Aging and erythropoiesis: Current state of knowledge

doi:10.1016/j.bcmd.2008.04.005

Blood Cells, Molecules, and Diseases

Volume 41, Issue 2, September–October 2008, Pages 158-165

https://doi.org/10.1016/j.bcmd.2008.04.005 Get rights and content

Abstract

Many studies now document the high prevalence of anemia in the elderly and its association with poor outcomes. Study of these anemic patients reveals that in most cases the underlying abnormality is diminished erythropoieis. This analysis outlines some of the salient observations underlying the evolution of current concepts of how aging impacts erythropoiesis, and suggests areas for future exploration and research.

Introduction

There are now many studies documenting the high prevalence of anemia in the elderly [1] and its association with poor health outcomes. Even mild degrees of anemia in men and women 65 and older have been associated with significant morbidity, including frailty [2], decreased bone density [3], decreased skeletal muscle strength and density [4], decreased physical performance [5] and decline in physical performance over time [6], and increased mortality [7], [8]. Although these studies have not established causality, they do raise speculation as to the role that anemia plays in initiating or aggravating adverse clinical outcomes. While there is no uniformity of opinion regarding the importance or even existence of so-called “anemia of the aged”, increasing attention has focused on its widespread prevalence and clinical importance, including an agenda-setting conference co-sponsored by both the National Institute of Aging (NIA) and the American Society of Hematology [9] to address a “public health crisis in hematology” [10]. This issue is particularly important in light of the aging population: by the year 2030, men and women age 65 and older are estimated to comprise almost 20% of the total United States population, reaching almost 71 million persons [11].

When analyzed according to classical hematologic practice, most of the anemias in this setting turn out to be caused by defective or deficient red blood cell production, i.e. diminished erythropoiesis. Thus it becomes important to try to understand how aging impacts erythropoiesis, and where age-related defects in erythropoiesis may arise. Age-related changes in erythropoiesis can broadly be classified into two general mechanistic categories: 1) alterations intrinsic to erythroid progenitor or hematopoietic stem cells and/or the local hematopoietic microenvironment, and 2) alterations in humoral control mechanisms, particularly related to secretion of the hormone erythropoietin and possible deterioration of hypoxia-sensing mechanisms, but also other changes in the endocrine milieu. Understanding how each of these impacts erythropoiesis in the aging human has evolved concomitantly with the tools that have been available over the past century.

Section snippets

Marrow cellularity

When evaluated by a standard morphological approach, a decrease in overall hematopoietic tissue in the bone marrow, with a concomitant increase in adipose tissue, has been well known to occur with aging [12], [13]. However, these one-time static measurements, although lending themselves to speculation regarding important changes both in hematopoietic cellularity and the hematopoietic microenvironment, are potentially prone to sampling error. In addition, gross estimations of marrow cellularity

Erythropoietin levels

In adults, erythropoietin is produced primarily in the kidneys, and acts on the erythroid progenitors to prevent cell death [38], [39]. Basal erythropoietin levels are approximately 10-20 mU/ml [40] and the normal response to decreased oxygen tension in the blood is a logarithmic increase in erythropoietin levels upwards of 1000-fold over basal levels in the case of severe anemia [41]. In contrast, patients with renal disease have a blunted erythropoietin response to anemia [42], and worsening

Summary

The impact of aging on erythropoiesis can be viewed in the context of two general mechanistic categories: 1) alterations intrinsic to hematopoietic stem or erythroid progenitor cells and/or the local hematopoietic microenvironment, and 2) alterations in humoral control mechanisms. Despite major advances in understanding of human hematopoietic stem and erythroid progenitor cell biology in the past century, the available data regarding the impact of aging on these cell populations remain

Areas for future exploration

Potential areas for further exploration include the quantitative evaluation of hematopoietic stem cells, common myeloid progenitors and megakaryocyte–erythrocyte progenitors in young non-anemic, elderly non-anemic and elderly anemic populations. Elderly anemic populations could further be analyzed according to the etiology of the anemia, with a focus on those with unexplained anemia, who are most likely to demonstrate age-related defects in erythropoiesis. Careful studies could provide

Acknowledgments

Acknowledgments to Dr. Stanley L. Schrier and Dr. Linda Boxer for critical review of this manuscript.

