LINUS
PAULINGINSTITUTE

OREGON STATE UNIVERSITYRESEARCH NEWSLETTERFALL 2023

HONORING THE MEMORY OF DR. LINUS PAULING JR. LOOK INSIDE

THE BENEFITS OF MULTIVITAMINSMultivitamin Use Improves Nutritional Status in Older Men

Multivitamins are often recommended to help older adults fill nutritional gaps
and improve their vitamin and mineral status, but do they work as intended?
The results of a new clinical trial from Dr. Tory Hagen and colleagues at the
Linus Pauling Institute show that older men do benefit from taking a daily
multivitamin, with gains that go beyond meeting nutritional needs.
A balanced diet is essential to health for many reasons. For one, it provides the vitamins
and minerals that are needed for proper bodily function. However, many people do notmeet their vitamin and mineral needs.
Older adults are at greater risk for deficiencies in certain vitamins and minerals. One
possible reason is that as we age, we tend to eat less food, leading to lower micronutrient
intake. Other factors contribute to poor micronutrient status in older adults, suchas changes in dietary habits, food preferences, decreased nutrient absorption,
gastrointestinal problems, inflammation, and the influence of certain medications.
“All of this creates a strong case for multivitamins on top of a balanced diet,” says
Dr. Tory Hagen, one of the principal investigators focused on healthy aging at the Linus
Pauling Institute. This is one reason the Institute recommends that all adults, especiallyolder adults, take a daily multivitamin supplement that contains 100% of the daily
value (DV) for most vitamins and minerals.
Continued on page 4

IN THIS ISSUE
The Benefits ofMultivitamins...........1
From the Director.....2
Developments..........2
In Memoriam, Dr. Linus
Carl Pauling Jr..........3
Changing the Gut
Microbiome..............6

FROM THE DIRECTOR
I hope you are having a wonderful fall
and are looking forward to an amazing
new year! It is exciting to reflect on
the successful year that we had at theInstitute, and I am eagerly anticipating
all of the new events coming in 2024.
Photo credit: Karl Maadsam

We held our 12th biennial Diet andOptimum Health conference on
September 19th and 20th. The
event was filled with fascinatingpresentations and panel discussions
on the topic of precision health.
Emily Ho, PhD

Endowed Chair and Director,
Linus Pauling InstituteIn this issue, we highlight apresentation from one of ourconference’s Young Investigator Awardwinners, Paige Jamieson. More details
from the conference will be publishedin the next issue of the LPI Digital
Digest, scheduled for early 2024.
Speaking of the LPI Digital Digest,
our inaugural issue was released in
October. If you signed up for a print
copy, this has already been sent toyou. You can still sign up for print
copies of the LPI Digital Digest bycontacting us by mail or email.

On December 12, I presented Aging
Well & Optimal Health: The Role ofMicronutrients – a webinar reviewing
the micronutrients older adults should
consider for optimal health. If you’reinterested in watching the recording,please use the link on the back cover.
Our first event of 2024 will happen on
Linus Pauling Day – February 28 (Linus
Pauling’s birthday) – when we will holdan open house at the Linus Pauling
Science Center in Corvallis. You are all
invited; please let us know if you plan toattend. I enjoyed connecting with somany of you at last year’s event, and
we look forward to showcasing ourlatest discoveries for you again.
This is only the beginning of what wehave planned for 2024. Our webinar
series will continue, and other inperson events will follow. Please watch
this newsletter, the LPI Digital Digest,and our emails to know when an eventis happening near you.
Here’s to a happy andhealthy new year!

Developments
Dear Friends,
My name is Jessica, and I am the new Senior Development Director for the
Linus Pauling Institute. I bring over a decade of experience in higher education
fundraising and passion for helping people achieve their philanthropic goals.
I am honored to be a part of this community. Please consider me your resource
for learning how to support the Institute.

Jessica Merkner, JD
Senior Development Director,
OSU Foundation

Your generosity ensures that the Linus Pauling Institute continues to makediscoveries and innovations that benefit us all. Your commitment to research
excellence and the next generation of scientists inspires OSU faculty, staff,
and students to make great strides in advancing science.
If you have any questions about making a gift before the end of the year, please
let me know. I would love to hear your story and why you choose to donate to
the Institute. You can best reach me at jessica.merkner@osufoundation.org
or (541) 543-8337.
We are so grateful for all that you do for us. Thank you.

