LINUS
PAULINGINSTITUTE
OREGON STATE UNIVERSITYRESEARCH NEWSLETTERFALL 2021

Photo credit: Hannah O’Leary

LIVING LONGER & BETTER:

IN THIS ISSUE

Exploring Dietary Factors and HealthspanFor nearly half a century, the Linus Pauling
Institute has focused on how dietary factors
can help you reach your optimum health.
Instead of focusing on extending lifespan,
however, our researchers seek new ways
to increase our years free from disease
and disability. This is a concept known as
healthspan. Or, to paraphrase Dr. Pauling:
to live better, longer.
In this article, we explore the basics ofhealthspan and why it is a driving factor
behind the Institute’s research on aging.
Ultimately, research has revealed that a
quality diet is one of the major determinantsof healthspan. And while meeting our basic
micronutrient needs is an essential partof health, the key to healthy aging may
include micronutrients and other dietarycomponents that go beyond these basic
needs in order to support optimal health.

Lifespan versus Healthspan
The term lifespan is typically used toreflect the health and longevity of a
population. While it can vary amongindividuals, lifespan is the maximum
number of years that any species can live.
Changes in human lifespan are often
used as a gauge of wellness. The average
lifespan in the United States has nearly
doubled in the last century from 45 to justshort of 80 years. Largely due to publichealth initiatives, infants and children
today are less likely to die, and adults are
more likely to survive into old age.
But are we living healthier lives?
Unfortunately, lifespan does not reflect
quality of life – it tells us how long people
usually live, not how well they are living.
Continued on page 4

Living Longer &Better: Exploring
Dietary Factors and
Healthspan..................1
From the Director......2
Reader Question.........2
Accolades...................3
LPI Student Highlight:
Two New PhDs!..........6

FROM THE DIRECTOR
Photo credit: Hannah O’Leary

Looking back over the past year makes
me feel immensely grateful to all of thefriends of the Linus Pauling Institute.
As we continue to celebrate our 25th
anniversary at Oregon State University
this year, your support means more to
us than words can convey.

Emily Ho, PhD
Endowed Chair and Director,
Linus Pauling InstituteAs I mentioned in our last issue, we arecontinuing our anniversary webinar
series. In July, Dr. Kathy Magnusson
presented her webinar on the aging
brain. In August, Dr. Tory Hagen
presented a webinar dedicated to ahealthspan approach to successful
aging. Concepts from these two
webinars form the foundation of ourcover article on healthspan in this issueof this newsletter.
September was the first month ofDiet and Optimum Health Online, thevirtual version of our biennial scientificconference. By the time you read this,we will have just completed our final
session: Dietary Factors for a Healthy
Immune System. We plan on bringing
you some of the key messages fromthese sessions in the winter edition ofthis newsletter.

I also wanted to let you know that wehave one more webinar left in our 25th
anniversary series. On December 7, 2021,
I will present Cancer Fighter: Harnessing
the Power of Broccoli (see back cover).
This webinar will explore how vegetables
modify cancer risk with a special focus
on broccoli. I hope you are able to attend.
And there is more to come! Linus
Pauling Day (February 28, 2022) is fast
approaching, and there will be special
events leading up to that day.
Also, this next year will reveal newofferings for our donors. I don’t wantto spoil the surprise, so look for details
coming soon.
Thank you for celebrating with us thisyear – it certainly has been one for thehistory books. Your support has meant
everything to us.
Hope you have a great holiday season!

Emily Ho

READER QUESTION
Dr. Linus Pauling’s books, he talks about “ascorbic
Q. Inacid”
being vitamin C. However, there are otherwebsites that say ascorbic acid is not vitamin C
because it is synthetic!
Did Dr. Pauling want people to take natural vitamin C?
What is the difference?
— D.M. by emailacid is produced in many plants and
A. Ascorbic
animals. There is no difference between the ascorbic
acid created in a laboratory and the ascorbic acidfound in plants. Their chemical structures are
identical.
Ascorbic acid – regardless of the source – is vitamin C.
We know this because if you give either natural orsynthetic ascorbic acid to someone with scurvy, it will
cure them. That’s the definition of a vitamin.

