In healthy human cells, DNA is packaged up inside the nucleus and mitochondria. When DNA leaks out into the fluid component of the cell known as the cytosol, it means that something is wrong. Cytosolic DNA is a danger signal associated with infections, cellular stress, cancer, and other diseases. Cells have a warning system to detect DNA in the cytosol, which involves activation of STING, which in turn coordinates inflammation necessary to combat these threats. While short bursts of STING-mediated inflammation are crucial, in some people this pathway is chronically "on," a state that has been linked with neurodegeneration and other diseases of aging, as well as normal aging.

To learn more about potential benefits of STING activation in response to diverse stresses, researchers analyzed the full set of proteins within cells. They found that when STING was activated, two transcription factors called TFEB and TFE3 were shuttled to the nucleus of cells, where they activated genes that resulted in the production of more lysosomes. Lysosomes are organelles that are involved in autophagy, a cellular process that cleans up damaged material, almost like a housekeeping or recycling system. Both lysosomes and autophagy are tightly linked with longevity and healthspan, the length of time that a person is healthy, suggesting that this protective function of STING is important for healthy aging.

STING-blocking therapies are currently being explored within the context of age-related diseases, but the new findings suggest that this strategy should be reconsidered because it would also block the autophagy/lysosome-promoting functions of STING. Instead, selectively targeting components of the inflammation pathway downstream of STING may be a better approach because it would preserve the protein's beneficial functions.

Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING.

Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.

Aging is a complex process, associated with the accumulation of damaged molecules, progressive loss in structure and function of cells, tissues, and organs, and increased vulnerability to death. Even if the aging process is multifaceted and diverse, laboratory manipulation of genes in different laboratory model animals has increased the lifespan of these organisms. Most genes that are associated with increasing lifespan are part of the nutrient-sensing pathway and the mutation in these genes mimics the state of food shortage. Different mechanisms of fasting and calorie restriction (CR) have been linked with healthy aging trajectories in different organisms. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored.

Alongside other systems in the body, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. Of the two systems, the adaptive part of the immune system is most impacted by aging. Inflammation is a crucial process that facilitates the maintenance and restoration of tissue and the clearance of pathogens. On the other hand, chronic inflammatory processes are linked with different pathologies, like rheumatoid arthritis. Aside from this pathological involvement of chronic inflammation, the aging process is linked with a low-grade, chronic, and sterile inflammation (an inflammation without infection) termed as "inflammaging."

In general, evidence-based scientific experiments on fasting and calorie restriction have shown to promote healthy aging as well as to alleviate some markers of immunosenescence and inflammaging. Thus, similar to regular exercise, a vegetarian diet, etc., fasting/calorie restriction should also be considered part of a healthy lifestyle. Furthermore, fasting and calorie restriction increases the fitness of the immune system in fighting infection and cancer which are more common in the elderly. However, more data are needed especially on nutritional approaches including, the amount of nutrients, type of nutrients, and combination of nutrients that promote healthy aging and an effective immune response in humans. Furthermore, strategies on how to integrate fasting/calorie restriction in boosting immune response like the length of the intervention, and at what age is best to start fasting still need to be standardized so that its actual effect on the aging immune system can be clarified and used.

Longevity Escape Velocity Foundation (LEVF) today welcomes two very generous donations from long-time supporter of longevity research and activism, Didier Coeurnelle. The first donation is 220,000. The second donation, of up to another 220,000, is dependent on LEVF receiving matching gifts from other donors from 1st October until the end of the month (October 31st). These donations enable a key set of pre-study pilots ahead of the next phase of LEVF's groundbreaking investigations into the effects of combining different damage-repair interventions for middle-aged mice.

Longevity Escape Velocity (LEV) Foundation exists to conduct and inspire research to proactively identify and address the most challenging obstacles on the path to the widespread availability of comprehensively effective treatments to cure and prevent human age-related disease. Donations are processed free of charge by Every.org, a 501(c)3 non-profit, which will issue a tax receipt to you and disburse the full value of your gift (excluding only any applicable third-party fees) to us. Our partnership with Every.org markedly reduces administrative and regulatory overheads related to donations, enabling us to focus solely on realizing our mission.

A primary focus of LEV Foundation's work is to empirically demonstrate the feasibility and value of the divide-and-conquer approach to treating age-related disease - that is, the simultaneous deployment of therapies that independently address the distinct classes of damage that accumulate in aging bodies. In partnership with Ichor Life Sciences, we'll be conducting large-scale mouse lifespan studies of such therapeutic mixtures. To ensure the results of these studies are rapidly translatable to humans already in middle and old age, this program will focus solely on late-onset interventions. We anticipate that this program will deliver dramatic results both in scientific terms, and in illustrating to the general public the extraordinary potential of comprehensive rejuvenation medicine.

