Autophagy is one of the housekeeping processes responsible for recycling damaged mechanisms and structures in cells before they can cause further harm. A type of organelle called the lysosome performs the recycling, but lysosomal activity is impacted over the course of aging by an accumulation of metabolic byproducts that cannot be broken down, such as the constituents of lipofusin most notably found in retinal cells. As a consequence of being laden with this waste, lysosomes bloat and become dysfunctional, especially in long-lived cells.
The immune system also declines and changes with aging, becoming less effective in its primary tasks of defending the body and eliminating potentially harmful cells, while at the same time also generating ever higher levels of chronic inflammation. Some of this is due to various forms of cellular and molecular damage known to contribute to degenerative aging, while some of it is structural, inherent in having what is a more or less fixed-sized system that tries to devote resources to remembering every pathogen it encounters. It works well at the outset but eventually runs out of space.
These researchers are investigating links between immune system function and declining autophagy, adding another voice to those already suggesting that ways to enhance natural levels of autophagy would be of general benefit in the treatment of aging and age-related disease:
Macrophages provide a bridge linking innate and adaptive immunity. An increased frequency of macrophages and other myeloid cells paired with excessive cytokine production is commonly seen in the aging immune system, known as 'inflammaging'. It is presently unclear how healthy macrophages are maintained throughout life and what connects inflammation with myeloid dysfunction during aging.
Autophagy, an intracellular degradation mechanism, has known links with aging and lifespan extension. Here, we show for the first time that autophagy regulates the acquisition of major aging features in macrophages. In the absence of the essential autophagy gene Atg7, macrophage populations are increased and key functions such as phagocytosis and nitrite burst are reduced, while the inflammatory cytokine response is significantly increased - a phenotype also observed in aged macrophages. Furthermore, reduced autophagy decreases surface antigen expression and skews macrophage metabolism toward glycolysis.
We show that macrophages from aged mice exhibit significantly reduced autophagic flux compared to young mice. These data demonstrate that autophagy plays a critical role in the maintenance of macrophage homeostasis and function, regulating inflammation and metabolism and thereby preventing immunosenescence. Thus, autophagy modulation may prevent excess inflammation and preserve macrophage function during aging, improving immune responses and reducing the morbidity and mortality associated with inflamm-aging.