Opportunities and Challenges of targeting an aging immune system

Cellular senescence, a stable terminal state of growth arrest is characterized by acquired anti-apoptotic pathways leading to the accumulation of senescent cells in multiple tissues (1). Through the secretion of pro-inflammatory factors, the so-called senescence associated secretory phenotype (SASP), senescence can be initiated in surrounding, non-senescent cells (2). Since the accumulation of senescent cells is linked to a variety of age-associated diseases, clinical trials are currently testing the effects of senolytics, agents that eliminate senescent cells by promoting apoptosis (1). Our own experimental data have previously shown an impressive prolongation of graft survival if organ donors had been treated with senolytics (3).

Immunosenescence also affects hematopoietic stem cells (HSCs) resulting in impaired functions including compromised self-renewal capacities, homing abilities, engraftment defects and limited myeloid biased. Clinically, the age of the donor is considered carefully in HSC transplantation (HSCT) with grafts from younger donors showing superior outcomes (4). Thus, ‘rejuvenating’ old HSCs and restoring their function is of clinical significance. That rejuvenation is possible has been shown in experimental models of parabiosis in which the capacity to ‘renew’ brain, heart, and muscle function has been documented. Furthermore, transferring plasma from young into old mice improved the plasticity of hippocampal neurons and enhanced cognitive function.

In a recent ‘Journal of Experimental Medicine’ manuscript, Emmanuelle Passegue and co-workers delineated the effects of ‘systemic factors’ including blood, microenvironment, calorie restriction, exercise, and genetic alterations of premature aging on old HSCs and their bone marrow (BM) niche using models that spanned from transplantation, parabiosis, plasma transfer, exercise, caloric restriction to the utilization of aging mutant mice (5). Although a blood exchange between heterochronic (Het) parabiotic young (Y) and old (O) mice had been established, the authors did not observe effects on either young or old HSCs. In their hands, they detected a persistence of high amounts of HSCs expressing CD150 levels in O-Het and a persistence of young HSC in Y-Het parabiotic animals. Furthermore, old HSCs maintained a myeloid-biased output and an inferior regenerative capacity compared to young HSCs in transplantation assays, regardless of the exposure to young blood. Notably, despite engraftment into healthy young BM niches, old HSCs showed persistent nuclear γH2AX foci and delayed replication kinetics in addition to high CD150 levels in the absence of functional improvements. These results suggest that old HSCs are not rejuvenated or functionally improved after the exposure to young blood or in a young microenvironment. In addition, the authors also demonstrated that systemic anti-aging interventions including calorie restriction and exercise had limited effects on slowing HSC aging. The authors also showed that young HSCs are not affected by old blood or blood-derived factors.

The work by Yousefzadeh and co-workers published in ‘Nature’ highlights the significant impact of an aging immune system on non-lymphoid cells/tissues. In detail, the authors showed an augmented damage and accelerated senescence in non-lymphoid organs after being exposed to aged immune cells (6). To delineate how immunosenescence drives systemic aging, the authors used a Cre-Lox system to selectively delete Ercc1 in hematopoietic cells. By removing this DNA repair enzyme, they caused an accelerated degenerative process in the immune system, in many ways reflecting physiological aging. For example, serum levels of antibodies against keyhole limpet hemocyanin (KLH) were reduced both in old wild type (24 months) and ‘middle-aged’ Ercc1-deleted mice (5 months), showing that both, old wild type and mutant mice lost the ability to mount an effective immune response after being exposed to KLH. In contrast, young Ercc1-deleted mice (2 months) demonstrated a normal immune response indicating that the young immune system works effectively, however, degenerates in genetically modified animals due to the limited repair of DNA.

Senescence markers (SASP factors, p16^Ink4a and p21^Cip1) had significantly increased in B and T Cells, Natural Killer cells and macrophages in mutant mice when compared to their littermates without the Ercc1-deletion. Additionally, older Ercc1-deleted mice (8–11 months) demonstrated elevated senescence markers in several non-lymphoid tissues when exposed to senescent immune cells. Moreover, elevated tissue damage markers in mutant mice revealed that an aging immune compartment causes organ damage, effects that may contribute to the inferior lifespan in mutant mice.

Previously published data have shown that the transfer of labelled senescent adipocytes and mesenchymal cells resulted into novel populations of senescent cells causing muscle weakness and other frailty-like disabilities that persisted for at least 6 months (7). Transplanting splenocytes from mutant into p16^ink4a-luciferase reporter mice resulted in an amplified luciferase signal. Additionally, elevated levels of p16, p21 and luciferase reporter mRNA were observed in several non-lymphoid organs when transplanting splenocytes from mutant or old naïve mice. Lifespans were reduced in recipient mice when administering mutant splenocytes, indicating that even small populations of senescence cells have systemic effects. On a ‘positive’ note, transplanting young splenocytes from 2-month-old wild type mice into 3-month-old mutant mice reduced circulating SASP factors and senescence markers in several tissues (Aorta, Kidney, Liver, Spleen, Lung, Skin), indicating that young immune cells may ameliorate senescence. Notably, expression of p16 and p21 in CD3⁺ peripheral T cells were decreased while anti-KLH and white blood cell counts had increased when treating animals with the mTOR inhibitor rapamycin.

Our own data have previously shown that the augmented immunogenicity of old organs is communicated by old passenger leukocytes rather than by old non-immune cells of the parenchyma itself (8). Targeting key players of the aging immune system may therefore represent a promising therapeutic approach to reduce graft immunogenicity and to prevent the transfer of senescent cells with the transplantation of older organs. The transfer of these cells has the potential to accelerate aging in recipients with consequences of deteriorating affecting health conditions. On the flip side, although entirely speculative, transplanting young organs may contribute to rejuvenation (9). Thus, interfering with aging does appear possible. Nevertheless, it will be an oversimplification to assume and hope that this process will be straightforward.

Indeed, as shown by Passague and co-workers, young blood and a young environment have not been sufficient to rejuvenate old HSC. At the same time, senolytics including navitoclax (ABT263) have previously been shown to clear senescent HSCs in the bone marrow (10). Moreover that senolytics prolonged graft survival in experimental models is encouraging (3). Clearly, the potential of interfering with (immune)senescence has opened the door to a broadly relevant application for and beyond organ transplantation.