What it Takes
to Reach...
The secrets to staying young may lie
in the DNA of the oldest among us.
BY LINDA MARSA“There are just two of us left now,” Jemima
Westcott says wistfully. Only she and her kid
brother, a sprig at age 94, remain of a oncethriving family. Westcott’s older sisters diedat age 105 and 107, and she marked her own
105th birthday in January at a dinner party
in her cozy condo in Brandon, Manitoba,
surrounded by her children and grandchildren.
Widowed for 50 years, she still lives alone,cooking and cleaning for herself — her only
concession to old age is using a walker.
Westcott has lived through iconic eventsof the 20th century. She has vivid memoriesof the celebrations when soldiers returned
home from World War I; of big picnics onher family’s farm on the windswept prairies;
of gas rationing during the second world
war, when she was a young mother with five
kids; and of traveling across Europe, North
Africa and the U.S., and even diving in the
Great Barrier Reef during a yearlong stint inAustralia after she retired.
“I’ve had an adventurous life,” says theformer schoolteacher, an admitted night
owl who stays up into the wee hours and

28 DISCOVERMAGAZINE.COM

likes to sleep in. Her secret to a long life?
“Resilience.”
Westcott may be on to something. She’s aparticipant in the New England Centenarian
Study, a long-term research project at the
Boston Medical Center that studies why
people like her enjoy such exceptional
longevity. What they’ve found, thus far, isthat healthy habits and positive attitudes will
only get you so far: Centenarians are winnersof the genetic lottery and, like Westcott, havea clustering of long-lived relatives. They are
remarkably intact mentally, and up to 90
percent of them can function independently
into their ninth decade. Surviving past age
100 means they’ve largely evaded the scourgesthat kill their peers before they reach their90s (what’s called compressed morbidity),or sidestepped the worst aspects of theselife-threatening diseases — even if they strikesooner — because they have combinationsof protective genes, what researchers call“greater functional reserves.”“Even though they have these illnesses, theyhandle them better than other people andOctober 2016 DISCOVER

29

WILLIAM ZUBACK/DISCOVER; CANDLE ILLUSTRATION BY JAY SMITH

have better protective mechanisms,”
says Thomas Perls, a geriatrician at
Boston University and director of the
New England Centenarian Study. “Inother words, the older you get, thehealthier you have been.”
Now scientists like Perls are
sifting through millions of DNA
markers to spot the constellationof longevity genes that’s carriedin every cell of these centenarians’bodies. Perls and his colleagues
have uncovered 281 genetic markers
that seem to perform a protectivefunction, slowing aging and making
this group less vulnerable to disease.
Other researchers, in sequencing the
genome of centenarians, have foundthey possess fewer of the genes that
contribute to major diseases. “Theylive longer, in part, because they don’t
get sick,” says Stuart Kim, one of thestudy co-authors and a geneticist at
Stanford University.
How does this happen? Scientists
suspect there may be some kind of
intrinsic biological clock that runs
slower in some people and quicker inothers, which would accelerate aging
and wear down the body’s protective
processes. Those with faster clocks arethen more vulnerable to the onset of
fatal diseases and die sooner. Research
into the genetics of long-livers, andinto other biological systems that may
influence aging, offers some tantalizing
clues into the underlying mechanics ofthese clocks. Deciphering precisely how

30 DISCOVERMAGAZINE.COM

they work could enable us to tinker
with these internal timepieces andgenuinely slow down the aging process.

