Eaten alive: the double-edged sword of autophagy

I can’t believe how many months I procrastinated in writing this blog post. Among deadlines and diaper changes, it just took me that much time to put my thoughts in order regarding a part of aging that I thought was crystal clear: aging leads to slow clearance therefore autophagy induction must always be a good thing. Wrong!

At a very crude level, turning on autophagy is not that hard. During most mornings, I barely have time to drink my tea instead of eating some calorie-rich breakfast. I wish I could burn fewer calories to reach that elusive normal weight range but tasks just pile up and ideas come to me so fast that I end up as an underweight, sleep-deprived polymath. You see, turning on autophagy is easy once you stress your body: with fasting and/or lots of exercise.
Lots of other negligibly senescent species have an upregulated autophagy, not because they have too many ideas that must be implemented sooner or later, but because they have evolved in harsh environments, deprived of too much oxygen, warmth or nutrients. Autophagy is an ancient evolutionary mechanism that makes organisms more resistant to stress. What doesn’t kill you may help you survive far longer as mild stress is known to induce autophagy and hence, make it more likely for cells to survive and less likely to commit suicide by apoptosis. Unless the stress is too much to handle.
Or unless you don’t want those cells to survive in the first place! This is an angle that I didn’t consider beforehand with my simplistic thinking that inducing autophagy is always a good thing in order to slow down aging.

It so happened that doing something completely unrelated, I stumbled upon the package leaflet of ambroxol, a mucolytic drug used for productive cough and from there to the hypothesis that this drug – and its parent, bromhexine– could be used in parkinsonism because it induces autophagy.

So I thought to myself: if aging impairs autophagy and mucolytic drugs are so cheap and widely available, could this be a path to slow down the inevitable onset of neurodegenerative diseases if one lives long enough?

While autophagy can be modulated by lifestyle (fasting, calorie restriction, exercise which all upregulate it) or by genetic engineering (in lab animals, at least), many commonly used medications induce it. Drugs known for inducing autophagy include rapamycin and metformin. Most people interested in life extension know about these two but here are many others I found that do the same: EGFR antagonists and tamoxifen (mostly used in oncology), clonidine, rilmenidine and verapamil (all three used as antihypertensive agents), mood stabilizers such as lithium, carbamazepine and valproic acid, dietary supplements such as resveratrol, vitamin D, spermidine and coenzyme Q and many others you can check in this review paper.

So there is a huge potential to test autophagy induction in clinical trials and see how that impacts aging-related biomarkers as well as average and maximum lifespan. But given that autophagy upregulation is not a magical solution, I think it would be best if it could be upregulated in short bursts at a time and only after some screening tests for cancers, chronic infections and maybe even for autoimmune diseases and allergies. Since these conditions can occur at any age, it would be great if autophagy could be intermittently modulated on demand. Even better, drugs that could activate autophagy for specific substrates only, whether these include protein aggregates, organelles or microorganisms, would provide the most benefits with the least side effects. For improved aging-related protein clearance, pharmacological modulation of autophagy could also be used together with proteasome modulation when additional proteinopathies are due to unfolded proteins instead of aggregated ones (for example, bortezomib in multiple myeloma).

Autophagy is upregulated in many negligibly senescent species but is it a good idea in humans too?

Mild stress that activates autophagy leads to cytoprotection and given how many somatic cells in adults can’t divide anymore (because we are not hydras, particularly the ones that don’t age), it’s no wonder that people who exercise regularly and who maintain a normal weight range, ideally toward the lower limit of that range, get to collect many decades of life. At the same time, some cells must die to allow the organism as a whole to survive – the same metabolic pathway of autophagy can increase the survival of cancer cells, especially those living in hypoxic areas due to not building up enough blood cells to satisfy their greedy demand for oxygen and nutrients.
Most physicians encounter cancer among their patients but every day, oncologists get to see cellular evolutionary battles in action. Malignant cells are very aggressive and they’ll take advantage of anything, including their own parent cells. Autophagy blockers could sensitize tumor cells to cytotoxic chemotherapy and radiotherapy. Mild stress increases autophagy and may lower the risk of cancer but once a tumor is on its way to taking down the host, blocking autophagy to impair the adaptation of malignant cells to the stress inherent in being a greedy, demanding cell as well as to the stress induced by the many biological therapies that block growth factors – so necessary for them to build a network of blood cells – as well as to the stress induced by toxic therapies like chemotherapy and radiotherapy may be just what is needed to prevent dormant tumor cells from reactivating later on.
Fortunately, two autophagy blockers are already in clinical trials in oncology: chloroquine and hydrochloroquine. These are lysosomal inhibitors and are already used as treatment in malaria and systemic lupus erythematosus.

If autophagy inducers will one day be used widely to slow down aging, especially to postpone the onset of age-related metabolic disorders (diabetes, obesity, steatohepatitis) and neurodegenerative diseases (dementias of all sorts), patients should be screened for cancer. Long-term autophagy induction may improve the housekeeping of cells and make them less likely to divide like crazy but once an individual has cancer, autophagy blockers coupled with toxic therapies prescribed by the oncologist may prove to be a safer bet. Additionally, whether a tumor has defective or intact genes for autophagy may also influence whether autophagy should be increased or decreased in such a patient.

