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Introduction
This month, we take a deep dive into skin aging and explore ways to maintain a youthful appearance. When people think of skin aging, they often picture wrinkles, sagging, and pigmentation changes. While these are prominent features, aging skin undergoes many other transformations, including loss of lip fullness, the development of small dilated blood vessels (spider veins), and a reduction in fat tissue (Ng et al., 2025). Although this article focuses on the cosmetic aspects of skin aging, it is important to acknowledge its broader health implications. Aging skin is more susceptible to certain diseases, and many preventive measures that slow visible aging also reduce the risk of these conditions. One well-documented risk factor is UV exposure, which significantly increases the likelihood of skin cancer. A single day in the sun can cause up to 100,000 UV-induced DNA damages per cell (Hoeijmakers, 2009). Just four tanning bed sessions per year raise the risk of basal cell carcinoma by 15% and squamous cell carcinoma by 11% (Curti et al., 2022). Additionally, experiencing five or more sunburns doubles the risk of skin cancer (D’Orazio et al., 2013). UV radiation is estimated to be responsible for 65% of melanoma cases—the deadliest form of skin cancer—and up to 90% of non-melanoma skin cancers (D’Orazio et al., 2013). Overall, skin cancer is among the most common cancers worldwide, with approximately 1.5 million new cases reported in 2022 (IARC, 2022). Beyond skin cancer, aging also impairs wound healing, a problem further exacerbated by smoking. Cigarette smoking accelerates visible skin aging while simultaneously reducing the skin’s ability to repair itself. By understanding the mechanisms of skin aging and adopting protective habits, one can not only maintain a youthful appearance but also promote overall skin health and longevity. The structure and function of the skin The skin is one of the body's largest organs, consisting of three primary layers: the epidermis, the dermis, and the hypodermis.
Dermatologists classify skin’s response to UV exposure using the Fitzpatrick Scale, which categorizes skin into six phototypes based on melanin levels and susceptibility to sunburn. People with phototypes I and II (fair skin) are highly vulnerable to UV damage—over 90% of non-melanoma skin cancers occur in individuals with these skin types (WHO, 2002). Beyond its protective role, the skin also plays a crucial role in Vitamin D production. Upon exposure to sunlight, the skin synthesizes Vitamin D, which is essential for bone health and immune function. However, this process is self-regulated—prolonged sun exposure converts excess Vitamin D into inactive molecules, preventing an overdose (Mostafa & Hegazy, 2015). Skin aging Skin aging can be broadly divided into intrinsic and extrinsic aging:
As we age, the skin undergoes several degenerative changes, including:
On a microscopic level, one of the most significant changes is the loss of collagen and elastin:
From early adulthood onwards, collagen levels in the skin decrease by approximately 1% per year (Shuster et al., 1975). Additionally, the skin contains many immune cells, which play a key role in defense against infections. With age, their function declines, increasing susceptibility to skin infections (Chambers & Vukmanovic, 2020). Certain diseases can significantly speed up the aging process of the skin. Segmental progeroid syndromes, such as Hutchinson-Gilford Progeria Syndrome and Werner Syndrome, are hereditary conditions characterized by extreme premature aging, including accelerated skin aging (Lessel and Kubisch, 2019). While these genetic disorders cannot currently be prevented, other conditions linked to premature skin aging can be managed or mitigated. One such condition is type 2 diabetes mellitus (T2DM). In individuals with T2DM, chronically elevated blood glucose levels damage collagen and other extracellular matrix (ECM) proteins in the skin through a process called non-enzymatic glycation (Sjöberg and Bulterijs, 2009). As a result, T2DM patients tend to have reduced skin elasticity and deeper wrinkles compared to those with normal blood sugar levels (Moraes et al., 2023). Additionally, T2DM may increase susceptibility to solar lentigines—darkened patches of skin caused by excessive sun exposure (Moazzami et al., 2017). By managing preventable diseases such as diabetes, individuals can not only improve their overall health but also slow down premature skin aging. Slowing down skin aging Skin aging is highly influenced by lifestyle factors. Below, we will focus on two main modifiable contributors to skin aging namely smoking and UV exposure. However, other factors such as air pollution and nutrition also play a role in skin aging (Wong and Chew, 2021). For example, up to 30% of wrinkle formation may be influenced by dietary choices (Perner et al., 2011). We will finish this section with a discussion on several interventions that can be used to slow down skin aging. Smoking Smoking accelerates visible aging significantly. Research indicates that every 10 years of smoking adds approximately 2.5 years to a person’s apparent age (Rowe et al., 2010). Another study found that individuals who smoke 20 cigarettes a day can appear up to 10 years older than non-smokers (Leung and Harvey, 2002). Smoking has numerous detrimental effects on the skin, including increased dryness, delayed wound healing, reduced skin barrier function, and the formation of lines and wrinkles (Morita, 2007; Sorensen et al., 2009). Cigarette smoke reduces collagen