Introduction: Anemia is a risk factor for all-cause mortality in older adults. Iron deficiency may also be associated with adverse outcomes, independent of its role in causing anemia. This study tested the hypotheses that anemia, and low ferritin among non-anemic participants, were associated with all-cause and cause-specific mortality in a community-based cohort of older adults. Methods: Fasting blood was obtained from 5,070 ARIC participants (median age: 75 years) in 2011–2013. Anemia was defined by hemoglobin concentrations <12 g/dL in women and <13 g/dL in men. We classified 4,020 non-anemic participants by quartiles of plasma ferritin, measured by the SomaScan proteomics platform. Cox proportional hazards regression was used. Mortality was ascertained via phone calls with proxies as part of twice-yearly cohort follow-up, surveillance of local hospital discharge indexes, state death records, and linkage to the National Death Index. Results: Of the total participants, 21% had anemia at baseline. Over a median of 7.5 years, there were 1,147 deaths, including 357 due to cardiovascular disease (CVD), 302 to cancer, and 132 to respiratory disease. Compared to those with normal hemoglobin, participants with anemia had a higher risk of all-cause mortality (hazard ratio 1.81 [95% CI: 1.60–2.06]), and mortality due to CVD (1.77 [1.41–2.22]), cancer (1.81 [1.41–2.33]), and respiratory disease (1.72 [1.18–2.52]) in demographics-adjusted models. In fully adjusted models, associations with all-cause mortality (1.37 [1.19–1.58]) and cause-specific mortality were attenuated. In non-anemic participants, lower ferritin levels were not associated with all-cause or cause-specific mortality, though associations were observed among participants with lesser evidence of inflammation (CRP below the median level of 1.9 mg/L) and for cancer mortality in men only. Conclusion: Anemia is common among older adults and is associated with all-cause mortality, as well as mortality due to CVD, cancer, and respiratory disease. Our results do not provide evidence that iron deficiency, independent of anemia, is associated with mortality in this population.

1.
Guralnik
JM
,
Eisenstaedt
RS
,
Ferrucci
L
,
Klein
HG
,
Woodman
RC
.
Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia
.
Blood
.
2004
;
104
(
8
):
2263
8
.
2.
Le
CH
.
The prevalence of anemia and moderate-severe anemia in the US population (NHANES 2003-2012)
.
PLoS One
.
2016
;
11
(
11
):
e0166635
.
3.
Hsu
HS
,
Li
CI
,
Liu
CS
,
Lin
CC
,
Huang
KC
,
Li
TC
, et al
.
Iron deficiency is associated with increased risk for cardiovascular disease and all-cause mortality in the elderly living in long-term care facilities
.
Nutrition
.
2013
;
29
(
5
):
737
43
.
4.
Philip
KEJ
,
Sadaka
AS
,
Polkey
MI
,
Hopkinson
NS
,
Steptoe
A
,
Fancourt
D
.
The prevalence and associated mortality of non-anaemic iron deficiency in older adults: a 14 years observational cohort study
.
Br J Haematol
.
2020
;
189
(
3
):
566
72
.
5.
Schrage
B
,
Rübsamen
N
,
Schulz
A
,
Münzel
T
,
Pfeiffer
N
,
Wild
PS
, et al
.
Iron deficiency is a common disorder in general population and independently predicts all-cause mortality: results from the Gutenberg health study
.
Clin Res Cardiol
.
2020
;
109
(
11
):
1352
7
.
6.
Stahl-Gugger
A
,
de Godoi Rezende Costa Molino
C
,
Wieczorek
M
,
Chocano-Bedoya
PO
,
Abderhalden
LA
,
Schaer
DJ
, et al
.
Prevalence and incidence of iron deficiency in European community-dwelling older adults: an observational analysis of the DO-HEALTH trial
.
Aging Clin Exp Res
.
2022
;
34
(
9
):
2205
15
.
7.
Thein
M
,
Ershler
WB
,
Artz
AS
,
Tecson
J
,
Robinson
BE
,
Rothstein
G
, et al
.
Diminished quality of life and physical function in community-dwelling elderly with anemia
.
Medicine
.
2009
;
88
(
2
):
107
14
.
8.
Kabat
GC
,
Kim
MY
,
Verma
AK
,
Manson
JE
,
Lessin
LS
,
Kamensky
V
, et al
.
Association of hemoglobin concentration with total and cause-specific mortality in a cohort of postmenopausal women
.
Am J Epidemiol
.
2016
;
183
(
10
):
911
9
.
9.