Proteasomes are protein complexes that break down faulty proteins into smaller peptides. On the other hand, autophagy is a process by which cells degrade and recycle larger structures, including protein aggregates, through the formation of specialized vesicles. Both systems work in concert to maintain proteostasis, but the mechanism of their synergistic activation to mitigate the effects of aging is not well understood. "A few years ago, I learned from an academic conference that a certain drug called IU1 can enhance proteasomal activity, which encouraged our group to test its anti-aging effects."

The researchers employed an animal model for studying the aging process: fruit flies from the genus Drosophila. Since fruit flies have a short lifespan and their age-related muscle deterioration is quite similar to that in humans, Drosophila constitutes a valuable model for studying aging. They treated flies with the drug IU1 and measured various behavioral and proteostasis-related parameters. "Inhibiting the activity of ubiquitin specific peptidase 14 (USP14), a component of the proteasome complex, with IU1 enhanced not only proteasome activity but also autophagy activity simultaneously. We demonstrated that this synergistic mechanism could improve age-related muscle weakness in fruit flies and extend their lifespan."

Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging.

Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.

White matter hyperintensity (WMH) volume measured with magnetic resonance imaging (MRI) serves as a significant indicator of the extent of cerebral white matter lesions, typically associated with ischemia due to small vessel disease. WMHs are frequently found in older cognitively unimpaired individuals, are linked with worse cognitive performance, particularly executive functions and processing speed, are associated with genetic risk of neurodegenerative disease, and can potentially impact both the onset and advancement of dementia related to both Alzheimer's disease (AD) and cerebrovascular disease (CVD). Here, we examine the potential associations of physical activity (PA) and sedentary behaviors (SBs), two modifiable lifestyle factors, with WMH volumes in middle-aged to older adults. In the UK Biobank, we found associations of both moderate-to-vigorous physical activity (MVPA) and SB with WMH volume, and the associations are not fully independent of each other.

A large number of studies have shown that engaging in greater amounts of MVPA is associated with improved vascular health and that SB is associated with vascular pathology and chronic disease. One potential vascular mechanism that could underlie these results is that MVPA may increase cerebral blood flow, which in turn may help prevent the development of high WMH loads. SB, on the other hand, has been linked with reduced cerebral blood flow which may lead to increased lesion load, though this finding has not been consistently replicated.

Our results also align with the growing body of literature emphasizing the synergistic effects of higher PA and reduced SB on various health outcomes. While previous studies have independently linked excessive SB and lack of MVPA with adverse brain health, our study demonstrates how these behaviors interact in their associations with WMH volumes. It is possible that the mechanisms linking PA and SB with WMH volumes may only partially overlap. For example, while both SB and MVPA have been linked with cerebral blood flow and vascular health in previous work, MVPA is also associated with the upregulation of neurotrophic factors (eg, Brain Derived Neurotrophic Factor or BDNF) that may provide additional compensatory protection against the impact of increased WMH volumes.

While our study was not designed to determine whether mechanistic pathways are fully or partially independent, the interactions found here suggest more work is needed to better understand how these two lifestyle behaviors may differentially impact brain lesion loads that may, in turn, influence the risk for cognitive decline and dementia related to both AD and CVD. Overall, our results highlight the importance of considering interactions between these key modifiable behaviors when examining their associations with brain health outcomes.

Diminished mitochondrial function underlies many rare inborn errors of energy metabolism and contributes to more common age-associated metabolic and neurodegenerative disorders. Thus, boosting mitochondrial biogenesis has been proposed as a potential therapeutic approach for these diseases; however, currently we have a limited arsenal of compounds that can stimulate mitochondrial function.

In this study, we designed molybdenum disulfide (MoS2) nanoflowers with predefined atomic vacancies that are fabricated by self-assembly of individual two-dimensional MoS2 nanosheets. Treatment of mammalian cells with MoS2 nanoflowers increased mitochondrial biogenesis by induction of PGC-1α and TFAM, which resulted in increased mitochondrial DNA copy number, enhanced expression of nuclear and mitochondrial-DNA encoded genes, and increased levels of mitochondrial respiratory chain proteins. Consistent with increased mitochondrial biogenesis, treatment with MoS2 nanoflowers enhanced mitochondrial respiratory capacity and adenosine triphosphate production in multiple mammalian cell types.