2

IN MEMORIAM

Dr. Linus Carl Pauling Jr.
Linus Pauling’s eldest son, Dr. Linus
Carl Pauling Jr. was born in Pasadena,
California on March 10, 1925. Although
in his early life he felt a certain
obligation to follow in his father’sfootsteps, he soon discovered that
research was not his passion andinstead pursued a career in medicine.
Pauling Jr. graduated from Harvard
Medical School in 1952. He enjoyed along and successful career in psychiatrywith more than 35 years in private
practice and as an administrator of
psychiatric services at The Queen’s
Medical Center in Honolulu, Hawaii.
He retired from practice in 1990.
Pauling Jr. also served on the Board ofTrustees of the Linus Pauling Instituteof Science and Medicine (LPISM) fromits inception. In the early 90s, Pauling
Jr. took on an increasingly active roleand served as LPISM president and thechair of the Board of Trustees.

Unfortunately, this was during a timeof financial instability for the Institute.
Because of this, the Board of Trustees
decided that the legacy of Linus
Pauling and the Institute would be bestsustained and enhanced by associatingwith a university.
After the elder Pauling died in 1994,
Pauling Jr. and Stephen Lawson, thenChief Executive Officer of LPISM, madethe choice to move to Oregon State
University (OSU). Rebranded as theLinus Pauling Institute, it has operated
as one of OSU’s research centers
since 1996.
Linus Pauling Jr. died in Honolulu in
June 2023 at the age of 98.

Pauling Jr. visited theInstitute in 2011 for the
dedication of the Linus
Pauling Science Center,
where he gave the
keynote address entitled,“Out of the Ashes,
the Phoenix Rose.” He
expressed great pleasurethat his father’s legacy inorthomolecular medicine
would continue in sucha fine, modern researchbuilding.

Everyone at the Institute is deeply
indebted to him for his selfless work
on behalf of his father and his legacy.
We would not be here today without
him.

Left photo: Three generations together in 1949: with Linus Carl Pauling (left), Linus Carl Pauling Jr. (right), and baby
Linus Jr.’s eldest son, Linus Fowler Pauling. Right photo: Linus Pauling Jr. at an event with his father in 1971.
3

Continued from Cover

However, only a few studies have examined
how multivitamin use improves vitamin andmineral status in older adults. Ideally, thisstatus would be assessed by an objective
measure of the effect of multivitamins on thebody, such as a blood or cellular biomarker.
For multivitamins to be deemed effective,
they would need to improve micronutrient
status over time.
To tackle the question of the effectivenessof multivitamins in older adults, Dr. Hagen
assembled a team of Linus Pauling Instituteresearchers to conduct a randomized
controlled trial in men 67 years of age andabove. The study was recently published in
the journal Nutrients.

Room for Improvement
To enroll in the study, men had to begenerally healthy for their age, althoughsome were taking prescription medications
to treat chronic health conditions. Many
used supplements regularly; participants
needed to cease the use of any supplements
containing vitamins and minerals prior
to and during the trial. An exception wasmade for vitamin D because it is often
recommended by physicians.
At the beginning of the study, eachparticipant gave blood samples to assess
their baseline vitamin status. For eachvitamin measured, the researchers usedliterature reports to classify participants as“optimal” (i.e., blood vitamin levels that wereconsidered ideal) or “suboptimal” (i.e., lower
than “optimal”; for more detail, see below).
“Overall, we certainly found room for
improvement,” Hagen points out.

The blood tests revealed that almost allof the participants started the study with
“suboptimal” vitamin concentrations.
More than half of the participants werefalling short in three or more vitamins.
In particular, vitamin B12, vitamin C, andvitamin D were at less-than-ideal levels
for this group of older men. Vitamin E andvitamin K concentrations were also low insome individuals.
Although several minerals were measured
in the blood samples, the analysis did
not reveal anything notable. This was
not surprising because mineral levels inthe blood stay relatively steady and are
generally not considered good biomarkersof adequacy except in the case of severe
deficiency. No severe mineral deficiencies
were detected in these participants.

The Impact of Multivitamins
To test the effects of supplementation,
half of the 35 men participating in thisstudy took Centrum Silver Men (a daily
multivitamin supplement containing
vitamins, minerals, and other dietaryfactors) for approximately eight months.
The other half took an identical placebo
pill. Neither group knew what they weretaking, nor did the investigators.
At the end of the study, participants inthe multivitamin group had statisticallysignificant increases in blood concentrationsof several vitamins compared to theplacebo group. This was notable for vitamin
B6, vitamin D, and vitamin E, as well asß-carotene, a carotenoid compound that
contributes to vitamin A status.

What is “optimal” vitamin status?
One of the challenges for this trial, and for precision nutrition in general, is defining “optimal” status. Many
researchers around the globe neither agree on an appropriate biomarker for status, such as blood vitaminconcentration, nor what these biomarkers may indicate for health.
“Suboptimal” vitamin status is slightly easier to define. This may range from overt deficiency with noticeable

negative health outcomes to more subtle effects like increased risk for disease over a lifetime.

