Rare gene tied to longer life helps brain cells fix DNA damage in lab

Why do some people carry a gene version that seems to shield the brain as it ages? A team at the Buck Institute for Research on Aging reports one possible answer. In a study published in the journal Aging Cell, the researchers found that a rare version of a gene called APOE helps brain cells repair damage to their DNA and resist a worn-out state linked to aging¹. The work was done in lab-grown human cells and mice, and the coverage does not describe any memory tests¹.

This is the first Biohack article in a thread following genes that may protect the aging brain.

What happened

People inherit one of three common versions of the APOE gene: APOE2, APOE3 or APOE4¹. APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease, while APOE2 has long been associated with a lower risk of dementia and a longer lifespan¹. Scientists did not fully understand why APOE2 seemed to help¹.

“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.

That quote appears in the coverage by The Economic Times¹. Ellerby added that the team’s 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”¹.

What the researchers measured

The team used genetically engineered human stem cells (cells that can be turned into other cell types, here brain nerve cells) and mouse models¹. Nerve cells carrying APOE2 built up less DNA damage, switched on stronger DNA repair systems, and were more resistant to cellular senescence¹. Senescence is a damaged state in which cells stop working normally; it is linked to aging and to diseases that wear down the brain¹.

The researchers also tried a transfer test. When they added APOE2 protein to nerve cells carrying the high-risk APOE4 version, those cells showed less DNA damage after stress¹. That suggests some of APOE2’s protective effect may carry over to other cells, according to the coverage¹.

The pattern held across different types of nerve cells and in both human cells and mouse brain tissue¹. Co-first author Cristian Gerónimo-Olvera, a postdoctoral fellow at the Buck Institute, said: “APOE2 neurons aren’t just less damaged at baseline, they recover faster when stressed”¹.

What it does not show yet

The findings are about what happens inside cells, not about whether people or animals stay sharper. The coverage does not describe memory or behavior tests, and it does not give the number of mice or cell lines used¹. The coverage itself says the research is still at the laboratory stage¹.

It also does not show a treatment. The researchers believe future therapies that improve DNA repair, or that remove senescent brain cells, could copy some of APOE2’s natural protection, especially for people carrying APOE4¹. That is a hope about future work, not a result. No such therapy was tested in this study, according to the coverage¹.

Mouse findings in this field come with a general caution. Writing about separate Alzheimer’s gene research in mice, Mindgrow notes that mice do not get Alzheimer’s on their own, and that even lab-grown human tissue lacks the decades of wear a real aging brain carries².

Who is behind it

The study comes from the Buck Institute for Research on Aging, an independent research institute focused on aging, with Lisa Ellerby as senior author and Cristian Gerónimo-Olvera as a co-first author¹. The coverage available to Biohack does not say who funded the work or whether any authors have company ties¹.

Ellerby framed the result as a shift in focus. “Until now, the APOE field has focused largely on lipid handling and amyloid-beta biology,” she said, referring to the gene’s role in handling fats and the sticky protein clumps seen in Alzheimer’s brains¹. She said the study “connects a major longevity gene to two of the most actively studied hallmarks of aging”¹.

How it fits the field

APOE2 is not the only gene researchers have studied as a possible brain protector, and APOE4 is the gene they most want to counter.

The risk gene

Carrying one copy of APOE4 makes a person more than three times as likely to develop Alzheimer’s, and two copies raise the risk by 10 times or more, according to Scientific American³. Still, not every carrier is diagnosed³. Estimates of how common it is differ between sources: Scientific American put it at 15 to 20 percent of the population or more³, while Mindgrow says about a quarter of people carry at least one copy².

In late September 2026, two teams at Mount Sinai reported that APOE4 damages the brain’s tiny blood vessels through one overactive signal, called TGF-β, and that blocking it in aged mice carrying the human APOE4 gene reversed the vessel damage². That work has not been shown to work or be safe in a living person, and repairing vessels may not bring back nerve cells already lost².

Other protective genes

In 2020, a Stanford-led analysis of data from more than 20,000 people found that APOE4 carriers aged 60 to 80 who also had a certain version of a gene called klotho were 30 percent less likely to be diagnosed with Alzheimer’s than carriers without it³. Klotho is described as a possible longevity gene³. Two earlier, smaller studies had disagreed on whether it helped, and the people in the Stanford paper were of northwestern European descent³.

Boosting a gene in mice

The idea of raising a gene’s activity to protect memory has been tested before in animals. In 2014, Carlos Saura’s group at the Universitat Autònoma de Barcelona reported in The Journal of Neuroscience that a gene therapy which reactivated a protein called Crtc1 reversed memory loss in mice with early stages of an Alzheimer’s-like disease⁴. The gene was injected into the hippocampus, the brain’s memory region⁵. Saura said the therapy was “effective in preventing memory impairment in a mouse model of AD”⁴. That work, too, was in mice, and the team described drugs that activate Crtc1 as a future goal⁴.

What to watch next

• Memory tests in animals. Whether APOE2’s effects on DNA repair translate into better memory or thinking in aging mice has not been described in the coverage of this study¹.
• Copying the protection. The researchers point to DNA repair boosters and treatments that clear senescent brain cells as possible ways to mimic APOE2¹. Any such approach would need its own testing.
• Links to APOE4 research. The Mount Sinai work points to a possible path of human trials of a TGF-β blocker aimed at APOE4 carriers early, though blocking that signal throughout the body could cause problems².
• Studies in more diverse groups. Experts quoted on the klotho finding called for research in people who are not of northwestern European descent³.

For now, the APOE2 result offers a proposed explanation, drawn from cells and mice, for why one gene version is linked to longer life and lower dementia risk¹. Whether that explanation leads to anything that keeps human brains sharp is still unknown.