C1A0 Guide Book

Symposium Acciaroli (Cilento-Salerno) ITALY May 21–25, 2025

C1A0 THE CIAO STUDY

A DECADE OF SCIENCE ON

HEALTHY AGING, STEM CELLS AND THE REVEALED SECRETS OF LONGEVITY

A collaboration between Sanford Burnham Prebys, University La Sapienza, Sanford Stem Cell Institute at UC San Diego and Great Health Science

OVERVIEW The residents of Cilento, Vallo di Diano and the Alburni Na-

been working to understand the biological, psychological

tional Park in southern Italy are known for their remarkably

and social factors that promote their remarkable health

long lives, robust health and low incidence of disease.

and longevity.

For more than a decade, researchers from Sanford Burn-

Their published findings and ongoing research through

ham Prebys, the University of California San Diego, Great

the CIAO study (Cilento Initiative on Aging Out­comes)

Health Science and University La Sapienza in Rome have

have relevance to the health and well-being of everyone.

CONTENTS 4

Sponsoring Organizations

5–7

A Note of Welcome and Introduction

8–14

News Releases

15–19

Scientists Who Presented

20–21

Symposium Program

22–26

Scenes from the Symposium

27–33

Background What Is Longevity Science? • What Science Understands about Aging and Living (Long and Well) • Blue Zones • What Is the Mediterranean Diet? • The CIAO Study and a Select Survey of Recent Research • Stem Cells: Biology and Therapeutic Potential

34–35

Published Research

36-37

Additional Reading

38

Institutional Contacts for Media

2

DEDICATION On behalf of organizers and participants, a special note of gratitude and appreciation to T. Denny Sanford for his enduring support and generosity in the study of human longevity, which have helped make the CIAO study and this symposium possible.

3

SPONSORING ORGANIZATIONS

Sanford Burnham Prebys is an independent bio-

Launched in 2022 with a $150 million gift from

medical research institute dedicated to under-

philanthropist T. Denny Sanford, the Institute is a

standing human biology and disease and advancing

leader in developing and delivering the therapeutic

scientific discoveries to profoundly impact human

promise of human stem cells to treat, remedy or

health. For more than 49 years, our research has

cure a vast array of conditions and diseases.

produced breakthroughs in cancer, neuroscience, immunology and children’s diseases, and is an-

Visit stemcells.ucsd.edu

chored by our NCI-designated Cancer Center and advanced drug discovery capabilities.

Visit sbpdiscovery.org

Formally known as the Università degli Studi di

An international collaboration with public and pri-

Roma “La Sapienza,” abbreviated simply as Sapien-

vate research organizations to promote and conduct

za (“wisdom”). It is a public research university lo-

studies and clinical trials aimed at developing new

cated in Rome, Italy, founded in 1303. With 122,000

knowledge and managing patients with acute and

students, it is the largest university in Europe—and

chronic diseases, focusing particularly on healthy

ranked among the world’s major education and re-

aging and longevity.

search centers.

Visit greathealthscience.com

Visit uniroma1.it/en/pagina-strutturale/home

4

A NOTE OF WELCOME In late May 2025, researchers from around the world gathered in Acciaroli on the coast of the Cilento-Salerno region of central Italy.

The town is tiny but of particular global interest: Its citizens and those of the many villages in the region are particularly long-lived — 100 years and older, but still remarkably healthy.

For a decade, scientists participating in the Cilento Initiative on Aging Outcomes or CIAO study have studied, interviewed, measured and monitored the centenarians of Cilento, seeking to better understand the secrets to their longevity and healthy lives.

The gathering in May was a unified effort to review more than 10 years’ worth of studies, data and findings, to understand what has been learned and plan for next steps. This document contains content from the original program, plus the news releases issued before and after to media around the world.

– Tatiana Kisseleva, MD, PhD

5

INTRODUCTION The idea of aging—and resisting its effects—traces back to the earliest written records. Our desire to live very long and healthy lives is older than even our most optimistic aspirations.

Before the emergence of science, attempts to con-

The CIAO study represents one of the first and

trol aging, disease and death employed notions of

few coordinated, international efforts to parse the

magic and supernatural agencies. The idea of ag-

mysteries of healthy aging and longevity using the

ing was gradually developed in Greek and Roman

most advanced scientific tools and approaches.

medicine and incorporated into religious beliefs and social practices, observed the late-English

The study was launched in Cilento because it is

psychologist Dennis Basil Bromley (1925-2015) in

recognized by UNESCO and others as the origi-

his seminal 1966 book, “The Psychology of Human

nator of the Mediterranean diet, first described by

Ageing.”

Ancel Keys in the late 1950s.

Modern scientific approaches to aging did not

Over the past two years, we have been using state-

clearly emerge until the 17th century “with system-

of-the-art techniques that push the boundaries of

atic medical and statistical inquiries into the caus-

regenerative medicine.

es of death, and later, in the 19th and 20th centuries, into the biological mechanisms of aging.”

Conducted by Project Lead Tatiana Kisseleva,

We’ve learned a lot about how and why humans

MD, PhD, with David Brenner, MD, and Salvatore

age, from the inner workings of cells to the physi-

Di Somma, MD, PhD, and supported by the San-

cal, psychological and social drivers of life expectancy.

ford Stem Cell Institute at UC San Diego under the supervision of Catriona Jamies, MD, PhD, we are

We’ve begun to tap the extraordinary regenerative

creating novel analyses of the genetic, epigenetic,

powers of stem cells, which possess two important

transcriptomic, metabolic, proteomic and environ-

properties. They are self-renewing, and they can

mental factors that contribute to extraordinary

become almost any kind of cell in the body. Both

longevity.

abilities are the foundation of regenerative medicine and represent great potential in treating not

The goal is to identify the key factors associated

just age-related diseases, but perhaps aging itself.

with healthy aging and the mechanisms of their

Still, great mysteries remain in the details: Why and

regulation.

how do a relatively small number of humans age more gracefully, with sustained and better health, than the rest of us?

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We are also using induced pluripotent stem cell (iPSC) technology to generate stem cells from the blood of centenarians to model age-related stresses in human 3D organoids. This work will provide new insights into the development of regenerative medicine strategies that promote healthy aging and also for treating age-related conditions. Preliminary collaborative research work will be presented at the meeting.

David A. Brenner, MD

This symposium is an update on how far the collaborative sciences of healthy aging, longevity and stem cells have come and where they go next.

Within this program, you will find a listing of symposium speakers, their topics, days and times, plus background information on longevity science, aging research, Blue Zones, the Mediterranean diet, the CIAO study, stem cells, published research and

Salvatore Di Somma, MD, PhD

further reading.

Sincerely, Symposium President David A. Brenner, MD President and CEO, Sanford Burnham Prebys Donald Bren Chief Executive Chair Symposium Chair Salvatore Di Somma, MD, PhD Professor, University La Sapienza Rome

Tatiana Kisseleva, MD, PhD

Scientific Board Tatiana Kisseleva, MD, PhD Professor, UC San Diego School of Medicine Catriona Jamieson, MD, PhD Director, Sanford Stem Cell Institute, UC San Diego

Catriona Jamieson, MD, PhD 7

PRE-SYMPOSIUM NEWS RELEASE May 5, 2025 CIAO Study: A long and ongoing look at the secrets of human longevity and healthy aging

One-hundred-and-one-year-old resident Nicolina (center) of Cilento, Italy with CIAO study researchers.

