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. 2011 Sep 16;219(5):574–581. doi: 10.1111/j.1469-7580.2011.01423.x

Changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging

Sonal R Tuljapurkar 1,*, Timothy R McGuire 2,*, Susan K Brusnahan 1,3, John D Jackson 4, Kevin L Garvin 5, Margaret A Kessinger 6, Judy T Lane 7, Barbara J O' Kane 1, John G Sharp 1
PMCID: PMC3191309  NIHMSID: NIHMS316260  PMID: 21923862

Abstract

Hematological deficiencies increase with aging, including anemias, reduced responses to hematopoietic stress and myelodysplasias. This investigation tested the hypothesis that increased bone marrow (BM) fat content in humans with age was associated with decreased numbers of side population (SP) hematopoietic stem cells, and this decrease correlated with changes in cytokine levels. BM was obtained from the femoral head and trochanteric region of the femur removed at surgery for total hip replacement (N = 100 subjects). In addition, BM from cadavers (N = 36), with no evidence of hip disease, was evaluated for fat content. Whole trabecular marrow samples were ground in a sterile mortar and pestle, and cellularity and lipid content determined. Marrow cells were stained with Hoechst dye and SP profiles were acquired. Plasma levels of insulin-like growth factor (IGF)-1, stromal-derived factor (SDF)-1 and interleukin (IL)-6 were measured using ELISA. Fat content in the BM of human subjects and cadavers increased with age. The numbers of SP stem cells in BM as well as plasma IGF-1 and SDF-1 levels decreased in correlation with increased BM fat. IL-6 had no relationship to changes in marrow fat. These data suggest that increased BM fat may be associated with a decreased number of SP stem cells and IGF-1 and SDF-1 levels with aging. These data further raise a more general question as to the role of adipose cells in the regulation of tissue stem cells.

Keywords: adipocytes, aging, bone marrow, cytokines, stem cells

Introduction

Side population (SP) hematopoietic stem cell (HSC) numbers decline in the bone marrow (BM) as individuals age (Garvin et al. 2007; Brusnahan et al. 2010). This decline may be associated with the increased frequency of anemias, myelodysplasias and other hematopoietic disorders that are seen in the elderly (Guralnik et al. 2005).

Neumann (1882) reported that active hematopoietic (red) BM declined with age, and converted to fatty (yellow) marrow from the periphery towards the axial skeleton. This has been referred to as Neumann's law (Tavassoli, 1989). Both the causes and consequences of this change are uncertain, as is the role of fat in the BM regulation (Gimble et al. 1996). The postulates of this role range from being passive space filler to having an active regulatory role (Gimble et al. 1996). Increased fat content within BM exposes the elderly to fracture risk beyond that associated with low bone mineral density alone (Kuk et al. 2009). In addition to hematological effects, information on the changing distribution of marrow fat with aging is of potential relevance to orthopedic surgical procedures, as there is evidence that fractures involving sites of yellow marrow heal less readily than sites at which the medullary cavity contains red marrow (Rosen et al. 2009) and, therefore, may require more support or longer healing times (Friedl et al. 2009). Patients with osteoporosis commonly exhibit fatty infiltration in the BM (Parhami et al. 2000; Rodriguez et al. 2008), a condition possibly associated with increased fracture risk beyond that of low bone mineral density (Justesen et al. 2001).

Recently, Naveiras et al. (2009) reported that murine BM fat is inhibitory to HSC (Naveiras et al. 2009). The present investigation was devised to test in humans whether an increase in marrow fat with aging corresponded to a decline in the number of SP-HSC. Furthermore, the potential was evaluated that changes in marrow fat might be associated with differing levels of several cytokines that change with aging.

