After "deep-diving" into autophagy and impaired autophagy, one of the twelve hallmarks of aging, it makes sense to shine some light on its equally important (however not so famous) partner in cellular housekeeping: the proteasome. It ́s primary function is breaking down proteins that are no longer needed, damaged, or misfolded [1]. Similar to autophagy, it is our body's and skin's very own trash and recycling system, working 24/7 to keep our cells healthy and functioning [2]. The human body is composed of approximately 16-20% protein by weight. This percentage can vary based on factors like age, sex, and overall body composition. Skin, is particularly rich in proteins, about 25-30% of the total protein in the human body is found in the skin and the dry weight of skin is approximately 70% protein. Loss of proteostasis (balance of protein synthesis, folding, and degradation) is one of the twelve hallmarks of aging and the proteasome is an important mechanism within the proteostasis network [3].

THE PROTEASOME
The proteasome is a large, barrel-shaped protein complex found in all eukaryotic cells, responsible for the degradation of intracellular proteins [4]. It plays a crucial role in maintaining cellular homeostasis by selectively breaking down short-lived, damaged, or misfolded proteins [5]. The 26S proteasome consists of a 20S core particle and one or two 19S regulatory particles [6]. Proteins targeted for degradation are typically tagged with ubiquitin molecules, which are recognized by the 19S regulatory particle, allowing the protein to be unfolded and fed into the 20S core for proteolysis [7]. The ubiquitination process provides a highly selective mechanism for targeting proteins for degradation in comparison to other systems like lysosomes. 
Proteasomal degradation is an ATP-dependent process:

1. Proteins are tagged with ubiquitin molecules by enzymes called ubiquitin ligases [8].
2. The proteasome recognizes these ubiquitin tags [9].
3. The regulatory particles unfold the protein and feed it into the core [10].
4. The core particle's β subunits break down the protein into short peptides [11].

This process is crucial for:

• Maintaining protein quality control [12]
• Regulating cellular processes by controlling protein levels
• Recycling amino acids for new protein synthesis

The proteasome is involved in numerous vital cellular processes, including:

• Cell cycle regulation
• Transcriptional control
• Immune responses
• Neuronal plasticity

Its proper function is essential for cellular health, and dysfunction of the proteasome system has been implicated in various diseases, including neurodegenerative disorders and cancer.

The proteostasis network
The proteostasis network (PN) is a complex system of cellular machinery that maintains the integrity of the proteome consisting of collaborating systems to ensure proper protein folding, repair damaged proteins and eliminate those beyond repair.

• Molecular chaperones and co-chaperones
• The ubiquitin-proteasome system (UPS)
• Autophagy machinery
• Translational machinery

PROTEASOME VS AUTOPHAGY
Complementary cleaning and recycling systems
While the proteasome primarily handles short-lived and soluble proteins, autophagy is responsible for degrading long-lived proteins, protein aggregates, and even entire organelles [13]. The proteasome plays critical roles in cell cycle control, gene expression, protein quality control, and immune responses,  while other systems like autophagy are more involved in bulk degradation and cellular remodeling. The systems are not entirely independent and often work together to maintain cellular health [14].

The ubiquitin-proteasome system (UPS) and autophagy interact through various mechanisms:

1. Compensatory activation: Inhibition of the proteasome can lead to increased autophagic activity as a compensatory response [15].
2. Shared signaling pathways: Both systems are regulated by common signaling molecules, such as mTOR and AMPK [16].
3. Reciprocal degradation: Components of each system can be degraded by the other, helping to maintain balance [17].

This ensures efficient protein quality control and cellular homeostasis [18].
 
PROTEASOME AND EPIGENETICS
The proteasome also plays a significant role in epigenetics - the study of heritable changes in gene expression that don't involve changes to the underlying DNA sequence and recognised as one of the hallmarks of aging [19]. The proteasome influences epigenetics through several mechanisms:

• Histone regulation + modification: The proteasome degrades histones, proteins that package DNA, influencing chromatin structure and gene accessibility [20].. 
• Transcription factor control + regulation: By regulating the levels of transcription factors, the proteasome indirectly affects gene expression patterns [21].
• Epigenetic modifier turnover + DNA methylation: The proteasome controls the levels of enzymes that modify histones and DNA, such as histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) [22].
• Non-proteolytic functions: Some proteasome subunits have been found to directly interact with chromatin, suggesting a more direct role in gene regulation [23].

These interactions create a complex feedback loop between protein degradation and gene expression, highlighting the proteasome's far-reaching influence on cellular function

PROTEASOME AND (SKIN) HEALTH
The proteasome is likely present in skin cells and in extracellular fluids associated with skin, such as sweat and plays a vital role in maintaining health and skin quality by regulating the turnover of various proteins.

Proteins are fundamental to life for several reasons:

1. Structural components: Proteins form the structural framework of cells and tissues, including skin, muscles, and organs.
2. Enzymatic functions: Most biochemical reactions in the body are catalyzed by protein enzymes.
3. Signaling molecules: Many hormones and neurotransmitters are proteins or peptides.
4. Transport: Proteins like hemoglobin transport vital molecules throughout the body.
5. Immune defence: Antibodies, which are proteins, play a crucial role in the immune system.
6. Cellular regulation: Proteins control gene expression and cellular processes.
7. Energy source: When necessary, proteins can be broken down for energy.

Important proteins in skin and the human body based on their overall impact and prevalence:

1. Collagen: Most abundant protein in the human body. Provides structure and strength to skin, bones, and connective tissues.
2. Hemoglobin: Essential for oxygen transport in blood. Critical for cellular respiration and energy production.
3. Albumin: Most abundant protein in blood plasma. Maintains osmotic pressure and transports various molecules.
4. Insulin: Regulates blood glucose levels. Crucial for metabolism and energy utilisation.
5. Actin: Key component of the cytoskeleton. Essential for cell structure, division, and movement.
6. Keratin: Major structural protein in skin, hair, and nails. Provides protection and waterproofing.
7. Elastin: Provides elasticity  to skin and blood vessels. Crucial for tissue flexibility and resilience.
8. Fibronectin: Important for cell adhesion, wound healing and is the "organiser" of the ECM. Plays a role in tissue repair and embryonic development.
9. Filaggrin: Essential for skin barrier function. Helps maintain skin hydration and pH balance.

Dysfunction of the proteasome in skin cells can lead to various dermatological issues, including

• accelerated aging of skin cells
• reduced collagen production and increased breakdown
• impaired elastin function
• wrinkles, sagging and loss of elasticity
• impaired wound healing and barrier function
• increased susceptibility to UV damage and DNA damage [26]

Or more skin conditions like:

• Psoriasis: Altered proteasome function may contribute to the excessive proliferation of skin cells.
• Atopic dermatitis: Impaired proteasome activity may lead to increased inflammation and compromised skin barrier function.
• Skin cancer: Proteasome inhibitors have shown promise as potential treatments for certain types of skin cancer.

