Autophagy was initially classified under "altered proteostasis" as part of the hallmarks of aging. However as autophagy is involved in various other aspects of aging, such as DNA repair and metabolism,  it's now seen as an "integrative hallmark". Autophagy is the cell´s way of cleaning up and recycling it´s own parts to maintain health and efficiency [1] by breaking down various parts of the cell, such as proteins, fats, and small structures called organelles. This breakdown happens in special compartments within the cell called lysosomes, which contain enzymes that can digest these cellular components. Impaired autophagy is a cause of aging and not just a consequence. When the efficiency of autophagy declines, it contributes to the accumulation of damaged cellular components, affecting other hallmarks of aging and the progression of health and beauty (skin health) problems [1][2]. 

SIMPLIFIED HOW AUTOPHAGY WORKS
▌Initiation: The process begins when a cell is under stress, such as during nutrient deprivation or oxidative stress.
▌Formation of the autophagosome: A double-membrane structure called a phagophore forms and expands to engulf damaged or unnecessary cellular components.
▌Encapsulation: The phagophore completely surrounds the targeted cellular material, forming a sealed vesicle called an autophagosome.
▌Fusion with lysosome: The autophagosome travels through the cell and fuses with a lysosome, forming an autophagolysosome - see picture below
▌Breakdown and recycling: Inside the autophagolysosome, lysosomal enzymes break down the captured cellular material into basic building blocks like amino acids, fatty acids, and nucleotides.
▌Reuse of materials: The broken-down components are released back into the cell's cytoplasm, where they can be reused to build new cellular structures or generate energy.

THREE MAIN TYPES OF AUTOPHAGY

1. Macroautophagy: The most common form, involving the formation of autophagosomes that engulf cellular components and fuse with lysosomes for degradation.
2. Microautophagy: Direct engulfment of cytoplasmic material by lysosomes.
3. Chaperone-mediated autophagy: Selective degradation of specific proteins with the help of chaperone proteins.

Various impairments in these autophagy mechanisms can occur:
▌Autophagosome formation
▌Decreased lysosomal function
▌Impaired fusion of autophagosomes with lysosomes
▌Accumulation of non-degradable material in lysosomes  
These impairments lead to the accumulation of damaged cellular components, contributing to the aging process.

CONSEQUENCES DECLINE AUTOPHAGIC ACTIVITY 

1. Accumulation of damaged proteins and organelles: Impaired autophagy leads to the buildup of dysfunctional cellular components, which can interfere with normal cellular processes [1]. Malfunctioning autophagy disrupts proteostasis and cellular quality control [3]. 
2. Mitochondrial dysfunction: Autophagy is crucial for mitochondrial quality control. Its decline contributes to the accumulation of damaged mitochondria, leading to reduced energy production and increased oxidative stress [1][2].
3. Increased susceptibility to age-related diseases: Impaired autophagy is associated with various age-related pathologies, including neurodegenerative diseases, cardiovascular disorders, and cancer [1][2].
4. Stem cell exhaustion: Autophagy is essential for maintaining stem cell function. Its decline contributes to reduced tissue regeneration capacity [1].
5. Cellular senescence: Impaired autophagy promotes the accumulation of senescent cells, which can contribute to chronic inflammation and tissue dysfunction [1][2].
6. Proteostasis network: Autophagy is part of the proteostasis network, essential for cellular quality control. Malfunctioning autophagy disrupts proteostasis, contributing to the aging process [3].
7. Metabolic Stress: Conditions like sarcopenic obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) are characterized by metabolic derangements and intracellular stresses, which are aggravated by impaired autophagy [4].​​

GENERAL CAUSES IMPAIRED AUTOPHAGY - HEALTH
Disruption of key regulatory pathways
Autophagy is tightly regulated by several molecular pathways, and disruption of these can impair the process:
▌Nutrient sensing pathways: Inhibition of AMPK and SIRT1 or activation of mTOR can suppress autophagy initiation [1][5]. 
▌Mutations affecting proteins like ULK1, Atg13, or other autophagy-related genes can disrupt autophagosome formation [5].
▌Dysregulation of transcription factor TFEB, which controls expression of autophagy and lysosomal genes, can impair the process [1][5].
Defects in autophagosome formation or maturation
Problems with the machinery involved in forming or maturing autophagosomes can impair autophagy:
▌Disruption of membrane sources like the ER or mitochondria can affect autophagosome formation [6].
▌Mutations affecting proteins involved in autophagosome-lysosome fusion, like Dynein, can block completion of autophagy [6].
Lysosomal dysfunction
Since lysosomes are crucial for the degradation step of autophagy, lysosomal defects can severely impair the process:
▌Lysosomal storage disorders, like Pompe disease, directly impair the degradative capacity of lysosomes [1].
▌Accumulation of undegraded material in lysosomes can overwhelm their function over time [1].
Cellular stress and damage
Various cellular stressors can both induce and potentially overwhelm autophagy:
▌Oxidative stress and mitochondrial dysfunction can both trigger and potentially impair autophagy if severe [7][8].
▌Accumulation of protein aggregates, as seen in neurodegenerative diseases, can overwhelm autophagic capacity [6][7].
Metabolic imbalances
Disruptions in cellular metabolism can impair autophagy:
▌Chronic exposure to excess nutrients, like in obesity or alcoholic liver disease, can suppress autophagy through mTOR activation [1][5].
▌Energy deficits can potentially impair autophagy if severe enough to disrupt basic cellular functions [5]. 
In many cases, impaired autophagy results from a combination of these factors, often creating a vicious cycle where initial dysfunction leads to further cellular stress and damage, progressively worsening autophagic impairment over time [1][7][8]. This is particularly evident in age-related and neurodegenerative diseases, where multiple factors converge to disrupt cellular homeostasis and autophagic function.