Credit: Sanford Burnham Prebys

It’s notable when a scientific study reaches the decade mark, but when the topic is the healthy aging of people who have lived 10 times as long, it just means there’s still a lot more to learn.

Launched in 2016, the CIAO study seeks to identify key factors (biological, psychological and social) that promote healthy aging and extreme longevity.

The Natural Park of Cilento region in southern Italy is home to roughly 300 residents who are more than100 years old and in robust health. The broader region is notable for the long lives of its residents. It

This month, researchers participating in the Cilen-

was the original source of research for Ancel Keys,

to Initiative on Aging Outcomes or CIAO study will

the American physiologist who studied the influence

gather in Acciaroli (Pollica-Cilento) Salerno, Italy to

of diet on health and first promoted the benefits of

review a decade of work and plan their next steps.

the Mediterranean diet.

8

Scientists hope to reveal the longevity secrets of

what our key questions and steps will be in the next

the Cilento region using an array of tools to mea-

10 years.”

sure metabolomics, biomes, cognitive dysfunction and protein biomarkers for risk of heart disease,

One current CIAO project leverages genetic, epi-

Alzheimer’s, kidney disease and cancer, along with

genetic, transcriptomic, metabolic, proteomic and

psychological, social and lifestyle surveys.

environmental analyses to identify key contributors to extreme longevity. Supported by the Sanford

“There is no single secret to living a long, healthy

Stem Cell Institute at UC San Diego, researchers

life,” said Salvatore DI Somma, MD, the study’s lead

are using induced pluripotent stem cell (iPSC) de-

Italian investigator, founder of Great Health Sci-

rived from the centenarians to model age-related

ence and symposium co-chair. “It is many secrets,

and metabolic stresses in human 3D organoids.

most of which we are only beginning to understand and more importantly, learn how they might be ap-

“This study will provide new insights into the devel-

plied to the well-being of everybody. The remark-

opment of regenerative medicine strategies for pro-

able centenarians in our study are leading the way.”

moting healthy aging and treating age-related conditions,” said Tatiana Kisseleva, MD, PhD, professor

The CIAO study is a multi-institution collaboration

of surgery at UC San Diego School of Medicine and

that includes Sanford Burnham Prebys, an inde-

director of the Sanford Stem Cell Fitness and Space

pendent, nonprofit biomedical research institute in

Medicine Center. Preliminary findings are expected

San Diego, the Sanford Stem Cell Institute at Uni-

to be presented at the symposium.

versity of California San Diego, University La Sapienza in Rome and Great Health Science, a network

The CIAO study has already generated multiple

of public and private research organizations based

published papers and intriguing findings. Among

in Rome, Italy.

them:

The May 22-23 symposium, officially called the

•

In a 2016 presentation, researchers reported

“CIAO Study: A decade of science on healthy aging,

that the oldest residents participating in the

stem cells and the revealed secrets of longevity,”

CIAO study exhibited robust microcirculation

will feature a series of scientists and physicians de-

of blood comparable in efficiency to people 30

scribing their work and findings, from general de-

years younger. They also noted that low blood

mographic and epidemiological aspects to deeper

levels of the peptide hormone adrenomedullin

dives into brain cell aging, the regenerative powers

were an indicator for good microcirculation.

of stem cells and RNA biology.

•

In 2018, using a mix of scales to measure mental

“Understanding how we age and how we might

and physical well-being, resilience, optimism,

age better is a timeless pursuit,” said David Bren-

anxiety, depression and perceived stress, re-

ner, MD, president and CEO of Sanford Burnham

searchers assessed 29 nonagenarians and 51

Prebys and co-chair of the symposium. “Ten years

family members between the ages of 51 and 75.

in, with the benefit of new and emerging technolo-

•

They found the study participants aged 90

gies and global collaborations, we’ve come a long

and older had worse physical health but better

way. It’s important to look at where we are now and

mental well-being than their younger coun-

9

terparts. Exceptional longevity was charac-

tween loneliness and wisdom compared differ-

terized by a balance between acceptance of

ent age cohorts in San Diego and Cilento, using

and grit to overcome adversities, along with a

two validated loneliness scales. They found no

positive attitude and close ties to family, reli-

significant differences in levels of loneliness

gion and the land, providing purpose in life.

among the groups, but a strong inverse correlation between loneliness and wisdom in all

•

In 2020, a cross-sectional sampling of no-

groups. Loneliness worsened general health,

nagenarians and centenarians, along with

sleep quality and feelings of happiness, while

younger co-inhabitants from Cilento, eval-

wisdom improved these measures.

uated

key

lifestyle,

medical,

echocardio-

graphic and electrocardiographic features to identify the cardiovascular profile and

Select Media Coverage

lifetstyle factors associated with longevity.

•

In contrast to their younger co-inhabitants, the older group did not smoke, had lower fasting glucose levels and lower LDL cholesterol despite being half as likely to be taking statins.

They were physically active and enjoyed comparatively low levels of cardiovascular disease — even persons with structural heart abnormalities experienced fewer symptoms.

•

Also in 2020, researchers sought to define the neurocognitive profiles of 29 residents of the Cilento region at least 90 years old and 49 younger residents ages 50 to 75 years. They found that the older cohort appeared to enjoy cognitive status comparable to their younger cohabitants without significant differences in oxidative stress markers or the APOE genotype — a genetic variation that determines a person’s risk for developing certain diseases, particularly Alzheimer’s. The authors concluded that the results might be related to the older group’s optimal adherence to the Mediterranean diet, though other lifestyle factors and positive personality traits might be contributing to their healthy aging.

•

Researchers investigating the relationship be-

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La Repubblica newspaper (Italy)

•

The Daily Telegraph (England)

•

Brief (US)

•

EurekAlert (US)

•

ScienMag (US)

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Newswise (US)

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Science Daily (US)

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World News Today (US)

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WDC TV News (US)

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Press-News.org (US)

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Bioengineer.org (US)

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News Medical-Life Sciences (US)

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Today News (US)

POST-SYMPOSIUM NEWS RELEASE June 3, 2025 CIAO Study: Lessons learned on living longer and better (with more to come)

CIAO study scientists gather with an elderly resident of Cilento, Italy with CIAO study researchers.

Credit: Sanford Burnham Prebys

On May 22-23, a select group of scientists from around the world gathered in the small town of Acciaroli in the Cilento-Salerno region of Italy to review a decade’s worth of research in the ongoing Cilento Initiative on Aging Outcomes (CIAO), a longitudinal study of local residents 100 years and older.