This proposed reciprocal relationship of marrow fat and hematopoiesis was evaluated by quantitating femoral BM fat content, together with multipotent SP stem cells, at two adjacent sites, the femoral head and trochanteric region of the diaphysis in subjects undergoing elective hip replacement surgery. Furthermore, the hematopoietic status of these subjects was evaluated together with interleukin (IL)-6, stromal-derived factor (SDF)-1 and insulin-like growth factor (IGF)-1 cytokine levels. IL-6 is elevated in the elderly, especially frail elderly, and also mobilizes HSC from the marrow to the blood (Maggio et al. 2006), and may correlate with increases in marrow fat. SDF-1 is a chemoattractant for stem cells (Hattori et al. 2001). IGF-1 levels decrease with age, and this growth factor is implicated in skeletal maintenance (Zofkova, 2003) and cardiovascular health (Ungvari et al. 2010). Also, in an attempt to exclude the possibility of hip problems in the living subjects contributing to the observations, cadaver subjects with no history, or evidence, of hip disease, were analyzed grossly and histologically for changes in fat content for comparison to the living subjects enrolled in this investigation.

Materials and methods

Human subjects

These studies enrolled adults undergoing elective hip replacement surgery in this Institutional Review Board-approved research study. The subjects were predominantly Caucasian and approximately equal in male : female ratio, and were in the age range of 27–87 years (median and mean age was 61 years). The subjects provided signed informed consent and had no complicating factors such as intercurrent infection. Subjects with a diagnosis of avascular necrosis, any anatomical BM condition, a history of malignancy, or any previous chemotherapy or radiation therapy were excluded from the study. An InnoMed drill bit was used to obtain a core sample of the medullary cavity and surrounding bone of the excised femoral head and diaphysis at the level of the trochanteric processes (Garvin et al. 2007). These cores were termed the femoral (F) and trochanteric (T) samples (Garvin et al. 2007; Fig. 1A). In order to exclude the possibility that disease might be the cause of changes, cadaver subjects with no evidence of hip disease were also studied.

Fig. 1.

Fig. 1

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(A) Core sample processing. During the surgical procedure, an InnoMed drill bit was employed to obtain a core sample of medullary cavity bone of the femoral head and the femoral diaphysis at the level of the trochanteric processes. Subsequently, these were termed as the femoral (F) and trochanteric (T) samples. These were pulverized using a mortar and pestle to generate a cell suspension. Each sample was photographed digitally to measure the extent of the supernatant fat layer along with the total depth of the samples. This allowed calculation of the amount (mm g−1) of fat in the sample, which was plotted vs. the age of the subject. On the left is a sample obtained from a 29 year old, in the center from a 61 year old and on the right from an 87 year old. There was greater amount of fat in the femoral head samples (yellow brackets) compared with the trochanteric samples (white brackets). (B) Cross-section of cadaver bone sample. Typical cross-sections of the proximal femur and femoral head cadaver subjects of a range of ages were obtained. On the left is the sample from a 22-year-old cadaver showing mostly red marrow. In the center is a 68-year-old cadaver sample with fatty infiltration in the femoral head (yellow arrow) as compared with the trochanteric region (white arrow). Rightmost is the sample from an 86-year-old cadaver depicting entirely fatty marrow. There was generally more marrow fat accumulated in the femoral head as compared with the trochanteric region.

Cadaver subjects

Subjects of age range between 22 and 110 years who had donated their bodies to the Nebraska Anatomical Board for education and research purposes were employed with the permission of the Anatomical Board of the State of Nebraska. Each cadaver was examined in the region of each hip for signs of a surgical scar, the area was checked by using a metal-detecting ‘wand’ for the absence of metal prostheses, and brief histories of the subjects from their physician and the death certificate were checked to ensure there was no evidence of malignancies of bone or hip disease. The proximal femur was dissected and divided along its central longitudinal axis. The internal surface of each half was photographed employing a high-resolution digital camera (Fig. 1B). A circular graticule of fixed size and a diameter slightly smaller than that of the femoral head or the femoral diaphysis at the level of the trochanters was superimposed on the pictures of the medullary cavity of the femoral head and in the region of the trochanteric processes of the embalmed cadavers. The areas of deep red-brown marrow, yellow marrow and intermediate areas were estimated independently by three observers and tabulated. The intermediate areas were arbitrarily proportioned into half red and half yellow marrow. The total estimated amount of yellow marrow on a scale of 0–100% was plotted against the age of the subjects.

