Proposing Cross-Linking in the Extracellular Matrix to Contribute to Immunosenescence

In this interesting open access paper, the authors propose that too little attention has been given to immune cell behavior in tissues rather than in blood, and that means that researchers have overlooked the possibility that age-related changes in the extracellular matrix structures that support tissues might be a significant cause of the growing immune dysfunction that takes place in later life. One of the more important of these changes in the extracellular matrix is the growing presence of cross-links, persistent sugary compounds produced as a byproduct of normal metabolic operations that chain together the large molecules of the extracellular matrix. In doing so these cross-links change the chemical and structural properties of the matrix and the tissue as a whole, producing results such as loss of elasticity in skin and blood vessels, which in turn contribute to a variety of age-related diseases. If cross-linking does indeed contribute to immunosenescence, the decline of the immune system with age, then that only increases the importance of ongoing research funded by the SENS Research Foundation aimed at safely breaking down this unwanted form of metabolic waste. In humans near all persistent cross-links appear to involve a single class of compound, glucosepane. So in theory there is only a single target here, needing just one drug development program to make a large difference to long-term health and longevity.

Immunosenescence is defined as age-related changes in the immune system. It is associated with a progressive deterioration of the ability to mount immune responses and with a higher mortality rate in the elderly. Immunosenescence is currently thought to depend on lifelong antigen load, leading to the senescence of cells in the immune compartment, with a prominent role attributed to the chronic anti-cytomegalovirus (anti-CMV) response. There seems to be an increasing use of immune resources allocated to the anti-CMV response with aging, a process that ultimately leads to exhaustion. The cause remains unclear and in humans the few studies examining the presence of viral reactivation in the blood, found it negative. More data are therefore needed in the field of human aging in order to conclude on this point. The role of CMV in immunosenescence is clearly important, but, rather than being directly causal, can also be interpreted as a consequence of more general age-related changes in the three-dimensional microenvironment in which most immune cells are mobile and operate, the extracellular matrix (ECM). Immunologists have neglected the implications of such changes, partly because most of the studies carried out on immunosenescence, at least until very recently, focused on blood because it is the most accessible source of cells and biological fluid in humans. Although of value, these data, lead to an overestimated qualitative and quantitative importance of this compartment in the understanding of the immune system physiology. The recent discovery of resident memory T cells, or TRM, showed immune surveillance to be largely local and, therefore, not readily accessible through studies on blood.

Here, we argue that efforts to decipher immunosenescence must consider both blood and the ECM. The TRM are located in the ECM, and the known biochemical and biophysical modifications to this medium associated with aging consequently hampers local immune surveillance by these cells. ECM proteins and proteoglycans have well-documented roles in scaffolding, but they also have a profound effect on cell behavior, through interactions with secreted ligands or cell-transmembrane receptors, in particular integrins. We suggest that the progressive and irreversible age-related changes in the extracellular matrix may actually provide a unifying framework explaining all the molecular and cellular features of immunosenescence. The key point is that for the immune cells to be functional, they must be free to recirculate, navigate and rest within the extracellular matrix, in tissues and organs. This point is instrumental in tissue surveillance and protection even in the absence of peripheral lymphocytes. We will consider immunosenescence within this framework, focusing on the adaptive immune system and T cells in particular, even though these cells are neither the only ones to be affected during aging nor the only ones concerned with mobility.

We argue that the mobility of immune cells in non-lymphoid tissues is a necessary element for effective immunity. A lack of immune cell mobility, either intrinsic, as in hereditary defects affecting actin remodeling for example, or extrinsic, as in aging, results in an impairment of immune responses. No three-dimensional (3D) model of deregulated cell mobility has ever been proposed or explored in the context of immunosenescence. We hope that this hypothesis which is based on reviews of fields that have not hitherto be connected together will promote future studies, in silico and in vitro, to validate this theory experimentally. The 3D model can reconcile many features of aging, such as the altered responses to vaccination, which is in essence both a memory and a local process, and dysfunctions of peripheral tolerance (autoimmunity). The chronic process of T cell death due to mechanical stress within the cross-linked mesh of the aged ECM may also account for activation of the inflammasome, leading to inflammaging, and to a state of immune deficiency typical of aged subjects. In conclusion, we propose an update of the theoretical framework of immunosenescence, based on a novel hypothesis: the increasing stiffness and cross-linking of the senescent ECM lead to a progressive immunodeficiency due to an age-related decrease in T cell mobility and eventually the death of these cells. A key element of this mechanism is the mechanical stress to which the cell cytoplasm and nucleus are subjected during passage through the ECM.



If and when someone does come up with a means of breaking glucosepane cross links, how will this be tested? I know the Spiegel lab have come up with a way of synthesizing glucosespane, but that would only allow in vitro tests. Are there any decent animal models of glucosepane cross links?

Posted by: Jim at December 12th, 2016 9:24 AM

@Jim: I believe the generation of animal models is also on the todo list. There won't be good natural models in the short lived mammals, I'd think. Not the right sort of cross-links in their tissues. It may well be better to move to engineered human tissue sections or donor tissue or biopsy samples rather than animal models as a next step.

Posted by: Reason at December 12th, 2016 10:23 AM

Mice certainly do appear to accumulate glucosepane, though we have only minimal information on how much and where. They may or may not be a great model for functional effects of glucosepane breakers, but they should provide adequate evidence of in vivo cleavage activity.

Remember, one of the many reasons SENS Research Foundation sponsored the Yale group's synthesis of glucosepane was in order to enable the development of antibodies against it. Indeed, they have successfully generated glucosepane immunogens (peptides with embedded glucosepane crosslinks) and are currently evaluating candidate anti-glucosepane antibodies. Once we have those, scientists will finally be able to conveniently test biological samples from animals that have or have not been treated with candidate glucosepane breakers and get quantitative information on their effects on the crosslink in tissues of interest.

Posted by: Michael at December 12th, 2016 12:48 PM

I know I'm just betraying my own ignorance here, but I always thought the main problem with glucosepane in general is how unreactive it is; therefore, isn't it difficult to have an antibody for it? It seems to me that if you have something that can selectively attach itself to glucosepane affixed to collagen, that's the first step to breaking it off. Is it at all feasible to learn anything about potential breakers just by determining how these antibodies do their job?

(By the way - you guys must be absolutely enthused that Peter Thiel and assorted pro-rejuvenation cohorts have pull with the incoming executive branch of American government now...!)

Posted by: Slicer at December 12th, 2016 7:32 PM

We know cancer and immunosenescence are tightly linked and the immune system controls cancer. In that regard, Alakhani et al. Demonstrated that glycation of the ECM was actually beneficial in causing cancer cells to apoptosis when they came in contact with one another. And we have an antibody to glucosepane.

Posted by: Dr. Obrenovich at December 18th, 2016 1:23 PM
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