Background:Sirtuin 6 gene (SIRT6) is a longevity gene that is involved in a variety of metabolic pathways, but the relationship between SIRT6 methylation and longevity has not been clarified. Methods: We conducted a case-control study on 129 residents with a family history of longevity (1 of parents, themselves, or siblings aged ≥90 years) and 86 individuals without a family history of exceptional longevity to identify the association. DNA pyrosequencing was performed to analyze the methylation status of SIRT6 promoter CpG sites. qRT-PCR and ELISA were used to estimate the SIRT6 messenger RNA (mRNA) levels and protein content. Six CpG sites (P1–P6) were identified as methylation variable positions in the SIRT6 promoter region. Results: At the P2 and P5 CpG sites, the methylation rates of the longevity group were lower than those of the control group (p < 0.001 and p = 0.009), which might be independent determinants of longevity. The mRNA and protein levels of SIRT6 decreased in the control group (p < 0.0001 and p = 0.038). The mRNA level negatively correlated with the methylation rates at the P2 (rs = −0.173, p = 0.011) and P5 sites (rs = −0.207, p = 0.002). Furthermore, the protein content positively correlated with the methylation rate at the P5 site (rs = 0.136, p = 0.046) but showed no significant correlation with the methylation rate at the P2 site. Conclusion: The low level of SIRT6 methylation may be a potential protective factor of Chinese longevity.

1.
Armstrong
NJ
,
Mather
KA
,
Thalamuthu
A
,
Wright
MJ
,
Trollor
JN
,
Ames
D
, et al
Aging, exceptional longevity and comparisons of the Hannum and Horvath epigenetic clocks
.
Epigenomics
.
2017
;
9
(
5
):
689
700
.
2.
Lazarus
J
,
Mather
KA
,
Thalamuthu
A
,
Kwok
JB
.
Genetic factors and epigenetic mechanisms of longevity: current perspectives
.
Epigenomics
.
2015
;
7
(
8
):
1339
49
.
3.
Egger
G
,
Liang
G
,
Aparicio
A
,
Jones
PA
.
Epigenetics in human disease and prospects for epigenetic therapy
.
Nature
.
2004
;
429
(
6990
):
457
63
.
4.
Benayoun
BA
,
Pollina
EA
,
Brunet
A
.
Epigenetic regulation of ageing: linking environmental inputs to genomic stability
.
Nat Rev Mol Cell Biol
.
2015
;
16
(
10
):
593
610
.
5.
Antequera
F
,
Bird
A
.
CpG islands: a historical perspective
.
Methods Mol Biol
.
2018
;
1766
:
3
13
.
6.
Law
JA
,
Jacobsen
SE
.
Establishing, maintaining and modifying DNA methylation patterns in plants and animals
.
Nat Rev Genet
.
2010
;
11
(
3
):
204
20
.
7.
Van Meter
M
,
Simon
M
,
Tombline
G
,
May
A
,
Morello
TD
,
Hubbard
BP
, et al
JNK phosphorylates SIRT6 to stimulate DNA double-strand break repair in response to oxidative stress by recruiting PARP1 to DNA breaks
.
Cell Rep
.
2016
;
16
(
10
):
2641
50
.
8.
Salameh
Y
,
Bejaoui
Y
,
El Hajj
N
.
DNA methylation biomarkers in aging and age-related diseases
.
Front Genet
.
2020
;
11
:
171
.
9.
Kwabi-Addo
B
,
Chung
W
,
Shen
L
,
Ittmann
M
,
Wheeler
T
,
Jelinek
J
, et al
Age-related DNA methylation changes in normal human prostate tissues
.
Clin Cancer Res
.
2007
;
13
(
13
):
3796
802
.
10.
Sahin
K
,
Yilmaz
S
,
Gozukirmizi
N
.
Changes in human sirtuin 6 gene promoter methylation during aging
.
Biomed Rep
.
2014
;
2
(
4
):
574
8
.
11.
Jones
MJ
,
Goodman
SJ
,
Kobor
MS
.
