LongeCityNews Last Updated: 21 November 2025 - 08:38 AM

Epigenetic clocks have existed for long enough for numerous large study databases to include data on their use. Thus meta-analysis papers are emerging to assess this body of data as a whole. This is a necessary part of the process of gaining confidence in the ability of epigenetic clocks, and indeed aging clocks in general, to rapidly assess the potential of any novel form of intervention intended to slow or reverse aspects of aging. This is a much needed capability. In many ways, efforts to treat aging as a medical condition proceed blindly, given just how much time and funding is required in order to understand whether one approach is better or worse than another. If there was a way to quickly assess the quality of an anti-aging therapy immediately after its application, then the field could adjust quickly to pursue the best paths forward. The hope is that aging clocks can be that tool - but we are clearly not there yet.

Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.

24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28,325 participants (14,757 female; median of mean age 65.2 years). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11,162; standardised β coefficient 0.06), PhenoAge EAA (eight studies; n=10,371; standardised β coefficient 0.07), GrimAge EAA (eight studies; n=10,371; standardised β coefficient 0.11), and pace of ageing (five studies; n=7,895; standardised β coefficient 0.10) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6,143; standardised β coefficient 0.02) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.

In conclusion, higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.

Link: https://doi.org/10.1016/j.lanhl.2025.100773

TDP-43 is one of a small number of proteins in the brain that can misfold or otherwise become altered in ways that allow toxic aggregates to form, or even encourage other molecules of the same protein to become dysfunctional in the same way. TDP-43 aggregation in later life is a relatively recent discovery, and has a neurodegenerative condition newly named for it, limbic-predominant age-related TDP-43 encephalopathy (LATE). It has also been found that TDP-43 is likely important in amyotrophic lateral sclerosis (ALS), and thus progress on that front seems likely to help with other forms of TDP-43 pathology. Here, researchers report a promising discovery in the biochemistry of TDP-43 aggregation in the context of ALS.

Amyotrophic lateral sclerosis (ALS) is a lethal adult-onset motor neuron disease, characterized by disruption of neuromuscular junctions (NMJs), axonal degeneration and neuronal death. Most ALS cases are linked to TDP-43 pathology, characterized by its mislocalization from the nucleus to the cytoplasm and the formation of phosphorylated aggregates. TDP-43 is a multifunctional DNA-binding/RNA-binding protein with roles in transcriptional and splicing regulation, RNA processing and RNA transport/subcellular localization.

Recently, we showed that TDP-43 co-localizes with the core stress granule component G3BP1 in axonal condensates of patients with ALS and mice. These TDP-43-G3BP1 condensates sequester RNA and inhibit local protein synthesis, resulting in mitochondrial malfunction and NMJ disruption with subsequent axonal degeneration. Furthermore, recent studies revealed aggregation of TDP-43 in peripheral motor axons of patients with ALS during initial diagnosis. Thus, axonal TDP-43 condensates exert pathological regulation over essential local synthesis events.

Here, we studied the localized accumulation of TDP-43 in axons and NMJs. Our findings highlight the presence of distal TDP-43 pathology in patients with SOD1 ALS and mouse models. We found that TDP-43 accumulates at NMJs due to aberrant local synthesis triggered by a reduction in miR-126a-5p within muscle extracellular vesicles. This chain of events ultimately initiates neurodegeneration. Notably, delivery of miR-126 is neuroprotective in neuromuscular co-cultures, delays TDP-43 accumulation at NMJs, and postpones the onset of motor symptoms in the SOD1G93A mouse model of ALS.

Link: https://doi.org/10.1038/s41593-025-02062-6

The human gut microbiome is made up of a few thousand distinct microbial species. The relative sizes of these populations shift in response to day to day circumstances, such as variations in diet, but one would expect consistency from one year to the next. Over longer spans of time, the gut microbiome ages. Populations producing beneficial metabolites are reduced in number, while populations that provoke the immune system into chronic inflammatory behavior grow in number. This data is derived from both animal and human studies. One can control what happens to a mouse over the course of its life, but for human data the detailed history of any particular individual is largely a mystery.

Antibiotics and a range of other pharmaceuticals produce dramatic short-term effects on the composition of the gut microbiome. To a large degree, the gut microbiome restores itself once the pharmaceutical is no longer present. That said, we might well ask how much of the observed human data on gut microbiome aging is produced by, say, antibiotic use. Researchers have observed gut microbiome changes in population studies taking place as early as the mid-30s, and it is hard to envisage any form of meaningful degeneration taking place at that age. But exposure to antibiotics and other pharmaceuticals? That is very prevalent. In later life, given the presence of chronic diseases of aging, there is a great deal more chronic pharmaceutical use, as well as the employment of pharmaceuticals with meaningful side effects. We might again ask how much of the observed aging of the human gut microbiome at the population level results from the use of these treatments versus mechanisms of aging.

