LINUS
PAULINGINSTITUTE
OREGON STATE UNIVERSITYRESEARCH NEWSLETTERDECEMBER – FEBRUARY
2022/23

NEW WEBINAR ON ZINC AND HEALTH FROM DR. EMILY HO LOOK INSIDEVITAMIN C AND E IN CYSTIC FIBROSISMaintaining adequate blood levels of vitamin E can be challenging for people withcystic fibrosis. New research by Dr. Maret Traber and her colleagues shows that thisproblem might be solved indirectly by supplementing with vitamin C. Results of
their recent clinical trial reveal that vitamin C supplementation increases vitamin E
bioavailability in patients with cystic fibrosis. Additionally, these findings suggestthat this strategy may help improve the vitamin E status of millions of people withchronic inflammation worldwide, leading to improved global health outcomes.
Although commonly thought of as alung disease, cystic fibrosis affects manyorgans throughout the body, including thepancreas and liver. Because of this, people
with cystic fibrosis have limited ability todigest and absorb fats and often struggle
with malnutrition.

Dr. Maret Traber, a world-renowned
expert on vitamin E and Ava Helen Pauling
Professor at the Linus Pauling Institute, isconcerned with the issues that surroundpoor fat absorption. These problems candramatically impact health and qualityof life.

Cystic fibrosis is a genetic disorderoften accompanied by high levels of
inflammation. With inflammation comesan increased production of free radicals
and oxidative stress, increasing the needfor antioxidants. Many different antioxidant
therapies have been proposed and studiedin patients with cystic fibrosis, with limited
success.

The inability to properly absorb dietary
fat concurrently decreases the uptakeof the fat-soluble vitamins A, D, E, and K.
Since both vitamins A and E contribute toantioxidant defenses, inadequate levelsof these vitamins can exacerbate cycles
of inflammation within the body.
Continued on page 4

IN THIS ISSUE
Vitamin C and E in
Cystic Fibrosis........1
From the Director....2
LPI Students:
A Focus on
Alzheimer’s..............3
Vitamin E Webinar
Q&A Follow-Up.........5
Research in Brief:
Licorice Extracts......6
Research in Brief:
Zinc and theMicrobiome..............7

Photo credit: Hannah O’Leary

FROM THE DIRECTOR

Emily Ho, PhD
Endowed Chair and Director,
Linus Pauling InstituteOn December 6, I presented
Galvanizing Your Health: Why You
Need Zinc, a webinar on my favorite
element. The presentation and Q&A
touched on several aspects of zinc andhealth. The recording is now available
online (see below).

This is fitting because this conference– and the Linus Pauling Institute as awhole – will be focused on precision
health and extending the healthspan,
which are extensions of the ideasthat Dr. Pauling introduced nearly
40 years ago.

As planning begins for our 2023
webinar series, we are looking forward
to February when we will produce
another edition of our immensely
popular Linus Pauling Day webinar
focused on vitamin C. Stay tuned forthe details.

Everyone is welcome to attend.
Information can be found on the backpage of this issue. The conference
content will be more technical than our
webinar series, which is designed fora general audience. If you can’t join us
in person at the conference, we plan tobring you summaries of some of thepresentations and themes in future
LPI Research Newsletter issues.

We are also excited to bring you more
in-person events once again. Personally,
I am eager to connect face-to-face withyou once more – it has been too long!
I look forward to holding social eventsat the Linus Pauling Science Center inthe coming year. We are also planningspeaking engagements across thecountry – and hopfeully at a locationnear you.
Next year’s big event is the Diet andOptimum Health conference, which
returns to the Corvallis campus in
September. The theme of Diet andOptimum Health 2023 will be“Precision Health: Living Longer,
Better,” which pays homage to
Dr. Linus Pauling’s book How to Live
Longer and Feel Better.

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This is only the beginning of what wehave planned. Other webinars andin-person events will follow throughout
the year, so please keep your eye on
this newsletter and our emails to know
when an event is happening near you.
Hopefully, you can join us to make 2023
an unforgettable year for the Institute.
Here’s to your good health in the
new year!

