This could be because of variation in who inherited a genetic “signature” associated with longevity, wrote the team.

They then transformed blood cells from 45 centenarians into iPSCs. The people they chose were “at the extremes of health and functionality,” the team wrote. Because of their age, they initially expected that turning back the clock might not work on old blood cells.

Luckily, they were wrong. Several proteins showed the iPSCs were healthy and capable of making other cells. They also mostly maintained their genomic integrity—although surprisingly, cells from three male centenarians showed a slight loss of the Y chromosome.

Previous studies have found a similar deletion pattern in blood cells from males over 70 years of age. It could be a marker for aging and a potential risk factor for age-related conditions such as cancer and heart disease. Women, on average, live longer than men. The findings “allow for interesting research opportunities” to better understand why Y chromosome loss happens.

Unraveling Aging

Turning blood cells into stem cells erases signs of aging, especially those related to the cells’ epigenetic state. This controls whether genes are turned on or off, and it changes with age. But the underlying genetic code remains the same.

If the secrets to longevity are, even only partially, hidden in the genes, these super-aging stem cells could help researchers figure out what’s protective or damaging, in turn prompting new ideas that slow the ticking of the clock.

In one example, the team nudged the stem cells to become cortical neurons. These neurons form the outermost part of the brain responsible for sensing and reasoning. They’re also the first to decay in dementia or Alzheimer’s disease. Those derived from centenarians better fought off damage, such as rapidly limiting the spread of toxic proteins that accumulate with age.

Researchers are also using the cells to test for resilience against Alzheimer’s. Another experiment observed cell cultures made of healthy neurons, immune cells, and astrocytes. The latter, supporting cells that help keep brains healthy, were created using centenarian stem cells. Astrocytes have increasingly been implicated in Alzheimer’s, but their role has been hard to study in humans. Those derived from centenarian stem cells offer a way forward.

Each line of centenarian stem cells is linked to its donor—their demographics, cognitive, and physical state. This additional information could guide researchers in choosing the best centenarian cell line for their investigations into different aspects of aging. And because the cells can be transformed into a wide variety of tissues that decline with age—muscles, heart, or immune cells—they offer a new way to explore how aging affects different organs, and at what pace.

“The result of this work is a one-of-a-kind resource for studies of human longevity and resilience that can fuel the discovery and validation of novel therapeutics for aging-related disease,” wrote the authors.

Image Credit: Danie Franco on Unsplash

A new study published in Nature Aging analyzed brain imaging data from nearly 11,000 healthy adults, middle-aged and older, using AI to gauge their “brain age.” Roughly half of participants had their blood proteins analyzed to fish out those related to aging.

Scientists have long looked for the markers of brain aging in blood proteins, but this study had a unique twist. Rather than mapping protein profiles to a person’s chronological age—the number of years on your birthday card—they used biological brain age, which better reflects the actual working state of the brain as the clock ticks on.

Thirteen proteins popped up—eight associated with faster brain aging and five that slowed down the clock. Most alter the brain’s ability to handle inflammation or are involved in cells’ ability to form connections.

From these, three unique “signatures” emerged at 57, 70, and 78 years of age. Each showed a combination of proteins in the blood marking a distinct phase of brain aging. Those related to neuron metabolism peaked early, while others spurring inflammation were more dominate in the twilight years.

These spikes signal a change in the way the brain functions with age. They may be points of intervention, wrote the authors. Rather than relying on brain scans, which aren’t often available to many people, the study suggests that a blood test for these proteins could one day be an easy way to track brain health as we age.

The protein markers could also help us learn to prevent age-related brain disorders, such as dementia, Alzheimer’s disease, stroke, or problems with movement. Early diagnosis is key. Although the protein “hallmarks” don’t test for the disorders directly, they offer insight into the brain’s biological age, which often—but not always—correlates with signs of aging.

The study helps bridge gaps in our understanding of how brains age, the team wrote.

Treasure Trove

Many people know folks who are far sharper than expected at their age. A dear relative of mine, now in their mid-80s, eagerly adopted ChatGPT, AI-assisted hearing aids, and “Ok Google.” Their eyes light up anytime they get to try a new technology. Meanwhile, I watched another relative—roughly the same age—rapidly lose their wit, sharp memory, and eventually, the ability to realize they were no longer logical.

My experiences are hardly unique. With the world rapidly aging, many of us will bear witness to, and experience, the brain aging process. Projections suggest that by 2050, over 1.5 billion people will be 65 or older, with many potentially experiencing age-related memory or cognitive problems.

But chronological age doesn’t reflect the brain’s actual functions. For years, scientists studying longevity have focused on “biological age” to gauge bodily functions, rather than the year on your birth certificate. This has led to the development of multiple aging clocks, with each measuring a slightly different aspect of cell aging. Hundreds of these clocks are now being tested, as clinical trials use them to gauge the efficacy of potential anti-aging treatments.

Many of the clocks were built by taking tiny samples from the body and analyzing certain gene expression patterns linked to the aging process. It’s tough to do that with the brain. Instead, scientists have largely relied on brain scans, showing structure and connectivity across regions, to build “brain clocks.” These networks gradually erode as we age.

The studies calculate the “brain age gap”— the difference between the brain’s structural integrity and your actual age. A ten-year gap, for example, means your brain’s networks are more similar to those of people a decade younger, or older, than you.

Most studies have had a small number of participants. The new study tapped into the UK Biobank, a comprehensive dataset of over a million people with regular checkups—including brain scans and blood draws—offering up a deluge of data for analysis.

The Brain Age Gap

Using machine learning, the study first sorted through brain scans of almost 11,000 people aged 45 to 82 to calculate their biological brain age. The AI model was trained on hundreds of structural features of the brain, such as overall size, thickness of the cortex—the outermost region—and the amount and integrity of white matter.

They then calculated the brain age gap for each person. On average, the gap was roughly three years, swinging both ways, meaning some people had either a slightly “younger” or “older” brain.

Next, the team tried to predict the brain age gap by measuring proteins in plasma, the liquid part of blood. Longevity research in mice has uncovered many plasma proteins that age or rejuvenate the brain.

After screening nearly 3,000 plasma proteins from 4,696 people, they matched each person’s protein profile to the participant’s brain age. They found 13 proteins associated with the brain age gap, with most involved in inflammation, movement, and cognition.

Two proteins particularly stood out.

One called Brevican, or BCAN, helps maintain the brain’s wiring and overall structure and supports learning and memory. The protein dwindles in Alzheimer’s disease. Higher levels, in contrast, were associated with slower brain aging and lower risk of dementia and stroke.

The other protein, growth differentiation factor 15 (GDF15), is released by the body when it senses damage. Higher levels correlated with a higher risk of age-related brain disease, likely because it sparks chronic inflammation—a “hallmark” of aging.