SKIN AGING
Autophagy impairment contributes significantly to skin aging through multiple mechanisms: [9]
▌Reduced collagen and elastin production by fibroblasts
▌Accumulation of damaged ECM components
▌Altered keratinocyte differentiation and reduced barrier function (thinning)
▌Reduced stem cell function and altered cellular metabolism
▌Accumulation of cellular damage and reduced stress resistance 
Impaired autophagy in fibroblasts and keratinocytes leads to wrinkles and reduced skin elasticity [10][11] and more visible signs of aging skin.

SKIN SPECIFIC CAUSES IMPAIRED AUTOPHAGY - BEAUTY
Autophagy decline was observed in both intrinsic and extrinsic skin aging [12].
Oxidative stress and environmental factors
Skin cells are constantly exposed to environmental stressors that can impair autophagy:
▌Ultraviolet (UV) radiation is a major factor that can disrupt autophagy in skin cells, particularly keratinocytes and melanocytes [13][14].
▌Reactive oxygen species (ROS) generated from various environmental factors can deactivate key autophagy regulators like Akt and mTORC1, leading to impaired autophagy initiation [15].
Aging and senescence
As skin cells age, their autophagic capacity tends to decline:
▌Premature skin aging is associated with decreased autophagy in various skin cell types [13].
▌Senescence of mesenchymal cells in the dermis is linked to impaired autophagy and contributes to skin aging [14].
Dysregulation of autophagy pathways
Several molecular pathways can become dysregulated, leading to impaired autophagy:
▌Mutations or alterations in autophagy-related genes (ATGs) can disrupt the formation of autophagosomes and impair the process [15][16].
▌Dysfunction of the mTORC1 signaling pathway, a key regulator of autophagy, can lead to autophagy impairment [17].
Cellular energy imbalances
Disruptions in cellular metabolism can impair autophagy in skin cells:
▌Low cellular energy levels (high AMP/ATP ratio) can abnormally trigger AMPK activation, disrupting normal autophagy regulation [17].
▌Nutrient imbalances can affect mTORC1 activity, which is crucial for proper autophagy function [17].
Inflammatory processes
Chronic inflammation in the skin can interfere with normal autophagy:
▌Inflammatory skin conditions like psoriasis and atopic dermatitis are associated with impaired autophagy in various skin cell types [16][17].
Lysosomal dysfunction
Since lysosomes are crucial for the final stages of autophagy, their dysfunction can severely impair the process:
▌Accumulation of undegraded material in lysosomes, which can occur with aging or in certain skin conditions, can overwhelm lysosomal function and impair autophagy completion [15][14].

ROLE OF UV AND BLUE LIGHT IN AUTOPHAGY IMPAIRMENT
IMPLICATIONS FOR SKIN HEALTH AND PHOTOAGING

UV Radiation and autophagy:
UV exposure has a complex effect on autophagy in skin cells. Acute UV exposure activates autophagy as a protective mechanism. This process helps degrade oxidized lipids and metabolic wastes, potentially slowing photoaging. However, chronic UV exposure leads to autophagy impairment and accelerated skin aging [13]. 
UV radiation modulates several signaling pathways involved in regulating autophagy: [14] [18]
1. mTOR (mechanistic target of rapamycin): A negative regulator of autophagy
2. AMPK (AMP-activated protein kinase): Promotes autophagy
3. PI3K/Akt pathway: Influences autophagy regulation
4. p53: Plays a role in UV-induced autophagy response
UV exposure also affects the expression and activity of autophagy-related genes like Atg5, Atg7, and LC3 [14]. The UV-induced DNA damage and oxidative stress contribute significantly to autophagy dysfunction over time.
Blue light and autophagy:
▌Blue light induces approximately 50% of the oxidative stress in skin cells compared to UV.
▌It penetrates deeper into the skin, affecting both epidermal keratinocytes and dermal fibroblasts.
▌Prolonged exposure may lead to autophagy impairment, contributing to premature skin aging and pigmentation issues.
Molecular mechanisms and key players: [14]
Several molecular mechanisms and key players are involved in the UV-autophagy relationship:

1. Sirtuins, especially SIRT1, regulate both autophagy and aging processes.
2. FoxO transcription factors are involved in autophagy regulation and are affected by UV exposure.
3. PPARδ activation can induce autophagy markers and protect against photoaging.
4. Heat shock proteins like HSP70 are involved in chaperone-mediated autophagy and are affected by UV exposure.
5. Nrf2, an important regulator of antioxidant responses and autophagy, is modulated by UV radiation.
6. The heme oxygenase (HO) system, especially HO-1, is induced by UV radiation and linked to autophagy regulation.
7. NF-κB activation by UV radiation plays a role in photoaging and is connected to autophagy processes.

AUTOPHAGY AND DNA REPAIR 
Autophagy plays a crucial role in maintaining cellular homeostasis and genomic stability, particularly in skin health and DNA repair [19]. When UVB radiation hits our skin, it activates AMPK, which in turn boosts the autophagy process in our cells [18]. This mechanism is essential for repairing various types of DNA damage, including broken DNA strands, small structural changes, and errors that occur during DNA replication [20]. Autophagy positively regulates the recognition of DNA damage by nucleotide excision repair (NER) and enhances the repair of UV-induced lesions, particularly through the removal of oxidized proteins and lipids [21]. By responding to various DNA lesions and regulating multiple aspects of the DNA damage response (DDR), autophagy helps maintain the integrity of our genetic material and promotes overall skin health.