PROTEASOME AND CELLULAR SENESCENCE
The proteasome plays a crucial role in preventing cellular senescence, a state of permanent cell cycle arrest associated with aging:

1. Oxidative stress management: The proteasome degrades oxidized proteins, preventing their accumulation and subsequent cellular damage.
2. Cell cycle regulation: By controlling the levels of cell cycle regulators, the proteasome influences cellular senescence and proliferation.
3. Telomere maintenance: Proteasomal activity is involved in the regulation of telomere-associated proteins, impacting cellular lifespan.

PROTEASOME AND IMMUNE FUNCTION
The proteasome is integral to immune system function:

1. Antigen processing: A specialized form of the proteasome, the immunoproteasome, is crucial for generating peptides for MHC class I antigen presentation.
2. Inflammation regulation: The proteasome controls the levels of pro-inflammatory factors, helping to modulate immune responses.
3. T-cell activation: Proteasomal activity is essential for proper T-cell activation and differentiation.

 The proteasome is thus important in maintaining immune homeostasis and combating infections.

Glycosylated proteins
Proteins connected to sugar molecules, known as glycosylated proteins, can be targeted by the proteasome:

• The ubiquitin-proteasome system (UPS) is capable of degrading many types of glycoproteins [29].
• However, hyperglycemia (high blood sugar) can impair proteasome function. Glucose-derived compounds like methylglyoxal (MGO) can modify proteasome subunits, reducing their activity [29].

Amyloids
The proteasome's relationship with amyloids (involved in for example Alzheimer's disease) is more complex.
The proteasome can degrade some amyloid precursor proteins and smaller amyloid aggregates [30]. However, larger amyloid fibrils often overwhelm or inhibit the proteasome:

• Amyloid aggregates can clog the entrance to the proteasome's catalytic core.
• Some amyloids can directly inhibit proteasome activity.

 
INFLUENCERS PROTEASOME ACTIVITY
Challenges in protein clearance
Several factors can hinder the proteasome's ability to clear modified or aggregated proteins:
Glycation: Advanced glycation end products (AGEs) formed in hyperglycemic conditions can modify the proteasome, reducing its activity [29].
Oxidative stress: Often associated with aging and disease, it can damage both proteins and proteasomes [29].
Aging: Proteasome activity generally declines with age, reducing the cell's capacity to clear problematic proteins [30].

The proteasome's activity is sensitive to pH changes:

• Optimal pH range for proteasome function is typically between 7.5-8.0.
• Acidic conditions tend to inhibit proteasome activity, while alkaline conditions can enhance it to a certain extent.
• Skin pH, which is typically slightly acidic (around 4.7-5.75), may influence extracellular proteasome activity.

Oxidative stress has complex effects on the proteasome system in skin:

• Mild oxidation (hormesis) can stimulate proteasomal degradation, while severe oxidation inhibits it
• Oxidative stress can cause the 26S proteasome to disassemble into its 20S core and 19S regulatory components [25]
• In skin, oxidative stress from UV radiation or environmental pollutants may affect proteasome function
• Severely oxidized proteins may form non-degradable aggregates that can bind to and inhibit the proteasome [24]
• Oxidative stress can reduce cellular ATP levels, affecting the ATP-dependent 26S proteasome function [25]
• Oxidative stress can alter the association of chaperone proteins like HSP70 with the proteasome, affecting its function and assembly [25]
    

Temperature can significantly impact proteasome function:

• The optimal temperature for proteasome activity is typically around 37°C (human body temperature) [27]
• Higher temperatures may initially increase proteasome activity but can eventually lead to denaturation and loss of function.
• Low temperatures reduce proteasome activity by slowing down enzymatic reactions.
• Skin, being exposed to environmental temperature changes, may experience fluctuations in proteasome activity.

MAINTAIN AND IMPROVE PROTEASOME
Several strategies can help maintain and improve proteasomal function:
Exercise: Regular physical activity has been shown to enhance proteasome activity.
Diet:

• Protein: Ensuring adequate intake of high-quality proteins provides the building blocks for maintaining a healthy proteome
• Polyphenols: Found in green tea, berries, and red wine, can stimulate proteasome function.
• Omega-3 fatty acids: May help maintain proteasome activity and reduce oxidative stress.
• Sulforaphane (found in broccoli sprouts): Activates Nrf2, which enhances proteasome function.
• Spermidine: This natural polyamine has been shown to enhance autophagy and improve proteostasis.
• Curcumin: This compound from turmeric has been shown to enhance proteostasis and have anti-aging effects 
• Caloric restriction or intermittent fasting: May enhance proteasome activity and promote cellular health.

Stress management: Chronic stress can impair proteasome function, so stress reduction techniques will be beneficial.
Adequate sleep: Crucial for cellular repair and protein homeostasis.
Skincare + ingredients:

•  Sun protection: Use broad-spectrum sunscreens to protect skin from photo-damage, which can impair proteasome function.
•  Retinoids: May enhance proteasome activity in skin cells.
•  Peptides: Certain peptides have been shown to stimulate proteasome function.
•  Licochalcone A: Activates Nrf2, which in turn enhances proteasome function.
•  Niacinamide: Supports proteasome function and improves skin barrier health.

In-office treatments:

•  Low-level laser therapy: May improve proteasome function in skin cells.
•  Chemical peels: Can stimulate cellular renewal and potentially enhance proteasome activity.

MISCELLANEOUS PROTEASOME FACTS

• Ancient origins: Proteasomes are found in all three domains of life (bacteria, archaea, and eukaryotes), suggesting they evolved over 2 billion years ago.
• Rapid recyclers: A single proteasome can degrade about 2 million proteins over its lifetime.
• Circadian rhythm regulation: The proteasome plays a crucial role in maintaining our body's internal clock by degrading clock proteins at specific times.
• Stress response: Under stress conditions, cells can form large assemblies of proteasomes called "proteasome storage granules" to quickly respond to changing protein degradation needs.