There was also a surprising result.

Plasma protein levels didn’t change linearly with age. Instead, changes peaked at three chronological ages—57, 70, and 78—with each stage marking a distinctive phase of brain aging.

At 57, for example, proteins related to brain metabolism and wound healing changed markedly, suggesting early molecular signs of brain aging. By 70, proteins that support the brain’s ability to rewire itself—some strongly associated with dementia and stroke—changed rapidly. Another peak, at 78, showed protein changes mostly related to inflammation and immunity.

“Our findings thus emphasize the importance and necessity of intervention and prevention at brain age 70 years to reduce the risk of multiple brain disorders,” wrote the authors

To be clear: These are early results. The participants are largely of European ancestry, and the results may not translate to other populations. The 13 proteins also need further testing in animals before any can be validated as biomarkers. But the study paves the way.

Their results, the authors conclude, suggest the possibility of earlier, simpler diagnosis of age-related brain disorders and the development of personalized therapies to treat them.

To optimists in the longevity field, the rapid rise in life expectancy will likely continue at a steady, if not accelerated, pace.

Others have a more pessimistic view. In their predictions, humans will hit a natural ceiling, with the average person in developed countries living to an age far less than 100.

A new study adds to the debate with analysis of data from 1990 to 2019. After examining life expectancy from eight countries with the longest living populations, plus those from Hong Kong and the US, the team reached a troubling conclusion: Despite innovations in healthcare, the increase in overall life expectancy is slowing down.

“Most people alive today at older ages are living on time that was manufactured by medicine,” said study author S. Jay Olshansky, a veteran researcher of aging at the University of Illinois. “But these medical Band-Aids are producing fewer years of life even though they’re occurring at an accelerated pace, implying that the period of rapid increases in life expectancy is now documented to be over.”

The team’s analysis suggests that only 15 percent of females and 5 percent of males will live to 100 years old. In other words, “unless the processes of biological aging can be markedly slowed, radical human life extension is implausible in this century,” they wrote.

The paper is sparking heated discussion between scientists and investors in the field.

“One of the most intriguing and lively scientific disputes concerns the future of human lifespan,” wrote Dmitri Jdanov and Domantas Jasilionis at the Max Planck Institute for Demographic Research and the Max Planck–University of Helsinki Center for Social Inequalities in Population Health, respectively, who were not involved in the study.

A Divided View

Human life extension sounds sci-fi. But thanks to modern medicine, it’s already happened. Medical innovations and public health measures have dramatically increased human life expectancy over the last century.

Rewinding back to the late 19th and early 20th centuries, antibiotics weren’t available as a first-line treatment for a scrape or a wound. Few vaccines were widely used against a variety of spreadable diseases—typhoid, cholera, and plague. Handwashing was just starting to be adopted by surgeons—although shockingly, the practice wasn’t mandated until the 1980s.

The recent explosion of biomedical technologies lends itself to an optimistic outlook on life extension. Engineered immune cells can now fight off previously untreatable cancers and are beginning to tackle deadly autoimmune diseases. Organ transplant and “smart” implants can rejuvenate broken down organs. Medical imaging technologies capture diseases at early stages and help expecting mothers track pregnancies, lowering the risk during delivery. If the pace of discovery continues, more treatments and technologies could be on the horizon.

The pessimists also have a case. In their view, human lifespan has a hard ceiling. Like houses, cars, or other complex structures, our bodies eventually break down. Cells deteriorate, aggregating clumps of toxic waste that cloud the brain. Heart cells and blood vessels struggle to keep blood pumping. Kidneys and livers lose their function. Efforts to reverse age-related diseases—dementia, heart disease, cancer, sensory, and metabolic problems—only temporarily reverse or slow aging.

“Our bodies don’t operate well when you push them beyond their warranty period,” Olshansky told Scientific American. “As people live longer, it’s like playing a game of Whac-a-Mole…Each mole represents a different disease, and the longer people live, the more moles come up and the faster they come up.”

An Age Ledger

Olshansky has been skeptical of radical life extension since 1990, when he predicted that human life expectancy gains would slow down regardless of medical interventions. But he’s interested in the fundamental question: How much longer are humans capable of living?

In 1990, his team had already “hypothesized that humanity is approaching an upper limit to life expectancy” at roughly 85 years. But some argued the initial study didn’t take into account the potential of future advances in medicine and biology.

Almost four decades later, the new results support his original finding. For the study, the team examined death rates and life expectancies from 1990 to 2019 for the eight countries with the longest-living individuals. They’re spread across the globe—South Korea, Japan, Australia, France, Italy, Switzerland, Sweden, and Spain, along with Hong Kong and the US, both of which have relatively reliable medical records. Much of the data came from the Human Mortality Database, which hosts health measures and life expectancy of people between 1950 and 2019.

From 1950, the average life expectancy increased continuously throughout all populations until 2019.  However, regardless of country, overall increases in life expectancy have slowed down in the past decade—with an especially large drop in the US.

South Korea and Hong Kong fared the best, with a less dramatic downturn in life expectancy. Even so, only roughly 14 percent of female children and roughly 4.5 percent of male kids born in 2019 are expected to reach 100 years of age. The US fared worse, with only a little over 3 percent of female children and one percent of males born around 2019 expected to live to 100.

Overall, this means that if a man and a woman live to 50 years of age, she’ll likely live to 90 on average, whereas he’d hit 85.

“Our result overturns the conventional wisdom that the natural longevity endowment for our species is somewhere on the horizon ahead of us—a life expectancy beyond where we are today,” Olshansky said.

Long Road Ahead

According to a previous analysis, no country has shown a continuous increase in life expectancy since the 19th century. But that doesn’t mean records can’t be broken. The study left the fundamentals of biological aging—why our tissues break down, why we struggle with age-related diseases—to further research.

“Additional insights into future longevity prospects” may arise from studying exceptionally long-lived groups, wrote Jdanov and Jasilionis. Dubbed “longevity vanguards,” these people hold record life expectancy. By analyzing their biology, diets, and other life-long practices, such as religion, scientists are beginning to discover why. Similar to analyzing public health trends, adding social factors, such as education, could make the predictions more accurate—not just for the vanguards, but for humanity as a whole. To be clear, these analyses can’t estimate a single person’s life expectancy. Rather, they gauge an overall picture of longevity trends.

Olshansky expects the new results to be controversial. But instead of focusing on life extension—the number of years people can live—he wants the field to zero in on extending healthspan—that is, the number of healthy years people enjoy.

The team acknowledges their projections didn’t factor in current methods for battling age-related treatments—for example, metformin, senolytics that target “zombie cells,” or genetically engineered cells that can wipe out toxic immune cells during aging.