REAL AGE
Timing seems to be a key piece ofthe puzzle. Biological age doesn’t
always match what’s on a person’sbirth certificate. After all, we’re notsurprised to see a 70-somethingdebilitated by illness, or a 74-year-old
who barnstorms around the country,
running for president. Some people
simply age faster than others, andscientists are beginning to understandwhy. New research using data from alandmark longitudinal study has been
particularly eye opening. Known as
the Dunedin study, it followed morethan 1,000 people from their births in
the early 1970s in the same hospital insouthern New Zealand.
Most research looks at aging inolder people, but the seeds of agerelated diseases are planted decades
earlier — that’s why these researchers

believe it’s crucial to study aging in theyoung. They aim to shed light on why
we become vulnerable to the assaultsof time and the chronic diseases linked
to aging, such as cancer, heart disease,diabetes, and loss of mental acuity.
Scientists in the U.S., U.K., Israel and
New Zealand looking at the Dunedin
data used it to track 18 biologicalmeasures, including liver and kidney
function, blood sugar and cholesterollevels, balance, cognitive ability,
cardiovascular fitness and even gum
recession in 954 study participants.
As expected, most people’s
biological age clustered aroundtheir early 40s, within a few yearsof their actual ages, according toresults released last year. But there
were wide variations: A handful
were up to a decade younger, while
many had a biological age in their
50s; one participant had a biologicalage of 61. Even before midlife, someparticipants were aging much faster.
They were already having trouble withTIM SMITH

Scientists suspect
there may be somekind of intrinsic
biological clockthat runs slower insome people andquicker in others,
which would
accelerate aging
and wear down the
body’s protective
processes.

Jemima Westcott

climbing stairs and difficulties solving
unfamiliar mental tasks, their balance
was worse, their livers were startingto fail, and they were in poorer
overall health.
“When we assembled all the data,
we were quite struck about thecoordinated changes we did see in all
the systems of the body,” says Daniel
Belsky, the study’s lead author anda gerontologist at Duke University’s
Center for Aging. “Clearly, there arebasic molecular mechanisms of aging
that cause the various diseases that
disable and ultimately kill us.”

UNIVERSITY ARCHIVES PHOTOGRAPH COLLECTION/GEORGE A. SMATHERS LIBRARIES/UNIVERSITY OF FLORIDATHE CELLULAR COUNTER
More than 50 years ago, a researcher
uncovered the first clues that aninternal biological clock might
regulate age — and that it’s not justthe daily assaults from the external
wear and tear of life that cause us towither and eventually die. That’s when
Leonard Hayflick discovered what
would become known as the Hayflick
limit. In the late 1950s, as a young
microbiologist at the Wistar Institutein Philadelphia, Hayflick studied
viruses that might cause cancer. While
there, he worked with cell culturesderived from human fetal tissue.
One day, the cell division in one of theflasks seemed to be slowing down, andafter about the 40th doubling, the cells
stopped reproducing.
At that time, scientists believed
all cells were immortal — marinate
them in the proper nutrients, and theywould divide forever. Hayflick thought
he had made a technical mistake orthat the cells were contaminated.
But then he observed the same halt
in cell division in other cultures withdifferent fetal tissues. He went backthrough his records, looking for clues
to the anomaly, and discovered thatof the many cultures he had made, it
was always the oldest ones that had
stopped replicating.
While cancer cells are immortal —their hallmark is wildly reproducing
out of control — Hayflick discoveredthat normal cells have a limited life
span. Even when cells are frozen
for months, subsequent researchdemonstrated, when they thaw out,
they pick up their cell division where
they left off until they hit between 40
and 60 doublings.
“When I discovered that normal
cells had a memory, I nearly fellof my chair. No one ever thought
normal cells had a memory,” Hayflickrecalls. “There had to be some sortof intracellular counting mechanism

Leonard Hayflickor meter that tells the cells how
many divisions it has gone through.
But where?”In 1975, Hayflick and graduate
student Woodring Wright proved thecounting device was in the cell nucleus,
but they didn’t have the technologicaltools to unlock the precise mechanism.
Even though Hayflick’s discoveries
went against accepted scientific dogma— “I was the first one to show thataging had its origins inside the cell,”
he now says — they ultimately sparked
an explosion in the study of aging.
But another decade would pass before
a candidate emerged for Hayflick’s“replicometer.”

