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Autophagy is the process of ‘renovation,’ crucial in cell fate decisions.[1] Full Free Article It is also a catabolic adaptive survival response. Autophagy is the decomposition and recycling of redundant or dysfunctional cellular components (including proteins, lipids, glycogens, nucleotides) by the lysosome. This ensures cellular survival during starvation by maintaining cellular energy levels and other nutrients (for construction). Full Free Article


Like the body, each cell contains specialised organs, called organelles. Lysosomes resemble the digestive system. Lysosomes (pH 4.8) contain weak bases with lipophilic properties and hydrolase enzymes (such as acid sphingomyelinase) that break down waste materials and cellular debris. The membrane keeps the enzymes inside. Autophagic vacuoles (trucks carrying waste) fuse with the lysosomes, which dispense their digestive enzymes into the vacuoles. Alternatively, materials may cross the lysosomal barrier by the mediation of a chaperone complex (extremely selective, due to a membrane-bound protein receptor recognition system). Materials from the cytoplasm may also directly engulf (by inward folding of the lysosomal membrane) into the lysosome (microautophagy). Lysosomes may process / digest remainders of dying cells or dysfunctional organelles, invading microbes / bacteria and cell surface receptor proteins. Lysosomes also produce protein and may serve as a patch for when the plasma membrane is damaged, 'sealing' the wound. Moreover, lysosomes act as metabolic sensors and orchestrate the response (such as lipid degradation in different organelles) to fasting.[2] The lysosomal/autophagy pathway is a critical regulator of cellular metabolism, controlling intracellular signaling. Factors affecting lysosomal homeostasis can influence whole-body metabolism. [3]


Autophagy helps to preserve organelles [4] and to keep cells functioning, as cells require a constant supply of nutrients (supplied by autophagy). [5] By doing so (recycling protein), autophagy reduces the overall burden of protein synthesis. [6] Full Free Article Energetic needs during starvation and stress are partly met by elevated autophagy. Stimulation of autophagy may also help cells to eliminate pathogens (viruses[7], bacteria etc). Failure of autophagy is thought to be one of the main reasons for the accumulation of cell damage and aging. [8] Autophagy protects against diseases such as cancer [9] [10], neurodegenerative disorders [11] [12], bacterial [13] [14] and viral [15] infections, ageing [16] [17], inflammatory diseases [18] [19] and insulin resistance [20] [21]. (supported by animal studies Full Free Article) Aging of the heart is accelerated when autophagy is impaired. [22] long-term caloric restriction may preserve cardiac function by promoting autophagy. [23] Melatonin (an endogenous antioxidant) modulates autophagy [24] increasing superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and total glutathione (GSH) levels [25] Vitamin D also induces autophagy, mediated by (antimicrobial) cathelicidin. [26]


Enzymes required for the breakdown of unused cells, the so-called "silent information regulator 2 -family" are implicated in age-related disorders and longevity. [27] Full free article "There is a striking similarity between the signalling aspects of ageing and autophagy". Nutritional deprivation and calorie restriction can enhance autophagy and increase lifespan. "Such striking similarities indicate that lifespan is strongly dependent on autophagy." [28] Long-term calorie restriction without malnutrition results in some of the same metabolic and hormonal adaptations related to longevity in calorie restriction rodents.[29] Autophagic proteolysis and sirtuin activity are downregulated by the insulin signaling pathway. Brain aging is associated with a progressive imbalance between antioxidant defenses and intracellular concentrations of ROS, as exemplified by increases in products of lipid peroxidation, protein oxidation, and DNA oxidation. [30] Full Free Article Long myelinated nerve fibers (that convey information between the CNS and organs) are particularly susceptible to age-related changes, as maintenance requires extensive synthesis and processing of many proteins. Intermittent fasting (IF) and calorie restriction (CR) preserve neural function.[31]


