Posted on 3 February 2022
Just as cars slowly accumulate wear-and-tear from repeated use and exposure to the elements, our cells accumulate damage from continuous exposure to background radiation and harmful chemicals. The vast majority of the latter are products of vital chemical reactions taking place within our cells themselves. To repair this damage, cells have evolved a waste disposal system called autophagy, meaning ‘self-eating’ – damaged molecules and organelles (cellular organs) are bagged up and degraded by enzyme-containing sacs, preventing a toxic build-up of waste products.
Unfortunately, this system eventually fails. With age, autophagy becomes less active, and is eventually overwhelmed by waste products. Though it’s not fully understood how, failure of autophagy seems to promote more rapid ageing and the development of age-related diseases. This begs the question: can we slow ageing and delay the onset of disease by giving autophagy a boost?
In 2014, Salwa Sebti and her colleagues at the University of Texas Southwestern Medical Center in Dallas tried to answer that question in mammals for the first time. For over two years, they followed mice with genetically enhanced autophagy to see if they were healthier and longer-lived than their counterparts with normal autophagy. It worked: after almost two years, the modified mice began to show health improvements such as lower cancer incidence and reduced tissue scarring. They also lived about 10% longer than the controls. Further studies revealed other benefits, such as slowing cognitive decline and organ degeneration. It seemed that scientists had identified a fundamental process linked to the development of many age-related diseases, making it an ideal target for future treatments.
Genetically boosting autophagy in mice is one thing, but if we want to develop a drug that will ‘fix’ autophagy in ageing humans, we need to understand exactly how it works and how it goes wrong, which may vary from one disease to another. Autophagy is a multistep process in which waste is first packaged into sack-like structures called phagophores. These phagophores mature into autophagosomes, which finally fuse with enzyme-containing sacs called lysosomes. This process is coordinated by a complex system of signalling molecules and molecular tags – target the wrong part of the system, and you might just make the situation worse. For example, boosting the packaging speed when degradation is the rate-limiting step might just make the trash pile up faster.
There are also the inherent problems that come with trying to translate any intervention from animal models into a human treatment. Many proposed drug interventions haven’t even been shown to be effective in animals yet. Together, these problems have led many anti-ageing researchers to reserve their enthusiasm when it comes to targeting autophagy. Some, however, are going all-in.
How are scientists approaching this problem? One strategy is to target a specific type of autophagy known as chaperone-mediated autophagy, or CMA. In this process, helper proteins called chaperones transport damaged proteins directly to lysosomes to be digested. In the view of Ana María Cuervo from Life Biosciences, one of the companies aiming to use CMA as a therapeutic target, the strength of this approach is its high specificity. Even when CMA is enhanced by drugs, only proteins tagged by the chaperone protein can be degraded, potentially making it a safer approach compared to targeting regular autophagy pathways, which are less discriminating in what they eat.
Compounds targeting CMA have shown some success in ameliorating age-related disease in mice, but have a major limitation – many proteins and other types of cellular waste simply don’t interact with the chaperone protein system. For example, when mitochondria (the cell’s power plants) become damaged, they need to be removed by autophagy. This process is important enough to be given its own name, mitophagy, and its failure during ageing is thought to play a fundamental role in the ageing process (read more about that here). Because of this, targeting mitophagy specifically might be particularly valuable, and there are several candidate drugs that have shown promising results in animal models using this approach.
In addition to these new drugs, there are also several autophagy-enhancing drugs that already exist, and that have well established safety in humans. At least two of these should be familiar to anyone who follows anti-ageing research: the diabetes treatment metformin, and the immune system suppressant rapamycin. Both seem to extend lifespan in mice, though due to their wide range of actions, it’s difficult to say how much of this may be due to effects on autophagy.
Other researchers are working backwards from the DNA itself to develop new ways to enhance autophagy. Caraway Therapeutics, for example, has studied the most devastating mutations in genes coding for proteins affecting autophagy pathways in humans, and is looking to promote the function of those same proteins therapeutically.
Finally, there’s the enticing possibility of manipulating autophagy to treat other diseases, by directing disease-causing proteins into the autophagy system. In this study, for example, researchers develop a compound that can escort mutant huntingtin protein, the gene product responsible responsible for Huntington’s disease, to phagophores for destruction.
Autophagy-enhancing drugs that prevent or treat age-related diseases in humans would be great, but are still many years away, and that’s assuming they work. At Gowing Life, we like to ask the question: what do we know about the mechanisms of ageing that are actionable. In other words, is there anything the average person can do to boost autophagy within their own cells?
Autophagy is part of the cell’s response to stressors, and is cranked up when the cell needs to prioritise survival over growth and division. One reliable way to trigger this response is to restrict the nutrients that are available to cells, in particular glucose (sugar). Research suggests that calorie restriction and fasting can promote autophagy in mice and increase their maximum lifespan. This autophagy-enhancing effect occurs after around 24 hours of fasting in mice, and peaks at 48 hours. However, there are no conclusive human studies indicating the optimal period of fasting needed to achieve autophagy, and it’s still unknown whether fasting even has an effect on maximum human lifespan.
There’s evidence that exercise can boost autophagy by putting cells, especially muscle cells, under stress. There’s also evidence that autophagy follows the sleep-wake cycle and is disrupted by disturbed sleep. In both cases, most evidence comes from animal studies. Additionally, some polyphenols such as curcumin as well as polyphenols found in coffee and tea have been found to promote autophagy in mice.
So, while there’s evidence that autophagy can be promoted through lifestyle choices, we don’t really know how to this optimally in humans, nor do we understand the associated benefits.
The biological clean-ups that could combat age-related disease: doi: https://doi.org/10.1038/d41586-022-00075-w
Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds: https://doi.org/10.1038/s41586-019-1722-1
Short-term fasting induces profound neuronal autophagy: https://dx.doi.org/10.4161%2Fauto.6.6.12376
Exercise induces autophagy in peripheral tissues and in the brain: https://doi.org/10.4161/auto.21327
Rheostatic Balance of Circadian Rhythm and Autophagy in Metabolism and Disease: https://doi.org/10.3389/fcell.2020.616434
Curcumin: A naturally occurring autophagy modulator: https://doi.org/10.1002/jcp.27404
Coffee induces autophagy in vivo: https://dx.doi.org/10.4161%2Fcc.28929
Role of Herbal Teas in Regulating Cellular Homeostasis and Autophagy and Their Implications in Regulating Overall Health: https://dx.doi.org/10.3390%2Fnu13072162