Restoration of Autophagy as a Goal in the Treatment of Aging

The processes of autophagy act to remove damaged molecular machinery and structures in the cell. Autophagy becomes dysfunctional with age, however. This is likely downstream of underlying causes of aging that cause changes in gene expression that degrade the function of autophagic processes in one way or another. For example mitophagy, the clearance of damaged mitochondria by autophagy, is indirectly negatively impacted by changes in mitochondrial dynamics resulting from altered gene expression. Equally, age-related changes in gene expression produce defects in the formation of autophagosomes, and this affects all aspects of autophagy.

Many of the known interventions that slow aging in animal models appear to improve the efficiency of autophagy, and functional autophagy is required for the extension of healthy life span via calorie restriction to take place. While improvement of autophagy has been a goal in the research community for quite some time, surprisingly little concrete progress has been made towards the development of therapies that specifically target dysfunction in autophagic processes.

Calorie restriction mimetics such as mTOR inhibitors improve autophagy, and mitochondrially targeted antioxidants and NAD+ upregulation may act to restore mitophagy. These were not designed with the enhancement of autophagy in mind; rather, it has been found to be one of their outcomes. The research and development communities have yet to see success in the development of narrowly targeted means of restoring a youthful function of autophagy in old tissues, though a few groups, such as the startup Selphagy Therapeutics that emerged from work on LAMP2A upregulation in the liver, are working in that area.

Selective Autophagy as a Potential Therapeutic Target in Age-Associated Pathologies

Cellular garbage disposal is critical for recycling defective cell constituents, such as proteins and organelles, towards the maintenance of cellular homeostasis. One of the main degradative molecule pathways is autophagy, which is a physiological catabolic process shared by all eukaryotes. Derived from the Greek words 'auto' meaning self, and 'phagy', meaning eating, autophagy, it was initially considered to be a bulk degradation process, while now its highly selective nature is increasingly appreciated. This self-digestive mechanism relieves the cell from proteotoxic, genotoxic, oxidative, and nutrient stress. It is accomplished in an intricate stepwise manner, which leads to clearance of damaged cell constituents, in the degradative organelle, the lysosome. Failure to complete this procedure has been implicated in many age-related diseases.

Homeostatic mechanisms that respond to mitochondrial damage are less efficient during aging. Mitophagy is a physiological eukaryotic pathway, which involves the degradation of superfluous or damaged mitochondria. When perturbed, normal mitochondrial function is hindered, resulting in the production of excessive reactive oxygen species (ROS). This ultimately leads to cellular dysfunction and tissue damage. Defective mitophagy is evident in a variety of age-related pathologies such as neurodegeneration, metabolic syndromes, and myopathies.

Aggrephagy degrades aggregation-prone proteins via targeted macroautophagy, in addition to chaperone-mediated autophagy and the proteasomal pathway. These proteins typically form aggresomes near the nucleus, which are surrounded by intermediate filament cytoskeleton, and are further processed to be degraded by autophagy. Protein aggregation usually occurs due to misfolding and can cause, among others, dysregulation of calcium homeostasis, inflammation, neurotoxicity.

Recycling of peroxisomes is also regulated by autophagy. These small dynamic single membrane organelles regulate fatty acid oxidation, production of bile acid and other lipids, while also producing ROS, which is neutralized by catalase. Moreover, peroxisomes interact with a multitude of other cellular constituents, such as lipids, the endoplasmic reticulum (ER), and mitochondria. Pexophagy and peroxisome biogenesis have recently been implicated with disease. During aging, peroxisomal targeting signal 1 (PTS1) protein import deteriorates and catalase function is diminished. Peroxisomes become more abundant and PEX5 accumulates on their membranes. This causes increased production of ROS, which further blocks peroxisomal protein import and contributes to aging.

With regard to therapeutic intervention, several pharmacological compounds have been shown to activate mitophagy and alleviate symptoms of age-related diseases, dependent on dysfunctional mitochondria. Rapamycin activates AMPK, while blocking mTOR, maintaining energetic demands and preventing neurological symptoms, such as neuroinflammation. Metformin and pifithrin induce Parkin by inhibiting p53 activity and alleviating diabetic phenotypes. Resveratrol, mainly found in grape skin, as well as, NAD+ precursors found in natural compounds activate mitophagy and mitochondrial biogenesis through the sirtuin 1 (SIRT1)-PGC-1α axis. Urolithin A, an intestinal microbiome-derived metabolite from dietary intake, induces both mitochondrial degradation and biogenesis, and increases health span of model organisms such as C. elegans and mice.