IMPACT ON SKIN CELLS
The skin, being the largest organ, is significantly affected by impaired autophagy, which impacts various skin cells differently, leading to visible signs of aging such as wrinkles, reduced skin thickness, and pigmentation changes. Ethnic differences in autophagy capacity may influence susceptibility to skin damage [12]. 
Autophagy has different effects in three categories of skin cells: [13] 
▌stem cells: autophagy supports self-renewal and quiescence. Declining autophagy can lead to stem cell loss over time.
▌short-lived differentiating cells: like keratinocytes, autophagy contributes to differentiation processes like cornification but is less impacted by aging.
▌long-lived differentiated cells (hair follicles and sweat glands): autophagy maintains cell survival and function. Decreased autophagy leads to accumulation of damaged components.
The roles of autophagy in skin aging are complex and cell type-specific [13].

Keratinocytes
Keratinocytes, the primary cell type in the epidermis, rely heavily on autophagy for differentiation and barrier function [16]. Different autophagy proteins showed distinct localization patterns in the epidermis [12]. LC3 and ATG9L1 were enriched in granular layers, while ATG5-ATG12 and ATG16L1 were in basal/spinous layers [12]. Autophagy plays a critical role in keratinocyte cornification, the process by which these cells form the outermost layer of the skin. Autophagy protects keratinocytes against UV-induced DNA damage and inflammation, potentially slowing photoaging [13]. 
Impaired autophagy in keratinocytes can lead to:
▌Reduced barrier function
▌Increased susceptibility to environmental stressors [14] 
▌Altered epidermal differentiation
▌Accumulation of damaged proteins and organelles 
▌Increased DNA damage, senescence, and aberrant lipid composition after oxidative stress [14][22].
mTOR inhibition directly promoted keratinocyte differentiation [12].

Fibroblasts
Dermal fibroblasts are responsible for producing extracellular matrix (ECM) components, including collagen and elastin. Fibroblast autophagy helps clear lipofuscin (age pigment) and damaged proteins that accumulate with age. 
Autophagy impairment in fibroblasts can result in:
▌Reduced proteostasis and ECM production (collagen and elastin production) [13]
▌Accumulation of senescent cells and DNA damage [13]
▌Increased matrix metalloproteinase (MMP) activity, leading to ECM degradation
▌Altered cellular metabolism and energy production
▌Accumulation of autophagosomes, resulting in the deterioration of dermal integrity and skin fragility [10][11]
​These changes contribute to the formation of wrinkles and loss of skin elasticity [14].

Melanocytes
Melanocytes, responsible for skin pigmentation, are particularly sensitive to autophagy impairment [13]. Autophagy defects disturb melanosome biogenesis and transport, leading to pigmentation disorders. Autophagy-deficient melanocytes display a senescence-associated secretory phenotype (SASP), contributing to inflammation and pigmentation changes [23]. Declining melanocyte autophagy may contribute to age-related pigmentation changes and hair graying.
The consequences of impaired autophagy:
▌Accumulation of damaged melanosomes
▌Altered melanin production and distribution
▌Increased susceptibility to oxidative stress, inflammation and senescence
▌Pigmentation disorders like vitiligo and hyperpigmentation

Stem cells
Skin stem cells, including those in hair follicles and the interfollicular epidermis, rely on autophagy for maintenance and function.
Impaired autophagy in stem cells can lead to:
▌Reduced self-renewal capacity
▌Altered differentiation potential
▌Accumulation of damaged cellular components
▌Premature stem cell exhaustion
These effects contribute to reduced skin regeneration and repair capacity with age [14].

Sweat glands and sebaceous glands 
Autophagy is essential for normal sebum production in sebaceous glands (long-lived cells) and in sweat glands suppresses accumulation of lipofuscin ("age pigment") during aging and maintains gland function [13]. Autophagy plays a crucial role in the function of sweat glands and sebaceous glands.
Impairment can result in:
▌Reduced sweat production, affecting thermoregulation
▌Altered sebum composition and production - can affect skin barrier function and contribute to conditions like acne [24] 
​▌Increased susceptibility to infections and skin disorders

Merkel cells
Autophagy regulates serotonin signaling in Merkel cells and may impact age-related changes in touch sensation [13]. 

Hair follicles
In hair follicles, (long lived cells) autophagy promotes hair growth [14] and may counteract age-related hair loss when pharmacologically activated [13]. 

PIGMENTATION
Dysregulation of autophagy in melanocytes affects melanin synthesis and transfer, leading to pigmentation disorders [23]. Autophagy activity correlates with skin lightness measurements and plays a role in  melanosome degradation in keratinocytes . autophagy proteins like LC3, p62, ATG9L1, ATG5-ATG12 and ATG16L1 were decreased in hyperpigmented skin, while mTORC1 activity was increased in hyperpigmented elbow skin [12]. 
Autophagy impairment can lead to various pigmentation disorders: [12]
▌Hyperpigmentation: Accumulation of damaged melanosomes and altered melanin distribution
▌Hypopigmentation: Potential link to vitiligo through increased melanocyte sensitivity to oxidative stress
▌Uneven skin tone: Dysregulation of melanin production and transfer to keratinocytes
Restoring autophagy (inhibiting mTORC1 with Torin 1) improved both pigmentation (maintaining skin color uniformity) and epidermal differentiation (barrier function) [12] and could be a therapeutic approach for photoaging and hyperpigmentation.

