Every human cell can be seen as a tightly run metropolis. To keep things humming, it relies on macroautophagy, a process akin to a high-tech recycling system [1].

Here’s how it works: damaged proteins and organelles are wrapped in a double-membraned autophagosome structure. These sacs then join with lysosomes, which act like molecular incinerators. They break down waste and recycle the parts.

This elegant machinery is guided by signaling pathways like mTOR and AMPK. mTOR is the nutrient-sensing gatekeeper, and AMPK is the energy crisis manager. Together, they help keep cells strong and efficient [2].

The cellular cleanup crew goes rogue

However, as cells age, this well-oiled system falters [3]. Autophagosomes form more slowly. Lysosomes lose their acidic power, and the cell’s waste builds up. Proteins misfold [4], mitochondria sputter out [5], and debris accumulation begins to outpace the cleanup.

Even worse, the damaged mitochondria leak reactive oxygen species (ROS) and fragments of mitochondrial DNA (mtDNA). These substances spill into the cytoplasm like toxic fumes, setting off inflammatory alarms [6].

The breakdown of autophagy doesn’t just clog up cellular operations, it initiates a vicious cycle. Damaged mitochondria fuel more ROS production, damaging the autophagy machinery itself. This cellular degeneration spreads inflammation across tissues, eventually tipping the scales toward age-related diseases like neurodegeneration, cardiovascular disease, and cancer [7-9].

At its core, disabled macroautophagy is more than just a cellular housekeeping failure. It’s a critical vulnerability that undermines the cell’s ability to adapt, repair, and survive. Breaking this cycle could hold one of the keys to slowing aging and restoring cellular balance.

The decline of autophagy causes gridlock

Let’s revisit the cell as a bustling city, but this time with a closer look at the logistics. Macroautophagy acts as the distribution center and recycling plant combined. Damaged parts get picked up, sorted into autophagosomes, and shipped to lysosomes for breakdown and repurposing. It’s a marvel of efficiency, until it isn’t.

With age, the system becomes sluggish. Autophagosomes take longer to form. Lysosomes lose their acidic strength. The whole process slows down like a worn-out supply chain [10].

What makes this decline particularly treacherous is that autophagy isn’t just cleanup, it’s crisis management. When this process stalls, damaged proteins, and organelles, particularly mitochondria, accumulate like unsorted packages in a warehouse. The ROS that mitochondria leak act like sparks in a room full of dry paper. These ROS amplify damage within the cell and its neighbors, creating a domino effect of dysfunction [6].

The clogged cellular streets lead to ripple effects. Damaged components release distress signals that turn up inflammation across the system. Cytokines like IL-6 and IL-1β pour out, creating a low-grade firestorm known as inflammaging. Over time, this long-term inflammation works like a slow poison. It can lead to diseases like arthritis, diabetes, and neurodegeneration [11].

Even more frustrating, aging cells often know that something is wrong. They attempt to crank up autophagy pathways, like activating AMPK to suppress mTOR. Ordinarily, this would jump-start the cleanup process, but the machinery has rusted, and the signals can’t translate into effective action [10]. It’s the biological equivalent of calling in more garbage trucks when the roads are already gridlocked.

The failure of autophagy doesn’t just disrupt the cellular present, it reshapes the future. Allowing damaged mitochondria and aggregated proteins to persist paves the way for age-related degeneration. In the end, the faltering city turns into a paralyzed metropolis, and the body cannot adapt and repair.

Consequences of autophagic dysfunction

When autophagy stops working, the effects spread out. It is like cracks in a building’s foundation. These cracks can grow until the whole structure groans under its own weight. At first, the issues seem localized, such as damaged mitochondria, protein aggregates, and cellular clutter, but these seemingly isolated problems quickly grow into system-wide crises.

When damaged and not cleared by mitophagy, mitochondria that would normally be energy-producing dynamos become more like broken factories. Instead of making useful energy, they produce harmful byproducts, like reactive oxygen species (ROS). ROS attack DNA, lipids, and proteins, accelerating cellular decline.