2

Dr. Pauling supported the use of synthetic vitamin C.
He took synthetic vitamin C supplements andsupported the companies that produced them.
Experiments in his laboratory (and in many otherlaboratories around the world) defining the healthbenefits of vitamin C were conducted with thesynthetic form of the vitamin.
Unfortunately, the superiority of “naturally derived
vitamin C” is a myth often repeated in the marketingof dietary supplements. This misbelief is exacerbatedby the fact that the synthetic and natural forms do
differ for other vitamins, such as vitamin E.
While there are no known additional benefits oftaking natural-source vitamin C versus synthetic,
eating a diet rich in fruit and vegetables has
numerous health benefits.
— Alexander Michels, PhD

ACCOLADESMARET TRABER NAMED AS A 2021 ASN FELLOWIn June, the American Society for Nutrition (ASN) inducted 15 individuals into its
Class of 2021 Fellows. Included on this year’s list is the Linus Pauling Institute’s
own Dr. Maret Traber for her pioneering work on vitamin E.
With this award, the ASN acknowledges Dr. Traber’s trailblazing research and pivotal
contributions to understanding the role of vitamin E in human health. In addition,
the Society formally recognizes Dr. Traber’s legacy in vitamin research and thanks
her for inspiring the next generation of nutrition scientists worldwide.

RICHARD VAN BREEMEN IS PART OF THE POWER LIST
Each year, The Analytical Scientist publishes its “Power List” – a list of the world’s mostinfluential analytical scientists. To develop the Power List, this industry publication heldopen nominations for candidates. A panel of independent judges then selected the top
100 scientists in the field.
For the second year in a row, the Linus Pauling Institute’s Dr. Richard van Breemen
has been included as one of the top 100 analytical scientists on this list. This recognizes
Dr. van Breemen’s talent, ingenuity, and leadership in the field of analytical chemistry,
particularly in natural products chemistry.

THE FUTURE IS BETTER HEALTHNOW MORE THAN EVER, people all over the world are focused on
maintaining good health. The Linus Pauling Institute has been
discovering the pathways to optimal health for nearly 50 years.
We know that there is power in science-based information – knowing
more about the food you eat and supplements you take will not only
empower you to make better decisions about health, but it will shape
the healthspan of generations to come.
The future of health starts today. Will you join us?
Making a donation in support of the Linus Pauling Institute today
will allow you to:••••

Support research at the Institute that matters to you
Sustain our outreach and education programs
Empower students to learn from the Institute
Explore possible tax benefits of charitable giving

Don’t wait! Contact Andrew Norwood to learn more about theways you can support the LPI mission!
Andrew.Norwood@osufoundation.org
3Senescence is thenatural, progressive, andirreversible process of
biological aging at thecellular level. As cells getolder, they progress intoa senescent state. As thenumber of senescentcells increase with aging,
this increases the risk for
disease, reducing overall
health and longevity forthe entire organism.

Continued from coverThus, researchers in the field of aging
developed the concept of healthspan.
Although in its strict definition, healthspanrefers to the number of years one spends
free of disease, it can also include yearsof living with a high quality of life despite
chronic health conditions.

Basic Biology of Aging
No matter what we do, the cells in our body
have a finite limit – they simply cease tofunction at some point. Ideally, everyone
would live free of disease until the momentof death, and many people would be able
to live until a healthy old age.
In reality, many people develop chronic
diseases decades before they die,translating to many years of declining
health, potential suffering, and poor qualityof life. Lifespan is almost always longer
than healthspan. However, the gap
between lifespan and healthspan does
not have to be as wide as it is today.
Extending our healthspan requires
knowledge of the underlying causes of agerelated diseases. Researchers often referto this as the “basic biology of aging.” For
the last few decades, scientists have beencharacterizing a cellular process called
senescence, which seems to hold the key
to the aging process.
4

