In recent years, research has begun to reveal that the lines of communication between the body’s organs are key regulators of aging. When these lines are open, the body’s organs and systems work well together. But with age, communication lines deteriorate, and organs don’t get the molecular and electrical messages they need to function properly.
A new study from Washington University
School of Medicine in St. Louis identifies, in mice, a critical communication
pathway connecting the brain and the body’s fat tissue in a feedback loop that
appears central to energy production throughout the body. The research suggests
that the gradual deterioration of this feedback loop contributes to the
increasing health problems that are typical of natural aging.
The study — published Jan. 8 in the
journal Cell Metabolism — has implications for developing future interventions
that could maintain the feedback loop longer and slow the effects of advancing
age.
The researchers identified a specific
set of neurons in the brain’s hypothalamus that, when active, sends signals to
the body’s fat tissue to release energy. Using genetic and molecular methods,
the researchers studied mice that were programmed to have this communication
pathway constantly open after they reached a certain age. The scientists found
that these mice were more physically active, showed signs of delayed aging, and
lived longer than mice in which this same communication pathway gradually slowed
down as part of normal aging.
“We demonstrated a way to delay aging
and extend healthy life spans in mice by manipulating an important part of the
brain,” said senior author Shin-ichiro Imai, MD, PhD, the Theodore and Bertha Bryan Distinguished
Professor in Environmental Medicine and a professor in the Department of Developmental Biology at Washington University. “Showing this effect
in a mammal is an important contribution to the field; past work demonstrating
an extension of life span in this way has been conducted in less complex
organisms, such as worms and fruit flies.”
These specific neurons, in a part of the
brain called the dorsomedial hypothalamus, produce an important protein —
Ppp1r17. When this protein is present in the nucleus, the neurons are active
and stimulate the sympathetic nervous system, which governs the body’s fight or
flight response.
The fight or flight response is well
known for having broad effects throughout the body, including causing increased
heart rate and slowed digestion. As part of this response, the researchers
found that the neurons in the hypothalamus set off a chain of events that
triggers neurons that govern 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 that can be used to fuel physical
activity. The activated fat tissue also releases another important protein — an
enzyme called eNAMPT — which returns to the hypothalamus and allows the brain
to produce fuel for its functions.
This feedback loop is critical for
fueling the body and the brain, but it slows down over time. With age, the
researchers found that the protein Ppp1r17 tends to leave the nucleus of the
neurons, and when that happens, the neurons in the hypothalamus send weaker
signals. With less use, the nervous system wiring throughout the white adipose
tissue gradually retracts, and what was once a dense network of interconnecting
nerves becomes sparse. The fat tissues no longer receive as many signals to
release fatty acids and eNAMPT, which leads to fat accumulation, weight gain
and less energy to fuel the brain and other tissues.
With age, the researchers found that the
protein Ppp1r17 tends to leave the nucleus of the neurons, and when that
happens, the neurons in the hypothalamus send weaker signals. With less use,
the nervous system wiring throughout the white adipose tissue gradually
retracts, and what was once a dense network of interconnecting nerves (left)
becomes sparse (right). Credit: Kyohei Tokizane
The researchers, including first author
Kyohei Tokizane, PhD, a staff scientist and a former postdoctoral researcher in
Imai’s lab, found that when they used genetic methods in old mice to keep
Ppp1r17 in the nucleus of the neurons in the hypothalamus, the mice were more
physically active — with increased wheel-running — and lived longer than
control mice. They also used a technique to directly activate these specific
neurons in the hypothalamus of old mice, and they observed similar anti-aging
effects.
On average, the high end of the life
span of a typical laboratory mouse is about 900 to 1,000 days, or about 2.5
years. In this study, all of the control mice that had aged normally died by
1,000 days of age. Those that underwent interventions to maintain the brain-fat
tissue feedback loop lived 60 to 70 days longer than control mice. That
translates into an increase in life span of about 7%. In people, a 7% increase
in a 75-year life span translates to about five more years. The mice receiving
the interventions also were more active and looked younger — with thicker and
shinier coats — at later ages, suggesting more time with better health as well.
Imai and his team are continuing to
investigate ways to maintain the feedback loop between the hypothalamus and the
fat tissue. One route they are studying involves supplementing mice with
eNAMPT, the enzyme produced by the fat tissue that returns to the brain and
fuels the hypothalamus, among other tissues. When released by the fat tissue
into the bloodstream, the enzyme is packaged inside compartments called
extracellular vesicles, which can be collected and isolated from blood.
“We can envision a possible anti-aging
therapy that involves delivering eNAMPT in various ways,” Imai said. “We already
have shown that administering
eNAMPT in extracellular vesicles increases cellular energy
levels in the hypothalamus and extends life span in mice. We look forward to
continuing our work investigating ways to maintain this central feedback loop
between the brain and the body’s fat tissues in ways that we hope will extend
health and life span.
Source: https://medicine.wustl.edu/news/life-span-increases-in-mice-when-specific-brain-cells-are-activated/
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