*Be sure to start with An Introduction to Autophagy and then Autophagy: When, What, Where, and Why.
I think we can all agree at this point that autophagy is pretty badass. The catabolic process (the act of breaking something down) of autophagy is key in maintaining homeostasis (a stable equilibrium) within the body by cleaning house on a regular basis. Autophagy is like engaging a wonderful home manager who oversees all aspects of upkeep, like snow removal, replacing damaged windows, organizing roof repair, and similar routine maintenance tasks. All of us know what ensues when we choose to ignore the constant insults our homes experience over time from weather, pests, self-identified ‘handy’ partners who overestimate their skill set, and simple aging.
Well, the body is no different. If we’re lucky, our bodies take care of things without us really even recognizing it. It tends to happen quietly under the surface. But when it doesn’t, all hell breaks loose. We get hurt, we get sick, we feel awful, we develop disease, we age. Yes, aging is being acknowledged more and more as a pathology in and of itself. Sometimes our house manager takes a vacation or gets burned out. At other times our house manager goes a little too far and decides to completely replace the roof in the middle of winter instead of addressing a single defunct shingle. As is the case with every single process in the body, autophagy must be tightly regulated. Too much or too little will wreak havoc on the tranquility and functionality of the homestead.
Given its crucial role in metabolism, it comes as no surprise that abnormal autophagy has been implicated in myriad conditions, from cancer to neurodegenerative diseases (1, 2, 3). As damaged cells, organelles, and other cellular components build-up, homeostasis is disturbed. All of this defective cargo sickens the cells around it and leads to dysfunction in neighboring tissues. It’s like letting your child with the flu go to school and expecting the other kids not to fall ill. Kids play, kids explore, kids get up close and personal and the virus invariably spreads. Pretty soon you have an entire classroom of miserable children, and then a whole school. Sorry if this is giving you PTSD as a consequence of our recent experience with COVID, but it is a perfect example of what happens when adequate precautions are not exercised.
What instigates a decline in this incredible, typically protective mechanism of autophagy? Unfortunately, aging does not play kindly with autophagy and is commonly associated with aberrant autophagic processes (1, 2, 3). Recall how autophagy is a response to stress by providing an alternate energy source through the recycling of damaged or old components that are no longer pulling their weight. Aging is correlated with a reduced ability to cope with stress, leading to lazier autophagosomes that fail to keep up. Combine this with a general rise in noxious molecules given off by fragile, elderly cells, and you have a recipe for failing health.
As a quick side note of encouragement, aging might be more of a symptom than a root cause. As we age, we often take our health less seriously. Historically, we tend to accept aging as unmodifiable and unavoidable. The good news is that there is quite a bit we can do to stall ‘aging’ as we know it today. More on that in the next post…
One condition that seems to exacerbate with age is that of glycemic control (1, 2, 3). When we eat, we release a hormone called insulin that is responsible for telling our cells, “Hey! There’s food! Come and get it!” As we age, our cells tire of insulin’s bossy directions and we start to ignore it. Naturally, insulin gets louder in an effort to overcome this apathy. The louder insulin becomes, the more autophagy is suppressed because all of the cells are under the impression that we don’t need any more food. We don’t need to break down faulty cellular components to supply building blocks for growth and development. That’s way more work than just using what’s available. So autophagy chills on the couch with a bowl of popcorn, aimlessly scrolling social media.
What else happens with aging? Well, you know all those signaling molecules we mentioned that direct autophagy to act in the right way? They start to dissipate with age, too (1). So we have insulin giving stop signals to autophagy, we have autophagy mediators that are slowly disappearing, and we have inflammation skyrocketing because of this accumulation of injured or dysfunctional cellular components (2, 3). Clearly, we have a vicious cycle on our hands.
Now we start to encounter diseases that are exacerbated by aging, such as cancer and neurodegeneration. Usually, autophagy will attack pre-cancerous cells that have undergone mutations and appear mischievous (1). With age we have a decline in autophagy clean-up and subsequently an accrual of casualties that instigates inflammation and noxious stimuli, collectively promoting cancer onset (2). Injury to the DNA of cells enables them to develop mutations that permit uncontrolled growth and proliferation, eventually leading to tumor formation (3). P53 is a key gene involved in the regulation of cell growth and is commonly found to be mutated in cancer (1). Mutation of p53 further compromises autophagy by failing to manage a particular signaling pathway called Akt/mTOR which is also implicated in cell growth.