During senescence, cells enter a different
metabolic state where they cease todivide and communicate this change tosurrounding cells.
This change is not always harmful, but
studies of senescence demonstrate thatsome of these senescent cells are behaving
badly. The presence of senescent cells canirritate neighboring healthy cells, initiating
unwanted inflammation.
Senescence is an irreversible and naturalchange that occurs more frequently as
we get older. This increasing number ofsenescent cells is often associated witha decline in physiological function that
ultimately increases the risk ofdeveloping disease.
Therefore, in order for our healthspan tomatch our lifespan, we need to minimize
the impact of senescence. Delaying theonset of cellular senescence is one strategy
that is generally believed to be effective.
Alternatively, targeting and destroying
senescent cells in the body has alreadydemonstrated clinical benefits. There areindications that some markers of agerelated disease can be reversed throughthe use of these “senolytics,” which is thename for these compounds that target
senescent cells.

How to Address HealthspanLong before the term healthspan wascoined, Dr. Linus Pauling addressed thisconcept in his book How to Live Longer andFeel Better. His recommendations for good
health still hold true today and are echoedin many of the current recommendations of
the National Institute on Aging.
While genetics and environment do playa role in determining our healthspan, dietmay be a greater factor than both of these
combined. Therefore, the Linus Pauling
Institute is uniquely positioned to address
healthspan research with its focus on diet,dietary compounds, and healthy aging.
One area of active research at the
Linus Pauling Institute is the role thatmicronutrients (vitamins and minerals)
play in health. This includes understanding
when and how micronutrient deficiencies
occur and who is more prone tomicronutrient shortfalls.
Adequate micronutrient intake is directly
related to healthy aging. The healthconsequences of not consuming thenecessary vitamins and minerals include
premature aging and an increased risk ofdeveloping age-related diseases. There
are also indications that micronutrient
deficiencies may promote the formation ofsenescent cells.

Although many are found in foods, bothanimal and clinical trials often use thesecompounds at levels much higher thanwhat would be obtained by consuming
the plant.
Current phytochemical research at theInstitute looks to combat age-relateddisease. For instance, Dr. Emily Ho isexamining the role of isothiocyanates,
especially sulforaphane, in reducing cancer
risk. Drs. Fred Stevens and Adrian Gombart
are investigating the biological effectsof xanthohumol – a flavonoid from thehops plant – and evaluating its potential
in combating metabolic syndrome (seepages 6 and 7 for more details on thisresearch).
Aging research at the Institute also
includes seeking applications for othernatural compounds, such as lipoic acid,acetyl-L-carnitine, and N-acetylcysteine.
These compounds provide metabolites
that decline with age and/or bolster the
stress response of aging cells.
Many of the compounds mentioned above
have shown promise in animal models, andthis lays the groundwork for clinical trials.
While research in these areas is exciting,
we have a long road ahead before any
recommendations for humans can be made.

For More Information

Several lines of research at the Institutefocus on the potential challenges ofobtaining adequate micronutrients,
as well as the changing micronutrient
requirements throughout life, especiallyin older age.

The Linus Pauling Institute’s Healthy
Aging Program has been making strides inunderstanding the basic biology of aging
while searching for how diet and dietaryfactors might improve our chancesof living a longer, healthier life.

In a recent clinical trial, Dr. Adrian Gombart
showed that multivitamin supplement use
reduced the severity of respiratory illness
symptoms in older adults, suggesting
effects on immune function. Drs. Tory
Hagen and Kathy Magnusson are currently
examining the effect of multivitaminsupplements on the nutritional status ofolder men in an ongoing trial.

Many of the concepts discussed here
were presented in a webinar in August2021 by Dr. Tory Hagen: Keeping Life inYour Years: Dietary Factors Affecting
Healthspan and Longevity.