References (131)

J.M. Guralnik et al.
Prevalence of anemia in persons 65 years and older in the United States: evidence for a high rate of unexplained anemia
Blood
(2004)
B.W. Penninx et al.
Anemia and decline in physical performance among older persons
Am. J. Med.
(2003)
S.L. Schrier
Hematology, ASH, and the anemia of the aged
Blood
(2005)
J.J. Marx
Normal iron absorption and decreased red cell iron uptake in the aged
Blood
(1979)
C.A. Baraldi-Junkins et al.
Hematopoiesis and cytokines. Relevance to cancer and aging
Hematol. Oncol. Clin. North. Am.
(2000)
D.A. Lipschitz et al.
Effect of age on hematopoiesis in man
Blood
(1984)
G.S. Chatta et al.
Effects of in vivo recombinant methionyl human granulocyte colony-stimulating factor on the neutrophil response and peripheral blood colony-forming cells in healthy young and elderly adult volunteers
Blood
(1994)
J.W. Adamson et al.
The kidney and erythropoiesis
Am. J. Med.
(1968)
H.W. Radtke et al.
Serum erythropoietin concentration in chronic renal failure: relationship to degree of anemia and excretory renal function
Blood
(1979)
M. Mori et al.
Serum erythropoietin titers in the aged
Mech. Ageing Dev.
(1988)

C.M. Bruno et al.

Circulating erythropoietin in microalbuminuric type 2 diabetic patients with normal renal function: a pilot study

J. Diabetes its Complicat.

(2006)

S.H. Ahn et al.

Low erythropoietin level can cause anemia in patients without advanced renal failure

Am. J. Med.

(2004)

Y.S. Yun et al.

Reduced erythropoietin responsiveness to anemia in diabetic patients before advanced diabetic nephropathy

Diabetes Res. Clin. Pract.

(1999)

K. Kojima et al.

Anemia due to reduced serum erythropoietin concentration in non-uremic diabetic patients

Diabetes Res. Clin. Pract.

(1995)

M.C. Thomas

The high prevalence of anemia in diabetes is linked to functional erythropoietin deficiency

Semin. Nephrol.

(2006)

M.C. Thomas et al.

Tubular changes in early diabetic nephropathy

Adv. Chronic. Kidney Dis.

(2005)

M.C. Thomas et al.

Low-molecular-weight AGEs are associated with GFR and anemia in patients with type 2 diabetes

Kidney Int.

(2004)

K. Obayashi et al.

Mechanism of anemia associated with autonomic dysfunction in rats

Auton. Neurosci.

(2000)

B.L. Ebert et al.

Regulation of the erythropoietin gene

Blood

(1999)

G.L. Semenza

Hypoxia-inducible factor 1: master regulator of O2 homeostasis

Curr. Opin. Genet. Dev.

(1998)

A. Rivard et al.

Age-dependent defect in vascular endothelial growth factor expression is associated with reduced hypoxia-inducible factor 1 activity

J. Biol. Chem.

(2000)

G. Frenkel-Denkberg et al.

The function of hypoxia-inducible factor 1 (HIF-1) is impaired in senescent mice

FEBS Lett.

(1999)

J.E. Morley et al.

Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men

Metabolism

(1997)

D.C. Cattran et al.

A controlled trial of nondrolone decanoate in the treatment of uremic anemia

Kidney Int.

(1977)

R. Alexanian

Erythropoietin and erythropoiesis in anemic man following androgens

Blood

(1969)

P.H. Chaves et al.

Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II

J. Gerontol., A, Biol. Sci. Med. Sci.

(2005)

M. Cesari et al.

Bone density and hemoglobin levels in older persons: results from the InCHIANTI study

Osteoporos. Int.

(2005)

M. Cesari et al.

Hemoglobin levels and skeletal muscle: results from the InCHIANTI study

J. Gerontol., A, Biol. Sci. Med. Sci.

(2004)

B.W. Penninx et al.

Anemia is associated with disability and decreased physical performance and muscle strength in the elderly

J. Am. Geriatr. Soc.

(2004)

N.A. Zakai et al.

A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study

Arch. Intern. Med.

(2005)

P.H. Chaves et al.

What constitutes normal hemoglobin concentration in community-dwelling disabled older women?

J. Am. Geriatr. Soc.

(2004)

J.M. Guralnik et al.

Anemia in the elderly: a public health crisis in hematology

Hematol. Am. Soc. Hematol. Educ. Program

(2005)

U.S. Interim Projections by Age, Sex, Race, and Hispanic Origin...

R.J. Hartsock et al.

Normal variations with aging of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. A study made from 177 cases of sudden death examined by necropsy

Am. J. Clin. Pathol.

(1965)

J. Justesen et al.

Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis

Biogerontology

(2001)

R.L. Huff et al.

Plasma and red cell iron turnover in normal subjects and in patients having various hematopoietic disorders

J. Clin. Invest.

(1950)

C.A. Finch et al.

Ferrokinetics in man

Medicine (Baltimore)

(1970)

F. Hosain et al.

Blood ferrokinetics in normal man

J. Clin. Invest.

(1967)

R.S. Hillman et al.