Drug-mediated disruption of the aging gut microbiota and mucosal immune system

The dynamic relationship of gut microbiota, mucosal immunity, aging, and pharmaceutics interventions has a significant impact on overall physiological functions and disease susceptibility. Aging is associated with changes in the gut microbiome including decreased microbial diversity, reduced short-chain fatty acid (SCFA) production, and elevated pathobiont proportions. These changes are associated with impaired mucosal immunity, increased intestinal permeability, and heightened systemic inflammation in the host, which can exacerbate age-related disorders.

Medications such as proton pump inhibitors (PPIs), metformin, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and antibacterials also influence gut microbiota function. PPIs may alter microbial colonies and induce overgrowth of pathogenic bacteria, which compromises the mucosal defenses and in severe cases, the resulting infections may cause ulcers. Metformin, through its metabolic benefits, causes Akkermansia muciniphila to increase in relative abundance, which is associated with improved gut barrier composition. NSAIDs, because of their strong anti-inflammatory properties, disturb gut homeostasis by increasing intestinal permeability, reducing prostaglandin synthesis, and inducing dysbiosis in the host. Corticosteroids, through their immunosuppressive mechanisms, reduce microbial diversity and secretory immunoglobulin A levels, impairing mucosal immunity and enhancing the host's susceptibility to infections. Antibacterials are a major disruptor of the gut microbiota, causing a decline in beneficial bacteria and an increased risk for opportunistic infections such as Clostridium difficile.

To address drug-induced dysbiosis, probiotics and prebiotics products may be helpful to restore microbial balance, enhance SCFA production, and reinforce mucosal defenses. Individualized gut microbiota profiling may enable safer medication usage by identifying patients that are at an increased risk for dysbiosis-related complications. Additionally, development of microbiota-sparing medications and targeted therapies may help to enhance gut health outcomes in aging populations. Future research should address the long-term effects of pharmacological agents on gut microbiota and mucosal immunity in aging populations, as well as identification of connections between microbiota, immune function, and the effects of medications. Integrating microbiome-conscious approaches into clinical practice could allow healthcare providers to optimize patient care

A recent review in the Journal of Ovarian Research summarizes current knowledge of the impact of various polyphenols on different aspects of ovarian aging. The researchers discuss that polyphenol supplementation could be used as an intervention to delay ovarian aging [1].

Every woman’s problem

Ovarian aging and cessation of proper ovarian functioning precede aging in other organs. Ovarian aging is related to a reduction of oocyte quality and quantity, which is the main reason for age-related infertility.

Beyond the fertility problems, ovarian aging impacts lifespan and is also linked to many age-related conditions, such as osteoporosis, cardiovascular disease, and neurodegenerative disorders. Therefore, finding ways to delay it is in the interest of every female, regardless of her childbearing goals.

At this moment, hormone replacement therapy and assisted reproductive technologies are used to address ovarian aging-related problems; however, they are unable to reverse female reproductive aging and the declining ovarian reserve. Longevity researchers are currently seeking ways to extend the female reproductive span, but before effective therapies are on the market, lifestyle factors can be utilized to address ovarian aging.

The authors of this review highlight polyphenols, naturally occurring metabolites found in fruits, vegetables, nuts, seeds, herbs, spices, and medicinal plants, as one possible intervention. Polyphenols exhibit strong biological activities, including antioxidant, anti-inflammatory, antibacterial, and antiviral properties, and demonstrate numerous beneficial effects. Studies also suggest that they can reduce the risk of cardiovascular disease and neurodegenerative disorders [2].

Delaying ovarian aging

The first part of this review discusses resveratrol, a plant-derived polyphenol that has antioxidant and anti-apoptotic properties. Multiple studies have shown that resveratrol’s dietary supplementation or oral administration ”alleviated ovarian oxidative stress damage, restored hormone levels, reduced ovarian cell apoptosis, and improved reproductive performance in animals” [3-7]. It also positively affected epigenetic changes and gene expression in the aging ovary.

Polyphenols extracted from tea leaves were shown to reduce inflammatory responses and oxidative stress and to improve ovarian reserve and ovarian function in animal models of induced ovarian damage [8, 9]. Human, mice, and other mammalian research also suggested their benefits in “alleviating ovarian aging and improving reproductive performance by enhancing oocyte quality and reducing oxidative stress” [10-12].

Quercetin was described as having strong antioxidant properties. It can promote in vitro maturation of oocytes from aged mice and humans [13] and slow down the aging of human ovarian cells [14]. Experiments in middle-aged mice also showed that oral administration improved estrous cycles, pregnancy rate, and ovarian reserve [14]. In polycystic ovary syndrome (PCOS) models, quercetin reversed many detrimental changes, such as irregular ovulation and hormone secretion, or increased ovarian cell apoptosis and inflammation [15, 16]. Similar beneficial effects were also seen in experiments in livestock and poultry animals.