Processing of the medullary cores

Each sample was weighed on a scale and then placed in Hank's balanced salt solution (Invitrogen, Carlsbad, CA, USA) without Ca or Mg, containing 20% fetal bovine serum (Hyclone, Logan, UT, USA), 13.5 μg mL−1 DNAse, (Sigma-Aldrich, St Louis, MO, USA) and 10 U mL−1 sodium heparin (Elkins-Sinn, Cherry Hill, NJ, USA), and pulverized using a mortar and pestle to generate a cell suspension that was then transferred to a 50-mL polypropylene tube (Sarstedt). Each sample was photographed digitally and the depth of the supernatant fat layer measured along with the total depth of the samples (illustrated in Fig. 1A). On the left is the sample obtained from a 29 year old, in the center is a 61 year old and on the right is an 87-year-old female (Fig. 1A). This allowed calculation of the amount (mm g−1) of fat in the sample that was plotted against the age of the subject. The fat layer was removed for the analysis of mesenchymal stromal cell content, and the remaining cells separated with a ficoll gradient to obtain mononuclear cells. A sample of these cells was analyzed as described previously (Goodell et al. 1996), to enumerate the multipotent SP stem cell content. Analysis was performed by flow cytometry using a dual-laser FACSAria (Becton-Dickinson, San Jose, CA, USA). The Hoechst-33342-stained cells were excited at 354 nm (UV), and emission fluorescence measured at 675 nm (red, 675/20 bp filter) and 440 nm (blue, 440/40 bp filter) wavelengths. Emissions were separated using a 505-nm-long pass dichroic mirror and data analyzed on linear axes.

The distribution of marrow fat with age in the living subjects and cadaver subjects was compared and averaged. The distributions with age were compared, and the best fit line to these values tested for linearity at a significance level of P ≤ 0.05. Evidence for a hematological effect was sought by examining red cell, white cell and platelet counts, and effects on HSC determined by plotting the number of SP cells against the extent of BM fat. To determine if the BM fat might be associated with changes in the levels of IGF-1, SDF-1 and IL-6, individual values for femur fat and the cytokine levels were compared for each subject. The hematological parameters were obtained from pre-surgical blood samples and plasma cytokine levels were measured by ELISA (R&D Systems, Minneapolis, USA).

IGF-1

Twenty microliters of plasma was diluted 1 : 100 with acidified buffer to allow dissociation of IGF-1 from plasma proteins. The dynamic range of the assay was between 0.025 ng mL−1 and 6 ng mL−1, with inter-assay and intra-assay coefficient of variation below 10%. Concentrations of IGF-1 in plasma were calculated from the standard curve to account for the 1 : 100 dilution.

SDF-1

One-hundred microliters of plasma was analyzed for SDF-1 concentrations. The dynamic range of the assay was between 10 pg mL−1 and 10 ng mL−1, with inter-assay and intra-assay coefficient of variation below 10%.

IL-6

One-hundred microliters of plasma was analyzed for IL-6 concentrations. The dynamic range of the assay was between 0.7 pg mL−1 and 300 pg mL−1. Concentrations of IL-6 that exceeded the upper limit of the assay were diluted 1 : 4 and re-analyzed. The lower limit of sensitivity was 0.7 pg mL−1, and inter-assay and intra-assay coefficient of variation was < 5%.

Statistics

A small number of assays failed quality control requirements, so variations in the number of subjects per assay occurred. Simple linear regression was used to analyze the trends in research covariates with age. The correlation coefficient (r) measures the strength of the linear relationship between two dependent variables, with positive values indicating a direct correlation and negative values an inverse correlation. Also, the r-value is inversely proportional to the variance in the data set.

The effect of low (< 1.0 mm g−1), intermediate (1.0–1.5 mm g−1) and high (> 1.5 mm g−1) trochanteric fat on corresponding trochanteric SP stem cell numbers was analyzed using Kruskall–Wallis with Dunn's multiple comparison test. Significant differences are noted in each figure, with statistical significance set at P ≤ 0.05.

Results

Previously it has been demonstrated by our group that SP HSC numbers decrease with an increase in age (Brusnahan et al. 2010). The present study evaluated if there were anatomical correlates to this observation. It was observed that changes in human BM fat content were associated with changes in HSC numbers and cytokine levels with aging.

