MARROW ADIPOSITY AND HEMATOPOIESIS IN AGING AND OBESITY: EXERCISE AS AN INTERVENTION

Abstract

Purpose of Review

Changes in the bone marrow microenvironment, which accompany aging and obesity, including increased marrow adiposity, can compromise hematopoiesis. Here we review deleterious shifts in molecular, cellular and tissue activity, and consider the potential of exercise to slow degenerative changes associated with aging and obesity.

Recent Findings

While bone marrow hematopoietic stem cells (HSC) are increased in frequency and myeloid-biased with age, the effect of obesity on HSC proliferation and differentiation remains controversial. HSC from both aged and obese environment have reduced hematopoietic reconstitution capacity following bone marrow transplant. Increased marrow adiposity affects HSC function, causing up-regulation of myelopoiesis and down-regulation of lymphopoiesis. Exercise, in contrast, can reduce marrow adiposity and restore hematopoiesis.

Summary

The impact of marrow adiposity on hematopoiesis is determined mainly through correlations. Mechanistic studies are needed to determine a causative relationship between marrow adiposity and declines in hematopoiesis, which could aid in developing treatments for conditions that arise from disruptions in the marrow microenvironment.

Bone Marrow Microenvironment

Bone marrow is a multicellular tissue located in the cavity of bones, encased by trabecular and cortical bone. Vasculature in the bone marrow not only delivers nutrients to the marrow, but also carries blood cells born within the marrow out into systemic circulation [1]. The complex and dynamic microenvironment of the marrow supports formation and function of many different types of cells, including undifferentiated multipotent stem cells, cells at different developmental stages, and terminally differentiated cells. Two principal types of multipotent stem cells that reside in adult marrow are mesenchymal stem cells (MSC) and hematopoietic stem cells (HSC), each critical to the regenerative and inflammatory response of the organism.

MSC are capable of differentiating into bone forming cells (osteoblasts), adipocytes, chondrocytes, myocytes, fibroblasts and epithelial cells, in addition to self-renewal [2]. MSC have been shown to make up about 0.6–1% of the bone marrow in mice [3], a fraction which is much smaller in humans, ranging between 0.001–0.02% of total cells [4]. Although bone marrow has been considered the primary source of MSC, recent studies have found multipotent stem cells in other tissues as well, such as adipose tissue, liver, and pancreas [5–7]. While locally these resident MSC can aide in tissue repair and regeneration by differentiating into local tissue cell types, they have the potential to differentiate into any cell type from the mesenchymal lineage in-vitro, given the proper differentiation conditions [7, 8]. MSC fate selection in the body is susceptible to environmental cues and systemic insults, such that an obese environment can prompt MSC to differentiate into adipocytes and away from other cell types [9, 3, 10]. Biasing MSC differentiation towards adipogenesis in the obese state might have a negative impact systemically on bone health and marrow architecture [11, 12]. Due to close proximity in the marrow space, a disrupted MSC environment may ultimately influence HSC fate.

HSC are the primary source of all the blood and immune cells in the body. HSC can differentiate into red blood cells, platelets, and leukocytes [13]. A single multipotent HSC has the ability of reconstituting the whole adult bone marrow under systemic stress such as irradiation [14]. Multipotent HSC in the bone marrow exist as dormant cells, in a state of long-term quiescence, and only divide five times over their lifetime [15]. These long-term HSC comprise approximately 0.01–0.03% and 0.04% of the marrow cellularity in mice [16] and in humans [17], respectively. While HSC are continuously differentiating to maintain the body’s demand for various blood and immune cells, HSC differentiation is also impacted by systemic insults, such as severe blood loss, irradiation, infection, and chronic inflammation.