The role of the proteasome in protein quality control, cellular regulation, interplay with autophagy, epigenetics, telomeres, cell senescence and more, makes it a key player in maintaining our health and beauty and an interesting target for new strategies to enhance longevity [28], health span and beauty span. 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:
[1] Glickman MH, Ciechanover A. Physiol Rev. 2002;82(2):373-428.
[2] Lecker SH, et al. Annu Rev Biochem. 2006;75:629-649.
[3] López-Otín C, et al. Cell. 2013;153(6):1194-1217.
[4] Tanaka K. Proc Jpn Acad Ser B Phys Biol Sci. 2009;85(1):12-36.
[5] Goldberg AL. Nature. 2003;426(6968):895-899.
[6] Finley D. Annu Rev Biochem. 2009;78:477-513.
[7] Pickart CM, Cohen RE. Nat Rev Mol Cell Biol. 2004;5(3):177-187.
[8] Hershko A, Ciechanover A. Annu Rev Biochem. 1998;67:425-479.
[9] Thrower JS, et al. EMBO J. 2000;19(1):94-102.
[10] Smith DM, et al. Mol Cell. 2005;20(5):687-698.
[11] Groll M, et al. Nature. 1997;386(6624):463-471.
[12] Balch WE, et al. Science. 2008;319(5865):916-919.
[13] Mizushima N, Komatsu M. Cell. 2011;147(4):728-741.
[14] Dikic I. Trends Biochem Sci. 2017;42(11):873-886.
[15] Ding WX, et al. Am J Pathol. 2007;171(2):513-524.
[16] Zhao J, et al. Cell Metab. 2015;21(6):898-911.
[17] Pandey UB, et al. Nature. 2007;447(7146):859-863.
[18] Korolchuk VI, et al. Mol Cell. 2010;38(1):17-27.
[19] Greer EL, Shi Y. Nat Rev Genet. 2012;13(5):343-357.
[20] Qian MX, et al. Cell. 2013;153(5):1012-1024.
[21] Muratani M, Tansey WP. Nat Rev Mol Cell Biol. 2003;4(3):192-201.
[22] Gu B, Lee MG. Mol Cell. 2013;49(6):1134-1146.
[23] Geng F, et al. Proc Natl Acad Sci USA. 2012;109(5):1437-1442.
[24] Bach SV, et al. Biomol Concepts. 2016;7(4):215-227. doi:10.1515/bmc-2016-0016
[25] Bonea D, et al. BMC Plant Biol. 2021;21:486. doi:10.1186/s12870-021-03234-9
[26] Minoretti P, et al. Cureus. 2024;16(1):e52548. doi:10.7759/cureus.52548
[27] Groll M, et al. Nat Struct Biol. 2005;12(11):1062-1069. doi:10.1038/nsmb1006
[28] Galatidou S, et al. Mol Hum Reprod. 2024;30(7):gaae023. doi:10.1093/molehr/gaae023
[29=41] Queisser MA, et al. Hyperglycemia impairs proteasome function by methylglyoxal. Diabetes. 2010
[28=42] Mao, Y. Structure and Function of the 26S Proteasome. In: Harris, J.R., Marles-Wright, J. Macromolecular Protein Complexes III. Springer, 2021.
[29=43] Schipper-Krom, S. Visualizing Proteasome Activity and Intracellular Localization. Front. Mol. Biosci. 6, 2019.
[30=44] Lifespan.io. Loss of Proteostasis. Lifespan.io Topics. Accessed 2024.

Mitochondria are the "powerhouses" or "lungs" of our cells and bioenergetic semi-autonomous organelles with their own genomes and genetic systems. [1] They are responsible for generating the energy that fuels a wide range of cellular processes in the skin, including cell signaling, pigmentation, wound healing, barrier integrity [2], metabolism and quality control.  [3] Mitochondria exist in each cell of the body and are generally inherited exclusively from the mother. Their primary role is cellular respiration; a process converting the energy in nutrients (like glucose) into a usable form of energy called ATP or Adenosine Triphosphate. Mitochondria are particularly abundant in the skin, reflecting the skin's high metabolic demand. When the functionality of mitochondria is impaired or declines, it impacts skin's vitality, health and beauty. Mitochondrial dysfunction is 1 of the 12 hallmarks of skin ageing. 

The skin is particularly susceptible to mitochondrial stress due to its constant exposure to environmental insults, such as UV radiation, pollution, and other oxidative stressors. These factors can damage mitochondrial DNA, leading to increased production of reactive oxygen species (ROS) and disrupting the delicate balance of cellular processes. [4] In aged post-mitotic cells, heavily lipofuscin-loaded lysosomes perform poorly, resulting in the enhanced accumulation of defective mitochondria, which in turn produce more reactive oxygen species causing additional damage (the mitochondrial-lysosomal axis theory). [5]

Optimal mitochondrial function is indispensable for sustaining the specialized functions of each cell type, like keratinocyte differentiation, fibroblast ECM production, melanocytes melanin production and distribution, immune cell surveillance, sebocytes and adipocytes. [6] Mitochondrial dysfunction is both directly and indirectly linked to chronological ageing and photo-ageing. [7] As mitochondrial function declines, the skin's ability to regenerate and repair itself is decreased. [2] This results in visible signs of aging, such as wrinkles, loss of elasticity, dryness, uneven pigmentation, melasma, age spots, lipomas, impaired wound healing. [2-4-5-8-9] Mitochondrial dysfunction also has been implicated in skin conditions like acne, eczema, lupus, psoriasis, vitiligo, atopic dermatitis and even skin cancer. [10]

Ageing is associated with changes in mitochondrial morphology, including [6] 
▌Hyperfusion or increased fragmentation
▌Loss of mitochondrial connectivity [11-7]
▌Decline in the efficiency of oxidative phosphorylation, leading to reduced ATP production
▌Decline mitochondrial membrane potential (ΔΨM)
▌Compromised cellular energy metabolism
▌Reduced mitochondrial turnover (downregulated biogenesis)
▌Impaired mitochondrial quality control such as mitophagy (removal of damaged mitochondria through autophagy) [6]

These alterations are related to the increased production of ROS exhibited by mitochondria during ageing, the accumulation of which causes oxidative damage to mitochondrial and cell components contributing to cellular senescence. [12] 

Good mitochondrial function or metabolism: [7]
▌Redox homeostasis: (the way of reducing oxidative stress) - mitochondrial respiration and ROS production are essential for keratinocyte differentiation
▌ATP production: Adenosine Triphosphate provides energy to drive and support many processes in living cells (and GTP)
▌Respiration: mitochondrial respiration is the most important generator of cellular energy
▌Biogenesis: allows cells to meet increased energy demands, to replace degraded mitochondria and is essential for the adaptation of cells to stress [6]
▌Calcium homeostasis
▌Cellular growth
▌Programmed cell death (apoptosis) reducing cell senescence [13]
▌Mitochondrial protein synthesis: mitochondria typically produce 13 proteins encoded by mitochondrial DNA (mtDNA)

Dysfunctional Mitochondria: [7]
▌Oxidative stress
▌Decreased ATP levels
▌Dysfunctional OXPHOS: Oxidative phosphorylation, a metabolic pathway in which enzymes oxidize nutrients to release stored chemical energy in the form of ATP
▌Altered mitochondrial biogenesis 
▌Calcium imbalance
▌Cell death

Mitochondrial proteins
Mitochondria contain >1,100 different proteins (MitoCoP) that often assemble into complexes and supercomplexes such as respiratory complexes and preprotein translocases. The chaperones Heat Shock Proteins HSP60-HSP10 are the most abundant mitochondrial proteins. [3] Small heat shock proteins form a chaperone system that operates in the mitochondrial intermembrane space. Depletion of small heat shock proteins leads to mitochondrial swelling and reduced respiration. [14]