However, the damage doesn’t stop there. Fragments of mitochondrial DNA leak into the cytoplasm and act like false alarms. They trick the immune system to start unnecessary inflammatory responses [6]. It is like a fire alarm triggered by a burnt piece of toast, but it happens in cell after cell, tissue after tissue.

Autophagy is meant to clean up protein aggregates, but when it falters, proteins misfold and stick together, causing a biological traffic jam. These aggregates are the hallmarks of neurodegenerative diseases such as Alzheimer’s (beta-amyloid plaques) and Parkinson’s (alpha-synuclein clumps) [12, 13].

The result is that neurons suffocate in their own cellular waste, leading to cognitive decline, motor dysfunction, and, eventually, irreparable damage. However, one of the worst effects of failed autophagy is the inflammaging.

Senescent cells, which should have been cleared out, remain in the body. They release a cocktail of inflammatory cytokines called the senescence-associated secretory phenotype (SASP) [14]. These inflammatory signals also encourage neighboring cells to become senescent, spreading the problem like a biological chain reaction. Over time, this inflammation becomes the backdrop for many age-related diseases, from cardiovascular disease to metabolic disorders [15].

Autophagy, when it works, is a tumor suppressor. Clearing out damaged DNA and malfunctioning organelles reduces the risk of cancerous mutations taking hold. However, when the process fails, damaged cells accumulate mutations unchecked. The inflammatory environment that they foster promotes tumor growth. Dysfunction flips autophagy from guardian to accomplice, tipping the scales toward malignancy [16].

Data from animal models underscores just how pivotal autophagy is. Mice with impaired autophagy show accelerated aging, organ degeneration, and shortened lifespans [17].

Meanwhile, boosting autophagy through fasting [18], genetic interventions, or drugs can delay age-related diseases [19]. It can also extend healthy lifespan. It’s as if restarting the cleanup process revitalizes individual cells and the entire organism.

The consequences of autophagic dysfunction aren’t confined to one cell or tissue, they cascade outward. They drive many of the degenerative processes that are associated with aging. It’s a failure of infrastructure at the molecular level, and its effects are felt everywhere.

Restarting the cleanup

If disabled macroautophagy is like a city drowning in garbage, then the logical next step is to find a way to bring back the cellular sanitation crew and get the streets clear again. Cutting-edge research suggests that this might be possible, and scientists are exploring ways to activate autophagy again.

One of the simplest and most ancient interventions is fasting. When cells sense a shortage of nutrients, they shift gears, shutting down growth and prioritizing maintenance, including ramping up autophagy. Imagine a city imposing rationing during a crisis, forcing resources to be reused and waste to be minimized.

Studies on intermittent fasting and caloric restriction show that these practices can jumpstart the autophagy machinery, reducing the accumulation of damaged proteins and organelles. This leads to a cleaner, more resilient cellular environment and, in many cases, extended lifespan [20, 21].

As not everyone wants to skip meals, scientists are exploring compounds that mimic the effects of fasting. Spermidine, for example, a molecule found in wheat germ, soy, and aged cheese, has shown promise in activating autophagy. It’s like a molecular wake-up call for the cell’s recycling centers. It revitalizes their ability to break down and reuse damaged components.

As NAD+ levels drop with age, another option is NAD+ precursors to restore this vital molecule. NAD+ is linked to energy production and the activation of autophagy [22, 23]. NAD+ is like the fuel that powers the cleanup fleet; the more fuel, the more trucks on the road.

There are also high-tech options: pharmacological interventions designed to target specific pathways in the autophagy process. Rapamycin, for examplee, is an mTOR inhibitor that has long been studied for its ability to extend lifespan in animal models. By reducing mTOR activity, rapamycin changes the cell’s focus from growth to repair. mTOR promotes growth but stops autophagy [24-26].

Other experimental drugs try to improve certain steps in autophagy. This includes forming autophagosomes and fusing them with lysosomes [24, 27, 28]. These compounds are like hiring specialized crews to tackle different parts of the cleanup [29].