Han
SV
,
Park
M
,
Kwon
YM
,
Yoon
HJ
,
Chang
Y
,
Kim
H
, et al
.
Mild anemia and risk for all-cause, cardiovascular and cancer deaths in apparently healthy elderly Koreans
.
Korean J Fam Med
.
2019
;
40
(
3
):
151
8
.
10.
Wouters
HJCM
,
van der Klauw
MM
,
de Witte
T
,
Stauder
R
,
Swinkels
DW
,
Wolffenbuttel
BHR
, et al
.
Association of anemia with health-related quality of life and survival: a large population-based cohort study
.
Haematologica
.
2019
;
104
(
3
):
468
76
.
11.
Paul
BT
,
Manz
DH
,
Torti
FM
,
Torti
SV
.
Mitochondria and Iron: current questions
.
Expert Rev Hematol
.
2017
;
10
(
1
):
65
79
.
12.
Beard
JL
.
Iron biology in immune function, muscle metabolism and neuronal functioning
.
J Nutr
.
2001
;
131
(
2S-2
):
568S
80S
; discussion 80S.
13.
Silvestre
OM
,
Gonçalves
A
,
Nadruz
W
,
Claggett
B
,
Couper
D
,
Eckfeldt
JH
, et al
.
Ferritin levels and risk of heart failure-the atherosclerosis risk in communities study
.
Eur J Heart Fail
.
2017
;
19
(
3
):
340
7
.
14.
Rössler
J
,
Schoenrath
F
,
Seifert
B
,
Kaserer
A
,
Spahn
GH
,
Falk
V
, et al
.
Iron deficiency is associated with higher mortality in patients undergoing cardiac surgery: a prospective study
.
Br J Anaesth
.
2020
;
124
(
1
):
25
34
.
15.
Guedes
M
,
Muenz
DG
,
Zee
J
,
Bieber
B
,
Stengel
B
,
Massy
ZA
, et al
.
Serum biomarkers of iron stores are associated with increased risk of all-cause mortality and cardiovascular events in nondialysis CKD patients, with or without anemia
.
J Am Soc Nephrol
.
2021
;
32
(
8
):
2020
30
.
16.
Fishbane
S
,
Pollack
S
,
Feldman
HI
,
Joffe
MM
.
Iron indices in chronic kidney disease in the national health and nutritional examination survey 1988-2004
.
Clin J Am Soc Nephrol
.
2009
;
4
(
1
):
57
61
.
17.
Klip
IT
,
Comin-Colet
J
,
Voors
AA
,
Ponikowski
P
,
Enjuanes
C
,
Banasiak
W
, et al
.
Iron deficiency in chronic heart failure: an international pooled analysis
.
Am Heart J
.
2013
;
165
(
4
):
575
82.e3
.
18.
Nickol
AH
,
Frise
MC
,
Cheng
HY
,
McGahey
A
,
McFadyen
BM
,
Harris-Wright
T
, et al
.
A cross-sectional study of the prevalence and associations of iron deficiency in a cohort of patients with chronic obstructive pulmonary disease
.
BMJ Open
.
2015
;
5
(
7
):
e007911
.
19.
Jankowska
EA
,
Tkaczyszyn
M
,
Suchocki
T
,
Drozd
M
,
von Haehling
S
,
Doehner
W
, et al
.
Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials
.
Eur J Heart Fail
.
2016
;
18
(
7
):
786
95
.
20.
Salah
HM
,
Savarese
G
,
Rosano
GMC
,
Ambrosy
AP
,
Mentz
RJ
,
Fudim
M
.
Intravenous iron infusion in patients with heart failure: a systematic review and study-level meta-analysis
.
ESC Heart Fail
.
2023
;
10
(
2
):
1473
80
.
21.
Dignass
A
,
Farrag
K
,
Stein
J
.
Limitations of serum ferritin in diagnosing iron deficiency in inflammatory conditions
.
Int J Chronic Dis
.
2018
;
2018
:
9394060
.
22.
Wright
JD
,
Folsom
AR
,
Coresh
J
,
Sharrett
AR
,
Couper
D
,
Wagenknecht
LE
, et al
.
The ARIC (Atherosclerosis risk in Communities) study: JACC focus seminar 3/8
.
J Am Coll Cardiol
.
2021
;
77
(
23
):
2939
59
.
23.
Gold
L
,
Ayers
D
,
Bertino
J
,
Bock
C
,
Bock
A
,
Brody
EN
, et al
.
Aptamer-based multiplexed proteomic technology for biomarker discovery
.
