Epigenomics (Epub ahead of print) ISSN 1750-1911
part of
Research Article
10.2217/epi-2016-0179 © 2017 Future Medicine Ltd
Aim: To examine the relationships between two epigenetic clocks, aging and
exceptional longevity. Materials & methods: Participants were from three adult
cohorts with blood DNA methylation data (Illumina 450 K, n = 275, 34–103 years).
Epigenetic age (DNAmage) and age acceleration measures were calculated using
the Hannum and Horvath epigenetic clocks. Results: Across all cohorts, DNAmage
was correlated with chronological age. In the long-lived cohort (Sydney Centenarian
Study; 95+, n = 23), DNAmage was lower than chronological age for both clocks. Mean
Sydney Centenarian Study Hannum age acceleration was negative, while the converse
was observed for the Horvath model. Conclusion: Long-lived individuals have a young
epigenetic age compared with their chronological age.
First draft submitted: 16 December 2016; Accepted for publication: 16 February 2017;
Published online: 30 March 2017
Keywords: acceleration•age•aging•centenarians•DNAmage•epigeneticclock
•longevity
Aging is a complex and multifactorial pro-
cess that is influenced by genetic, environ-
mental and stochastic factors. There are a
number of cellular and molecular hallmarks
of aging such as genomic instability, telomere
attrition, epigenetic alterations, dysregu-
lated nutrient-sensing, mitochondrial dys-
function, cellular senescence and stem cell
exhaustion [1] . Despite this knowledge, our
understanding of the biological aging process
remains rudimentary.
Exceptionally long-lived individuals, such
as those aged 95 years and over, can be seen as
exemplars of healthy/successful aging. Many
long-lived individuals have delayed morbid-
ity until late in their life or have even escaped
age-related diseases altogether (defined as
onset of an age-related disease 100 years+) [2]
and thus represent a unique human ‘model’
to study the molecular determinants of suc-
cessful aging.
There has been little success in identifying
genetic factors associated with exceptional
longevity [3] , suggesting that epigenetic and/
or environmental factors also play impor-
tant roles. DNA methylation is an epigenetic
modification that is relatively stable and easy
to measure in human population studies.
Recently, age-related differentially methyl-
ated loci have been identified using partici-
pants from across the lifespan [4,5] . Several
research groups have used methylation data
from such loci to calculate an ‘epigenetic
clock’ or an ‘epigenetic age signature’, which
is highly correlated with chronological age [6] .
The majority of epigenetic clocks have been
based on DNA methylation data from periph-
eral blood cells, such as those constructed
by Hannum et al. [7] , Florath et al. , [4] and
Weidner et al. [5] . The correlations between
chronological and predicted methylation age
in these studies ranged from 0.88 to 0.93. In
contrast the epigenetic clock of Horvath [8]
utilized data from multiple tissues (r [age
and predicted methylation age] = 0.97) and,
therefore, may be useful across a broad range
Aging, exceptional longevity and
comparisons of the Hannum and Horvath
epigenetic clocks
Nicola J Armstrong
‡,1,2
, Karen
A Mather
‡,1
, Anbupalam
Thalamuthu
1
, Margaret
J Wright
3,4
, Julian N
Trollor
1,5
, David Ames
6,7
,
Henry Brodaty
1,8
, Peter R
Schofield
9,10
, Perminder
S Sachdev
1,11
& John B
Kwok*
,9,10,12
1
CentreforHealthyBrainAging,School
ofPsychiatry,UNSWAustralia,Sydney,
Australia
2
DepartmentofMathematics&Statistics,
MurdochUniversity,Perth,Australia
3
QueenslandBrainInstitute,Universityof
Queensland,Brisbane,Australia
4
CentreforAdvancedImaging,University
ofQueensland,Brisbane,Australia
5
DepartmentofDevelopmentalDisability
Neuropsychiatry,UNSWAustralia,
Sydney,Australia
6
AcademicUnitforPsychiatryof
OldAge,UniversityofMelbourne,
Melbourne,Australia
7
NationalAgingResearchInstitute,
Melbourne,Australia
8
DementiaCollaborativeResearch
Centre–Assessment&BetterCare,
UNSWAustralia,Sydney,Australia
9
NeuroscienceResearchAustralia,
Sydney,Australia
10
SchoolofMedicalSciences,
UNSWAustralia,Sydney,Australia
11
NeuropsychiatricInstitute,Princeof
WalesHospital,Randwick,Australia
12
BrainandMindCentre–Universityof
Sydney,Camperdown,Australia
*Authorforcorrespondence:
john.kwok@sydney.edu.au
‡
Equalfrstauthors