A new study from the Buck Institute for Research on Aging, published in Aging Cell, suggests that APOE2 helps neurons protect their DNA and avoid senescence. Senescence is a damaged, poorly functioning cellular state that becomes more common with age and is believed to contribute to neurodegeneration.

The results point to a role for APOE that goes beyond its familiar involvement in cholesterol transport. They suggest that different versions of the gene may also influence how well brain cells preserve and repair their genetic material over time.

“We’ve known for years that APOE2 carriers tend to live longer and have a lower risk of Alzheimer’s, but the protective mechanism has been a black box,” says senior author Lisa M. Ellerby, PhD, professor at the Buck Institute. “Our work shows that APOE2 neurons are better at preventing and repairing DNA damage, and they resist the cellular aging program that drives so much of late-life decline. Our findings point to entirely new therapeutic directions.”

Comparing the Three APOE Variants

APOE exists in three common forms, APOE2, APOE3, and APOE4. These versions differ by only two amino acids, yet they are associated with very different effects on brain aging.

APOE4 is the strongest known genetic risk factor for late-onset Alzheimer’s disease (typically after age 65). APOE2, by contrast, has repeatedly been linked in population studies to longer life and a reduced risk of dementia.

To study how the APOE variants influence neuronal aging, the researchers used human induced pluripotent stem cells (iPSCs) that had been genetically engineered so that they differed only at the APOE locus.

The team turned these cells into two types of neurons. One group consisted of inhibitory GABAergic neurons, while the other consisted of excitatory glutamatergic neurons. The researchers then compared how APOE2, APOE3, and APOE4 affected each cell type.

They also studied hippocampal tissue from older mice engineered to carry the human APOE2, APOE3, or APOE4 gene.

APOE2 Neurons Show Less DNA Damage

The researchers found that APOE2 neurons accumulated less damage to their DNA.

Bulk and single-cell RNA sequencing showed that APOE2 GABAergic neurons strongly activated pathways involved in DNA repair and damage response. APOE4 neurons, meanwhile, displayed patterns of gene activity associated with Alzheimer’s disease.

Direct measurements of DNA strand breaks supported those findings. APOE2 neurons had significantly less DNA damage than neurons carrying the other gene variants.

Brain Cells Resist Cellular Senescence

APOE2 neurons also appeared to be more resistant to senescence.

The team exposed excitatory neurons to radiation or the chemotherapy drug doxorubicin, both of which can damage DNA and place cells under severe stress. APOE2 neurons showed lower levels of senescence markers (including p16 and CRYAB) than APOE3 and APOE4 neurons.

They also had smaller nucleoli and better-preserved nuclear architecture, both signs that the cells were maintaining a healthier internal structure.

APOE2 Protein May Transfer Some Protection

The researchers also tested whether APOE2’s protective effect could benefit neurons that carried APOE4.

When they added recombinant APOE2 protein to APOE4 neurons, the cells showed reduced DNA damage signaling after radiation exposure. The result offers an early indication that at least part of APOE2’s protective effect may be transferable rather than being limited to people born with the gene variant.

Similar Signs Appear in Mouse Brains

The mouse experiments produced a similar pattern.

Older APOE2 knock-in mice had smaller nucleoli, higher levels of the nuclear scaffolding protein Lamin A/C, and better-preserved heterochromatin in the hippocampus than mice carrying APOE3 or APOE4.

These characteristics are associated with healthier aging in brain cells and added further support to the findings from the human neuron experiments.

A New View of APOE and Brain Aging

DNA damage and cellular senescence are increasingly recognized as major contributors to aging and age-related diseases, including Alzheimer’s disease.

“Until now, the APOE field has focused largely on lipid handling and amyloid-beta biology,” says Ellerby. “By showing that APOE alleles also tune how neurons defend their genome, this study connects a major longevity gene to two of the most actively studied hallmarks of aging.”

According to Ellerby, the findings raise the possibility that treatments designed to improve DNA repair or remove senescent cells from the brain could reproduce some of APOE2’s natural benefits. Such strategies might eventually help people who carry the higher-risk APOE4 variant.

