There are brain neurons that suppress aging!
Neurons that inhibit aging
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Activation of DMH Ppp1r17 neurons reduces fat and increases the concentration of eNAMPT enzyme.
It was confirmed that the lifespan of the experimental group of mice was extended.
Crosstalk regulates aging?
In recent years, research has emerged to support the idea that crosstalk between body tissues is a key regulator of aging. When crosstalk between tissues occurs smoothly, bodily organs and systems function properly. However, as we age, crosstalk systems deteriorate, preventing organs from receiving the signals and molecules they need to function properly.
*Crosstalk: A phenomenon in which one signaling pathway affects another signaling pathway.
In mammals, interactions between the hypothalamus and other tissues play a crucial role in aging. For example, hypothalamic neurons harbor the NMN receptor Slc12a8, which regulates skeletal muscle function and energy metabolism. Increased NMN receptor activity in brain regions suppresses muscle weakness , a hallmark of aging . This supports the idea that crosstalk between the hypothalamus and other tissues, such as muscles, contributes to slowing aging and extending lifespan.
*Hypothalamus: A part of the brain that controls the autonomic nervous system
*Neuron: nerve cell
Figure 1. Muscle changes according to Slc12a8 concentration in young and old mice, respectively.
Another interaction involves crosstalk between the hypothalamus and adipose tissue . When specific neurons in the hypothalamus are activated, the brain signals fat cells to "increase exercise, reduce fat," and delay aging.
Figure 2. Appearance of a specific neuron
Life extension through hypothalamic neurons
Here are 'old rat A ' and 'rat B with specific neurons activated that are associated with lifespan .'
Figure 3. Comparison of eNAMPT enzyme release in aged rat A and rat B with activated life-related neurons.
'Aged Rat A ' has suppressed neuronal activity associated with lifespan . The 'Ppp1r17 protein' present in neurons falls off from brain neurons due to aging, and the sympathetic nervous system signaling responsible for the 'fight-or-flight response' is blocked. As a result, the connection between the nervous system and adipose tissue is blocked, and the 'eNAMPT enzyme ' (extracellular nicotinamide phosphoribosyltransferase) released from fat decreases . eNAMPT is an enzyme that synthesizes NMN (nicotinamide mononucleotide) from nicotinamide and increases NMN concentration . In Rat A, eNAMPT is no longer released, so the concentration of NMN and NAD+ in the body decreases . As a result, Rat A continues to age .
*Ppp1r17 protein: A protein present in neurons of the hypothalamus that promotes crosstalk between the nervous system and adipose tissue, thereby inducing the release of eNAMPT enzyme in adipose tissue.
*Fight-or-flight response: A biochemical and neurological response to an acute stressful stimulus, such as encountering a threatening object.
In contrast, in ' Rat B with activated specific neurons ', 'Ppp1r17 protein' is produced, the sympathetic nervous system is activated, and a large amount of eNAMPT enzyme is released from adipose tissue . Therefore, as NMN is synthesized, the lifespan of Rat B is extended .
*NMN: Nicotinamide mononucleotide, a substance that is converted into NAD+ in the body when consumed
*NAD+: Nicotinamide adenine dinucleotide, a cofactor that plays an important role in numerous chemical reactions within cells. As aging progresses, NAD+ content decreases and is a substance closely related to longevity.
Which neurons should we activate to prevent aging?
So which of the many neurons in the hypothalamus should we stimulate to prevent aging? A key neuron for longevity was discovered in the medial hypothalamus (DMH) . The neurons discovered in the DMH had 15 times higher gene activity for the Ppp1r17 protein than other neurons, leading to their being named the DMH Ppp1r17 neuron . When this neuron is activated, the brain sends a signal to the fat cells, which increases physical activity, reduces body fat percentage, and delays aging .
In the graph below, we will evaluate the level of fat reduction , eNAMPT release concentration , and relative lifespan following stimulation of DMH Ppp1r17 neurons .
1) Level of fat reduction according to stimulation of DMH Ppp1r17 neurons
● Animal model: C57BL/6J male mice
● Experimental group : Ppp1r17 , mice engineered to have lower levels of Ppp1r17 protein in neurons
● Control group: fLuc , healthy mice
● Ppp1r17 mice were administered 0.5 mg/kg of Agonist 21 intraperitoneally for 8 days.