PLoS One
.
2010
;
5
(
12
):
e15004
.
24.
Kraemer
S
,
Vaught
JD
,
Bock
C
,
Gold
L
,
Katilius
E
,
Keeney
TR
, et al
.
From SOMAmer-based biomarker discovery to diagnostic and clinical applications: a SOMAmer-based, streamlined multiplex proteomic assay
.
PLoS One
.
2011
;
6
(
10
):
e26332
.
25.
Candia
J
,
Cheung
F
,
Kotliarov
Y
,
Fantoni
G
,
Sellers
B
,
Griesman
T
, et al
.
Assessment of variability in the SOMAscan assay
.
Sci Rep
.
2017
;
7
(
1
):
14248
.
26.
Raffield
LM
,
Dang
H
,
Pratte
KA
,
Jacobson
S
,
Gillenwater
LA
,
Ampleford
E
, et al
.
Comparison of proteomic assessment methods in multiple cohort studies
.
Proteomics
.
2020
;
20
(
12
):
e1900278
.
27.
Inker
LA
,
Eneanya
ND
,
Coresh
J
,
Tighiouart
H
,
Wang
D
,
Sang
Y
, et al
.
New creatinine- and cystatin C-based equations to estimate GFR without race
.
N Engl J Med
.
2021
;
385
(
19
):
1737
49
.
28.
Kadoglou
NPE
,
Biddulph
JP
,
Rafnsson
SB
,
Trivella
M
,
Nihoyannopoulos
P
,
Demakakos
P
.
The association of ferritin with cardiovascular and all-cause mortality in community-dwellers: the English longitudinal study of ageing
.
PLoS One
.
2017
;
12
(
6
):
e0178994
.
29.
Zakai
NA
,
Katz
R
,
Hirsch
C
,
Shlipak
MG
,
Chaves
PH
,
Newman
AB
, et al
.
A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the cardiovascular health study
.
Arch Intern Med
.
2005
;
165
(
19
):
2214
20
.
30.
Penninx
BW
,
Pahor
M
,
Woodman
RC
,
Guralnik
JM
.
Anemia in old age is associated with increased mortality and hospitalization
.
J Gerontol A Biol Sci Med Sci
.
2006
;
61
(
5
):
474
9
.
31.
Wangping
J
,
Ke
H
,
Shengshu
W
,
Yang
S
,
Shanshan
Y
,
Wenzhe
C
, et al
.
Associations between anemia, cognitive impairment, and all-cause mortality in oldest-old adults: a prospective population-based cohort study
.
Front Med
.
2021
;
8
:
613426
.
32.
Wu
CY
,
Hu
HY
,
Chou
YJ
,
Huang
N
,
Chou
YC
,
Li
CP
.
What constitutes normal hemoglobin concentrations in community-dwelling older adults
.
J Am Geriatr Soc
.
2016
;
64
(
6
):
1233
41
.
33.
Palmer
SC
,
Navaneethan
SD
,
Craig
JC
,
Johnson
DW
,
Tonelli
M
,
Garg
AX
, et al
.
Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease
.
Ann Intern Med
.
2010
;
153
(
1
):
23
33
.
34.
Gao
S
,
Ma
JJ
,
Lu
C
.
Venous thromboembolism risk and erythropoiesis-stimulating agents for the treatment of cancer-associated anemia: a meta-analysis
.
Tumour Biol
.
2014
;
35
(
1
):
603
13
.
35.
Patel
KV
,
Harris
TB
,
Faulhaber
M
,
Angleman
SB
,
Connelly
S
,
Bauer
DC
, et al
.
Racial variation in the relationship of anemia with mortality and mobility disability among older adults
.
Blood
.
2007
;
109
(
11
):
4663
70
.
36.
Denny
SD
,
Kuchibhatla
MN
,
Cohen
HJ
.
Impact of anemia on mortality, cognition, and function in community-dwelling elderly
.
Am J Med
.
2006
;
119
(
4
):
327
34
.
37.
Dong
X
,
Mendes de Leon
C
,
Artz
A
,
Tang
Y
,
Shah
R
,
Evans
D
.
A population-based study of hemoglobin, race, and mortality in elderly persons
.
J Gerontol A Biol Sci Med Sci
.
2008
;
63
(
8
):
873
8
.
38.
Jankowska
EA
,
von Haehling
S
,
Anker
SD
,
Macdougall
IC
,
Ponikowski
P
.
Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives
.
Eur Heart J
.
2013
;
34
(
11
):
816
29
.
You do not currently have access to this content.