For this study, the research team relied on literature reports that related the blood concentrations of agiven vitamin to an increased risk for disease or death. Concentrations above this amount were considered“optimal” status.
4For some vitamins, the response to themultivitamin supplement was mixed.
No improvement was noted in men whobegan the study with higher-than-average
blood concentrations of folate, vitamin B12,
vitamin C, and vitamin K, which was not
surprising. Yet, a dramatic improvement
was observed in those participants whostarted off with the lowest baseline levels.
Ultimately, participants taking themultivitamin improved their vitamin status.
Many participants in this group moved
from “suboptimal” vitamin status to bloodlevels that were considered optimal.
By contrast, the blood vitamin status ofmany participants in the placebo groupdeclined. In fact, several participants who
had “optimal” vitamin status at the start of
the trial fell into “suboptimal” status after
taking a placebo for eight months.
To connect these findings to a measurable
impact on bodily function, Hagen analyzed
oxygen consumption in the participants’white blood cells. This is because many
vitamins are used by the body’s cells
to produce the energy that maintains
metabolism, and cells consume oxygen inthat process.
Interestingly, in the placebo group, a
noticeable decrease in cellular oxygen
consumption was observed between the
beginning and the end of the study. By
contrast, cellular oxygen consumption was
sustained in participants supplemented
with multivitamins – and the difference
between groups was significant.

The Bottom Line
Results of this study show that taking
a daily multivitamin has notable
nutritional benefits for healthy older
men. In some cases, a multivitamin can
improve blood vitamin levels, and inother cases, it can prevent the declines
associated with a less-than-perfect diet.
The findings also indicate thatmultivitamins could influence metabolic
health in older adults. This could be one
way that multivitamin use influences
the risk for chronic disease.
Future studies in older women will
determine if these results are influenced
by sex.

Centrum Silver formulas
are specifically formulated
for older adults and differ
in nutrient content formen and women.
The researchers choseto initially focus on men.

Additionally, it would be helpful to study
the effects of multivitamins in younger
adults, to determine the dependency
on life stage.
References:
Michels et al. Nutrients 15 (2023);
doi: 10.3390/nu15122691
Wallace et al. J Nutr Gerontol Geriatr 38 (2019);
doi: 10.1080/21551197.2019.1656135
Blumberg et al. Nutrients 9 (2017);
doi: 10.3390/nu9080849

Hagen believes that these data reinforce
the connections between micronutrientsand metabolism.
“We know that multiple nutrients present in
the multivitamin supplement are importantto the mitochondria and will help sustain
metabolic function in older adults,” heexplained. “Now we would like to know
which are the most important. It might help
explain why oxygen consumption dropped
so dramatically in the placebo group.”
Mitochondria consume oxygen in the production of energy for the cell.
Thus, the cellular oxygen consumption rate can be used as a proxy forenergy metabolism.

5CHANGING THE GUT MICROBIOME:
Understanding Enterotypes
By Paige Jamieson
Paige Jamieson, a PhD student in the Nutrition program at Oregon State
University, works in the laboratory of Dr. Fred Stevens, a principal investigatorat the Institute. At our recent Diet and Optimum Health Conference, Paige
presented her work examining gut microbiome data from a clinical trial ofxanthohumol supplementation. She found that the response to xanthohumol
appeared to be tied to enterotype – a classification of bacterial communities
in the human gut. She shares more about that work below.
Paige’s graduate studies
have been supported by the
Marion T. Tsefalas Graduate
Fellowship, the Caron and
Donald Reed Fellowship,
and the Simone and Balz
Frei Graduate Fellowship.

I became interested in the gut microbiome during my work with the Xanthohumol
Microbiome and Signature study (also known as the XMaS trial) led by my PhD
mentor, Dr. Fred Stevens. This was a randomized, placebo-controlled trial in healthy
adults investigating the safety of a dietary supplement called xanthohumol,a compound from the hops plant.
One of the trial’s objectives was to learn about the impact of xanthohumol on thehuman gut microbiome, which is connected to work we conduct in animals (seepage 7, sidebar). This investigation also led to observations about “enterotypes,”which are related to the gut microbiome and may be key to understanding
xanthohumol’s role in gut health.

