Lysosomes, Autophagy and Longevity

Autophagy means “eating of self” (from Ancient Greek “autó”= self;  and “phagein” = to devour). Lysosomes are the storage structures of intra-cellular enzymes. In this page, i will first review the basics on autophagy 7 Lysosomes (Section A) and follow up on their link with longevity (Section B)

Section A

The basics

What are Lysosomes ?

Lysosomes are the main catabolic organelles of a cell and play a pivotal role in a plethora of cellular processes, including responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation. In line with this pleiotropic importance for cellular and organismal life and death, lysosomal dysfunction is associated with many age-related pathologies like Parkinson’s and Alzheimer’s disease, as well as with a decline in lifespan.
Conversely, targeting lysosomal functional capacity is emerging as a means to promote longevity. The current knowledge on the prominent influence of lysosomes on aging-related processes, such as their executory and regulatory roles during general and selective macroautophagy, or their storage capacity for amino acids and ions suggests that that lysosomes are key in the aging process. (Source)

What is Autophagy?

Autophagy is the way cells break down misbehaving or nonfunctional organelles and proteins in the cell[1,2]. This means autophagy can consume organelles, such as mitochondria, peroxisomes, and the endoplasmic reticulum[1].

Mitochondria are the power plants of your cells that convert nutrients into cellular energy. Peroxisomes are small, membrane-enclosed organelles that contain enzymes involved in various metabolic reactions, including aspects of energy metabolism. The endoplasmic reticulum is a network of membranous tubules within the cytoplasm of a eukaryotic cell, continuous with the nuclear membrane. It usually has ribosomes attached and is involved in protein and lipid synthesis.

Aberrant proteins and organelles, if left unchecked, could potentially damage the cell. At the very least, they can fail to perform their needed functions[1]. One good example of this is dysfunctional mitochondria. Autophagy can selectively remove aberrant mitochondria that have no membrane potential. If not removed, these mitochondria can release reactive oxygen species which can promote apoptosis (destruction of the cell)[2].

Autophagy is also one way our cells deal with energy shortages[2]. For example, after a period of fasting, a body’s cells will respond by breaking down some of their organelles and proteins for energy.

Finally, you can also think of autophagy as a recycling mechanism. During autophagy, proteins and organelles go through catabolism, a process that breaks them down into amino acids and other small components. These small components can be reused to create new proteins and organelles[1, 2].

Summed up, autophagy does the following things: clears out impaired proteins and organelles[1], allows the harvest of energy when it breaks down proteins and organelles during energy shortages[2], and allows recycling of the catabolised proteins and organelles into new ones[1].

How Does Autophagy Work?

Say a cell has a misfolded protein. Before it can be broken down or digested, it needs to be separated off from everything else. If this wasn’t the case, the proteases (proteins that break down other proteins) would sabotage the cell by breaking down both healthy and dysfunctional parts haphazardly.

A membrane called a phagophore, also known as the isolation membrane[2], separates the aberrant protein from everything else[1]. This double membrane wraps around the protein to form what is called an autophagosome. From there, this bubble (the autophagosome) makes its way to a lysosome[1].

Lysosome

The lysosome is a protease packed vesicle organelle that breaks down unwanted parts of the cell. Think of it as a membrane-bound sack of digestive proteins ready to break down anything the cell doesn’t want anymore. One useful metaphor for the lysosome is, if the cell was a city, the lysosome would be the dump and recycling center[3]. The autophagosome fuses with a nearby lysosome to form the autolysosome[1]. (See video below).

Our protein is now getting exposed to proteases that can digest it. Once the protein has been digested into amino acids, permeases and transporters carry off the amino acids to wherever they can be used[1]. Permeases are proteins that help substances get through membranes. Likewise, transporters are proteins that, predictably, transport things.

If you had to teach a young child how autophagy works, you’d explain that a small bubble forms around the protein (autophagosome). Then, it fuses with another bubble (a lysosome) to form a new one (an autolysosome). There, the protein breaks into smaller pieces. Other proteins aid in transporting these pieces elsewhere so that they can be used for building new structures.

In summary, the main steps of autophagy are: separation of the protein/organelle into an autophagosome by the phagophore, autolysosome creation via the fusion of  the autophagosome with a lysosome, breakdown of protein/organelle by acid proteases found in the lysosome, and shuttling of amino acids (and other products of catabolism) by permeases and transporters to be recycled [1].

Why is it beneficial?

As previously mentioned, autophagy functions as a survival mechanism when energy gets low, and it aids the development of several lower-model organisms, including yeast, Drosophila, and C. elegans[1]. In mouse models, autophagy seems to aid cytosol changes during embryonic and postnatal development[5]. It alleviates the issue of aggregated or misfolded proteins. It also rids the cell of some types of damaged organelles[1], and it serves as an innate immune system defense against both viral and bacterial pathogens[6].

Despite its noxious-sounding name, autophagy serves more of a protective role than a harmful one. This was observed in studies in which rodents were subjected to damage of the heart, nervous system, liver, and kidney[2]. It also seems to help protect against neurodegeneration, cancer, diabetes, and heart, liver, and autoimmune disease[1]. Autophagy can recycle aberrant mitochondria and can reduce unnecessary cell death in cells after they divide[2].