“What surprised us was how consistent the picture was across two very different neuron types and across human cells and mouse brain tissue,” said co-first author Cristian Gerónimo-Olvera, PhD, a postdoctoral fellow at the Buck Institute. “APOE2 neurons aren’t just less damaged at baseline, they recover faster when stressed.”

Future Treatments Inspired by APOE2

The researchers say they still do not know exactly how APOE2 stabilizes the nuclear envelope and strengthens DNA repair.

Future work will investigate whether APOE2-mimetic compounds or targeted DNA repair treatments can provide similar protection in people with APOE4, the group with the highest genetic risk for Alzheimer’s disease.

Other collaborators include: Stephen M. Scheeler, Carlos Galicia Aguirre, Genesis Vega-Hormazabal, Daniela Garcia, Long Wu, Natalia Murad, Kevin Schneide, Kenneth A. Wilson, Nikola T. Markov, | Jesse Simons, Akos A. Gerencser, Emily Parlan, Eric Verdin, Judith Campisi, Tara E. Tracy, David Furman, Simon Melov, Buck Institute; Sicheng Song and Sean D. Mooney, Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, Washington

This work was supported by the National Institute on Aging (R01AG061879, P01AG066591, T32 AG000266), the Paul F. Glenn Center for Biology of Aging, the Hevolution Foundation (HF-PART-23-1422047), and a CatalystX award from Alex and Bob Griswold and the Valley Foundation Fellowship.

“We document how one orca holds the sunfish and lets go just before another orca hits it at high speed, causing the tissue to break apart into thousands of pieces,” said first author of the Frontiers in Ethology article, Dr. Kathryn Ayres, a scientist at Beneath The Waves, a non-profit organization promoting ocean health. “We think this may help younger orcas feed more easily or it could also just be for fun. Orcas are known for playing with their food.”

Orcas Shatter Sunfish at High Speed

Sunfish can exceed three meters in length and weigh as much as 2,000 kg. Although they travel through different levels of the ocean, they often rise to the surface to rest, regulate their body temperature, or have parasites removed. That behavior leaves them exposed to predators.

In the Gulf of California, sunfish are among the animals most frequently hunted and eaten by orcas. The newly reported behavior was recorded during two separate events that took place slightly more than a year apart.

In July 2024, Ayres watched a group of orcas, including a juvenile, handle a dead sharp-tail sunfish that they had already killed. A female gripped the fish by its large tail fin, which provided a secure hold, while a male gained speed and charged toward them.

The female released the sunfish just before the male struck it. The force of the collision broke the fish’s tissue into fragments that drifted through the water. The juvenile then ate the smaller pieces, while the adults consumed the remaining carcass but left the scattered fragments behind. [See link to video after the end of the article.]

A second incident was filmed by Héctor Franz in September 2025. It followed the same sequence of holding, releasing, ramming, and feeding.

A Newly Documented Food Processing Strategy

The forceful collisions caused much of the prey’s tissue to disintegrate. Researchers say ramming has not previously been documented as an orca predation strategy.

In both cases, the animals appeared to work together. One orca held the carcass steady, allowing the other to strike it with greater precision. Because the sunfish were already dead, the researchers believe the impacts were used to process the prey rather than kill it.

Sunfish have a gelatinous outer layer known as capsule, and both this layer and the skin contain a distinct microbiome. When the tissue breaks apart, the microbial taxa living within it spread into the surrounding water and change its nutrient composition.

This fragmentation may increase contact between sunfish and orca microbiomes. Researchers suggest that such exposure could offer nutritional advantages or other benefits, including possible immune regulation.

Smaller Pieces for Young Orcas

The behavior may also represent parental investment. Breaking the carcass into smaller portions would make it easier for a calf or juvenile to feed, which is consistent with other known orca behaviors.

“Orcas often tear apart prey and share it with other members of the group, including calves and juveniles,” said Ayres.

However, feeding may not have been the only purpose. The interactions could also have had a social function, or the orcas may simply have been playing.

Clues About Sharp-Tail Sunfish

The observations may also reveal something unusual about sharp-tail sunfish. So far, this type of tissue fragmentation has only been recorded in that species.

The researchers suggest that sharp-tail sunfish tissue may respond to powerful impacts in a distinctive way. Other, larger sunfish species may not break apart as easily under similar conditions.

