Autophagy
Autophagy and Aging
Autophagy is how cells recycle their parts, and it declines with age. Fasting triggers it in lab studies, but nothing aimed at it has extended human life.
Autophagy used to live in biology textbooks. Now it turns up in fasting apps and supplement ads, usually pitched as a deep clean your cells run while you skip breakfast. Not bad for a word that means “self-eating.” If you’re sorting out autophagy and aging, the biology is real and prize-winning. For Humanic Blue, the open question is whether turning it up helps anyone live longer.
Autophagy is how cells break down and recycle their own worn-out parts. It seems to slow with age, and aging researchers now list its breakdown as one of 12 hallmarks of aging. In the lab, fasting switches it on, and rapamycin, a drug that nudges cells toward recycling, extends lifespan in mice. But measuring the full recycling process inside a living person is difficult, and a year-long trial of spermidine, a supplement linked to autophagy, found no memory benefit. Nothing aimed at autophagy has been shown to slow aging or extend human life.
In This Article
- What autophagy is, and the starved yeast behind a Nobel Prize
- Cellular recycling seems to slow with age
- Fasting triggers it in the lab; human timing is harder to establish
- Rapamycin extends mouse lifespan, and it’s a transplant drug
- A year of spermidine didn’t improve memory
- The studies and details behind all of this
Key Takeaways
- Autophagy is the cell’s recycling system, and the discovery of how it works earned a 2016 Nobel Prize.
- Autophagy appears to decline with age in many species, and its breakdown is now counted among the hallmarks of aging.
- Fasting and calorie restriction trigger autophagy in lab studies. Those findings do not establish a fasting hour when it increases throughout a person’s body.
- Rapamycin extends lifespan in mice. It’s a prescription immune suppressant with serious risks, and it isn’t approved for aging.
- A year-long trial of a spermidine supplement in older adults found no memory benefit compared with placebo.
- No autophagy-targeted approach has been shown to extend human life.
What is autophagy?
The Nobel Assembly at Karolinska Institutet, which awards the medicine prize, gave the 2016 Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi “for his discoveries of mechanisms for autophagy.” Its announcement calls autophagy “a fundamental process for degrading and recycling cellular components.”
The idea is older than the prize. In the 1960s, researchers saw cells wrap some of their own contents in membrane sacs and ship them to the lysosome, the cell’s recycling compartment. Christian de Duve, the Belgian Nobel laureate who discovered the lysosome, coined the word. In the early 1990s, Ohsumi, then running his own lab at the University of Tokyo, starved baker’s yeast to find the genes that drive the process. He later showed that “similar sophisticated machinery is used in our cells.”
Put simply, autophagy is cellular recycling. Worn-out proteins and damaged parts get packed up, broken down and turned into fuel and building blocks for new ones. The discovery in more detail
Why it matters to aging
The Nobel announcement describes cells using autophagy to clear damaged proteins and cell parts, “a quality control mechanism that is critical for counteracting the negative consequences of aging.”
A 2021 review in Nature Aging by 15 autophagy and aging researchers, with Evandro F. Fang of the University of Oslo as senior author, says the evidence “suggests that autophagic activity declines with age in diverse organisms.” Most of it comes from worms, flies and rodents. In people, the authors note, several autophagy genes seem to be switched on less with age. They also write that the relationship among autophagy, aging and disease “remains unclear.”
In 2023, the researchers behind the hallmarks-of-aging framework, led by Carlos López-Otín of Spain’s University of Oviedo, expanded their list from nine hallmarks to 12. Disabled macroautophagy, the form usually meant by the word autophagy, became a hallmark of its own. The framework, and its critics, are covered in Hallmarks of Aging Explained. How the review and the hallmarks were built
Can fasting switch on autophagy in people?
Fasting triggers autophagy in laboratory studies. The studies described here do not establish when, or how much, it increases throughout a living person’s body.
Fasting and calorie restriction have a long lab record as autophagy triggers. A 2018 review in Ageing Research Reviews, led by Mohammad Bagherniya of Mashhad University of Medical Sciences in Iran, described them as especially powerful non-genetic autophagy stimulators and concluded that food deprivation induces the process across many tissues and organs.
