Controlling Triggers of Age-Related Inflammation Could Extend 'Healthspan'

From ScienceDaily website (see original article)

Oct. 21, 2013 — Inflammation is the common denominator of many chronic age-related diseases such as arthritis, gout, Alzheimer's, and diabetes. But according to a Yale School of Medicine study, even in the absence of a disease, inflammation can lead to serious loss of function throughout the body, reducing healthspan -- that portion of our lives spent relatively free of serious illness and disability.

Published as the cover article in the October issue of Cell Metabolism, the study found that immune sensor Nlrp3 inflammasome is a common trigger of this inflammation-driven loss of function that manifests itself in insulin-resistance, bone loss, frailty, and cognitive decline in aging.

As the elderly population increases, clinicians are seeing a spike in age-related diseases, but scientists did not fully understand the role of inflammation. What is commonly known is that as we age, our cells change, leading the immune system to produce chronic, low-level inflammation throughout the body.
Aging is also a major risk factor for multiple chronic diseases, but according to the researchers, biomedical enterprise spends billions of dollars to tackle each age-dependent disease separately.

"This is the first study to show that inflammation is causally linked to functional decline in aging," said lead author Vishwa Deep Dixit, professor of comparative medicine and immunobiology at Yale School of Medicine.
"There are multiple cellular triggers of inflammation throughout the body, but we've pinpointed Nlrp3 as the specific sensor that activates inflammation with age."

"If aging is indeed a common factor for multiple diseases, the unanswered question is, can we identify the triggers of aging that cause low-level inflammation so that 'switching off' the trigger can slow the onset of multiple chronic diseases that are age-dependent at their onset," Dixit added. "Since aging affects us all, if this goal can be achieved, it is likely to significantly improve the healthspan and may also lower healthcare costs as the aging population increases in the U.S."

Dixit and his colleagues investigated the normal aging process of mice that were free of diseases, and fed a normal diet.
The research team found that immune sensor Nlrp3 inflammasome is activated in response to aging.
They then tested mice to determine if reducing the activity of Nlrp3 inflammasome lowers inflammation, and aging-associated decline in function.
Results showed that animals with lower Nlrp3 activation were protected from many age-related disorders such as dementia, bone loss, glucose intolerance, cataracts, and thymus degeneration.
Functionally, the mice also performed better, were less frail, and ran for longer durations.
The researchers also tested another immune sensor called caspase11, which is activated in response to certain infections, and found that it was not linked to the age-related inflammation process.

"Now that we've identified this mechanism in the Nlrp3 sensor, we might be able to manipulate this immune sensor to delay, or reduce inflammation," Dixit said.
"This could lead to the possibility of prolonging healthspan, potentially leading to an old age relatively free of disease or disability."

Dixit said additional studies are needed to explore whether the Nlrp3 mechanism can be safely manipulated without impairing the immune system.
He points out that although there are several anti-inflammatory drugs available, none seem to be effective in expanding the healthspan.
"One of our long-term goals is to develop therapies or specific diets that could dampen the excessive inflammation process as a means to prevent chronic diseases," he said.

Vitamin D, Omega-3 May Help Clear Amyloid Plaques Found in Alzheimer's

From Science Daily website (see original article).

Feb. 5, 2013 — A team of academic researchers has pinpointed how vitamin D3 and omega-3 fatty acids may enhance the immune system's ability to clear the brain of amyloid plaques, one of the hallmarks of Alzheimer's disease.

In a small pilot study published in the Feb. 5 issue of the Journal of Alzheimer's Disease, the scientists identified key genes and signaling networks regulated by vitamin D3 and the omega-3 fatty acid DHA (docosahexaenoic acid) that may help control inflammation and improve plaque clearance.

Previous laboratory work by the team helped clarify key mechanisms involved in helping vitamin D3 clear amyloid-beta, the abnormal protein found in the plaque.
The new study extends the previous findings with vitamin D3 and highlights the role of omega-3 DHA.

"Our new study sheds further light on a possible role for nutritional substances such as vitamin D3 and omega-3 in boosting immunity to help fight Alzheimer's," said study author Dr. Milan Fiala, a researcher at the David Geffen School of Medicine at UCLA.

For the study, scientists drew blood samples from both Alzheimer's patients and healthy controls, then isolated critical immune cells called macrophages from the blood. Macrophages are responsible for gobbling up amyloid-beta and other waste products in the brain and body.

The team incubated the immune cells overnight with amyloid-beta. They added either an active form of vitamin D3 called 1alpha,25–dihydroxyvitamin D3 or an active form of the omega-3 fatty acid DHA called resolvin D1 to some of the cells to gauge the effect they had on inflammation and amyloid-beta absorption.

Both 1alpha, 25-dihydroxyvitamin D3 and resolvin D1 improved the ability of the Alzheimer's disease patients' macrophages to gobble-up amyloid-beta, and they inhibited the cell death that is induced by amyloid-beta.
Researchers observed that each nutrition molecule utilized different receptors and common signaling pathways to do this.