production while simultaneously increasing its breakdown, leading to a loss of skin structure and elasticity. A study applying cigarette smoke extract to mice three times a week for six months observed a significant loss of collagen (Tanaka et al., 2007), demonstrating the destructive impact of smoking on skin integrity. Sun exposure While the dangers of sun exposure in relation to skin cancer are widely known, its role in premature aging is less recognized. For example, a study in Greece found that 66% of mothers of pediatric patients were aware of sun exposure’s link to skin cancer, yet only 5% knew it contributed to skin aging (Kakourou et al., 1995). Similarly, a recent study from the Arabian Peninsula revealed that although over 80% of respondents acknowledged the connection between sun exposure and skin cancer as well as skin aging, more than half still believed that a suntan could be healthy if sunburn was avoided (Sultana, 2020). In Malta, nearly half of respondents held the same misconception (Scerri et al., 2002). Another misconception is that a suntan will protect your skin from further sun damage. Even a deep tan on fair skin provides no more than SPF 4—far less than the SPF 50+ offered by many sunscreens (WHO, 2002). In reality, tanning is a biological response to sun-induced damage, meaning any level of tanning reflects compromised skin health. Another common misconception is that sun protection is unnecessary on cloudy days. In fact, clouds block visible light more effectively than UV radiation. Under certain conditions, they may even enhance UV exposure (Calbó et al., 2005). Ultraviolet radiation is classified into three types based on wavelength:
Approximately 90-95% of UV radiation that reaches the Earth's surface is UVA, while only 5-10% is UVB (D’Orazio et al., 2013). Though UVB is blocked by glass, UVA can pass through windows, leading to significant exposure even indoors (Nicolaidou et al., 2006). Specialized window coatings can help mitigate this effect. UVB primarily causes DNA damage by inducing the formation of thymine dimers, while UVA generates reactive oxygen species (ROS, such as singlet oxygen), which can damage DNA and other cellular structures. These harmful effects highlight the importance of year-round sun protection, regardless of weather conditions or indoor environments. Some individuals are more vulnerable to the harmful effects of UV radiation than others. People with lighter skin tones, red or blond hair, or blue, green, or gray eyes are at higher risk of UV-induced damage. Additionally, individuals with a greater number of moles face an increased likelihood of developing melanoma—the deadliest form of skin cancer—following sun exposure. The Global Solar UV Index is a useful tool for determining the strength of UV radiation at a given time and location. The World Health Organization (WHO) provides the following guidelines for sun protection based on UV levels (WHO, 2002):
The UV Index is a linear scale meaning that someone who would get a sunburn after half an hour of exposure at UV Index 6 radiation would be expected to get the same sunburn after only 15 minutes at UV Index 12 radiation. The UV Index is highest near the equator and decreases with increasing latitude. However, altitude also plays a significant role—UV levels rise with elevation, making exposure more intense on mountains or at high altitudes, such as in airplanes. UV radiation is strongest when the sun is highest in the sky, meaning it varies by time of day and season. Outside the tropics, the UV Index is highest around midday and during summer (WHO, 2002). Even if you're in the shade, UV radiation can still reach you through reflection—especially from certain surfaces like snow, sand, and water. Fresh snow can bounce back as much as 80% of UV radiation, while seafoam 25% and dry beach sand 15% (WHO, 2002). Airline pilots and cabin crew have been found to experience approximately double the incidence of melanoma compared to the general population, likely due to increased UV exposure at high altitudes (Sanlorenzo et al., 2015). At 9,000 meters (30,000 feet), UV radiation levels are about twice as high as those at ground level. This risk is further heightened when flying over dense cloud cover or snow, as these surfaces reflect additional UV radiation. Preventing photoaging Since UV radiation is one of the primary causes of skin aging, minimizing sun exposure is essential. The most effective protection combines avoidance and shielding. 1. Avoidance: Limiting Direct Sun Exposure
However, despite these recommendations, surveys show that most people do not stay indoors during midday hours (Kakourou et al., 1995; Robinson et al., 2000). 2. Shielding: Physical & Chemical Protection Physical protections:
Chemical protection (sunscreen) are categorized into two main types:
Recommendations for a good sunscreen:
Sunscreen plays a crucial role in protecting the skin from harmful UV radiation. However, no sunscreen offers complete protection, and long-wavelength UVA (UVA I) remains particularly difficult to block. While sunscreen is an essential tool for protecting the skin, it should not be used as an excuse to stay in the sun longer. Many people feel overly protected when wearing sunscreen, which can lead to excessive sun exposure and increased UV damage. A study calculated that using an SPF 8 sunscreen (which protects against both UVA and UVB radiation) increases the time one can stay in the sun without developing redness from about 20 minutes to 2.5–3 hours. However, despite offering UVA protection, the total UVA dose absorbed by the skin actually increases.
