The Autophagy Advantage: Epigenetics, Cellular Cleanup, and Longevity

Autophagy is the eukaryotic cell’s waste management system; it collects and recycles damaged organelles and proteins. Unlike eukaryotic cells, bacteria lack lysosomes—the specialized structures that perform this task—so they rely on simpler methods to manage waste.

More memorably, autophagy can be thought of as controlled cannibalism. From Greek, the word translates to “self-eating.” In mammals, it takes three principal forms: micro, macro, and chaperone-mediated (Shu, 2023).

Of the three, macroautophagy is the best studied. In a healthy body, autophagy assists in cellular maintenance, ridding the body of excessive or damaged organelles. Dysfunction of this process is correlated with a litany of serious pathologies, including liver, lung, and heart disease, as well as aging and cancer (Parzych, 2014; Wirawan, 2012).

The accumulation of intracellular and extracellular junk is identified as two of the Seven Deadly SENS (de Grey, 2023) and is a major contributor to the aging process. Autophagy predominantly removes waste within the cell, although it (albeit indirectly) assists in removing extracellular waste as well.

Will a pill be as good, or better, than fasting?

As covered in a previous article, caloric restriction (CR) is the current gold standard for longevity interventions, but it has drawbacks.

It cannot be easily practiced—if at all—by those who stand to gain the most from it, like the elderly. Limiting food intake can interfere with proper nutrition, and the loss of lean body mass decimates metabolic health. Muscle mass protects against hypertension, high cholesterol, insulin insensitivity, and their associated ills (Kim, 2020; Al-Ozairi, 2021).

Mutations in key autophagy genes negate the health benefits of CR, highlighting its indispensability (Chung, 2019).

Where does epigenetics enter the picture?

Epigenetic mechanisms alter gene expression; they do not alter DNA sequences. They change how the code is read, which in turn determines which, how much, and when proteins are expressed. Some of these alterations include DNA methylation, histone modification, and chromatin remodeling (Handy, 2011).

Many signals modulate autophagy, from nutrient availability to DNA damage to external stressors. It was once thought this happened almost exclusively in the cell’s main compartment (cytoplasm), but it’s now known that the cell’s control center (nucleus) is also involved. This process is influenced by changes in how DNA is packaged, proteins that control gene activity, and minute RNA molecules that fine-tune gene expression (Hu, 2019).

Certain compounds mimic aspects of fasting. One of these is spermidine. Spermidine enhances autophagy, promotes longevity in model organisms, and, as far as we can tell, is correlated with longevity biomarkers in humans. CR boosts spermidine while blocking its synthesis and blunts fasting’s benefits (Madeo, 2019; Hofer, 2024).

The mTOR pathway is another hot topic in longevity research. Rapamycin, which inhibits mTOR, extends lifespan in multiple animal models. However, its potential uses are limited by side effects like immunosuppression. Safer mTOR-targeting compounds could provide the same life-extending benefits without the risks.

For those unable or unwilling to practice CR, intermittent fasting (IF) is a flexible and increasingly popular alternative. Studies suggest that IF improves cardiometabolic health, enhances neurocognitive function, and may reduce cancer risk. This raises the intriguing possibility of developing drugs that mimic the metabolic effects of IF, offering a more accessible route to reaping its rewards (Washington University School of Medicine. (n.d.).

This is where CR mimetics—drugs that replicate CR’s effects— could come to the rescue. Although CR puts other longevity-enhancing processes into motion, enhanced autophagy is particularly appealing as replicating the full spectrum of fasting’s effects remains a challenge.

As always, the dose makes the poison. Autophagy is not necessarily a net positive; under the right conditions, it is restorative; in the wrong ones, it tips the scales too far toward dissolution. While it suppresses tumor progression in the early stages, it may promote tumor survival if the cancer is more advanced (Bhutia, 2013; Li, 2020).

