Researchers here note the interactions between the cellular maintenance processes of autophagy and cellular senescence. Upregulated autophagy can prevent cells from falling into the senescent state, observed in the use of mTOR inhibitors, for example. Once a cell is senescent, either sabotaging or increasing autophagy can destroy it, or at least make it more vulnerable to senolytic treatments that provoke programmed cell death. Regardless, small molecule therapies that upregulate autophagy in every cell they can reach would still likely be beneficial even in people with a high burden of senescent cells. The immune system of an older individual still clears senescent cells, just slowly, and thus reducing the number of new cells that become senescent in the age-damaged tissue environment can allow clearance to catch up over time.
The relationship between cellular senescence and autophagy is regarded as paradoxical. Autophagy activation in response to stress can successfully resolve it and thus spare the cell from entering senescence. However, if a cell does commit to senescence by other ways, autophagy becomes essential for cell survival and senescence establishment. Indeed, senescence-associated secretory phenotype (SASP) production imposes its burden on the secretory pathway, calling for increased proteostasis maintenance. In this regard, the first-ever demonstration of selective pharmacological elimination of senescent cells consisted in depriving therapy-induced senescent lymphoma of adaptive autophagy, leading to proteotoxic stress overload due to SASP expression.
Senolysis can actually be achieved by modulating autophagy in either direction: inhibiting autophagy can lead to proteotoxic stress in senescent cells producing an abundant SASP, and conversely, further activating autophagy can selectively kill senescent cells through type II autophagic cell death, i.e. excessive "self-eating".
Beyond bulk autophagy flux modulations to cope with increased secretory demands, finer processes appear to be at play in regulating proteostasis in senescence. Recently, it was shown that the stability of a defined set of proteins was regulated by selective autophagy in senescence through differential interactions with ATG8 family receptors. This selective autophagy network was fundamental in shaping several facets of the senescent phenotype, including SASP production and proteostasis. These studies pave the way for a more precise understanding of autophagy regulation in the physiology and the proteostasis of senescent cells, and the discovery of potentially more potent senolytic strategies.