Taken together, this study reveals that predefined atomic vacancies in MoS2 nanoflowers stimulate mitochondrial function by upregulating the expression of genes required for mitochondrial biogenesis.

The aging process involves numerous molecular changes that lead to functional decline and increased disease and mortality risk. While epigenetic aging clocks have shown accuracy in predicting biological age, they typically provide single estimates for the samples and lack mechanistic insights. In this study, we challenge the paradigm that aging can be sufficiently described with a single biological age estimate. We describe Ageome, a computational framework for measuring the epigenetic age of thousands of molecular pathways simultaneously in mice and humans.

Ageome is based on the premise that an organism's overall biological age can be approximated by the collective ages of its functional modules, which may age at different rates and have different biological ages. We show that, unlike conventional clocks, Ageome provides a high-dimensional representation of biological aging across cellular functions, enabling comprehensive assessment of aging dynamics within an individual, in a population, and across species. Application of Ageome to longevity intervention models revealed distinct patterns of pathway-specific age deceleration. Notably, cell reprogramming, while rejuvenating cells, also accelerated aging of some functional modules. When applied to human cohorts, Ageome demonstrated heterogeneity in predictive power for mortality risk, and some modules showed better performance in predicting the onset of age-related diseases, especially cancer, compared to existing clocks.

Together, the Ageome framework offers a comprehensive and interpretable approach for assessing aging, providing insights into mechanisms and targets for intervention.

Michael Ringel of Boston Consulting Group gave a deep and fascinating talk on the evolutionary origins of aging. Geroscientists are mostly focused on how aging happens, but why it happens is also important. Several theories have been proposed. According to Ringel, those explanations can be divided into three broad categories: Mechanistic, Weakening Selection, and Optimization. The first one posits that aging happens due to the inability of evolution to eliminate physical constraints such as the damage that arises from normal biological processes. Basically, miracles don't happen. The second one means that, as organisms age and survival declines, there is less evolutionary pressure to maintain the traits that would keep them healthy later in life. Selection becomes so weak that random mutations, including those that accelerate aging or cause diseases, are no longer removed effectively from the gene pool. This allows aging and late-life deterioration to persist in the population. Michael argued that current empirical evidence is best explained by the optimization paradigm. This has an important implication: a vast majority of pro-longevity mutations, just like other mutations, are a step away from that carefully optimized state. If you look at a broader context of reproductive fitness, you will probably find how it is hurt by the mutation.

Some longevity biotechs don't shy from making big claims, and Maxwell Biosciences is one of them. Its goal is to create "a synthetic immune system" that would give us wide protection against microbial pathogens. Bacteria and viruses evolve quickly, developing drug resistance. Fungi can wreak a lot of havoc and are understudied. The body has defense mechanisms, but they dwindle and get overwhelmed as we age. One such mechanism is the antimicrobial peptide LL-37. Maxwell's LL-37-mimicking candidate kills viruses and bacteria by permeating their membranes and is effective even against highly resistant bacterial strains. Maxwell runs several high-profile collaborations and is wrapping up a study in rhesus macaques with results expected later this month. Human clinical trials will begin next year.

John Sedivy of Brown University reminded the audience that about half of our genome consists of repeated sequences, mostly transposons associated with viruses. While some transposons are benign "viral fossils" that lost their ability to replicate, a majority can still do it if the patches of the chromatin where they are located are derepressed. Transposon reactivation increases with age and has been linked to multiple age-related conditions. This can happen in a positive feedback loop: cellular senescence leads to chromatin opening, LINE-1 (the most ubiquitous retrotransposon) derepression, antiviral response, and then to chronic inflammation. Transposon Therapeutics, the company that John advises, is built on the idea that we can use existing reverse transcriptase inhibitors (such as anti-HIV drugs) against age-related retrotransposon activation. Studies in animal models show that these drugs can have a massive effect on inflammation, cellular senescence, and age-related cognitive decline. The company is already deep in clinical trials with censavudine, a reverse transcriptase inhibitor.

As cellular power plants and critical production sites of reactive oxygen species (ROS), mitochondria play a pivotal role in the process of aging, and their dysfunction has been associated with age-related diseases. Mitochondria profoundly influence their cellular environment through their central roles in ATP production, ROS generation, ion homeostasis, and signaling events. Besides, once released into the extracellular space, several mitochondrial constituents, such as mitochondrial nucleic acids or metabolites, can act as danger-associated molecular patterns (DAMPs) that trigger innate immune responses and inflammation. Similarly, mitochondria can also be shed by stressed cells in extracellular vesicles, which carry DAMPs and can act in a paracrine and endocrine manner.