Selective autophagic induction by genetic intervention or chemical compound administration is currently being investigated in multiple diseases as potential therapeutic approach, although no drug has reached the clinic yet. Indeed, clinical studies concerning druggable autophagy targets remains limited. This highlights the complexity and intricacies of selective autophagic pathways, which in humans, cannot be easily targeted due to context-dependence and extensive crosstalk with other functional networks. Thus, initial optimism has subsided, with research now focusing on specific compounds that could target specific aspects of selective autophagy. An important objective of the collective efforts of the research community and pharmaceutical companies is to achieve targeting selective autophagy mediators, while not affecting other cellular processes.


since rapamycin is one of (if not the) most powerful MTOR ihnibitors (hence the R in the MTOR abbreviation) it should be used as golden standard for efficacy .

I wonder if rapamycin is taken during fasting would the fasting effects be enhanced or basically that is reaching the limit

Posted by: Cuberat at September 16th, 2021 3:50 PM

Autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis.
Autophagy is inhibited by mTORC1, a central cell-growth regulator that integrates nutrient signals.

ULK1 is an upstream component of the core autophagy machinery, initiating autophagy.

AMPK phosphorylates ULK1 in response to cellular energy starvation to control ULK1 kinase function and autophagy induction. When nutrients are sufficient, mTORC1 phosphorylates ULK1, preventing its association and activation by AMPK.

During fasting AMPK initiates autophagy, mTORC1 won't be active due to lack of nutrients.
There won't be much that rapamycin can add.

Posted by: Jones at September 16th, 2021 4:27 PM


Exercise and fasting should be the golden standard!

Posted by: Stephan at September 16th, 2021 6:11 PM

AFAI understand the issue rapamycin's value is that it inhibits mTOR in tissues/cells with deregulated mTOR activity, i.e. mTOR is active even though there're not sufficient nutrients.
A likely cause for this seems to be mitochondrial ROS distress and dysfunction.
mTOR overactivation seems to be an issue in aging, hence rapamycin shows some beneficial effect in that it allows AMPK/ULK1 induced autophagy to happen by mTOR inhibition.

Posted by: Jones at September 17th, 2021 1:09 AM

Remember that rapamycin has an effect on histone count and thus DNA packing efficiency which is also important in aging in particular the genomic instability and epigenetic alteration hallmarks. Rapamycin does not just work via mTOR targeting and it is NOT "just a caloric restriction mimetic" as some people keep on repeating despite new evidence to the contrary.

Posted by: Steve Hill at September 17th, 2021 7:11 AM

Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice

'Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair-deficient Ercc1∆/- mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair-deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action.'

Posted by: Jones at September 17th, 2021 4:19 PM

Just if one wanted to have some autophagy going without having to starve, using prescription drugs off-label to meddle with mTOR and/or shelling out lots of money.

Trehalose causes low-grade lysosomal stress to activate TFEB and the autophagy-lysosome biogenesis response

'The autophagy-lysosome system is an important cellular degradation pathway that recycles dysfunctional organelles and cytotoxic protein aggregates. A decline in this system is pathogenic in many human diseases including neurodegenerative disorders, fatty liver disease, and atherosclerosis. Thus there is intense interest in discovering therapeutics aimed at stimulating the autophagy-lysosome system. Trehalose is a natural disaccharide composed of two glucose molecules linked by a ɑ-1,1-glycosidic bond with the unique ability to induce cellular macroautophagy/autophagy and with reported efficacy on mitigating several diseases where autophagy is dysfunctional. Interestingly, the mechanism by which trehalose induces autophagy is unknown. One suggested mechanism is its ability to activate TFEB (transcription factor EB), the master transcriptional regulator of autophagy-lysosomal biogenesis. Here we describe a potential mechanism involving direct trehalose action on the lysosome. We find trehalose is endocytically taken up by cells and accumulates within the endolysosomal system. This leads to a low-grade lysosomal stress with mild elevation of lysosomal pH, which acts as a potent stimulus for TFEB activation and nuclear translocation. This process appears to involve inactivation of MTORC1, a known negative regulator of TFEB which is sensitive to perturbations in lysosomal pH. Taken together, our data show the trehalose can act as a weak inhibitor of the lysosome which serves as a trigger for TFEB activation. Our work not only sheds light on trehalose action but suggests that mild alternation of lysosomal pH can be a novel method of inducing the autophagy-lysosome system.'

Posted by: Jones at September 18th, 2021 1:17 PM
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