Those approaches may be next steps. Compared to last century, we already know so much more about how and why our bodies age.

Olshansky agrees. “There’s plenty of room for improvement…We can push through this glass health and longevity ceiling with geroscience and efforts to slow the effects of aging.”

Image Credit: Gerd Altmann / Pixabay

A myriad of anti-aging therapies are in the works, and a new one just joined the fray. In mice, blocking a protein that promotes inflammation in middle age increased metabolism, lowered muscle wasting and frailty, and reduced the chances of cancer.

Unlike most previous longevity studies that tracked the health of aging male mice, the study involved both sexes, and the therapy worked across the board.

Lovingly called “supermodel grannies” by the team, the elderly lady mice looked and behaved far younger than their age, with shiny coats of fur, less fatty tissue, and muscles rivaling those of much younger mice.

The treatment didn’t just boost healthy longevity, also known as healthspan—the number of years living without diseases—it also increased the mice’s lifespan by up 25 percent. The average life expectancy of people in the US is roughly 77.5 years. If the results translate from mice to people—and that’s a very big if—it could mean a bump to almost 97 years.

The protein, dubbed IL-11, has been in scientists’ crosshairs for decades. It promotes inflammation and causes lung and kidney scarring. It’s also been associated with various types of cancers and senescence. The likelihood of all these conditions increases as we age.

Among a slew of pro-aging proteins already discovered, IL-11 stands out as it could make a beeline for testing in humans. Blockers for IL-11 are already in the works for treating cancer and tissue scarring. Although clinical trials are still ongoing, early results show the drugs are relatively safe in humans.

“Previously proposed life-extending drugs and treatments have either had poor side-effect profiles, or don’t work in both sexes, or could extend life, but not healthy life, however this does not appear to be the case for IL-11,” said study author Dr. Stuart Cook in a press release. “These findings are very exciting.”

Strange Coincidence

In 2017, Cook zeroed in on IL-11 as a treatment target for heart and kidney scarring, not longevity. Injecting IL-11 triggered the conditions, eventually leading to organ failure. Genetically deleting the protein protected against the diseases.

It’s easy to call IL-11 a villain. But the protein is an essential part of the immune system. Produced by the bone marrow, it’s necessary for embryo implantation. It also helps certain types of blood cells grow and mature, notably those that stop bleeding after a scrape.

With age, however, the protein tends to goes rogue. It sparks inflammation across the body, damaging cells and tissues and contributing to cancer, autoimmune disorders, and tissue scarring. A “hallmark of aging,” inflammation has long been targeted as a way to reduce age-related diseases. Although IL-11 is a known trigger for inflammation, it hasn’t been directly linked to aging.

Until now. The story is one of chance.

“This project started back in 2017 when a collaborator of ours sent us some tissue samples for another project,” said study author Anissa Widjaja in the press release. She was testing a method to accurately detect IL-11. Several samples of an old rat’s proteins were in the mix, and she realized that IL-11 levels were far higher in the samples than in those from younger mice.

“From the readings, we could clearly see that the levels of IL-11 increased with age, and that’s when we got really excited,” she said.

Longevity Blocker

The results spurred the team to shift their research focus to longevity. A series of tests confirmed IL-11 levels consistently rose in a variety of tissues—muscle, fat, and liver—in both male and female mice as they aged.

To see how IL-11 influences the body, the team next deleted the gene coding for IL-11 and compared mice without the protein to their normal peers. At two years old, considered elderly for mice, tissues in normal individuals were littered with genetic signatures suggesting senescence—when cells lose their function but are still alive. Often called “zombie cells,” they spew out a toxic mix of inflammatory molecules and harm their neighbors. Elderly mice without IL-11, however, had senescence genetic profiles similar to those of much younger mice.

Deleting IL-11 had other perks. Weight gain is common with age, but without IL-11, the mice maintained their slim shape and had lower levels of fat, greater lean muscle mass, and shiny, full coats of fur. It’s not just about looks. Cholesterol levels and markers for liver damage were far lower than in normal peers. Aged mice without IL-11 were also spared shaking tremors—otherwise common in elderly mice—and could flexibly adjust their metabolism depending on the quantity of food they ate.

The benefits also showed up in their genetic material. DNA is protected by telomeres—a sort of end cap on chromosomes—that dwindle in length with age. Ridding cells of IL-11 prevented telomeres from eroding away in the livers and muscles of the elderly mice.

Genetically deleting IL-11 is a stretch for clinical use in humans. The team next turned to a more feasible alternative: An antibody shot. Antibodies can grab onto a target, in this case IL-11, and prevent it from functioning.

Beginning at 75 weeks, roughly the equivalent of 55 human years, the mice received an antibody shot every month for 25 weeks—over half a year. Similar antibodies are already being tested in clinical trials.

The health benefits in these mice matched those in mice without IL-11. Their weight and fat decreased, and they could better handle sugar. They also fought off signs of frailty as they aged, experiencing minimal tremors and problems with gait and maintaining higher metabolisms. Rather than wasting away, their muscles were even stronger than at the beginning of the study.

The treatment didn’t just increase healthspan. Monthly injections of the IL-11 antibody until natural death also increased lifespan in both male and female mice by up to 25 percent.

“These findings are very exciting. The treated mice had fewer cancers and were free from the usual signs of aging and frailty… In other words, the old mice receiving anti-IL-11 were healthier,” said Cook.

Although IL-11 antibody drugs are already in clinical trials, translating these results to humans could face hurdles. Mice have a relatively short lifespan. A longevity trial in humans would be long and very expensive. The treated mice were also contained in a lab setting, whereas in the real world we roam around and have differing lifestyles—diet, exercise, drinking, smoking—that could confound results. Even if it works in humans, a shot every month beginning in middle age would likely rack up a hefty bill, providing health and life extension only to those who could afford it.

To Cook, rather than focusing on extending longevity per se, tackling a specific age-related problem, such as tissue scarring or losing muscles is a better alternative for now.

“While these findings are only in mice, it raises the tantalizing possibility that the drugs could have a similar effect in elderly humans. Anti-IL-11 treatments are currently in human clinical trials for other conditions, potentially providing exciting opportunities to study its effects in aging humans in the future,” he said.

Image Credit: MRC LMS, Duke-NUS Medical School

Meanwhile, in 2023, Guinness World Records recognized Pat the mouse as the oldest mouse alive at a little over nine and a half years old—just a sliver in years compared to humans.

When it comes to lifespan, we mammals have an astonishing range. The common shrew lives less than two years; bowhead whales thrive for at least 211 years. Why the discrepancy?