Other dietary compounds are an additional
area of interest for healthspan research at
the Institute, as many have the potential
to influence the course of age-relateddisease. One area of focus is purified
phytochemicals, or plant compounds,
which can be used as dietary supplements.

The basic biology of brain aging and theeffects of diet and lifestyle on cognitive
function were presented in a webinar in
July 2021 by Dr. Kathy Magnusson:
Why You and Your Dog Can’t Find Your
Keys: This is Your Brain on Aging.
For more of the basics about senescence,see our highlight of Dr. Viviana Pérez’​​sresearch in our Fall-Winter 2017 ResearchNewsletter, available on our website.

5

Dr. Hagen’s webinar
can be viewed at:
lpi.pub/HagenWebinar

Dr. Magnusson’s
webinar can beviewed at:
lpi.pub/
MagnussonWebinar

LPI
HIGHLIGHT:
TWO NEW PHDS!
LPISTUDENTGRADUATESTUDENTS
Graduate students at the Linus Pauling Institute must complete and successfully defend theirdissertation to fulfill the requirements of a PhD program. Their success is not only that of theInstitute but of all who supported their work.

We feature research projects of graduate students supported by Linus Pauling Institute fellowships,
which are supported by generous donations. In this issue, we highlight two recent graduates fromthe Institute: the newly hooded Drs. Isabelle Logan and Ines Paraiso.
Working with Drs. Fred Stevens (Paraiso) and Adrian Gombart (Logan), both students completed
their dissertations on xanthohumol, a compound from hops that is found in beer. Their success is areflection of the long-term collaboration between Drs. Stevens and Gombart to explore the healthbenefits of xanthohumol.

Xanthohumol & Health: The Role of Gut Microbes
Previous studies showed that animals fed
a high-fat diet experience some degree of
insulin resistance and elevated blood sugar
levels. Adding xanthohumol to their dietreversed some of these changes, but it was
not understood how this worked.

Isabelle Logan, PhD
Formerly of theGombart Laboratory

Isabelle’s research
was funded by boththe George andAudrey Varseveld
and the Mark
Sponenburgh
Endowed Fellowships
at the Linus Pauling
Institute

For more about
germ-free mice andhow they are used in
microbiome research,see our Fall-Winter2019 newsletter.

Working with Dr. Gombart, Isabelle Logan
started looking deeper into the metabolic
effects of xanthohumol as part of her PhD
dissertation project.
Isabelle first examined the role that microbes
played in the guts of these animals. This
was a logical starting point, as diets highin saturated fat are known to change thepopulation of microorganisms in the intestineand could contribute to metabolic syndrome
in animal models.
To determine the influence of gut bacteria
in xanthohumol’s biological effects, Isabelle
needed to work with mice with absolutely no
gut bacteria, known as “germ-free mice.”
To test the effects of xanthohumol, animals
were fed a normal (low-fat) diet, a diet high insaturated fat, or this same high-fat diet withxanthohumol. Half of the animals in this study
were germ-free mice, and the other half had
normal gut bacteria.
As expected, the animals eating a high-fat
diet developed insulin resistance and elevatedblood sugar levels compared to animals on
the normal diet. These changes happenedin both the germ-free mice and those withnormal gut bacteria.

6However, when xanthohumol was included
with the high-fat diet, it prevented theinsulin and blood sugar issues – but onlyin animals with normal gut bacteria.
Germ-free mice still developed insulin
resistance and elevated blood sugar levels
despite the xanthohumol added to the diet.
Isabelle’s findings show that xanthohumol’s
health benefits are somehow related to gut
bacteria. This supports the idea that gut
bacteria chemically transform xanthohumol
into something else – perhaps a beneficial
compound that acts in the intestine or canenter the bloodstream.
There are also indications that
xanthohumol changes the composition ofgut bacteria. While it is too soon to say ifxanthohumol can completely reverse thechanges induced by a diet high in saturated
fat, this is an exciting avenue for future
research.
In the spring of 2021, Isabelle defended her
dissertation with Dr. Gombart and earned
her PhD in Biochemistry and Biophysics.
Dr. Logan is now working with Dr. Maria
Clara Franco at Oregon State University,
looking at the effects of protein nitration in
the immune system.
References
Logan et al. Mol Nutr Food Res (2021); e-publicationahead of printdoi: 10.1002/mnfr.202100389
Logan et al. Microorganisms 8 (2020);
doi: 10.3390/microorganisms8040520