This example highlights a major concern: sunscreens can create a false sense of security, leading to longer exposure and potentially greater cumulative UVA damage—a key factor in skin aging and skin cancer risk. “Sunscreen should never be used to prolong the duration of sun exposure” (WHO, 2002). Indeed, in one study, volunteers received SPF 30 sunscreen followed by UV exposure that should just induce redness in individuals protected by SPF 15 but not at SPF 30. Indeed, the individuals wearing SPF 30 sunscreen did not show redness after UV exposure but biopsies showed dying (apoptotic) cells demonstrating that even exposure to sunlight at doses below which redness occurs already results in significant skin damage (Kaidbey, 1990). SPF (Sun Protection Factor) measures a sunscreen’s ability to protect against sunburn. Because sunburns are mainly caused by UVB and not UVA radiation, the SPF does not indicate the protection offered against UVA rays (Gasparro et al., 1998). To address this, the Protection Grade of UVA (PA) system was introduced. The PA rating is based on how well a sunscreen protects against tanning, which is primarily caused by UVA exposure. It ranges from PA+ (weakest) to PA++++ (strongest protection). One plus indicates that the use of the sunscreen allows you to sustain between 2 and 4 times as much UVA compared to when not using the product while four plusses indicate 16 times or more protection. Sunscreen is needed in surprising places, such as inside cars or near reflective surfaces like water and snow. A 2016 study found that while the windscreen of cars generally offered good UV protection, the side windows were considerably less protective and the protection factor differed strongly between brands (Wachler, 2016). Clouds reduce UV light but don't block it entirely, so sun protection is necessary even on overcast days. Finally, most people are probably aware that snow reflects UV light and so that solar protection is needed during outdoor activities in the snow such as skiing but snow is not the only reflective surface. Water for example is another reflective surface. Many people focus on protecting their faces but neglect their hands, which receive frequent sun exposure. This often results in visible aging on the hands, revealing one’s true age. Using sunscreen and wearing gloves can help preserve youthful-looking hands. In addition to sun exposure, there are a few other sources of UV light including indoor tanning, germicidal UV lamps, and welding. Shockingly, approximately 36% of adults have engaged in indoor tanning at one point in their lives and among university students this is even higher at 55% (Wehner et al., 2014). Finally, one important consideration is that complete sun avoidance may lead to vitamin D deficiency. To maintain optimal health, it's advisable to check your vitamin D levels and supplement if necessary. Visible light contributes to skin aging Visible light has been shown to induce reactive oxygen species (ROS) production, inflammation, and enzymes that degrade the skin matrix. However, it requires significantly higher doses compared to UVA/UVB exposure. Specifically, studies have found that it takes 30 times more visible light (180 J/cm²) to generate the same level of ROS and inflammation as UVA/UVB exposure. Interestingly, even at the lowest tested dose (65 J/cm²), visible light still triggered a significant 5-fold increase in ROS and a 2-fold increase the release of matrix metalloproteinase-1 (MMP-1), an enzyme that breaks down collagen and contributes to skin aging. Notably, UVA/UVB sunscreens provided minimal protection against the harmful effects of visible light. The authors also extended their findings to humans by measuring free radical production in forehead skin. Treatment with visible light increased free radicals by almost 86% (Liebel et al., 2012). In contrast to UV radiation, visible light penetrates deeper into the dermis and consequently could have a substantial effect on skin aging. For a more in-depth discussion on visible light-induced photoaging, we recommend an excellent review by Pourang et al. (2022). A common question is whether the light doses used in laboratory studies are realistic compared to daily sun exposure. To answer this, we can calculate real-world visible light exposure levels:
This calculation shows that the visible light doses used in in vitro studies are highly relevant to real-world conditions. A person exposed to sunlight for an hour on a regular day can easily experience similar light doses as those tested in studies, reinforcing the importance of broad-spectrum sun protection that includes defense against visible light. With increased screen time, concerns have emerged about the potential harmful effects of blue light exposure (Arjmandi et al., 2018; Kumari et al., 2022). While LED screens emit significant amounts of violet-blue light, the total blue light dose from screens is still much lower than outdoor sunlight exposure (Dain, 2020). Blue light penetrates deeper in the skin than UV light (SCENIHR, 2012). Exposure to blue light induces ROS production in skin cells and potentially distorts