by Hannah Smith
figures by Xiaomeng Han

If you ask any aging researcher, “What is the easiest way to make an animal in the lab live longer,” they will likely say “change what, or how much, they eat.” However, new research shows that it’s not just the food we eat that changes how we age, but that aging is also affected by the food we smell. 

Studies linking diet and aging go all the way back to the 1920s when researchers showed that giving flies or rats less food made them live longer. This method, called dietary restriction, which means reducing food intake while still providing enough key nutrients, has since been found to extend lifespan in a wide range of animals including nematode worms, fruit flies, mice, and rhesus monkeys. Aging researchers have even found that cutting out specific nutrients, like certain kinds of protein, without cutting total calories is enough to make animals live longer. But despite all of this work, we still don’t fully understand how diet influences aging! 

A new study using the nematode worm called C. elegans shows that just the smell of food can influence lifespan. These tiny worms are frequently used in aging research because their lifespan is only about 3 weeks, they are transparent so you can see what’s going on inside of them with high-power microscopes, and they share a lot of their biology with humans. The food of choice for C. elegans is bacteria and it has long been known that dietary restriction (feeding the worms less bacteria) extends their lifespan. In this study, the researchers amended the classic dietary restriction method to measure the impact of a new element: food odors. The researchers took plates of worms that were either fully fed or on dietary restriction and grew additional bacteria on the lids of the plates so that the worms could smell the food but couldn’t eat it. They found that worms on the normal diet were unaffected but worms on dietary restriction didn’t live as long anymore (Figure 1). In other words, just the smell of food partially reversed the longevity benefits of dietary restriction in these worms, demonstrating that both the consumption and the perception of food are important in regulating lifespan.

But how does it work?

How does a smell end up changing how long a worm lives? The researchers tracked down a chain of events that starts in the neurons and ends up all the way in the intestine of the worm. The key players in responding to food odors are called neurotransmitters, chemicals that neurons send to each other or to other types of cells to relay information. 

When worms have less food around them, like when they are on dietary restriction, a set of neurons called the RIC (ring interneuron C) neurons are activated and release a neurotransmitter called octopamine, which is received by cells in the intestine. The octopamine in the intestine causes the activation of an energy sensor called AMPK (AMP-activated kinase) that has previously been found to be important in the lifespan extension resulting from dietary restriction. However, when food odors are present, the RIC neurons are inhibited and no longer release octopamine; therefore, AMPK in the intestine isn’t activated as much, and the lifespan extension resulting from dietary restriction is blunted.

This study marks the first identification of a distinct “brain-to-gut” signaling cascade that is initiated by food odors and influences aging. What’s even more interesting is that this signal shortens the lifespan of the worms fed less food (dietary restriction) without affecting the lifespan of the fully-fed worms. One reason that worms with a restricted diet might be more affected by the smell of food is that hunger has previously been found to sensitize the body to food odors as a method of driving the organism to seek out something to eat. 

Not just a worm thing

This work is one of the most thorough investigations to date of how smell regulates aging, but there is evidence from past research that this biology is likely relevant in other animals, too. In 2007, a study in flies showed that the smell of yeast (the food of choice for flies) moderately reduced the lifespan of long-lived flies on dietary restriction but did not affect fully fed flies with a normal lifespan. Moreover, flies that were genetically modified so that they couldn’t smell lived longer than normal flies. In mice, sense of smell hasn’t directly been linked to aging, but it has been shown to affect weight gain and neuronal signaling. Mice fed a high-fat diet rapidly gain weight, but mice that can’t smell don’t gain weight when they eat the high-fat diet. This work shows that, like in worms, the effect of food on the response of a mouse to a certain diet depends not only on the diet itself, but also on the mouse’s perception of the food by its sense of smell. 

So, where do we go from here?

Will smelling a piece of pizza be enough to ruin the benefits of that diet you’re on? Can we forfeit our sense of smell, eat whatever we want, and then live long and healthy lives? In short, no. There is evidence that altering smell in humans can alter eating habits, but there are also clear disadvantages to targeting smell as an aging intervention. One human trial showed that wearing a silicone insert in the nose for a few hours a day to block smell resulted in weight loss, reduced appetite, and reduced cravings for sweet foods. However, losing your sense of smell to free yourself from late-night dessert cravings might not be worth it. A study based in the UK found that among people with anosmia, a chronic loss of their sense of smell, there are high rates of anxiety, depression, and relationship issues. Not being able to smell often leads to a general loss of interest in cooking and eating, can be a safety concern (for example if you can’t smell smoke when there is a fire), and can make everyday tasks difficult (how would you know when to change a baby’s diaper or if you need to put deodorant on?). 

Overall, this research sheds new light on the importance of the brain as a central regulator of aging. The nervous system holds a unique role within the body as it receives information from both the external environment (sight, smell, sound, taste, touch) and the internal environment (nutrient levels, signals from different organs) and can combine all of these factors to make decisions about how to use energy, how fast to grow, when to reproduce, and, ultimately, the rate at which an animal ages. As this study shows, the brain’s perception of a set of circumstances, like how much food is available, is a powerful force that can alter an animal’s lifespan, even if the actual conditions don’t match what the brain has perceived. Recognizing the influence of the brain and studying the ways that neurons can signal to other tissues will be crucial in the quest to truly understand the forces that drive human aging.

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Hannah Smith is a third year Ph.D. student in the Biological Sciences in Public Health program. She uses the nematode worm C. elegans to study the relationship between food and aging in the lab. She is particularly interested in the role of the brain in sensing nutrients and then signaling to other tissues to regulate lifespan and health. 

Xiaomeng Han is a graduate student in the Harvard Ph.D. Program in Neuroscience. She uses correlated light and electron microscopy to study neuronal connectivity.

For More Information:

• Curious about dietary restriction and aging? Check out this article on the history of dietary restriction research, including a wild human experiment called “Biosphere.”
• To learn more about the mouse study on olfaction and weight gain, check out this news article about the study.
• Why are we even studying aging in worms? Read more about aging research in C. elegans here.