(The CIAO study is a multi-institution collaboration that includes Sanford Burnham Prebys, an independent, nonprofit biomedical research institute in San Diego, the Sanford Stem Cell Institute at University of California San Diego, University La Sapienza in Rome and Great Health Science, a network of public and private research organizations based in Rome, Italy.)

“The centenarians of the CIAO study are remarkably robust and healthy, and can be found here in numbers per capital greater than most places on Earth,”

11

said Salvatore DI Somma, MD, the study’s lead Ital-

brain decline.

ian investigator, founder of Great Health Science and co-chair of the recently concluded symposium.

Additionally, most centenarians were physically

“Some aspects responsible for their long and

active on a regular basis and socially engaged with

healthy aging seem apparent, but beneath them lie

friends and family.

the deeper elements of genetics, epigenomics, metabolomics and other new bio-analytical tools and

“Despite their advanced chronological age, many

assessments. Our goal when we began the CIAO

Cilento centenarians maintain cognitive integrity,

study back in 2015 — and our continuing mission —

emotional stability and adaptive neurological func-

is to more precisely define the underlying drivers of

tion,” said Paola Antonini, MD, PhD, chief medical

a long, healthy life and to use those discoveries to

and scientific officer at Great Health Science.

help the rest of us also live longer, healthier lives, in part by slowing or preventing diseases related to

“They exhibit notable resilience against age-relat-

aging.”

ed neurodegenerative conditions, including Alzheimer’s, Parkinson’s and cerebrovascular disorders.

Two major components of why the centenarians of

Psychologically, they are emotionally resilient and

Cilento live longer and better was reaffirmed in mul-

stable. They use optimism as a coping strategy.

tiple studies: Diet and lifestyle.

They have low levels of neuroticism, but a strong sense of purpose and sustained social/family en-

Ninety percent of the centenarians in the CIAO study

gagement.”

adhere to the Mediterranean diet, which is rich in fresh fruits, vegetables, whole grains, legumes, nuts

Recent CIAO research findings are further parsing

and olive oil, with minimal red meat consumption.

the underlying biological mechanisms. The goal is to apply the most advanced techniques in bio-

“The Mediterranean diet is not a meal plan. It’s not a

medical research to study the centenarians, which

fad,” said di Somma. “It’s a way of life.”

include single nuclear multi-omics, metabolomics, proteomics, biomarkers, and cytokine measure-

The diet appears to pay health dividends, both short-

ments.

and long-term. In one study, researchers reported that after just six days after shifting from a northern

Centenarians display a coordinated immune response to health threats

European diet to a Mediterranean diet. metabolites (substances produced during metabolism) linked to a decreased risk of future type 2 diabetes and cor-

The epigenome is the multitude of chemical com-

onary artery disease increased significantly while

pounds that tell the genome (complete set of DNA in

biomarkers associated with red meat consumption

genes) what to do. As we age, progressive epigen-

(a risk factor for multiple diseases) declined.

etic alterations disrupt gene expression programs, compromise cell identity and impair genomic sta-

A related analysis of olive oil produced in the Cilento

bility — all contributing to chronic inflammation,

region and widely consumed by its residents found

reduced regenerative potential and cell senes-

it to be low in fatty acids and compounds associated

cence, a state in which a cell permanently enters a

with increased risk of heart disease or accelerated

zombie-like state: It no longer divides, but remains

12

metabolically active and can release inflammatory

and treatments, and help identify drug targets for

factors that contribute to age-related diseases.

personalized medicine.

“Epigenomically, no two individuals are alike, no

CIAO study scientists assessed 128 centenarians

epigenome is the same,” said Allen Wang, PhD, se-

and 50 controls. They found that 2,812 of the 32,514

nior associate director at UC San Diego’s Center for

metabolites measured differed significantly in cen-

Epigenomics. “That, along with the actual complexi-

tenarians, either in higher or lower levels. Of those

ty of disease, complicates the search for therapeutic

2,812 metabolites, 1,540 were significantly asso-

biomarkers.”

ciated with cardiometabolic disease and 268 were deemed potentially protective against cardiometabolic disease.

Nonetheless, Wang said rapidly developing tools like single nucleus multi-omic profiling of blood samples, which allows researchers to simultaneously analyze

Using

proprietary

artificial

intelligence

and

several aspects of individual cell nuclei (RNA, DNA,

multi-omics tools developed by Sapient, a San Di-

etc.) is providing clues.

ego-based biotechnology company founded by UC San Diego professor of medicine and pharmacology

For example, in single-cell epigenomic analyses of

Mohit Jain, MD, PhD, the researchers then deter-

36 Cilento centenarians, researchers found that

mined the biological age of study participants based

their T-cells, part of the body’s response to infection

on 24 key blood metabolite measurements.

and disease, exhibited notably coordinated immune activation and cytokine regulation. Cytokines are

Based on those blood samples, the majority of

small proteins that act as critical chemical messen-

centenarians were biologically younger than their

gers, primarily within the immune system.

chronological age by an average of 8.3 years. Controls, who are also from Cilento, also appeared bi-

The centenarians also showed elevated antiviral

ologically younger, but the difference was not as

and inflammatory programs, and greater communi-

pronounced.

cation among immune response cells.

Contrarily, the researchers found that inflammatory markers in centenarians were elevated. Chronic or

Centenarians are biologically younger than their chronological age

excessive inflammation can be a risk factor for heart disease, autoimmune disorders and cancer.

Researchers surveyed metabolites associated with centenarians and cardiometabolic disease, a cluster

“Our initial hypothesis was that centenarians have

of conditions that increase the risk for developing

increased inflammatory mediators, which are ex-

cardiovascular disease or metabolic disorders like

pected to increase with aging,” said David Brenner,

type 2 diabetes.

MD, president and CEO of Sanford Burnham Prebys and a CIAO study principal investigator. “However,

Metabolites have various functions, including fuel,

the centenarians also have increased anti-inflam-

structure, signaling and acting as catalysts for

matory mediators which may protect the centenari-

chemical reactions. They can also serve as biomark-

ans from inflammation and tissue injury.”

ers for different diseases, improving both diagnoses 13

Centenarians enjoy better blood circulation

A simple takeaway

Past studies with Cilento centenarians have shown

physician in Gisborne, Victoria, Australia, recruited

they enjoy robust microcirculation of blood compa-

23 patients (six females, 17 males) between the ages

rable in efficiency to people 30 years younger. The

of 55-79 to follow a “health checklist” for three years.

findings also indicate low blood levels of adreno-

There were five parts:

In a small pilot study, Robert Hetzel, MD, a family

medullin (bio-ADM), a peptide hormone that regulates blood pressure, maintains vascular integrity and may have potential protective actions in various diseases.

Low levels of bio-ADM is considered an indicator of good vascular microcirculation, and good microcirculation is an indicator for increased longevity.

