When my grandad celebrated his 100th birthday with a bowl of noodles, his first comment was, “Nice, but this is store-bought.” He then schooled everyone on the art of making noodles from scratch, sounding decades younger than his actual age.
Most of us know people who are mentally sharper than their chronological age. In contrast, some folks seem far older. They’re easily confused, forget everyday routines, and have a hard time following conversations or remembering where they parked their car.
Why do some brains age faster, while others avoid senior moments even in the twilight years? Part of the answer may be in our genes. This month, a team from China’s Zhejiang University described an AI they’ve developed to hunt down genes related to brain aging and neurological disorders using brain scans from nearly 39,000 people.
They found seven genes, some of which are already in the crosshairs of scientists combating age-related cognitive decline. A search of clinical trials uncovered 28 existing drugs targeting those genes, including some as common as hydrocortisone, a drug often used for allergies and autoimmune diseases.
These drugs are already on the market, meaning they’ve been thoroughly vetted for safety. Repurposing existing drugs for brain aging could be a faster alternative to developing new ones, but they’ll have to be thoroughly tested to prove they actually bring cognitive improvements.
How Old Is My Brain?
The number of candles on your birthday cake doesn’t reflect the health of your brain. To gauge the latter—dubbed biological age—scientists have developed multiple aging clocks.
The Horvath Clock, for example, measures signatures of gene activity associated with aging and cognitive decline. Researchers have used others, such as GrimAge, to measure the effects of potential anti-aging therapies, such as caloric restriction, in clinical trials.
Scientists are still debating which clock is the most accurate for the brain. But most agree the brain age gap, or the difference between a person’s chronological age and brain age, is a useful marker. A larger gap in either direction means the brain is aging faster or slower than expected.
Why one or the other might be true for people is still mysterious.
“There is a general consensus that the trajectories of brain aging differ substantially among individuals due to genetic factors, lifestyles, environmental factors, and chronic disease of the patient,” wrote the team. Finding genes related to the brain age gap could bring new drugs that prevent, slow down, or even reverse aging. But studies are lacking, they added.
A Brain-Wide Picture
How well our brain works relies on its intricate connections and structure. These can be captured with magnetic resonance imaging (MRI). But each person’s neural wiring is slightly different, so piecing together a picture of an “average” aging brain requires lots of brain scans.
Luckily, the UK Biobank has plenty.
Launched in 2006, the organization’s database includes health data from half a million participants. For this study, the team analyzed MRI scans from around 39,000 people between 45 and 83 years of age, with a roughly equal number of men and women. Most were cognitively healthy, but over 6,600 had a brain injury, Alzheimer’s disease, anxiety, depression, and other disorders.
They then pitted seven state-of-the-art AI models against each other to figure out which model delivered the most accurate brain age estimate. One, called 3D-ViT, stood out for its ability to detect differences in brain structure associated with the brain age gap.
Next, the team explored whether some brain regions contributed to the gap more than others. With a tool often used in computer vision called saliency maps, they found two brain regions that were especially important to the AI’s estimation of the brain age gap.
One, the lentiform nucleus, is an earbud-like structure that sits deep inside the brain and is involved in movement, cognition, and emotion. The other is part of a neural highway that controls how different brain regions communicate—particularly those that run from deeper areas to the cortex, the outermost part of the brain responsible for reasoning and flexible thinking. These mental capabilities tend to slowly erode during aging.
Unsurprisingly, a larger gap also correlated with Alzheimer’s disease. But stroke, epilepsy, insomnia, smoking, and other lifestyle factors didn’t make a significant difference—at least for this population.
Genes to Drugs
Accelerated brain aging could be partly due to genetics. Finding which genes are involved could reveal new targets for therapies to combat faster cognitive decline. So, the team extracted genetic data from the UK Biobank and ran a genome-wide scan to fish out these genes.
Some were already on scientists’ radar. One helps maintain bone and heart health during aging. Another regulates the brain’s electrical signals and wires up neural connections.
The screen also revealed many new genes involved in the brain age gap. Some of these kill infected or cancerous cells. Others stabilize neuron signaling and structure or battle chronic inflammation—both of which can go awry as the brain ages. Most of the genes could be managed with a pill or injection, making it easier to reuse existing drugs or develop new ones.
To hunt down potential drug candidates, the team turned to an open-source database that charts how drugs interact with genes. They found 466 drugs either approved or in clinical development targeting roughly 45 percent of the new genes.
Some are already being tested for their ability to slow cognitive decline. Among these are hydrocortisone—which is mainly used to treat autoimmune disorders, asthma, and rashes—and resveratrol, a molecule found in red wine. They also found 28 drugs that “hold substantial promise for brain aging,” wrote the team, including the hormones estradiol and testosterone. Dasatinib, a senolytic drug that kills off “zombie cells” during aging, also made the list.
The work builds on prior attempts to decipher connections between genes and the brain age gap. A 2019 study used the UK Biobank to pinpoint genes related to neurological disorders that accelerate brain aging. Here, the team connected genes to potential new or existing drugs to slow brain aging.
“Our study provides insights into the genetic basis of brain aging, potentially facilitating drug development for brain aging to extend the health span,” wrote the team.
Source link
#Massive #Analysis #Genes #Related #Brain #Agingand #Drugs #Slow
