Can Weight Loss Drugs Like Ozempic Slow Ageing?

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Several recently published studies have made headlines when they suggested that Semaglutide – the generic name for breakthrough weight loss drugs Ozempic and Wegovy – might protect against multiple diseases, perhaps even slowing the ageing process. From diabetes treatment to weight loss and now to anti-ageing, these drugs just seem to keep on giving, but what exactly are they doing? We thought it would be worth having a deep dive into the science – read on if you’re interested in how these drugs work and whether they really have a chance of slowing the ageing process.

Key points:

• Ozempic, Wegovy, Mounjaro and Zepbound are all members of a class of drugs called incretin mimetics.
• First used to treat diabetes, they were subsequently found to promote weight loss mostly through appetite suppression.
• Recent research shows that these drugs reduce the risk of many age-related diseases in humans with diabetes or obesity, leading to speculation that they may slow ageing.
• It’s unclear how much of this is due to weight loss as opposed to the drugs themselves.
• Test tube studies show that these drugs may slow some of the biological processes underlying ageing.

The Birth Of A ‘Miracle Drug’?

So, just what are these drugs and where did they come from? Semaglutide (AKA Ozempic and Wegovy) and its cousin tirzepatide (AKA Mounjaro and Zepbound) are all members of a class of drug known as incretin mimetics. What are incretin mimetics? Certain parts of the digestive system – but mainly the small intestine – release hormones called incretins when food is being digested. These incretins work to stimulate the release of the blood sugar-lowering hormone insulin, which helps get the glucose out of the blood and into storage, while also preventing the liver from converting other nutrients into glucose. Incretin mimetics mimic the effects of one or both of the main incretins (GLP-1 for semaglutide, GLP-1 and GIP for Tirzepatide), thereby lowering blood sugar. These drugs are also commonly referred to as GLP-1 agonists, which means they activate GLP-1 receptors. We’re mainly going to be referring to GLP-1 agonists from now on, as that’s where most of the scientific focus currently lies. Due to their blood sugar-lowering effects, these were initially developed for the treatment of diabetes mellitus. However, that’s not where the story ended.

How Do Incretin Mimetics Promote Weight Loss?

It wasn’t long before researchers noticed that diabetics taking GLP-1 and GIP agonists also lost a lot of weight. At the time, the reasons for this were poorly understood, and still are to an extent. The weight loss seems to be largely due to appetite suppression; when incretins are released in response to food ingestion, they slow gastric emptying and activate certain neurons in the brain that promote the sensation of satiety. However, there’s another critical component to these drugs that may give them their edge when it comes to weight loss.

Humans seem to have evolved to resist weight loss, and for good reason. During most of our evolution, excess fat would have been more of a help than a hindrance – you never know when the next famine might come. As a result, when humans start to lose weight, compensatory systems kick in to increase hunger while reducing energy expenditure by slowing down the metabolism. This is called the adaptive response to weight loss, and it’s great if you’re a hunter-gatherer trying to survive a long winter, but not so good if you’re obese and trying to lose weight. However, for reasons that are unclear, the adaptive response to weight loss doesn’t seem to occur (at least, not enough to matter) in people taking GLP-1 or GIP agonists. This seems to be related to the suppression of certain neurons in the brain.

Can Incretin Mimetics Slow Ageing?

Now onto the meat of the matter: can these antidiabetic and weight loss drugs also slow ageing? The idea that this might be possible has been around for a while, as test tube studies have shown that drugs that mimic GLP-1 can combat several of the molecular processes thought to be driving ageing. For example, they can prevent DNA damage, improve the function of mitochondria in Alzheimer’s disease cells while protecting against inflammation and more. 

This evidence doesn’t mean much by itself – to have practical value as an anti-ageing drug, incretin mimetics would need to reduce the risk of age-related diseases in humans (beyond what would be expected from a reduction in diabetes and obesity). That’s why some of the recently published research is so intriguing.

Cardiovascular disease:

Multiple studies analysing data from clinical trials like the SELECT trial (a randomised, placebo-controlled trial of semaglutide in non-diabetics with cardiovascular disease and who are overweight or obese) have now shown that such people taking semaglutide are less likely to die from cardiovascular events. In a recent analysis published in the Lancet, participants of the SELECT trial were found to be 28% less likely to die from major cardiovascular events if they were taking semaglutide.

That’s not particularly surprising given that obesity is a huge risk factor for cardiovascular death. However, there are some indications that weight loss doesn’t fully explain the benefits of semaglutide in these studies. Preliminary evidence, again from the SELECT trial, suggests that the starting weight or degree of weight loss when taking semaglutide doesn’t necessarily correlate with the level of risk reduction, meaning even people who lose little to no weight on semaglutide may still see a reduction in cardiovascular death (at least for people who have CVD). Why? It’s not entirely clear. Researchers say it may be related to reductions in blood pressure, blood sugar, inflammation, or other effects on blood vessels that are yet to be explored.