PIGMENTATION ISSUES 
1. Senile Lentigo (Age Spots):
Studies have shown that autophagy declines in hyperpigmented skin areas such as senile lentigocompared to even-toned skin [12]. This decline in autophagy is associated with increased melanin deposition and melanocyte proliferation in the epidermis [13]. The impaired autophagy in these areas also correlates with reduced levels of late epidermal differentiation markers like filaggrin and loricrin [13].
2. Photoaging:
Ultraviolet (UV) radiation, a major cause of photoaging, affects autophagy in skin cells. While UV exposure initially increases autophagy as a protective mechanism, chronic exposure leads to impaired autophagic function. This impairment contributes to the accumulation of damaged cellular components and oxidized proteins, accelerating the photoaging process [14][12].
3. Xerotic hyperpigmentation:
In areas of skin with severe xerosis (dry skin) and hyperpigmentation, an exacerbated decline in autophagy has been observed. This decline is accompanied by severe dehydration and barrier defects, showing correlations with deteriorating skin physiological conditions [13=10]. The impaired autophagy in these areas contributes to both pigmentation abnormalities and compromised epidermal differentiation.
 
These examples demonstrate that impaired autophagy is associated with various aspects of skin aging, including pigmentation changes, barrier function decline, and altered epidermal differentiation. The decline in autophagic activity appears to be both a result of aging processes and a contributing factor to the progression of skin aging symptoms [12][13][14].
 
SOLAR ELASTOSIS
Solar elastosis is characterized by the accumulation of abnormal elastotic material (broken elastin fibres due to sun damage) in the dermis.
While not directly linked to impaired autophagy, the loss of autophagy and/or it's housekeeping partner proteasome could be a contributing factor.
1. Autophagy is crucial for cellular homeostasis: Autophagy is described as "an essential cellular process that maintains balanced cell life" and is responsible for "clearing surplus or damaged cell components notably lipids and proteins" [12].
2. Impaired autophagy in photoaging: Loss of autophagy leads to both photodamage and the initiation of photoaging in UV exposed skin [12][18].
3. UV radiation affects autophagy: UV exposure can both stimulate and impair autophagy, depending on the circumstances. For example, repeated UVA radiation negatively affects the autophagy process in fibroblasts due to modifications in lysosomal functioning [25].
4. Accumulation of damaged components: When autophagy is impaired, there's a reduced ability to clear damaged cellular components. This could  include broken down elastin fibres. The proteasome and autophagy work closely together in cleaning up and recycling proteins like elastin. 
5. Chronic inflammation: Photoaging is characterized by a chronic inflammatory response, which can be exacerbated by defects in autophagy. In turn, defects in autophagy have also been shown to cause severe inflammatory reaction in the skin [12].

AUTOPHAGY FAT CELLS
Autophagy in fat cells, or adipocytes, plays a significant role in regulating adipose tissue biology and metabolism. 
1. Role in adipose tissue biology: Autophagy is crucial for maintaining cellular homeostasis in adipose tissue by degrading and recycling cellular components. It influences adipogenic differentiation and affects the size and function of adipose tissue depots [26].
2. Influence of obesity: In obesity, autophagy is often altered. Adipocytes in obese individuals show increased autophagic activity, which is associated with enhanced lipid mobilization and metabolic activity [27]. This process can be influenced by proinflammatory cytokines, leading to selective degradation of lipid droplet proteins like Perilipin 1 [27].
3. Adipocyte browning: Autophagy is involved in the browning of white adipose tissue, which is associated with increased energy expenditure and protection against obesity [28]. Suppression of autophagy can block adipogenesis and lipid accumulation, indicating its role in fat storage and metabolism [28].
4. Response to fasting: During fasting, autophagy is upregulated in adipose tissue to promote fat breakdown and support metabolic processes like ketogenesis [29]. This response involves the regulation of genes that influence autophagic activity.
5. Regulation by mTOR: The mTOR signaling pathway is a major regulator of autophagy in adipocytes. Under conditions of nutrient deprivation or stress, mTOR activity is inhibited, leading to the activation of autophagy [17].
 
AUTOPHAGY AND INSULIN RESISTANCE
​Activation of autophagy is beneficial for improving insulin sensitivity without compromising insulin production [30][31].
Impaired autophagy as a cause of insulin resistance
1. Accumulation of cellular debris: When autophagy is impaired, damaged organelles and proteins accumulate in cells, leading to cellular stress and inflammation that can contribute to insulin resistance [32].
2. ER stress: Autophagy inhibition can cause severe endoplasmic reticulum stress in adipocytes, which can suppress insulin receptor signaling and contribute to peripheral insulin resistance [33].
3. Mitochondrial dysfunction: Impaired autophagy can lead to accumulation of damaged mitochondria, which can disrupt cellular metabolism and contribute to insulin resistance [32].
4. Reduced insulin signaling: Knockdown of autophagy genes like Atg7 in adipocytes can reduce insulin-stimulated phosphorylation of insulin receptor subunits and IRS-1, directly impairing insulin signaling [33].
Insulin resistance as a cause of impaired autophagy
1. Hyperinsulinemia: Chronic exposure to high insulin levels, as seen in insulin-resistant states, can suppress autophagy through activation of mTORC1 and inhibition of FoxO1 [30].
2. Nutrient excess: The excess nutrients associated with obesity and insulin resistance can inhibit autophagy through mTORC1 activation [32][33].
3. Altered gene expression: Insulin resistance can downregulate the expression of genes encoding major autophagy components, further impairing autophagic function [34]. 

Bidirectional relationship
The relationship between insulin resistance and impaired autophagy often creates a vicious cycle:
1. Initial insulin resistance can lead to suppression of autophagy.
2. Impaired autophagy then exacerbates cellular stress and dysfunction.
3. This cellular dysfunction further worsens insulin resistance.
4. The cycle continues, progressively worsening both conditions [32][33].

