Normal tissue regeneration is disrupted in various ways in later life, such as the tendency for increased fibrosis, scar tissue formation rather than normal regrowth. Researchers here theorize on the role of growing numbers of lingering senescent cells in this age-related loss of function, a complex situation because the transient creation of senescent cells, soon destroyed, is an important part of the normal wound healing process. Despite their positive function in that scenario, the accumulation of long-lasting senescent cells is nonetheless one of the root causes of aging. These cells produce a harmful effect on surrounding tissue through the potent mix of signals they generate, known as the senescence-associated secretory phenotype (SASP), which drives chronic inflammation, among other items.
The inability of adult tissues to transitorily generate cells with functional stem cell-like properties is a major obstacle to tissue self-repair. Nuclear reprogramming-like phenomena that induce a transient acquisition of epigenetic plasticity and phenotype malleability may constitute a reparative route through which human tissues respond to injury, stress, and disease. However, tissue rejuvenation should involve not only the transient epigenetic reprogramming of differentiated cells, but also the committed re-acquisition of the original or alternative committed cell fate. Chronic or unrestrained epigenetic plasticity would drive aging phenotypes by impairing the repair or the replacement of damaged cells; such uncontrolled phenomena of in vivo reprogramming might also generate cancer-like cellular states. We herein propose that the ability of senescence-associated inflammatory signaling to regulate in vivo reprogramming cycles of tissue repair outlines a threshold model of aging and cancer.
The degree of senescence/inflammation-associated deviation from the homeostatic state may delineate a type of thresholding algorithm distinguishing beneficial from deleterious effects of in vivo reprogramming. First, transient activation of NF-κB-related innate immunity and senescence-associated inflammatory components (e.g., IL-6) might facilitate reparative cellular reprogramming in response to acute inflammatory events. Second, para-inflammation switches might promote long-lasting but reversible refractoriness to reparative cellular reprogramming. Third, chronic senescence-associated inflammatory signaling might lock cells in highly plastic epigenetic states disabled for reparative differentiation. The consideration of a cellular reprogramming-centered view of epigenetic plasticity as a fundamental element of a tissue's capacity to undergo successful repair, aging degeneration or malignant transformation should provide challenging stochastic insights into the current deterministic genetic paradigm for most chronic diseases, thereby increasing the spectrum of therapeutic approaches for physiological aging and cancer.
If the loss of differentiation features following reprogramming is not accompanied by re-acquisition of the original or alternative differentiated cell fate, the resulting tissue plasticity might impair the repair or replacement of damaged cells. The ability of SASP-associated pro-inflammatory cytokines to regulate stemness and nuclear reprogramming raises the notion that a SASP-impaired local environment could interfere with tissue rejuvenation by imposing the so-called "stem-lock" state. Chronic inflammatory conditions via exposure to IL-1, which normally functions as a key "emergency" signal and a master regulator of SASP by inducing downstream effectors such as IL-6, has been shown to impair tissue homeostasis and to induce an aged appearance of the hematopoietic system by restricting stem cell differentiation.
While counterintuitive, given the ability of SASP factors including IL-6 to transiently create a permissive environment for in vivo reprogramming capable of inducing cellular plasticity and tissue regeneration, a prolonged promotion of such progenerative response might reduce tissue rejuvenation and promote aging by self-enhancing futile cycles of SASP/IL-6-driven reparative cellular reprogramming. Compared with young tissues containing few senescent cells where transient creation of senescent cells might cause temporary reprogramming and differentiation/proliferation to replenish cells, the prolonged accumulation of senescent cells in tissues that are old or under high levels of stress (e.g., following medical procedures such as chemotherapy) might be accompanied by a defective clearance of damaged, senescent cells, which can promote further SASP accumulation. A situation of chronic SASP secretion might not only counter the continued regenerative stimuli by promoting cell-intrinsic senescence arrest in single damaged cells but also paradoxically impose a permanent, locked gain of stem cell-like cellular states with blocked differentiation capabilities in surrounding cells.