Infectious diseases: 

So, GLP-1 agonists can reduce mortality in overweight and obese people with cardiovascular disease. However, recent studies suggest that the benefits of these drugs actually extend beyond even that. Last month, a study appeared in the Journal of the American College of Cardiology that further analysed SELECT trial data. They confirmed that semaglutide was indeed associated with a reduction in cardiovascular deaths, but they also looked at non-cardiovascular deaths. They found that semaglutide was associated with a 23% reduction in such deaths compared with placebo, and that this was mainly due to fewer deaths from infections – mainly COVID-19, though there was no reduction in incidence of the disease.

This could have been due to weight loss – the study does not say whether or not this reduction in non-cardiovascular mortality was independent of weight loss. People in the placebo group were about 51% more likely to die from Covid than the semaglutide group, while having a BMI over 35 is associated with a 40%-90% increase in risk. However, there are also reasons to suspect that weight loss was not the only factor at play. For other weight loss treatments, there is usually a significant lag between when the weight loss occurs and when the health benefits kick in. For example, it took 5 years before the reduced mortality associated with bariatric surgery was detectable. The SELECT trial started at the end of 2018, with most Covid deaths occurring in 2020 and 2021. The fact that participants taking GLP-1 agonists were protected during the pandemic is not proof that they protect against Covid directly, but is worth further research given that these drugs do seem to suppress inflammation.

Dementia:

Just one month before that last study, another study published in the Lancet reported a different surprising finding. They followed patients taking GLP-1 agonists (this time for diabetes, not weight loss) for an average of 4.3 years, and found that they were associated with a 23-31% reduction in dementia incidence when compared to other diabetes drugs. However, diabetes is a significant risk factor for dementia, so this reduction could be due to GLP-1 agonists being more effective or working on diabetes in a different way to other drugs. Furthermore, just because participants with obesity were not specifically selected for this study, this does not necessarily mean that weight loss did not play a role in the reduced dementia risk as well.

Cancer:

There’s even some evidence from a study published late last year to suggest that GLP-1 agonists reduce the risk of cancer, at least in people with diabetes. The study found that people taking these drugs were 44% less likely to get colorectal cancer than people taking insulin, and 25% less likely compared to those taking metformin. The same caveats apply as in the dementia study, though this time the researchers investigated the role of weight loss and found that the benefits did not depend on participants being overweight.

The Implications:

So, GLP-1 agonists seem to lower the risk of multiple age related diseases. Yet there’s an important caveat that we’ve already mentioned and that is arguably not stressed enough in much of the reporting on these drugs, so it’s worth discussing it again. All of the clinical trials of GLP-1 agonists that have been conducted in humans concern people who are either overweight or who have diabetes. These are interconnected metabolic conditions that can both, through various mechanisms, accelerate ageing and the development of age related diseases. Because of this, it’s impossible to know whether GLP-1 agonists are acting directly on the ageing process, or whether they are just addressing problems caused by diabetes and obesity.

As mentioned earlier, there is evidence from test tube and animal studies that GLP-1 agonists can protect against some of the biological processes widely accepted to be drivers of ageing, such as oxidative stress, cellular senescence and chronic inflammation. There’s even some evidence that old mice given GLP-1 agonists are rejuvenated at the cellular level and gain physical and cognitive performance. However, these studies actually have some of the same interpretation problems as the human trials, given that the mice used are usually highly inbred and develop multiple diseases, including obesity and early-stage diabetes. Ultimately, until a study shows that healthy humans taking GLP-1 agonists get less age-related disease, we aren’t going to know if they work. 

No Such Thing As A Miracle Drug?

Drugs this impressive don’t come around often without some kind of catch, and GLP-1 agonists are no exception. There are some concerns that people losing weight when taking GLP-1 agonists lose an abnormal amount of muscle mass. To be clear, losing muscle mass when losing weight is completely expected, but there are some reports that patients taking semaglutide lose more muscle mass as a proportion of total weight loss than patients who lose weight just through diet and exercise. This topic requires further research – people who are losing a lot of weight, with the aid of drugs or otherwise, should also be undergoing resistance training in order to preserve as much muscle as possible. Some research suggests that if proper precautions are taken, weight loss can be achieved without excessive loss of muscle mass or strength.

Definitively answering whether GLP-1 agonists directly trigger muscle loss will be important if they turn out to have anti-ageing properties, as muscle strength is strongly correlated with lifespan.

The Take Home Message:

There are some early indications that GLP-1 agonists might protect against age-related diseases, perhaps by slowing down some of the core processes responsible for ageing. However, in the midst of the considerable hype behind these drugs, much of the reporting may have been a little too eager to attribute these benefits to the drugs themselves as opposed to the weight loss they promote. We will keep you updated as more research emerges.