Scientists do not know whether the same orcas participated in both events. More high-quality footage is needed, particularly clear views of dorsal fins and eye patches, which can be used to identify individual animals.

“Collecting good identification photographs whenever possible is key: we are still seeing new techniques of how orcas hunt and process their prey,” concluded Ayres. “They’re one of the most iconic marine predators in the world, yet they continue to surprise us.”

“Dietary habits in early life can have lasting health consequences,” said senior study author Vasanti Malik, Sc.D., M.Sc., an associate professor and Canada Research Chair in Nutrition and Chronic Disease Prevention in the department of nutritional sciences at Temerty Faculty of Medicine at the University of Toronto, and an adjunct faculty member in the department of nutrition at the Harvard T.H. Chan School of Public Health in Boston.

“High blood pressure is also emerging earlier in life, with growing rates being seen in younger adults, in children and adolescents, which highlights the importance of early detection and prevention,” she said.

Why Early Blood Pressure Risk Matters

High blood pressure can increase the risk of serious health problems, including heart attack and stroke. Some risk factors, such as family history, age, gender and race, cannot be changed. However, lifestyle factors including poor diet, smoking and low levels of physical activity can also contribute to the development of high blood pressure.

The new analysis included more than 25,000 participants enrolled in a long-running study of U.S. youths. Through questionnaires completed every 1 to 4 years, participants reported how often they consumed sugar-sweetened beverages such as soda, fruit punch, lemonade, sweetened tea and sports drinks. They also reported their consumption of fruit juice, whole fruit and other foods and beverages, along with information about body measurements, physical activity and smoking.

Researchers examined whether total fructose intake and the consumption of sugar-sweetened beverages, fruit juice and whole fruit were associated with self-reported diagnoses of high blood pressure. They also created statistical models to estimate what might happen if participants replaced sugary beverages or fruit juice with whole fruit, milk or water. Participants were followed for as long as 25 years.

Sugary Drinks Linked to a 52% Higher Risk

Participants who consumed two or more servings of sugar-sweetened beverages each day had a 52% higher risk of developing high blood pressure later in life compared with those who drank fewer than three servings per week. One serving was defined as a 12-ounce can or glass.

Different types of sugary drinks showed varying levels of risk. Each daily serving of soda was associated with a 23% higher risk of high blood pressure, while each daily serving of sports drinks was linked to a 36% higher risk.

Fruit juice was also associated with increased risk when consumed in larger amounts. Participants who drank 1.5 or more servings of fruit juice per day had a 35% higher risk of developing high blood pressure than those who consumed less than one serving per week. A serving of fruit juice was defined as an 8-ounce glass.

Among specific juice types, each daily serving of orange juice was associated with a 20% higher risk of high blood pressure. Apple juice and other juices were not associated with the same increase. However, the researchers cautioned that some orange-flavored beverages containing added sugar may have been incorrectly reported as orange juice.

Whole Fruit May Be a Better Choice

The substitution models suggested that replacing one daily serving of a sugary beverage with whole fruit could be associated with a 22% lower risk of developing high blood pressure.

Replacing one daily serving of fruit juice with whole fruit was associated with a 19% lower risk.

The models also found that replacing sugar-sweetened beverages with milk or water was associated with up to a 13% lower risk of high blood pressure. However, replacing fruit juice with milk or water was not associated with a significant change in risk.

The connection between sugary drinks, fruit juice and high blood pressure remained even after researchers considered overall diet quality, physical activity and other factors.

“Sugar-sweetened beverages, such as soda and sports drinks, which are often marketed as somewhat healthy, should be limited,” Malik said. “Fruit juice intake may be harmless at low levels yet harmful at higher intake levels. They should always be 100% fruit juice, and even so, consumed only in moderation. Whole fruit should be emphasized over sugary beverages.”

The Source of Sugar May Matter

A 2026 Dietary Guidance to Improve Cardiovascular Health scientific statement from the American Heart Association recommends minimizing added sugar in foods and beverages.

American Heart Association volunteer expert Amit Khera, M.D., FAHA, vice-chair of the dietary guidance writing committee, said the association between sugar-sweetened beverages and higher hypertension and cardiovascular risk has been generally consistent across previous research. However, he said the new findings provide several additional insights.