Part of it, according to Dr. Steve Horvath and colleagues at the University of California, Los Angeles, comes down to epigenetics: the chemical tags attached to DNA that flip genes on or off. The type and position of these tags shift through major life events—puberty, aging—and even with dietary changes.

Unlike genetics, the study of genes coded in DNA, epigenetics better captures the “here and now” of gene expression as we go through life. Previously, Horvath and others have tapped epigenetics to develop “aging clocks” that predict a person’s biological age—that is, how old your body is biologically, rather than the number of candles on your birthday cake.

In a new study in Science Advances, Horvath’s team expanded their epigenetic clocks to predict three life-changing traits: gestation time—how long the next generation fully grows in the womb—puberty, and maximal lifespan.

“Many have suggested that epigenetic mechanisms play a role in determining lifespan,” wrote the team in the paper.

Taking advantage of data from the Mammalian Methylation Consortium, they analyzed one type of epigenetic modification in over 15,000 tissue samples across 348 mammals and developed multiple epigenetic predictors for the three life-history traits across species.

The predictors were reliable. When challenged with lifestyle and demographic factors often associated with changing epigenetic markers—for example, weight, race, and biological sex—they retained their accuracy. Surprisingly, even notable methods for extending lifespan in the lab, for example, caloric restriction, had little effect on the clock’s measures.

“This [epigenetic] signature may be an intrinsic property of each species that is difficult to change,” the team wrote.

Epigenetic Islands

Horvath is no stranger to epigenetic clocks.

Back in 2022, his team analyzed over 13,000 human tissue samples across decades of ages to develop a “measuring tape” for biological age. It sounds silly—I know how old I am. But decades of research shows that cells, tissues, and people have a biological age that doesn’t necessarily correspond to their years on Earth—“you look a lot younger than you are!”—which may be reflected in the epigenome.

The key to the aging clock was a type of epigenetic change dubbed methylation, and more specifically sections of DNA called CpG islands. In epigenetics, chemical tags usually tack on or off like Velcro. But in puberty or aging, some permanently cling onto genes, essentially shutting them off.

In other words, this particular type of epigenetic change—methylation on CpG islands—can hide a wealth of information on development, aging, and health across mammalian species. Horvath and collaborators used their results to found the Clock Foundation, a non-profit that makes epigenetic aging clocks and data more accessible for scientists to predict healthspan—how long you stay healthy with age—and lifespan.

The Mammalian Methylation Consortium is a core resource in the work. The international effort has profiled over 15,000 samples from 348 mammals, including an impressive library of exotic tissue samples—blood from harbor seals, sheep ear, naked mole rat skin. With a custom-made methylation array, the collaboration has captured roughly 36,000 highly conserved CpG islands.

Previous studies analyzing the data focused on humans; the new study took a bird’s-eye view across species.

Predicting Life History

The team focused on three major “life-history traits:” gestation time, age at maturity, and maximum lifespan. To be clear, lifespan analysis is based on current records—that is, the longest living example documented for any species, rather than a theoretical projection of potential increase in lifespan.

Developing several algorithms, the team matched their prediction to a public database, AnAge, which includes extensive longevity records of multiple species. The predictor for maximum lifespan “aligned closely with those recorded in anAge,” wrote the team.

Gestation time was even more accurate—likely because it’s easier to measure—whereas the algorithm struggled to predict puberty.

Playing around with the algorithm, the team next built a separate lifespan predictor using data from young animals, before the age of five and before the onset of puberty. Surprisingly, it also worked. For species with a lifespan over 20 years, analyzing methylation had “remarkable accuracy,” wrote the team. It suggests that the maximum lifespan is somehow already imprinted into DNA samples of a species, regardless of age.

Overall, the “epigenetic indicators of life-history traits” when looking at specific species and individuals don’t always correlate with age, wrote the team.

Ready, Steady

A main criterion for any epigenetic clock is reliability. Maximum lifespan isn’t necessarily set—it’s influenced by many factors we don’t yet fully understand. Weight, demographics, diet, and hormones are already proven to lengthen or shorten overall lifespan.

The team next put their epigenetic predictor through several challenges known to alter the epigenome.

One was diet. A high-fat diet tends to slash how long mice live. The predictor linked liver samples from mice given a “cheese and butter” diet to lower maximal lifespan for these critters, compared to peers with a normal diet. However, caloric restriction, a widely used intervention that promotes longevity, didn’t change the predictor’s results. Overall, the predictor seems to be relatively stable to dietary changes that could affect lifespan, at least for mice, the team explained.

In another test, the team used the predictor to assess the maximum lifespan from blood samples of two major human studies—the Framingham Heart Study and the Women’s Health Initiative, with over 4,500 samples in total. Smoking, race, weight, metabolism, and cognitive function had no influence on the epigenetic predictor for maximum lifespan.

So, what did make a difference? Across the board, the main factor was biological sex. In 17 out of 18 analyzed mammalian species—including humans—females tended to have methylation factors that increased their lifespan by roughly one percent compared to males.

What to make of all of this?

For one, the results suggest that lifestyle behaviors—what you eat, drink, and such—may not influence the maximum bounds of lifespan, at least when measured using these epigenetic predictors. It’s a controversial idea, and the team adds caveats in their conclusion. A main one is that methylation data for human samples was obtained using a different sequencing platform, which could trip up the analysis. “Future research should revisit these findings” using a screening array similar to that used by the consortium, the team explained.

The tool also generated different predictions depending on tissue samples, with blood generally predicting a longer lifespan than, say, brain or kidney. The study used an average of all samples for their algorithm. But finding the reason behind tissue-specific differences could lead to insights into how their methylation changes with age—for any mammal.

“Together our results suggest that species maximum lifespan is strongly associated with an epigenetic signature,” wrote the team. As a next step, they hope to find interventions that can alter epigenetic lifespan.

Image Credit: Jon Tyson / Unsplash

Each unit has a unique specialty. Some cells directly kill invading foes; others release protein “markers” to attract immune cell types to a target. Together, they’re a formidable force that fights off biological threats—both pathogens from outside the body and cancer or senescent “zombie” cells from within.

With age, the camaraderie breaks down. Some units flare up, causing chronic inflammation that wreaks havoc in the brain and body. These cells increase the risk of dementia, heart disease, and gradually sap muscles. Other units that battle novel pathogens—such as a new strain of flu—slowly dwindle, making it harder to ward off infections.

All these cells come from a single source: a type of stem cell in bone marrow.

This week, in a study published in Nature, scientists say they restored the balance between the units in aged mice, reverting their immune systems back to a youthful state. Using an antibody, the team targeted a subpopulation of stem cells that eventually develops into the immune cells underlying chronic inflammation. The antibodies latched onto targets and rallied other immune cells to wipe them out.

