It has been a question for some time as to whether immune cells expressing p16 and β-galactosidase, markers of cellular senescence, are in fact all or even majority senescent. Macrophages, for example, can certainly express these proteins without entering a senescent state. Some assays of cellular senescence and associations with disease published in past years are thus likely reflective of both (a) the burden of senescence, but also (b) other responses to aging or processes of aging taking place in immune cell populations, particularly those resident in tissues.
With that in mind, today’s open access paper is an interesting exploration of what exactly it is that these maybe-senescent p16 and β-galactosidase expressing immune cells might be doing in the aged body. The authors draw in the concept of disease tolerance, which might be thought of as covering all of the ways in which cells might act, individually or in collaboration, to reduce the impact of infectious disease without killing the pathogens involved. It is not what one might think of the immune system being involved in, but nonetheless, that may be an evolved role for p16 and β-galactosidase expressing immune cells.
Does this mean that it is a bad idea to clear a large fraction of the p16-expressing or β-galactosidase-expressing cells in the body? Probably not, provided one restricts clearance to a short period of time, and avoids doing it while the patient is infected or injured. It has always been known that senescent cells do have useful roles when present for the short-term, including wound healing, suppression of potentially cancerous cells, and so forth. The problem in aging is that there are too many lingering senescent cells, to the point at which any benefit is buried by the downside of constant pro-inflammatory signaling. Getting rid of the excess in a short period of time should allow the useful processes to pick up again.
Substantial experimental evidence suggests that the accumulation of senescent cells is an important factor in age-related tissue deterioration as it is associated with the production of different molecules capable of restructuring the extracellular matrix, modifying the behavior of neighboring cells and systemically affecting the activity of the immune system. Despite these deleterious functions of senescent cells in the aging process, accumulating evidence supports cellular heterogeneity among p16High cells with some mediating important homeostatic functions that have been identified during embryonic development as well as in adult skin, liver and lung. This suggests that depending on the context, p16High senescent cells could be either beneficial or detrimental. What defines either group remains however largely unknown.
The development of different genetic mouse models is now facilitating the further identification and characterization of p16High cells in vivo. Among the different p16High subtypes, cells of the immune system, including T cells and macrophages, have been identified and further analysis revealed that some express additional markers of senescence such as enhanced senescence-associated β-galactosidase (SA-β-gal) activity and DNA damage. Furthermore, the frequency of such cells increases significantly in animals during natural and accelerated aging, which may highlights their potential importance. On the other hand, a modest or even transient activation of p16, as well as excessive lysosomal activity (and thus higher SA-β-gal activity) in phagocytic cells such as macrophages has been observed under different conditions. Whether such activation indeed reflects classical pathways of senescence activation is unclear.
In our current study, we used a genetic mouse model to trace cells with high expression of p16 in vivo. We found that the p16High program was activated during aging not only in long-lived macrophages and T cells, but in all the immune subsets analyzed. Our detailed analysis of T cells and tissue-resident macrophages as well as the use of a genetic model for selective ablation of p16High cells, allowed us to determine that p16High immune cells play an important regulatory functions in vivo. These functions were further critical for animal survival after severe inflammation and tissue damage. While the ability of an organism to overcome infectious diseases has traditionally been linked to killing invading pathogens, evidence indicates that, apart from restricting pathogen loads, organismal survival is coupled to an additional yet poorly understood mechanism called disease tolerance. Here we argue that induction of p16High immune cells is a key mechanism in establishing disease tolerance.