The studies described here do not establish when, or how much, autophagy increases throughout a person’s body. University of Tokyo autophagy researcher Noboru Mizushima and Saori Yoshii of the University of Basel wrote in a 2017 methods review that “it remains practically impossible to monitor autophagy properly in humans.” Human tissue is hard to sample fresh and repeatedly. A snapshot showing more recycling sacs cannot distinguish faster recycling from a backlog of material that is not being broken down.
So a fasting window can’t be translated into a verified hour when autophagy increases throughout your body. The fasting research itself, including what it shows about weight and lifespan, is in Does Intermittent Fasting Help You Live Longer? The measurement problem in detail
What would a human study need to measure before assigning an autophagy start time?
Rapamycin: the mouse result and the fine print
Rapamycin, also called sirolimus, is an immune-suppressing drug. In the US it’s approved to prevent organ rejection after kidney transplants and to treat a lung disease called lymphangioleiomyomatosis. It blocks mTOR, a growth signal. Turning mTOR down is one of the standard switches that starts autophagy, according to the Nature Aging review.
In a 2009 study in Nature, the National Institute on Aging’s Interventions Testing Program fed rapamycin to genetically mixed mice at three US labs, starting at 600 days old. The authors describe that as roughly the equivalent of a 60-year-old person. Both males and females lived longer. The age at which 90% of the mice had died was about 9% to 14% higher with rapamycin than without it. The Nature Aging authors add that, in lab animals, dietary restriction, rapamycin and spermidine all need working autophagy machinery to extend life.
The fine print matters. US prescribing information for sirolimus carries a boxed warning: “Increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression.” It isn’t approved for aging. Its place in aging research is covered in What Is Geroscience? The mouse study and the label
Did the SmartAge supplement trial find a benefit?
The year-long SmartAge trial did not find a memory benefit from the spermidine supplement it tested.
Spermidine is a compound the body makes and that’s also in food. The Nature Aging review calls it an “autophagy-inducing metabolite”—a compound involved in metabolism that can stimulate cellular recycling—and notes that its levels fall in human immune cells with age. It’s also sold in supplement form.
The SmartAge trial, published in JAMA Network Open in 2022, tested one. A team at Charité–Universitätsmedizin Berlin, with first author Claudia Schwarz and senior author Agnes Flöel of University Medicine Greifswald, randomly assigned adults aged 60 to 90 with memory worries to a spermidine-rich wheat-germ supplement (about 0.9 mg of spermidine a day) or a placebo for 12 months in Germany.
The trial did not establish an improvement in its main memory outcome. “Over 12 months, no significant changes were observed in mnemonic discrimination performance,” the main memory test, and the other outcomes showed no statistically significant changes either. Side effects were balanced between the groups. The authors concluded that spermidine “did not modify memory and biomarkers compared with placebo.”
The authors raise their own limits. The dose added only about 10% to a typical day’s spermidine, kept low partly because of reports of high levels of polyamines, the family of compounds that includes spermidine, in some cancers. Hints of benefit for verbal memory and inflammation, they write, “need to be validated in future studies at higher dosage.”
The supplement came from The Longevity Labs, which also helped fund development of the extract, and several investigators held equity or advisory roles there, one as its chief executive during the trial. (Note 1) The null main result stands regardless. The trial in full
How does a tested memory outcome differ from evidence of an autophagy mechanism?
What’s Interesting
The Nobel-winning experiment was, in a way, a fast. Ohsumi starved yeast cells and watched undigested recycling sacs pile up within hours. More than three decades later, the fasting-and-autophagy story still rests mostly on that kind of setting: cells and lab animals, where researchers can look inside.
That leaves autophagy in an odd spot. The basic science has a Nobel Prize behind it. The studies described here do not connect that discovery to a verified fasting countdown or a capsule that improves human health by increasing autophagy.
What This Means in Practice
For the question of living longer and better, the missing link is a human trial showing that increasing autophagy improves health or survival. Findings in cells, animals and a selected trial population do not establish how an approach would affect any one person.
- A fasting clock is not a recycling measurement. Yoshii and Mizushima’s methods review describes why a tissue snapshot cannot measure the full process or establish a body-wide start time.
- The tested supplement did not improve memory. SmartAge’s result applies to its wheat-germ extract, dose and study population; it does not establish that all doses work or fail.
- Rapamycin has serious labeled risks. It is a prescription immune suppressant with a boxed warning and has no approval for aging.
- Fasting has population-specific risks. Johns Hopkins Medicine lists children and teens, pregnant or breastfeeding women, people with type 1 diabetes who take insulin, and people with a history of eating disorders among those who shouldn’t try intermittent fasting.
