It’s weird, isn’t it? How as the years seem to fall away, the numbers on the scales seemingly don't. Sure, you’ve heard that your metabolism slows down with age, but what does that even mean?
For all intents and purposes, you’re as active, if not more, than you were at a younger age; and you’re still just as hungry.
Why is it, then, that it becomes so easy to pile on a few extra pounds?
The answer, at least according to recent research published in the journal Cell Metabolism, could lie in changes in the shapes of melanocortin-4 (MC4) receptors in our brains.
Never heard of them before? Yeah, almost no one has. But they could be crucial to understanding and preventing age-related obesity.
What’s an MC4 receptor and how’s it related to my weight?
When it comes to weight gain and obesity, the MC4 receptor has been in the scientific spotlight for some time.
Here’s what we know so far:
First off, MC4 receptors are concentrated in an area of your brain called the hypothalamus, which is sort of like your body's control centre. Here, the receptors are found on neurons, particularly those involved in integrating signals from various hormones to regulate appetite and energy balance.
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“The MC4 receptor is known as a receptor that receives the satiety signal and functions for anti-obesity by promoting metabolism and inhibiting appetite,” Prof Kazuhiro Nakamura, physiologist at Nagoya University and senior author of the study, tells BBC Science Focus.
The “satiety signal”, Nakamura explains, is how your body tells if it is full. It's controlled by the hormones melanocortin and leptin that act on MC4 and other receptors to tell our body when to stop eating and when to increase energy expenditure.
How much food we take in and how much energy we use, as you’re probably aware, is central to how our bodies lose or gain weight, and MC4 receptors are right at the heart of this circuitry.
Previous research has shown that people with genetic mutations leading to deficiencies in MC4 receptors tend to gain weight much more easily from childhood.
For example, despite only 1 in every 500 people having a genetic deficiency, the prevalence in severely obese children could be as high as 5 in every 100, making MC4 receptor deficiency the most common monogenic (involving or controlled by a single gene) cause of obesity.
So MC4 receptors are clearly fundamental to our weight, but that doesn’t explain why we gain a little timber as we age. Thankfully, the new research from Nakamura and the team might.
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What happens to MC4 receptors as we age?
According to the new study, when rats age, the ‘antennae’ of neurons – known as ‘primary cilia’ – that bear MC4 receptors get shorter, which decreases the number of MC4 receptors accordingly.
Nakamura explains that “this age-related shortening of the antennae leads to a reduction in metabolism and an increase in appetite, resulting in obesity in middle age.”
Though the study focuses on rats, past research links changes to MC4 receptors with weight gain in both species, meaning it’s worth paying attention to. “We believe that a similar mechanism exists in humans as well," Nakamura says.
To back up their findings, the team also shortened the antennae of younger rats artificially using genetic engineering. In turn, they found that the younger rats ate more, burned less fat and put on weight as a result.
They also tried injecting the now MC4 receptor-deficient rats with the appetite-suppressing hormone leptin and found, as is the case with obese humans, that the rats seemed to be resistant to it.
But other researchers have urged caution about jumping to conclusions. “I would say it's a bit too early to say because it's only been done in rats and some of the key pieces of the puzzle are missing,” says Sadaf Farooqi, professor of metabolism and medicine at the University of Cambridge.
She points out that age-related weight gain is a complex picture, involving but not limited to, hormones, muscle loss and lower metabolic rates.
“But it does suggest something quite interesting, which is that maybe some of the key genes or molecules in the brain that we know regulate weight, maybe their levels change as we age,” she says.
All is not lost. Here’s what you can do
There is a silver lining in the new findings. The antennae shortening process can be slowed down using a pretty simple, albeit slightly unsatisfying, solution.
Eating healthy and restricting calories. We know these help us maintain a healthy weight, but the new research suggests that they’re key for keeping those lovely MC4 receptor-rich antennae as long as possible as we age.
On a fatty diet, the MC4-bearing cilia in the rats shrank faster than for rats on a healthier, more restricted diet. A healthier diet may even reverse the shrinking.
“Our research findings indicate that we should avoid overeating,” says Nakamura.
“Many people know that calorie restriction, which I know is painful, reduces fat accumulation in the body due to excessive energy intake.
“However, our data suggest that moderate eating habits are also important to maintain the antennae long enough to keep the brain’s anti-obesity system in good shape even as we age.”
So, you heard it here last: eating healthy and not overeating when you’re younger helps keep you slim when you get older.
Exercise is the other key, but not just because it burns calories in and of itself. "There's a particularly beneficial role for exercise because in that middle age group onwards it can have really beneficial effects on muscle," Farooqi says.
Muscle is a really efficient calorie burner, so maintaining it as you age helps maintain a high metabolism. Resistance training and eating enough protein (experts recommend about 20 grams per meal) are great ways to do that.
If you’re looking for a more high-tech solution, then you shouldn’t be too disappointed. Nakamura explains that the team successfully managed to manipulate a protein that enables this antenna shortening to stop functioning. In response, the rats successfully lost weight.
Meanwhile, Farooqi notes that for people really struggling with middle-aged weight gain, such as some women going through menopause, the study hints that treatments designed to strengthen the MC4 pathway could be beneficial.
“It’s a bit early for that yet because we don't have enough evidence, but it is a first clue that it's worth looking at,” she says.
About our experts
Kazuhiro Nakamura is a professor at the Graduate School of Medicine, at Nagoya Univesity, Japan. His research interests focus on the central neural circuit, thermoregulation and metabolism, among others. Nakamura's studies have appeared in prestigious journals such as Frontiers in Bioscience, Nature Neuroscience and the Journal of Neuroscience.
Sadaf Farooqi is a professor of metabolism and medicine at the University of Cambridge and an Honorary Consultant in diabetes and endocrinology at Addenbrooke’s Hospital, Cambridge. She is an internationally leading clinician-scientist who has made seminal contributions to understanding the genetic and physiological mechanisms that underlie obesity and its complications. With colleagues, she discovered and characterised the first genetic disorders that cause severe childhood obesity and established that the principal driver of obesity in these conditions was a failure of the control of appetite.
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