This open access paper reviews the interactions between cellular senescence, autophagy, and immunosenescence, with chronic infection as a mediating mechanism. Given the present state of knowledge and biotechnology, it is challenging enough to look at any two aspects of the aging body and consider how they might interact in isolation, but this can only ever be a thin slice of the bigger picture. All systems and states in our biochemistry interact with one another in some way, directly or indirectly, and examining ever larger sets of relationships between greater numbers of systems and states is the path to greater understanding of aging as a phenomenon. It is also somewhat beyond present capabilities, a complex, challenging endeavor for the scientists of future decades, which is why bypassing the need for this sort of understanding is highly desirable when working towards therapies to treat aging. We cannot afford to wait for a near complete knowledge of the progression of aging.
The state of cellular senescence, in which replication is shut down, can be a reaction to damage. It is one of the ways in which cancer risk is sufficiently minimized to allow higher forms of multicellular life to exist. Senescent cells are unfortunately harmful to surrounding tissues, and their accumulation with age is one of the root causes of degenerative aging. Autophagy is a collection of cellular damage control processes, responsible for recycling broken and unwanted proteins or structures in the cell. Loss of autophagy to the point of excessive accumulation of molecular damage is one way for cells to become senescent, and unfortunately autophagy declines with age. Immunosenescence is the aged state of the immune system, characterized by chronic inflammation and incapacity. In later life, the immune system becomes far less effective in removing damaged cells, such as senescent cells, as well as less effective when it comes to a defense against invading pathogens.
Even when simply considering just these three line items, the potential interactions are complex and challenging to rigorously prove. The authors of this paper advance the common view that chronic infection impairs autophagy, and thus in turn generates increased numbers of senescent cells, which accelerates the progression of immunosenescence.
Cellular senescence is induced as a consequence of cellular damage accumulation, with the extent of activation directly depending on a fine-tuned balance between cellular conditions generating damage and those involved in counteracting them. The autophagic pathway plays a key role in preventing cell damage accumulation, however, the aging process leads to a decrease in autophagy capacity, and therefore also its effectiveness. In this context, senescence activation shows a more preponderant protective role.
The immune system does not escape from aging effects and displays senescence characteristics in aged individuals. Immunosenescence refers to the state of dysregulated immune function that contributes to the increased susceptibility to infections, autoimmune diseases, or cancer. Aged individuals are predisposed to more severe symptoms from certain infections and they do not mount an effective immune response upon vaccination. In general, aged populations fail to generate an appropriate innate and adaptive immune response against microorganisms, thus it becomes clear that senescence is involved in this failure.
Besides the normal occurrence of immunosenescence, several pathogen microorganisms accelerate the activation of senescence and predisposal to premature immunosenescence. For instance, hosts infected with bacteria such as P. aeuruginosa, M. tuberculosis, or H. pylori, some viruses, including HCMV, or the parasite T. cruzi, show characteristics of immunosenescence. A common issue of all of these pathogens is that they are able to generate chronic infections. In each of these, regardless of the fact that the host is faced with the same antigen several times during its lifetime, the immune response is inefficient. Furthermore, data shows that this condition generates an immune exhaustion and immunosenescence seems to be the major causative factor offering the pathogens an extra advantage since their elimination by the host tends to be even less effective.
Interestingly, a common characteristic of chronic infections is the autophagy blockage that usually occurs during autophagosome maturation, representing a factor that could contribute to or accelerate immunosenescence activation since it predisposes cells to damage accumulation. Deeper exploration to elucidate whether the activation of senescence in chronic infection is a consequence of autophagy impairment produced by pathogens to avoid degradation or, alternatively, whether it is a mechanism employed by the host to diminish infection spreading when the degradation of the pathogens has been halted. This exploration is needed to further understand the infection-autophagy-senescence relationship. With the available data, we hypothesize that chronic infections induce senescence with similar characteristics of aging, i.e., increase of inflammatory state and autophagy inhibition.