DNA methylation and healthy human aging
.
Aging Cell
.
2016
;
14
(
6
):
924
32
.
12.
Terry
DF
,
Wilcox
MA
,
McCormick
MA
,
Pennington
JY
,
Schoenhofen
EA
,
Andersen
SL
, et al
Lower all-cause, cardiovascular, and cancer mortality in centenarians’ offspring
.
J Am Geriatr Soc
.
2004
;
52
(
12
):
2074
6
.
13.
Gentilini
D
,
Mari
D
,
Castaldi
D
,
Remondini
D
,
Ogliari
G
,
Ostan
R
, et al
Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians’ offspring
.
Age
.
2013
;
35
(
5
):
1961
73
.
14.
Stefanska
B
,
Karlic
H
,
Varga
F
,
Fabianowska-Majewska
K
,
Haslberger
A
.
Epigenetic mechanisms in anti-cancer actions of bioactive food components: the implications in cancer prevention
.
Br J Pharmacol
.
2012
;
167
(
2
):
279
97
.
15.
Knoblich
N
,
Gundel
F
,
Brückmann
C
,
Becker-Sadzio
J
,
Frischholz
C
,
Nieratschker
V
.
DNA methylation of APBA3 and MCF2 in borderline personality disorder: potential biomarkers for response to psychotherapy
.
Eur Neuropsychopharmacol
.
2018
;
28
(
2
):
252
63
.
16.
Marcon
F
,
Siniscalchi
E
,
Andreoli
C
,
Allione
A
,
Fiorito
G
,
Medda
E
, et al
Telomerase activity, telomere length and hTERT DNA methylation in peripheral blood mononuclear cells from monozygotic twins with discordant smoking habits
.
Environ Mol Mutagen
.
2017
;
58
(
8
):
551
9
.
17.
Miozzo
F
,
Arnould
H
,
de Thonel
A
,
Schang
AL
,
Sabéran-Djoneidi
D
,
Baudry
A
, et al
Alcohol exposure promotes DNA methyltransferase DNMT3A upregulation through reactive oxygen species-dependent mechanisms
.
Cell Stress Chaperones
.
2018
;
23
(
1
):
115
26
.
18.
Lim
CS
.
Is SIRT6 a new biomarker for oxidative stress and longevity assurance gene?
Med Hypotheses
.
2007
;
69
(
1
):
231
.
19.
Mahlknecht
U
,
Ho
AD
,
Voelter-Mahlknecht
S
.
Chromosomal organization and fluorescence in situ hybridization of the human Sirtuin 6 gene
.
Int J Oncol
.
2006
;
28
(
2
):
447
56
.
20.
Toiber
D
,
Erdel
F
,
Bouazoune
K
,
Silberman
DM
,
Zhong
L
,
Mulligan
P
, et al
SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling
.
Mol Cell
.
2013
;
51
(
4
):
454
.
21.
Cui
X
,
Yao
L
,
Yang
X
,
Gao
Y
,
Fang
F
,
Zhang
J
, et al
SIRT6 regulates metabolic homeostasis in skeletal muscle through activation of AMPK
.
Am J Physiol Endocrinol Metab
.
2017
;
313
(
4
):
E493
505
.
22.
Zhai
XY
,
Yan
P
,
Zhang
J
,
Song
HF
,
Yin
WJ
,
Gong
H
, et al
Knockdown of SIRT6 enables human bone marrow mesenchymal stem cell senescence
.
Rejuvenation Res
.
2016
;
19
(
5
):
374
84
.
23.
Ghiraldini
FG
,
Crispim
AC
,
Mello
ML
.
Effects of hyperglycemia and aging on nuclear sirtuins and DNA damage of mouse hepatocytes
.
Mol Biol Cell
.
2013
;
24
(
15
):
2467
76
.
24.
Van Gool
F
,
Gallí
M
,
Gueydan
C
,
Kruys
V
,
Prevot
PP
,
Bedalov
A
, et al
Intracellular NAD levels regulate tumor necrosis factor protein synthesis in a sirtuin-dependent manner
.