Typical cross-sections of the proximal femur and femoral head of cadaver subjects of a range of ages are illustrated in Fig. 1B. On the left was a sample from a subject aged 22 years, which displayed red marrow throughout, with no evidence of a significant amount of fat. The sample on the right from an 86 year old showed the converse. The medullary cavity was occupied completely with yellow marrow, with no evidence of red marrow or hematopoiesis. The center sample, from a 68 year old, showed both red and yellow marrow, with the former especially evident in the area of the trochanters. The femoral head also showed red and yellow marrow, but the latter predominated, for example in the 68-year-old subject (arrows), as in the sample from the living subjects (Fig. 1). These observations indicate a more complex pattern of red/yellow BM distribution than previously suggested by ‘Neumann's law’.

The percentage of fat in both the femoral head and trochanteric BM samples obtained from cadavers increased with age (Fig. 2a,b; P< 0.01), and this was more pronounced in the femoral head as noted above (Fig. 1B).

Fig. 2.

Fig. 2

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Fat increased with age: cadaver samples. The percentage of marrow fat in both (a) femoral head and (b) trochanteric BM samples obtained from cadavers increased with age.

Evaluation of BM fat in living human subjects demonstrated that the fat in the femoral head as well as the trochanteric region, as measured in mm g−1 of sample, increased with age (Fig. 3a,b). The greater amount of yellow marrow in cadavers could be because there was a greater representation of older subjects and/or may relate to pre-mortem changes in the BM reflecting the health of subjects prior to their death. The hematological values for the living subjects were generally in the normal range for their age, and there was no evidence of serious anemias or disturbances of the white blood cell or platelet counts (data not shown).

Fig. 3.

Fig. 3

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Fat increased with age: living human subjects. Evaluation of BM fat in living human subjects demonstrated that fat in (a) the femoral head as well as (b) the trochanteric region, as measured in mm g−1 of sample, increased with age.

Previous studies have shown that the contribution of non-HSC populations to the SP is negligible (Goodell et al. 1996). Consequently, the SP content of the sample was considered a measure of the HSC content of the marrow sample. HSC numbers, as measured by SP analysis, were plotted against femur and trochanteric fat (mm g−1), as well as against age (years). There was a decrease in BM SP stem cells per 105 BM mononuclear cells as femur fat increased (P< 0.001) and with an increase in age (P< 0.001) (Fig. 4a). Also, SP HSC decreased with an increase in trochanteric fat (P< 0.05) as well as with increasing age (P< 0.05; Fig. 4b). It is important to mention that SP HSC were plotted against the average age of each group representing different fat levels.

Fig. 4.

Fig. 4

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Side population (SP) HSC per 105 mononuclear cells (MNC) declined with an increase in BM fat and increasing age. HSC as measured by SP analysis were plotted against femur and trochanteric fat (mm g−1) and age (years). (a) There was a decrease in SP stem cells as femur fat increased (P< 0.001), as well as with an increase in age (P< 0.001). Statistically significant differences for SP stem cells were between fat categories of 1.0 vs. 1.0–1.5 (P< 0.05) and < 1.0 vs. 1.5 (P< 0.01), and for age between fat categories of 1.0 vs. 1.0–1.5 (P< 0.05) and < 1.0 vs. > 1.5 (P< 0.001). (b) SP stem cells decreased with an increase in trochanteric fat (P< 0.05), as well as with increasing age (P< 0.05). Statistically significant differences for SP stem cells were between the fat categories of < 1.0 vs. 1.0–1.5 (P< 0.05), and for age between fat categories of < 1.0 vs. 1.0–1.5 (P< 0.05) and < 1.0 vs. > 1.5 (P< 0.05).

Previous studies have shown that plasma IGF-1 levels decline, whereas IL-6 levels increase with an increase in age (Brusnahan et al. 2010). In the present investigation, BM (femur and trochanter) fat amounts of living subjects were evaluated and plotted against plasma IGF-1, SDF-1 and IL-6 levels. At lower femur fat levels, IGF-1 levels were higher, with a statistical significance value of P< 0.01 (Fig. 5a), and so were plasma SDF-1 levels (P< 0.05; Fig. 6a), indicating an inverse association of IGF-1 and SDF-1 levels and femoral fat. However, both IGF-1 and SDF-1 plasma concentrations did not significantly change with increases in trochanteric fat amounts (Figs 5b and 6b). Unexpectedly, IL-6 levels were also not significantly altered in association with the increases in either femur or trochanteric fat (Fig. 7a,b).