“First, the focus on childhood and the importance of health behaviors in childhood with adult risk factor development provides a critical opportunity for prevention. As has been seen in adults, the total amount of fructose seems less important for the development of hypertension than the type of food where it is consumed, so sugar-sweetened beverages and fruit juice relate to increased risk, while whole fruit does not.

“Secondly, there has been a misconception about fructose in general being harmful for cardiovascular health regardless of the source, and that fruit juices are beneficial for health. This study demonstrates that neither seems to be correct,” added Khera, the director of preventive cardiology and clinical chief of cardiology at the University of Texas Southwestern Medical Center in Dallas.

Khera also pointed out that the study population consisted mostly of White children and adults. “however, non-Hispanic Black and Hispanic American populations have the highest sugar-sweetened beverages intake, so these findings may be even more relevant for those groups.”

Policies Aimed at Reducing Sugary Drink Intake

The American Heart Association supports science-based policies designed to reduce the consumption of sugary drinks. These include establishing taxes on sugary beverages, strengthening nutrition standards for school meals, improving “informed dining” in restaurants and raising diet quality within the Supplemental Nutrition Assistance Program (SNAP).

Research Highlights

Over a follow-up period lasting as long as 25 years, people who consumed more sugary beverages and fruit juice beginning in childhood had a greater risk of developing high blood pressure than those who consumed less.

Replacing one daily serving of a sugary beverage with whole fruit, milk or water was associated with a lower risk of high blood pressure. Replacing fruit juice with whole fruit was also associated with lower risk.

Study Design and Participant Details

Participants came from the Growing Up Today Study (GUTS), which included GUTS I, launched in 1996, and GUTS II, launched in 2004. Children of participants in the Nurses’ Health Study II were recruited from across the United States.

The study followed 25,749 participants who were ages 9 to 16 at enrollment, (about 55% female and 96% non-Hispanic White participants) for up to 25 years. By the end of the follow-up period, the median participant age was 36.

Participants completed 132-item food frequency questionnaires annually from 1996 through 1998, followed by additional questionnaires in 2001, 2004, 2006, 2008, 2011 and 2015. Children who already had high blood pressure or lacked dietary information at the beginning of the study were excluded from the analysis.

The questionnaires asked participants how often they consumed a standard serving of each food or beverage, with responses ranging from “never or less than once per month” to “6 or more per day.” A serving was defined as a 12-ounce can or glass for sugar-sweetened beverages and an 8-ounce glass for fruit juice.

Sugar-sweetened beverages included sodas, fruit punches, lemonades, iced teas, sports drinks and non-carbonated fruit drinks. Fruit juice included orange juice, apple juice and other 100% fruit juice beverages. Whole fruits included apples, oranges, bananas, mangos, grapes, pears, melons, strawberries and peaches.

For the substitution analysis, researchers compared one daily serving of a sugar-sweetened beverage or fruit juice with one serving of fruit juice, milk (1%, 2% and whole milk but not chocolate or flavored milk), water or whole fruit.

Study Limitations

Blood pressure outcomes were self-reported in questionnaires completed from 2010 through 2021. Participants were asked whether a healthcare professional had ever diagnosed them with high blood pressure. In the 2010 questionnaire, the earliest option for the year of diagnosis was “before 1996” and responses extended through “2010+.”

Because the study relied on questionnaires and self-reported diagnoses, it cannot prove that sugary drinks or fruit juice directly caused high blood pressure. Other factors not included in the analysis may also have influenced the results. In addition, because most participants were non-Hispanic White, the findings may not apply equally to populations that were not well represented in the study.

A new study published in Nature, led by Monash University researcher Dr. Felicity McCormack of Securing Antarctica’s Environmental Future (SAEF), examines how reliably scientists can predict future ice loss from Antarctica and how those predictions could improve sea level planning.

Antarctica’s Potential Impact on Global Sea Levels

Reports from the Intergovernmental Panel on Climate Change (IPCC) indicate that global sea levels could rise by more than two meters by 2100 under high emission scenarios if large parts of the Antarctic Ice Sheet collapse.