Control of marrow production by the level of iron supply

J. Clin. Invest.

(1969)

C. Ricketts et al.

Ferrokinetics and erythropoiesis in man: an evaluation of ferrokinetic measurements

Br. J. Haematol.

(1977)

J.J. Marx et al.

Ferrokinetics and red cell iron uptake in old age: evidence for increased liver iron retention?

Haematologica

(1982)

T.R. Bradley et al.

The growth of mouse bone marrow cells in vitro

Aust. J. Exp. Biol. Med. Sci.

(1966)

Y. Hirota et al.

Haematopoiesis in the aged as studied by in vitro colony assay

Eur. J. Haematol.

(1988)

H. Nilsson-Ehle et al.

Bone marrow progenitor cell growth and karyotype changes in healthy 88-year-old subjects

Eur. J. Haematol.

(1995)

K. Sudo et al.

Age-associated characteristics of murine hematopoietic stem cells

J. Exp. Med.

(2000)

S.J. Morrison et al.

The aging of hematopoietic stem cells

Nat. Med.

(1996)

D.J. Rossi et al.

Cell intrinsic alterations underlie hematopoietic stem cell aging

Proc. Natl. Acad. Sci. U. S. A.

(2005)

D.J. Pearce et al.

Age-dependent increase in side population distribution within hematopoiesis: implications for our understanding of the mechanism of aging

Stem Cells

(2007)

S.M. Chambers et al.

Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation

PLoS Biol.

(2007)

S.M. Chambers et al.

Hematopoietic stem cell aging: wrinkles in stem cell potential

Stem Cell Rev.

(2007)

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ReviewAging and erythropoiesis: Current state of knowledge

Abstract

Introduction

Section snippets

Marrow cellularity

Erythropoietin levels

Summary

Areas for future exploration

Acknowledgments

Blood

Am. J. Med.

Blood

Blood

Hematol. Oncol. Clin. North. Am.

Blood

Blood

Am. J. Med.

Blood

Mech. Ageing Dev.

J. Diabetes its Complicat.

Am. J. Med.

Diabetes Res. Clin. Pract.

Diabetes Res. Clin. Pract.

Semin. Nephrol.

Adv. Chronic. Kidney Dis.

Kidney Int.

Auton. Neurosci.

Blood

Curr. Opin. Genet. Dev.

J. Biol. Chem.

FEBS Lett.

Metabolism

Kidney Int.

Blood

Impact of anemia and cardiovascular disease on frailty status of community-dwelling older women: the Women's Health and Aging Studies I and II

J. Gerontol., A, Biol. Sci. Med. Sci.

Bone density and hemoglobin levels in older persons: results from the InCHIANTI study

Osteoporos. Int.

Hemoglobin levels and skeletal muscle: results from the InCHIANTI study

J. Gerontol., A, Biol. Sci. Med. Sci.

Anemia is associated with disability and decreased physical performance and muscle strength in the elderly

J. Am. Geriatr. Soc.

A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study

Arch. Intern. Med.

What constitutes normal hemoglobin concentration in community-dwelling disabled older women?

J. Am. Geriatr. Soc.

Anemia in the elderly: a public health crisis in hematology

Hematol. Am. Soc. Hematol. Educ. Program

Normal variations with aging of the amount of hematopoietic tissue in bone marrow from the anterior iliac crest. A study made from 177 cases of sudden death examined by necropsy

Am. J. Clin. Pathol.

Adipocyte tissue volume in bone marrow is increased with aging and in patients with osteoporosis

Biogerontology

Plasma and red cell iron turnover in normal subjects and in patients having various hematopoietic disorders

J. Clin. Invest.

Ferrokinetics in man

Medicine (Baltimore)

Blood ferrokinetics in normal man

J. Clin. Invest.

Control of marrow production by the level of iron supply

J. Clin. Invest.

Ferrokinetics and erythropoiesis in man: an evaluation of ferrokinetic measurements

Br. J. Haematol.

Ferrokinetics and red cell iron uptake in old age: evidence for increased liver iron retention?

Haematologica

The growth of mouse bone marrow cells in vitro

Aust. J. Exp. Biol. Med. Sci.

Haematopoiesis in the aged as studied by in vitro colony assay

Eur. J. Haematol.

Bone marrow progenitor cell growth and karyotype changes in healthy 88-year-old subjects

Eur. J. Haematol.

Age-associated characteristics of murine hematopoietic stem cells

J. Exp. Med.

The aging of hematopoietic stem cells

Nat. Med.

Cell intrinsic alterations underlie hematopoietic stem cell aging

Proc. Natl. Acad. Sci. U. S. A.

Age-dependent increase in side population distribution within hematopoiesis: implications for our understanding of the mechanism of aging

Stem Cells

Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation

PLoS Biol.

Review
Aging and erythropoiesis: Current state of knowledge