Bile Receptors: The Key to Xanthohumol’s Actions?
When rodents eat a diet high in fat, theyquickly gain weight. However, if xanthohumol
is included with that high-fat diet, theanimals gain less weight. Because of this,xanthohumol is being explored as a possible
treatment for obesity.

Ines first looked at the effect ofxanthohumol in the liver. As expected,
xanthohumol increased FXR’s activity,
resulting in a decreased activity of genes
involved in fat synthesis and stimulation ofgenes involved in bile acid production.

Current research in this area focuses on
uncovering the mechanisms of action ofxanthohumol. One protein that has emerged
as a possible target for xanthohumol is called
the Farnesoid X Receptor – or FXR for short.

However, in the intestine, something
different was occurring. As Isabelle Logandiscovered (page 6), xanthohumol can
induce changes in the composition of gut
bacteria. As was seen in Isabelle’s work,
Ines observed that the altered populationof the gut bacteria changed bile acids into
new compounds that seemed to inhibit
FXR activity in the intestine.

FXR is a receptor protein that exists in manyorgans throughout the body. In the intestineand liver, it binds to and regulates the
production of bile acids. FXR is so importantto the function of bile acids that it was
originally called the “Bile Acid Receptor.”
Working in Dr. Stevens’ laboratory, Ines
Paraiso focused her research on determining
whether xanthohumol’s effect was due
to changes in FXR activity. Since FXR
regulates some aspects of lipid and glucose
metabolism, it was a good target forxanthohumol’s activity.
But activating FXR can have different effects
based on the organ in which it is working.
Compounds that stimulate FXR in the liver
help improve the metabolism of fat. On theother hand, activating FXR in the intestine
could promote weight gain.
In order to be considered an effective weightloss treatment, xanthohumol would need tostimulate FXR in the liver and also inhibit its
activity in the intestine.

Ines Paraiso, PhD
Formerly of theStevens Laboratory

So it appears that xanthohumol is pulling
double duty: stimulating FXR in the liver
directly and inhibiting FXR in the intestine
through bile acid metabolism via gut
bacteria. Combined, these effects lead to an
overall change in fat metabolism that could
explain reduced weight gain in animals.
In the spring of 2021, Ines defended her
dissertation with Dr. Stevens and earned
her PhD in Medicinal and Pharmaceutical
Chemistry. Dr. Paraiso is now working with
Dr. Nika Danial at the Dana-Farber Cancer
Institute, part of the Harvard Medical School
in Boston.
References
Paraiso et al. Front Pharmacol 12 (2021);
doi: 10.3389/fphar.2021.643857
Paraiso et al. Mol Nutr Food Res 64 (2020);
doi: 10.1002/mnfr.202000341

Xanthohumol isnormally found in theflowers of the hops
plant (also known as“cones”). While thiscompound is foundin beer in varying
amounts depending onstyle, these researchstudies used amountsof xanthohumol thatdwarf those foundin beer.

7

LINUS PAULING INSTITUTERESEARCH NEWSLETTER
Alexander Michels, Newsletter Editor
Victoria J. Drake, Associate Editor
Sandra Uesugi, Assistant Editor
Oregon State University
307 Linus Pauling Science Center
Corvallis, Oregon 97331
phone: 541-737-5075
fax: 541-737-5077
email: lpi@oregonstate.edu
website: lpi.oregonstate.edu

INSIDE: NEW DISCOVERIES BY LINUS PAULING INSTITUTE GRADUATE STUDENTS!