The Hallmark of Ageing 5: Disabled Autophagy
What is Autophagy
Autophagy (pronounced aw · to · fuh · jee) is essentially your body’s microscopic caretaker - tidying up your cells and sparking joy at the cellular level. But instead of organising wardrobes, it's recycling worn-out cellular parts and clearing out biological clutter.
Picture this: Throughout your day, whether exercising, working or sleeping (in fact particularly when you’re sleeping) an invisible army of caretakers are hard at work around the clock, hunting down cellular rubbish like damaged proteins, worn-out organelles and invading germs. However, these microscopic heroes don't just throw things away, they’re environmentally conscious (the environment being your body) as the body’s master recyclers! They package waste into tiny bubble-like structures called autophagosomes and whisk them off to specialised recycling centres (lysosomes) where they're either completely broken down or transformed into fresh energy for your healthy cells!
The Ageing Plot Twist
Here's where the story takes an important turn. As you age, this remarkable cellular cleanup system starts losing its effectiveness. The autophagy-related genes that once worked efficiently begin to slow down, becoming less active or even disabled [1,2].
What does this mean for you?
Instead of getting that thorough daily cellular deep-clean, you're left with a less effective maintenance routine. Cellular debris starts accumulating, creating conditions for:
Increased cellular stress
Disrupted energy systems
Chronic low-grade inflammation (scientists call this "inflammaging")
You are Not Doomed by Your Genes
BUT, and this is a very important but, our longevity is not solely determined by our genes.
Genes load the gun, but environment and lifestyle pull the trigger.
You have the power to reactivate this system through lifestyle and dietary strategies that modulate your gene expression - this is what we call ‘Epigenetics’ in action. Epigenetics is how your daily habits - what you eat, how you move, how you sleep - control your gene expression like dimmer switches. You’re not changing your DNA itself, but you can turn genes up or down, influencing how your body functions [3].
Meeting the Hallmark of Ageing Criteria [4]
Meeting the criteria: 1. It should naturally occur as part of the ageing process.
We know that autophagy naturally declines with age because studies have found that key parts of this cellular clean-up system slow down over time without any experimental interference. In both humans and animals, the genes and proteins that help carry out autophagy become less active as we get older. For example, scientists have observed fewer autophagosomes (the “rubbish bins” of the cell) forming in ageing cells, and important clean-up proteins are found at much lower levels in older tissues like the brain and joints [5].
Therefore, impaired autophagy meets the first hallmark criterion as a naturally occurring feature of the ageing process.
Meeting the Criteria: 2. Experimental acceleration or increase of the biological process should measurably speed up the ageing process.
When researchers deliberately switch off autophagy in animals, they observe early organ damage, systemic inflammation, and rapid functional decline - classic signs of accelerated ageing. In humans, inherited disruptions in autophagy are associated with age-related diseases such as Alzheimer’s, heart disease, and type 2 diabetes, further underscoring its essential role [6,7].
Therefore, autophagy meets the second hallmark criterion by showing that its disruption directly accelerates ageing.
Meeting the criteria: Mitigating the process (actionably reducing or slowing it down) should, in turn, slow down normal ageing.
The good news is that finding ways to support this process shows real promise in protecting against the effects of ageing. In animal studies, mice genetically enhanced to produce more of the key proteins involved in cellular cleanup lived longer, stayed more active, and maintained healthier metabolism as they grew older [6]. Stimulating other parts of the same system delayed the onset of age-related diseases. In humans, natural compounds known to encourage autophagy have shown encouraging effects. Spermidine, for example - found naturally in certain foods - has been linked to improvements in memory and cardiovascular health in older adults [8].
These findings suggest that by actively enhancing the body's own cellular renewal mechanisms, it may be possible to slow down the ageing process itself - thereby meeting the third criterion.
Future Prospects
So, as it becomes increasingly clear how essential autophagy is for healthy ageing, where is research heading to address this? Scientists are now exploring exciting new ways to both monitor it more precisely and routinely as well as enhancing it.
One promising area is the development of blood-based biomarkers (compounds within the blood that are associated with autophagic activity) that can measure autophagy activity in real-time, allowing doctors to track how clean-up system is functioning in each individual based on the level of these ‘biomarkers’ within the blood [9,10]. This could help to catch a decline in autophagy early, inform more tailored treatment, as well as monitor the effects of lifestyle changes or therapies aimed at enhancing autophagy.
Additionally, researchers are investigating drugs known as "autophagy modulators" that can safely enhance the process without triggering side effects. Early-stage trials are looking at how certain compounds could be used to treat neurodegenerative diseases, cardiovascular conditions, and even some cancers by boosting autophagy [11]. Advanced gene technologies like gene-editing and precision medicine may one day actually allow us to correct faulty autophagy pathways at the genetic level. Wearable devices and AI-driven diagnostics are also being developed to help monitor metabolic health and provide personalised recommendations to keep autophagy functioning optimally. While many of these advances are still in early stages, they represent an exciting frontier that may revolutionise how we prevent and manage age-related diseases in the future.