Mitochondrial hyperpigmentation
Emerging research has shed light on the intricate relationship between mitochondrial dysfunction and the development of hyperpigmentation, a condition characterized by the overproduction and uneven distribution of melanin in the skin. One of the key mechanisms underlying this connection is the role of mitochondria in the regulation of melanogenesis, the process by which melanin is synthesized. Mitochondria are involved in the production of various cofactors and signaling molecules that are essential for the activity of tyrosinase, the rate-limiting enzyme in melanin synthesis. [15] When mitochondrial function is impaired, it can lead to an imbalance in the production and distribution of these cofactors and signaling molecules, ultimately resulting in the overproduction and uneven deposition of melanin in the skin. [15] This can manifest itself as age spots, melasma, and other forms of hyperpigmentation. The link between mitochondrial dysfunction and hyperpigmentation has been further supported by studies on genetic disorders that involve mitochondrial dysfunction, such as mitochondrial DNA depletion syndrome. In these conditions, patients often exhibit a range of pigmentary skin changes, including patchy hyper- and hypopigmentation, as well as reticular pigmentation. [16]

Mitochondrial crosstalk and exosomes
Mitochondria can crosstalk and move beyond cell boundaries. [17] Mitochondria-derived material might be transferred to neighboring cells in the form of cell-free mitochondria or included in extracellular vesicles [18-19]. This process supports cellular repair and contributes to vital mitochondrial functions. Besides restoring stressed cells and damaged tissues due to mitochondrial dysfunction, intercellular mitochondrial transfer also occurs under physiological and pathological conditions. [20] The transfer of active mitochondria from mesenchymal stem cells (MSCs) has been identified as a repair mechanism for rejuvenating damaged skin fibroblasts. [21] 

MITOCHONDRIAL SUPPORT
Move
According Martin Picard phD being physically active is a protective factor against almost everything health related. Exercise stimulates the production of mitochondria as more energy is required. 

Be hungry sometimes
If there is too much supply of energy acquired via food leads to mass shrinking of mitochondria or fragmentation. Don´t over-eat, be calorie neutral and sometimes being calorie deficient is good for mitochondria. Maintain a healthy weight, preferably with a mediterranean diet containing phenolic and polyphenolic compounds (increase mitochondrial function and number) nitrate rich vegetables, soybeans and cacao beans. 

​Mitohormesis
In model organisms, lifespan can be improved by compromising mitochondrial function, which induces a  hormetic response (“mitohormesis”), provided that this inhibition is partial and occurs early during development.

Feel good
Feeling good (positivity), especially at night, has a scientifically proven positive effect on mitochondrial health index, it is even a predictive factor. 

​Q10 or Coenzyme Q10 (CoQ10)
Q10 is part of the mitochondrial respiration chain and essential for cellular energy production. About 95% of our cellular energy is generated with support of Q10, which is produced by the human body itself. During skin ageing, both the cellular energy production and levels of Q10 are declined. Q10 is a powerful anti-oxidant [22], thus protecting cells from oxidative stress and damage and has proven to be able to "rescue" senescent cells by decreasing elevated senescent markers like p21 levels and β-Galactosidases positive cell numbers (in-vitro). Q10 is bio-active, increasing collagen type I and elastin production. [23] Q10 can be supplemented via nutrition, however also via topical application and is considered an evidence based active ingredient in skin care products.  Ubiquinol (reduced form) shows higher bioavailability compared to ubiquinone (oxidized form). [23] 

Pyrroloquinoline quinone (PQQ)
Q10 improves the energy in the mitochondria, however PQQ has shown to increase the number of mitochondria and a redox maestro. I´ve written a full post about this compound, which can be found as skincare ingredient and supplement. Read more about PQQ

Glutathione
Glutathione is formed in cell's cytoplasm from glutamic acid, cysteine and glycine. It is present in 2 forms: reduced (GSH) and oxidized (GSSG). Reduced GSH is an active anti-oxidant, while the presence of inactive GSSG is increased under oxidative stress. The ratio between GSH and GSSH is considered a measure of oxidative stress. Glutathione participates in redox reactions, acts as co-factor of many anti-oxidant enzymes and is the most important non-enzymatic anti-oxidant, essential for synthesis of proteins and DNA. Low Glutathione results in accelerated ageing and inflammatory skin diseases. Mitochondrial glutathione (mGSH) is the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death. [24] Glutathione can be increased via supplementation via precursors cysteine or N-acetylcysteine (not recommended for pregnant women), a combination of Glycine and NAC (called GlyNAC) part of the popular "power of three" supplementation, or the reduced form of Glutathione itself, or increased via topical active ingredients like Licochalcone A. [25] 
I´ve written about GlyNAC in my post on autophagy.

Nicotinamide
NR nicotinamide ribosome which is the precursor of NMN nicotinamide mononucleotide which is the precursor of NAD+ nicotinamide adenine dinucleotide all could have a protective effect on mitochondria. Nicotinamide adenine dinucleotide is present in living organisms as ions NAD+ and NADP+ and in reduced forms NADH and NADPH. NADH is a cofactor of processes inside mitochondria:
▌ATP production
▌Activation of "youth proteins" sirtuins
▌Activation of PARP Poly (ADP-ribose) polymerase, a family of proteins involved in many cellular processes such as DNA repair, genomic stability and programmed cell death
▌Reduction of ROS (free radicals)
NAD levels as lowered during ageing. [26] One of the fans of NMN supplementation is Harvard Professor David Sinclair, best known for his work on understanding why we age and how to slow its effects and also featured in my article about hormesis. There are about 14 studies done to date with NMN supplementation in humans, one of which was done by Professor Sinclair. NMN supplementation does raise NAD levels, however there aren't substantial proven health benefits, unless you are unhealthy.

Resveratrol
Although systemically Resveratrol promotes mitochondrial biogenesis. [27] Other data shows that UVA (14 J/cm(2)) along with resveratrol causes massive oxidative stress in mitochondria. As a consequence of oxidative stress, the mitochondrial membrane potential decreases which results in opening of the mitochondrial pores ultimately leading to apoptosis in human keratinocytes. [28]

Magnesium
Magnesium supplementation has been shown to improve mitochondrial function by increasing ATP production, decreasing mitochondrial ROS and calcium overload, and repolarizing mitochondrial membrane potential. There are many forms of Magnesium, however Citrate, Malate and Orotate are particularly good for energy. 

L-Carnitine
Placebo-controlled trials have shown positive effects of L-Carnitine supplementation on both pre-frail subjects and elderly men. The effect is possibly mediated by counteracting age-related declining L-carnitine levels which may limit fatty acid oxidation by mitochondria. 