What is an Enterotype?
The gut microbiome refers to the diverse community of microorganisms, primarily
bacteria and fungi, that inhabit our gastrointestinal tract. This complex ecosystem
consists of trillions of microorganisms that play crucial roles in various bodilyfunctions, such as digestion, metabolism, and even regulation of immune function.
The term enterotype is a classification of gut microbial communities found in
healthy people. Since our guts have many different types of organisms present,
and describing them all would be difficult, an enterotype is a way of grouping
based on the dominant types of bacteria present.
Importantly, these classifications are a part of healthy variation in gut microbiomes.
The classifications are stable but can change over time since they are influenced byfactors like diet, lifestyle, and the environment.

What Enterotype Do You Have?
Scientists have identified two primary enterotypes that are commonly found in thehuman gut. It is only possible to know which type you have through testing. Although
we still have a lot to learn about these enterotypes, each is associated with different
long-term dietary patterns.
The first is the Prevotella enterotype, associated with diets low in protein and richin carbohydrates and simple sugars. Individuals with a Prevotella-dominant gut
microbiome often consume plant-based diets.
The second is the Bacteroides enterotype, associated with diets high in protein
and animal fat. Individuals who consume a Western diet tend to have enriched
Bacteroides populations in their microbiome.
Other enterotypes may exist in the human gut, but they are currently not welldefined. So for the purposes of my work, I only considered the role of these twoclassifications.
6Exploring the Effects of
Tetrahydroxanthohumol

How Does This Inform Xanthohumol Research?
The XMaS trial was focused on xanthohumol metabolism and its
effects on the gut microbiome. Previous research in laboratory animals
suggests that some of the health benefits of xanthohumol might beconnected to specific actions on the gut microbiome. In these studies,
xanthohumol was both a prebiotic, enhancing beneficial bacteria, andan antibiotic towards other bacteria.

Tetrahydroxanthohumol (TXN) is asynthetic xanthohumol derivativethat – in laboratory animals – cancounteract some of the negative
effects of eating a high-fat diet.

In humans, we found that the response to xanthohumol was quite
different from person to person within the trial. Some people’s gut
microbiome appeared to change with xanthohumol supplementation,
while others did not.

With collaborators at Oregon State
University, Dr. Adrian “Fritz” Gombart
and Dr. Fred Stevens used a newcomputational method called a“Transkingdom Network Analysis”
to explore connections between
TXN, the gut microbiome, and genes
associated with the development ofdisease in animals. One of the key
findings in their latest publication isthat TXN supplementation modulates
the growth of bacteria species in thegut associated with negative healthoutcomes.

To look for the reason for this variation, we examined each participant’s
gut microbiome enterotype. We observed that xanthohumol
supplementation only influenced the gut bacterial population of people
with the Prevotella enterotype. Those with the Bacteroides enterotype
did not show any change.

Implications for Health and Wellness
Understanding your gut microbiome enterotype can offer insights
into how your body responds to different dietary components andsupplements. And this knowledge will help inform a personalized
approach to nutrition.

For example, animals eating a high-fat
diet had higher-than-normal amountsof Oscillibacter species in the gut andincreased inflammatory signals from
immune cells in the animal’s adipose(fat) tissue. However, animals eating ahigh-fat diet supplemented with TXN
had reduced gut levels of Oscillibacter,
reduced inflammation, improved
glucose metabolism, and lessweight gain.

Further research in this area holds promise for the development oftargeted dietary and therapeutic interventions for various healthconditions related to the gut microbiome.
The next step for our research with xanthohumol is to investigate its use
as a therapy for inflammatory bowel diseases. Since these diseases caninvolve a dysfunctional gut microbiome, we think xanthohumol might
help ameliorate those pathologies.
Considering our work on enterotypes, we now believe that xanthohumol
may only be effective in individuals with a Prevotella enterotype.

This connection with specific gut
bacteria provides a solid foundation
for future investigations with TXN andthe potential to develop innovative
therapies for metabolic disorders.
References:

Image Credit: Alteza Films

Newman et al. Microbiome 11 (2023);
doi: 10.1186/s40168-023-01637-4

Two students from the Stevens laboratory, Roza Thavrin (center) andPaige Jamieson (right), received a Young Investigator Award from
Director Emily Ho (left) for outstanding oral presentations at the2023 Diet and Optimum Health Conference.
7

Miranda et al. Sci Rep 8 (2018);
doi: 10.1038/s41598-017-18992-6

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
2900 SW Campus Way
Corvallis, Oregon 97331
phone: 541-737-5075
fax: 541-737-5077
email: lpi@oregonstate.edu
website: lpi.oregonstate.edu

GIVE TO THE
INSTITUTE TODAY!
We believe that no matter where you are in life, you canachieve your best health. Supporting the Linus Pauling
Institute helps us advance research you care about.
Together, we will find the ways to live longer, better.