Regularly Refresh Your Cells: How to Naturally Boost Autophagy
Discover how to unlock your body's most powerful anti-ageing weapon, autophagy, using simple, natural strategies that can transform your cellular health and longevity from the inside out [11].
1. Exercise
Turn your workout into a cellular rejuvenation session - high-intensity interval training and resistance training don't just build muscle and burn fat, they trigger autophagy throughout your body, whilst aerobic exercise specifically activates brain autophagy to sharpen cognition and protect against neurodegeneration.
2. Intermittent Fasting and Calorie Restriction
Skip breakfast and unlock your body's repair mode - intermittent fasts are a great way to activate autophagy and force your cells into deep-cleaning overdrive. Several of us at the Oxford Longevity Project (including running legend Sir Christopher Ball) have adopted a simple two-meal daily routine.
3. Diet
Certain dietary compounds are known autophagy activators - these include spermidine, nobiletin, and curcumin. These compounds help reactivate your cells’ clean-up crew and promote cellular renewal.
Beyond these, a diet rich in natural polyphenols - such as those in dark chocolate, green tea, and colourful fruits and vegetables - as well as omega-3 fatty acids from fatty fish, can further support autophagy pathways. For some, ketogenic diets may also play a role in enhancing cellular recycling.
4. Lifestyle Factors
Mastering the healthy lifestyle fundamentals can also boost autophagy: stay properly hydrated for optimal cellular function, manage stress through meditation to prevent autophagy shutdown, and prioritise 7-9 hours of quality sleep when your cellular cleanup crew works overtime (short nights cut your cellular clean short).
References:
[1] Palmer JE, Wilson N, Son SM, Obrocki P, Wrobel L, Rob M, Takla M, Korolchuk VI, Rubinsztein DC. Autophagy, aging, and age-related neurodegeneration. Neuron. 2025 Jan 8;113(1):29-48. doi: 10.1016/j.neuron.2024.09.015. Epub 2024 Oct 14. PMID: 39406236
[2] Levine B, Kroemer G. Biological Functions of Autophagy Genes: A Disease Perspective. Cell. 2019 Jan 10;176(1-2):11-42. doi: 10.1016/j.cell.2018.09.048. PMID: 30633901; PMCID: PMC6347410
[3] Shu, F., Xiao, H., Li, QN. et al. Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets. Sig Transduct Target Ther 8, 32 (2023). https://doi.org/10.1038/s41392-022-01300-8
[4] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023 Jan 19;186(2):243-278. doi: 10.1016/j.cell.2022.11.001. Epub 2023 Jan 3. PMID: 36599349
[5] Lim, S. H. Y., Hansen, M., & Kumsta, C. (2024). Molecular Mechanisms of Autophagy Decline during Aging. Cells, 13(16), 1364. https://doi.org/10.3390/cells13161364
[6] Aman Y, Schmauck-Medina T, Hansen M, Morimoto RI, Simon AK, Bjedov I, Palikaras K, Simonsen A, Johansen T, Tavernarakis N, Rubinsztein DC, Partridge L, Kroemer G, Labbadia J, Fang EF. Autophagy in healthy aging and disease. Nat Aging. 2021 Aug;1(8):634-650. doi: 10.1038/s43587-021-00098-4
[7] Cassidy LD, Young ARJ, Young CNJ, Soilleux EJ, Fielder E, Weigand BM, Lagnado A, Brais R, Ktistakis NT, Wiggins KA, Pyrillou K, Clarke MCH, Jurk D, Passos JF, Narita M. Temporal inhibition of autophagy reveals segmental reversal of ageing with increased cancer risk. Nat Commun. 2020 Jan 16;11(1):307. doi: 10.1038/s41467-019-14187-x. PMID: 31949142; PMCID: PMC6965206
[8] Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, Harger A, Schipke J, Zimmermann A, Schmidt A, Tong M, Ruckenstuhl C, Dammbrueck C, Gross AS, Herbst V, Magnes C, Trausinger G, Narath S, Meinitzer A, Hu Z, Kirsch A et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016 Dec;22(12):1428-1438. doi: 10.1038/nm.4222. Epub 2016 Nov 14. PMID: 27841876; PMCID: PMC5806691
[9] Yoshii SR, Mizushima N. Monitoring and Measuring Autophagy. Int J Mol Sci. 2017 Aug 28;18(9):1865. doi: 10.3390/ijms18091865. PMID: 28846632; PMCID: PMC5618514
[10] Zhang Z, Singh R, Aschner M. Methods for the Detection of Autophagy in Mammalian Cells. Curr Protoc Toxicol. 2016 Aug 1;69:20.12.1-20.12.26. doi: 10.1002/cptx.11. PMID: 27479363; PMCID: PMC4982470
[11] McCarty MF. Nutraceutical and Dietary Strategies for Up-Regulating Macroautophagy. Int J Mol Sci. 2022 Feb 12;23(4):2054. doi: 10.3390/ijms23042054. PMID: 35216170; PMCID: PMC8875972
Author: Georgia Pilling
