Autophagy is the process by which every cell degrades and recycles its own damaged components inside the lysosome, its internal recycling centre. This clean-up mechanism maintains internal balance (homeostasis) and, when it loses efficiency with age, it is associated with cellular ageing. Understanding what autophagy is helps to explain why science studies it as a central piece of longevity.
What is autophagy?
The name says almost everything: the word comes from the Greek auto (self) and phagein (to eat), literally "to eat oneself". Far from being self-destructive, it works as a quality-control system. The cell encapsulates worn-out organelles and misfolded proteins (proteins that have lost their functional shape) and carries them to the lysosome, the organelle that acts as a recycling plant, where they are broken down into reusable building blocks. This constant recycling preserves cellular homeostasis, the internal balance that allows the cell to function.
How it was discovered: from De Duve to Ohsumi (Nobel 2016)
The concept was born in 1963, when the Belgian biochemist Christian de Duve —the discoverer of the lysosome— coined the term "autophagy". For decades it was a phenomenon that was hard to observe. The decisive leap came in the 1990s with Yoshinori Ohsumi, who identified 15 genes (the so-called ATG genes) essential for autophagy in yeast, laying the foundations of the modern field. In 2016, the Nobel Assembly at the Karolinska Institute awarded him the Nobel Prize in Physiology or Medicine for these discoveries.
Three milestones in the discovery of autophagy
From a term coined in 1963 to a Nobel Prize half a century later.
Christian de Duve
The Belgian biochemist, discoverer of the lysosome, coins the term "autophagy".
Yoshinori Ohsumi
Identifies 15 genes (ATG genes) essential for autophagy in yeast.
Nobel Prize
Ohsumi receives the Nobel Prize in Physiology or Medicine for these discoveries.
Why is autophagy linked to cellular ageing?
As the years go by, autophagic activity tends to decline. That loss of efficiency in cellular recycling is one of the traits that research associates with cellular ageing: when the clean-up slows down, damaged proteins and defective organelles accumulate. Autophagy is a central molecular pathway for preserving the organism's homeostasis, and its dysfunction has been associated with ageing and several age-related diseases. Research even considers it a determinant of the organism's longevity. A nuance is in order: this refers to an observed association, not to autophagy on its own causing or treating any disease.
What activates autophagy? Fasting, calorie restriction and lifestyle
Several factors linked to nutrient scarcity up-regulate autophagy. Among the most studied:
- Fasting and calorie restriction: the most potent non-genetic stimuli described.
- Food deprivation: induces autophagy in multiple tissues and organs.
- Calorie-restriction mimetic compounds: reproduce part of that biochemical signal.
- Metabolic stress of exercise: a subject of active research.
Fasting and calorie restriction
Fasting and calorie restriction (reducing calorie intake without reaching malnutrition) promote —up-regulate— autophagy across a wide variety of tissues and organs. A 2018 review describes them as the most potent non-genetic stimulators documented to date. What is more, a 2019 review describes calorie restriction and fasting as one of the best-documented strategies for extending healthy life expectancy (healthspan, the years lived in good health) in mammals, including non-human primates; direct evidence in humans is still limited.
A note of honesty: there is no validated threshold of fasting hours in humans beyond which "autophagy switches on". A good part of the evidence comes from tissues and laboratory models, so any specific number of hours should be taken with caution.
Exercise and other metabolic stressors
Physical exercise is a metabolic stress that activates the cell's nutrient-sensing pathways —proteins such as AMPK and mTOR, the sensors that tell the cell whether there is an abundance or a scarcity of energy. Its direct relationship with autophagy in humans remains a subject of research, so it is best not to over-interpret it. On the compound side, calorie-restriction mimetics promote autophagy by reducing the acetylation of proteins, a chemical modification that regulates their activity. It is the same biochemical language the body uses when it perceives nutrient scarcity.