DNA FRAGMENTS
Despite all the accolades heaped upon
her for groundbreaking research,
Elizabeth Blackburn retains thehomespun warmth, sharp wit andAt the time,scientists believed
all cells wereimmortal —marinate themin the proper
nutrients, andthey would divide
forever.
plucky spirit of her native Australia.
Early this year, the Nobel Prizewinning biochemist left her lab at
the University of California, San
Francisco, to head up the Salk Institute,the scientific incubator founded bypolio vaccine pioneer Jonas Salk. The
center is housed in a cluster of modern
concrete and glass buildings perched on
the coast in La Jolla, Calif. We sit at aconference table in her airy office, withfloor-to-ceiling windows looking out
on the Pacific.
Blackburn, who hails from
Tasmania, an island off the coastof Australia, earned her doctorate
degree in molecular biology from the
University of Cambridge in England.
In the 1970s she landed at Yale
October 2016 DISCOVER

31

University, where she sequenced thetips of chromosomes of a single-celledorganism, Tetrahymena — “pondscum,” she cheerfully offers. These tiny
strips of DNA, called telomeres, cap
the end of chromosomes. Scientists
long suspected they stabilized thestructure of the chromosome,preventing the tips from fraying, much
like the plastic sheaths at the endsof shoelaces to prevent them fromunraveling. But how?
Each time a cell divides, the telomere
gets shorter, but its function had long
been unclear. “We had the seeds of an
idea [that] there could be a clocklike
thing, because every time the DNA
replicated, the end of the chromosome
wasn’t replicated,” Blackburn recalls.
It wasn’t until the late 1980s that astrong connection was made between
telomeres and cellular aging, in a
breakthrough that resulted from a bitof scientific serendipity. Blackburn’sformer graduate student, Carol Greider,
was dating a biologist who shared lab
space with Calvin Harley, a biochemist
studying aging at McMaster University
in Ontario. Casual conversations in thelab grew into a full-scale collaborationthat melded Harley and Greider’sareas of expertise — cell senescenceand telomeres.
The result was two landmark papers
published in 1990 and 1992 that madea convincing case that telomeres might
be the cellular timing device behindthe Hayflick limit. With each cell
division, telomeres dwindle until they
are just tiny nubs, which prompt cells
to malfunction, stop replication andfinally die off. This research provided“some good clues that we were goingin the right direction,” says Blackburn,“but it took years and years ofobservations by lots of scientists before
the puzzle pieces were put together toform a real picture of what happens.”

STUNTED TELOMERES
Telomere shortening is now considereda biomarker of cellular aging, andmore evidence suggests that these tiny
fragments of DNA may be one of theculprits behind age-related decline.
Subsequent studies have shown thatshortened telomeres are linked to many
age-related diseases, including heartdisease, diabetes, Alzheimer’s, stroke
and obstructive lung disease. “These
are the major killers of the elderly,”says Blackburn. “We’re starting to go

beyond just correlations and seeing areal element of causality here.”
Even chronic stress can wear away
our telomeres, according to researchdone in the early 2000s that lookedat mothers caring for children withchronic diseases. Blackburn and UCSF
psychologist Elissa Epel’s work foundthat the most stressed-out women
had shorter telomeres that translated
into an extra decade or so of aging
compared with their matched controls— showing that external stressors canthrow a monkey wrench into the cell’smolecular mechanics.
More recent research, presented ata scientific meeting in 2012, analyzed
saliva samples from more than 100,000
people who belonged to Kaiser
Permanente, an HMO in Northern
California. The major take-homemessage: People with stunted telomeres
die at younger ages. What was equally
intriguing is that even though women
outlive men, as young adults theirtelomeres are about the same length.
While everyone’s telomeres dwindle
as they grow older, a big split occurs
after age 50, when telomere shortening
among men accelerates. The genderdivision continues to widen until about

TELOMERES AND AGING

Elizabeth Blackburn talks about the link.
Telomeres are tiny fragmentsof DNA at the end of eachchromosome. Nobel laureate
Elizabeth Blackburn has spent
her career studying theirfunction. Here, she talks about
the role they play in aging.
DISCOVER: Are telomeres theclock behind aging?
BLACKBURN: As a loose
approximation, aging isclocklike because there’s a
progressiveness to it. But
we’ve got to be smarter about
what that word aging reallymeans. Is human aging yourrisk of getting the diseasesof aging? Well, in that case,