- Evidence on other approaches to longevity is covered in What Are the Best Habits for Longevity?
A primary care clinician or a registered dietitian can talk through fasting safety. A clinician can weigh the risks of any off-label drug.
Bottom Line
Autophagy is the cell’s recycling system, whose mechanisms earned a 2016 Nobel Prize, and its decline is now counted among the hallmarks of aging. Fasting and calorie restriction induce it in lab studies, and rapamycin extends mouse lifespan. Measuring the full recycling process in people remains a difficulty described by the methods review, and a year-long trial of an autophagy-linked supplement found no memory benefit. No autophagy-targeted approach has been shown to slow human aging or extend life. The open questions are whether an intervention can reliably increase autophagy in human tissues and whether doing so reduces disease or deaths. Until trials answer it, a clinician is the right person to weigh fasting plans or off-label drugs against your own health.
A NOTE FROM LONGEVITY365
We read research, consult expert perspectives and work to make complicated health information easier to understand. What you’re reading here reflects how we’ve interpreted and organized that information. It is educational content—not personal medical advice, diagnosis or treatment guidance.
We’re not perfect, and neither is the available research. Evidence changes, new studies emerge and what’s appropriate for one person may not be appropriate for another.
Use this article as a starting point for your own research and conversations with qualified professionals. Always talk with your doctor or another trusted healthcare professional before making decisions that could affect your health, particularly if you take medications, are receiving treatment, have existing health conditions, are pregnant or have other circumstances that could affect what’s appropriate for you.
Reader Questions
A few questions to carry into the comments or your next conversation. Please leave out identifying or personal medical details.
- 01What did this article make clearer about the gap between an aging mechanism and a proven human outcome?
- 02Which claim would you want to see tested in people before it affected a real health decision?
- 03What question should readers keep asking when "Autophagy and Aging" shows up in longevity marketing?
Extra Insights & Sources
For readers who want the details behind each claim above.
What We Know
- Autophagy is a fundamental cellular recycling process. Established.
- Autophagic activity appears to decline with age in many organisms, and disabled macroautophagy is one of the 12 hallmarks in the 2023 framework. Supported (mostly animal) / Established (as a framework category).
- Fasting and calorie restriction induce autophagy in laboratory studies. Supported.
- Rapamycin extended lifespan in genetically diverse mice, even when started late in life. Supported (animal).
- Spermidine at 0.9 mg a day didn’t improve memory in a 12-month trial in older adults. Supported (null).
What We Don’t Know
- How long a person must fast for autophagy to increase meaningfully in their tissues. Unknown. Yoshii and Mizushima’s 2017 review reported no established method to measure autophagic flux, the amount of material recycled, in people.
- Whether increasing autophagy in people slows aging or prevents disease. Unknown.
- Whether a higher spermidine dose would do anything the 0.9 mg dose didn’t. Unknown.
- Whether any autophagy-targeted intervention extends human lifespan. Unknown.
The Nobel discovery in detail
The Nobel Assembly’s 2016 press release explains that the word comes from the Greek “auto-,” meaning “self,” and “phagein,” meaning “to eat.” Christian de Duve, awarded the 1974 Nobel Prize for discovering the lysosome, coined the term; the sacs that carry cargo to the lysosome were named autophagosomes.
Ohsumi started his own lab in 1988. He cultured mutant yeast lacking vacuolar degradation enzymes and stimulated autophagy by starving them. “Within hours, the vacuoles were filled with small vesicles that had not been degraded,” the press release says. He published the result in 1992, then screened thousands of yeast mutants and identified 15 genes essential for autophagy. According to the release, “virtually identical mechanisms operate in our own cells.” It adds: “Disrupted autophagy has been linked to Parkinson’s disease, type 2 diabetes and other disorders that appear in the elderly.” Ohsumi has been a professor at the Tokyo Institute of Technology since 2009.