•

Consume a Mediterranean diet, with two low-calorie, alcohol-free days each week

•

Exercise 60 minutes daily (aerobics, muscle-building and balance)

•

Sleep 7-8 hours each night

•

Engage the brain through puzzles, creative arts, music

•

Develop social connections

Andreas Bergmann, PhD, chief scientific advisor for SphingoTec, a Germany-based company that devel-

When the study concluded earlier this year, Hetzel

ops biomarkers, and colleagues have gone further to

reported that 10 patients had significantly changed

identify an enzyme called dipeptidyl alpha amidating

health behaviors, eight had significantly increased

monooxygenase or PAM, which potentially can be

their exercise time and five had fully adopted a Med-

used to restore bio-ADM to healthy levels and serve

iterranean diet. Anecdotally, many of the patients

as a biomarker for impaired peptide activation.

reported weight loss, better health and an improved outlook on life.

In mouse studies, therapeutic application of PAM substantially restored vascular leakage at the blood-

Hetzel cautioned that the pilot study’s findings were

brain barrier and improved cerebral brain flow in an

not conclusive, but were encouraging.

animal stroke model.

“A sample size of 20 patients is too small and a folIn related research, researchers found that study

low-up after just two years too short, but the study

participants in northern Europe and in the Cilento

results suggest creating a health list for patients to

region who focused on a Mediterranean Diet for six

follow can be effective,” said Hetzel, who has pro-

days experienced increased bio-ADM activation and

posed a larger study with annual follow-ups over

PAM levels mirroring improvement of endothelial

five years and more specific testing for elements like

function and microcirculation.

blood lipid levels and metabolites and more specific questions about health behaviors.

“PAM improves age- and Alzheimer’s disease-related cerebral malfunctions,” said Bergmann. “It im-

“We are generating an unprecedented amount of

proves cognition and reduces amyloid load and neu-

data,” said Brenner. “The next steps are to develop a

roinflammation, both factors in neurodegeneration.

platform to integrate these enormous data sets, and

The Cilento lifestyle and diet help too.”

interrogate the data with AI to gain new insights into the drivers of healthy aging.”

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SCIENTISTS AND PHYSICIANS WHO PRESENTED AT THE SYMPOSIUM Corina Antal, PhD

Antal studies the interplay between epigenetics, RNA

Assistant professor, UC San Diego

processing and cell signaling to uncover new mechanisms underlying cancer progression.

Paola Antonini, MD, PhD

Antonini is a highly regarded expert in clinical science,

Great Health Science

translational research and the development of innovative products encompassing cancer vaccines, biological agents for hematological and oncological conditions, autoimmune disease therapies, medical devices and radiopharmaceuticals.

Andreas Bergmann, PhD

Bergmann is a serial entrepreneur, having founded or

Founder—SphingoTec, Adrenomed AG and 4teen4 Pharmaceuticals GmbH

co-founded more than 10 biotechnology companies. He has been a leader in the discovery and routine adoption of important blood biomarkers, as well as the development of drug candidates for critical care diseases.

David A. Brenner, MD

Brenner is a physician-scientist, having led health sci-

President and CEO, Sanford Burnham Prebys Donald Bren Chief Executive Chair

ences at several major academic institutions while being a recognized leader in the field of gastroenterology research, with more than 200 peer-reviewed publications, two patents and ranking among Highly Cited Researchers by Web of Science and Clarivate Analytics.

Giovanni D’Arena, MD

The D’Arena laboratory represents a center of excel-

Biologist; founder of Laboratory D’Arena in Vallo della Lucania (Salerno-Italy)

lence for high-quality, advanced laboratory testing and biomarkers. It is certified by the National Research Council of Italy.

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Luigi Di Gregorio, MD

Di Gregorio coordinates all the general practitioners in

Surgeon and general practitioner; president of Parmenide GPs Association of Cilento region

Cilento for networking and data collection for research

Salvatore Di Somma, MD, PhD

Di Somma is a former professor of medicine at Uni-

Professor, University La Sapienza Rome Great Health Science

versity La Sapienza and founder of Great Health Sci-

purposes, focusing on epidemiological data related to longevity and life expectancy.

ence, an international academic research organization focusing on healthy aging and longevity. He has published more than 300 papers on clinical internal medicine, acute cardiac care, cardiology and emergency medicine, and is co-principal Investigator of the CIAO study. He is a Stellar Scholar in the Sanford Stem Cell Fitness and Space Medicine Center, part of the Sanford Stem Cell Institute at UC San Diego.

Nicola Ferrara, MD

Ferrara is the former president of the Italian Associa-

Former professor of geriatrics, University of Naples Federico II

tion of Geriatrics and Gerontology and is an expert in

John Hetzel, MD

Hetzel works with colleagues around the world to

Physician, Victoria, Australia

study and compare the drivers of longevity and healthy

the clinical settings of healthy aging.

aging.

Mohit Jain, MD, PhD

Jain directs a multi-disciplinary research team of

Professor, Center for Microbiome Innovation, UC San Diego

chemists, engineers, mathematicians, epidemiologists and physicians at UC San Diego focused on the development of next-generation mass spectrometry systems and their application for human discovery.

Catriona Jamieson, MD, PhD

Jamieson is a leading physician-scientist in cancer

Director, Sanford Stem Cell Institute, UC San Diego Director, CIRM Alpha Clinic, UC San Diego Sanford Stem Cell Institute Chancellor’s Endowed Chair in Regenerative Medicine

stem cell biology and a specialist in myeloproliferative disorders and leukemia. Her research also explores how space alters cancer progression. Her mission is to discover life-saving therapies for cancer that tackle the root cause of the disease, and to advance therapeutics that enhance stem cell regeneration.

16

Alexander Khalessi, MD

Khalessi is a board-certified neurosurgeon, chair of

Surgeon and professor, UC San Diego Health and School of Medicine

the Department of Neurological Surgery, the Don and Karen Cohn Chancellor’s Endowed Chair in Neurosurgery and co-director of the Brain Tumor program at the Sanford Stem Cell Institute. He specializes in complex cranial surgeries, endovascular neurosurgery, stroke care and neurological oncology; as well as basic research into tumor heterogeneity, potential therapeutic targets and treatment innovations.

Tatiana Kisseleva, MD, PhD

Kisseleva is a trained physician-scientist who studies

Professor, UC San Diego School of Medicine

the origins of fibrogenic myofibroblasts (liver scarring) and identifying novel targets for anti-fibrotic therapy.

She is director of the Sanford Stem Cell Fitness and Space Medicine Center, part of the Sanford Stem Cell Institute. She holds a Sanford Stem Cell Institute Endowed Chair.

Giuseppe Leonardi, MD

Leonardi is an expert in heart failure, the management

Cardiologist, University of Catania

of cardiovascular diseases, and their genetic and epigenetic aspects.

Barbara Maiese, PhD

Maiese is an authority in psychological assessments

Psychologist

behavior in elderly populations. She is also an expert in evaluations of neurological assessments of cognitive status in adults.

Sheldon Morris, MD, MPH

Sheldon studies the prevention, diagnosis, pathogene-

Clinical professor, UC San Diego School of Medicine

sis and treatment of infectious diseases, especially HIV and other sexually transmitted infections. He is deputy director and data management lead for the Sanford Stem Cell Clinical Center’s CIRM Alpha Clinic, which provides inpatient and outpatient cell/gene/stem cell therapies and conducts regenerative medicine clinical trials. He holds a Sanford Stem Cell Institute Endowed Chair.