In elderly mice, the one-shot treatment reinvigorated their immune systems. When challenged with a vaccine, the mice generated a stronger immune response than non-treated peers and readily fought off later viral infections.

Rejuvenating the immune system isn’t just about tackling pathogens. An aged immune system increases the risk of common age-related medical problems, such as dementia, stroke, and heart attacks.

“Eliminating the underlying drivers of aging is central to preventing several age-related diseases,” wrote stem cell scientists Drs. Yasar Arfat Kasu and Robert Signer at the University of California, San Diego, who were not involved in the study. The intervention “could thus have an outsized impact on enhancing immunity, reducing the incidence and severity of chronic inflammatory diseases and preventing blood disorders.”

Stem Cell Succession

All blood cells arise from a single source: hematopoietic stem cells, or blood stem cells, that reside in bone marrow.

Some of these stem cells eventually become “fighter” white blood cells, including killer T cells that—true to their name—directly destroy cancerous cells and infections. Others become B cells that pump out antibodies to tag invaders for elimination. This unit of the immune system is dubbed “adaptive” because it can tackle new intruders the body has never seen.

Still more blood stem cells transform into myriad other immune cell types—including those that literally eat their foes. These cells form the innate immune unit, which is present at birth and the first line of defense throughout our lifetime.

Unlike their adaptive comrades, which more precisely target invaders, the innate unit uses a “burn it all” strategy to fight off infections by increasing local inflammation. It’s a double-edged sword. While useful in youth, with age the unit becomes dominant, causing chronic inflammation that gradually damages the body.

The reason for this can be found in the immune system’s stem cell origins.

Blood stem cells come in multiple types. Some produce both immune units equally; others are biased towards the innate unit. With age, the latter gradually take over, increasing chronic inflammation while lowering protection against new pathogens. This is, in part, why elderly people are advised to get new flu shots, and why they were first in line for vaccination against Covid-19.

The new study describes a practical approach to rebalancing the aged immune system. Using an antibody-based therapy, the scientists directly obliterated the population of stem cells that lead to chronic inflammation.

Blood Bath

Like most cells, blood stem cells have a unique fingerprint—a set of proteins that dot their surfaces. A subset of the cells, dubbed my-HSCs, are more likely to produce cells in the innate immune system, which triggers chronic inflammation with age.

By mining multiple gene expression datasets from blood stem cells, the team found three protein markers they could use to identify and target my-HSCs cells in aged mice. They then engineered an antibody to target the cells for elimination.

Just a week after infusing it into elderly mice, the antibody had reduced the number of myHSC cells in their bone marrow without harming other blood stem cells. A genetic screen confirmed the mice’s immune profile was more like that of young mice.

The one-shot treatment lasted “strikingly” long, wrote Kasu and Signer. A single injection reduced the troublesome stem cells for at least two months—roughly a twelfth of a mouse’s lifespan. With my-HSCs no longer dominant, healthy blood stem cells gained ground inside the bone marrow. For at least four months, the treated mice produced more cells in the adaptive immune unit than their similarly aged peers, while having less overall inflammation.

As an ultimate test, the team challenged elderly mice with a difficult virus. To beat the infection, multiple components of the adaptive immune system had to rev up and work in concert.

Some elderly mice received a vaccine and the antibody treatment. Others only received the vaccine. Those treated with the antibody mounted a larger protective immune response. When given a dose of the virus, their immune systems rapidly recruited adaptive immune cells, and fought off the infection—whereas those receiving only the vaccine struggled.

Restoring Balance

The study shows that not all blood stem cells are alike. Eliminating those that cause inflammation directly changes the biological “age” of the entire immune system, allowing it to better tackle damaging changes in the body and fight off infections.

Like a leaking garbage can, innate immune cells can dump inflammatory molecules into their neighborhood. By cleaning up the source, the antibody could have also changed the environment the cells live in, so they are better able to thrive during aging.

Additionally, the immune system is an “eye in the sky” for monitoring cancer. Reviving immune function could restore the surveillance systems needed to eliminate cancer cells. The antibody treatment here could potentially tag-team with CAR T therapy or classic anti-cancer therapies, such as chemotherapy, as a one-two punch against the disease.

But it isn’t coming to clinics soon. Without unexpected setbacks or regulatory hiccups, the team estimates three to five years before testing in people. As a next step, they’re looking to expand the therapy to tackle other disorders related to a malfunctioning immune system.

Image Credit: Volker Brinkmann

Yet a new study led by Dr. Corina Amor Vegas at Cold Spring Harbor Laboratory describes a treatment that brings the dream to life—at least for mice. Given a single injection in young adulthood, they aged more slowly compared to their peers.

By the equivalent of roughly 65 years of age in humans, the mice were slimmer, could better regulate blood sugar and insulin levels, and had lower inflammation and a more youthful metabolic profile. They even kept up their love for running, whereas untreated seniors turned into couch potatoes.

The shot is made up of CAR (chimeric antigen receptor) T cells. These cells are genetically engineered from the body’s T cells—a type of immune cell adept at hunting down particular targets in the body.

CAR T cells first shot to fame as a revolutionary therapy for previously untreatable blood cancers. They’re now close to tackling other medical problems, such as autoimmune disorders, asthma, liver and kidney diseases, and even HIV.

The new study took a page out of CAR T’s cancer-fighting playbook. But instead of targeting cancer cells, they engineered them to hunt down and destroy senescent cells, a type of cell linked to age-related health problems. Often dubbed “zombie cells,” they accumulate with age and pump out a toxic chemical brew that damages surrounding tissues. Zombie cells have been in the crosshairs of longevity researchers and investors alike. Drugs that destroy the cells called senolytics are now a multi-billion-dollar industry.

The new treatment, called senolytic CAR T, also turned back the clock when given to elderly mice. Like humans, the risk of diabetes increases with age in mice. By clearing out zombie cells in multiple organs, the mice could handle sugar rushes without a hitch. Their metabolism improved, and they began jumping around and running like much younger mice.

“If we give it to aged mice, they rejuvenate. If we give it to young mice, they age slower. No other therapy right now can do this,” said Amor Vegas in a press release.

The Walking Dead

Zombie cells aren’t always evil.

They start out as regular cells. As damage to their DNA and internal structures accumulates over time, the body “locks” the cells into a special state called senescence. When young, this process helps prevent cells from turning cancerous by limiting their ability to divide. Although still living, the cells can no longer perform their usual jobs. Instead, they release a complex cocktail of chemicals that alerts the body’s immune system—including T cells—to clear them out. Like spring cleaning, this helps keep the body functioning normally.