Hematopoiesis

The process by which long-term HSC replenish the blood and immune cells in the body is known as hematopoiesis. In healthy adults, there is a high turnover of blood and immune cells daily leading to continuous hematopoiesis in the marrow. Average lifespan of a red blood cell, erythrocyte, in the circulation after being released from the bone marrow is ~115 days in healthy adults [18]. Once these cells reach senescence, they are removed via phagocytosis, prompting the release of erythropoietin, which signals the bone marrow to produce close to 200 billion new erythrocytes daily [19]. Platelets have a shorter lifespan of ~8–10 days and there are close to one trillion platelets in circulation at all times, creating a high level of daily need for platelet production in the bone marrow [20, 21]. Lifespan for lymphocytes is more complex. The naïve B and T cells have a short lifespan in circulation of only a few days to a few weeks [22]. However, if these naïve cells come in contact with a foreign antigen, they get converted into effector or memory cells that can survive indefinitely [22]. Neutrophils have an average lifespan of a few hours to a few days, leading to ~50–100 billion neutrophils produced by the bone marrow daily [23, 24]. Eosinophils are primarily found in much larger quantities in tissues, such as gut, rather than in circulation [25]. Their average lifespan ranges from 2–5 days in tissue, however, it can increase to 14 days in the presence of increased levels of cytokines [25]. Basophils only make up about 0.5% of the cells in circulation under homeostatic conditions and their average lifespan is ~1–2 days [26]. Intravascular monocytes have a lifespan of ~4 days, whereas monocytes with an ability to extravasate in response to an inflammatory response have a lifespan of ~11 days [27]. Thus, bone marrow hematopoiesis is a dynamic process, producing billions of cells daily to meet the body’s demand for sustaining a healthy immune and circulatory system.

Traditionally, hematopoiesis is thought to be a tree-like hierarchical process, such that long-term HSC give rise to short-term multipotent progenitor cells (MPP), which then further segregate into either common lymphoid progenitor (CLP) or common myeloid progenitor (CMP) [19]. CLP gives rise to B cells, T cells and natural killer cells [19]. CMP further segregates into either megakaryocyte-erythroid progenitor (MEP), which can produce erythrocytes and platelets, or granulocyte-macrophage progenitor (GMP), which can produce macrophages, eosinophils, basophils, neutrophils and mast cells [19]. A recent study led by Velten, et al. challenges this notion [28]. Using flow cytometry, transcriptomic and functional data acquisition at single-cell resolution, this study shows that HSC and MPP are initially part of a continuum of low-primed undifferentiated hematopoietic stem and progenitor cells (CLOUD-HSPC), which is characterized as Lin⁻CD34⁺CD38⁻. Lineage restriction is only shown to begin with CD38 upregulation, when the stem cell modules and certain early priming modules are turned off and specific lineage modules are activated [28]. Thus, HSC differentiation in young adults is shown to be a continuous process, where cells in CLOUD-HSPC have the propensity to convert into any lineage (lymphoid, myeloid, megakaryocytic, or erythroid) without any binary branch points.

Various cells in the bone marrow niche can regulate hematopoiesis. MSC have been shown to support HSC growth, viability and hematopoiesis by secreting growth factors and cytokines such as stromal cell derived factor 1, stem cell factor, leukemia inhibitory factor, macrophage colony stimulating factor, osteopontin, interleukin 6, and interleukin 11 [29–31]. MSC also regulate immune cell behavior outside of the bone marrow by reducing proliferation of lymphocytes in-vivo and in-vitro, by prompting a change in macrophage polarity to secrete anti-inflammatory cytokine interleukin 10, and by modulating secretion of pro-inflammatory cytokines via TNF-α stimulated gene/protein 6 [32–34]. MSC-derived osteoblasts also regulate and support proliferation, maturation and activation of cells in the hematopoietic lineage by secreting granulocyte colony stimulating factor, macrophage colony stimulating factor, interleukin 1 and interleukin 6 [35]. In addition, osteoblasts play a major role in osteoclast proliferation and activation, and in attracting them to the mineralized surfaces to initiate bone resorption [36, 37]. Conversely, as shown in-vitro, osteoclasts can control osteoblast chemotaxis by platelet derived growth factor bb/platelet derived growth factor receptor β signaling [38]. Coupling between osteoblasts and osteoclasts mediates bone remodeling and aids in maintaining healthy bone phenotype. The osteoblasts embedded in the bone matrix, known as osteocytes, play a role in maintaining the osteoblast-osteoclast coupling [39]. Osteocytes also influence myelopoiesis in the bone marrow, potentially by Gsα-dependent signaling, which controls the production of granulocyte colony stimulating factor [40]. Hence, multiple cells in the bone marrow microenvironment closely regulate hematopoiesis to maintain a delicate balance between many cell types in the bone marrow, and ultimately, in circulation, at all times.