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Alysson Muotri, PhD

Muotri investigates the biological complexities of the

Professor, UC San Diego School of Medicine

human brain, specifically the factors that fuel neuronal diversity and make human brains singular and unique.

His work spans studying stem cell functions in space to how infectious diseases like the Zika virus effect the brain. He also creates brain organoids derived from the stem cells of patients with neurological diseases to study the effects of rapid aging, stress and microgravity. Muotri is director of the Sanford Integrated Space Stem Cell Orbital Research Center, part of the Sanford Stem Cell Institute, where he holds an endowed chair.

Vincenzo Pizza, MD, PhD

Pizza is the head of the neurology department at Vallo

Neurologist, Vallo della Lucania Hospital, Salerno

della Lucania hospital and is an expert in cognitive dis-

Giovanni Rizzo, MD

Rizzo is an expert in blood sampling and processing

Physician, laboratory medicine

procedures for molecular biology studies based at the

orders, especially in the elderly population of Cilento.

D’Arena laboratory in Salerno.

Silvia Ruggieri, BME

Ruggieri is a biomedical engineer skilled in the clinical

Great Health Science

development of medical devices, artificial intelligence software research and project management. She has expertise in data analysis, statistical methods and clinical trial coordination.

Giuseppe Scarano, MD

Scarano is director of Preventive Medicine and Health

Physician

Service at Vallo della Lucania district of Salerno Community Health Service. He is an expert in the Mediterranean diet and is one of the founders of the MuSea (Museum of the Sea – Pioppi) and of the Living Museum of the Mediterranean Diet in Pioppi – Cilento region–Salerno. Scarano is also a co-principal investigator of the CIAO study.

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Xiao Tian, PhD

Tian investigates the fundamental mechanisms of ag-

Assistant professor, Sanford Burnham Prebys

ing and their roles in driving age-related diseases, with the goal of mitigating the effects of aging using genetic and epigenetic interventions.

Allen Wang, PhD

Wang uses large-scale epigenomic datasets and dis-

Senior associate director, Center for Epigenomics, UC San Diego

ciplines like spatial transcriptomics, developmental biology, epigenomics and human genetics to drive epigenomics discoveries via deep and productive collaborative projects with teams of multi-disciplinary investigators.

Gene Yeo, PhD, MBA

Yeo’s research interests are in understanding and ma-

Professor, UC San Diego School of Medicine

nipulating RNA processing in development and disease using induced pluripotent stem cell and murine models.

His lab is an active participant in RNA genomics technology and therapeutics development. Yeo is director of the Sanford Stem Cell Innovation Center, which focuses on developing new genomic technologies, including spatial multi-omics, to identify novel therapeutic targets in aging-related and developmental diseases. He holds an endowed chair at the Sanford Stem Cell Institute.

Su-Chun Zhang, MD, PhD

Zhang is a stem cell science pioneer whose work has

Professor, Sanford Burnham Prebys

profoundly changed the understanding of how brain cells work and has led to novel approaches for repairing or replacing them in diseases like Alzheimer’s and Parkinson’s. He holds the Jeanne and Gary Herberger Leadership Chair in Neuroscience.

19

SYMPOSIUM PROGRAM Thursday, May 22 CIAO study La Pineta Hotel Beach & Spa Acciaroli, Italy 9am–5:15pm, with lunch from 1:05–2:05pm Chairs David A. Brenner, MD Salvatore Di Somma, MD, PhD

La Pineta Hotel Beach & Spa

Speakers and Topics Morning session Time periods include final five minutes for discussion.

9am

11:25–11:50am Paola Antonini, MD, PhD (Italy)

Registration

New and ongoing research protocols and descriptions

9:15–9:45am

Welcome from local officials and government representatives

11:50am–12:15pm Silvia Ruggeri, BME (Italy)

9:45–10:10am Nicola Ferrara, MD (Italy)

CIAO study update

12:15–12:40pm Giovanni D’Arena, MD (Italy)

Italy aging—demographic and epidemiological aspects

Routine lab testing and analyses in centenarians

10:10–10:35am Luigi Di Gregorio, MD (Italy)

12:40–1:05pm Giovanni Rizzo, MD (Italy)

Epidemiology of centenarians in Cilento; the general practitioners’ perspective

Laboratory data collection, processing and routine results

10:35–11:00am John Hetzel, MD (Australia)

1:05–2:05pm

Trialing longevity health checks in a rural general family medical practice

Lunch

11:00–11:25am Salvatore Di Somma, MD, PhD (Italy)

CIAO study—a decade of scientific findings

20

Afternoon session 2:05–2:30pm Vincenzo Pizza, MD, PhD (Italy)

3:50–4:20pm Xiao Tian, PhD (USA)

2:30–2:55pm Barbara Maiese, PhD (Italy)

4:20–4:50pm Alexander Khalessi, MD (USA)

Neurological behavior in Cilento centenarians

Ameliorating aging through epigenetic interventions

Psychological assessment in Cilento centenarians

The operating theater as living laboratory: neurological lessons on the science of aging

2:55–3:20pm Giuseppe Scarano, MD (Italy)

4:50–5:20pm Su-Chun Zhang, MD, PhD (USA)

Nutritional value of the Mediterranean diet

Stem Cell Model of Brain Aging

3:20–3:50pm Giuseppe Leonardi, MD (Italy)

Genetics in non-ischemic cardiomyopathies—a new point of view

Friday, May 23

Stem cells and longevity La Pineta Hotel Beach & Spa Acciaroli, Italy 10am–5pm, with lunch from 1–2pm

Morning session 10-10:30am Sheldon Morris, MD, MPH (USA)

11:30am-12pm David Brenner, MD (USA)

10:30-11am Allen Wang, PhD (USA)

12-12:30pm Alysson Muotri (USA)

A study designed to evaluate centenarians’ health

Proteomics results from the CIAO study

Mapping human health through cohort-scale, singlecell epigenomics

Space-induced neural senescence and disease modeling

11-11:30am Mohit Jain, MD, PhD (USA)

12:30-1:00pm Andreas Bergmann (Germany)

Metabolomic markers of aging and longevity in the Cilento population

Peptidyl alpha amidating monooxygenase: A key enzyme in healthy longevity?

1-2:30pm

Afternoon session

Lunch

2:30-3pm Catriona Jamieson (USA)

4-4:30pm Gene Yeo (USA)

3-3:30pm Tatiana Kisseleva (USA)

4:30-5pm

Stem cell Pathways Aging and Cancer Evolution (SPACE)

Aging and RNA biology. Presenting via Zoom

Closing remarks

The role of senescence in aging

3:30-4pm Corina Antal (USA)

The aging pancreas: insights into RNA processing dysregulation in pancreatic cancer.