Nat Med
.
2009
;
15
(
2
):
206
10
.
25.
Mostoslavsky
R
,
Chua
KF
,
Lombard
DB
,
Pang
WW
,
Fischer
MR
,
Gellon
L
, et al
Genomic instability and aging-like phenotype in the absence of mammalian SIRT6
.
Cell
.
2006
;
124
(
2
):
315
29
.
26.
Jia
G
,
Su
L
,
Singhal
S
,
Liu
X
.
Emerging roles of SIRT6 on telomere maintenance, DNA repair, metabolism and mammalian aging
.
Mol Cell Biochem
.
2012
;
364
(
1–2
):
345
50
.
27.
Tasselli
L
,
Zheng
W
,
Chua
KF
.
SIRT6: novel mechanisms and links to aging and disease
.
Trends Endocrinol Metab
.
2017
;
28
(
3
):
168
85
.
28.
Zhong
L
,
Mostoslavsky
R
.
SIRT6: a master epigenetic gatekeeper of glucose metabolism
.
Transcription
.
2010
;
1
(
1
):
17
21
.
29.
Lefort
K
,
Brooks
Y
,
Ostano
P
,
Cario-André
M
,
Calpini
V
,
Guinea-Viniegra
J
, et al
A miR-34a-SIRT6 axis in the squamous cell differentiation network
.
EMBO J
.
2013
;
32
(
16
):
2248
63
.
30.
Kanfi
Y
,
Naiman
S
,
Amir
G
,
Peshti
V
,
Zinman
G
,
Nahum
L
, et al
The sirtuin SIRT6 regulates lifespan in male mice
.
Nature
.
2012
;
483
(
7388
):
218
.
31.
Hirvonen
K
,
Laivuori
H
,
Lahti
J
,
Strandberg
T
,
Eriksson
JG
,
Hackman
P
.
SIRT6 polymorphism rs117385980 is associated with longevity and healthy aging in Finnish men
.
BMC Med Genet
.
2017
;
18
(
1
):
41
.
32.
Lin
R
,
Zhang
Y
,
Yan
D
,
Liao
X
,
Gong
G
,
Hu
J
, et al
Lack of association between polymorphisms in the SIRT6 gene and longevity in a Chinese population
.
Mol Cell Probes
.
2016
;
30
(
2
):
79
.
33.
Li
Y
,
Qin
J
,
Wei
X
,
Liang
G
,
Shi
L
,
Jiang
M
, et al
Association of SIRT6 gene polymorphisms with human longevity
.
Iran J Public Health
.
2016
;
45
(
11
):
1420
6
.
34.
Michishita
E
,
McCord
RA
,
Berber
E
,
Kioi
M
,
Padilla-Nash
H
,
Damian
M
, et al
SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
.
Nature
.
2008
;
452
(
7186
):
492
6
.
35.
Lombard
DB
,
Schwer
B
,
Alt
FW
,
Mostoslavsky
R
.
SIRT6 in DNA repair, metabolism and ageing
.
J Intern Med
.
2008
;
263
(
2
):
128
41
.
36.
Grabowska
W
,
Sikora
E
,
Bielak-Zmijewska
A
.
Sirtuins, a promising target in slowing down the ageing process
.
Biogerontology
.
2017
;
18
(
4
):
447
30
.
37.
Yang
J
.
An analysis of the longevous population in Bama
.
Chin J Popul Sci
.
1992
;
4
(
4
):
351
6
.
38.
Li
C
,
Li
X
,
Lu
H
,
Li
Y
,
Wang
J
,
Liang
X
, et al
The correlationship of DNA methylation and longevity in Guangxi Bama region
.
Chin J Gerontol
.
2015
;(
4
):
865
70
.
39.
Bollati
V
,
Schwartz
J
,
Wright
R
,
Litonjua
A
,
Tarantini
L
,
Suh
H
, et al
Decline in genomic DNA methylation through aging in a cohort of elderly subjects
.
Mech Ageing Dev
.
2009
;
130
(
4
):
234
9
.
