Autophagy is a prominent topic in aging research. This is also the case for other forms of cellular maintenance processes, but autophagy is by far the most studied and understood at this time. Here when I say autophagy I mean macroautophagy. There other other, less well cataloged forms, but it is usually the case that when someone refers to autophagy without qualification, then they are talking about macroautophagy. In this type of autophagy, damaged molecules and cell structures are isolated inside a specially constructed membrane, and that then fuses with one of the cellular recycling system known as lysosomes. A lysosome is packed with molecules capable of dismantling near all biological compounds it is likely to encounter, rendering them into raw materials for reuse.
All forms of quality control within cells appear to be quite influential in health and longevity over the long term. Damaged cellular components that linger cause secondary harms, and so the more efficiently they are removed the better the operation of the cell. Then multiply that by all the cells in a tissue. Unfortunately, cellular processes of repair and maintenance appear to succumb to forms of damage as the years pass. In the case of autophagy, one problem is caused by the accumulation of metabolic waste products that the lysosome is not equipped to handle. Lysosomes become bloated and unable to perform their normal tasks efficiently. Cells malfunction or die, and the waste products continue to build up in cells and cellular debris until they are visible as lipofuscin. This is how wear and tear proceeds in a self-repairing system: first the repair mechanisms start to fail, then everything else heads downhill ever more rapidly thereafter.
Beyond the varieties of autophagy, cells boast a panoply of other systems intended to fix problems and clear out unwanted junk, ranging from DNA repair to proteasomes to, as a last resort, encapsulating excess waste material and kicking it out into the space between cells. Not all are well understood. The few open access papers below cover some of this range, and are indicative of the level of attention given to cellular quality control in the medical research community. It isn't a coincidence that these papers focus on the brain and neurodegenerative conditions; that is where much of the academic funding for aging research is directed these days. Alzheimer's research alone accounts for a very large share of the public research funding directed towards aging as a whole, and it is plausible that private funding tends to mirror this distribution.
The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's disease.
Autophagy and the DNA damage response (DDR) are biological processes essential for cellular and organismal homeostasis. Herein, we summarize and discuss emerging evidence linking DDR to autophagy. We highlight published data suggesting that autophagy is activated by DNA damage and is required for several functional outcomes of DDR signaling, including repair of DNA lesions, senescence, cell death, and cytokine secretion. Uncovering the mechanisms by which autophagy and DDR are intertwined provides novel insight into the pathobiology of conditions associated with accumulation of DNA damage, including cancer and aging, and novel concepts for the development of improved therapeutic strategies against these pathologies.
Autophagy is emerging as one of the core orchestrators of healthy aging. This self-degradation process is present in all mammalian cells and tissues, including the central nervous system (CNS), and specializes in directing unnecessary or damaged intracellular material to the lysosome, the major cellular organelle that digests and recycles all types of macromolecules. Autophagy, as a constitutive mechanism, participates in the basal turnover of long-lived proteins and organelles, playing a major role as a checkpoint for quality control. On the other hand, stressful situations such as metabolic starvation or functional damage induce an adaptive autophagic response to restore cellular homeostasis. Thus, adaptive autophagy provides the cell with nutrients and energy during metabolic shortage and relieves it from toxic components during functional damage. Accordingly, a correct completion of the autophagic response is central for optimal CNS physiology and the promotion of neuronal survival. This is evidenced by the elevated number of connections made between the dysregulation of autophagy, aging, and neurodegeneration.
In this review, we will describe the role of autophagy (dys)regulation in the aged and diseased brain. Particularly, we will focus on microglia, the brain's resident macrophages with intrinsic capability to respond to CNS damage, promoting repair and a correct brain function. First, we will briefly outline the process of autophagy and its regulation, and summarize key technical aspects for the correct monitoring of autophagy at the experimental level. Then we will review the role of autophagy in neurons and the impact of autophagy failure in neurodegeneration. Finally, we will detail the current state of the literature on the role of autophagy in peripheral macrophages and microglia, including the regulation of phagocytosis and the inflammatory response.