But it’s not only tumors that should be screened.

Chronic infections should be tested too. Microorganisms either block autophagy to evade being digested and/or recognized by the host’s immune system (herpes viruses like HSV-1 in neurons and human CMV in fibroblasts, human HIV-1 in CD4 lymphocytes and macrophages, Porphyromonas gingivalis which is involved in parodontosis and atherosclerosis) or induce autophagy in order to take advantage of the autophagic machinery itself, to get some nutrients for growth and replication, to facilitate viral release from the host cell or to use the autophagosome as a shield and then prevent it from being fused with the lysosome for digestion (HIV in bystander lymphocytes, HCV and HBV in hepatocytes, picornaviruses, Dengue virus, Francisella tularensis, Coxiella burnetii, Brucella abortus). Just like with cancer, it depends whether inducing or blocking autophagy would work in patients with acute or chronic infections, especially if those microorganisms are intracellular. Differences could also occur between what we know about autophagy from in vitro and ex vivo versus what actually happens in vivo, especially if the studied host-microbe pair doesn’t share a long evolutionary history. Because it’s not only hosts that can undergo autophagy.

Microbes can undergo autophagy too, especially if they are eukaryotes themselves.

Autophagy in microorganisms could make them more resistant to stress when nutrients are scarce; alternatively, the stress that leads to autophagy may be necessary for their differentiation into infective forms necessary to attack mammalian hosts like us. In cases of infection, whether autophagy can be detected in vivo or not depends a lot on the host-microorganism pair. It takes two to tango. If the two share a long evolutionary history together, it is very probable that the microorganism learned to either block or subvert autophagy in the host but if you infect cells from another species with that same microorganism, autophagy in the host cell may be more intense because the microorganism didn’t have time to adapt to it.

If you were looking for new pharmacological targets and substances to either induce or block autophagy, microorganisms that share a long history in infecting humans are probably a low-hanging fruit in discovering such molecules.

By virtue of the microorganism involved, such molecules would also be specific to a certain type of tissue and/or substrate.

It would be ideal if such molecules could stimulate or inhibit the autophagy pathway of a certain microorganism in an infected patient but not autophagy in the host. For example, that could be useful in cryptococcosis where the fungus causing it needs autophagy to survive and replicate.

Aging is associated with an increase in microbial load which I previously wrote about here. While drafting this blog post, I mused over neurotropic viruses like HSV-1 whose prevalence increases with age and whether silencing autophagy by such viruses – and probably other microorganisms as well – could explain the age-related increases in protein aggregates, tumors and apoptosis rates in post-mitotic somatic cells. Similarly, could the age-related upregulation of the mTOR metabolic pathway be partially explained by the frequent CMV infection in humans, a virus that activates mTOR to inhibit autophagy for its own good? The virus does this in fibroblasts, cells that produce collagen and glycosaminoglycans. These are the cells that create our structure (which is visibly diminished when wrinkles set in) and also the cells that produce scars when wounds inevitably appear.

There is another way through which autophagy could have mixed effects on maximum lifespan.

If stress is mild, adaptation to that stressor increases and if the stress is too much to handle, the cell will commit suicide by apoptosis. But the stress can also be somewhere in between and the cell will avoid turning into a malignant one by autophagy-enabled senescence. This could be a good thing for the immune system because it would continue to be exposed to antigens related to that stressor (whether the affected cell was dividing too often or whether it was infected with who knows what kind of microorganism) but it could also be a bad thing if too many non-dividing cells become senescent and maintain the organism in a state of chronic inflammation.

In mice and C. elegans at least, autophagy also impacts sexual reproduction, being necessary for degrading the components of the oocyte cytoplasm, for eliminating the paternal mitochondria after fertilization and during the early neonatal starvation period. In case autophagy plays the same role in humans too, family planning should also be taken into consideration before prescribing autophagy inhibitors, if such drugs would be deemed necessary. At least if humans will still reproduce by nature instead of by tech.

Apart from the need to adequately monitor autophagy, preferably non-invasively, side effects of intermittent or even long-term autophagy modulation should be monitored as well.

• Do patients with long-term autophagy upregulation have fewer mycobacterial or other intracellular infections? Do they develop a chronic inflammatory phenotype due to an increased number of senecescent cells that their body won’t remove on its own? Are cancers missed in such patients more likely to progress to metastases?

• On the other hand, are patients taking autophagy inhibitors on the long term more likely to develop secondary tumors, infectious or autoimmune diseases? Are they more likely to develop age-related metabolic and neurodegenerative diseases?

The incidence, prevalence and severity of such diseases must be monitored if this double-edged sword called autophagy is to be used for increased lifespan and quality of life with the least side effects possible.

Anca Ioviţă is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, don’t forget to sign up to receive updates on longevity news and novel book projects!

Don’t miss out on the Pinterest board on calorie restriction with optimal nutrition where she pins new recipes every day.
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