LPI STUDENTS: A FOCUS ON ALZHEIMER’S
Cellular senescence is one mechanismof normal aging. During this process,cells enter a special metabolic state
where they no longer divide or growbut remain metabolically active.
However, some senescent cells produce
inflammatory signals that disrupt thefunction of neighboring cells.
An increased number of senescentcells is one hallmark of humanneurodegenerative disorders,
including Alzheimer’s disease. Since
these diseases are more common
with advanced age, it is logical tohypothesize that senescent cells playa role in their development. However,
the importance of senescent cells in the
progression of Alzheimer’s disease isstill under debate.
As a PhD candidate, Ruben Riordansought to shed light on the information
surrounding Alzheimer’s disease andcellular senescence. His doctoral
mentors were Dr. Viviana Pérez, an
expert on cellular senescence andaging, and Dr. Kathy Magnusson, an
expert on cognitive decline and aging.
Testing several different mouse models
for Alzheimer’s disease, Ruben foundthat only two supported a cellularsenescence theory, meaning that thesenescent cell numbers increased
concurrently with the onset of
cognitive decline. On the other hand,
three other mouse models exhibited
cognitive decline without an increase insenescent cells.

To do so, he bred mice that exhibited
cellular senescence during Alzheimer’s
disease progression and that also could
not make Nrf2.
The mice that could not produce Nrf2
exhibited symptoms of Alzheimer’s
disease earlier and more rapidly thansimilar mice that produced Nrf2,
suggesting that Nrf2 activity influenced
the onset of the disease. It is thoughtthat Nrf2 activity is likely helping brainneurons cope with the stress of thedisease, preserving memory and bodilyfunction for longer periods of time.
Strangely, the absence of Nrf2 did
not increase or decrease the numberof senescent cells in these animals.
This suggests that senescent cells
are not an integral part of the disease– at least as it presents in this animalmodel. Alternatively, it could suggestthat senescence is important for some
aspects of the disease but not those
influenced by Nrf2.

Ruben Riordan, PhD
Recent Graduate from theLinus Pauling Institute andOregon State University

Ruben recently graduated from the
Department of Biochemistry andBiophysics and the Linus Pauling
Institute with his doctoral degree. He
accepted a postdoctoral research
position with Dr. Brian Kraemer at the
University of Washington, researching
Alzheimer’s disease and relateddementias.
Congratulations, Ruben!

This is an important finding but perhaps
not surprising. Researchers in the fieldof Alzheimer’s disease have struggled
to develop animal models that mimic
the mechanisms and progression ofsymptoms observed in most people,
pointing to the importance of Ruben’swork.

Dr. Viviana Pérez was recently
selected for a position in the Cell
Biology Program at the National
Institute on Aging within the
National Institutes of Health.
All of us at the Linus Pauling
Institute wish her the best in her
new position promoting cellularsenescence research at thenational level.

Focusing on the mice that did display
cellular senescence, Ruben examined
the interaction with a protein called
Nrf2, a master regulatory protein for
detoxification responses.

3

Continued from Cover

However, just providing more vitamin E topatients with cystic fibrosis might not be
the best solution. High levels of systemic
inflammation increase the likelihood thatvitamin E oxidizes before it reaches tissues,
making supplementation ineffective.
Therefore, Dr. Traber wondered if there
was another strategy: adding vitamin C.
Vitamins C and E are both antioxidants,
contributing to cellular antioxidant defenses.
When vitamin E is oxidized and deactivatedby free radicals, vitamin C can rejuvenate
the oxidized vitamin E back to its active state(see below). This allows vitamin E to continue
protecting cells for longer periods of time.
Vitamin C might also help lower persistentlevels of inflammation, particularly in theintestine, where increased inflammation
could diminish vitamin E absorption.
Additionally, vitamin C may help protect
vitamin E from oxidation as it travels in the
blood, allowing it to remain active longer.
In a recent clinical trial by Dr. Traber and hercolleagues at the University of California,
Davis, six participants with cystic fibrosis(3 female, 3 male) took 500 mg of vitamin C
orally twice a day for 25 days. Before andafter vitamin C supplementation, theresearch team gave each participant alabeled form of vitamin E as a supplement,so they could more accurately monitor
vitamin E blood levels over time.
After vitamin C supplementation, morelabeled vitamin E was detected in plasma
as compared to the period before
supplementation. Vitamin E also remained incirculation at least six hours longer after the
supplementation period than before.