In skeletal muscle, autophagy is required to maintain myofiber integrity. A lack of autophagy results in muscle degeneration and wasting. [32] Both nutrient depletion and exercise induce autophagy, and they both due so through sensing (by AMP-activated protein kinase (AMPK)) the cellular ratio of AMP to ATP.[33] Full Free Article In return, cellular autophagy function is partially required for normal levels of exercise-induced muscle AMPK activation.[34] Exercise increases autophagy (also in the absence of nutrient depletion), particularly evoking the conversion of protein for energy.[35] Full Free Article During strenuous exercise, mammals undergo metabolic changes to increase skeletal muscle glucose uptake/utilization efficiency, including increased insulin sensitivity and redistribution of glucose transporters, such as GLUT4 (also known as SLC2A4), to the plasma membrane [36] [37] which is essential for exercise-stimulated glucose uptake [38], and which are impaired when autophagy is defective.[39] Full Free Article

Autophagy is activated by low levels of energy (AMP to ATP) in muscle cells,[40], induced by both exercise and caloric restriction Full Free Article. Autophagy is essential in skeletal muscle homeostasis, preventing accumulation of damaged mitochondria, excessive apoptosis [41] and damaged collagen fibres [42] Full Free Article, which is reversed by autophagy induced by maintenance on a low protein diet (autophagy is involved in protein quality control[43], recycling amino acids[44]) or longer starvation periods. Full Free Article Physical exercise promotes mitochondrial biogenesis, improves mitochondrial function and prevents muscle fibril degeneration by triggering autophagy.[45] Exercise may prevent chronic and inflammatory disease.[46] Full Free Article

  • In a study of 2357 healthy men (1981-2006), regular exercise was associated with a nearly 30% lower mortality risk.[47]


Insulin inhibits autophagy. Serum insulin is suppressed during exercise and fasting (caloric and protein restriction) and elevated due to significant intake of protein or carbs. Probably by increasing insulin, excessive sugar may eliminate methionine restriction-induced autophagy.[48] Activation of bile acid receptors (which may be activated by dietary fat) also strongly suppresses the induction of autophagy in the fasting state.[49]

Caloric restriction

Through the use of various animal models, it is now well established that by reducing calorie intake (with adequate nutrition) one can not only increase life span [50] but also lower the risk of various age related diseases such as cancer.[51] (a meta-analysis of 14 studies found that calorie restriction results in 55% fewer tumors, regardless of what nutrient is restricted[52]) Autophagy is required for full extension of chronical lifespan by calorie restriction (CR). [53] Dietary derived energy and autophagy are complementary regarding normal cell energy use. Autophagy is increased in response to nutrient depletion. Autophagy is shut off during nutrient abundance. [54] Nutrient depletion evokes autophagy [55]; the degradation of membrane lipids and proteins generates free fatty acids and amino acids reused to fuel mitochondrial ATP energy production and maintain protein synthesis. [56] The beneficial effects of CR are due to modification of specific nutrient-responsive pathways, such as the insulin/insulin-like growth factor IGF-1) pathway [57], the target of rapamycin (TOR) signaling pathway [58], and the NAD+-dependent deacetylases sirtuins.[59]

ROS production in mitochondria is nutrient-sensitizing. [60] Mitochondrial-derived ROS induces autophagy (as mitochondrial antioxidant capacity).[61][62] Acute nutrient deprivation may induce autophagy through the increases of ROS [63], contrasting to the effect of constitutive nutrient deprivation (calorie restricted diet; independent of mitochondrial-derived ROS).[64] Thus constitutive and acute stress-induced autophagy may differ in the levels of resulting ROS in skeletal muscle.[65]

Unicellular organisms lacking autophagy genes (viable in normal growth conditions) die rapidly during starvation.[66] [67] Dietary restriction prolonges lifespan, but not when autophagy is inhibited. [68] Full Free Article Endogenous alpha-Ketoglutarate (a Krebs Cycle intermediate; produced by deamination of glutamate) levels are increased on starvation. alpha-Ketoglutarate (α-KG) mediates longevity by dietary restriction. ATP synthase is the main cellular energy-generating machinery and is highly conserved throughout evolution. α-KG inhibits ATP synthase.[69]

