Study Identifies 7 Genes Associated with Brain Aging and 13 Drugs that May Help Extend the Healthspan

Consider two 70-year-olds.

Cliff seems slightly confused and forgetful, and has difficulty following conversations and instructions. Roxanne is always alert and leads conversations, bringing up new topics and easily adding details to other’s ideas. They are the same age, yet far apart in cognition. Researchers call the difference between age in years and age in behavior and physical condition the brain age gap, or BAG.

Researchers in China have identified a set of genes that play a role in whether someone is a Cliff or a Roxanne. It measures the difference between an individual’s predicted age, derived from machine learning models trained on magnetic resonance imaging (MRI) data, and chronological age. The confused Cliff has a bigger BAG than the alert Roxanne.

Extending the Healthspan

BAG is a standard measure of brain health – it is higher in people with mild cognitive impairment (MCI) and dementia, and is a marker of MCI that is likely to progress to dementia. And it can be predictive. In older people with normal cognition but a higher BAG, risk is elevated for cardiovascular disease, amyloid deposition in the brain, and subsequent dementia.

In the new study, published in Science Advances, Fan Yi and colleagues identify 7 genes that affect healthspan – the number of years that a person is healthy, without major disabilities or chronic diseases.

But there’s more. The functions of these genes enable prediction of not only how many “good” years remain, but suggest 13 existing, commonly used drugs that may be repurposed to forestall impending decrepitude (which I can say because I’m the same age as Cliff and Roxanne).

The researchers site studies showing that a 2% delay in the manifestations of aging could save $7.1 trillion in health care costs over 50 years. (The paper uses the phrase “delay aging,” but this is not possible. In my textbooks, I define “aging” as biological changes to the body that occur with time – so without a time machine, one can’t actually fight aging, despite all those “anti-aging” ads for wrinkle creams and such.)

The data in the study are from the UK Biobank, which includes medical and biological information on half a million people 40 to 69 years old at enrollment. The biobank has been amassing data since 2006. The study used information from nearly 39,000 participants. A similar effort in the US is All of Us, which I hope survives the gutting of the NIH.

MRI Wed to Genetic Analysis Paints a Portrait of Brain Aging

Investigators compared brain MRIs of study subjects to brain MRIs AI-trained on “cognitively healthy” individuals to track how the brain’s biological age compares with chronological age.

Then the team compared the participants’ brain MRIs to those from people with 18 psychiatric and neurological brain disorders (including Alzheimer’s, Parkinson’s, schizophrenia, stroke, epilepsy, OCD, PTSD, and sleep, anxiety, bipolar, and major depressive disorders), as well as to 8 measurable characteristics: intelligence, neuroticism, insomnia, obesity, years of education, alcoholic drinks per week, cigarettes per day, and age of smoking initiation.

The higher the BAG, the more likely bipolar disorder and Alzheimer’s disease are to develop. And in general, a larger gap between biological and chronological age correlates with a bigger impact on intelligence.  

From Genes to Drugs

The 7 genes that led the researchers to their drug list are:

microtubule associated protein tau (MAPT), which controls stability of axons, the major extensions of nerve cells

tumor necrosis factor (TNFSF12), which promotes inflammation in injury, infection, and autoimmune conditions

granzyme B (GZMB), which kills infected and cancerous cells

signal regulatory protein beta 1 (SIRPB1), an antibody and signaling molecule

granulysin (GNLY), which punctures bacterial cell walls

neuromedin B (NMB), which regulates appetite

complement subcomponent like (C1RL), part of the inflammatory response

Overall, this protective gene set controls nerve cell stability, appetite, inflammation, response to infection and cancer. It’s easy to see how differences among these key aging genes might explain why one 70-year-old is frequently sick, injured, and rundown, and another still runs 10k races with ease.

The researchers used the identified BAG genes to interrogate data from other clinical trials on aspects of aging. And they identified familiar drugs that might be repurposed to extend the healthspan – many of which are already being evaluated for their effect on forestalling cognitive decline.

The drugs include hydrocortisone, estradiol, the HIV drug zidovudine, several NSAIDS, a kinase inhibitor cancer drug, the immunosuppressant siroliumus, anti-inflammatory antioxidant reseveretrol (from red grapes), as well as methylene blue (boosts oxygen in blood), vitamin D, and the anti-hypertensive Enalapril.

I suspect analyzing the incidence and pace of cognitive decline among people who take these drugs regularly to treat other conditions is already underway.

The Bigger Picture

Sometimes findings of genetic studies that are complex and packed with data boil down to confirm things we already knew, or suspected. That’s the case with this elegant investigation.

The several anti-inflammatories associated with extending the healthspan jibe with the excess inflammation that lies behind many conditions: cardiovascular diseases, gastrointestinal disorders, lung conditions like COPD and asthma, and autoimmune conditions such as rheumatoid arthritis and lupus.

We cannot control which genes we inherit at conception, but we can control, to an extent, how those genes are expressed. I can imagine the findings from this study used to develop a genetic healthspan profile that indicates the brain age gap. And if it’s big, measures such as changes to diet and exercise habits can help to extend the good years – to be more like Roxanne than Cliff.