However, there are challenges. Autophagy isn’t something you want running at full throttle all the time. Too much autophagy can destabilize healthy cells, stripping them of necessary components and interfering with their function.

The goal is precision and targeting cells or tissues where autophagy has stalled. The ideal would be to target neurons overloaded with protein aggregates and tissues riddled with senescent cells while leaving well-functioning systems untouched.

Restoring autophagy may not only slow aging but also mitigate its most devastating effects. Age-related diseases such as Alzheimer’s, Parkinson’s and cancer could all be potentially avoided. This, then, may be the key to the city’s forgotten infrastructure, and with it, we may be able to unlock its ability to repair itself.

The streets could be cleared, the power grid restored, and the entire organism revitalized. This isn’t just wishful thinking, either. It’s the promise of a future in which aging becomes a manageable condition rather than an inevitable decline.

Key Literature

[1] Dafsari, H.S.; Martinelli, D.; Saffari, A.; Ebrahimi-Fakhari, D.; Fanto, M.; Dionisi-Vici, C.; Jungbluth, H. An update on autophagy disorders. J Inherit Metab Dis 2025, 48, e12798.

[2] Galluzzi, L.; Green, D.R. Autophagy-Independent Functions of the Autophagy Machinery.. Cell 2019, 177, 1682–1699.

[3] Wagner, K.-D.; Wagner, N.; Guerrero-Navarro, L.; Jansen-Dürr, P.; Cavinato, M. Age-Related Lysosomal Dysfunctions. Cells 2022, Vol. 11, Page 1977 2022, 11, 1977.

[4] Menzies, F.M.; Moreau, K.; Rubinsztein, D.C. Protein misfolding disorders and macroautophagy. Curr Opin Cell Biol 2011, 23, 190–197.

[5] Somasundaram, I.; Jain, S.M.; Blot-Chabaud, M.; Pathak, S.; Banerjee, A.; Rawat, S.; Sharma, N.R.; Duttaroy, A.K. Mitochondrial dysfunction and its association with age-related disorders. Front Physiol 2024, 15, 1384966.

[6] Guan, X.; Li, H.; Zhang, L.; Zhi, H. Mechanisms of mitochondrial damage-associated molecular patterns associated with inflammatory response in cardiovascular diseases. Inflammation Research 2025 74:1 2025, 74, 1–22.

[7] Friuli, M.; Sepe, C.; Panza, E.; Travelli, C.; Paterniti, I.; Romano, Autophagy and inflammation an intricate affair in the management of obesity and metabolic disorders: evidence for novel pharmacological strategies? Front Pharmacol 2024, 15, 1407336.

[8] Liu, J.; Wu, Y.; Meng, S.; Xu, P.; Li, S.; Li, Y.; Hu, X.; Ouyang, L.; Wang, G. Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives. Molecular Cancer 2024 23:1 2024, 23, 1–30.

[9] Mathew, R.; Karantza-Wadsworth, V.; White, E. Role of autophagy in cancer.. Nature Reviews Cancer 2007 7:12 2007, 7, 961–967.

[10] Palmer, J.E.; Wilson, N.; Son, S.M.; Obrocki, P.; Wrobel, L.; Rob, M.; Takla, M.; Korolchuk, V.I.; Rubinsztein, D.C. Autophagy, aging, and age-related neurodegeneration.. Neuron 2025, 113, 29–48.

[11] Tylutka, A.; Walas, Ł.; Zembron-Lacny, A. Level of IL-6, TNF, and IL-1β and age-related diseases: a systematic review and meta-analysis. Front Immunol 2024, 15, 1330386.

[12] Cardinale, A.; Chiesa, R.; Sierks, M. Protein Misfolding and Neurodegenerative Diseases. Int J Cell Biol 2014, 2014, 217371.

[13] Gianni, S.; Brunori, M. The folding and misfolding of multidomain proteins Mol Aspects Med 2025, 101, 101337.