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What does autophagy have to do with aging?

Autophagy and aging seem to be intimately connected. When the genes that cause autophagy are inhibited in mammalian cells, we observe degeneration. Much of this degeneration resembles the degeneration we see in aging. Aging itself often comes with reduced autophagy. When we stimulate autophagy, we seem to mitigate aging. Conversely, when we curtail it, we exacerbate aging[2].

The numerous strategies for slowing aging in model organisms also often cause autophagy to occur. This begs the question of whether these interventions work because they cause autophagy, and this might be the case. When we inhibit autophagy during some lifespan-extending therapies (such as calorie restriction, insulin growth factor pathway inhibition, spermidine, resveratrol, or rapamycin), it erodes the anti-aging effects[2].

We can also see the beneficial effects of autophagy in the study of age-related diseases, such as atherosclerosis[4]. Atherosclerosis is a circulatory disease characterized by hardening and narrowing of the arteries caused by plaque formation. Unabated, atherosclerosis can lead to heart attacks, strokes, and other forms of circulatory disease[7]. One study established a connection between reduced autophagy and the formation of the plaques responsible for atherosclerosis. Researchers bred mice to have enhanced autophagy via increasing the expression of a gene called TFEB.  The change seemed to have a protective effect against atherosclerosis caused by a Western diet. Furthermore, they showed that trehalose, a naturally occurring sugar, enhances autophagy. It reduced the signs of atherosclerosis when it was injected into the body cavities of mice[4].

Case in point: artherosclorosis, macrphages and autophagy

In the case of macrophages, the cells that protect our blood vessels from damage by the toxic byproducts of cholesterol, they can become dysfunctional from the accumulation of waste in the lysosomes that the cell cannot break down. Macrophages work by surrounding these toxic byproducts and breaking them down in their lysosomes into useful materials the cell can use.

Macrophages are responsible for cleaning up many kinds of cellular waste, including misfolded proteins, excess fat droplets, and dysfunctional organelles and are the housekeepers of the body. Over time, macrophages consume ever more amounts of toxic materials, and eventually their lysosomes become filled with insoluble waste that cannot be destroyed.

This causes the macrophages to eventually stop functioning and either become trapped and immobile in the artery wall or simply die. It is the buildup of trapped macrophages in the artery wall that is the basis of arterial plaques, or what most people know as heart disease. Eventually, once the plaques grow too large, the injury swells and bursts, sending out clots that trigger strokes and heart attacks.

One of the potential ways to address this problem this is by increasing autophagy in macrophages, which makes them better at dealing with the toxic waste and helps them resist stress. It is the hope of some researchers to find ways to improve autophagy, thereby making macrophages more robust and slowing the accumulation of lysosomal waste, preventing heart disease.

Improving autophagy could help combat heart disease

This new study published in nature communications demonstrates that finding ways to make macrophages more efficient and more resistant to stress can help to slow the progression of atherosclerosis. The approach also has the potential to treat other diseases, such as fatty liver disease and type 2 diabetes.

The research team found that a natural sugar known as trehalose boosts autophagy in macrophages, encouraging them to improve their housekeeping efforts. These enhanced macrophages are then better able to deal with the toxic materials and break down the atherosclerotic plaques that have built up inside arteries and cause heart disease.

In the study, the researchers showed that mice prone to atherosclerosis had reduced plaque levels in their arteries after being injected with trehalose. The sizes of the plaques measured at the aortic root were variable, but on average, the plaque size measured 0.35 square millimeters in control mice versus 0.25 square millimeters in the mice given trehalose. This was approximately a 30 percent reduction of plaque size and is therefore statistically significant.

Conclusion

Autophagy shows promise as an important maintenance and repair mechanism, especially in the context of aging. A number of research efforts are working on increasing the level of autophagy in cells in order to make the body work more efficiently.

Reference and Precision Notes

[1]Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. The Journal of Pathology, 221(1), 3-12. doi:10.1002/path.2697

[2]Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011). Autophagy and Aging. Cell,146(5), 682-695.

[3] (2012, February20). Retrieved July 19, 2017, from https://www.youtube.com/watch?v=cj8dDTHGJBY

[4]Sergin I, Evans TD, Zhang X, Bhattacharya S, Stokes CJ, Song E, Ali S, Dehestani B, Holloway KB, Micevych PS, Javaheri A, Crowley JR, Ballabio A, Schilling JD, Epelman S, Weihl CC, Diwan A, Fan D, Zayed MA, Razani B. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nature Communications. June 7, 2017.

[5] Cecconi, F., & Levine, B. (2008). The Role of Autophagy in Mammalian Development: Cell Makeover Rather than Cell Death. Developmental Cell, 344-357. doi:10.1016/j.devcel.2008.08.012

[6] Wileman, T. (2013). Autophagy as a defence against intracellular pathogens. Essays in Biochemistry, 153-163. doi:10.1042/bse0550153

[7] Atherosclerosis: What role does it play? Retrieved August 17, 2017, from https://www.heart.org/HEARTORG/Conditions/Cholesterol/WhyCholesterolMatters/Atherosclerosis_UCM_305564_Article.jsp

 

 

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