Abstract
Macroautophagy is a “cell cleansing” process that rids cells of protein aggregates and damaged organelles that may contribute to disease pathogenesis and the dysfunctions associated with aging. Measures which boost longevity and health span in rodents typically up-regulate macroautophagy, and it has often been suggested that safe strategies which can promote this process in humans may contribute to healthful aging. The kinase ULK1 serves as a trigger for autophagy initiation, and the transcription factors TFEB, FOXO1, ATF4 and CHOP promote expression of a number of proteins which mediate macroautophagy. Nutraceutical or dietary measures which stimulate AMPK, SIRT1, eIF5A, and that diminish the activities of AKT and mTORC1, can be expected to boost the activities of these pro-autophagic factors. The activity of AMPK can be stimulated with the phytochemical berberine. SIRT1 activation may be achieved with a range of agents, including ferulic acid, melatonin, urolithin A, N1-methylnicotinamide, nicotinamide riboside, and glucosamine; correction of ubiquinone deficiency may also be useful in this regard, as may dietary strategies such as time-restricted feeding or intermittent fasting. In the context of an age-related decrease in cellular polyamine levels, provision of exogenous spermidine can boost the hypusination reaction required for the appropriate post-translational modification of eIF5A. Low-protein plant-based diets could be expected to increase ATF4 and CHOP expression, while diminishing IGF-I-mediated activation of AKT and mTORC1. Hence, practical strategies for protecting health by up-regulating macroautophagy may be feasible.
Highlights
Effective macroautophagy is often referred to as “cell cleansing”, and, when of moderate intensity, and appropriately balanced by synthesis of new proteins and organelles— mitochondria, produced in the complex process of “mitochondrial biogenesis”—it is generally thought to enhance health span [1,2,3,4]. Measures which are known to increase median and maximal lifespan in rodents typically are associated with increased autophagy
AMPK, which is activated by elevation of AMP+ADP, and serves as a monitor for the availability of the biochemically useful free energy provided by ATP, confers an activating phosphorylation on ULK1 [14,15,16,17]. mammalian target of rapamycin complex 1 (mTORC1), whose activity is enhanced by growth factor activity via AKT and decreased by a cellular deficit of certain amino acids, phosphorylates ULK1 in a way that inhibits its activity [13,18]
transcription factors EB (TFEB) is considered the master transcriptional regulator of the synthesis of a great number of proteins required for both lysosome and autophagosome formation [24]. It promotes the transcription of genes carrying a CLEAR regulatory element in their promoters, to which TFEB binds; at least 471 such genes have been identified [25]. mTORC1 and ERK2 can phosphorylate TFEB on Ser142 and Ser211; by enabling binding of TFEB to the chaperone 14-3-3, these phosphorylations tend to promote the nuclear export of TFEB, such that it cannot drive transcription [26,27]
Summary
Activation of the serine/threonine kinase ULK1 is a trigger for initiating the formation of phagophores, which are elongated into the autophagosomes that engulf cell contents during their formation [11,12]. AMP-activated kinases (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) act as key functional antagonists modulating ULK1 activity [13]. MTORC1, whose activity is enhanced by growth factor activity via AKT and decreased by a cellular deficit of certain amino acids, phosphorylates ULK1 in a way that inhibits its activity [13,18]. Like AMPK, the deacetylase SIRT1 functions as a detector of cellular energy deficit; its obligate substrate is NAD+, and a relative paucity of oxidizable substrate enhances its activity by boosting the cytosolic NAD+/NADH ratio. SIRT1 activity can stimulate ULK1 indirectly, by increasing AMPK activation via LKB1. The serine/threonine kinase LKB1 activates AMPK via phosphorylation of Thr472 [22]. SIRT1 promotes LKB1-mediated activation of AMPK, leading to increased ULK1 activity. Transcription factors EB (TFEB), forkhead box O1 (FOXO1), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP) play a prominent role in this regard, and measures which boost their synthesis and/or activity can thereby enhance autophagy
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