Fig. 5.

Fig. 5

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Plasma insulin-like growth factor (IGF)-1 levels and BM fat. (a) Femur fat and (b) trochanteric fat amounts were plotted against plasma IGF-1 levels (ng mL−1). Plasma IGF-1 levels showed a significant decline with increases in femur fat (P< 0.01). However, there was no significant change observed in plasma IGF-1 levels with increases in trochanteric fat (P< 0.7).

Fig. 6.

Fig. 6

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Plasma stromal-derived factor (SDF)-1 levels and BM fat. Plasma SDF-1 levels were measured by ELISA and plotted against (a) femur fat and (b) trochanteric fat amounts. There was a significant decrease in plasma SDF-1 levels observed with an increase in femur fat (P< 0.05), but not with an increase in trochanteric fat (P< 0.3).

Fig. 7.

Fig. 7

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Plasma adipokine levels [interleukin (IL)-6] did not change with increases in BM fat. Plasma IL-6 levels were measured by ELISA and plotted against (a) femur fat and (b) trochanteric fat amounts. No significant differences were observed.

Discussion

The results of this study were generally consistent with previous observations, summarized by Tavassoli (1989), that the content of fat in the femoral BM in man increases with age. This was observed in subjects undergoing hip replacement surgery and confirmed in cadavers with no evidence of hip disease, so it is an intrinsic characteristic of BM with age. This was an important result, because osteoporosis is increased in areas of BM fat, and fractures of bones containing yellow marrow were slower to heal (Rosen et al. 2009). These results, however, expanded a strict interpretation of Neumann's law that the conversion of red to yellow marrow proceeded progressively from the periphery to the axial skeleton. In cadaver subjects aged 60–70 years, the marrow in the trochanteric region of the femoral diaphysis was primarily red, while the marrow of the femoral head had converted over to yellow, fatty marrow. However, the estimate of fat in the younger age group of cadaveric samples is likely an underestimate compared with that in the living subjects, because there will be scattered fat cells in the red marrow that were not detected in the photographs (compare Figs 3 and 4; 30–50 years age group). There is also considerable intrinsic variability between subjects, as indicated by r-values in Fig. 3. This anatomical distinction may be important, because the major blood supply to this area is from the nutrient arteries arising from the femoral circumflex artery, which penetrates the bone in the region of the trochanter. This area likely had more optimal blood supply compared with the femoral head. The femoral head is more distant and its blood supply is supplemented minimally and inconsistently by a small artery associated with the ligament to the femoral head. This anatomic design implicates the vascular supply as a possible etiological factor in the loss of red marrow with age. It has been shown that aging reduces skeletal blood flow (Prisby et al. 2007). Endothelial cell health is, in part, dependent on vitamin D, and low levels accentuate the increased risk of fractures of this area (Simon et al. 2002). Lahtinen et al. (1981) employed the Xenon-133 washout method to evaluate the effect of age on blood flow to the proximal femur in man (Lahtinen et al. 1981). Perfusion decreased significantly in older subjects, especially in the proximal femur in osteoporotic subjects. Marrow perfusion also decreased as marrow fat increased (Griffith et al. 2008). A similar association was noted in the lumbar spine (Griffith et al. 2006), raising the question of whether these blood flow changes are associated with accumulation of marrow fat. This study also showed that the numbers of SP stem cells in the BM were decreased as BM (femur and trochanter) fat increased in aging humans (Fig. 4a,b), similar to the situation documented in the mouse where authors looked at adipocytes content at different sites in the same animal and also manipulated adipocyte numbers by using mice with genetic defects (fatless mice) and mice treated to reduce numbers of adipocytes (Naveiras et al. 2009). Potentially, a direct regulatory interaction between HSC and fat may exist in the BM. Alternatively, an independent underlying cause, in the guise of declining blood flow, influencing both stem cell numbers and differentiation of mesenchymal precursor cells to adipocytes may exist. Although SDF-1, when injected acutely, mobilizes stem cells from the BM to the blood, there was no evidence that such effects were required for maintenance of hematopoiesis in the studied subjects, as their hematological parameters were stable. Recently, Povsic et al. (2010) demonstrated a decrease in more differentiated CD34 and CD133 stem cell numbers in the circulation with age, without any changes in BM stem cell numbers (Povsic et al. 2010). Similarly, Brusnahan et al. (2010) reported a decrease in blood SP HSC with age as well as a decrease in BM. It would be interesting to determine if these results are related to declining SDF-1 levels. The difference between SP HSC and CD34 and CD133 stem cells in BM could also arise because the latter amplify to compensate for the loss of the former cells. Although the extent of active red BM was declining and being replaced with fat, there was no evidence of these effects on steady state hematopoiesis in this study. This is consistent with previous observations of hematopoiesis in the elderly, that baseline hematopoiesis can generally be maintained, but responses to stress can be compromised. For example, a decrease in hematopoietic capacity could underlie the decreased ability of elderly subjects to react to hematological stress including bleeding and their increased sensitivity to chemotherapeutic agents (Chatta et al. 1994; Chatta & Dale, 1996; Balducci, 2001). The lost BM reserve may have been replaced by inactive yellow marrow. In this circumstance, a compensatory response to hematopoietic stress might take time, especially if the red marrow compartment has to expand as a component of the response. Potentially, these changes may be irreversible. This is worthy of further study.

