Brain-Fat Tissue Loop Explored for Human Longevity

In recent years, scientific research has highlighted the importance of communication between the body’s organs as a key factor in regulating aging. The efficiency of these communication lines diminishes with age, leading to a decline in the molecular and electrical messages vital for proper organ function.

A new study from Washington University School of Medicine in St. Louis, focusing on mice, uncovers a critical communication pathway between the brain and the body’s fat tissue. This pathway, constituting a feedback loop, plays a central role in energy production throughout the body. The findings suggest that the gradual breakdown of this feedback loop contributes to the health problems associated with natural aging. 

Published in the journal Cell Metabolism, the study holds potential implications for developing interventions that could extend the maintenance of this feedback loop, thereby slowing the effects of aging.

The researchers pinpointed specific neurons in the hypothalamus, a region of the brain, which, when active, send signals to the body’s fat tissue, instructing it to release energy. Using genetic and molecular methods, the researchers manipulated mice to have this communication pathway consistently open after reaching a certain age. 

The mice with the sustained communication pathway exhibited increased physical activity, signs of delayed aging, and longer lifespans compared to mice where the same communication pathway naturally slowed down with age. Senior author Shin-ichiro Imai, MD, Ph.D., emphasized the significance of the study’s findings, stating, “We demonstrated a way to delay aging and extend healthy lifespans in mice by manipulating an important part of the brain.” This represents a notable achievement, as previous studies demonstrating lifespan extension were mainly conducted on less complex organisms such as worms and fruit flies. 

The specific neurons identified in the dorsomedial hypothalamus produce a crucial protein called Ppp1r17. When this protein is present, the neurons become active and stimulate the sympathetic nervous system, responsible for the body’s fight or flight response.

Activation of this response triggers a chain of events leading to the stimulation of neurons governing white adipose tissue, a type of fat tissue stored under the skin and in the abdominal area. 

The activated fat tissue releases fatty acids into the bloodstream, providing fuel for physical activity. Additionally, the activated fat tissue releases another important protein, an enzyme called eNAMPT, which returns to the hypothalamus, enabling the brain to produce fuel for its functions. This feedback loop is vital for fueling both the body and the brain but tends to slow down with age. As the protein Ppp1r17 leaves the nucleus of the neurons, the signals from the hypothalamus weaken, leading to a reduction in the neural network within white adipose tissue. 

With less neural signaling, the fat tissues accumulate, resulting in weight gain and decreased energy for the brain and other tissues. The researchers found that maintaining Ppp1r17 in the nucleus of neurons in the hypothalamus, either through genetic methods or by directly activating the neurons, led to increased physical activity and extended lifespans in mice. 

On average, mice subjected to interventions targeting the brain-fat tissue feedback loop lived 60 to 70 days longer than control mice, translating to a 7% increase in lifespan. In human terms, a 7% increase in a 75-year lifespan would amount to about five additional years. The study also noted that the mice receiving interventions appeared more active and exhibited signs of improved health, suggesting prolonged periods of better overall well-being. 

Moving forward, the researchers are exploring ways to sustain the feedback loop between the hypothalamus and fat tissue. One avenue involves studying the supplementation of mice with eNAMPT, the enzyme produced by fat tissue.

The team envisions potential anti-aging therapies involving the delivery of eNAMPT through various means, building on their previous findings that administering eNAMPT in extracellular vesicles increases cellular energy levels in the hypothalamus and extends lifespan in mice. The ongoing research aims to explore methods to maintain this crucial feedback loop, offering potential avenues to extend health and lifespan. 

Journal Reference  

Kyohei Tokizane et al, DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication, Cell Metabolism (2024). DOI: 10.1016/j.cmet.2023.12.011.