Telomeres: tiny caps with big impact

​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].​

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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 

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WATCH VIDEO ABOUT DNA DAMAGE AND REPAIR

References
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