Intermittent fasting

Intermittent fasting (IF) may be more effective than chronic caloric restriction.[70] IF increases longevity through enhancing protein ubiquitination (tagging for degradation) and reducing protein carbonylation (ROS promoted protein breakdown producing reactive ketones or aldehydes).[71] Full Free Text The efficacy of alternate fasting does not depend on calorie restriction. IF reduces mitochondrial generation of reactive oxygen species (ROS), associated with increased SOD activity in spleen mitochondria. [72] Intermittent fasting improves recovery after stroke.[73] Short-term fasting (24 hours) also induces a dramatic upregulation of autophagy in brain neurons.[74] Intermittent caloric restriction may be more protective than chronic calorie restriction regarding the prevention of tumors.[75][76]

Protein restriction

Rats and mice, when subjected to methionine restriction, may live longer with beneficial changes to their mitochondria, due to autophagy.[77] Starvation induces proteolysis (non-digestive break down of protein) connected to autophagy in cells. This is inhibited by amino acids; particularly methionine, accounting for 75% of that inhibitory effect.[78] Insulin inhibits autophagy, and amino acids stimulate insulin secretion, but amino acids also directly inhibit autophagy. Leucine, tyrosine, phenylalanine, methionine and histidine have been shown to be autophagy-regulating amino acids in rats. Besides those 5, proteolysis is also inhibited by serine, glutamine and isoleucine (but not in cancer patients)[79]

In rats, offspring nursed by protein-restricted mothers showed peculiar low-fat accretion through adulthood and preserved insulin sensitivity even after exposure to the western diet.[80]


Various lipids influence autophagy. ω-6 PUFAs (AA and DGLA, not EPA) activate autophagy. Inactivation of C. elegans autophagy components reverses the increase in life span conferred by supplementing the C. elegans diet with these fasting-enriched ω-6 PUFAs." [81] DHA and EPA can be converted to their ethanolamine derivatives, docosahexaenoyl ethanolamine (DHEA) and eicosapentaenoyl ethanolamine (EPEA), which may induce autophagy. [82] EPA and DHA can form endocannabinoids that increase autophagy. [83] EPA can concomitantly induce autophagy [84], but may also counteract palmitate-mediated increase of autophagy in cardiac cells. [85] DHA may induce apoptosis, but also autophagy (accompanied by p53 loss). [86] DHA stimulates autophagy, inhibiting apoB100 secretion. [87]

Autophagy is coregulated by 4-hydroxynonenal (HNE), a major product of omega-6 fatty acid peroxidation [88] Autophagy is inhibited (by 40%) by modifications caused by lipid peroxidation products HNE and malonaldehyde (MDA), which may contribute to cell dysfunction [89] Unsaturated lipid oxidation products HNE and acrolein activate autophagy. Lipid peroxidation-derived aldehydes stimulate autophagy, which removes aldehyde-modified proteins. Inhibition of autophagy precipitates cell death in aldehydes-exposed cells [90]


Energy-restricted metabolic states (CR, IF), extend lifespan in animals, not requiring overall reduced caloric intake [91][92], but necessarily associated with elevations in ketone bodies. In starvation mode, when liver glycogen is depleted, the major source of fuel for the brains (and other tissues) shifts from glucose to ketone bodies (derived from fatty acids and ketogenic amino acids). The main ketone bodies used for energy are acetoacetate and β-hydroxybutyrate. Levels of β-hydroxybutyrate increase dramatically on a ketogenic diet [93], after 12–16 hours of fasting [94][95], and after 90 minutes of intense exercise [96].