Tissue-specific effects
The relationship between autophagy and insulin sensitivity can vary depending on the tissue:
1. In insulin-responsive tissues like muscle, liver, and adipose tissue, moderate activation of autophagy can improve insulin sensitivity by reducing cellular stress and inflammation [30][32].
2. In pancreatic β-cells, however, excessive autophagy can reduce insulin storage and secretion, potentially worsening glucose intolerance despite improved peripheral insulin sensitivity [30]. 
​
PREVENTION AND TREATMENT OPTIONS
Targeting nutrient-sensing pathways (mTORC1, AMPK, SIRT1) can enhance autophagic activity and mitigate age-related cellular damage [4][35][36]      
The most efficient and evidence-based methods to improve autophagy are:

1. Intermittent fasting (IF):
▌The 16/8 method (16 hours fasting, 8 hours eating window) is commonly recommended [37][38].
▌Alternate-day fasting and the 5:2 diet (5 days normal eating, 2 days restricted calories) are also effective [38][39].
▌Fasting periods of 18-72 hours show increasing benefits for autophagy [37].
Fasting a lot is not recommended for women in their reproductive age, the use of geroprotectors (a few mentioned under point 6) are more suitable.

2. Calorie restriction (CR): [4]
▌Reducing daily calorie intake by 10-40% can trigger autophagy [38].
▌Long-term calorie restriction increases the expression of autophagy-related genes [40].

3. Exercise: [4]
▌Both aerobic exercise and resistance training stimulate autophagy [37][41].
▌Aerobic exercise (lower intensity, longer duration) may be more effective for autophagy than high-intensity exercise [37].

4. Ketogenic diet:
▌A high-fat, low-carb diet can mimic fasting effects and trigger autophagy [41]. 

5. Sleep:
▌Good quality sleep supports autophagy, as it follows the sleep-wake cycle [41].

6. Specific nutrients and supplements:
▌Spermidine (naturally occurring in our body and food) has been shown to enhance autophagy [40][42] and is on top of the list.
▌Resveratrol, found in red wine and grapes, may induce autophagy [40] (in very high doses), however there are contradicting study outcomes.
▌Curcumin (from turmeric) has shown potential in animal studies [41].
▌Green tea contains compounds that may support autophagy [40].
▌GlyNAC - more information below

7. Stress management:
▌Chronic stress can interfere with autophagy, so stress reduction techniques like meditation or yoga may be beneficial [38].

8. Pharmacological Interventions: 
▌Several antidiabetic medicines and other pharmacological agents are being explored to modulate autophagy and slow aging [3][4]. 
▌Genetic approaches to upregulate autophagy-related genes (e.g., ATG7, BECN1) are being investigated as potential therapeutic strategies for neurodegenerative diseases [35][43].    

9. Hormetic stress activates autophagy:
Hormesis influences and activates autophagy through various mechanisms, contributing to cellular stress resistance and potential health benefits.
▌Hormesis appears to be executed by a variety of physiological cellular processes, including autophagy that cooperatively interact and converge  [44].
▌Hormetic heat shock activates autophagy in human RPE cells [45]. Heat shock factor 1 (HSF1) plays a role in hormetic autophagy activation [46=73]. HHS enhances the expression of fundamental autophagy-associated genes in ARPE-19 cells through the activation of HSF1 [45]. 
▌Inhibition of mTOR (mechanistic target of rapamycin) is a key pathway for hormetic autophagy activation. Inhibition of mTOR (specifically dephosphorylation of mTOR complex 1) triggers augmented autophagy [44]. 
▌Hormetic autophagy contributes to stress resistance, longevity, and improved proteostasis [46].

10. Sunscreen: 
I promote the use of sunscreens, particularly ones with the natural compounds Licochalcone A (powerful anti-oxidant, Nrf2 activator, Glutathione stimulator and MMP1 inhibitor) [47][48][49][50] and Glycerrhetinic Acid (supports DNA repair) [51]. The regular use of sunscreen can decrease the risk of impaired autophagy in skin:
▌Reduction of oxidative stress: By blocking UV rays, sunscreen helps prevent the generation of excessive ROS, which can impair autophagy [18].
▌Prevention of DNA damage: Sunscreen protects skin cells from UV-induced DNA damage, which can interfere with autophagy-related gene expression [18][21].
▌Maintenance of cellular homeostasis: By reducing overall UV-induced stress on skin cells, sunscreen helps maintain the balance necessary for proper autophagy function [21].
Several studies have demonstrated the link between UV protection and autophagy preservation. A study published in the Journal of Investigative Dermatology showed that UV radiation can dysregulate autophagy in skin cells, and that protecting against UV exposure can help maintain normal autophagy function [21]. Research published in the International Journal of Molecular Sciences highlighted that sunscreen use can prevent UV-induced damage to autophagy-related proteins and pathways in skin cells [18]. A review in Frontiers in Pharmacology discussed how sunscreen, as part of a comprehensive photoprotection strategy, can help preserve autophagy function in skin by reducing overall UV-induced cellular stress [21].
By using sunscreen regularly, individuals can significantly reduce their risk of impaired autophagy in skin cells, contributing to overall skin health and  slowing the photoaging process.

11. Red light therapy:
Red light therapy, particularly at a wavelength of 660 nm, has been shown to promote autophagy, the cellular process of cleaning out damaged cells and regenerating healthier ones. Studies indicate that this therapy can enhance autophagy in various contexts, such skin health [57]. Additionally, red light therapy is often used in combination with fasting to further boost cellular repair processes associated with autophagy. Red light activates autophagy in retinal cells: Studies have shown that red light exposure can activate multiple steps of the autophagy process in retinal pigment epithelium (RPE) cells. It increases autophagy-related proteins and promotes the formation of autophagosomes [58].

12. Polynucleotides:
1. DNA damage response: DNA damage can trigger autophagy as a protective mechanism. Polynucleotides, particularly damaged DNA, can activate autophagy pathways [59].
2. RNA-mediated regulation: Certain RNA molecules, such as microRNAs and long non-coding RNAs, can modulate autophagy-related gene expression and signaling pathways [59].

