The ability of cells to adapt to environmental and genetic insults decreases with age. The promotion of autophagy may decrease the rate of ageing and promote health span. Caloric restriction (CR) refers to the reduction in caloric intake without malnutrition. It has been observed that CR is able to counteract ageing-associated properties. However, it has been found difficult to apply CR to humans. Caloric restriction mimetics (CRMs) are pharmacological agents which mimic the biochemical properties of CR. They mainly result in an overall reduction of protein acetylation and in stimulation of autophagy. Aspirin and salicylate (the active metabolite of aspirin) are able to induce autophagy due to their ability to inhibit the acetyltransferase EP300. Salicylate acts as a competitive inhibitor, binding to the catalytic domain of EP300 instead of acetyl coenzyme A. Therefore, aspirin is able to act as an CRM.

 

What is Autophagy?

The process of autophagy is an evolutionary well-conserved process. This process occurs in all eukaryotic cells, from yeast cells to human cells. There are 3 main forms of autophagy; macro-autophagy, micro-autophagy and chaperone-mediated autophagy. All three forms of autophagy involve lysosomal degradation. Macro-autophagy, which is also referred to as autophagy, is the most common form of autophagy.

 

Phagophores are synthesized at the endoplasmic reticulum-mitochondrial interface. The phagophores are then further elongated by the Golgi and plasma membranes. Once autophagy has been induced, any damaged cell organelles or proteins aggregates are isolated by phagophores. The phagophores eventually mature into autophagosomes, which are double membrane vesicles. The autophagosomes then fuse with acidic lysosomes to form autolysosomes, which degrade and recycle the damaged cell organelles and proteins aggregates.

 

Autophagy is an important housekeeping process that maintains cellular homeostasis. It has been shown, both under physiologic and pathologic conditions, how important this process is in maintaining cellular homeostasis.

 

How is Autophagy related to Ageing?

As stated earlier, autophagy is an important housekeeping process that maintains cellular homeostasis under normal and/or pathological conditions. Under stress conditions (such as nutrient deficiency), autophagy is activated to maintain proper cell function and promote cell survival. It has been observed that autophagy is altered in various ageing studies. Apart from this, the dysregulation of autophagy has been linked with a number of age-associated diseases.

 

Caloric restriction (CR) has diverse effects in counteracting ageing. However, the mechanisms which modulate such processes are still controversial. Recent studies have shown that the activation of autophagy has been linked to the beneficial anti-ageing effect and that CR induced a robust autophagy response in a number of metabolic tissues. It has also been observed that the inhibition of autophagy attenuated the anti-ageing effect of CR.

 

Caloric Restriction Mimetics (CRMs) as Autophagy Inducers

CRMs are drugs or compounds which are able to mimic the effect of CR, mainly the deacetylation of cytosolic proteins. The development of CRMs is based on the pathways and proteins that appear to be altered under CR conditions. Therefore, targets of CRMs include:

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• The glycolysis pathway

• mTOR

• EP300

• AMPK

 

There are several drugs and other compounds which have been shown to be able to act as CRMs through a number of different mechanisms. CRMs can be divided into 3 classes based on their mode of action:

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• Direct inhibitors of protein acetyltransferases and inhibitors of autophagy repressor histone acetyltransferase EP300

• Inhibitors of acetyl CoA biosynthesis

• Activators of protein deacetylases, mainly sirtuin 1

 

How does Aspirin act as a CRM?

Studies have shown that aspirin and salicylate are able to activate autophagy through the inhibition of the enzymatic activity of EP300. Salicylate acts as a competitive inhibitor as it competes with acetyl CoA for binding to the catalytic domain of EP300. Through inhibition of EP300 and possible other acetyltransferases, aspirin inhibits the acetylation of cellular proteins and thus, induces autophagy. In animal models, it was also observed that treatment with aspirin can promote targeting of mitochondria to lysosomal degradation. This indicates that aspirin is able to stimulate mitophagy (selective degradation of mitochondria by autophagy) in vivo. It has been speculated, but further research needs to be carried out, that aspirin may mediate its anti-cancer effects via the induction of autophagy.