Marrow Adipose Tissue

Adipose tissue is functionally divided into brown adipose tissue (BAT) and white adipose tissue (WAT). BAT aids in heat production during early development and gradually gets replaced by WAT after birth [41]. WAT plays vital roles in temperature regulation and mechanical cushion, but its primary role is energy storage [42]. WAT located just underneath the skin is known as subcutaneous adipose tissue (SAT), whereas the WAT deposited in and around internal organs is known as visceral adipose tissue (VAT). In healthy individuals, a majority of WAT consists of SAT, which can promote adipogenesis to facilitate excess energy storage [43]. With high calorie intake, more energy gets stored in the form of VAT, which can impede normal functionality of internal organs such as liver, pancreas, kidneys, testes, intestines, and heart, and lead to metabolic syndrome [11]. Besides the abdominal and the thoracic cavities, adipose tissue can also be found in the bone marrow.

Marrow adipose tissue (MAT) has recently been of interest due to its proximity to stem and immune cells in the bone marrow. Under normal physiological conditions, while almost all of the bone marrow at birth consists of hematopoietic red bone marrow [44], by adulthood, 50% or more of the bone marrow gets occupied by the fatty yellow bone marrow [45]. MAT development starts in distal regions of the bone and moves proximally with time [46]. This has repeatedly been shown in rodents. In long bones, distal marrow is mostly yellow, while proximal marrow is mostly red; similarly, the caudal vertebrae have mainly yellow marrow, while the lumbar vertebrae mainly has red marrow [47–49].

A recent study by Scheller, et al. highlights region-specific differences in MAT using a murine model [49]. Distal MAT, which consists of densely packed adipocytes that resembles WAT and contains high levels of unsaturated lipids, is called constitutive MAT (cMAT). While proximal MAT, which consists of loosely dispersed adipocytes in the red marrow surrounded by cells in the hematopoietic lineage and contains high levels of saturated lipids, is called regulated MAT (rMAT). cMAT and rMAT have functional differences as well; for instance, cold exposure leads to 56–71% reduction in rMAT in tibial epiphysis and proximal tibia, and no loss of cMAT in distal tibia in mice, suggesting that rMAT might be more responsive to environmental cues [49].

The presence of MAT is not necessarily pathological and has been shown to have physiological functions. Cawthorn, et al. demonstrate that MAT increases in the initial stage of anorexia nervosa and secretes adiponectin, a protein shown to play a role in mitigating inflammation, atherosclerosis, and metabolic syndrome [50]. However, in the late stage of anorexia nervosa, MAT decreases, suggesting that MAT is utilized to account for calorie deficit [51]. Hence, in the presence of inadequate amount of WAT, MAT can serve as an energy depot. In addition, MAT might be playing a role in delaying metabolic syndrome as evident through congenital vs. acquired lipodystrophy. Congenital lipodystrophy is often paralleled by insulin resistance and type 2 diabetes, whereas the onset of these comorbidities is delayed in acquired lipodystrophy. Interestingly, patients with congenital lipodystrophy have reduced proportions of MAT, whereas MAT proportions are preserved in patients with acquired lipodystrophy [52]. MAT might also be aiding in preventing disuse-induced bone loss, such that genetic deficiency to produce MAT led to increased bone loss when the mice were subjected to hindlimb unloading, compared to wild-type mice [53]. The function of MAT is still not very well defined. The studies that show beneficial effects of MAT are comparing genetic deficiency to produce MAT with the presence of physiological levels of MAT. This redirects our attention to differences in cMAT vs rMAT as outlined by Scheller, et al. We hypothesize that the presence of cMAT might be necessary for normal physiological functions, however, increased accumulation of rMAT might still have pathological consequences since rMAT is located within the hematopoietic red marrow, which might disrupt function of surrounding cells in the marrow.