After taking vitamin C, every participant
had lower blood concentrations of a
key oxidative stress biomarker calledmalondialdehyde, as compared topre-supplementation levels. This suggeststhat the addition of vitamin C supplements– combined with the noted improvements
in circulating levels of vitamin E – reduced
the free radical damage to cells.
These findings suggest that extra
vitamin C can provide a protective
environment for vitamin E. This longer
circulation period could allow vitamin E
more time to enter tissues and protect
cell membranes. The combination ofvitamins C and E may then be responsible
for the reduced levels of inflammation.
Although this was a small trial with limited
scope, it does reinforce the idea that
supplementation with antioxidant vitamins
can have great benefits for those who
suffer from persistent inflammation.
Dr. Traber emphasizes that the implicationsof this work may can extend far beyond
patients with cystic fibrosis, as theinterplay between vitamin C and E isespecially important for anyone with highlevels of inflammation.
References:Traber et al. Nutrients 14 (2022);
doi: 10.3390/nu14183717
Traber et al. Am J Clin Nutr 105 (2017);
doi: 10.3945/ajcn.116.138495

Vitamin C and vitamin E work
together in the antioxidant network.
When lipids in our cell membranes
become oxidized, they can spread thatoxidation to other lipids. Vitamin E(α-Toc) will block that from happening,but only by becoming oxidized itself.
Vitamin C (Asc) can restore vitamin E,
which itself is recycled by glutathione.

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VITAMIN E WEBINAR Q&A FOLLOW-UP
In our June webinar, Dr. Maret Traber presented All You Wanted To Know About
Vitamin E But Were Afraid To Ask. Dr. Traber discussed what vitamin E is, what it does,
and why people aren’t getting enough from the foods they eat. She also addressed
the persistent myth that vitamin E supplements are dangerous.
Due to time constraints, Dr. Traber was not able to address all of your questions, so
she addresses some of the most common questions here.

Who is at high risk forvitamin E deficiency?

How does vitamin E act asan antioxidant?

People with impaired fat absorption may
be at an increased risk for a vitamin E
deficiency (see cover article). Also,
taking certain fat-blocking drugs likecholestyramine and orlistat can result in a
deficiency.

Vitamin E is found where fats exist in thebody, most commonly in cell membranes,
protecting the cell against oxidation. Whenfats in your cell membranes are oxidized,a “runaway” oxidation reaction can occur.
This means that one oxidized fat molecule
will cause another one to become oxidized,
and so on, and so on – spreading damage
throughout the cell.

My colleagues and I believe that somepeople with really high blood levels ofcholesterol may also have issues withvitamin E metabolism. While they appear
to have normal vitamin E levels in theirblood, our research indicates that they
have trouble getting vitamin E into thetissues that need it.

Thankfully, vitamin E reacts with these
oxidized fats 1,000 times faster than theoxidation reaction. Just one molecule ofvitamin E in a cell membrane is enough tobreak the chain reaction and prevent someoxidative damage from occurring.

Do I need to get all thedifferent forms of vitamin E? What foods have the mostvitamin E?
There are eight different molecules that arevery similar in shape and function: alpha-,beta-, gamma-, and delta-tocopherol,
and alpha-, beta-, gamma-, and deltatocotrienol. However, alpha-tocopherol(sometimes written as α-tocopherol) is
the only form of vitamin E required by thehuman body.
While individual tocotrienols anddelta-tocopherol are thought to be better
scavengers of some free radicals thanalpha-tocopherol, the body cannot store
these versions of vitamin E. Therefore,
we have trouble evaluating their overall
importance in health.

The most abundant dietary sources ofvitamin E are wheat germ, sunflower
seeds, hazelnuts, almonds, and their oils.
But other excellent sources of vitamin E
are fortified cereal, a fruit called mamey
sapote, peanut butter, avocado, andcanned tomato sauce.
Green leafy vegetables like collard greensand chard also contain vitamin E. While not
the richest sources of the vitamin, thesevegetables are excellent choices because
they are nutrient dense.

Does heat from cooking
destroy vitamin E?
For the most part, no. Vitamin E is morestable than many other vitamins, so thecooking method does not matter too
much.

5

The recording of thewebinar is available at
lpi.pub/Traber2022

RESEARCH IN BRIEF:
LICORICE EXTRACTS
Licorice, the name given to the roots andrhizomes of the plants in the Glycyrrhiza
genus, has been used as a medicinal herb
and flavoring agent since antiquity. Licoricesupplements may have potent antioxidant,
anti-inflammatory, and antimicrobial effects
that may help ease the symptoms of upper
respiratory infections, treat ulcers, and aid
digestion.
Licorice contains a variety of unique
phytochemical compounds. Some ofthese compounds have estrogenic activity,
which has made licorice a popular dietary
supplement to alleviate menopausal
symptoms.
As part of a larger study on natural products,
Dr. Richard van Breemen, one of the experts
in natural products at the Linus Pauling
Institute, wanted to see if women taking
licorice supplements for menopausal
symptoms could have unanticipated druginteractions.
This study was conducted with Dr. van
Breemen’s collaborators at the Universityof Chicago and involved 14 healthy
perimenopausal and postmenopausal
women. These participants consumed 75 mg
of a standardized licorice extract twice
daily for two weeks. To measure the impact
on drug metabolism, the participants also
took a mixture of four drugs representing
common drug metabolism pathways before
and after the licorice treatment.