With age, however, zombie cells linger. They amp up inflammation, leading to age-related diseases such as cancer, tissue scarring, and blood vessel and heart conditions. Senolytics—drugs that destroy these cells—improve these conditions and increase life span in mice.

But like a pill of Advil, senolytics don’t last long inside the body. To keep zombie cells at bay, repeated doses are likely necessary.

A Perfect Match

Here’s where CAR T cells come in. Back in 2020, Amor Vegas and colleagues designed a “living” senolytic T cell that tracks down and kills zombie cells.

All cells are dotted with protein “beacons” that stick out from their surfaces. Different cell types have unique assortments of these proteins. The team found a protein “beacon” on zombie cells called uPAR. The protein normally occurs at low levels in most organs, but it ramps up in zombie cells, making it a perfect target for senolytic CAR T cells.

In a test, the therapy eliminated senescent cells in mouse models with liver and lung cancers. But surprisingly, the team also found that young mice receiving the treatment had better liver health and metabolism—both of which contribute to age-related diseases.

Can a similar treatment also extend health during aging?

A Living Anti-Aging Drug

The team first injected senolytic CAR T cells into elderly mice aged the equivalent of roughly 65 human years old. Within 20 days, they had lower numbers of zombie cells throughout their bodies, particularly in their livers, fatty tissues, and pancreases. Inflammation levels caused by zombie cells went down, and the mice’s immune profiles reversed to a more youthful state.

In both mice and humans, metabolism tends to go haywire with age. Our ability to handle sugars and insulin decreases, which can lead to diabetes.

With senolytic CAR T therapy, the elderly mice could regulate their blood sugar levels far better than non-treated peers. They also had lower baseline insulin levels after fasting, which rapidly increased when given a sugary treat—a sign of a healthy metabolism.

A potentially dangerous side effect of CAR T is an overzealous immune response. Although the team saw signs of the side effect in young animals at high doses, lowering the amount of the therapy was safe and effective in elderly mice.

Young and Beautiful

Chemical senolytics only last a few hours inside the body. Practically, this means they may need to be consistently taken to keep zombie cells at bay.

CAR T cells, on the other hand, have a far longer lifespan, which can last over 10 years after an initial infusion inside the body. They also “train” the immune system to learn about a new threat—in this case, senescent cells.

“T cells have the ability to develop memory and persist in your body for really long periods, which is very different from a chemical drug,” said Amor Vegas. “With CAR T cells, you have the potential of getting this one treatment, and then that’s it.”

To test how long senolytic CAR T cells can persist in the body, the team infused them into young adult mice and monitored their health as they aged. The engineered cells were dormant until senescent cells began to build up, then they reactivated and readily wiped out the zombie cells.

With just a single shot, the mice aged gracefully. They had lower blood sugar levels, better insulin responses, and were more physically active well into old age.

But mice aren’t people. Their life spans are far shorter than ours. The effects of senolytic CAR T cells may not last as long in our bodies, potentially requiring multiple doses. The treatment can also be dangerous, sometimes triggering a violent immune response that damages organs. Then there’s the cost factor. CAR T therapies are out of reach for most people—a single dose is priced at hundreds of thousands of dollars for cancer treatments.

Despite these problems, the team is cautiously moving forward.

“With CAR T cells, you have the potential of getting this one treatment, and then that’s it,” said Amor Vegas. For chronic age-related diseases, that’s a potential life-changer. “Think about patients who need treatment multiple times per day versus you get an infusion, and then you’re good to go for multiple years.”

Image Credit: Senescent cells (blue) in healthy pancreatic tissue samples from an old mouse treated with CAR T cells as a pup / Cold Spring Harbor Laboratory

They could also regulate longevity with an unexpected partner: the brain.

A new study in mice found a “phone line” between fatty tissues and a group of neurons inside the hypothalamus—a region at the bottom of the brain that controls basic bodily functions such as temperature regulation and breathing.

When young, these neurons signal fatty tissues to release energy fueling the brain. With age, the line breaks down. Fat cells can no longer orchestrate their many roles, and neurons struggle to pass information along their networks.

Using genetic and chemical methods, the team found a marker for these neurons—a protein called Ppp1r17 (catchy, I know). Changing the protein’s behavior in aged mice with genetic engineering extended their life span by roughly seven percent. For an average 76-year life span in humans, the increase translates to over five years.

The treatment also altered the mice’s health. Mice love to run, but their vigor plummets with age. Reactivating the neurons in elderly mice revived their motivation, transforming them from couch potatoes into impressive joggers.

“We demonstrated a way to delay aging and extend healthy life spans in mice by manipulating an important part of the brain,” said study author Dr. Shin-ichiro Imai at Washington University.

The Brain-Body Internet

Longevity is complicated. Multiple factors influence how fast our tissues and organs age, such as genetic typos, inflammation, epigenetic changes, and metabolic problems.

But there is a throughline: Decades of work in multiple species have found that cutting calories and increasing exercise keeps multiple organ functions young as we age. Many of the benefits come from interactions between the brain and body.

The brain doesn’t exist in a vat. Although protected by a very selective barrier that only lets certain molecules in, neurons react to blood components which bypass the barrier to alter their functions—for example, retaining learning and memory functions in old age.

Recent studies have increasingly pinpointed multiple communication channels between the brain and muscles, skeleton, and liver. After exercise, for example, proteins released by the body alter brain functions, boosting learning and memory in aging mice and, in some cases, elderly humans. When these communication channels break down, it triggers health problems associated with aging and limits life span and health span (the number of healthy years).

The brain-body connection works both ways. Tucked deep in the base of the brain, the hypothalamus regulates myriad hormones to modify bodily functions. With its hormonal secretions, the brain region sends directions to a wide range of organs including the liver, muscle, intestines, and fatty tissue, changing their behavior with age.

Often dubbed the “control center of aging,” the hypothalamus has long been a target for longevity researchers.

Back in 2013, one team found that reprogramming immune responses in the brain region could increase life span. In the same year, Imai’s team found activating the brain region turned back the clock in elderly mice. Like younger peers, they exercised more, had a healthier metabolism, and maintained their body temperatures more easily in environments outside their usual comfort zone. They also slept better, and their brains sent faithful directions to their muscles, letting them parkour around their environments.

Yet a question gnawed at the team: Why did it work?

Open Lines

The new study hunted down neurons in the hypothalamus that link fatty tissues to the brain and longevity.

They first zeroed in on a subset of neurons within the hypothalamus from a pool previously known to regulate aging. These cells have a high level of a protein called Ppp1r17—basically, a marker differentiating them from all other cell types in the hypothalamus—and reach far across the brain and into the body.

The neurons “may signal to a specific tissue and regulate its function,” wrote the team. In other words, they could potentially establish a brain-body connection.

