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Today, we want to point out a new study suggesting that senescent cells in bone marrow cell populations contribute to the decline of the hematopoietic system, particularly the hematopoietic stem and progenitor cells (HSPCs) that live in the bone marrow and produce our blood cells [1].

The hematopoietic system and immunosenescence

The hematopoietic system is the system of organs and tissues, including the bone marrow, spleen, thymus and lymph nodes, involved in the creation of cellular blood components.

The production of blood cells includes our immune cells, and, as we age, that supply begins to dwindle, leading to the decline of our immune system in a process known as immunosenescence. The decline of the immune system is directly correlated with reduced longevity and an increased risk of cancer as suggested by the immunological model of cancer.

This is no surprise given that as immune function declines, we become more vulnerable to pathogens and less able to mount an effective response to them.

With age, the bone marrow typically experiences inflammaging, the same age-related, low-grade chronic inflammation that we see in other tissues. This smoldering, constant inflammation most likely contributes to the dysfunction or even inhibition of the HSPCs in the marrow in the same way that it affects stem cell populations in other tissues.

Senescent cells in the bone marrow

Mesenchymal stromal cells (MSCs), which also reside in the bone marrow, actively support the HSPCs and allow them to self-renew and keep working; they are an essential component that keeps the blood cell-producing assembly line running. However, little is known about how MSCs change with age and how this influences the interaction between them and the HSPCs.

The researchers studied MSCs from the bone marrow of both young and aged donors and found that aged MSCs were enlarged compared to young MSCs. This cell enlargement is a characteristic of aged and senescent cells, has been observed in a number of studies recently, and is a potential biomarker of aging.

Aged and senescent cells appear to experience changes to their DNA-to-cytoplasm ratio, which leads to this enlarged state. In particular, the nucleoli of aged, senescent, and progeric cells tend to be enlarged, and smaller, more compact, nucleoli are a possible indicator of longevity and are the foundation of the ribosomal clock.

The researchers also noticed that aged MSCs also had a reduced ability to proliferate compared to younger MSCs. They also observed increases in SA‐β‐galactosidase and pro‐inflammatory senescence‐associated secretory phenotype (SASP) factors. High levels of these factors are typically encountered in senescent cells, and they impair stem cell function and tissue regeneration.

The aged MSCs also had a reduced immunomodulatory ability, meaning that they were less able to appropriately regulate the immune system by either suppressing or activating an immune response.

Finally, they exposed young HSPCs to the factors being secreted by the aged MSCs and found this impairment of HSPC function. In other words, aging MSCs in the bone marrow secrete SASP signals, which effectively shut down HSPCs and gradually strangle the supply of replacement immune and blood cells.

Abstract

Hematopoietic stem and progenitor cells (HSPC) reside in the bone marrow (BM) niche and serve as a reservoir for mature blood cells throughout life. Aging in the BM is characterized by low‐grade chronic inflammation that could contribute to the reduced functionality of aged HSPC. Mesenchymal stromal cells (MSC) in the BM support HSPC self‐renewal. However, changes in MSC function with age and the crosstalk between MSC and HSPC remain understudied. Here, we conducted an extensive characterization of senescence features in BM‐derived MSC from young and aged healthy donors. Aged MSC displayed an enlarged senescent‐like morphology, a delayed clonogenic potential and reduced proliferation ability when compared to younger counterparts. Of note, the observed proliferation delay was associated with increased levels of SA‐β‐galactosidase (SA‐β‐Gal) and lipofuscin in aged MSC at early passages and a modest but consistent accumulation of physical DNA damage and DNA damage response (DDR) activation. Consistent with the establishment of a senescence‐like state in aged MSC, we detected an increase in pro‐inflammatory senescence‐associated secretory phenotype (SASP) factors, both at the transcript and protein levels. Conversely, the immunomodulatory properties of aged MSC were significantly reduced. Importantly, exposure of young HSPC to factors secreted by aged MSC induced pro‐inflammatory genes in HSPC and impaired HSPC clonogenic potential in a SASP‐dependent manner. Altogether, our results reveal that BM‐derived MSC from aged healthy donors display features of senescence and that, during aging, MSC‐associated secretomes contribute to activate an inflammatory transcriptional program in HSPC that may ultimately impair their functionality.

Conclusion

One potential solution seems clear: if we wish to restore the hematopoietic system to a healthy and more youthful state, we must purge the harmful senescent MSCs from the bone marrow. This could improve the immune system and ameliorate the aged milieu, which could result in a reduction of global inflammation.

The tools to do this are currently in human trials in the form of senolytic drugs, so it seems only a matter of time before researchers discover effective solutions to clearing out senescent cell populations from human beings.

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Literature

[1] Gnani, D., Crippa, S., Della, L. V., Rossella, V., Conti, A., Lettera, E., … & Di, R. M. (2019). An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program. Aging cell, e12933-e12933.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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