Overall, aging populations likely need more autophagy rather than less. It is well-established that autophagy declines with time. In turn, it contributes to the development of age-related diseases. This decline is observed in skeletal muscle, brain, and liver tissues. Its inhibition leads to degenerative changes resembling those associated with aging (Li, 2017).

Autophagy dysfunction is also linked to neurodegenerative diseases like Alzheimer’s, Parkinson’s, Huntington’s, and ALS/FTD. These conditions are characterized by the accumulation of toxic protein aggregates due to impaired clearance. Inducing autophagy can reduce these protein aggregates, suggesting therapeutic potential (Corti, 2020).

This process is all carefully orchestrated by the interplay of epigenetics mechanisms, including DNA methylation, histone modifications, and microRNAs, which work in concert to regulate autophagy-related genes. This is why specific enzymes, like DNMTs, HDACs, EZH2, and G9a, are promising targets (Shu, 2023).

Epigenetic mechanisms have immense therapeutic potential for cancer as well as by eliciting cell cycle arrest, apoptosis, and differentiation. Personalizing treatment is key, but in cancer’s early stages, autophagy suppresses tumor formation. It also plays a pivotal role in maintaining genomic stability and preventing DNA damage (Bates, 2020; Shi, 2021).

When a cell incurs damage, autophagy excites anti-tumorigenic action. Dual autophagic effects are associated with epigenetic drug treatments, which occur as a mechanism of synergy to bolster therapeutic response (Shu, 2023).

Cancer could be partially controlled by epigenetically modulating autophagy. Because it facilitates the recycling of damaged and senescent protein substrates, it is fundamental to maintaining homeostasis. As its deregulation encourages carcinogenesis, its timely restoration could help to put things right (Parveen, 2022).

Due to their reversibility, epigenetic therapeutics could become as commonplace as multivitamins. Autophagy, the maestro of cellular homeostasis, is paramount to enhancing healthy human longevity. As the cogs driving this process are unraveled, harnessing its power to combat humanity’s oldest scourges is becoming increasingly plausible.

References

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Suggested Reading

• Autophagy, Cellular Aging, and Age-related Human Diseases. PubMed Central, December 31, 2019.
• Autophagy in Ageing and Ageing-Related Neurodegenerative Diseases. Open Access Publishing, July 14, 2021.
• Autophagy in Healthy Aging and Disease. Nature Aging, August 12, 2021.
• Non-canonical Autophagy in Aging and Age-related Diseases. Frontiers in Cell and Developmental Biology, February 23, 2023.
• Bejarano, E., & Cuervo, A. M. Chaperone-mediated autophagy. Proceedings of the American Thoracic Society, 7(1), 29-39, February 2010.
• Eisenberg, D. T. A., et al. The Role of Spermidine in Autophagy and Longevity. Nature Reviews Molecular Cell Biology, 19(12), 725-726, 2018.
• Hansen, M., et al. A role for autophagy in the extension of lifespan by dietary restriction in C. elegans. PLoS Genetics, 4(2), e24, 2008.
• Longo, V. D., & Mattson, M. P. Fasting: Molecular Mechanisms and Clinical Applications. Cell Metabolism, 19(2), 181-192, 2014.
• Majchrzak-Celińska, A., et al. Novel Approaches to Epigenetic Therapies: From Drug Combinations to Epigenetic Editing. Genes (Basel), 12(2), 208, 2021.
• Morselli, E., et al. Caloric Restriction and the mTOR Pathway: A New Perspective on Aging. Nature Reviews Molecular Cell Biology, 15(8), 495-507, 2014.
• Qi, Y., et al. HEDD: the human epigenetic drug database. Database (Oxford), baw159, 2016.
• Tian, W., et al. Recent advances of IDH1 mutant inhibitor in cancer therapy. Frontiers in Pharmacology, 13, 982424, 2022.
• Wang, L., et al. The emerging mechanisms and functions of microautophagy. Nature Reviews Molecular Cell Biology, 24(3), 186–203, 2023.