The Interactions Between Aging and Autophagy are Complicated
Autophagy is a collection of processes responsible for recycling protein structures in the cell. There are numerous moving parts, not all of which are fully understood or characterized. Firstly, there is the question of how structures are identified for recycling, a process that is quite different on a structure by structure basis. Mitophagy, autophagy targeted to mitochondria, is very different in its opening stages to ribophagy, autophagy targeted to ribosomes, to pick one comparison of many. Secondly, there is the engulfment of the structure to be recycled into an autophagosome, a membrane assembled specifically for this purpose. Thirdly, there is the transport of that autophagosome to a lysosome where it merges to deliver its cargo to the lysosome interior. Lastly, there is the internal lysosomal activity in which enzymes break down the delivered structure into amino acids for reuse.
Autophagy is clearly important to aging, in that interventions known to modestly slow aging tend to upregulate autophagic activity. Autophagy is difficult to measure, however, and there is some debate over whether and how it slows with advancing age. One can pick any given molecular aspect of autophagy to measure, but it will not be clear as to whether an increase or decrease of that measure reflects an overall enhancement or decine of autophagy. A decreased measure could mean that efficiency has increased, while an increased measure could mean that some dysfunction is leading to futile overactivity in one part of the process. Further, aging could affect autophagy very differently in different tissues or even different cell populations in the same tissue. Average measures may blur out useful information, or a measure obtained in one place may provide misleading data. Most studies of autophagy make only one measure, and are thus subject to this sort of criticism.
Once thought to be an acute stress response, our previous work established that mitophagy is a basal, homeostatic process that operates during normal physiology to clear damaged mitochondria through the autophagic pathway. This steady-state mitochondrial turnover occurs independently of mitochondrial stress-induced PINK1-Parkin signaling in a cell- and tissue-specific fashion with a complex regulatory network. In short-lived model organisms such as yeast and nematodes, mitophagy levels decrease with age, leading to the widely held hypothesis that mitophagic capacity may also decline in aged mammalian tissues and could contribute to age-related neurodegeneration. Significant translational efforts are underway to enhance or restore mitophagy levels in these pathological contexts. However, because short-lived and long-lived species have distinct evolutionary pressures, it remains unclear whether lessons learned from short-lived organisms and cell lines actually translate to mammalian physiology - a question that has great translational significance. Mammalian postmitotic neurons survive for decades, have high energy demands and are particularly sensitive to homeostatic impairments. Understanding organelle homeostasis in long-lived mammals is crucial, given how aging accelerates cognitive decline and disease.
How natural aging modifies mammalian mitophagy in distinct brain regions and cellular subtypes remains to be examined, because profiling mitophagy within intact tissues and brain circuits is not straightforward using conventional techniques. Thus, while major insights have been possible from tractable short-lived model organisms, the question of how autophagy pathways are modulated in natural mammalian aging has remained an intractable question. Overcoming these limitations, genetically encoded optical reporter mouse models have recently emerged as powerful tools to monitor specific stages of physiological autophagy and mitophagy in intact tissues at high resolution with cell-specific precision.
Here, using two genetically encoded reporter mouse strains, we tracked mitophagy and autophagy longitudinally throughout the mouse lifespan in several pathophysiologically important brain regions, with cell types including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia, and interneurons. We defined aging-related dynamics in mitophagy and autophagy, providing strong evidence that decreased mitophagy and autophagy are not general features of healthy mammalian brain aging. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.