Effect of Aging and Obesity on Marrow Architecture and Hematopoiesis

Aging

Aging can adversely affect bone marrow microenvironment. In humans, bone marrow cellularity has been shown to decrease immensely between ages 80 and 100, partly due to increased apoptosis, and decreased lymphocytes and macrophage populations [54]. On the other hand, the number of HSC in the marrow increases with age in both mice and humans, partially due to reduced quiescence in the HSC population, which promotes cell proliferation [17, 55]. However, old HSC are functionally inferior to young HSC due to accumulation of oxidative stress, which reduces their capacity of self-renewal and of reconstituting the hematopoietic system [56]. Aging also leads to altered hematopoiesis. Aging leads to myeloid bias in the marrow, with increased proportion of myeloid progenitor cells and decreased proportion of lymphoid progenitor cells [17, 57]. To the contrary, the repopulation capacity of human HSC to generate myeloid population decreases with age, as confirmed by in-vivo transplantation in a murine model and in-vitro colony-forming assay [57]. Certainly, more studies are needed to determine the degree to which aging alters or compromises HSC function and potential.

Aging also leads to altered bone marrow microarchitecture with increased marrow adiposity [58–60]. There are gender-associated differences in MAT accumulation with aging. In females, MAT increases dramatically between the ages of 55 and 65, whereas in males, it increases gradually throughout the life [59]. Females over 60 years old have 10% higher MAT than males of the same age group [59]. Excessive fat content in the marrow with aging can limit space for other cells to grow and can also alter functionality of surrounding cells, such that the MSC in the fatty marrow might have reduced potential to support hematopoiesis [61].

Obesity

Obesity leads to bone marrow hyperplasia with ~20–30% increased marrow cellularity [62, 63]. Effect of obesity on long-term HSC and progenitor cells varies in diet-induced obesity (DIO) murine models. Eighteen weeks of 45% kcal from fat diet led to decreased HSC and HSPC population in the bone marrow, by reducing proliferation and promoting differentiation [64]. Six weeks of 60% kcal from fat diet did not alter bone marrow HSPC population as compared to regular diet controls [12]. Conversely, 12 weeks of 60% kcal from fat diet had increased HSC population in the bone marrow compared to controls [65]. The differences in the HSC and HSPC populations in DIO murine models might be due to different percentage of fat in the diet or due to the varying duration of high fat diet feeding. Further studies are needed to confirm the effect of obesity on HSC and HSPC populations in the bone marrow.

Obesity also promotes secretion of granulocyte colony stimulating factor and granulocyte macrophage colony stimulating factor in the bone marrow [63]. Consequently, most studies have shown increased myelopoiesis, and suppressed lymphopoiesis in bone marrow HSC during obesity [12, 65, 63, 11]. However, one study has shown increased lymphopoiesis and no significant change in myelopoiesis with 162 days of 45% kcal from fat diet [62]. In competitive bone marrow transplantation, HSC from obese mice have deteriorated multi-lineage reconstitution capacity [64]. Outside of the marrow, obesity creates a systemic chronic inflammatory state, leading to increased immune cell populations in circulation both in mice and in humans [66–68], immune cell influx to tissues in the visceral cavity, and pro-inflammatory cytokine release [5, 69, 70].