[14] Kwon, Y.; Kim, J.W.; Jeoung, J.A.; Kim, M.S.; Kang, C. Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot. Mol Cells 2017, 40, 607–612.

[15] Mikuła-Pietrasik, J.; Sosinska, P.; Janus, J.; Rubis, B.; Brewinska-Olchowik, M.; Piwocka, K.; Ksiãzek, K. Bystander senescence in human peritoneal mesothelium and fibroblasts is related to thrombospondin-1-dependent activation of transforming growth factor-β1. International Journal of Biochemistry and Cell Biology 2013, 45, 2087–2096.

[16] Chavez-Dominguez, R.; Perez-Medina, M.; Lopez-Gonzalez, J.S.; Galicia-Velasco, M.; Aguilar-Cazares, D. The Double-Edge Sword of Autophagy in Cancer: From Tumor Suppression to Pro-tumor Activity. Front Oncol 2020, 10, 578418.

[17] Kuma, A.; Komatsu, M.; Mizushima, N. Autophagy-monitoring and autophagy-deficient mice. 2017, 13, 1619–1628..

[18] Alirezaei, M.; Kemball, C.C.; Flynn, C.T.; Wood, M.R.; Whitton, J.L.; Kiosses, W.B. Short-term fasting induces profound neuronal autophagy. Autophagy 2010, 6, 702–710.

[19] Kroemer, G. Autophagy: Autophagy: a druggable process that is deregulated in aging and human disease. J Clin Invest 2015, 125, 1.

[20] Varady, K.A.; Cienfuegos, S.; Ezpeleta, M.; Gabel, K. Cardiometabolic Benefits of Intermittent Fasting. Annu Rev Nutr 2021, 41, 333–361, doi:10.1146/ANNUREV-NUTR-052020-041327.

[21] Mattson, M.P.; Longo, V.D.; Harvie, M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev 2017, 39, 46–58.

[22] Imai, S. ichiro; Guarente, L. NAD+ and sirtuins in aging and disease. Trends Cell Biol 2014, 24, 464–471.

[23] Covarrubias, A.J.; Perrone, R.; Grozio, A.; Verdin, E. NAD+ NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology 2020 22:2 2020, 22, 119–141.

[24] Miller, R.A.; Harrison, D.E.; Astle, C.M.; Fernandez, E.; Flurkey, K.; Han, M.; Javors, M.A.; Li, X.; Nadon, N.L.; Nelson, J.F.; et al. Rapamycin-mediated lifespan increase in mice is dose and sex dependent and metabolically distinct from dietary restriction. Aging Cell 2014, 13, 468–477.

[25] Wilkinson, J.E.; Burmeister, L.; Brooks, S. V.; Chan, C.C.; Friedline, S.; Harrison, D.E.; Hejtmancik, J.F.; Nadon, N.; Strong, R.; Wood, L.K.; et al. Rapamycin slows aging in mice. Aging Cell 2012, 11, 675–682.

[26] Badria, S.A.E.-F.A. Where and How in the mTOR Pathway Inhibitors Fight Aging: Rapamycin, Resveratrol, and Metformin. In; IntechOpen: Rijeka, 2018; p. Ch. 5 ISBN 978-1-78984-995-0.

[27] Wang, G.; Fu, Y.; Liu, B. Targeting autophagy with pharmacological small molecules to treat human diseases. Drug Discovery Stories: From Bench to Bedside 2025, 177–191.

[28] Galluzzi, L.; Bravo-San Pedro, J.M.; Levine, B.; Green, D.R.; Kroemer, G. Autophagy-Independent Functions of the Autophagy Machinery. Nature Reviews Drug Discovery 2017 16:7 2017, 16, 487–511.

[29] Liu, M.; Pi, H.; Xi, Y.; Wang, L.; Tian, L.; Chen, M.; Xie, J.; Deng, P.; Zhang, T.; Zhou, C.; et al. KIF5A-dependent axonal transport deficiency disrupts autophagic flux in trimethyltin chloride-induced neurotoxicity. Autophagy 2021, 17, 903–924.