Presenting via Zoom 21

SCENES FROM THE SYMPOSIUM

Nicola Ferrara, MD

Luigi Di Gregorio, MD

John Hetzel, MD

Salvatore Di Somma, MD, PhD

Paola Antonini, MD, PhD

Giovanni D’Arena, MD

Giovanni RIzzo, MD

Vincenzo Pizza, MD

Barbara Maiese, PhD

Giuseppe Scarano, MD

Giuseppe Leonardi, MD

Xiao Tian, PhD

Alexander Khalessi, MD

Su-Chun Zhang, MD

David A. Brenner, MD

Alysson Muotri, MD

Andreas Bergman PhD

Catriona Jamieson, MD

Tatiana Kisseleva, MD, PhD

22

23

24

Archaeological Park of Paestum

Buffalo mozzarella farm

25

Living Museum of the Mediterranean Diet in Pioppi

Gioi village

Ancel Keys office in Pioppi

26

BACKGROUND What Is Longevity Science?

The oldest human on record is a French woman named Jeanne Calment, who lived to the age of 122 years, 164 days before passing away in 1997. Calment is the only person in history who has been verified to have reached the age of 120.14 The odds of anybody currently alive matching or exceeding Clement’s long life are almost astronomical.

It’s been calculated that the probability of someone living to age 125 in any given year is less than one in 10,000. Put another way: A 125-year-old human is a once-in-a-10,000-year occurrence.

Jeanne Calment at age 20 in 1895

On the other hand, more people are living longer.

Why some people live considerably longer than oth-

The United Nations estimates that there are roughly

ers is a primary question of longevity science. It’s

722,000 centenarians (people 100 and older) cur-

been proposed that lifestyle factors account for 80

rently alive in the world. Japan has the largest cen-

percent of the reason, with genetics making up the

tenarian population at 146,000, followed by the U.S.

other 20 percent. That’s a matter of ongoing debate.

at 108,000 and China at 60,000.

But hanging on to life for a century or more isn’t Centenarians represent a fast-growing population.

nearly so appealing if those later years are dark-

By 2054, the global centenarian population is pro-

ened by disease, disability and a diminished quality

jected to be almost four million, with close to half a

of life. The more pertinent goal—at least for most

million in the United States alone.

people—is how to live longer well.

27

What Science Understands about Aging and Living (Long and Well)

After decades of average life expectancies rising around the world due to medical and technological advancements (everything from water sanitation to antibiotics), new research suggests that humans may be reaching peak life span.

behaviors that will “cure” it. We grow old because all vertebrate animal species have a natural life span defined by their gene sets and, more broadly, the inexorable biology of senescence.

Some of the most recent research suggests that for the vast majority of humans, life expectancy is

In some places, life expectancy increases have slowed, stalled or declined. A baby born in the United States in 2021, for example, had almost a one-year drop in life expectancy. A baby born one year earlier has a 1.8-year drop. That two-year decline in life expectancy is the biggest since 1921– 23, almost 100 years earlier.

Today, the Centers for Disease Control says average life expectancy in the United States is 77.5 years (74.8 for males, 80.2 for females). The main driver in the recent decline was the COVID pandemic, with other factors like accidents and unintentional injuries (primarily drug overdoses) also playing

pretty much what it is now: approximately 87 years

roles.

(84 for men, 90 for women). It’s obviously higher in some places, lower in others.

The idea that aging can be prevented, stopped or reversed is, in fact, a timeless grift. Claims that new

Debate will no doubt continue about whether there

discoveries or technologies will allow humans to

is maximum human life span, and if we’ve reached

routinely live to 120 years or longer are unprovable.

it. The science of healthy aging, however, offers

We would all first have to live that long.

much greater and livelier hope and opportunity.

Aging is not a disease, at least in its most universal

Obesity, cancer and cardiovascular disease are all

definition. There are no potions, pills, remedies or

strongly linked to lifestyle and behavior choices. So, 28

well-being—and shorten our lives.

too, is the rising calamity of chronic disease: More than half of U.S. adults have at least one of 10 common chronic conditions: arthritis, cancer, chron-

As a result, most serious longevity research and re-

ic obstructive pulmonary disease, coronary heart

lated endeavors focus on discovering or parsing bi-

disease, asthma, diabetes, hepatitis, hypertension,

ological and social factors that promote health, and

stroke and weak or failing kidneys. One in four U.S.

thus presumably a longer, healthier life.

adults have multiple chronic conditions.

Other public health threats, like the global scourge of loneliness,5 further harm our overall health and

Blue Zones

In recent years, the concept of “blue zones” has garnered widespread popular attention. These are geographical regions where residents consistently live to be 100 years old.

Regions considered to be blue zones are Okinawa, Japan; Sardinia, Italy; the Nicoya peninsula in Costa Rica; Ikaria, a Greek island; and Loma Linda, California. (The term blue zone comes from the blue pen

Given its similarities to the five designated blue

used by researchers to mark these areas on a map.)

zones, Cilento has been proposed as a sixth.13 But the blue zone concept remains controversial, in

Using epidemiological data, statistics, birth certifi-

part because there is a dearth of uniform, well-doc-

4

cates and other research, blue zone advocates say

umented, empirical evidence, such as solid data on

they’ve identified several common characteristics

life expectancy and health in all of these locations.

of long-living inhabitants. Among them:

Muddying the issue are commercial or non-science efforts to promote blue zone projects and products.

•

They are physically active.

•

They have a purpose in life.

•

They avoid or manage stress.

Projects like the CIAO study and others represent

•

They eat in moderation, with a diet that

an effort to apply mainstream scientific principles

is mostly plant-based.

and methods to the blue zone concept and find, if

•

They consume little or no alcohol.

it exists, acceptable, measurable and reproducible

•

They enjoy rich social lives.

markers of its effects on longevity and health.

29

What is the Mediterranean Diet?

The Cilento region of southern Italy is generally considered by scientists to be the cradle of the Mediterranean diet, though there are many versions. It is more of an eating pattern than a strictly regimented diet plan.12

The emphasis is on healthy fats, such as olive oil, or fats found in avocados, nuts and oily fish like salmon and sardines. Other proteins, such as poultry and dairy, are eaten in smaller quantities and less frequency; red meat is limited to a few times per month.

Water is the primary daily beverage, with moderate intake of wine with meals (one to two glasses for men,

The diet is primarily plant-based, with daily con-

one glass for women).

sumption of whole grains, olive oil, fruits, vegetables, beans and other legumes, nuts, herbs and spic-

Daily physical activity is stressed.

es. Animal proteins are eaten in smaller quantities, with the preference being fish and seafood.

30

The CIAO Study and a Select Survey of Recent Research

In the 1950s, American physiologist Ancel Keys (who also had a doctorate in biology from the Scripps Institution of Oceanography) took note that the residents of a small Italian coastal town called Acciaroli seemed to enjoy remarkably long and healthy lives. The reason, Keys hypothesized, was at least partly due to their distinctly local diet.

Keys, who earlier in his career had famously (or no-

Italy in the Campania region. The noted longevity of

toriously) invented the K ration that fed U.S. soldiers

its residents is broadly shared in the region, making

during World War II, argued that there was a link be-

it the focus of much scientific study on human aging

tween dietary cholesterol and heart disease.

and health.

