Spring Cleaning Your Cells: A Look at Autophagy and Senescence

Spring cleaning is an excellent way to make your home feel fresh and clutter-free—but it can also apply to our bodies. Cellular spring cleaning involves boosting autophagy and clearing out senescent cells, which can be achieved with various dietary and lifestyle methods.

In this article, we’ll detail what exactly autophagy and senescence are, and how practices like fasting, senolytics, exercise, supplements, and sleep can help these processes along—not to worry; your cells will be sparkly clean in no time.  

Autophagy: Spring Cleaning For Your Cells

Autophagy is a fundamental cellular process for longevity that removes toxic and dysfunctional cells or cell parts.

People with low autophagy are more likely to experience accelerated aging or develop age-related conditions. Autophagy is commonly referred to as our housekeeping or recycling systems—or, in this case, spring cleaning! With this cellular cleaning, autophagy allows for the degradation and removal of cellular components to maintain healthy functionality. 

Studies show that upregulating autophagy in animals and human cell lines extends lifespan or improves markers of health and longevity. Conversely, disruptions in the autophagy process lead to a buildup of dysfunctional and damaged cells in the body—like senescent cells.

How Senescence Clutters Your Cells

Senescence is a state of irreversible growth arrest when cells stop dividing and lose their function. It commonly occurs with older age or in response to stressors like inflammatory states or oxidative stress—the accumulation of reactive oxygen species that damage cells and DNA.

However, while these senescent cells lose function, they don’t die. Instead of undergoing the routine and programmed cell death called apoptosis, senescent cells enter a “zombie-like,” half-alive state that damages neighboring tissues and cells. This damage occurs through the senescence-associated secretory phenotype (SASP), which leads to the secretion of a cascade of destructive and inflammatory compounds. 

The number of senescent cells that secrete SASP compounds increases with age in many vital tissues, including the brain, lungs, kidneys, heart, and blood vessels. Therefore, a buildup of senescent cells and their subsequent inflammatory cascade contributes to age-related conditions in these organs and tissues. 

Another factor that plays a role in cells becoming senescent is telomere length. Telomeres can be imagined as the plastic casing protecting the tip of a shoelace, as these repetitive strands of DNA “cap” the ends of our chromosomes. These endcaps protect the critical genetic information inside the chromosome from damage and dysfunction. 

Telomeres and cellular senescence go relatively hand in hand, as telomeres shorten with each cell division. When a cell reaches the end of its telomere, it can no longer replicate and is considered senescent.

Autophagy and senescence are also related, as this internal housekeeping system has been shown to suppress cellular senescence under certain conditions, especially states of oxidative stress. However, there’s a delicate balance here—excessive oxidative stress can also impair autophagic activity, eventually leading to cellular senescence. Therefore, minimizing oxidative stress as much as possible is beneficial for suppressing senescence and maintaining autophagic ability. 

How to Target Senescence and Boost Autophagy

Fortunately, researchers have identified several ways to support autophagy and suppress senescence, including fasting, exercise, deep sleep, and certain senolytics or supplements. 

Fasting

One of the most researched dietary methods to increase autophagy is short-term fasting.  Whether through intermittent fasting, alternate-day fasting, time-restricted eating, or caloric restriction, all these types of food restriction are thought to support autophagy. 

When you fast, your body activates the AMPK (5′ AMP-activated protein kinase) signaling pathway, which inhibits mTOR (mammalian target of rapamycin). The inhibition of mTOR triggers autophagy and the ability to use excess fat for energy. Another mechanism by which fasting promotes autophagy is through the production of sirtuins, a family of proteins thought to support healthy aging and longevity. 

One small recent study looked at the effects of fasting (17 to 19 hours per day for 30 days) on 25 young males. After fasting, the men had increased expression of ATG5—a protein that suppresses autophagy when reduced—and higher ULK1, a protein responsible for sensing autophagy signals or nutrient depletion. Some markers of cellular senescence were also reduced after fasting. 

Animal studies also show that caloric restriction in rats leads to multiple health benefits, including longer lives and improvements in inflammatory and metabolic markers.  

However, excessive autophagy from extreme fasting or nutrient depletion is not beneficial and can trigger stressful conditions in the body, leading to oxidative stress, inflammatory states, and increased senescence. Therefore, if you fast, ensure adequate nutrient intake and do not do “extreme fasts” for several days or more.

Exercise

Exercise is another way to induce autophagy, especially in muscle tissues. A small study looked at autophagy markers in males after an eight-week exercise program. Two hours after participating in moderate-intensity cycling or moderate-intensity cycling interspersed with sprints (resembling a high-intensity interval training workout), skeletal muscle AMPK was increased in both groups, as well as other autophagy markers, including LC3I, LC3II, and BNIP3. 

In a study with rats, researchers wondered whether high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) benefitted autophagy more. The HIIT group saw higher mitochondrial biogenesis markers and muscular increases in autophagy markers, indicating that HIIT may provide an additional cellular benefit that moderate-intensity exercise does not, likely due to the increased hormetic effect of the HIIT workout.

In an animal study, older mice (about 65 to 70 in human years) that exercised on the treadmill saw improvements in autophagic processes. The hearts of the older mice who exercised had higher activity of several proteins, including LC3, a protein often used as a proxy for autophagic status.

Higher LC3 activity suggests an increased formation of autophagosomes—sac-like membranes that resemble the “garbage bag” containing the cellular trash in this scenario. The autophagosomal garbage bag and its contents get transported to the lysosome, which could be considered the trash dump or recycling center. Therefore, higher LC3 indicates that taking the autophagosome to the lysosome (i.e., taking the trash out) was increased. If translated to humans, these results support the notion that the otherwise-repressed autophagic states seen with aging can be restored by aerobic exercise later in life.  