Previous work by the team, based on the function of Alzheimer's patients' macrophages, showed that there are two groups of patients and macrophages.
In the current study, researchers found that the macrophages of the Alzheimer's patients differentially expressed inflammatory genes, compared with the healthy controls, and that two distinct transcription patterns were found that further define the two groups: Group 1 had an increased transcription of inflammatory genes, while Group 2 had decreased transcription. Transcription is the first step leading to gene expression.

"Further study may help us identify if these two distinct transcription patterns of inflammatory genes could possibly distinguish either two stages or two types of Alzheimer's disease," said study author Mathew Mizwicki, an assistant researcher at the David Geffen School of Medicine at UCLA.

While researchers found that 1alpha,25-dihydroxyvitamin D3 and resolvin D1 greatly improved the clearance of amyloid-beta by macrophages in patients in both groups, they discovered subtleties in the effects the two substances had on the expression of inflammatory genes in the two groups.
In Group 1, the increased-inflammation group, macrophages showed a decrease of inflammatory activation; in Group 2, macrophages showed an increase of the inflammatory genes IL1 and TLRs when either 1alpha,25-Dihydroxyvitamin D3 or resolvin D1 were added.

More study is needed, Fiala said, but these differences could be associated with the severity of patients' nutritional and/or metabolic deficiencies of vitamin D3 and DHA, as well as the omega-3 fatty acid EPA (eicosapentaenoic acid).

"We may find that we need to carefully balance the supplementation with vitamin D3 and omega-3 fatty acids, depending on each patient in order to help promote efficient clearing of amyloid-beta," Fiala said.
"This is a first step in understanding what form and in which patients these nutrition substances might work best."

According to Fiala, an active (not oxidized) form of omega-3 DHA, which is the precursor of the resolvin D1 used in this study, may work better than more commercially available forms of DHA, which generally are not protected against the oxidation that can render a molecule inactive.

The next step is a larger study to help confirm the findings, as well as a clinical trial with omega-3 DHA, the researchers said.

The Alzheimer's Association contributed to the initial phase of the study.
Fiala is a consultant for the Smartfish Company that is producing a drink with an active form of omega-3 DHA.

Green Tea and Red Wine Extracts Interrupt Alzheimer's Disease Pathway in Cells

From Science Daily website (see original article).

Feb. 5, 2013 — Natural chemicals found in green tea and red wine may disrupt a key step of the Alzheimer's disease pathway, according to new research from the University of Leeds.

In early-stage laboratory experiments, the researchers identified the process which allows harmful clumps of protein to latch on to brain cells, causing them to die.
They were able to interrupt this pathway using the purified extracts of EGCG from green tea and resveratrol from red wine.

The findings, published in the Journal of Biological Chemistry, offer potential new targets for developing drugs to treat Alzheimer's disease, which affects some 800,000 people in the UK alone, and for which there is currently no cure.

"This is an important step in increasing our understanding of the cause and progression of Alzheimer's disease," says lead researcher Professor Nigel Hooper of the University's Faculty of Biological Sciences.
"It's a misconception that Alzheimer's is a natural part of aging; it's a disease that we believe can ultimately be cured through finding new opportunities for drug targets like this."

Alzheimer's disease is characterised by a distinct build-up of amyloid protein in the brain, which clumps together to form toxic, sticky balls of varying shapes.
These amyloid balls latch on to the surface of nerve cells in the brain by attaching to proteins on the cell surface called prions, causing the nerve cells to malfunction and eventually die.

"We wanted to investigate whether the precise shape of the amyloid balls is essential for them to attach to the prion receptors, like the way a baseball fits snugly into its glove," says co-author Dr Jo Rushworth.
"And if so, we wanted to see if we could prevent the amyloid balls binding to prion by altering their shape, as this would stop the cells from dying."

The team formed amyloid balls in a test tube and added them to human and animal brain cells.
Professor Hooper said: "When we added the extracts from red wine and green tea, which recent research has shown to re-shape amyloid proteins, the amyloid balls no longer harmed the nerve cells.
We saw that this was because their shape was distorted, so they could no longer bind to prion and disrupt cell function.

"We also showed, for the first time, that when amyloid balls stick to prion, it triggers the production of even more amyloid, in a deadly vicious cycle," he added.

Professor Hooper says that the team's next steps are to understand exactly how the amyloid-prion interaction kills off neurons.

"I'm certain that this will increase our understanding of Alzheimer's disease even further, with the potential to reveal yet more drug targets," he said.

Dr Simon Ridley, Head of Research at Alzheimer's Research UK, the UK's leading dementia research charity, which part-funded the study, said: "Understanding the causes of Alzheimer's is vital if we are to find a way of stopping the disease in its tracks.
While these early-stage results should not be a signal for people to stock up on green tea and red wine, they could provide an important new lead in the search for new and effective treatments.
With half a million people affected by Alzheimer's in the UK, we urgently need treatments that can halt the disease -- that means it's crucial to invest in research to take results like these from the lab bench to the clinic."