To test the theory, the team genetically eliminated Ppp1r17 in the hypothalamus of three-month-old mice—roughly the age of a teenager. Within two months, the critters blew up in size. They began feasting during sleep time and no longer felt the urge to run in their running wheel—a previous favorite pastime.

The changes caught the team’s eye. Reducing calories and exercise is known to increase health span in lab mice and perhaps in humans.

With molecular analysis, the team found that neurons with Ppp1r17 changed how fat cells behave. The protein floats around both the nucleus—the walnut-like structure that encapsulates our DNA—and other parts of the cell.

In young mice, it sits inside the nucleus and activates a nerve highway regulating fatty tissues. It directs fat cells to release energy stores during exercise, for example, and to pump out a protein that provides energy in the brain. With age, the entire loop breaks down. The protein drifts from the nucleus into other parts of the neuron, kneecapping communications with fat cells.

In an attempt to restore the system in aging mice, the team genetically altered a “shuttle” protein to transport Ppp1r17 back into the nucleus. This trick slowed the signs of aging.

Meanwhile, the mice’s fat cells were also rejuvenated. They readily pumped out a hormone critical to keeping the hypothalamus healthy. Rather than languishing on the couch, the mice opted for a run on their wheel. Compared to similarly aged peers, they had fluffy and shiny fur, a sign of youth and health.

The results suggest that moving Ppp1r17 back into the nucleus keeps a mouse healthy even in old age. And “remarkably,” wrote the team, the engineered mice lived longer than their littermates by roughly seven percent.

Using another technology that specifically kept the protein inside the nucleus, the team recapitulated the results. These elderly mice also ran like the wind, kept their fatty tissues in working order, and experienced increased life span compared to their peers.

The study is the latest to map highways between the body and brain in pursuit of longevity. The team is further exploring ways to optimize the fat-to-brain feedback loop as we grow older.

Image Credit: Sandy Millar / Unsplash

This year, we inched closer to answers. Longevity research continued decoding the core causes of aging in the battle to ease age-related disease and extend health as we go grey.

A group of studies pinpointed a surprising blood protein that supports multiple anti-aging therapies, such as exercise and young blood. Together, they homed in on a critical driver for brain aging—long-lasting inflammation throughout the body. The results suggest that lowering inflammatory molecules in the body, rather than directly in the brain, could potentially rescue age-related cognition and prevent memory problems.

Scientists are also building increasingly sophisticated “aging clocks” to measure biological age—the accumulation of the hallmarks of aging, rather than the number of years we’ve lived.

It’s no surprise that people age differently due to genetics and lifestyle. However, a blood test found that different organs in the same person also age at their own paces. The insight could lead to personalized therapy. By detecting faster-aging organs, it’s possible we can predict a person’s risk for a variety of age-related diseases and provide early intervention. These tailored treatments could stave off age-related problems such as memory loss, bone weakness, diabetes, high blood pressure, or other chronic killers.

Outside the lab, the field has captured the imagination and pocketbook of notable donors. In November, the XPRIZE Foundation offered a staggering $101 million prize to scientists exploring methods to retain muscle, brain, and immune health as we age in the “largest competition in history.” The seven-year contest seeks to bring therapeutics for healthy aging to the clinics—so that we can live vibrant lives well into our sunset years.

Here are some other themes in longevity research that could guide the field into the future.

Goodbye Muffin

Slashing calories in flies, worms, and rodents lengthens their lifespans and maintains health in old age.

This year, one of the largest anti-aging studies extended the findings to humans. Called CALERIE, the study provided compelling evidence that cutting calories slows signs of aging in humans.

The randomized control trial—a gold standard in clinical research—recruited healthy volunteers between their 20s and 50s and asked half of the recruits to cut their daily calorie intake by 25 percent for two years. The calorie cut roughly works out to one less muffin a day.

Although the diet didn’t change volunteers’ biological age, it slowed the pace of aging compared to a control group that maintained their usual eating habits. The dieting group saw improvements in multiple metabolic biomarkers and reduced levels of senescent “zombie cells,” which accumulate with age. These cells lose their normal functions and pump out toxic molecules that increase inflammation and harm surrounding tissues.

The trial lasted only two years, so it’s too early to assess the long-term impact on health. But estimates suggest the lifestyle change could reduce mortality risk by up to 15 percent—similar to quitting smoking. More broadly, we now have evidence for one of the most prominent longevity theories in humans: That lowering calories by just a bit, without sacrificing nutrients, boosts healthy longevity.

Forget Dieting, How About a Taurine Feast?

Dieting for years isn’t exactly appealing. It’s also hard to maintain.

A study this year in mice and monkeys found it may be possible to slow aging by increasing a simple ingredient in the diet—taurine, a type of chemical called an amino acid that’s produced by our bodies and found in energy drinks and baby powder.

Amino acids usually make up the proteins supporting cellular processes and physical structure. Taurine’s an oddball, in that it doesn’t incorporate into proteins. Instead, it floats free inside the body to support brain development, eye health, and digestion. Our bodies readily produce taurine, but its levels drop precipitously with age.

The new study, decades in the making, asked if supplementing taurine levels slows aging. One test gave middle-aged mice taurine in addition to their normal diet. Compared to peers that didn’t receive the supplement, treated mice lived up to 12 percent longer and seemed younger. Their bones and muscles regained strength and flexibility. Their memory also improved. Similar benefits were seen in middle-aged monkeys with a steady diet of the supplement.

Mice and monkeys are not men. For now, it’s unclear if the amino acid works in humans. The dosages are far higher than the usual daily intake in humans.

But earlier studies suggest supplementing taurine benefits aging. For example, an analysis of nearly 12,000 people found that high taurine levels correlated with lower blood sugar and a protein marker associated with chronic inflammation and aging. In contrast, taurine levels tanked in people with age-associated disorders such as diabetes, whereas exercise—a well-known guardian against age-related problems—increased its levels. Initial results from small clinical trials suggest the amino acid lowers oxidative stress, a process that damages cells and contributes to aging.

An Aging Biomarker That Crosses Species

Humans live decades. Mice, a few years. It’s no wonder that most longevity studies are performed in lab animals with a far shorter lifespan. But can any resulting therapies apply to humans?

A comprehensive study suggests yes. The scientists analyzed RNA profiles from 41 different species to find common biomarkers for aging. The results bolstered previous findings for the biological mechanisms linked to age-related health decline. For example, reduced IGF-1 signaling, a protein that controls growth and blood sugar levels, increased lifespan across multiple species, likely by reducing inflammation. Mitochondria and metabolic health, which help convert food and oxygen into energy, were also essential for healthy aging.

The results show different species share common themes and biomarkers in aging, making it possible to rationally design and screen for anti-aging therapies that translate to humans.