When it comes to senescence, research shows that long-term intensive endurance exercise (like endurance running) is linked to reductions in senescent cells in the colons of older adults. 

Senolytics and Supplements

Senolytics are drugs or chemicals that remove senescent cells from the body. One commonly used senolytic is a combination referred to as DQ—dasatinib plus quercetin. However, while quercetin is a natural compound found in fruits and vegetables, dasatinib is a chemotherapeutic drug that can cause undesirable side effects.

Plant-based compounds studied for their role in reducing or clearing senescent cells include pterostilbene, fisetin, and berberine. The benefits of using natural plant-based senolytic compounds like these are wide-reaching, including their ability to selectively kill off senescent cells without causing toxic harm to normal, proliferating cells. Plus, they provide antioxidant activity, reducing the burden of oxidative stress. 

NAD+ precursors may also help to clear senescent cells. Although we don’t have research in humans, one study found that NMN (nicotinamide mononucleotide), a precursor to the vital coenzyme NAD+, fights cellular senescence in the retinal cells of the eye, while another showed that NMN reduced senescent alveolar cells in the lungs.

Regarding autophagy, researchers have identified several compounds to boost this internal spring cleaning, including resveratrol, spermidine, urolithin A, curcumin, and green tea extract. 

Sleep

One of the easiest ways to trigger autophagy is by getting enough high-quality sleep. Our circadian rhythms—our internal 24-hour body clocks—rely on the regulation of several pathways and markers of autophagy to function correctly, including mTOR, AMPK, and the sirtuin SIRT1.

Disruption of circadian rhythms and autophagy has been seen in neurodegenerative conditions and memory loss. In studies done on flies, the protein aggregates in the brain that are hallmarks of cognitive loss have been linked to a reduction in autophagy, which was then resolved once neural autophagy pathways were improved.

Melatonin, our primary sleep-related hormone, also depends on autophagy pathways, which control aging processes, especially in the brain. It’s important to underscore that not all sleep will increase autophagy—it has to be deep and restorative sleep. When sleep is fragmented, autophagy proteins are decreased, and memory and cognition can decline. 

Your Takeaways

The primary way to “spring clean” your cells is by boosting or supporting autophagy—our internal housekeeping system that clears cellular clutter and debris. Healthy levels of autophagy can also clear out senescent cells, the zombie-like cells that are not dead but not functioning, leaving trails of inflammatory debris in their wake. 

Strategies to support both healthy autophagic activity and clearance of senescent cells include moderate fasting, exercise (primarily aerobic and HIIT), deep sleep, and senolytics or supplements like resveratrol, NMN, spermidine, urolithin A, curcumin, pterostilbene, fisetin, berberine, and green tea extract.

References:

Brandt N, Gunnarsson TP, Bangsbo J, Pilegaard H. Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. Physiol Rep. 2018;6(7):e13651. doi:10.14814/phy2.13651

Carroll JE, Prather AA. Sleep and Biological Aging: A Short Review. Curr Opin Endocr Metab Res. 2021;18:159-164. doi:10.1016/j.coemr.2021.03.021

Cho JM, Park SK, Ghosh R, et al. Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts. Aging Cell. 2021;20(10):e13467. doi:10.1111/acel.13467

Demaria M, Bertozzi B, Veronese N, et al. Long-term intensive endurance exercise training is associated to reduced markers of cellular senescence in the colon mucosa of older adults. NPJ Aging. 2023;9(1):3. Published 2023 Feb 27. doi:10.1038/s41514-023-00100-w

Fang T, Yang J, Liu L, Xiao H, Wei X. Nicotinamide mononucleotide ameliorates senescence in alveolar epithelial cells. MedComm (2020). 2021;2(2):279-287. Published 2021 May 27. doi:10.1002/mco2.62

Kwon Y, Kim JW, Jeoung JA, Kim MS, Kang C. Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot. Mol Cells. 2017;40(9):607-612. doi:10.14348/molcells.2017.0151

Li FH, Li T, Ai JY, et al. Beneficial Autophagic Activities, Mitochondrial Function, and Metabolic Phenotype Adaptations Promoted by High-Intensity Interval Training in a Rat Model. Front Physiol. 2018;9:571. Published 2018 May 23. doi:10.3389/fphys.2018.00571

Mattson MP, Longo VD, Harvie M. Impact of intermittent fasting on health and disease processes. Ageing Res Rev. 2017;39:46-58. doi:10.1016/j.arr.2016.10.005

Nakamura S, Yoshimori T. Autophagy and Longevity. Mol Cells. 2018;41(1):65-72. doi:10.14348/molcells.2018.2333

Ratliff EP, Mauntz RE, Kotzebue RW, et al. Aging and Autophagic Function Influences the Progressive Decline of Adult Drosophila Behaviors. PLoS One. 2015;10(7):e0132768. Published 2015 Jul 16. doi:10.1371/journal.pone.0132768

Ren C, Hu C, Wu Y, et al. Nicotinamide Mononucleotide Ameliorates Cellular Senescence and Inflammation Caused by Sodium Iodate in RPE. Oxid Med Cell Longev. 2022;2022:5961123. Published 2022 Jul 18. doi:10.1155/2022/5961123

Shabkhizan R, Haiaty S, Moslehian MS, et al. The Beneficial and Adverse Effects of Autophagic Response to Caloric Restriction and Fasting. Adv Nutr. 2023;14(5):1211-1225. doi:10.1016/j.advnut.2023.07.006