Autophagy and aging research in detail
The Nature Aging review (2021). Yahyah Aman and Tomas Schmauck-Medina (joint first authors) and 13 co-authors, with senior author Evandro F. Fang (University of Oslo and Akershus University Hospital), reviewed autophagy’s links to aging and disease. The review describes three major types of autophagy (macroautophagy, microautophagy and chaperone-mediated autophagy) and uses “autophagy” to mean macroautophagy. It reports “an age-dependent reduction in lysosomal proteolytic function” in C. elegans, rodents and human cells, and says “findings in humans have suggested that the expression of autophagy-related genes, such as ATG5, ATG7 and BECN1, declines with age.” It adds that interventions that extend lifespan in model organisms, “including dietary restriction and treatment with pharmacological agents, such as rapamycin, spermidine and NAD+ precursors, require intact autophagic machinery,” and that mTOR inhibition and AMPK activation are “canonical inducers of autophagy.” Disclosures listed in the paper: Fang has a cooperative research and development agreement (CRADA), a research collaboration, with ChromaDex and consults for Aladdin Healthcare Technologies, the Vancouver Dementia Prevention Centre and Intellectual Labs; Guido Kroemer is a scientific co-founder of everImmune, Samsara Therapeutics and Therafast Bio; two other co-authors consult for companies. (Note 2)
The hallmarks of aging (2013 and 2023). The 2013 paper by Carlos López-Otín and colleagues in Cell listed nine proposed hallmarks, with loss of proteostasis but no separate autophagy hallmark. The 2023 update, also in Cell, proposed 12, adding disabled macroautophagy, chronic inflammation and dysbiosis. The framework requires a hallmark to appear with age, to accelerate aging when experimentally intensified and to offer a way to slow, stop or reverse aging when targeted. The 2023 paper’s disclosures state that Manuel Serrano is a shareholder and adviser of Altos Labs and other companies, and that Kroemer holds patents related to therapeutic targeting of aging and co-founded several companies, including Samsara Therapeutics. (Note 3)
Fasting and the measurement problem in detail
Mohammad Bagherniya and colleagues (senior author Amirhossein Sahebkar, Mashhad University of Medical Sciences) reported that blocking autophagy weakens calorie restriction’s effects in laboratory models, supporting a role for autophagy in the longevity response. They concluded that fasting and calorie restriction increase autophagy across many tissues and organs in response to food deprivation. CR is calorie restriction. (Note 4)
Saori Yoshii and Noboru Mizushima’s 2017 review in the International Journal of Molecular Sciences explains that measuring autophagy properly requires autophagic flux, “the amount of autophagic degradation,” which “remains complicated even in cultured cells and model organisms, and is currently unfeasible in humans.” Human autopsy or biopsy samples “are often limited in quality due to difficulty in obtaining fresh tissues,” and static analyses “cannot distinguish between autophagy upregulation and degradation inhibition.” Their conclusion: “Presently, there is no established method to measure autophagic flux in humans; therefore, it remains practically impossible to monitor autophagy properly in humans.” The authors declare no conflicts of interest. (Note 5)
Rapamycin: the mouse study and the label in detail
David E. Harrison of the Jackson Laboratory (first author) and colleagues, with Richard A. Miller as senior author, reported that rapamycin “extends median and maximal lifespan of both male and female mice when fed beginning at 600 days of age.” On the basis of age at 90% mortality, it increased lifespan by 14% for females and 9% for males, at three independent test sites in genetically heterogeneous mice. Disease patterns didn’t differ from control mice. A separate group started at 270 days also showed increased survival in an interim analysis. The authors wrote that “a 600-day-old mouse is roughly the equivalent of a 60-year-old person,” and that rapamycin “may extend lifespan by postponing death from cancer, by retarding mechanisms of ageing, or both.” The National Institute on Aging says the program tests compounds in genetically heterogeneous UM-HET3 mice at the Jackson Laboratory, the University of Michigan and the University of Texas Health Science Center at San Antonio. (Note 6)
The US prescribing information for sirolimus tablets (label version November 2025, read September 26, 2026) describes it as “an mTOR inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in patients aged ≥13 years receiving renal transplants” and for lymphangioleiomyomatosis. Its boxed warning covers immunosuppression and says use is not recommended in liver or lung transplant patients.
The SmartAge trial in detail
SmartAge was a 12-month, randomized, double-masked, placebo-controlled phase 2b trial run between January 2017 and May 2020 at the NeuroCure Clinical Research Center, Charité–Universitätsmedizin Berlin, described in the paper as “an academic clinical research center in Germany.” Participants were 60 to 90 years old with subjective cognitive decline (51 spermidine, 49 placebo; mean age 69; 49% women). The daily dose was 750 mg of wheat-germ extract in six capsules, corresponding to about 0.9 mg spermidine; the placebo was microcrystalline cellulose. Eighty-nine participants completed the intervention.