the circadian rhythm in skin cells (Kumari et al., 2022). Some sunscreens also offer protection against blue light (Ferreira et al., 2024). If you wish to reduce blue light exposure from screens, you can switch on the night modus. Oral collagen supplements In a meta-analysis it was found that oral collagen peptides significantly improve skin hydration and elasticity while they reduce wrinkles (de Miranda et al., 2021). A later meta-analysis, that included more studies, confirmed these findings (except they did not study the effect of collagen peptides on wrinkles) (Pu et al., 2023). However, it should be pointed out that many studies on oral collagen supplements have limitations, including small sample sizes (21–134 participants), short durations (2–16 weeks), and a lack of male data—only about 3% of participants in a meta-analysis of 26 studies were male (Pu et al., 2023). While collagen peptide supplementation appears safe, current evidence for its effectiveness remains limited and requires further high-quality research. Astaxanthin Astaxanthin belongs to the carotenoids, a family of pigments found in various plants, algae, bacteria, and fungi. Astaxanthin more specifically is found in certain algae and in animals that feed on them such as salmon and crustaceans where it is responsible for their red-orange color. Astaxanthin is a powerful antioxidant that may prevent UV-induced damage to the skin (Li et al., 2020). A meta-analysis concluded that oral astaxanthin use improves moisture content and skin elasticity but does not improve wrinkles (Zhou et al., 2021). However, the evidence here is even lower compared to the collagen peptide as the meta-analysis only included 86 astaxanthin-treated participants in the moisture content and 126 participants in the skin elasticity analysis (with individual studies contributing only 16-49 participants in the placebo and control group combined). Hence, more research is needed before we can draw conclusions about the effectiveness of oral astaxanthin on skin aging. Vitamin A derivatives Topical vitamin A derivatives are among the most widely used anti-aging treatments. Over-the-counter options include retinol and retinaldehyde, while prescription-strength all-trans retinoic acid (tretinoin) is significantly more potent—hundreds of times stronger than its non-prescription counterparts (Motamedi et al., 2021). Newer synthetic retinoids, such as adapalene, have been developed to provide similar benefits with fewer side effects (Tu et al., 2001). A randomized, placebo-controlled trial in individuals with moderate to severe photoaging found that daily application of tretinoin (0.05%) for two years significantly improved fine and coarse wrinkles, pigmentation irregularities, and skin sallowness (Kang et al., 2005). These findings were further validated by a meta-analysis of seven randomized controlled trials (Sitohang et al., 2022). Interestingly, a split-face study demonstrated that retinol at a concentration 10 times higher than tretinoin was equally effective in reducing photodamage (Babcock et al., 2015). Another study found that a 1.1% tri-retinol serum provided results comparable to 0.025% tretinoin (Ho et al., 2012). Despite their effectiveness, vitamin A derivatives can be harsh on the skin, often causing dryness and peeling. To minimize irritation, a hydrating moisturizer should be used alongside retinoids. Since these compounds increase UV sensitivity, they should only be applied in the evening, and daily sun protection is essential. Vitamin C serum Vitamin C is one of the most widely used ingredients in anti-aging skincare. It exists in multiple forms, including its free acid form (ascorbic acid) and various esters (e.g., magnesium ascorbyl phosphate and ascorbyl tetraisopalmitate). While ascorbic acid, the natural form found in citrus fruits, has potent antioxidant properties, its penetration into the skin is low. However, this can be improved by formulating it at a pH below 3.5. Another major drawback is its instability—ascorbic acid degrades easily upon storage. To counteract this, stabilizing antioxidants such as vitamin E and ferulic acid are often added. To enhance stability and absorption, researchers have developed various vitamin C derivatives, mainly through two types of modifications:
Despite these advances, there is no clear consensus on which form of vitamin C is most effective for anti-aging, as studies on absorption and efficacy often show conflicting or biased results (Enescu et al., 2022). A systematic review identified three studies that investigated the effect of vitamin c on photoaging. Improvements in fine wrinkling, sallowness, and hydration were observed (Correia and Magina, 2023). However, the total study population over the three studies was only 49 participants and assessment was done by visual scoring rather than more objective computational image analysis. In a double-blind, randomized placebo-controlled split face trial, women were given a placebo cream and a cream containing 1, 2 or 3% tetra-isopalmitoyl ascorbic acid. After 8 weeks, the side of the face treated with the tetra-isopalmitoyl ascorbic acid cream showed an improvement in wrinkles around the eye (Yokota and Yahagi, 2022). Vitamin C supports skin health through several key mechanisms:
