"Nature" Sub-Journal: Scientists first discovered that food smell and related olfactory nerves are involved in the regulation of dietary restriction and longevity process|Science Discovery

Studies have shown that dietary restriction can extend the lifespan of many organisms and reduce the incidence and progression of age-related diseases [1, 2].

Many scientists have explained the mechanism by which dietary restriction prolongs life span from the perspective of calories.

However, have you ever thought that perhaps the smell of food is also related to longevity.

Recently, a research team from the University of Michigan and Huazhong University of Science and Technology published a related study in the journal Nature Aging.

They found that in addition to nutrition, the perception of food smell also has an important impact on life span [3, 4].

The researchers suggested that food odors may inhibit the life-prolonging effects of dietary restrictions on organisms.

▲ Screenshot of the homepage of the paper.
Previous research in this field focused on how nutrients in food affect aging.

Scientists have discovered some nutritional signaling pathways that can regulate life span, the more famous ones are AMPK and mTOR signaling pathways [5-7].

However, food is not only composed of nutrients, other components are also related to food, such as volatile odors and various types of non-volatile, non-nutritive chemicals.

Like nutritional ingredients, these food ingredients may also affect aging [3].

For example, for Caenorhabditis elegans, chemoreceptor defects can change their lifespan, indicating that chemical signals play a role in the regulation of lifespan [8, 9].

But how do non-nutritive chemicals in food regulate lifespan? Is it through interaction with the brain? If so, how does it interact? How then does the brain interact with other parts of the body to change lifespan? ▲ This picture was published by Free-Photos on Pixabay.
Researchers have explored this problem through C.
elegans (C.
elegans is a genetic model organism widely used to study the biology of aging).

The scientists used nematode growth medium agar plates, while restricting the nematodes' diet, and added Caenorhabditis elegans food-live OP50 bacteria to the lid of the experimental group's plates.

In this way, it can be ensured that the nematodes on the plate that are subject to dietary restrictions do not directly contact the bacteria on the lid, and at the same time the smell of these bacteria can be smelled-the taste of the food is too bad.

The results show that food odors inhibit the lifespan of nematodes that are restricted by diet, but not the lifespan of nematodes that eat freely.

▲ I can smell it, but I can't eat it.
The small nematodes are too bad.
How does the smell of food inhibit the lifespan of the nematodes that are restricted by diet? Since odor is usually sensed by the nervous system, this process requires neurotransmission.
The researchers first asked: Does neurotransmission mediate the effect of odor on diet-limiting nematode lifespan? If the answer is yes, what types of neurotransmission are involved in the mediation? Through screening gene mutations and exploring the effects of specific gene mutations on experimental results, it was found that the inhibitory effect of food odor on dietary restriction of nematode life requires neurotransmission.

Through calcium imaging and transgenic technology, it was found that ADF, CEP and RIC neurons form an olfactory circuit, which mediates the inhibition of odor-induced diet-limiting nematode lifespan.

The researchers also found that in this pathway, ADF neurons act as the main sensory neurons, sensing the odor of food through a G protein-mediated transduction mechanism.

Then, ADF neurons stimulate CEP neurons, which in turn inhibit RIC neurons.

▲ Neural pathway researchers further asked: How does the olfactory circuit interact with the rest of the animal body to regulate diet and limit the lifespan of nematodes? Through genetic modification technology and RNA interference technology, the researchers found that the olfactory circuit sends a signal to the intestine to regulate the energy sensor AMPK to inhibit diet and limit the lifespan of nematodes, thus indicating that the brain-gut signal axis plays a role in this process.

So how does the olfactory circuit send signals to the intestines to regulate AMPK? Through experiments, it is found that the octopamine signal in the intestine stimulates the phosphorylation of AMPK through a Gq-PLCβ-CaMKK-dependent mechanism, and finally achieves longevity.

Considering that octopamine and norepinephrine are homologs, can norepinephrine signaling regulate AMPK in mammalian cells through a similar Gq-PLCβ-CaMKK-dependent mechanism? The researchers conducted further experiments with primary mouse subcutaneous adipocytes and primary hepatocytes, both of which express Gq-coupled α1A-adrenergic receptors.

As a result, the activation of norepinephrine signaling in primary mouse cells does regulate AMPK through a similar Gq-PLCβ-CaMKK-dependent mechanism.

Finally, the researchers proved that the effects of food odor and dietary restriction converge on AMPK to regulate life span [4].

▲ The complete pathway.
Interestingly, previous studies have found that blocking the olfactory receptors in mice can stimulate the sympathetic nerves to release norepinephrine and promote the signal transduction of norepinephrine in adipose tissue, thereby improving energy metabolism and Reduce obesity [10].

On the contrary, if the mouse's sense of smell is enhanced, it will cause insulin resistance and obesity [10].

This leads to a very interesting possibility that the sense of smell may inhibit the lifespan of mice through norepinephrine signaling.

So, it will be very interesting to test whether mice with olfactory defects live longer.

▲ This picture was published by DanaTentis on Pixabay.
This study emphasizes the idea that not only the nutritional content, but the odor in the food will also have an impact on the lifespan of people with dietary restrictions [3]. This effect works through the brain-gut axis.

This research opens up many new directions for the exploration of aging: Does food smell inhibit the life-prolonging effect of dietary restrictions on humans? If so, can we achieve the effect of prolonging life by reducing the emission of food odors, or reducing the inhalation of food odors, or weakening the perception of food odors? However, if you don’t even smell the taste when eating delicious food, will it still taste good? References [1] KOUBOVA J, GUARENTE L.
How does calorie restriction work? [J].
Genes & development, 2003, 17(3): 313-21.
[2] BISHOP NA, GUARENTE L.
Two neurons mediate diet- restriction-induced longevity in C.
elegans [J].
Nature, 2007, 447(7144): 545-9.
[3] GENDRON CM, CHAKRABORTY TS, CHUNG BY, et al.
Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception [J].
Annual review of physiology, 2020, 82: 227-49.
[4] ZHANG B, JUN H, WU J, et al.
Olfactory perception of food abundance regulates dietary restriction-mediated longevity via a brain-to- gut signal [J].
Nature aging, 2021, 1(3): 255-68.
[5] FONTANA L, PARTRIDGE L, LONGO V D.
Extending healthy life span--from yeast to humans [J].