13. Exosomes:
Exosomes have a complex relationship with autophagy:
1. Autophagy regulation: Exosomes can carry proteins and RNAs that influence autophagy in recipient cells. For example, some exosomal microRNAs can target autophagy-related genes [59].
2. Protein content alteration: Autophagy modulators can significantly alter the protein content of phosphatidylserine-positive extracellular vesicles (PS-EVs), including exosomes, produced by cancer cells [59].
3. Signaling molecules: Exosomes can contain important signaling molecules like SQSTM1 and TGFβ1 pro-protein, which are involved in autophagy regulation [59].
4. Intercellular communication: Exosomes derived from cells treated with autophagy modulators can influence the metabolism and phenotype of recipient cells [59].
5. Autophagy-related protein transport: Exosomes can carry autophagy-related proteins like LC3-II, potentially transferring autophagic capabilities between cells [59].
The relationship between exosomes and autophagy is bidirectional. Autophagy can also influence exosome production and content. The specific effects may vary depending on the cell type, physiological context, and the particular polynucleotides or exosomes involved.

GLYNAC AND AUTOPHAGY
GlyNAC, a combination of glycine and N-acetylcysteine, has shown promising effects on various aspects of cellular health, including autophagy. 

Glutathione synthesis and oxidative stress
GlyNAC supplementation has been shown to improve glutathione (GSH = body's master antioxidant) synthesis and reduce oxidative stress [52][53][54]. GSH is a crucial antioxidant that plays a role in regulating autophagy and DNA repair. By improving GSH levels, GlyNAC may indirectly support autophagic processes [52][53].
Aging hallmarks
GlyNAC supplementation has been shown to improve multiple hallmarks of aging, including mitochondrial dysfunction, oxidative stress, and inflammation [52][53][54].[55].These improvements may indirectly support autophagic processes, as these hallmarks are interconnected with autophagy regulation [1][2].
Direct evidence on autophagy
While direct evidence of GlyNAC's effect on autophagy is limited, some studies provide insights:
1. In a study on HIV patients, GlyNAC supplementation improved mitophagy markers, suggesting a potential role in enhancing selective autophagy of mitochondria [53].
2. N-acetylcysteine, a component of GlyNAC, has been shown to induce autophagy in various cellular models, potentially through its antioxidant properties and effects on mTOR signaling [56].
Potential mechanisms
The potential mechanisms by which GlyNAC might influence autophagy include:
1. Reduction of oxidative stress, which can promote autophagy induction [52][53][54].
2. Improvement of mitochondrial function, which is closely linked to mitophagy regulation [7][8][52][53].
3. Modulation of nutrient-sensing pathways, such as mTOR, which are key regulators of autophagy [53][56].
Future directions
While the evidence suggests that GlyNAC supplementation may have beneficial effects on cellular processes related to autophagy, more direct research is needed to fully elucidate its impact on autophagic flux and regulation.


By improving autophagy, we're not just investing in our appearance, but in the fundamental processes that keep our body healthy. Always consult a qualified healthcare professional to determine what the most suitable approach is for your needs and rejuvenation or regeneration goals. 

Take care!
Anne-Marie

References:
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[3] Kaushik, S. et al. (2021). Autophagy and the hallmarks of aging. Ageing Research Reviews, 72.
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Glycation is one of the basic root causes of endogeneous (intrinsic) skin ageing and a very challenging one or almost impossible one to reverse. Glycation is an ageing reaction which begins in early life, developing clinical symptoms at around 30, and progressively accumulates in tissues and skin due to the glycated collagens that are difficult to be decomposed. Glycation occurs naturally in the body when sugars react with proteins and lipids to form advanced glycation end products (AGEs). AGEs can be exogenously ingested (through food consumption), inhaled via tobacco or endogenously produced and formed both intracellularly and extracellularly. AGE modifications lead to dermal stiffening, diminished contractile capacity of dermal fibroblasts, lack of elasticity in the connective tissues, contribute to hyperpigmentation and a yellowish skin appearance. The formation of AGEs is amplified through exogenous factors, e.g., ultraviolet radiation. 

AGEs cause changes in the skin through 3 processes:

1. AGEs interact with specific cell receptors, altering the levels of soluble signaling molecules, such as cytokines, hormones, and free radicals.
2. In the process of non-enzymatic glycation reaction, a large number of reactive oxygen radicals are released, creating a state of oxidative stress, leading to a significantly reduced level of glutathione, Vitamin C, and Vitamin E in the body. This causes synthetic disorders of collagen in skin tissues. 
3. AGEs alter the physical and biological properties of the original extracellular matrix proteins, such as collagen. 

Many cells have AGEs receptors on the surface, such as macrophages, mesangial cells, fibroblasts, and endothelial cells, through which their function can be affected. They induce oxidative stress and trigger inflammatory pathways by forming crosslinks, altering protein structure, or by binding to AGEs receptors. AGEs cause cellular dysfunction through the modification of intracellular molecules and accumulate in tissues with ageing. This causes the skin and connective tissue to harden and lose their ability to regenerate healthy cells. They cause damage to extracellular proteins like collagen and elastin fibers, which are crucial for maintaining skin structure and firmness. This damage leads to the breakdown of these fibers. AGEs can also affect intracellular proteins like vimentin. AGEs can act as a catalytic site for free radical formation, exacerbate intracellular oxidative stress, and increase ROS production through a variety of mechanisms, reducing glutathione (skin's own anti-oxidant) storage, and activation of protein kinase C, etc., to accelerate the production and accumulation of AGEs. 