An increase of that scale would put one quarter of Australian residential properties at risk of flooding. It could also make large areas of sovereign territory across the Pacific uninhabitable and force hundreds of millions of people worldwide to leave their homes. Such an outcome would rank among the largest humanitarian and economic crises in history.

Despite the scale of the threat, the path of sea level rise through 2100 remains highly uncertain. Much of that uncertainty comes from the difficulty of determining how quickly Antarctica will lose ice.

In a worst-case scenario, the IPCC has estimated that the rate of sea level rise caused by Antarctic ice loss alone could almost double over the next 30 years. Until now, however, researchers have lacked a strong estimate of how much Antarctica may contribute to rising seas during the next several decades, the period most relevant to government policy and coastal planning.

Testing How Far Ahead Ice Loss Can Be Predicted

The research focused on two central questions: how much ice Antarctica may lose over the next 30 to 50 years, and whether that loss can be predicted with enough confidence to give governments and nations time to prepare.

To address these questions, the team evaluated how predictable sea level rise was across a range of ice sheet model projections during this relatively near-term period.

According to Dr. McCormack, Antarctic ice loss remains strongly and consistently predictable until around the middle of the century. This means models may be able to provide dependable estimates of Antarctica’s contribution to sea level rise during the decades most important for adaptation planning.

“If ice sheet models accurately reproduce the rates of ice loss we observe today, we can have confidence in using those same models to reliably predict Antarctica’s contribution to sea level rise over the next 30 to 50 years. Accurately predicting how much and how fast global sea levels will rise offers vital information for future coastal planning and government policy,” said Dr. McCormack.

Predictability Declines Later in the Century

That confidence weakens toward the end of the 21st century, when physical processes capable of rapidly increasing ice loss become more likely.

Some Antarctic ice rests on bedrock that lies below sea level. If this ice begins retreating quickly, the process can become difficult to stop or reverse. Once underway, it could produce far greater ice loss than near-term climate projections alone would suggest.

“The research findings provide a roadmap for future climate planning. By improving how ice sheet models represent critical physical processes that lead to rapid ice sheet retreat, we can narrow the deep uncertainty that hampers reliability of long-term sea level rise projections,” Dr. McCormack said.

The findings suggest that a meaningful opportunity for climate action still exists. Over the next three decades, sea level rise pathways are relatively well constrained, making this period especially important for long-range adaptation and infrastructure planning.

A Critical Window for Climate Action

Professor Steven Chown, Director of SAEF, said the world should use this period of greater predictability to act and invest in stronger systems for monitoring Antarctica.

“The predictability identified in this research does not reduce long-term risk; instead, it provides a defined period in which to act with greater confidence. Improvements in observational systems and ice sheet model developments will directly translate into more reliable sea level projections for short-term planning horizons,” Professor Chown said.

Professor Chown also said Australia is in a strong position to work with Indo-Pacific partners and help turn the findings into practical adaptation strategies.

“Pacific Island governments require reliable near-term projections to make decisions about infrastructure, community relocation, and long-term land use. Engagement on sea level science and adaptation planning represents a foreign policy opportunity and a regional responsibility,” Professor Chown said.

Turning Ice Sheet Forecasts Into Policy

Dr. McCormack said it is essential to create a clear process for incorporating ice sheet model projections into policies addressing sea level rise.

“When models replicate present-day observations of Antarctic ice mass loss, their projected ice mass loss rates over the coming several decades provide a reliable foundation for planning and adaptation, while longer-term sea level rise uncertainties highlight the need for ongoing development,” Dr. McCormack said.

The researchers argue that Antarctic forecasts may be most useful when presented across two distinct time periods: short-term ice loss that can be predicted with greater confidence, and longer-term change shaped by feedbacks that could rapidly accelerate retreat.

This two-stage approach could give policymakers a clearer basis for preparing for rising seas while also recognizing the much greater uncertainty that develops later in the century.

About Securing Antarctica’s Environmental Future

Securing Antarctica’s Environmental Future is a Monash-led research and workforce development program that forms a central part of the Australian Antarctic Program. SAEF conducts Antarctic and Southern Ocean research intended to support Australians, neighboring countries in the Asia-Pacific, and communities around the world as the climate continues to change.