40.
Mortimer
JA
,
Borenstein
AR
,
Ding
D
,
Decarli
C
,
Zhao
Q
,
Copenhaver
C
, et al
High normal fasting blood glucose is associated with dementia in Chinese elderly
.
Alzheimers Dement
.
2010
;
6
(
6
):
440
7
.
41.
Auley
MM
,
Jones
J
,
Wilkinson
D
,
Kirkwood
T
.
Modelling lipid metabolism to improve healthy ageing
.
BMC Bioinformatics
.
2005
;
6
(
Suppl 3
):
P21
.
42.
Kawahara
TL
,
Rapicavoli
NA
,
Wu
AR
,
Qu
K
,
Quake
SR
,
Chang
HY
.
Dynamic chromatin localization of Sirt6 shapes stress- and aging-related transcriptional networks
.
PLoS Genet
.
2011
;
7
(
6
):
e1002153
.
43.
Millán
J
,
Pintó
X
,
Muñoz
A
,
Zúñiga
M
,
Rubiés-Prat
J
,
Pallardo
LF
, et al
Lipoprotein TC/HDL ratios: physiological significance and clinical usefulness in cardiovascular prevention
.
Vasc Health Risk Manag
.
2009
;
5
:
757
65
.
44.
Jones
PA
.
Functions of DNA methylation: islands, start sites, gene bodies and beyond
.
Nat Rev Genet
.
2012
;
13
(
7
):
484
92
.
45.
Dynan
WS
,
Tjian
R
.
The promoter-specific transcription factor Sp1 binds to upstream sequences in the SV40 early promoter
.
Cell
.
1983
;
35
(
1
):
79
87
.
46.
Pugh
BF
,
Tjian
R
.
Mechanism of transcriptional activation by Sp1: evidence for coactivators
.
Cell
.
1990
;
61
(
7
):
1187
97
.
47.
Taatjes
DJ
,
Tjian
R
.
Structure and function of CRSP/Med2; a promoter-selective transcriptional coactivator complex
.
Mol Cell
.
2004
;
14
(
5
):
675
83
.
48.
Yang
H
,
Salz
T
,
Zajac-Kaye
M
,
Liao
D
,
Huang
S
,
Qiu
Y
.
Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators
.
FASEB J
.
2014
;
28
(
10
):
4265
79
.
49.
Lu
F
,
Zhou
J
,
Wiedmer
A
,
Madden
K
,
Yuan
Y
,
Lieberman
PM
.
Chromatin remodeling of the Kaposi’s sarcoma-associated herpesvirus ORF50 promoter correlates with reactivation from latency
.
J Virol
.
2003
;
77
(
21
):
11425
35
.
50.
Zhu
WG
,
Srinivasan
K
,
Dai
Z
,
Duan
W
,
Druhan
LJ
,
Ding
H
, et al
Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter
.
Mol Cell Biol
.
2003
;
23
(
12
):
4056
65
.
51.
Macleod
D
,
Charlton
J
,
Mullins
J
,
Bird
AP
.
Sp1 sites in the mouse aprt gene promoter are required to prevent methylation of the CpG island
.
Genes Dev
.
1994
;
8
(
19
):
2282
92
.
52.
Brandeis
M
,
Frank
D
,
Keshet
I
,
Siegfried
Z
,
Mendelsohn
M
,
Nemes
A
, et al
Sp1 elements protect a CpG island from de novo methylation
.
Nature
.
1994
;
371
(
6496
):
435
8
.
53.
Gao
XF
,
Li
QL
,
Li
HL
,
Zhang
HY
,
Su
JY
,
Wang
B
, et al
Extracts from Curcuma zedoaria inhibit proliferation of human breast cancer cell MDA-MB-231 in vitro
.
Evid Based Complement Alternat Med
.
2014
;
2014
:
730678
.
54.
Maier
T
,
Güell
M
,
Serrano
L
.
Correlation of mRNA and protein in complex biological samples
.
FEBS Lett
.
2009
;
583
(
24
):
3966
73
.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.