32 DISCOVERMAGAZINE.COM

centenarians never age. And
yet, they clearly do age: They
get wrinkled and frail andsmaller — they’re doing well
but they’re not young people.
Aging has multiple aspects,
and we tend to oversimplify
it. A lot of different kindsof things come into playin different stages. If weavoid all the major diseases,
there’ll still be an aging
process, which is not identical.
Telomere shortening seems
to underlie the risks for the
diseases that kill you.
DISCOVER: In what way?
BLACKBURN: Every sign,

Elizabeth Blackburn

including genetics, says
there’s some causality[between telomeres] andthe nasty things that happen

with aging, the really nasty
diseases that kill us — heartdisease, diabetes, cancer,
even Alzheimer’s. We knowWhat We Lose
With Agechromosomecell

As cells divide
over time . . .

telomeresDNA

TOP: GWEN SHOCKEY/SCIENCE SOURCE. BOTTOM: JANERIK HENRIKSSON/AFP/GETTY IMAGES. . . telomeres shorten, andeventually cell division stops.

telomere shortening drives
cells into senescence [aging].
If you look at people withwrinkled skin versus not
wrinkled skin, the people
with sagging, UV-damaged
skin have shorter telomeres
than people with smooth,unwrinkled skin. If you’re in
the bottom third of telomere
length, your cardiovasculardisease risk goes up 40
percent, which is not a trivial
number. Pessimism correlateswith shorter telomeres. So
you can put all this together
and say it’s reasonable thatsome of this is really driving
pathologies in humans.
DISCOVER: So the shorter thetelomeres, the more likely it isage 75, when those with the blunted
telomeres die from disease.
These results demonstrate ata molecular level what scientists
tracking centenarians had observed:
Longer-lived people have a biologicaladvantage that enables them to escapeor better withstand what Blackburncalls “the hail of bullets” that kill the
majority of us. “Most mortality inthe population happens around age
75, and anybody who lives longer has
been somehow biologically selected,”says Blackburn. “We know telomere
shortening drives cells into senescence.
So it is reasonable to say that this isdriving pathologies in humans.”
But telomeres aren’t the whole story.

THE EPIGENETIC CLOCK“There’s a knot in here that’s goingto give you trouble,” Jose Valencia
warns me, speaking in Spanish throughan interpreter while he massages thefleshy pad of skin between my left
thumb and index finger, then flashes
a mischievous, toothy grin, as if totell me I’d better be careful. Barely
5 feet tall and clad in crisp khakis anda short-sleeve striped shirt, Valencia
sits placidly on a bench in front of

you’ll be stricken with diseases
and that you’ll age faster?
BLACKBURN: If you inherit
very short telomeres, you
get this terrible disease now
being called the “telomere
syndrome.” It’s extremely rare
because these poor children
don’t survive into adulthood.
But because there are billions
of us on the planet, it’shappened often enough that
there are now hundreds ofindividuals and many afflictedfamilies around the world. A
child will come into the clinicwith a skin disorder, but that’s
not the real problem: They
have terrible gut disorders
and their whole body isfraught with problems,

the cinderblock house he shares withhis granddaughter, Keren Gonzales
Valencia, in El Torito, Costa Rica, atiny village honeycombed by dirt roads
where the rainforest meets the beach.
It is a sultry November day withtemperatures hovering in the low 90s.
It’s the end of the rainy season on the
Nicoya Peninsula in the northwest
corner of Costa Rica, and the jungle
is lush from months of torrential
downpours. A healer of local renown,
Valencia taught himself anatomy bydissecting chickens — three of which
lazily strut across the yard while wetalk. He massages strained muscles andfixes dislocated joints when doctors are
too busy, he says. Even the local expat
surfers and retirees come see him when
their backs hurt.
A farmer all his life, Valencia retired
at age 80 when he was diagnosed withleukemia, but it barely slowed him
down. He’ll be celebrating his 97th
birthday in a few days, he tells me,
and shares bittersweet recollections ofbeing a lovesick teenager eight decades
earlier: There were no roads, and theonly way he could visit his sweetheartin the next town was to walk along
the beach. He attributes his long life

