Upregulation of Autophagy to Treat Age-Related Disease

Regulation of autophagy has been a tremendously popular topic in the aging research community over the past twenty years, so much so that it is very surprising that little progress towards clinical therapies has been made. Search PubMed for autophagy and aging and you'll find a deluge of papers over this time frame, many of which express optimism on the topic of finding ways to upregulate autophagy to improve health and slow the aging process. It is the consensus in the research community that autophagy declines with age, and that there are benefits to be realized through increased autophagy. This may allow many age-related conditions to be treated, slowed, or postponed. All of this is taken as self-evident from the voluminous evidence accumulated to date.

What is autophagy? It is a collection of maintenance processes responsible for recycling broken or otherwise unwanted cellular structures and proteins. In the case of chaperone-mediated autophagy, target proteins are guided by a chaperone protein and imported into a lysosome for disassembly. For macroautophagy, an autophagosome membrane forms around the target structure, moves to a lysosome, and fuses with it. In microautophagy, a lysosome directly engulfs the target without assistance. In all cases, a lysosome is the final destination, a membrane packed with enzymes capable of taking apart near everything it will encounter inside a cell. The component parts are then released for reuse.

Many of the methods shown to slow aging and extend life span in short-lived laboratory species involve upregulation of autophagy. Calorie restriction is the canonical example, but increased autophagy is a common response to many forms of stress. Greater autophagy helps cells to survive, it reduces levels of cellular damage, it improves function. Brief stress can leads to lasting autophagy, and thus intermittent stresses tend to improve health and lengthen life - the process known as hormesis. That said, short-lived animals have much greater plasticity of life span than is the case for long-lived species such as our own. While calorie restriction, which arguably largely acts through autophagy, clearly improves human health significantly, we don't gain anywhere near the life extension observed in mice.

When are we going to see drugs that enhance autophagy? Calorie restriction mimetics such as mTOR inhibitors and the like work to some degree through upregulated autophagy. More rationally designed (rather than discovered) drugs aimed directly at the controlling mechanisms of autophagy are thin on the ground, however. If I'd been asked ten years ago how soon I thought that autophagy-targeted drugs of that sort would arrive on the scene, I'd have said imminently. Clearly I was wrong. The state of the research community on this topic looks exactly the same today as it did a decade ago, and no targeted autophagy enhancers are yet in evidence. About the only observable difference is that there might be one or two more companies working in this space, such as Selphagy Therapeutics, and a little more funding for those companies. I'd nonetheless throw up my hands and say I have absolutely no idea as to when targeting autophagy will become a going concern in the clinic.

Targeting Autophagy to Overcome Human Diseases

Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where the breakdown products are recycled back to cytoplasm. Dysregulation of autophagy can induce various disease manifestations, such as inflammation, aging, metabolic diseases, neurodegenerative disorders, and cancer. The understanding of the molecular mechanism that regulates the different phases of the autophagic process and the role in the development of diseases are only in an early stage. There are still questions that must be answered concerning the functions of the autophagy-related proteins.

Autophagy, Inflammation and Aging

Autophagy has been identified as main regulator of the inflammasome; a major innate immune pathway activated by exogenous stimuli, such as pathogenic microorganisms, or by endogenous mediators, such as reactive oxygen species (ROS), mitochondrial damage, and environmental irritants. Inflammasome activation involves formation and oligomerization of a protein complex, followed by release of proinflammatory cytokines, such as IL-1β and IL-18, from innate immune cells. In particular, when endogenous mediators induce massive inflammatory response, they can cause tissue damage and promote the onset of inflammatory diseases. Therefore, negative or positive regulation of inflammasome is essential to ensuring a good state of health.

As demonstrated by multiple studies, autophagy can negatively regulate inflammasome activation through different mechanisms, including by removing damaged organelles such as mitochondria, leading to reduced release of ROS and subsequent suppression of inflammasome activation. Autophagy deficiency causes inflammasome-related inflammatory diseases. Overall, data suggests that inflammasome and autophagy mutually regulate each other, favoring the balance between inflammatory response to defend itself from the host and prevention of excessive inflammatory response that can induce tissue damage and inflammatory disease. Recent studies have shown that the impaired autophagy activity that characterizes aging is due to accumulation of dysfunctional mitochondria, ROS, and NLRP3 inflammasome activation in macrophages. These factors predispose the cells to greater risk towards aging diseases, such as atherosclerosis and type 2 diabetes.

Autophagy and Neurodegenerative Disorders

The aggregation of misfolded proteins and some neuronal population losses are typical of the expression of pathological neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Autophagy has been reported to be involved in the occurrence of neurodegenerative disorders, being the main intracellular system for degrading damaged organelles and aggregated proteins. In neurodegenerative diseases, an alteration of the maturation mechanism of the autophagosome in the autophagolysosome has been found.

Moreover, autophagy plays an important role in the degradation of different proteins correlated with degenerative diseases, such as mutated α-synuclein in Parkinson's disease, mutant huntingtin in Huntington's disease, and the mutant TPD-43 in amyotrophic lateral sclerosis. In Alzheimer's disease, the presence of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, composed of hyperphosphorylated tau proteins aggregates, has been revealed. In the healthy brain, the autophagosome vesicles are not very visible; instead, in the Alzheimer's disease brain, numerous autophagosomes are noticeable. Accumulation of autophagy vacuoles arises from impaired clearance rather than autophagy induction, suggesting the late stages of autophagy modulation as a possible therapeutic strategy for Alzheimer's disease.

The role of autophagy in Parkinson's disease has been demonstrated by the presence in neurons of lysosomal and autophagosomes alterations; to support this evidence, when the lysosome is functionally altered, the amount of α-synuclein is elevated, indicating an alteration of the autophagy pathway. TFEB has been identified as the factor that positively regulates genes related to formation of autophagosomes and the lysosome fusion, increasing the clearance of lysosomal exocytosis. Recently, it has been shown that its overexpression can reduce the lysosome damage and thus improve the neurological disorders related with α-synuclein.

Comments

CR and fasting seem to boost autophagy. I wonder how to measure it in vivo

Posted by: cuberat at February 26th, 2019 5:03 PM

Yet just in the last week this study has received a lot of press.
https://www.nature.com/articles/s41467-019-08555-w

dimethoxychalcone (DMC). This flavonoid is highly present in Angelica keiskei, or ashitaba and boosts autophagy in cell studies.

Posted by: August at February 26th, 2019 6:51 PM

No reason to fear overpopulation. Annually there are 85 million unplanned pregnancies and when a non hormonal p-pill is developed for men there will be 85 million unplanned pregnancies less -

"They take one look at the 85 million unplanned pregnancies that happen every year and see a huge demand for contraceptives that don't currently exist. Filling this gap would help give women more control over their financial and medical lives, and may prevent some of the 25 million unsafe abortions performed worldwide each year."

https://www.wired.co.uk/article/male-contraceptive-pill-hormone-gel

Posted by: thomas.a at February 27th, 2019 2:01 AM

I agree, and that's why I and Apollo just launched Samsara Therapeutics to enhance autophagic flux. The 4,4'-DMC paper in Nature Comms is ours. :-)

https://samsaratherapeutics.com

Posted by: Sebastian Aguiar at March 3rd, 2019 5:13 PM

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