One study published in the Journal of Investigative Dermatology found that levels of AGEs were higher in the skin of older individuals compared to younger ones. The study also showed that there was a correlation between the level of AGEs and the severity of skin ageing. This suggests that inhibiting the production or accumulation of AGEs in the skin is a potential target for anti-ageing interventions or skin ageing management.

AGEs are complex and heterogeneous, more than a dozen AGEs have been detected (however not all) in tissues and can be divided into three categories according to their biochemical properties. 
​AGEs are formed through four pathways:

1. the Maillard reaction (non enzymatic reaction between amino groups of proteins and reducing sugars, binding sugars to proteins)
2. sugars auto-oxidation pathway (metal-catalyzed auto-oxidation of glucose or Wolff pathway) 
3. lipid peroxidation pathway (acetyl alcohol pathway)
4. polyols pathway (glucose is converted into fructose via the polyol pathway, which accelerates the production of AGEs)

GLYCATION INHIBITION IS KEY 
AGEs can be crosslinked through side chains to form a substance of very high molecular weight, which is not easily degraded. The consequences from skin glycation are irreversible. This makes prevention or inhibition of the process the best potential strategy to maintain skin health and ageing skin management. One way to do this is by altering the diet to reduce the intake of sugars and carbohydrates, which are known to contribute to glycation. Several studies have found that reducing sugar intake can result in significant improvements in skin health, including reducing wrinkles and improving skin texture. 

AGE inhibitors
Another potential strategy is the use of topical agents that inhibit the formation or accumulation of AGEs in the skin. One study published in the Journal of Cosmetic Science found that a cream containing carnosine, a peptide that inhibits glycation, improved skin elasticity and reduced the appearance of wrinkles in individuals with ageing skin. Skincare containing NAHP or Acetyl Hydroxyproline inhibits the formation of AGEs significantly (in vitro), most likely through a mechanism where NAHP competes with the proteins for the sugar. Finally, NAHP sacrifices itself in place of the proteins and gets (at least partially) glycated. NAHP also prevents loss of cellular contractile forces in a glycated in vitro dermis model and counteracts the diminished cell-matrix interaction that is caused by glyoxal-induced AGE formation. 

Take-aways from a study published in the International Journal of Cosmetic Science [2]:
1. NAHP significantly and dose-dependently inhibited the formation of advanced glycation end-products (AGEs) in a protein solution.
2. NAHP dose-dependently inhibited the formation of N-(carboxymethyl)lysine (CML), a specific AGE.
3. In fibroblast-populated collagen lattices, NAHP prevented the glycation-induced disturbance of fibroblast contractile capacity.
4. Ex vivo application of NAHP to skin explants decreased AGE fluorescence compared to glucose-treated samples.

​Anti-Oxidants
I would suggest to combine those ingredients with an ingredient like Licochalcone A. Numerous high ranked publications support that Licochalcone A protects cells from oxidative stress mediated by e.g. UV and HEVIS (blue light) induced reactive oxidative species (ROS). Due to the activation and nuclear translocation of the transcription factor NrF2, the expression of anti-inflammatory, antioxidant and detoxifying enzymes are induced. These enzymes protect the skin cells (like keratinocytes and fibroblasts) from ROS-induced damage, like lipid peroxidation and DNA as well as protein damage. If Licochalcone A is combined with L-Ascorbic Acid, (the most active form of Vitamin C), it supporting skin's own collagen production, provides superior biological cell protection amongst other relevant benefits. Vitamin C (and E) has shown to inhibit protein glycation [4].

SPRAY TAN
A study in Redox Biology indicates that sunless tanning with dihydroxyacetone (DHA) causes glycation and potential DNA damage in the epidermis [1].:
1. Glycation: DHA exposure led to the formation of advanced glycation end products (AGEs) in epidermal cells, confirmed by mass spectrometric detection of N-ε-(carboxyethyl)-l-lysine (CEL).
2. DNA damage: DHA induced a cellular stress response, including activation of stress-related genes and phosphoprotein signaling. While not directly measuring DNA damage, these responses are often associated with cellular stress that can lead to DNA damage.
3. Significance: The effects were observed at low millimolar concentrations of DHA, relevant to topical application. The stress response was rapid and pronounced, occurring within minutes of exposure.
4. Location: The effects were primarily observed in epidermal cells and reconstructs, with no mention of dermal effects.
This study suggests that sunless tanning with DHA may not be as safe as previously thought, warranting further investigation into its long-term effects on skin health [1], however no need to panic as this negative effect is only seen in the top layer of the skin.