and they have this whole
spectrum of very nasty, very
early onset diseases, which
are the ones that often
appear with age.
About 10 percent of themdie of some rare cancer,
and a lot of them die of
infections, and their guts
don’t work properly andthey’re really sickly. But then
you look at the parents andthe grandparents because
this gene has to come fromsomewhere. And you find the
grandparent with the gene
had pulmonary fibrosis. So
the molecular cause is exactly
the same base pair change
in a telomerase gene. But
it played out in the bodydifferently. The grandparent’s
telomeres were shorter
than their peers’ and theparent’s telomeres were evenshorter, and the child’s werereally short.
So what if people inherited
somewhat shorter telomeresand never completely
recovered or do things that
we know externally promote
shortening of telomeres, likesmoking or living in stressful
situations? They might do justfine, but if there’s somethingelse going on combined withthe shorter telomeres, thatmight be enough to kill them.
Telomeres are not the end of
the story, but they play a role.
— L.M.

October 2016 DISCOVER33

to hard work, good food and family— his wife died less than a year ago
and his extended family of children,
grandkids and great-grandkids
all live nearby.
But his longevity is not unusual
for the Nicoya Peninsula, an 85-mile
sliver of pristine beaches, cow pastures,
farms and wooded hills, whereresidents often reach ages of 90, 100 oreven 110. Despite their poverty, locals
live far longer than their wealthiercounterparts elsewhere. The peninsula
is one of the world’s five Blue Zones,
where more people live past 100 thanin other parts of the world. The otherfour longevity hot spots are Okinawa,
Japan; Loma Linda, Calif.; Sardinia,
Italy; and Ikaria, Greece.
In 2005, Costa Rican demographer
Luis Rosero-Bixby found that
Costa Ricans who survive to age
60 end up having the longest life

expectancy of anyone in the world.
Subsequent research in 2012 foundthat older residents of Nicoya lived
even longer, up to three years morethan other Costa Ricans. In research
published in 2013, Stanford University
epidemiologist David Rehkopf andhis colleagues wanted to find out why.
They took DNA samples from Nicoya
residents who were older than 60 tomeasure the length of their telomeres.
They turned out to be longer thanthose of other Costa Ricans, with anaverage difference of about 81 basepairs, equivalent to the benefits of

34 DISCOVERMAGAZINE.COM

Jose Valencia

quitting smoking or getting regularphysical activity.
Why do those on the Nicoya
Peninsula live so long? The key
seems to be in the nation’s familiar
catchphrase: pura vida, or “purelife.” Costa Rica, a centuries-old
democracy with universal health care,no standing army and the highest
literacy rate in Central America, hasbeen relatively insulated from thecorruption, narco-terrorism and civil
wars that have plagued neighbors like
Panama, Nicaragua and Guatemala.
Researchers believe Nicoyans’ leisurely
pace of life, plant-based diet, networkof family and friends, regular exercise
and purposeful lives seem to be theirrecipe for longevity.
While outside forces — stress,

poverty, environmental toxins — canaccelerate aging, the reverse seems
to be true, too. Our life experiences
exert a profound influence on how
we age and can even alter the ways
genes function without changing theunderlying DNA sequence; thesegenetic changes are called epigenetic
traits. A research team at UCLA led
by biostatistician Steven Horvath has
uncovered an epigenetic biologicalclock that may provide a key puzzle
piece in deciphering how this happens— and help explain why Nicoyans live
so long. “For those people who age
more slowly, somehow their epigenetic
clock ticks more slowly,” Horvath says.
“There’s an intrinsic process that drives
aging, and that may be what’s capturedby this epigenetic clock.”

LINDA MARSA

Our life experiences
exert a profoundinfluence on how
we age and canalter the ways
genes function
without changing
the underlying
DNA sequence;these genetic
changes are called
epigenetic traits.

