Antibody therapy rejuvenates elderly mice

2024-03-27 16:00:00
Stop aging and even rejuvenate our immune system to regain the years. That is what has been observed in a group of elderly mice using an antibody therapy described in an article published in ‘Nature’ this week. The technique, which targets abnormally aging stem cells, has been shown to rebalance blood cell production and reduce age-related immune decline. However, the authors, a team of researchers from Stanford University (USA), consider that preclinical and clinical studies are needed to determine whether this approach could be feasible in humans. Related News standard No World fertility is sinking and will fall below the replacement level by 2050 Rafael Ibarra Aging is an important risk factor for most chronic diseases. As the world’s population continues to age, interventions that mitigate the effects of aging could profoundly affect well-being, the economy, and society at large by prolonging the span of human health. Many diseases associated with age and decline in tissue function are related to alterations in the fitness and function of stem cells, including stem cells in the blood. Aging is known to be associated with a change in hematopoietic stem cells (HSCs), which give rise to all types of blood cells. Hematopoietic stem cells regenerate blood cells throughout life. Most of them, in young people, have the potential to differentiate into blood cells of any lineage or type (balanced HSC), but some HSC subsets show differentiation biased towards one lineage. With age, there is a substantial increase in the proportion of cells that are biased toward generating cells of the myeloid lineage, which include red blood cells, platelets, and cells of the innate immune system, such as monocytes, macrophages, and neutrophils. Restoring “youthful” MHC function could have a significant impact on increasing immunity, reducing chronic inflammatory diseases. In older people, increased myeloid cell production is related to compromised adaptive immunity, chronic inflammation, and a increased incidence of a group of blood cancers called myeloproliferative neoplasms, the researchers explain. It is believed that interventions that restore “youthful” hematopoietic stem cell function could have a significant impact on increasing immunity, reducing the incidence and severity of chronic inflammatory diseases, and preventing blood disorders. Aiming to restore balance to these aging blood stem cell populations, Irving Weissman’s team designed an immunotherapy aimed at depleting myeloid-prone blood cells. Based on their extensive experience with antibody-based therapies, the researchers established a protocol in which aged mice were treated with antibodies directed against the cell surface proteins identified by the authors. Target for antibodies In the study now published, cell surface proteins are identified in this HSC subset (which are not found in hematopoietic stem cells with balanced production) that could be a ‘target’ for antibodies. Additionally, the work demonstrates that this methodology can deplete myeloid-prone hematopoietic stem cells in aged mice, restoring characteristics of a younger immune system, while reducing markers of age-related immune decline, such as inflammation. But could residual HSCs in aged mice durably restore balanced, youthful blood production, or would intrinsic cellular defects, along with extrinsic alterations in the aged tissue microenvironment, persist to prevent rejuvenation? Surprisingly, the authors found that a single cycle of antibody conditioning was durable: the relative number of HSCs biased toward myeloid cells remained depressed for at least two months after treatment. In the research, treated mice showed enhanced immune responses to viral infection. And, although depletion of HSCs biased toward myeloid cells was not sufficient to completely rejuvenate adaptive immune responses, the results clearly demonstrate that disruptions in stem cell fate determination and normal hematopoietic differentiation can contribute to immune dysfunction in old people. Increased lymphoid production in the elderly could potentially increase the risk of tumor growth. In an accompanying commentary, Yasar Arfat Kasu and Robert Signer, from the University of La Jolla (USA), warn that increased Lymphoid production in older adults could potentially increase the risk of tumor growth (such as leukemia), which has been shown to be suppressed by reduced lymphoid production. Aging is associated with a higher prevalence of a condition called clonal hematopoiesis, in which a subpopulation of HSCs with the same genetic mutation expands and, in some cases, dominates the HSC pool, they write; «This, in turn, can increase the risk of developing blood cancer and cardiovascular diseases. Ross and colleagues argue that targeted depletion of myeloid-biased HSCs could preferentially eradicate these dominant or precancerous HSC clones. “However, antibody conditioning could, in fact, exacerbate the occurrence of clonal hematopoiesis by reducing the total HSC repertoire.” “However, the burden of increased risk of lymphoid leukemia could be offset by the greater protection against infection and reduced risk of other cancers that better immune surveillance would offer,” they add.
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