The NAD+/sirtuin pathway: the link between metabolism and autophagy
Energy metabolism and autophagy share a key messenger: NAD+ (nicotinamide adenine dinucleotide), a molecule present in every cell that takes part in energy production. Both autophagic activity and NAD+ levels decline with cellular ageing. And there is a bridge between the two: sirtuins (SIRT), a family of enzymes that depend on NAD+ to function, can directly regulate autophagy and the quality control of the mitochondria (the cell's power plants). The PARPs, another family of enzymes, also consume NAD+.
Here an essential nuance is needed: most of the health-span and life-span extension linked to this pathway has been documented in animals —that is, the evidence is mostly preclinical. Translating those findings into a guaranteed clinical benefit in people would go beyond what the evidence shows.
The NAD+ / sirtuin axis and autophagy
A link between energy metabolism and cellular recycling.
An important nuance: most of this relationship has been documented in animal models (mostly preclinical evidence). No food supplement can claim the ability to "activate autophagy".
This territory connects with the universe of cellular vitality, where NAD+ holds a central place. In the field of nutrition, some ingredients are associated with cellular protection through well-established pathways: vitamin C contributes to the protection of cells from oxidative damage. It is a mechanism distinct from autophagy —it does not "activate" it— but it shares the goal of caring for the cell; you can see the detail on the vitamin C page. All of this is part of the cellular vitality collection.
Within this approach, formulas such as PLENIAGE PRO NAD+ —which combines precursors and cofactors of NAD+ metabolism together with vitamin C— fall within this category of cellular care; also available as a specific precursor in PLENIAGE NR NAD+. An important limit: describing the mechanism of autophagy is science communication; no food supplement can claim the ability to "activate autophagy" or to reverse cellular ageing. For an overview of the topic, we bring everything together in the cellular vitality guide.
Frequently asked questions
Does fasting activate autophagy?
Fasting and calorie restriction promote —up-regulate— autophagy across a wide variety of tissues, and they are described as the most potent non-genetic stimuli documented. A good part of the evidence comes from laboratory models, so it is best interpreted with caution.
How many hours of fasting are needed to activate autophagy?
There is no validated threshold of hours in humans. The specific figures in circulation are not solidly backed in people: most of the data come from tissues and animal models.
Do supplements activate autophagy?
No food supplement can claim that it "activates autophagy", which is a physiological process. Describing its mechanism is science communication. Some nutrients, such as vitamin C, contribute to the protection of cells from oxidative damage, which is a different goal.
Does autophagy decrease with age?
Research describes a decline in autophagic activity with cellular ageing, along with a drop in NAD+ levels. This is an observed association, mostly in preclinical studies.
What is the relationship between NAD+ and autophagy?
NAD+ is the cofactor that sirtuins need, enzymes capable of regulating autophagy. Both NAD+ and autophagic activity decline with age, although most of the data on life-span extension come from animals.
Do NAD+ or its precursors (NR, NMN) activate autophagy?
In cell and animal models, raising NAD+ or providing precursors such as nicotinamide riboside favours autophagy and, above all, mitophagy (the recycling of mitochondria) through the sirtuins. It is a well-documented pathway in the laboratory, but not yet confirmed in clinical trials in humans, so it cannot be presented as a guaranteed benefit of any product.
What is mitophagy and why does it matter in ageing?
Mitophagy is the selective autophagy of mitochondria — the cell's power plants — when they become damaged. Removing faulty mitochondria helps maintain energy production. Both mitophagy and NAD+ levels tend to decline with age, a relationship studied mainly in preclinical models.
- Bagherniya M, et al. The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Research Reviews. 2018. PMID: 30172870.
- Wong SQ, et al. Autophagy in aging and longevity. Human Genetics. 2020. PMID: 31144030.
- Klionsky DJ, et al. Autophagy in major human diseases. The EMBO Journal. 2021. PMID: 34459017.
- Wilson N, et al. The autophagy-NAD axis in longevity and disease. Trends in Cell Biology. 2023. PMID: 36878731.
- Madeo F, et al. Caloric Restriction Mimetics against Age-Associated Disease: Targets, Mechanisms, and Therapeutic Potential. Cell Metabolism. 2019. PMID: 30840912.