Promoting Autophagy to Restore Function in the Aging Liver

The processes of autophagy recycle damaged and unwanted structures and proteins in cells. Increased autophagy is involved in the beneficial response to calorie restriction and numerous other mild forms of stress. A range of potential approaches to upregulate autophagy have been explored by the research community, but few have made much progress towards the clinic. It is entirely possible that increased autophagy is more beneficial in some tissues than in others - or to put it another way, perhaps some tissues are much more impaired than others by age-related loss of autophagy. Some of the most impressive data has centered on improved autophagy in the aging liver via LAMP2A upregulation, showing sizable increases in function. Again, these demonstrations have yet to make the transition to clinical medicine.

Aging leads to the accumulation of lipofuscin in the lysosome, which impairs the efficiency of autophagic enzymes. Moreover, aging causes a significant decrease in the number of autophagosomes, which may be related to the decline of activation capacity of AMPK. It further reduces autophagy activity. Liver resection not only triggers liver regeneration, but also induces autophagy of hepatocytes. Autophagy plays a crucial role in liver regeneration. Liver regeneration requires abundant energy, which is among others generated by recycling intracellular macromolecules derived from damaged organelles.

Autophagy activity in aged liver is significantly reduced compared to young liver. Therefore, improving autophagy through pharmacological intervention seems to be an effective treatment to promote regeneration in senescent livers. The mTOR pathway is the most common autophagy-related pathway. However, the mTOR pathway is not only the key regulatory pathway for autophagy, but also the pathway that modulates cell proliferation. Inhibition of mTOR activity can induce autophagy, but inhibits cell proliferation at the same time. In the case of liver resection, inhibition of cell proliferation is detrimental, since it causes impairment of liver regeneration.

Therefore, modulation of autophagy via the mTOR-independent pathway is a better strategy. Strikingly different drugs such as Carbamazepine, Amiodarone, Ezetimibe, and Lithium induce autophagy via these pathways. They are of documented or putative benefit for enhancing liver regeneration and should be explored in more depth. This is of special importance for the elderly population, where liver regeneration is already impaired, in part due to the age-dependent decrease of autophagic activity.

At present, many aging patients with malignant liver disease cannot be treated effectively because of the aging-related impairment of liver regeneration. Aging-related changes also lead to decreased autophagy activity, which is an important cause for insufficient liver regeneration. Age-specific strategies to promote liver regeneration for these patients at risk are needed. Evidence is accumulating that the modulation of autophagy via pharmacological intervention is an effective approach to promote liver regeneration. This is of utmost benefit for aging patients with impaired autophagy. However, choosing the appropriate autophagy pathway to activate autophagy is crucial.

Link: https://doi.org/10.3390/ijms21103606

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