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  • Many reports have well documented that signaling pathways pl

    2024-04-09

    Many reports have well documented that signaling pathways play a pivotal role in controlling longevity. The most studied of these pathways is the IGF-1 pathway [11,12]. A disruption of this pathway has been found to extend longevity in different groups of species starting from Caenorhabditis elegans (C. elegans) to humans via the mitigation of stress responses [11]. The IGF-1 pathway includes PtdIns 3-kinase, tyrosine kinase receptor, and Akt/PKB. Interestingly, Akt/PKB has been discovered to be a potent positive regulator of mTOR, which is an autophagic inhibitor. Therefore, the deregulation of Akt/PKB pathway may induce autophagy confirming the linking of the IGF-1 pathway to autophagy, which is extensively connected with the aging process. To further support the role of autophagy in aging, a report demonstrated that the lifespan could be extended when TOR kinase/let-363 is depleted [13]. In the context of the role of insulin in aging, it has been found that high levels of insulin in the plasma have a profound effect on aging. In an experiment, the administration of an anti-lipolytic drug, ACIPIMOX, which is known to decrease the insulin level and plasma-free fatty acids, was shown to decrease aging by enhancement of autophagy [14]. Recent reports illustrate the role of sirtuins in autophagy during aging. Sirtuins belong to the family of NAD-dependent deacetylases that are associated with an increase in longevity. The decline in the role of sirtuin1 (Sirt1) has been related to the decline in turnover of autophagic activity. Interestingly, increase in the arn 509 of Sirt1 has been shown to accelerate autophagy as depicted through the accumulation of LC3 II and the formation of GFP-LC3 puncta to regulate aging, indicating a sirtuin-mediated strong relation between autophagy and aging. Moreover, experimental evidence shows that Sirt1-/- mouse has increased p62 levels, which is a marker for impaired autophagy [15]. Consistent with the above findings, skeletal muscles of aged mice displayed decreased autophagic activity as reflected by the reduction in the conjugation of LC3B-I with PE upon decreased expression of Atg12-Atg5 and Atg3 protein levels. Apart from the alteration in conventional autophagy, selective autophagy gets affected during aging. For example, the expression of LAMP2A, Hsc70, and Drp1, PINK1 and PGC1α that regulate mitochondrial autophagy has been reported to decline with the progress of aging [16]. Similarly, recent experiments have demonstrated a decline in the mitochondrial biogenesis and autophagy in triceps brachii muscle of aged horses. The autophagy marker proteins, Atg5 and LC3-II, were found to decline in aged muscles than in young ones along with a decline in LAMP2, suggesting an impairment in autophagosome-lysosome fusion [17]. Further, the detrimental effect of aging on autophagy was experimented to be exaggerated by the overexpression of mitochondrial aldehyde dehydrogenase (ALDH2), an enzyme with a single-point mutation in humans. The overexpression of ALDH2 decreased longevity and compromised autophagy that included a decline in the phosphorylation of IKKβ, AMPK, and TSC2, and an increase in the mTOR phosphorylation [18]. The impairment in autophagy is also observed in old stromal vascular fractions (SVFs) that are related to the release of pro-inflammatory cytokines (MCP-1 and IL-6) [19]. Moreover, an experiment on mice has demonstrated that glycogen synthase kinase-3β (GSK-3β) has a role to play in aging and found to be inter-related with autophagy. GSK-3β has been found to diminish the cardiac aging via Ulk1 [20].
    Cancer: the autophagic dilemma Autophagy has been found to play an interesting role in cancer biology. It is considered to be a tumor-suppressive mechanism during tumor initiation and malignant transformation. It exerts its inhibitory effect on cancer by removing damaged cells and organelles, thereby limiting cell proliferation and genomic instability. An effective link between autophagy and tumorigenesis is accomplished by tumor suppressor p53 gene, a mutation in which significantly facilitates the progression of cancer. Earlier reports revealed that the gain of function of mutant p53 counteracts the autophagic process through Akt/mTOR pathways. Therefore, p53 shows an inverse relationship with autophagy, thereby regulating cancer progression [21]. Among the autophagy genes, Beclin 1 is reported to be a tumor-suppressor gene. It is observed that Beclin1 locus is deleted up to 75% in ovarian cancers and up to 50–70% in breast cancers [22]. It has also been reported that epidermal growth factor receptor (EGFR) inhibits autophagy by binding to Beclin1, which is involved in autophagic induction, thus allowing the cancer cells to survive against stress conditions. Additionally, it has been witnessed that administration of cetuximab drug inhibits EGFR through suppression of miR-216b that is involved in the inhibition of translation of Beclin1. Therefore, deactivating EGFR favors the up-regulation of Beclin1, thereby favoring autophagy in cancer cells [23]. A knockdown of Atg4 has also been shown to increase the susceptibility to fibrosarcoma in response to carcinogens [24].