Loma Linda,
California

Sardinia,
Italy
Ikaria,GreeceOkinawa,Japan

Nicoya,Costa Rica

Blue
Zones
Longevity hot spots

FROM TOP: ILDOGESTO/SHUTTERSTOCK; UCLA

across the globe.

THE MECHANICS OF AGING
For the German-born Horvath,a boyish 48-year-old with broadfeatures and a puckish sense ofhumor, the discovery is the fruition ofa lifelong dream, dating back to highschool, when he decided to devote his
career to prolonging the human life
span. But it wasn’t until 2006 that theadvent of big data allowed him to siftthrough millions of data points toferret out biomarkers that correlatedwith age.
His team focused on a naturally
occurring process that’s part ofthe body’s internal housekeeping
system, called methylation, whichmakes chemical modifications
to our genome that are strongly
influenced by environmental factors.
Horvath was able to obtain over 50
datasets — from researchers in Spain,
Germany, Italy, the U.S., U.K. andAustralia — that contained the genetic
profiles of thousands of subjects instudies looking at methylations inhealthy tissue.
Over the course of three years,
Horvath and his team analyzed
nearly 8,000 tissue samples fromthese datasets, which included blood,
saliva and cells from organs like thebrain and the colon. The UCLA
team identified 353 DNA markers
from 51 types of cells and tissues
and examined how age affects their
DNA methylation levels throughout
a lifetime. They then used the data
to devise an algorithm that canaccurately determine the age ofdiverse organs, tissues and cell types.

When they compared a tissue’s
biological age and its chronologicalage, the clock proved to be remarkably
accurate in predicting age. Stem cells
plucked from embryos were deemed
extremely young by the clock, whileneural cells from centenarians were
estimated to be about 100. And evencells that were young, such as whiteblood cells that may be just a few days
or weeks old, still carried the distinct
genetic imprint of their 50-year-old
donor. “The 353 markers on the DNA
provide a weighted average that gives
you a very accurate measure of theage of the tissue,” says Horvath.
Since then, he has used theepigenetic clock as a tool to begin
to understand the mechanics ofaging. Subsequent research on
Italian centenarians revealed thatthe offspring of these centenarians

Steven Horvathwere substantially younger, up to
about five years, according to theirepigenetic clocks, than the progeny of
non-centenarians.
But perhaps Horvath’s mostsignificant finding had its genesis in
2013, when researchers from the Los
Angeles Gerontology Research Group,
which studies supercentenarians(those who live to 110 and older),supplied him with tissue samples
from three centenarians and three
supercentenarians, one of whom
recently died at age 112. What
Horvath uncovered was astonishing— and may eventually lead the way toextending our life.
The research team analyzed theepigenetic age of up to 30 anatomic sites
from the 112-year-old woman. They
discovered that the cerebellum is the
youngest part of the body and didn’t age
nearly as fast as other areas. The neuronpacked brain region — it’s tucked
underneath the cerebral hemispheres
and plays a role in motor control andcognitive functions, such as attention
and language — seemed to stop aging at
the 80-year benchmark, which meant it
remained fully functional but somehow
impervious to deterioration of time for
decades.
Earlier this year, Horvath andhis colleagues took a step toward
answering this question. Their analysis
uncovered small variations in two
genes related to the accelerated agingof the cerebellum. What was especially“exciting” about this finding, he says,
is that these variations were near aneural highway that previous studies
have shown helps regulate life spanin worms and flies, and that stopping
chemical signals from this brain
pathway extends the life span of mice.
While this discovery is still not a“smoking gun,” says Horvath, “if we
can understand why the cerebellum
ages more slowly, we can figure out
how to slow down all the other partsand uncover interventions that might
be able to reverse this process.” D
Linda Marsa is a Discover contributing editor
and author of Fevered: How a Hotter Planet
Will Hurt Our Health and How We Can Save
Ourselves.

October 2016 DISCOVER35

© 2016 Discover Magazine