NEW Ergothioneine (EGT) 
Ergothioneine (EGT) is a sulfur-containing amino acid derivative known for its antioxidant properties, particularly in mitochondria. It is transported into cells and mitochondria via the OCTN1 transporter, where it helps reduce reactive oxygen species (ROS) and maintain cellular homeostasis [29]. EGT binds to and activates 3-mercaptopyruvate sulfurtransferase (MPST), enhancing mitochondrial respiration and exercise performance [30]. It also protects against oxidative stress and inflammation, potentially benefiting conditions like neurodegenerative diseases [31]. 

Melatonin
Not much talked about when it comes to mitochondria, however should not be ignored as mitochondria can benefit significantly from melatonin supplementation. 
1. Antioxidant protection: Melatonin acts as a powerful antioxidant within mitochondria, scavenging free radicals and reducing oxidative damage to mitochondrial DNA and proteins [32][34].
2. Regulation of mitochondrial homeostasis: Melatonin helps maintain electron flow, efficiency of oxidative phosphorylation, ATP production, and overall bioenergetic function of mitochondria [32][34].
3. Preservation of respiratory complex activities: Melatonin helps maintain the activities of mitochondrial respiratory complexes, which are crucial for energy production [32][34].
4. Modulation of calcium influx: Melatonin regulates calcium influx into mitochondria, helping prevent calcium overload which can be damaging [32][34].
5. Protection of mitochondrial permeability transition: Melatonin helps regulate the opening of the mitochondrial permeability transition pore, which is important for maintaining mitochondrial integrity [32][34].
6. Enhancement of mitochondrial fusion: Melatonin promotes mitochondrial fusion, which is part of the quality control process for maintaining healthy mitochondria [33].
7. Promotion of mitophagy: Melatonin enhances the removal of damaged mitochondria through mitophagy, helping maintain a healthy mitochondrial population [33].
8. Reduction of nitric oxide generation: Melatonin decreases nitric oxide production within mitochondria, which can be damaging in excess [32][34].
9. Selective uptake by mitochondria: Melatonin is selectively taken up by mitochondrial membranes, allowing it to exert its protective effects directly within these organelles [34].
10. Support of mitochondrial biogenesis: Some studies suggest melatonin may promote the formation of new mitochondria [33].

The key antioxidants used by mitochondria are Glutathione (GSH), Glutathione peroxidase (GPx), Coenzyme Q10 (CoQ10), Superoxide dismutase (SOD), Melatonin, Vitamin C (ascorbate) and Vitamin E (α-tocopherol).

​Red light therapy
By incorporating red light therapy into your skin care routine, you can help to counteract the damaging effects of mitochondrial dysfunction and support the skin's natural renewal processes.

As we continue to explore the 12 hallmarks of ageing, I am confident that we will gain even more valuable insights and develop breakthrough innovations that will improve skin quality, health, beauty and vitality. Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for your particular skin condition and rejuvenation goals. 

Take care!
Anne-Marie

References

1. Biological Sciences Why chloroplasts and mitochondria retain their own genomes and genetic systems: Colocation for redox regulation of gene expression John F. Allen et al. 2015
2. Experimental Dermatology Mitochondrial dysfunction: a neglected component of skin diseases René G. Feichtinger et al. 2014
3. Cell Metab. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context Marcel Morgenstern et al. 2021
4. Br J Dermatol Oxidative stress and ageing M A Birch-Machin et al. 2016
5. Antioxid Redox Signal Oxidative stress, accumulation of biological 'garbage', and aging Alexei Terman et al. 2006
6. Front. Physiol., Mitochondrial dynamics and metabolism across skin cells: implications for skin homeostasis and aging
   Ines Martic et al. 2023
7. Cell Death Dis. Mitochondria in skin health, aging, and disease Annapoorna Sreedhar et al. 2020
8. Journal of Dermatological Treatment. The skin aging exposome Krutmann, J. et al. 2017 
9. Experimental Dermatology Regulation of melanogenesis--controversies and new concepts. Schallreuter, K. U. et al. 2008
10. Int J Mol Sci. Dermatologic Manifestations of Mitochondrial Dysfunction: A Review of the Literature Nicole Natarelli et al. 2024
11. Review Cell Metab Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure
    Marc Liesa et al. 2013
12. Stem Cell Reviews and Reports Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases Xingyu Gao et al. 2022
13. Experimental & Molecular Medicine Mitochondria-associated programmed cell death as a therapeutic target for age-related disease
    Thanh T. Nguyen et al. 2023
14. Nature Cell Biology Small heat shock proteins operate as molecular chaperones in the mitochondrial intermembrane space
    Elias Adriaenssens et al. 2023
15. Review Exp Dermatol Regulation of melanogenesis--controversies and new concepts Karin U Schallreuter et al. 2008
16. Pigment Cell Melanoma Res. Mitochondrial DNA-depleter mouse as a model to study human pigmentary skin disorders Kyrene M. Villavicencio et al. 2021
17. J. Cell Biol. Mitochondria on the move: horizontal mitochondrial transfer in disease and health. Dong L.-F. 2023
18. Review Int J Mol Sci. Mitochondria Can Cross Cell Boundaries: An Overview of the Biological Relevance, Pathophysiological Implications and Therapeutic Perspectives of Intercellular Mitochondrial Transfer Daniela Valenti et al. 2021
19. Int J Mol Sci. Do Extracellular Vesicles Derived from Mesenchymal Stem Cells Contain Functional Mitochondria? Ljubava D. Zorova 2022
20. Review Signal Transduct Target Ther. Intercellular mitochondrial transfer as a means of tissue revitalization Delin Liu et al. 2021
21. Front. Physiol. Mesenchymal stem cells shift mitochondrial dynamics and enhance oxidative phosphorylation in recipient cells Newell C. et al. 2018
22. BioFactors Topical treatment with coenzyme Q10-containing formulas improves skin's Q10 level and provides antioxidative effects
    Anja Knott et al. 2015
23. Free Radical Biology and Medicine Anti-ageing effects of ubiquinone and ubiquinol in a senescence model of human dermal fibroblasts
    Fabio Marcheggiani et al. 2021
24. Antioxid Redox Signal. Mitochondrial Glutathione, a Key Survival Antioxidant Montserrat Marí et al. 2009
25. Exp Dermatol Licochalcone A activates Nrf2 in vitro and contributes to licorice extract-induced lowered cutaneous oxidative stress in vivo
    Jochen Kühnl et al. 2015
26. PLoS One Age-associated changes in oxidative stress and NAD+ metabolism in human tissue Hassina Massudi et al. 2012
27. Exerc Sport Sci Rev. Mitochondrial Protection by Resveratrol Zoltan Ungvari et al. 2011
28. J Photochem Photobiol B Resveratrol-sensitized UVA induced apoptosis in human keratinocytes through mitochondrial oxidative stress and pore opening Jean Z Boyer et al. 2012
29. Liu HM, Tang W, Wang XY, Jiang JJ, Zhang W, Wang W. Safe and Effective Antioxidant: The Biological Mechanism and Potential Pathways of Ergothioneine in the Skin. Molecules. 2023
30. Sprenger HG et al. Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST. bioRxiv [Preprint]. 2024 
31. Leow, D.M.-K.; Cheah, I.K.-M.; Fong, Z.W.-J.; Halliwell, B.; Ong, W.-Y. Protective Effect of Ergothioneine against 7-Ketocholesterol-Induced Mitochondrial Damage in hCMEC/D3 Human Brain Endothelial Cells. Int. J. Mol. Sci. 2023, 24, 5498. 
32. Daniel P. Cardinali et al. Publicado en Hormones and Behavior, 2012, Melatonin and mitochondrial dysfunction in the Central Nervous System
33. Lei Xudan et al. The potential influence of melatonin on mitochondrial quality control: a review Frontiers in Pharmacology 2024
34. Srinivasan V. et al. Int. J. Alzheimers Dis. Melatonin in mitochondrial dysfunction and related disorders (2011)