Proanthocyanidins are among the most potent natural antioxidants and possess several other beneficial characteristics. They have been linked to ovarian health in multiple studies. Research in rodents and human cells reported that proanthocyanidins reduced oxidative stress, inhibited ovarian cells apoptosis, improved oocyte viability and quality, modulated hormone levels, and alleviated PCOS [17-20].

Less commonly studied polyphenols also mitigate ovarian aging. Curcumin “has been found to delay the ovarian aging process by increasing follicular number, modulating hormone secretion, reducing oxidative stress, enhancing oocyte maturation and embryo development in an aged mouse model” [21]. Other polyphenols, such as chlorogenic acid, ferulic acid, and pterostilbene, have been shown to positively impact ovarian reserve, ovarian function, and oocyte quality by mitigating oxidative stress, reducing ovarian cell apoptosis, and reducing DNA damage [22-25].

It is worth noting that several studies have shown that a moderate dose of polyphenols can make a profound difference, and high doses of polyphenols can be toxic and cause ovarian damage and impair oocyte maturation. [17, 26-29].

Many mechanisms, one goal

The beneficial effects of polyphenols can be achieved through modulations of many molecular pathways. One of them involves oxidative stress and the excessive production of reactive oxygen species (ROS), which can contribute to an increase in inflammation and disrupt the redox balance, leading to damage to mitochondrial function, telomere shortening, apoptosis, and inflammation, all of which compromise the proper functioning of ovaries and contribute to ovarian aging.

Since polyphenols have antioxidant properties, the researchers investigated their role in delaying ovarian aging by examining the effects of resveratrol, quercetin, and epigallocatechin gallate (EGCG). Those polyphenols have been shown to modulate multiple molecular signaling pathways related to oxidative stress, improve ovarian antioxidant capacity, and reduce ovarian cell apoptosis [30-32]. A human randomized controlled trial also showed a positive role of plant polyphenols (curcumin or resveratrol supplementation) in alleviating ovarian aging by reducing oxidative stress [33, 34].

Polyphenols’ anti-inflammatory properties can also help alleviate ovarian aging by reducing inflammation, which negatively impacts ovarian health. These benefits were demonstrated in animal and human models of ovarian damage [8,35]. Reduction of inflammation and improved oocyte and embryo quality resulted from polyphenol supplementation in women with PCOS who received quercetin [36]. However, there is still a need for research on the impact of polyphenols on inflammation markers in naturally aging ovaries.

Aging-related hormonal dysregulation significantly impacts ovarian aging. The hypothalamic-pituitary-ovary (HPO) axis controls hormones related to the reproductive system. Aging-related dysregulation of the HPO axis contributes to the depletion of the ovarian reserve and decreased quality and quantity of ovarian cells [37]. A growing body of research suggests that plant polyphenols regulate the sensitivity and secretion of reproductive hormones, potentially mitigating ovarian aging. The impact of polyphenols on hormonal balance and ovarian health was tested in preclinical and clinical studies of women with PCOS, showing their benefits for ovarian health through the regulation of hormone secretion [38-40].

The microenvironment surrounding the ovaries is also essential. This environment normally supports ovary and oocyte maturation, but aging leads to the accumulation of metabolites that might disrupt the homeostasis. The gut microbiota and its metabolites influence the ovarian microenvironment via the gut-ovary axis. Through this axis, the ovary communicates with the gut microbiota via hormone secretion. On the other hand, gut microbes produce metabolic signalling molecules that can impact ovarian function. Studies that used fecal microbiota transplants suggest that maintaining “a youthful gut microbiota may help preserve ovarian function and reproductive health” [41]. Similarly, experiments with laying hens as a model suggested that polyphenol supplementation could improve ovarian function by modulating the gut microbiota [27, 42].

There appear to be many mechanisms and pathways through which polyphenols impact ovarian aging. This is unsurprising since polyphenols are a broad group of molecules with diverse chemical structures, resulting in distinct bioactivity profiles.

This knowledge can be used to design safe plant polyphenol-based interventions for female reproductive longevity that can be used alone or in combination with other treatments.

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[34] Ardehjani, N. A., Agha-Hosseini, M., Nashtaei, M. S., Khodarahmian, M., Shabani, M., Jabarpour, M., Fereidouni, F., Rastegar, T., & Amidi, F. (2024). Resveratrol ameliorates mitochondrial biogenesis and reproductive outcomes in women with polycystic ovary syndrome undergoing assisted reproduction: a randomized, triple-blind, placebo-controlled clinical trial. Journal of ovarian research, 17(1), 143.

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[39] Ali Fadlalmola, H., Elhusein, A. M., Al-Sayaghi, K. M., Albadrani, M. S., Swamy, D. V., Mamanao, D. M., El-Amin, E. I., Ibrahim, S. E., & Abbas, S. M. (2023). Efficacy of resveratrol in women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized clinical trials. The Pan African medical journal, 44, 134.

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