In 2016, a group of scientists from UC San Diego School of Medicine and the University of Rome La Sapienza launched the CIAO (Cilento on Aging Outcomes) study. The purpose was to better understand how people can live longer and in better health by focusing over time on 300 residents, all over 100 years old, living in Acciaroli.

That same year, scientists reported initial findings from a pilot study that found that the organs and

Ancel Keys

muscles of some centenarians were as efficient In 1958, he launched his landmark Seven Country

as those three decades younger. Specifically, they

Study to study the influence of diet on health. In the

possessed low blood levels of the peptide hormone

decades since, the ongoing research has produced

adrenomedullin, suggesting a well-functioning en-

many follow-up and related studies.

dothelial and microcirculatory system that provides plenty of oxygen and nutrients to organs and muscles.

Acciaroli is located on the Cilento coast of western

31

A deeper look at 29 nonagenarians and cente-

of clinical cardiovascular disease. And even among

narians found that while they experienced worse

those with structural heart abnormalities, symp-

physical health than younger persons, their men-

toms were low.16

tal well-being was considerably better. Specifically, they were characterized by “a balance between ac-

While all of the participants studied adhered to the

ceptance of and grit to overcome adversities, along

Mediterranean diet, researchers proposed that NCs may practice optimal adherence and benefit from other lifestyle factors, such as regular, rigorous exercise and positive personality traits.

Researchers

have

also

compared

middle-aged

populations in Cilento with Malmö, a city in Sweden, for prevalence of cardiovascular disease (CVD)and Antonio Vassalo, 100, and wife, Amina, 93. Credit: Getty

cancer. Both prevalence

with a positive attitude and close ties to family, reli-

rates were similar even though Cilento residents

gion, and land, providing purpose in life.”8

have more risk factors. When those are accounted for, the CVD prevalence rate is half that of Malmö.

Those early findings were followed in 2020 by a fuller

As for cancer, the prevalence rate was about one-

descriptive, cross-sectional analysis of 29 super-el-

third compared to Malmö.15

derly residents participating in the study (persons 90 years and older), comparing them to 49 younger

In 2020, after studying middle-aged and older

co-inhabitants, ages 50–75.1

adults in San Diego and Cilento, researchers found that the complex personality trait of wisdom may be a protective factor against loneliness.2

Notably, none of the nonagenarians and centenarians (NCs) exhibited severe cognitive impairment, and there was an extremely low incidence of dementia.

In 2021, researchers looked at whether the Mediter-

The majority of the NCs lived autonomous daily lives

ranean diet in Cilento was linked to both longevity

and enjoyed good physical health.

and potential prevention of prostate cancer. The findings were inconclusive, but the authors said they merited further investigation.9

A different pilot study found that NCs in Cilento enjoyed healthy metabolic profiles and a low prevalence

32

Stem Cells: Biology and Therapeutic Potential

Stem cells are a special type of cell with two important properties: They are able to make more cells like themselves (self-renew), and they can become other types of cells that do other things (differentiation). Depending on where the stem cells are located, they can become any of the cell types that function in blood or cells in the brain, heart muscle, liver, spleen or bone.

tissues and organs in which they reside.

Science has learned how to create induced pluripotent stem cells (iPSCs) in culture. In other words, to create stem cells outside the body and then induce them to become the cell type needed. As a result, iPSCs have become the foundation of regenerative medicine, as well as the idea that stem cell therapies can be used to regenerate and repair tissues that have been damaged or affected by disease, from cancers to dementia.6 That ability alone, already being shown in numer-

Stem cells are found in almost all tissues of the

ous current and experimental therapies, can dra-

body, and are critical to the maintenance and repair

matically impact human longevity by addressing

of tissues. Embryonic stem cells are the most ver-

age-related diseases. There is hope, however, that

satile since they can develop into all the cells of the

as stem cell therapies advance, they may become

developing fetus. The majority of stem cells in the

part of strategies to counter aging itself.7

body have fewer abilities to give rise to repair the

Reprogramming factors

Biopsy

Sox2

Oct4

Adult cells (e.g. skin fibroblasts)

Induction of pluripotency

Self renewal

c-Myc Klf4

iPS cells (resemble embryonic stem cells)

Donor/ Patient Transplantation of corrected cells

Differentiation

Disease models for drug discovery and compound screening

Gene correction

Disease affected cell type

adapted from M. Rossbach

33

PUBLISHED RESEARCH 1

Pizza V, Antonini P, Marino R, D’Arena G, Lucibello SG, Rizzo M, Brenner DA, Jeste DV, Somma SD. Cogni-

tive Health of Nonagenarians in Southern Italy: A Descriptive Analysis from a Cross-Sectional, Home-Based Pilot Study of Exceptional Longevity (Cilento Initiative on Aging Outcomes Or CIAO). Medicina (Kaunas).

2020 May 5;56(5):218. https://doi:10.3390/medicina56050218.

Jeste, D. V., Di Somma, S., Lee, E. E., Nguyen, T. T., Scalcione, M., Biaggi, A., … Brenner, D. (2020). Study of

2

loneliness and wisdom in 482 middle-aged and oldest-old adults: a comparison between people in Cilento, Italy and San Diego, USA. Aging & Mental Health, 25(11), 2149–2159. https://doi.org/10.1080/13607863.202 0.1821170 Aliberti, S.M.; Donato, A.; Funk, R.H.W.; Capunzo, M. A Narrative Review Exploring the Similarities between

3

Cilento and the Already Defined “Blue Zones” in Terms of Environment, Nutrition, and Lifestyle: Can Cilento Be Considered an Undefined “Blue Zone”? Nutrients 2024, 16, 729. https://doi.org/10.3390/nu16050729 Buettner D, Skemp S. Blue Zones: Lessons From the World’s Longest Lived. Am J Lifestyle Med. 2016 Jul

4

7;10(5):318-321. doi: 10.1177/1559827616637066. PMID: 30202288; PMCID: PMC6125071.

H.O., Cudjoe, T.K., Bu, F. et al. The state of loneliness and social isolation research: current knowledge and

5

future directions. BMC Public Health 23, 1049 (2023). https://doi.org/10.1186/s12889-023-15967-3 Zakrzewski W, Dobrzynski M, Szymonowicz M, Rybak Z. Stem cells: past, present, and future. Stem Cell Res ´

6

Ther. 2019 Feb 26;10(1):68. https://doi: 10.1186/s13287-019-1165-5.

Brunet, A., Goodell, M.A. & Rando, T.A. Ageing and rejuvenation of tissue stem cells and their niches. Nat

7

Rev Mol Cell Biol 24, 45–62 (2023). https://doi.org/10.1038/s41580-022-00510-w 8

Anna Scelzo, Salvatore Di Somma, Paola Antonini, Lori P. Montross, Nicholas Schork, David Brenner, Dil-

ip V. Jeste. Mixed-methods quantitative–qualitative study of 29 nonagenarians and centenarians in rural Southern Italy: focus on positive psychological traits. International Psychogeriatrics. Volume 30, Issue 1.