​Our DNA is as like precious book of life filled with information and instructions, with telomeres acting like the protective covers. Just as book covers get worn over time, our telomeres naturally shorten as we age. This shortening is like a biological clock, ticking away with each cell division.
 
Telomere shortening is considered one of the twelve key hallmarks of aging. Those hallmarks all play an important role in longevity, health-span, and skin quality, thus both health and beauty. Telomeres are the protective end-caps of chromosomes, similar to the plastic caps at the end  of shoelaces. They maintain genomic stability and prevent chromosomal damage.

Telomeres become slightly shorter each time a cell divides, and over time they become so short that the cell is no longer able to successfully divide. They shorten more rapidly in dermal fibroblasts compared to epidermal keratinocytes, hence there are significant differences amongst our cells. Telomeres in skin cells may be particularly susceptible to accelerated shortening because of both proliferation and DNA-damaging agents such as reactive oxygen species and sun exposure. [16]​​.

When a cell is no longer able to divide due to telomere shortening, this can lead to

1. Replicative senescence: The cell enters a state of permanent cell cycle arrest and stops dividing, also known as cellular senescence [1-8]. 
2. Activation of DNA damage response: The critically short telomeres are recognized as DNA double-strand breaks, triggering a DNA damage response [8].
3. Changes in gene expression: Senescent cells undergo changes in gene expression, including upregulation of cell cycle inhibitors like p16 and p21 [2].
4. Development of senescence-associated secretory phenotype (SASP): Senescent cells secrete various inflammatory factors, growth factors, and proteases that can affect surrounding cells and tissues [2][7]. 
5. Accumulation of senescent cells in tissues: As more cells reach replicative senescence, they accumulate in tissues over time, potentially contributing to age-related decline in tissue function [7][8]. 
6. Potential for apoptosis: In some cases, cells with critically short telomeres may undergo programmed cell death (apoptosis) instead of senescence [8].
7. Increased genomic instability: Very short telomeres can lead to chromosome fusions and genomic instability if cell cycle checkpoints are compromised [9].
8. Impaired tissue regeneration: The inability of cells to divide can impair the regenerative capacity of tissues [7].
9. Contribution to aging and age-related diseases: The accumulation of senescent cells is thought to be a major contributor to the aging process and various age-related pathologies [7][8].​

This consequently affects both health and beauty 

• Increased risk of cardiovascular diseases
• Higher susceptibility to certain cancers
• Accelerated cognitive decline
• Premature skin aging and reduced skin quality [10]​

FACTORS INFLUENCING TELOMERE SHORTENING
Sleep quality
Poor sleep quality significantly impacts telomere length:

• Obstructive sleep apnea is linked to shortened telomeres
• Shorter sleep duration, longer sleep latency, and lower sleep efficiency are associated with faster telomere shortening
• Sleep loss may activate DNA damage responses and cellular senescence pathways

Other Factors

• Chronic stress
• Poor diet: can lead to oxidative stress and inflammaging, hence ox-inflammaging. 
• Obesity is linked to accelerated telomere shortening
• Sedentary lifestyle: lack of physical activity may contribute to faster telomere shortening, especially in middle-aged and older adults
• Environmental pollutants and smoking
• Oxidative stress and inflammation [11]

INTERVENTIONS FOR TELOMERE PRESERVATION 
1. Possible strategies to preserve telomere length

• Use sunscreen to avoid oxidative stress, inflammation and of course DNA damage
• Telomerase activation (associated with cancer development!)
• Antioxidant protection
• DNA repair and protection
• Gene regulation (e.g., Klotho and FOXO3)
• Gene therapy (EXG-001, a gene therapy using a Sendai virus vector encoding ZSCAN4, has shown success in elongating telomeres in patients with telomere biology disorders) [12] and AAV9-TERT​[37]
• Senolytic therapie
• Epigenetic reprogramming: Reversing age-related changes in gene expression [13]
• NAD+ boosters
• In-office dermatological treatments (e.g., microneedling with growth factors, PRP therapy)
• Telomere shelterin protein, specifically the telomeric repeat binding factor 2 (TRF2), which safeguards telomeres from DNA damage. Given that TRF2 inhibition can expedite telomere shortening and DNA damage, restoring the compromised telomeric shelterin machinery could provide a potential approach to mitigate telomere attrition [14]
• Targeting the reverse transcriptase telomerase enzyme, which is responsible for creating new telomeric DNA from an RNA template [14]

Telomerase [15] 
Telomerase is an enzyme that plays a crucial role in maintaining the length of telomeres and skin cell function. Telomerase is a ribonucleoprotein enzyme, meaning it contains both protein (TERT plus dyskerin) and RNA components (TER or TERC). Its primary function is to add repetitive DNA sequences (telomeres) to the ends of chromosomes, preventing them from shortening during cell division. Telomerase is active in embryonic stem cells, some adult stem cells, cancer cells, certain skin cells, specifically:

• keratinocytes in the basal layer of the epidermis
• epidermal stem cells
• epidermal melanocytes derived from dermal stem cells
• epidermal stem cells and dermal stem cells
• almost undetectable in the dermis, specifically in dermal fibroblasts [16] this is probably why their telomeres shorten faster than in keratinocytes 

2. Sleep Optimization
Poor sleep quality is associated with shorter telomere length. Studies have found significant associations between shortened telomere length and poor sleep quality and quantity, including obstructive sleep apnea [17]. Not feeling well rested in the morning was significantly associated with shorter telomere length in older adults [18]. Sleep loss and poor sleep quality may activate DNA damage responses and cellular senescence pathways [17]. Poor sleep can increase oxidative stress and inflammation, which may accelerate telomere shortening [17]. Disruption of circadian rhythms due to poor sleep may negatively impact telomere maintenance [17].
Improving sleep quality through lifestyle changes and sleep hygiene practices may help preserve telomere length. [19]

•  Maintain a consistent sleep schedule
•  Create a relaxing bedtime routine
•  Optimize sleep environment
•  Limit screen time before bed

3. Stress Management
A study showed that diet, exercise, stress management, and social support could increase telomere length by approximately 10% over five years [20].