Obesity also leads to an aging-like shift in bone marrow microarchitecture, by increasing the proportion of marrow adiposity as shown in multiple murine models [71, 58, 12, 72, 73]. Six weeks of 60% kcal from fat diet led to 363% increase in MAT compared to regular diet control [12]. MAT proportion increased by 5-fold with a longer high fat diet feeding (12 weeks of 60% kcal from fat diet) [71]. This trend in MAT expansion with continued high-fat diet feeding is shown by Scheller, et al., where 12 week, 16 week, and 20 week of 60% kcal from fat diet feeding leads to approximately 3-fold, 5-fold, and 12-fold increase in MAT, respectively, in the proximal tibial metaphysis [72]. A less severe fat diet (45% kcal from fat) fed for 6 weeks led to 2.6-fold increase in MAT compared to controls [73]. Interestingly, MAT proportion reduces to the similar level as control mice following weight loss [72].

Effect of MAT on Hematopoiesis and Bone Remodeling

Increase in MAT, which parallels aging or obesity, adversely impacts hematopoiesis, due to HSC’s close interactions with other cells and tissues in the marrow space as summarized in Figure 1. Increased MAT has been shown to negatively correlate with plasma insulin-like growth factor 1 (IGF-1) and plasma stromal-derived factor 1 (SDF-1), as demonstrated in the bone marrow derived from the aged [60]. A similar trend is shown in obese women, where MAT is negatively correlated with IGF-1 and positively correlated with visceral adiposity [74]. IGF-1 has been shown to increase HSC engraftment following bone marrow transplantation in murine models, while also protecting HSC and HSPC from apoptosis and enhancing proliferation and differentiation of surviving cells [75, 76]. SDF-1 has been shown to promote hematopoietic reconstitution following lethal radiation and bone marrow transplantation [77, 78]. Thus, reduced level of IGF-1 and SDF-1, paralleled by increased MAT, can adversely affect HSC engraftment and hematopoiesis.

Figure 1.

Schematic summarizing the effect of marrow adiposity on hematopoiesis. Aging or obesity associated increase in marrow adiposity leads to elevated secretion of G-CSF, M-CSF, and GM-CSF, which subsequently results in elevated myelopoiesis (mediated by neutrophil elastase) and suppressed lymphopoiesis (mediated by IL-1). Marrow adipocytes can also secrete RANKL, which can prompt monocyte-macrophage progenitors towards osteoclasts. Osteoblasts then attract osteoclasts towards mineralized bone surfaces to initiate bone resorption, which can impair bone remodeling and bone health. [G-CSF – granulocyte colony stimulating factor, M-CSF – macrophage colony stimulating factor, GM-CSF – granulocyte macrophage colony stimulating factor, RANKL – receptor activator of nuclear factor kappa-B ligand, IL-1 – interleukin 1, HSC – hematopoietic stem cell, MSC – mesenchymal stem cell]

MAT has been shown to increase expression of receptor activator of nuclear factor kappa-B ligand (RANKL), osteoprotegerin, and macrophage colony stimulating factor, leading to increased osteoclast production, potentially suppressing other myeloid populations [79, 80]. In competitive bone marrow transplantation, animals with increased MAT showed reduced marrow cellularity and impaired hematopoietic reconstitution potential [58]. MAT is paralleled by reduced B lymphopoiesis, and increased myelopoiesis, as a precursor to systemic inflammation [12, 81]. MAT-induced depletion in B lymphopoiesis seems to be mediated by IL-1 since adding anti-IL-1 in bone marrow cultures in-vitro restores B lymphopoiesis [81]. Obesity-induced increased myelopoiesis seems to be mediated by secretion of neutrophil elastase, which gets up-regulated in response to high fat diet feeding [82]. Mice with neutrophil elastase deficiency had significantly reduced neutrophils and monocytes and significantly increased B-lymphocytes compared to wild type mice during obesity, not just in the bone marrow, but also in the blood and spleen [82].

