Sex Steroid Ablation Spurs Immune System Regeneration

The immune system is enormously complex and has many jobs. It isn't just a matter of destroying invading pathogens, but also clearing senescent, precancerous, and other unwanted cells. The decline of the immune system in old age is a major contribution to frailty, as not only are the old threatened by infections that the young can shrug off, but the immune system falters in destroying damaged cells that threaten health. The aged immune system falls into a state of ineffectiveness combined with constant overactivity that causes chronic inflammation. Systematic inflammation in turn contributes to the progression of many ultimately fatal age-related conditions. If the immune system could be even partially restored to a more youthful profile, that would go a long way towards improving health in old age.

There are a range of approaches to the problem of immune system aging, not least because there are numerous different contributions to the degeneration of immune function. The supply of new immune cells dries up in later life, leading researchers to propose stem cell therapies, introduction of new immune cells by infusion, or regeneration of the thymus tissues where immune cells mature. Equally the immune system becomes badly misconfigured due to the influence of persistent herpesviruses like cytomegalovirus (CMV). Ever more cells are devoted to uselessly fighting CMV rather than reacting to new threats. Here the direct path to a therapy is to work on ways to selectively destroy the unwanted immune cells, which should prompt the creation of replacements lacking the CMV fixation.

There are plenty of other points at which researchers could intervene by manipulating the processes of immune cell depletion and production, though the effects will probably be less impressive than a sweeping clearance of most unwanted cells. Even fairly simple interventions such as extended fasting have been shown to have some impact, clearing out and then repopulating sections of the immune system for a net benefit. The open access research linked below focuses on tinkering with the regulatory processes that steer creation of immune cells by hematopoietic stem cells in bone marrow, processes called lymphopoiesis and myelopoiesis that are balanced in youth but shift towards increasing myelopoiesis with aging. Like much of this research it is presented in the context of cancer treatments, as the most widely used therapies are hard on the immune system and the cancer community is in search of ways to compensate, but it may have broader implications over the long term for the treatment of immune system decline in aging:

Enhanced Hematopoietic Stem Cell Function Mediates Immune Regeneration following Sex Steroid Blockade

One key etiological factor underlying a wide range of diseases is the progressive decline in immune function with age. At its core is a reduction in lymphopoiesis within the bone marrow (BM) and thymus, attributed in part to a decrease in the number and function of lymphoid progenitors. Increasing evidence suggests that intrinsic changes to the earliest hematopoietic stem cells (HSCs) also contribute toward age-related immune degeneration. Deficiency in DNA repair, altered DNA methylation patterns, aberrant metabolism and reactive oxygen species, and skewed upregulation of myeloid- (at the expense of lymphoid-) associated genes all contribute to altered HSC function with age. However, in addition to intrinsic functional changes, extrinsic alterations to the HSC niche also likely to contribute toward the degeneration of HSC function with age.

Evidence suggests that sex steroids play at least some role in age-related degeneration of lymphopoiesis, and we, and others, have previously shown that sex steroid ablation (SSA) is able to rejuvenate aged and immunodepleted BM and thymus, enhance peripheral T and B cell function, and promote immune recovery following hematopoietic stem cell transplantation. However, the mechanisms underlying SSA-mediated immune regeneration are still unresolved. In this study, we sought to examine the events upstream of SSA-mediated lymphoid regeneration, focusing on the earliest HSPCs.

We herein show that, mechanistically, SSA induces hematopoietic and lymphoid recovery by functionally enhancing both HSC self-renewal and propensity for lymphoid differentiation through intrinsic molecular changes. Our transcriptome analysis revealed further hematopoietic support through rejuvenation of the bone marrow (BM) microenvironment, with upregulation of key hematopoietic factors and master regulatory factors associated with aging such as Foxo1. These studies provide important cellular and molecular insights into understanding how SSA-induced regeneration of the hematopoietic compartment can underpin recovery of the immune system following cell-damaging cancer therapies. These findings support a short-term strategy for clinical use of SSA to enhance the production of lymphoid cells and HSC engraftment, leading to improved outcomes in adult patients undergoing HSCT and immune depletion in general.