While vitamin C holds great promise for anti-aging, more research is needed to determine the most effective formulation for optimal skin benefits. Senolytics and senomorphics As we age, the number of senescent cells in the skin increases. These cells lose their ability to divide and contribute to aging by secreting inflammatory and tissue-degrading molecules, collectively known as the senescence-associated secretory phenotype (SASP). Senolytics are compounds that selectively target and eliminate senescent cells. Navitoclax (ABT-263) is one such senolytic that has shown promise in improving skin healing. A recent study found that topical pretreatment with ABT-263 significantly enhanced wound healing in mice. By day 18, one-third of the treated mice had fully healed wounds, whereas none of the control mice had healed. RNA sequencing (RNA-seq) revealed that ABT-263 stimulated collagen synthesis, suggesting its potential in promoting skin repair and rejuvenation (Shvedova et al., 2025). Unlike senolytics, rapamycin does not kill senescent cells but instead suppresses the SASP, reducing inflammation and tissue degradation (Wang et al., 2017). A small clinical trial investigated the effects of topical rapamycin (10 µM) applied to the hands of human volunteers. The treatment led to: a reduction in senescent cell markers, increased type VII collagen levels, and visible improvements in skin aging. The visual improvements included a reduction in fine wrinkles, increase in dermal volume, less sagging, and a more even skin tone (Chung et al., 2019). These findings suggest that both senolytics (e.g., ABT-263) and SASP inhibitors (e.g., rapamycin) hold potential as anti-aging treatments by either eliminating senescent cells or mitigating their harmful effects. Chemical peels Chemical peels involve the application of acidic solutions to the skin, creating a controlled injury that stimulates skin regeneration. They are categorized into superficial, medium, and deep peels based on their depth of penetration:
Conclusion Skin aging is not only a cosmetic concern but can also contribute to serious health issues, such as an increased risk of skin cancers and infections. As such, prioritizing skin health is essential by minimizing UV exposure, avoiding pollution, quitting smoking, and maintaining a nutritious diet. Additionally, we explored various interventions that could help slow down the aging process of the skin. Due to space limitations, we were unable to cover hair aging (graying and loss) and other interventions like platelet-rich plasma, Botox, fillers, red light therapy, and ablative lasers. Nor did we discuss the role of diet in skin aging. These topics require more detailed exploration and might be topics of future editions. Don’t miss out on next month’s deep dive into the exposome and its role in biological aging—subscribe now so you don’t miss any of our expert insights! References Adam J (1998). Sun-protective clothing. J Cutan Med Surg 3: 50-53. Arjmandi N et al. (2018). 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J Dermatol Sci 46: 69-71. Tu P et al. (2001). A comparison of adapalene gel 0.1% vs. tretinoin gel 0.025% in the treatment of acne vulgaris in China. J Eur Acad Dermatol Venereol 15 Suppl 3: 31-36. Wachler BSB (2016). Assessment of Levels of Ultraviolet A Light Protection in Automobile Windshields and Side Windows. JAMA Ophthalmol 134(7): 772-5. Wambier CG et al. (2019). Advanced chemical peels: Phenol-croton oil peel. J Am Acad Dermatol 81: 327-336. Wang R et al. (2017). Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2‐independent mechanism. Aging Cell 16: 564–574. Wehner MR et al. (2014). International Prevalence of Indoor Tanning A Systematic Review and Meta-analysis. JAMA Dermatol 150: 390–400. WHO (2002). Global Solar UV Index: A Practical Guide. Switzerland. Online available at: https://iris.who.int/bitstream/handle/10665/42459/9241590076.pdf Wong QYA, Chew FT (2021). Defining skin aging and its risk factors: a systematic review and meta-analysis. Sci Rep 11: 22075. Whiteman DC et al. (2019). When to apply sunscreen: a consensus statement for Australia and New Zealand. Aust NZ J Public Health 43:171-5. Yokota M, Yahagi S (2022). Evaluation of the anti-wrinkle effect of a lipophilic pro-vitamin C derivative, tetra-isopalmitoyl ascorbic acid. J Cosmet Dermatol 21: 3503-3514. Zhou X et al. (2021). Systematic Review and Meta-Analysis on the Effects of Astaxanthin on Human Skin Ageing. Nutrients 13: 2917. This newsletter does not constitute medical or investment advice. The author assumes no responsibility for the correctness, completeness, up-to-dateness, or quality of the information provided herein and assumes no liability for any loss or damage that may result from the use or application of the information contained in this newsletter. The opinions expressed are those of the author only and should not be considered as representative of any organization, company, or institution that the author is affiliated with.