Thus elevated levels of ketones are conditionary to, and stimulate autophagy. Just as a small group of other metabolic intermediates that affect gene expression via chromatin modifications [97], β-hydroxybutyrate (and butyrate[98] competitively [99], and at least four major structurally distinct classes[100]) acts as an endogenous inhibitor of HDACs class 1 and 2a.[101], which induces Foxo3a.[102] (Foxo3a is the mammalian ortholog of the stress-responsive transcriptional factor DAF16 that regulates lifespan in worms[103]) Class I HDACs are associated with the regulation of lifespan in model organisms.[104] Supplementary beta-hydroxybutyrate may maximally increase mean lifespan in C. elegans by 26%.[105] βOHB delivered via the diet in the form of a synthetic ester improves learning and memory.[106]

Ketogenic diets suppress fatty acid synthesis enzymes [107][108] and strongly induce regulation of ketogenic genes, and one of its crucial downstream targets, resulting in increased transcription of ketogenic enzymes [109][110]. A ketogenic diet also promotes mitochondrial biogenesis [111] and increases expression of SIRT1 [112], which is also increased during calorie restriction and regulates a variety of aging-related pathways (reviewed in [113]) β-hydroxybutyrate does not extend lifespan in a setting of dietary restriction indicating that β-hydroxybutyrate is likely functioning through a similar mechanism.[114]


Resveratrol evokes autophagy by upregulating sirtuin (the AMPK/ Sirt1 pathway) [115] and expressions of Beclin 1 and LC3β (required in autophagy).[116] Fruits contain varying levels of trans- and cis-resveratrol, with grapes containing the highest levels.[117] Resveratrol and piceatannol synergetically induce autophagy through distinct molecular pathways.[118]

N-acetylcysteine supplementation may enhance glutathione levels [119] prevent oxidative stress, mitochondrial damage and apoptosis [120], but also lower the mitochondrial antioxidant capacity, by reducing the Manganese superoxide dismutase expression and its enzyme activity. Thus, exogenous antioxidant supplement may lower inherent antioxidant capacity in mitochondria.[121] ROS may lead to Manganese superoxide dismutase upregulation, and N-acetylcysteine may block that.[122] Therefore, N-acetylcysteine or other anti-oxidants should be reconsidered carefully for young and healthy individuals, when used to promote muscle growth. Since acute nutrient deprivation (basal; no fasting) induced autophagy may be ROS dependent [123], N-acetylcystein supplementation may also inhibit acute nutrient deprivation-induced autophagy.[124]

Growth factors

Cell damage increases lipid peroxidation. Vascular damage and chronic arterial diseases increases exposure of vascular smooth muscle cells to specific growth factors. These growth factors activate autophagy, preventing (non-enzymatic) lipid peroxidation-induced cell death in vascular smooth cells. [125] Similarly, nerve growth factors preserve cell integrity of neurons. A lack of growth factors induces mitochondrial ROS and subsequent lipid oxidation (blocked by antioxidants). [126] Autophagy prevents ROS-mediated cell death (apoptosis) [127], by up-regulating p38 and nuclear factor-kappa B activation. [128]


The autophagy- and apotosis pathways are intertwined; Signals that activate apoptosis may also induce autophagy, and signals that inhibit apoptosis may also inhibit autophagy.[129] Free Full Text As autophagy is the recycling of (often reactive) cell material, it may be involved in apoptosis (clearing dead cells[130]), or prevent it. [131] And sometimes dying cells still use autophagy [132] Either too little (exposing cells to metabolic stress) or excessive autophagy (digesting healthy cell structures) can cause cell death, but in cells with intact apoptotic machinery, autophagy is primarily a pro-survival rather than a pro-death mechanism. [133] At any point in the process, the autophagy is reversed by growth factors or nutrients. [134] Autophagy genes prevent the onset of apoptosis during nutrient deprivation. [135] Full Free Article


In obese subjects, baseline autophagy in subcutaneous adipose tissue is elevated, and in response to caloric restriction, autophagy is decreased. Also in mice, upon caloric restriction, autophagy increases in lean mice, whereas it decreases in obese mice. Both obesity and caloric overfeeding are associated with the defective regulation of autophagy in the adipose tissue.[136]



Author of this article is Thijs Klompmaker, born in 1966