The primary outcome, mnemonic discrimination on the Mnemonic Similarity Task, showed no significant change (between-group difference −0.03; 95% CI −0.11 to 0.05; P = .47) in the intention-to-treat analysis, and secondary outcomes also showed no significant changes. The −0.03 is measured in units of the task’s mnemonic discrimination index, a score calculated from responses during the recognition part of the memory test; it is not a 3% decline in memory. It compares the two groups’ changes from their starting scores. The 95% confidence interval (CI) describes uncertainty around that difference and includes zero, meaning no difference between the groups, as well as changes favoring either group. Serious adverse events: 7 in the spermidine group and 12 in the placebo group, none rated as related to the supplement. Blood polyamine levels were not altered. Exploratory per-protocol and subgroup analyses suggested effects in people 70 and older, in men, in those with higher dietary spermidine intake and in those with more severe complaints; the authors say these “need to be interpreted with caution.”
The authors wrote that “the daily dose of 0.9 mg spermidine might not have been sufficient,” that the capsules added “about 10% of the average spermidine intake per day in developed countries,” and that the lower dose was chosen partly because of “higher polyamine levels in some malignant neoplasms” and increased kidney weight in mice at high doses. They also note that 12 months “might have been too short.” The trial is registered as NCT03094546.
Full disclosures, from the paper: Frank Madeo, Stephan Sigrist and Tobias Eisenberg reported equity interests in and advisory roles for The Longevity Labs GmbH (TLL); Slaven Stekovic “reported employment as chief executive officer of TLL during planning, initiation, and the time the trial was conducted and had equity interest at TLL until December 2019.” Madeo also reported adviser fees from Samsara Therapeutics and a US patent pending for spermidine-related technology. The supplement was supplied by The Longevity Labs, which “provided funds for supporting the development of spermidine-rich wheat germ extract during the conduct of the study.” The paper states that the funders had no role in the design, conduct, analysis or decision to publish. (Note 1)
Sources
- Nobel Assembly at Karolinska Institutet: The Nobel Prize in Physiology or Medicine 2016, press release
- Aman Y, et al. Autophagy in healthy aging and disease, Nature Aging, 2021: PubMed 34901876
- López-Otín C, et al. The hallmarks of aging, Cell, 2013: PubMed 23746838
- López-Otín C, et al. Hallmarks of aging: An expanding universe, Cell, 2023: PubMed 36599349
- Bagherniya M, et al. The effect of fasting or calorie restriction on autophagy induction, Ageing Research Reviews, 2018: PubMed 30172870
- Yoshii SR, Mizushima N. Monitoring and measuring autophagy, International Journal of Molecular Sciences, 2017: PubMed 28846632
- Harrison DE, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice, Nature, 2009: PubMed 19587680
- National Institute on Aging: Interventions Testing Program
- US National Library of Medicine, DailyMed: Sirolimus tablets prescribing information
- Schwarz C, et al. SmartAge, JAMA Network Open, 2022: PubMed 35616942
- Johns Hopkins Medicine: Intermittent Fasting: What is it, and how does it work?
Notes
Note 1: SmartAge was funded by Germany’s Federal Ministry of Education and Research (grant FKZ 01GQ1420B) and the Hans Gerhard Creutzfeldt scholarship, with support for the NeuroCure Clinical Research Center from the German Research Foundation and the Berlin Institute of Health, and additional support from the University of Graz; Frank Madeo also acknowledged Austrian Science Fund grants. The Longevity Labs GmbH provided funds for developing the wheat-germ extract.
Note 2: The Nature Aging review’s authors were supported by grants including the US National Institute on Aging, the UK Biotechnology and Biological Sciences Research Council, Cancer Research UK, the Wellcome Trust, the UK Medical Research Council and the Research Council of Norway.
Note 3: The 2023 hallmarks update’s funding isn’t listed in its public PubMed record; the paper states that none of the funders had a role in its preparation.
Note 4: The 2018 Ageing Research Reviews review’s funding isn’t listed publicly.
Note 5: Funded in part by the Japan Society for the Promotion of Science (KAKENHI grants 25111001 and 25111005) and a TOYOBO Biotechnology Foundation grant.
Note 6: Funded by the US National Institute on Aging.
Featured image: Image by xewex via Envato Elements.
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