•  Practice meditation, yoga, and breathing exercises, regular breaks, optimise work-life balance [19]

4. Nutrition
Adopt a plant-rich diet, such as the Mediterranean diet, which includes whole grains, nuts, seeds, green tea, legumes, fresh fruits (berries), vegetables (leafy greens), omega-3 fatty acids from sources like flaxseed and fish oil or fatty fish and foods rich in folate. This diet is rich in antioxidants and anti-inflammatory properties that help maintain telomere length​ [21]. 
5. Fasting 
Fasting, especially intermittent fasting, has attracted interest for its potential impact on health, including telomere preservation. Multiple studies have shown that intermittent fasting (IF) and other fasting regimens can reduce markers of oxidative stress and inflammation. Research on animals has demonstrated that caloric restriction and intermittent fasting can boost telomerase activity and enhance telomere maintenance in specific tissues. A human study by Cheng et al. (2019) found a correlation between intermittent fasting and longer telomeres, by reducing PKA activity and IGF1 levels, which are crucial for regulating telomerase function. A study showed that 36 hours of fasting induced changes in DNA methylation and another one histone modifications, hence fasting has the potential to induce epigenetic changes. Important note: Be careful with a time-restricted eating schedule (often seen as a form of intermittent fasting, where you eat all meals within an 8 hour time-frame), especially women in menopause or people with a pre-existing heart condition. The American Heart Association presented data indicating that people with a pre-existing heart condition have a 91% higher risk of of death of a heart disease when following the time-restricted eating schedule with an 8 hour window, compared to those who eat within a 12-16 hours window. However, several experts have criticised the data, which aren´t published in a peer reviewed journal. When considering fasting, or a time-restricted eating schedule, especially for a longer period, talk to a qualified HCP first.
6. Exercise

• Regular physical activity, particularly high-intensity interval training (HIIT) [22]

7. Oxygen therapy

• Intermittent Hypoxic Training (IHT) involves brief exposure to low oxygen levels, simulating high-altitude conditions, and has been explored for its effects on longevity, epigenetics, and telomeres, among other health aspects. IHT can induce changes in gene expression through hypoxia-inducible factors (HIFs), ​
• Hyperbaric Oxygen Therapy (HBOT) involves breathing pure oxygen in a pressurised environment, typically at 2-3 times normal atmospheric pressure, which can stimulate regenerative processes typically activated during hypoxia [23]. While traditionally used to treat decompression sickness and certain wound healing disorders, recent research has explored HBOT's potential effects on aging, longevity and telomeres. A groundbreaking 2020 study found that HBOT increased telomere length by over 20% in healthy aging adults following 60 daily sessions. The therapy also reduced the number of senescent cells, which are associated with aging ​[23]. 

​​8. Supplements

• Omega-3 fatty acids
• Vitamin D
• Resveratrol
• Astragalus root extract (TA-65) - also available as skincare ingredient
• N-acetylcysteine (NAC)
• Q10

9. Skincare ingredients

• Antioxidants: Vitamins C and E help reduce oxidative stress, a major factor in telomere shortening [10]
• Resveratrol or Polyphenols: Boosts telomerase activity, which can help preserve and extend telomeres [24]
• TriHex™ Technology: Reduces telomere shortening and upregulates anti-aging genes like Klotho and FOXO3 [25]
• Astragalus root extract (TA-65): protects telomeres [26]
• Juvinity: Protects telomeres effectively [27]
• Cycloastragenol (CAG), possibly more potent in comparison to Astragalus root extract [28]
• Photolyase from Anacystis nidulans and endonuclease from Micrococcus luteus are xenogenic DNA repair enzymes which elicited a significant reduction in the rate of telomere shortening compared to a negative control [14] (not availailable yet)

​
EMERGING TECHNOLOGIES IN TELOMERE-TARGETING SKINCARE
Small RNAs in skincare
Small RNAs play a significant role in the effectiveness of telomere-targeting skincare by influencing skin regeneration and cellular processes. Recent research has highlighted their potential in enhancing wound healing and reducing scarring, which are critical aspects of maintaining healthy skin. Small RNAs, such as microRNAs, are involved in regulating gene expression related to skin aging and and show potential in telomere maintenance [29]. They can modulate the expression of genes that control cellular senescence, oxidative stress response, and inflammation, all of which are crucial for preserving telomere integrity and function [30]. 

• miR-29: Associated with decreased elastin and collagen levels
• miRNA-19b: Biomarker of cellular aging, enhances collagen expression
• miR-34a: affects telomere maintenance and cellular senescence pathways in skin cells 

An epigenetic molecular clock based on miRNA expression profiles has been developed to predict biological skin age, suggesting miRNAs play a key role in skin aging processes [31].  Most biological skin age tests are based on DNA-methylation. Despite promising findings, the delivery of small RNAs into the skin remains challenging due to their negative charge and susceptibility to degradation by nucleases. 
RNAi technology in development
RNAi-based skincare approaches could target genes involved in telomere maintenance or have effects on markers related to telomere biology:

• SECosomes and DDC642 Liposomes for enhanced delivery of RNAi molecules [32]
• Plant Small RNA (PSR) Technology using baobab seedcake extract [33]
• Ionic Liquids for siRNA delivery ​[34]

One of the main hurdles is the delivery of RNAi molecules into the skin. Similar to miRNA molecules, they have a negative charge and moreover are relatively large, making it difficult for them to penetrate the skin barrier. Research is focused on developing effective delivery systems, such as modified liposomes, to overcome these challenges. Multiple patents have been filed for RNAi-based skincare solutions, indicating strong interest and potential for future products. However, as of now, these products have not yet reached the commercial market. 

RNA-based telomere extension is a method developed at Stanford University and uses modified RNA to extend telomeres in cultured human cells, allowing cells to divide more times than untreated cells [35].​

IN OFFICE DERMATOLOGICAL TREATMENTS
Aesthetic, regenerative treatments that support skin quality may indirectly support telomere preservation.

1. Anti-inflammatory or anti-oxidant approaches, including IV or red light therapy
2. Oxygen therapy or facials
3. Microneedling with growth factors
4. Exosomes
5. Polynucleotides 
6. Platelet-rich plasma (PRP) therapy

It's important to note that while these treatments show beneficial outcomes in various aspects of skin rejuvenation, their direct effects on telomeres in human skin cells are not yet established through clinical trials.  ​

Telomere shortening questionable as stand-alone hallmark [36]
Telomere length (TL) has long been considered one of the best biomarkers of aging. However, recent research indicates TL alone can only provide a rough estimate of aging rate and is not a strong predictor of age-related diseases and mortality. Other markers like immune parameters and epigenetic age may be better predictors of health status and disease risk. TL remains informative when used alongside other aging biomarkers like homeostatic dysregulation indices, frailty index, and epigenetic clocks. TL meets some criteria for an ideal aging biomarker (minimally invasive, repeatable, testable in animals and humans) but its predictive power for lifespan and disease is questionable. There is inconsistency in epidemiological studies on TL's association with aging processes and diseases. This has led to debate about TL's reliability as an aging biomarker. It's unclear if telomere shortening reflects a "mitotic clock" or is more a marker of cumulative stress exposure. TL is still widely used in aging research but there are ongoing questions about its usefulness as a standalone biomarker of biological age.