A recent study by Walji, et al., studied the effect of MAT accumulation on hematopoiesis in microfilbril-associated glycoprotein-1 deficient (Mfap2^−/−) mice, that display excess adiposity, without increased calorie intake, impaired glucose metabolism or aging [83]. By 10 weeks of age, these mice had 5-fold expansion of MAT compared with wild-type (WT) controls. Interestingly, despite drastic increases in MAT, Mfap2^−/− mice did not have altered bone marrow cellularity compared to WT. However, increased MAT was paralleled by increased proportion of macrophages, myeloid-derived dendritic cells, and B cells and reduced proportion of neutrophils [83]. Data from this study is not consistent with previous studies that show reduced B lymphopoiesis and increased myelopoiesis in response to increased MAT. Further studies are needed to determine whether knocking out microfibril-associated glycoprotein-1 triggers other physiological responses beyond increased adiposity that might be interfering with hematopoiesis.

The effect of increased MAT on osteoblasts and osteocytes remains unclear. However, a recent study by Fairfield, et al. demonstrates in-vitro and in-vivo that sclerostin, a Wnt-inhibitory molecule secreted by osteocytes, may be mediating marrow adipogenesis [84]. Circulating sclerostin levels have been shown to correlate with increased vertebral MAT in older men, indicating a potential relationship between osteocytes and MAT [85]. Further studies need to be conducted to determine whether increase in marrow adiposity affects osteocyte and osteoblast quantity and/or function. On the other hand, MAT-associated increase in RANKL can promote osteoclastogenesis and differentiation of CFU macrophages into osteoclast lineage [79, 86]. The imbalance in osteoblast-osteoclast coupling with increased marrow adiposity can result in impaired bone remodeling, leading to reduced bone formation and increased bone resorption. Indeed, MAT expansion in humans has been associated with bone loss, reduced bone mineral density and increased risk of fracture, the characteristics of osteopenia and osteoporosis, despite correcting for multiple confounding variables such as age, sex, race, ethnicity, menopausal status, and fat composition [87, 88].

Exercise as a Countermeasure

Exercise and MAT

Exercise has been shown to suppress MAT expansion in both mice and humans. In a study led by Styner, et al., six weeks of voluntary running wheel exercise led to 50% reduction in MAT in a model of diet-induced obesity [89]. Similarly, in young female athletes, exercise increased bone marrow density, as a predictor of marrow adiposity, by 0.5% [90]. Reduction in MAT, following exercise, may partially be mediated by increased level of perilipin 3, which has been shown to play a role in β-oxidation of lipids and basal lipolysis [89, 91, 92]. MAT expansion following 60 days of bed rest in young men was prevented when subjects underwent resistance training during the bed rest [93]. As a surrogate for exercise, whole body vibration (WBV), delivered with accelerations of approximately 0.7g (g = Earth’s gravitational force, 9.81 m/s²), strengthened resistance training’s ability to suppress MAT expansion [93]. WBV could also be effective as a stand-alone treatment in preventing MAT expansion as evident by 55% reduction in MAT with 6 weeks of vibration treatment (0.3g acceleration, 90 Hz frequency) in an ovariectomy murine model [94]. MAT can be used as a predictor of bone strength since it correlates with strength strain index, cortical area, and bone mineral density [90]. Reduction in MAT is paralleled by increase in bone quality as evident by 19% increase in trabecular bone volume fraction, following 48% reduction in MAT [89].

Exercise and Hematopoiesis

Although not many studies have evaluated the effect of exercise on HSC and hematopoiesis, exercise has been shown to promote HSC differentiation and increase HSC progenitors in both the bone marrow and in circulation [95–97]. Baker, et al., showed 78% reduction in MAT, paralleled by 49% and 229% increase in colony forming cells in the bone marrow and blood, respectively, following 10 weeks of exercise in mice [95]. Eight weeks of exercise in mice has been shown to increase HSC population in the vascular bone marrow by 20%, paralleled by 48% increased cellularity in the spleen colonies [96]. Interestingly, HSPC show an adaptive response to exercise, such that runners have 3–4 fold higher level of circulating HSPC compared to sedentary people at rest [97]. Although exercise affects HSC proliferation and differentiation, it does not alter HSC engraftment, homing, and self-renewal potential after bone marrow transplantation [96]. Similar to exercise, WBV has also been shown to restore lymphopoiesis, as demonstrated by 32% and 57% increase in B cells in the bone marrow and in circulation, respectively, following 4 months of WBV treatment (0.2g acceleration, 90 Hz frequency), in a murine model of diet-induced obesity [11]. Outside of the bone marrow, WBV can also regulate inflammatory response in the adipose tissue as evident by reduction in B cell, T cell, and macrophage populations (16%, 22%, and 13%, respectively) during obesity (Figure 2) [5]. A positive correlation has been demonstrated between circulating blood and immune cells (white blood cells, red blood cells, and platelets) and bone mineral density in post-menopausal women, suggesting a relationship between hematopoiesis and bone health [98].