2018. Pages 31-38. ISSN 1041-6102. https://doi.org/10.1017/S1041610217002721.

Ferro M, Lucarelli G, Buonerba C, Terracciano D, Boccia G, Cerullo G, Cosimato V. Narrative review of

9

Mediterranean diet in Cilento: longevity and potential prevention for prostate cancer. Ther Adv Urol. 2021 Jul 22;13:17562872211026404. https://doi:10.1177/17562872211026404.

34

Aliberti SM, De Caro F, Funk RHW, Schiavo L, Gonnella J, Boccia G, Capunzo M. Extreme Longevity:

10

Analysis of the Direct or Indirect Influence of Environmental Factors on Old, Nonagenarians, and Centenarians in Cilento, Italy. Int J Environ Res Public Health. 2022 Jan 30;19(3):1589. https://doi: 10.3390/ ijerph19031589. PMID: 35162611; PMCID: PMC8834812.

11

Aliberti SM, Funk RHW, Ciaglia E, Gonnella J, Giudice A, Vecchione C, Puca AA, Capunzo M. Old, Nonage-

narians, and Centenarians in Cilento, Italy and the Association of Lifespan with the Level of Some Physicochemical Elements in Tap Drinking Water. Nutrients. 2023 Jan 1;15(1):218. https://doi:10.3390/nu15010218.

Bifulco, M., Pisanti, S. The mystery of longevity in Cilento: a mix of a good dose of genetic predisposition

12

and a balanced diet based on the Mediterranean model. Eur J Clin Nutr 71, 1020–1021 (2017). https://doi. org/10.1038/ejcn.2017.91.

Aliberti SM, Donato A, Funk RHW, Capunzo M. A Narrative Review Exploring the Similarities between Ci-

13

lento and the Already Defined “Blue Zones” in Terms of Environment, Nutrition, and Lifestyle: Can Cilento Be Considered an Undefined “Blue Zone”? Nutrients. 2024 Mar 2;16(5):729. doi: 10.3390/nu16050729.

PMID: 38474857; PMCID: PMC10934765.

Robin-Champigneul F. Jeanne Calment’s Unique 122-Year Life Span: Facts and Factors; Longevity His-

14

tory in Her Genealogical Tree. Rejuvenation Res. 2020 Feb;23(1):19-47. doi: 10.1089/rej.2019.2298. PMID: 31928146.

Melander O, Antonini P, Ottosson F, Brunkwall L, Gallo W, Nilsson PM, Orho-Melander M, Pacente G,

15

D’Arena G, Di Somma S. Comparison of cardiovascular disease and cancer prevalence between Mediterranean and north European middle-aged populations (The Cilento on Ageing Outcomes Study and The Malmö Offspring Study). Intern Emerg Med. 2021 Sep;16(6):1567-1572. doi: 10.1007/s11739-020-02625-4.

Epub 2021 Jan 30. PMID: 33515187; PMCID: PMC8354896.

Smith E, Ottosson F, Ericson U, Hellstrand S, Rizzo M, Sukruang K, Pizza V, Orho-Melander M, Nils-

16

son PM, Kennbäck C, Fernandez C, Antonini P, Di Somma S, Melander O. Impact of a short-term Mediterranean diet intervention on plasma metabolites: a pilot study. Metabolomics. 2024 Jul 27;20(4):82. doi:10.1007/s11306-024-02154-7. PMID: 39066903; PMCID: PMC11283393.

Daniels LB, Antonini P, Marino R, Rizzo M, Navarin S, Lucibello SG, Maisel AS, Pizza V, Brenner DA,

17

Jeste DV, Di Somma S. Cardiovascular health of nonagenarians in southern Italy: a cross-sectional, home-based pilot study of longevity. J Cardiovasc Med (Hagerstown). 2020 Feb;21(2):89-98. doi: 10.2459/ JCM.0000000000000910. PMID: 31789688.

35

ADDITIONAL READING “Biomarker lifts a secret of old age.” European Biotechnology Life Science and Industry magazine. May 9, 2016.

“Good microcirculation indicates increased lifespan.” Sphingotec. September 5, 2016.

“Rosemary and Time: Does This Italian Hamlet Have a Recipe for Long Life?” Bryant Rousseau. The New York Times. October 19, 2016.

“Mediterranean Diet: The Right Way to Longevity?” Walter Milano, Vincenzo Pizza, Anna Capasso. Annals of Nutrition & Food Science. February 20, 2018.

“How Long Can We Live? The Limit Hasn’t Been Reached, Study Finds” The mortality rate flattens among the oldest of the old, a study of elderly Italians concludes, suggesting that the oldest humans have not yet reached the limits of life span. Carl Zimmer. The New York Times. June 28, 2018.

“A Visit to the Land of Happy Old People: Reflections on the Mediterranean diet as an antidote to encroaching middle age.” Nina Burleigh. Medium. June 4, 2019.

“People in the world’s ‘blue zones’ live longer—their diet could hold the key to why.” Justin Roberts, Joseph Lillis, Mart Cortnage. The Conversation. January 24, 2024.

“Life 101: Lessons from Nicolina.” Sanford Burnham Prebys. June 18, 2024.

“Opinion: There’s a secret to living long and healthy. Just follow this. Stay away from the American diet.”

David Brenner, MD. San Diego Union-Tribune. June 30, 2024.

36

“Have We Reached Peak Human Life Span? After decades of rising life expectancy, the increases appear to be slowing. A new study calls into question how long even the healthiest of populations can live.” Dana G. Smith. The New York Times. October 7, 2024.

“Research in Context: Can we slow aging?” NIH Research Matters. October 15, 2024.

“Do People in ‘Blue Zones’ Actually Live Longer? The premise is catchy, but some think it’s based on faulty data.” Dana G. Smith. The New York Times. October 24, 2024.

“Shades of Blue: Blue zones, supposed havens of longevity, have become a global brand. But skeptics think they rest on shaky science.” Igancio Amigo. Science. November 21, 2024.

“What’s the secret to living to 100? Centenarian stem cells could offer clues.

A bank of cells from people more than 100 years old gives scientists a new resource for studying longevity.” Smriti Mallapaty. Nature. November 29, 2024.

“What Matters More for Longevity: Genes or Lifestyle? It depends on what your goal is.” Dana G. Smith.

The New York Times. January 8, 2025.

“The secret to life as a super-ager.” Matt Villano. BrainWise.

37

INSTITUTIONAL CONTACTS FOR MEDIA Sanford Burnham Prebys sbpdiscovery.org

Sanford Stem Cell Institute (UC San Diego) stemcells.ucsd.edu

Scott LaFee VP, Communications slafee@sbpdiscovery.org

Danielle Lewis Marketing & Communications Director dmlewis@ucsd.edu

Monika Wert-Parkinson Senior Officer, Stewardship and Donor Relations mwert@sbpdiscovery.org

Great Health Science greathealthscience.com Valeria Albini External Communications valeria.albini@greatnetwork.org

38

NOTES

39

C1A0 THE CIAO STUDY

40