As research in regenerative medicine advances, we're seeing promising developments in therapies targeting telomere biology for longevity, health and beauty. While telomere research is exciting, it's important to remember that it's just one part of a comprehensive approach to aging, and future treatments will likely combine multiple strategies to target preferably all 12 hallmarks for the best results. Always consult a qualified healthcare professional or dermatologist to determine what the most suitable approach is for you.
​.
Take care!
Anne-Marie 

References
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[8] Lei Zhang et al. Cellular senescence: a key therapeutic target in aging and diseases JCI The Journal of Clinical Investigation 2022
[9] Muraki K, Nyhan K, Han L, Murnane JP. Mechanisms of telomere loss and their consequences for chromosome instability. Front Oncol. 2012 Oct 4;2:135. 
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[11] Bär C, Blasco MA. Telomeres and telomerase as therapeutic targets to prevent and treat age-related diseases. F1000Res. 2016 Jan 20;5:F1000 Faculty Rev-89. 
[12] Kasiani C. Myers et al.  Blood (2022) 140 (Supplement 1): 1895–1896. Gene therapies November 15 2022 Successful Ex Vivo Telomere Elongation with EXG-001 in a patients with Dyskeratosis Congenital Kasiani C. Myers et al.  
[13] Falckenhayn C, Winnefeld M, Lyko F, Grönniger E. et al. Identification of dihydromyricetin as a natural DNA methylation inhibitor with rejuvenating activity in human skin. Front Aging. 2024 Mar 4;4:1258184
[14] Minoretti P, Emanuele E. Clinically Actionable Topical Strategies for Addressing the Hallmarks of Skin Aging: A Primer for Aesthetic Medicine Practitioners. Cureus. 2024 Jan 19;16(1):e52548
[15] Guterres, A.N., Villanueva, J. Targeting telomerase for cancer therapy. Oncogene 39, 5811–5824 (2020). 
[16] Buckingham EM, Klingelhutz AJ. The role of telomeres in the ageing of human skin. Exp Dermatol. 2011 Apr;20(4):297-302.
[17] Debbie Sabot, Rhianna Lovegrove, Peta Stapleton, The association between sleep quality and telomere length: A systematic literature review, Brain, Behavior, & Immunity - Health, Volume 28, 2023, 100577, ISSN 2666-3546
[18] Iloabuchi, Chibuzo et al. Association of sleep quality with telomere length, a marker of cellular aging: A retrospective cohort study of older adults in the United States Sleep Health: Journal of the National Sleep Foundation, Volume 6, Issue 4, 513 – 521
[19] Rossiello, F., Jurk, D., Passos, J.F. et al. Telomere dysfunction in ageing and age-related diseases. Nat Cell Biol 24, 135–147 (2022)
[20] Elisabeth Fernandez Research September 16 2013 Lifestyle changes may lengthen telomeres, A measure of cell aging. Diet, Meditation, Exercise can improve key element of Immune cell aging, UCSF Scientist report 
[21] Martínez P, Blasco MA. Telomere-driven diseases and telomere-targeting therapies. J Cell Biol. 2017 Apr 3;216(4):875-887.​
[22] Guo, J., Huang, X., Dou, L. et al. Aging and aging-related diseases: from molecular mechanisms to interventions and treatments. Sig Transduct Target Ther 7, 391 (2022). 
[23] Hachmo Y, Hadanny A, Abu Hamed R, Daniel-Kotovsky M, Catalogna M, Fishlev G, Lang E, Polak N, Doenyas K, Friedman M, Zemel Y, Bechor Y, Efrati S. Hyperbaric oxygen therapy increases telomere length and decreases immunosenescence in isolated blood cells: a prospective trial. Aging (Albany NY). 2020 Nov 18;12(22):22445-22456
[24] Gutlapalli SD, Kondapaneni V, Toulassi IA, Poudel S, Zeb M, Choudhari J, Cancarevic I. The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling. Cureus. 2020 Nov 14;12(11):e11482. 
[25] Widgerow AD, Ziegler ME, Garruto JA, Bell M. Effects of a Topical Anti-aging Formulation on Skin Aging Biomarkers. J Clin Aesthet Dermatol. 2022 Aug;15(8):E53-E60. PMID: 36061477; PMCID: PMC9436220.
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An elastic liposomal formulation for RNAi-based topical treatment of skin disorders: Proof-of-concept in the treatment of psoriasis, International Journal of Pharmaceutics, Volume 500, Issues 1–2, 2016, Pages 268-274, ISSN 0378-5173
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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.

​Anti-Oxidants
Moreover, 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. My absolute favourite product is Eucerin Hyaluron-Filler Vitamin C Booster which I use daily as a serum in my morning routine.

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

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

Psoriasis occurs in many different forms and levels of severity. The first signs may appear between the age of 15 and 35 and 75% of patients are diagnosed before the age of 46 according to the World Health Organisation. As there is no cure for the disease, the highest prevalence is seen in a more mature age group age 50-69. Many of the treatments which are part of the standard treatment guidelines for psoriasis cause as a side effect premature ageing skin. For example PUVA, next to being an effective treatment, does cause (severe) photo-damage. Many patients will undergo such treatments on and off or continuously throughout their life.

Although the primary goal of dermatology is to improve the functional attributes of the skin (health) and lessen the tremendous burden psoriasis may cause, ultimately one aims to improve the skin's physical attributes (appearance).

Ageing skin is a biological degenerative process which influences the activity of collagen and hyaluronic acid producing cells (mainly fibroblasts) and leads to a decrease of skin components like collagen, hyaluron and functional elastin. Effective anti-aging skincare can support the protection of those cells and skin components (anti-oxidants and SPF) and thus slow down the fastened degenerative process. Some active ingredients (for example biologically active Glycine Saponin and Arctiin) have proven to effectively stimulate fibroblasts in the production of collagen and hyaluronic acid and thus replenish dermal components. Loss of those components and photo-damage eventually lead to visible signs of ageing.

Although ageing skin is natural, premature ageing skin isn't necessary. Most patients will probably already use a moisturising facial skincare product. It makes sense to recommend anti-ageing skincare instead to be used in conjunction with treatments which as a side effect cause premature ageing skin, particularly for exposed areas like the face. As psoriasis oftentimes doesn't occur in the face (except in the hairline), anti-ageing skincare will pose a low to no risk to aggravate facial skin and there are anti-ageing skincare products available which have proven to be suitable for psoriasis patients. 

Take care.