These sinister cancer cells can also manipulate autophagy to their advantage (1). Can you guess why autophagy might be a net benefit to the desire of cancer cells to divide and proliferate at an astonishing rate? FOOD! Yes, autophagy can supply another energy source to hungry cancer cells. Cancer cells can evolve mechanisms to actually upregulate autophagy and selfishly steal nutrients from other cells to serve their own purposes of invading surrounding tissues.
On to neurodegeneration. The brain as one of the most delicate organs is acutely sensitive to impaired autophagy (1). A failure in the process of misfolded protein identification and digestion is exceedingly toxic to the sensitive neurons in the brain (2). The brain is a very metabolically active organ that consequently is exposed to a number of metabolites that can induce injury. Mitochondria, our power plants, are abundant in our demanding brain. They are fantastic at producing energy but prone to generating reactive oxygen species given their high exposure to oxygen (3). I will definitely be writing a series about these slick little molecules, don’t worry. For now, just know that reactive oxygen species display important signaling functions, but they need to be balanced and counteracted to minimize their potentially nefarious activity.
I equate reactive oxygen species to sun exposure. We NEED sun. We literally can’t live without it. It initiates a variety of processes in our bodies, such as vitamin D synthesis that is critical to our survival. However, I’m not about to go from living in the midwest to sunbathing for hours on a beach in Hawaii with no sunscreen. I would be in a world of pain. Reactive oxygen species are just like the sun. We need the right amount to function, but too much and we will burn to the extent that we will be happy to never see the sun again. Scars on our skin might permanently remind us of the sun’s ill effects.
Mitochondria that become too ‘leaky’ by leaching out these reactive oxygen species are typically consumed by autophagosomes and replaced by younger, healthier versions (2). A decline in autophagy permits mitochondria to continue spewing out junk that further impairs autophagy, hurts their neighbors, and can exacerbate sticky protein tangles that poison neurons (1). Interestingly, degrading these toxic proteins can also potentiate the release of dangerous substances. As neurons die from assault by protein aggregates or inflammation, brain volume decreases and symptoms such as dementia become present (3).
Finally, we arrive at the three big, bad wolves. Diabetes, obesity, and heart disease afflict the vast majority of Americans, and disrupted autophagy has been found to be a contributor to the pathology of these diseases (1, 2, 3). Defective mitochondria are once again a culprit, causing impaired metabolic function and inflammation. Similar to neurodegenerative diseases, the autophagic machinery is commonly deficient in patients with obesity, diabetes, or cardiovascular disease. As the damage gets out of control, inflammatory conditions emerge in the arteries, adipose tissue, or pancreatic tissue. Inflamed arteries instigate changes in blood pressure and lead to plaque build-up. Necrotic adipose tissue creates a vicious cycle of spewing out noxious molecules that induce a host of comorbidities. In diabetes, cells of the pancreas die off, hindering adequate glucose control.
Seeing how much autophagy controls various processes implicated in disease, it is no wonder that dysregulated autophagy has been implicated in not only aging, cancer, and neurodegeneration, but also obesity, diabetes, infectious disease, autoimmunity, and heart disease, among others (1, 2, 3). The underlying theme we continuously see is that autophagy is a (mostly) protective mechanism of maintenance of homeostasis, clearing debris that would otherwise disrupt normal cellular processes by perpetuating an inflammatory state. I am excited to discuss how we might be able to keep autophagy working for us throughout our lifetimes in my subsequent post!
References
- Saha S, Panigrahi DP, Patil S, Bhutia SK. Autophagy in health and disease: A comprehensive review. Biomedicine & Pharmacotherapy. 2018;104:485-495. doi:10.1016/j.biopha.2018.05.007
- Ichimiya T, Yamakawa T, Hirano T, et al. Autophagy and Autophagy-Related Diseases: A Review. Int J Mol Sci. 2020;21(23):8974. Published 2020 Nov 26. doi:10.3390/ijms21238974
- Klionsky DJ, Petroni G, Amaravadi RK, et al. Autophagy in major human diseases. EMBO J. 2021;40(19):e108863. doi:10.15252/embj.2021108863