Graph 1. Body fat content (%) in mice with reduced Ppp1r17 protein concentration (red bar) and healthy mice (black bar)
Mice with lowered Ppp1r17 protein levels through genetic manipulation were assigned to the Ppp1r17 group , while healthy mice were assigned to the fLuc group . Compared to the fLuc group, the Ppp1r17 group showed a nearly 30% increase in fat mass . In addition, the Ppp1r17 experimental group showed a decrease in the interaction between the sympathetic nervous system, which is responsible for the fight-or-flight response, and adipose tissue . This confirms that DMH Ppp1r17 neurons can use the Ppp1r17 protein to regulate adipose tissue or activate the sympathetic nervous system and interact with adipose tissue .
*Agonist: A chemical substance that binds to specific cells and elicits a response from those cells.
2) Level of fat reduction according to stimulation of DMH Ppp1r17 neurons
● Animal model: C57BL/6J male mice
● Experimental group : hM3D , mice engineered to activate DMH Ppp1r17 neurons
● Control group: mCherry , non-genetically modified mice
● mCherry mice were administered 0.5 mg/kg of Agonist 21 intraperitoneally for 8 days.
Graph 2. Relative eNAMPT concentrations in mice manipulated to activate DMH Ppp1r17 neurons (green bar) and unmanipulated mice (black bar).
We created the mCherry group with non-genetically modified mice and the hM3D group with genetically modified mice to activate DMH Ppp1r17 neurons . We observed higher eNAMPT concentrations in the hM3D group when agonist21 was present together. In contrast, the mCherry group did not show significantly higher eNAMPT concentrations. Consequently, we confirmed that activating DMH Ppp1r17 neurons increased the release of eNAMPT from fat and additionally increased the wheel running capacity of the mice in which the neurons were activated . This suggests that activating DMH Ppp1r17 neurons prevents adipose tissue dysfunction caused by aging .
*PBS: Phosphate buffered saline, a buffer solution commonly used in biological research that helps maintain a constant pH.
3) Lifespan changes in response to stimulation of DMH Ppp1r17 neurons
● Animal model: C57BL/6J male mice
● Experimental group : hM3D , mice engineered to activate DMH Ppp1r17 neurons
● Control group: mCherry , non-genetically modified mice
● mCherry mice were administered 0.5 mg/kg of Agonist 21 intraperitoneally for 8 days.
Graph 3. Lifespan (days) of mice genetically engineered to activate DMH Ppp1r17 neurons (green bar) and unengineered mice (black bar)
The hM3D group, genetically engineered to stimulate the DMH Ppp1r17 neurons in the hypothalamus, showed an average lifespan increase of about 7% compared to the mCherry group, which was not genetically engineered. Furthermore, the hM3D group showed a maximum lifespan increase of about 20% compared to the mCherry group. For a person who typically lives to age 75, this translates to an additional five years of life .
Anti-aging therapy using eNAMPT
eNAMPT synthesized in adipose tissue returns to the brain, activates DMH Ppp1r17 neurons, and supplies fuel to the hypothalamus. Administering eNAMPT is one way to maintain crosstalk between the brain and adipose tissue. When eNAMPT is delivered, it is encapsulated in an extracellular vesicle. Using this mechanism of action , we experimentally confirmed that administering eNAMPT encapsulated in an extracellular vesicle extended the lifespan of mice .
It's not yet possible to administer eNAMPT to humans. However, NMN, the precursor of NAD+ synthesized by eNAMPT, is currently commercially available and can be administered orally. It is hoped that a method will be developed to administer eNAMPT to humans, allowing for the administration of both NMN and eNAMPT.
[References and Figure Source]
[1] Washington University Study Indicates Increasing NMN Transporter in the Brain Mitigates Age-Related Muscle Decline, by Brett J. Weiss, Published: 3:22 pm PST Aug 8, 2022
[2] Slc12a8 in the lateral hypothalamus maintains energy metabolism and skeletal muscle functions during aging, Naoki Ito 1 2 6, Ai Takatsu 1 2 7, Hiromi Ito 1 2 7, Yuka Koike 1 2, Kiyoshi Yoshioka 3 4, Yasutomi Kamei 4, Shin-ichiro Imai 1 2 5 8, Published: July 26, 2022
https://www.sciencedirect.com/science/article/pii/S2211124722009378
[3] Tokizane K, Brace CS, Imai SI. DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication. Cell Metab. 2024 Jan 1:S1550-4131(23)00462-X. doi: 10.1016/j.cmet.2023.12.011. Epub ahead of print. PMID: 38194970.
https://pubmed.ncbi.nlm.nih.gov/38194970/
[4] [Science Shot] Awakening Brain Cells Extends Healthy Lifespan by 6 Years
https://biz.chosun.com/science-chosun/medicine-health/2024/01/10/6TEKMW6T7VHNZOWOPBTLYRUI7Y/
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