In brief, the results showed that there was
no impact of this licorice extract on themetabolism of the drugs tested, at leastat the concentrations tested in this study(150 mg per day of licorice extract).
It is important to note that the licorice
extract used in this study contained
very little glycyrrhizic acid (<1%).
Glycyrrhizic acid is a potent phytochemicalthat can cause high blood pressure and low
blood potassium levels if taken in excess.
Some data also indicate that glycyrrhizic
acid can strongly affect enzymes involvedin drug metabolism.
If you choose to use licorice supplements,
consider using those with glycyrrhizic acidremoved or in amounts that have beenmeasured and controlled. As with any
botanical supplement, it is important topurchase from trustworthy sources thatcan provide you with detailed analyses of
their products. Also, make sure to discuss
supplement use with your healthcare
provider.
References:
Liu et al. Drug Metab Dispos 50 (2022);
doi: 10.1124/dmd.122.001050
Muchiri et al. J Am Soc Mass Spectrom 33(2022); doi: 10.1021/jasms.1c00318

While this work did not explore the healthbenefits of licorice extracts, previous workby Dr. van Breemen and his research teamshowed that a licorice compound calledlicochalcone A might be able to bind to
the spike protein in SARS-CoV-2. This
would suggest that licorice extracts might
be a potential therapeutic agent against
COVID-19, but further testing is needed toconfirm this with a live virus.

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RESEARCH IN BRIEF:
ZINC AND THE MICROBIOME
Many older adults are at increased risk
for zinc deficiency. In part, this is because
the ability to absorb and distribute zincthroughout the body naturally declines withage, making it hard to get zinc into cells
where it is needed. Since zinc is importantfor immune function and the responseto oxidative stress, deficiency can leadto uncontrolled immune responses andexcessive inflammation.
Alterations in the number and variety of
microbes living in our intestines can also
promote inflammatory responses. Known
collectively as the gut microbiome (thebacteria, yeast, and fungi that inhabit ourgastrointestinal tract), these microbes
influence the overall health of the humanbody. There is concern that age-relatedchanges in the gut microbiome could also
drive inflammation in older adults.

In older animals eating a high-zinc diet, theresearchers observed small changes in thegut microbiome that correlated with lower
blood inflammatory markers than thoseeating a low-zinc diet. This appeared tosupport the hypothesis that zinc, bacteria,
and age are interconnected. Overall,however, the dietary level of zinc was aminor factor in determining the types andnumbers of gut microbes present in the
animals.
By contrast, the age of the mice was a muchgreater factor in microbiome composition.
The microbiomes of older mice were very
different from those of younger mice,
regardless of diet. Overall, 150 out of
186 genera were significantly different
between the two age groups (a genus ismade up of dozens of bacterial species).

Since both low zinc levels andpro-inflammatory changes in the gut
microbiome are more likely as we age, it
is possible they are connected. Dr. Emily
Ho and her research team wanted tosee if changing the amount of zinc in thediet could influence the microbiome andexplain some of its effects on inflammation.
To test this hypothesis, the team started
with a group of young mice and a groupof old mice receiving a zinc-adequate
diet. Using fecal samples, the researchersdetermined the number and variety ofbacterial species living inside the gut ofboth age groups of animals.
Then they separated the animals into
groups that received either a low-zinc diet
(20% of the amount in the adequate diet)or a high-zinc diet (1,000% of the amountin the adequate diet). After six weeks,
the researchers examined the intestinalbacteria again to determine the effects of
the low- and high-zinc diets.

What would be important to determine in
future studies is if the age-related changes
in the microbiome reduce the ability of
the intestinal cells to absorb zinc. If this isindeed the case, interventions designed toreverse these microbiome changes may
be an important step in restoring optimum
zinc status and limiting inflammation.
Reference:
Davis II et al. Manuscript in Preparation;
Preprint article atdoi: 10.1101/2022.09.16.508248v1
Wong et al. Biometals 34 (2021);
doi: 10.1007/s10534-020-00279-5

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Zinc deficiencies inolder adults can comefrom many sources.
Aside from issues withabsorption, avoiding
certain foods can makezinc deficiencies worse.
People who choose to
eat less meat, beans,and nuts are the most
likely to be low in zinc.