DOUBLE TROUBLE: GLYCATION + UVB  [3]
The combination of GO-AGEs and UVB exposure has a more pronounced effect on skin inflammation and oxidative stress than either factor alone. This suggests a synergistic relationship between glycation and UV exposure in accelerating skin aging processes.
1. GO-AGEs combined with UVB irradiation significantly increased the secretion of pro-inflammatory cytokines (IL-1β, IL-6, IL-8) in skin cells compared to either GO-AGEs or UVB alone.
2. The GO-AGEs + UVB treatment group showed a more than three-fold increase in IL-6 and IL-8 mRNA levels compared to other groups.
3. GO-AGEs + UVB treatment induced significantly higher release of nitric oxide (NO) compared to other groups.
4. The combination of GO-AGEs and UVB enhanced reactive oxygen species (ROS) release, creating about 1.5 times more oxidative stress compared to control and other groups.
5. Cell viability was notably affected in the GO-AGEs, UVB, and GO-AGEs + UVB treatment groups compared to the control group.
These findings are significant as they demonstrate that the combination of GO-AGEs and UVB exposure has a more pronounced effect on skin inflammation and oxidative stress than either factor alone. This suggests a synergistic relationship between glycation and UV exposure in accelerating skin aging processes. Use sunscreen daily.
.
GLYCATION AND SKIN HEALTH
Acne
In addition to its role in ageing, glycation in the skin has also been linked to a range of skin health problems. One study published in the Journal of Cosmetic Dermatology found that the level of AGEs in the skin was significantly higher in individuals with acne than in those without acne. The study also showed that treating acne with a topical antibiotic significantly reduced the levels of AGEs in the skin.
Atopic Dermatitis
Another study published in the Journal of Investigative Dermatology found that individuals with atopic dermatitis had higher levels of AGEs in their skin than healthy individuals. This suggests that glycation may play a role in the development of inflammatory skin conditions.
Diabetes + Woundhealing
The correlation between high sugar levels and skin ageing can be seen in diabetic patients, where one-third of this population has skin complications. A prominent feature of ageing human skin is the fragmentation of collagen fibers, which severely damages the structural integrity and mechanical properties of the skin. Elevated levels of MMP-1 and MMP-2 and higher crosslinked collagen in the dermis of diabetic skin lead to the accumulation of fragmented and crosslinked collagen, thereby impairing the structural integrity and mechanical properties of dermal collagen in diabetes. Collagen crosslinking makes it impossible for them to easily repair, resulting in reduced skin elasticity and wrinkles. Keratinocytes and fibroblasts are the main cells involved in wound healing, but due to the high glucose (HG) microenvironment in diabetics, the functional state of these cells is impaired, thereby accelerating cellular senescence (programmed cell death).

Conclusion
We can't completely stop the glycation process, therefore it's important that we inhibit it from a young age onwards, hence monitor the sugar intake of our children, use daily SPF and invest in good dermo-cosmetic products containing ingredients like NAHP and powerful anti-oxidants like L-Ascorbid Acid (Vitamin C is needed for the production of collagen) and Licochalcone A (also anti-inflammatory). Preventing signs of ageing, specifically caused by glycation is most effective. If your skin shows (advanced) signs of ageing, you can get visible improvement using skin component (hyaluron, collagen and elastin) bio-stimulating ingredients like Retinol, Bakuchiol, Arctiin, Creatine or Glycine Saponin. Consult your dermatologist if you wish to improve your skin's appearance or skin health issues.

Take care
Anne-Marie

References
[1] Perer J, Jandova J, Fimbres J, Jennings EQ, Galligan JJ, Hua A, Wondrak GT. The sunless tanning agent dihydroxyacetone induces stress response gene expression and signaling in cultured human keratinocytes and reconstructed epidermis. Redox Biol. 2020 Sep;36:101594.
[2] Knoblich C, et al. N‐acetyl‐L‐hydroxyproline – A potent skin anti‐ageing active preventing advanced glycation end‐product formation in vitro and ex vivo. Int J Cosmet Sci. 2023;1-10. doi:10.1111/ics.12930
[3] Sultana, R., Parveen, A., Kang, MC. et al. Glyoxal-derived advanced glycation end products (GO-AGEs) with UVB critically induce skin inflammaging: in vitro and in silico approaches. Sci Rep 14, 1843 (2024). https://doi.org/10.1038/s41598-024-52037-z
[3] Sadowska-Bartosz I, Bartosz G. Prevention of protein glycation by natural compounds. Molecules. 2015 Feb 16;20(2):3309-34. doi: 10.3390/molecules20023309. PMID: 25690291; PMCID: PMC6272653.

Special thanks: Ph.D. dr Julia M. Weise Manager Biological Testing & Dorothea Schweiger Lab Manager Facial Skin Biology Beiersdorf HQ Hamburg

After about spending some time in bathtub or in the pool, we can notice that our skin on particularly finger tops and toes start to wrinkle up. This wrinkling effect is believed to have a function.

When wet, things tend to be more slippery and our sophisticated skin is designed to counteract this by wrinkling up in a pattern optimised to provide a drainage network that improves grip, much like the tires on a car according to a study. Link to original publication. However, other studies would contradict that there would be a functional benefit for so called aquatic wrinkles.

The osmosis theory
Water molecules moving trough a semipermeable membrane from a low concentration area to a high concentration area is a process called osmosis. The shrinking and expanding effects of osmosis takes place simultaneously outer layer of the skin, causing wrinkles.

The skin's outermost layer is also known as stratum corner could be responsible for this wrinkly reaction, The top layer of our skin consists of dead corneocytes. The longer these cells are attached to the skin, the bigger they are. The size of the corneocytes we actually use to objectively measure the skin's renewal and desquamation (shedding of cells) process. These dead (keratin containing) skin cells may absorb water and swell. The lower layer with living cells doesn't swell up. As top layer (which is increased in size) is still attached to the layer beneath, a wrinkly pattern is formed. The layer of dead skin cells is thicker at the palms of our hands and soles of our feet, the wrinkling effect is more evident. This response occurs more quickly in freshwater than seawater. Moreover, when we are exposed to water for a longer time, the water-repelling film on top of the outer layer of the skin may get impaired.

The sympathetic nervous system / microcirculation theory
It's known that there is a relationship between the wrinkling-effect and blood vessels constricting (narrowing) below the skin. When hands and feet are soaked in water, the nerve fibres in the skin shrink and the body temperature regulators loses volume. Therewith the top layer of the skin is pulled downward and the wrinkling pattern is formed. It is proven that wrinkling-effect response is impaired, if the nerves and/or blood vessels are damaged. Therewith the wrinkling effect can even be used to determine proper functioning of the sympathetic nervous system and/or skin's microcirculation. There is evidence that the wrinkling effect is impaired in patients suffering from diabetes: link to article. 

Regardless the cause, aquatic wrinkles disappear fast and the skin returns to normal once the water has evaporated.
​
Take care.