What’s Next?

With over 100 clinical trials in the works, the race for an “elixir of life” is moving at breakneck speed.

While exciting, the field needs to consider accessibility. Companies are already giving wealthy people experimental “anti-aging” therapies not yet approved for longevity use. Much of the globe is rapidly aging and access to health-extending drugs could lower the global burden of age-related chronic disease.

Longevity interventions could shake up social dynamics and change our perception of what it means to be “elderly” as well as impacting related regulations, such as retirement age or social programs.

This year, researchers called for “responsible” research and guidelines for how aging research can benefit society as a whole. Meanwhile, the United Nations released a comprehensive report outlining the economic, societal, and healthcare impacts of the world’s aging population—and a plan of action to transform scientific discoveries into therapy and policy.

Once maligned as a frivolous search for the fountain of youth, longevity research is now one of the fastest-growing biomedical fields. Let’s see what next year brings.

Image Credit: mhrezaa / Unsplash

A new study suggests that a way to wipe them out is a medicine already approved for eye problems.

Dubbed “zombie cells,” senescent cells slowly accumulate with age or with cancer treatments. The cells lose their ability to perform normal functions. Instead, they leak a toxic chemical soup into their local environment, increasing inflammation and damaging healthy cells.

Over a decade of research has shown eliminating these cells with genetic engineering or drugs can slow down aging symptoms in mice. It’s no wonder investors have poured billions of dollars into these “senolytic” drugs.

There are already hints of early successes. In one early clinical trial, cleaning out zombie cells with a combination of drugs in humans with age-related lung problems was found to be safe. Another study helped middle-aged and older people maintain blood pressure while running up stairs. But battling senescent cells isn’t just about improving athletic abilities. Many more clinical trials are in the works, including strengthening bone integrity and combating Alzheimer’s.

But to Carlos Anerillas, Myriam Gorospe, and their team at the National Institutes of Health (NIH) in Baltimore, therapies have yet to hit zombie cells where it really hurts.

In a study in Nature Aging, the team pinpointed a weakness in these cells: They constantly release toxic chemicals, like a leaky nose during a cold. Called SASP, for senescence-associated secretory phenotype, this stew of inflammatory molecules contributes to aging.

Lucky for us, this constant release of chemicals comes at a price. Zombie cells use a “factory” inside the cell to package and ship their toxic payload to neighboring cells and nearby tissues. All cells have these factories. But the ones in zombie cells go into overdrive.

The new study nailed down a protein pair that’s essential to the zombie cells’ toxic spew and found an FDA-approved drug that inhibits the process. When given to 22-month-old mice—roughly the human equivalent of 70 years old—they had better kidney, liver, and lung function within just two months of treatment.

The work “stands out,” said Yahyah Aman, an editor at Nature Aging. It’s an “exciting target for new senolytic drug development,” added Ming Xu at UConn Health, who wasn’t involved in the study.

A Molecular Metropolitan

Each cell is a bustling city with multiple neighborhoods.

Some house our genetic archives. Others translate those DNA codes into proteins. There are also acid-filled dumpsters and molecular recycling bins to keep each cell clear of waste.

Then there’s the ER. No, not the emergency room, but a fluffy croissant-like structure. Called the endoplasmic reticulum, it’s Grand Central for new proteins. The ER packages proteins and delivers them to internal structures, the cell’s surface, or destinations outside the cell.

These “secretory” packages are powerful regulators that control local cellular functions. Normally, the ER helps cells coordinate their responses with neighboring tissues—say, allowing blood to clot after a scrape or stimulating immune responses to heal the damage.

Senescent cells hijack this process. Instead of productive signaling, they instead release a toxic soup of chemicals. These cells aren’t born harmful. Rather, they’re transformed by a lifetime of injury—damage to their DNA, for example. Faced with so much damage, normal cells would wither away, allowing healthy new cells to replace them in some tissues like the skin.

Zombie cells, in contrast, refuse to die. As long as the harm stays below a lethal level, the cells live on, expelling their deadly brew and harming others in the vicinity.

These traits make zombie cells a valuable target for anti-aging therapies. And there have been promising treatments. Most have relied on existing knowledge or ideas about how zombie cells work. Researchers then seek out chemicals in massive drug libraries that might disrupt their function. While useful, this strategy can miss treatment options.

The new study went rogue. Rather than starting out with hypotheses, they screened the whole human genome to find new vulnerabilities.

A Wild West

In their hunt, the team turned to CRISPR. Famously known as a gene editor, CRISPR is now often used to pinpoint genes and proteins that contribute to cellular functions. Here, the team disrupted every gene in the human genome to pinpoint those that eliminated zombie cells.

Their work paid off. The screen found a protein pair critical for senescent cell survival. The team next looked for an FDA-approved drug to disrupt the pair. They found what they were looking for in verteporfin, a drug approved to treat eye blood vessel disease.

In several zombie cell cultures with the protein pair, the drug drove senescent cells into apoptosis—that is, the “gentle falling of the leaves,” a sort of cell death does no harm to surrounding cells.

Digging deeper, the drug seemed to directly target the zombie cells’ endoplasmic reticulum—their shipping center. Cells treated with the drug couldn’t sustain the delicate multi-layered structure, and it subsequently shriveled into a shape like a wet, crumpled paper towel.

“A shrunken ER triggered a metabolic crisis” in zombie cells, explained Anerillas and Gorospe. It “culminated with their death.”

Ageless Mice

As a proof of concept, the team injected elderly mice—roughly the age of a 70-year-old human—with verteporfin once a month for two months.

In just a week, mice treated with verteporfin showed fewer molecular signs of senescence in their kidney, liver, and lungs. Their fur was more luxurious compared to control mice without the drug.

As we age, immune cells often enter the lungs and cause damage. Verteporfin nixed this infiltration and reduced lung scarring in mice—which is often linked to decreased breathing capacity. Similarly, according to blood tests, the drug also helped restore function in the mice’s kidneys and liver.

Decreased numbers of senescent cells dampened inflammatory signals, which could explain the rejuvenating effects, explained the team. Verteporfin also stopped a “guardian” protein that protects senescent cells from death, further triggering their demise.

Tapping into a zombie cell’s unique vulnerabilities is a new strategy in the development of senolytics. There’s far more to explore. The endoplasmic reticulum isn’t the only cell component in the biological waste factory. Other cellular components that generate senescent cell poisons could also be blocked and help remove the cells themselves.

It’s a promising alternative to existing methods for wiping out senescent cells. The strategy could “greatly expand the catalog of senolytic therapies,” the team wrote.

Image Credit: A HeLA cell undergoing apoptosis. Tom Deerinck / NIH / FLICKR