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Introduction
Last month, I hosted a journal club (DM me to sign up for future journal clubs) focused on organ-specific proteomic clocks—an exciting and emerging area in longevity research. Given the growing interest in this topic, it seemed fitting to dedicate this month’s newsletter to it. Aging clocks Individuals do not age at the same rate. Some develop multiple age-related diseases and pass away in their 70s, while others remain in good health for decades longer, living into their 100s. This discrepancy highlights the limitations of using chronological age as a sole predictor of health and mortality risk. Instead, researchers have introduced biological age, a more precise metric of an individual's physiological state. Those who age prematurely tend to have a biological age older than their chronological age, whereas exceptionally long-lived individuals typically have a younger biological age. Over the past decade, scientists have developed various aging clocks to measure biological age—some based on DNA methylation, others on gene expression, and others on proteomic signatures. The age gap (ΔAge) represents the difference between an individual's model-predicted biological age and chronological age. A negative age gap indicates slower aging, meaning the individual’s biological age is younger than expected for their chronological age. Conversely, a positive age gap suggests accelerated aging, where biological age exceeds chronological age. Organ-Specific Aging Clocks Aging does not affect all tissues equally. It is possible for a person to have a young heart but an old brain. If different organs age at different rates, understanding organ-specific aging could provide crucial insights into disease susceptibility and guide targeted interventions. For example, individuals with accelerated vascular aging may benefit from more aggressive blood pressure control to prevent cardiovascular events. In a series of recent publications, Tony Wyss-Coray and colleagues developed eleven organ-specific aging clocks (Oh et al., 2023; Oh et al., 2024; Kivimäki et al., 2025). Two other research groups expanded upon this work by creating clocks for seven additional organs (Zhao et al., 2024; Goeminne et al., 2025). To construct these clocks, researchers first identified genes with high tissue specific expression, selecting those whose RNA expression levels were at least four times higher in a given organ than in any other. They then applied LASSO regression, a form of linear regression with regularization, to correlate gene expression patterns with chronological age. Later Tony Wyss-Coray and colleagues used the same methodology to construct eighteen organ aging clocks (and one conventional clock) trained on mortality data (Goeminne et al., 2025). Findings from the UK Biobank Applying these aging clocks to UK Biobank participants revealed substantial variability in organ aging (Oh et al., 2024). While twenty-seven percent of individuals exhibited normal aging, with no organs deviating more than 1.5 standard deviations from the mean, about fourteen percent had two to four aged organs, and another thirteen percent had two to four younger-than-expected organs. Another fourteen percent exhibited a mix of young and old organs. More extreme cases, including individuals with five or more aged or youthful organs, as well as those with a single significantly aged or youthful organ, were relatively rare, occurring in fewer than two percent of the population. Organ Aging and Disease Risk The researchers found a strong correlation between aged organs and an increased risk of future disease. As expected, individuals with older brains had a significantly higher likelihood of developing Alzheimer’s disease. However, some findings were less intuitive, such as the observation that people with aged lungs exhibited an elevated risk of rheumatoid arthritis. Among individuals with youthful brains, only 0.3 percent developed Alzheimer’s over a seventeen-year follow-up, compared to 4.6 percent of those with aged brains (Oh et al., 2024). In a broader analysis, individuals with multiple aged organs—whether between two and four or five and seven—showed an increased risk for nearly every disease studied. Conversely, those with multiple youthful organs had lower risks for many diseases but an unexpectedly higher risk of Parkinson’s disease and type 2 diabetes (Oh et al., 2024). Organ Aging and Mortality Risk An independent research team from China analyzed the same UK Biobank dataset and confirmed similar organ-specific aging patterns (Zhao et al., 2024). Their study extended the findings by examining mortality risk. The results showed that the more aged organs a person had, the higher their probability of death. After sixteen years, ninety percent of individuals with no aged organs were still alive, compared to only twenty percent of those with more than eight aged organs. Of all organs, brain aging emerged as the strongest predictor of mortality. Lifestyle and Organ Aging Aging clocks also provided insights into lifestyle factors that influence organ aging. Smoking, obesity, educational deprivation, and physical inactivity were all associated with an increased prevalence of multiple aged organs (Zhao et al., 2024). More than five percent of smokers had multiple aged organs, compared to only two percent of non-smokers. The impact of physical activity on organ aging was nonlinear. Only the least active quintile showed an increased risk of aged organs, while all other quintiles had similar risks. This suggests that beyond a minimal threshold, additional exercise may provide limited further benefit. However, because the study did not specify exact physical activity thresholds for each quintile, comparing this result