In the current investigation, no correlation was observed between plasma IL-6 levels and the amount of femur or trochanteric fat. This was surprising because it was thought likely that IL-6 levels might correlate with increased marrow fat levels as this cytokine is an adipokine. This was not the case. Consequently, the source of increased levels of IL-6 in older adults is currently unclear, although muscle is a candidate tissue of origin (Petersen & Pedersen, 2005).

In conclusion, our results show that, as the content of BM fat increased, the number of BM SP stem cells decreased with age. This observation may not be a result of a direct cause and effect relationship. These changes might be associated with declining BM blood flow. IL-6 levels increased with age (Brusnahan et al. 2010), but this does not appear to be due to BM fat production of IL-6 and is not indicative of hematological stress. IGF-1 and SDF-1 levels decreased with increasing femoral fat (Figs 5a and 6a), but there was only a slight decline observed with an increase in trochanteric fat that did not reach statistical significance (Figs 5b and 6b). This could be due to the extent and delayed onset of fat accumulation in the trochanteric region as compared with the femoral head.

The mechanisms and consequences of declining hematopoietic reserve with age and its relationship to BM fat in the elderly deserves additional investigation, especially as this cohort in the population is increasing rapidly with significant consequences for health care costs. In addition, aging of many tissues such as muscle has been associated with an increase in adipogenic activity of myoblasts (Taylor-Jones et al. 2002) and their precursors (Thornell, 2010), and declines in functions of various tissues are associated with fatty degeneration. Consequently, the role of adipose cells as negative regulators of tissue stem cells, especially with age, merits further evaluation.

Acknowledgments

We thank the patients who consented to participate in these studies and the donors who gave their bodies for study. We thank Carol Lomneth, PhD, and the State of Nebraska Anatomical Board for access to this material. We thank Sydney Clausen for excellent technical assistance, and Jennifer Mobley and Tami Houdesheldt who typed the manuscript. We also thank the reviewers for their helpful comments that have been incorporated in the manuscript. These studies were supported in part by the National Institute of Aging (AG024912). This support is gratefully acknowledged. These studies were included as a component of the PhD thesis of S. Tuljapurkar, University of Nebraska Medical Center, April 2010.

Author's Contributions

S.R.T. and S.K.B. performed experiments; T.R.M. measured cytokine levels. J.D.J. and B.J.O. oversaw the hematopoietic assays and histology. K.L.G. is an orthopedic surgeon who obtained the samples. M.A.K. was the PI of IRB and advisor on the human stem cell assays. J.T.L. interviewed the subjects for history and lifestyle factors, and consented subjects for the study. S.R.T. and T.R.M. analyzed results and prepared the figures; J.G.S. designed the research and supervised the writing of the paper.

Conflict of Interest Disclosure

The authors declare no competing financial interests.

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