Tissue regeneration falters with age throughout the body, and there are numerous contributing factors to this decline. It is uncertain as to exactly how these factors layer in terms of cause and effect, however. One can point to the loss of stem cell activity, for example, and then ponder the degree to which that is secondary to rising levels of chronic inflammation. That chronic inflammation is in part inherent disarray and misconfiguration in the immune system stemming from exposure to persistent pathogens, but also arises from the accumulation of senescent cells that secrete strongly inflammatory signals. Now consider that immune cells are generated by stem cells and that one of the jobs of the immune system is to remove senescent cells, and you can see why it becomes challenging to definitively assign causes and consequences when examining the messy later stages of aging. Everything influences everything else, and many dysfunctions interact with one another to form feedback loops.
When it comes to regeneration in mammals, the liver is something of a special case. It is highly regenerative, the only organ that in adults can regrow entire missing sections. Its regenerative processes are somewhat more complex and spread out across the cell populations of the organ when compared with the usual situation in other tissues. Other organs rely on small stem and progenitor cell populations that take on the burden of producing new cells as needed. Nonetheless, liver regeneration fails with age just as in other tissues. Points of comparison are almost always quite helpful in fundamental research, and scientists examine the aging of the liver in order to better understand why regeneration declines with age.
The open access paper here lists cellular senescence as an important contributing cause of declining regeneration, and this is likely mediated by the inflammatory signals produced by these cells. Regeneration is a complex dance involving different cell populations, and immune cells have a role to play. Short-term local inflammatory signaling is a necessary part of that process, and the temporary appearance of senescent cells is normal and expected when healing from injury. The long-term presence of lingering senescent cells and the consequent production of chronic inflammation disrupts normal regeneration, however.
Although adult hepatocytes are characterized by a very low replicative rate, they can rapidly reenter into the cell cycle following tissue loss or death. The best characterized experimental model to study liver regeneration consists of removal of 2/3 of hepatic parenchyma in rodents. In response, the remnant liver cells proliferate until the tissue mass is recovered (within 7 to 10 days). Since aging affects the regenerative response of the liver after chronic tissue injury or following surgical resection, it represents a critical problem in aged patients with liver disease. The first studies focusing on the effect of aging on liver regeneration date back to more than 50 years ago. At that time, it was found that the regenerative response, though preserved, was considerably reduced and retarded in aged rodents.
The long standing concept that hepatocytes lose their proliferative capacity with ageing has been challenged by experimental evidence based on a successful expansion of hepatocyes even after several rounds of transplantation. Remarkably, aged hepatocytes also retain their fully proliferative capacity if exposed to the treatment with direct mitogenic stimuli, such as ligands of the nuclear receptor CAR, which do not cause liver injury.
More recently, increasing evidence suggests that the age-dependent decline of the liver regeneration capacity is the consequence of multiple intertwining factors, both intra and extra-cellular, that cooperate to affect liver mass recovery after tissue damage. From the analysis of the latest literature reports, it emerges that the mass recovery of the injured liver in aged animals is compromised by at least three factors: (i) decreased expression of cell adhesion proteins leading to weakened microstructural adaptation after tissue injury and p21-dependent cell cycle arrest; (ii) change of hepatic stellate cell morphology which results in reduced liver perfusion and, consequently, leads to an impairment of tissue reconstitution after damage; (iii) chronic release of stemness-inducing pro-inflammatory proteins by senescent hepatocytes, which accumulate in the elderly due to a decline of the autophagy program. This senescence-associated secretory phenotype (SASP) maintains the neighboring recipient cells locked in a stem like state in aged tissues, affecting their capacity to replace lost cells.
On these bases, a potential therapeutic approach of direct mitogens to relieve the proliferative decline taking place in aged injured liver could be proposed. Treatment with nuclear receptor ligands could also be useful in liver transplantation and hepatic failure in order to restore liver function. Furthermore, therapeutic interventions aimed at eliminating senescent cells or blocking their effects may be useful to treat or delay age-related diseases. In this regard, it also would be interesting to evaluate if ligands of nuclear receptors could have a role in this process. Indeed, as nuclear receptors are ligand-induced transcription factors, their activation could unlock SASP-mediated senescence-stem locked cells by reprogramming their gene expression thus eliciting a similar hepatocyte proliferation response in young and aged livers.