Figure 2.

Visceral adiposity and infiltration of immune cells in gonadal adipose tissue in a murine model of diet-induced obesity (45% kcal from fat diet) in adult male C57BL/6J mice. All mice were fed their respective diets for 2wk, followed by 6wk of low intensity vibration (LIV; 90Hz, 0.2g peak acceleration (g = Earth’s gravitational force), 5d/wk) treatment, while continuing on high fat diet. Continued gain in visceral adiposity with high fat diet feeding in HFD and 1×30 LIV group, which was prevented with 2×15 LIV (A). Increased infiltration of B cells (B), T cells (C), and macrophages (D) in gonadal adipose tissue with high fat diet, which was mitigated by 2×15 LIV, but not 1×30 LIV. *p<0.05. All data are presented as mean±SD. (Figure modified from [5]). Used with permission from Nature Publishing.

Effectiveness of exercise, or specifically of mechanical element of exercise, reduces with aging, partly due to reduced cell mechanosensitivity with aging [99]. One potential solution to avoid plateauing of the response to exercise, could be insertion of rest periods between bouts of physical activity [100]. Insertion of a 3-hour rest period between bouts of WBV has been shown to reduce adipogenesis in MSC in-vitro, as evident by 70% reduction in adiponectin after 7 days of treatment (0.7g acceleration, 90Hz frequency) [101]. A recent study from our lab shows that this effect translates in-vivo as well in an adult murine model of diet-induced obesity. WBV was only effective in adult mice when 30 minutes of treatment (0.2g acceleration, 90Hz frequency) was separated in two bouts of 15 minutes with 5-hour rest period per day [5]. Indeed, inclusion of a rest period resulted in reduced visceral adiposity (Figure 2A) and restored B cell (Figure 2B), T cell (Figure 2C), and macrophage (Figure 2D) populations in the adipose tissue [5]. Further studies are needed to optimize the treatment duration and the rest period between bouts to achieve maximum response to physical activity.

Thus, exercise has been shown to simultaneously be beneficial for both MAT prevention and restoring hematopoiesis in the bone marrow. However, for patients who might not be capable of strenuous physical exertion, low magnitude WBV (<1.0g) can serve somewhat as surrogate to exercise.

Conclusion

Bone marrow contains a complex niche that maintains the balance between many cell types, including those from the mesenchymal and hematopoietic lineage. This specialized bone marrow microenvironment is sensitive to systemic stressors such as aging and obesity, which can increase the proportion of adipose tissue within the bone marrow, and lead to reduced engraftment, homing, and self-renewal capacity of HSC. Increased marrow adiposity affects HSC function by disrupting HSC differentiation pathways, biasing lineage selection towards myelopoiesis and away from lymphopoiesis. Marrow adiposity adversely affects bone health by reducing bone volume fraction and bone mineral density, and compromising the regenerative potential of the bone cell precursor pool, including osteoblasts (from MSC) and osteoclasts (from HSC). Exercise has been shown to prevent marrow adipose tissue expansion, protect the marrow phenotype, and to restore MAT-induced changes in hematopoiesis. There is early preclinical and clinical evidence that suggests that - for patients that are unable to perform strenuous exercise - low magnitude whole body vibration can serve as a simultaneous treatment for reducing marrow adiposity and restoring hematopoiesis.