with prior research on exercise dose-response remains challenging. Nonetheless, existing literature suggests that the most significant health benefits occur when individuals transition from a sedentary lifestyle to any form of physical activity. Wyss-Coray’s team also examined the effects of medications, supplements, and lifestyle behaviors on organ-specific aging (Oh et al., 2024). Smoking and alcohol consumption were associated with accelerated organ aging, while certain medications, such as Premarin, an estrogen therapy for postmenopausal women, were linked to reduced organ aging. The researchers noted that early menopause is a known contributor to aging acceleration and found that women who experienced early menopause exhibited increased organ aging across most clocks. In another recent study, Vadim Gladyshev and colleagues developed eighteen proteomic-based organ aging clocks (plus a conventional clock) trained on mortality data (Goeminne et al., 2025). These clocks outperformed even the strongest existing mortality biomarkers, including the epigenetic GrimAge clock. The analysis revealed that healthy dietary habits, such as consuming raw salads, vegetable dips, and oily fish, were associated with lower organ age gaps. In contrast, unhealthy food choices, including beer, spirits, sugar-sweetened beverages, processed meats, and white bread, correlated with higher organ-specific age gaps. Smoking was linked to significantly increased aging in nine out of nineteen organ clocks. The study also identified multiple medications associated with increased organ aging, including metformin, a drug widely investigated for its potential geroprotective properties. However, rather than directly accelerating aging, this correlation likely reflects the underlying disease burden of individuals taking these medications. Among supplements, glucosamine exhibited the strongest association with reduced organ aging. Interestingly, the previous study by Oh et al. (2024) that used organ age clocks trained on chronological age also identified glucosamine as a substance that slows aging. However, both clocks were trained on the same dataset (UK Biobank). Interestingly, previous observational studies have linked glucosamine use with lower all-cause mortality (Bell et al., 2012; King and Xiang, 2020; Li et al., 2020). Insights from the Whitehall II Study More recently, Wyss-Coray and colleagues analyzed data from the Whitehall II cohort, a study involving over six thousand middle-aged UK government employees between the ages of forty-five and sixty-nine at baseline (Kivimäki et al., 2025). After twenty years of follow-up, individuals with the largest organ age gaps exhibited an increased risk for thirty diseases. Six diseases were exclusively linked to the aging of their respective organs, such as lung cancer being associated with lung aging. Twelve diseases were linked to age gaps in both their respective organ and additional organs, while another twelve diseases were associated with increased age gaps in organs other than their primary affected organ. For example, dementia was linked to immune system aging rather than brain aging. This is in contrast with their earlier data from the UK Biobank study in which brain aging was the largest predictor of Alzheimer’s disease risk (Oh et al., 2024). The reason for this inconsistency remains unknown. Compensatory gene expression During the journal club, Josh Mitteldorf raised an intriguing point. He suggested that aging clocks may partially capture gene expression changes that are compensatory—adaptive responses of the body to counteract the stresses of aging and maintain homeostasis (Mitteldorf, 2024). For example, studies in C. elegans have shown that stress response pathways become increasingly activated with age (Li et al., 2019). However, other research has failed to replicate these findings (Dues et al., 2016). Thus, the extent to which compensatory gene expression influences aging clocks remains an open question. Current studies using aging clocks in humans are observational in nature. To strengthen the causal relationships between interventions and organ aging clocks, interventional studies would be needed. Thus, a very obvious next step would be to test organ age clocks at baseline and after treatment with placebo or a suspected geroprotective intervention. Conclusion The rapid advancement of organ-specific aging clocks is opening new frontiers in personalized medicine. These tools offer a more precise way to assess disease risk, identify lifestyle factors that influence aging at the organ level, and develop targeted anti-aging interventions. However, significant challenges remain. So far, only eighteen organ-specific clocks have been developed, leaving open the question of whether aging clocks for other systems—such as the reproductive system—can be reliably constructed. Future research should explore advanced machine learning models, including neural networks, to enhance predictive accuracy. Additionally, these clocks must be validated in more diverse populations, as most studies have focused on Western cohorts. Another key unanswered question is whether aging clocks respond to interventions in a causal way. While observational studies suggest correlations between certain behaviors, medications, and organ aging, controlled trials are needed to determine whether lifestyle changes, dietary modifications, or pharmacological interventions can directly slow or reverse organ aging. While this article focused on proteomic aging clocks, other promising approaches are emerging, including DNA methylation-based clocks (Sehal et al., 2023), clinical biomarker-based models (Tian et al., 2023), and multi-omics clocks that integrate diverse biological data (Ahadi et al., 2020; Nie et al., 2022). As research progresses, organ-specific aging clocks could transform longevity science, bringing us closer to precision aging medicine—where interventions are tailored to an individual's unique aging profile. Next month, we’ll dive into the science of skin aging and explore what can be done to slow it. Stay tuned! This newsletter does not constitute medical or investment advice. The author assumes no responsibility for the correctness, completeness, up-to-dateness, or quality of the information provided herein and assumes no liability for any loss or damage that may result from the use or application of the information contained in this newsletter. The opinions expressed are those of the author only and should not be considered as representative of any organization, company, or institution that the author is affiliated with. Introduction
One of my New Year’s promises was to start a newsletter—and here we are! What better way to kick things off than by reflecting on 2024 and looking ahead to 2025? Before diving in, I want to wish everyone a happy New Year! May 2025 bring you professional success, health, and happiness. Economic Overview The global economy thrived in 2024, with the S&P 500 achieving an impressive 23.3% gain, building on a 24.2% increase in 2023. This marked the first sustained winning streak of this magnitude in over 25 years (source). Other major indices followed suit, with the Core MSCI World Index surging over 27% (source). As we enter 2025, the big question looms: will this bull market persist, or are we approaching a correction? At the time of writing, the CNN Fear & Greed Index, a barometer of market sentiment, stands at 28, signaling growing investor apprehension (source). While caution is warranted, there is still hope that 2025 will extend this extraordinary rally into a third consecutive year. Biotech and Medical Advancements The FDA approved 50 novel drugs in 2024, slightly fewer than the 55 approved in 2023—a record year and the second highest in three decades (source). Still, 2024 was a strong year for innovation, particularly in addressing age-related diseases. Key approvals included Donanemab, a monoclonal antibody for Alzheimer’s disease, and Acoramidis, which treats transthyretin amyloidosis, an under-recognized cause of death in the oldest old. Other notable breakthroughs included Flurpiridaz 18F, a PET diagnostic agent for cardiovascular imaging; Aprocitentan, a hypertension treatment; and Ensifentrine, a promising therapy for chronic obstructive pulmonary disease (COPD), which affects 15–25% of smokers. Finally, multiple cancer treatments received approval. These advancements underscore significant progress in tackling chronic and age-related diseases. Aging Research Aging research continued to grow, with PubMed showing a 7.9% increase in publications mentioning “aging” compared to 2023—a remarkable 66% rise since 2015. The breadth of aging research conducted over the past year is staggering, making it impossible to cover even a small fraction of it. However, I would like to highlight one particularly noteworthy study the LEV Foundation’s Robust Mouse Rejuvenation (RMR1) trial. This ambitious trial tested four interventions—rapamycin, mTERT gene therapy, hematopoietic stem cell (HSC) transplantation, and the senolytic drug Gal-Nav—in combination and subsets of three (source). Preliminary results revealed significant sex differences. In female mice, the combination of all four treatments extended lifespan, although rapamycin alone was equally effective. For males, outcomes were more complex: while the four-intervention combination initially outperformed controls, late-surviving control mice outlived the treated group. Rapamycin alone outperformed controls but was less effective than the full combination of all four interventions, hinting at potential additive benefits. Interestingly, the combination of all treatments except mTERT appeared to increase early mortality in male mice but did not reduce maximum lifespan. This finding is even stranger when one considers the fact that mTERT alone worsened survival in male mice. Conversely, in female mice, the same combination boosted survival and nearly matched the full four-treatment protocol. Unlike in males, mTERT alone enhanced lifespan in females. These findings underscore the complexity of combinatorial treatments for lifespan extension and the importance of studying both sexes. Recent mandates by agencies like the NIH requiring male and female animals in studies reflect this growing awareness. However, given the preliminary nature of the findings and the absence of statistical analysis, these results should be interpreted cautiously. The complete results of this first trial—and the potential launch of an RMR2 trial—are eagerly awaited and may shed further light on these intriguing outcomes. Conclusion The future isn’t set in stone—we shape it with our actions. Let’s make 2025 a year of growth, discovery, and innovation. Whether advancing research, driving economic progress, or addressing global challenges, each of us has a role to play. Here’s to a bright and successful 2025! This newsletter does not constitute medical or investment advice. The author assumes no responsibility for the correctness, completeness, up-to-dateness, or quality of the information provided herein and assumes no liability for any loss or damage that may result from the use or application of the information contained in this newsletter. The opinions expressed are those of the author only and should not be considered as representative of any organization, company, or institution that the author is affiliated with. |
AuteurSchrijf iets over jezelf. Het hoeft niet heel uitgebreid te zijn, een overzicht is genoeg. Archieven
April 2025
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