As cells age, mitochondria experience a decline in function, characterized by mitochondrial DNA mutations, increased oxidative stress, DAMP formation, decreased mitochondrial energy conversion, and hampered mitochondrial turnover and dynamics. Consequently, understanding the multifaceted roles of mitochondria is fundamental in deciphering their impact on the process of aging and their potential as anti-aging targets.

The current review examines recent advances in understanding the interplay between mitochondrial dysfunction and organ-specific aging. Thereby, we dissect molecular mechanisms underlying mitochondrial impairment associated with the deterioration of organ function, exploring the role of mitochondrial DNA, reactive oxygen species homeostasis, metabolic activity, damage-associated molecular patterns, biogenesis, turnover, and dynamics. We also highlight emerging therapeutic strategies in preclinical and clinical tests that are supposed to rejuvenate mitochondrial function, such as antioxidants, mitochondrial biogenesis stimulators, and modulators of mitochondrial turnover and dynamics. Furthermore, we discuss potential benefits and challenges associated with the use of these interventions, emphasizing the need for organ-specific approaches given the unique mitochondrial characteristics of different tissues.

Age-related hearing loss (ARHL), recognized as the third most common chronic geriatric disease, affects approximately half of adults aged 85 years and over, significantly impairing the health and well-being of the elderly population, leading to communication challenges, social isolation, and cognitive decline. The relationship between aging and ARHL is complex, as the same molecular and cellular mechanisms that drive the aging process also contribute to the deterioration of auditory function. As the body ages, the auditory system becomes increasingly susceptible to the cumulative effects of multiple degenerative processes associated with aging, leading to the progressive hearing loss characteristic of ARHL. Despite advancements in identifying the age-related cellular and molecular changes in the inner ear, the long-standing question that remains is which precise mechanisms underlie the age-dependent degeneration of cochlear structure and function, as well as which methods can be used to preserve or reverse these processes.

Dysregulation of cellular pathways like senescence, autophagy, and oxidative stress, in addition to molecular pathways regulated by AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor-1 (IGF-1), and sirtuins (SIRTs) have each been implicated in hearing loss progression, but the specific causative factors and their direct roles on molecular and cellular pathways that lead to cochlear degeneration are not fully elucidated. Understanding how these pathways affect postmitotic hair cells, the stria vascularis, and the spiral ganglion cells is vital for elucidating the mechanisms of ARHL and developing therapeutic interventions to prevent or mitigate ARHL.

Calorie restriction (CR), well recognized for its healthspan and lifespan-extending properties, has also been shown to slow ARHL in both rodents and primates, but the specific molecular pathways modified by CR in the inner ear and the most effective CR mimetic compounds remain unclear. However, molecules targeting oxidative stress and mitochondrial dysfunction or using CR mimetics such as metformin and nicotinamide mononucleotide (NMN), as well as the potential of senolytics or senomorphics, may offer new treatment strategies for ARHL. Characterizing these fundamental aging pathways will not only enhance our understanding of general aging processes but also illuminate their role in ARHL.

Current rejuvenation strategies, which range from calorie restriction to in vivo partial reprogramming, only improve a few specific cellular processes. In addition, the molecular mechanisms underlying these approaches are largely unknown, which hinders the design of more holistic cellular rejuvenation strategies. To address this issue, we developed SINGULAR (Single-cell RNA-seq Investigation of Rejuvenation Agents and Longevity), a cell rejuvenation atlas that provides a unified systems biology analysis of diverse rejuvenation strategies across multiple organs at single-cell resolution. In particular, we leverage network biology approaches to characterize and compare the effects of each strategy at the level of intracellular signaling, cell-cell communication, and transcriptional regulation.

Our approach successfully identified several previously known age-related transcription factors (TFs). For instance, we found Arntl to be a master regulator in rejuvenation, corroborating its earlier identification as the TF with the most significant age-related decline in activity in at least one prior analysis. However, only three other matching TFs were identified, with the sign of TF activity changes varying substantially by cell type. This suggests notable differences between transcriptional changes associated with aging and the regulators of rejuvenation. It also uncovered previously undocumented mediators of rejuvenation interventions. Moreover, in cases where the transcriptional mediators are known, our analysis provides novel insights.

For example, while the AP-1 complex formed by Fos and Jun has been described to regulate diverse cell functions, and in particular the inflammaging response, our analysis further demonstrates that different subunits and cofactors serve as master regulators of the response to specific interventions. In light of our findings and a recent study that highlighted an up-regulation of the Jun-Fos dimer expression, which is accompanied by increasing inflammation, it is plausible that AP-1 dimers composed of other subunits are responsible for inducing anti-aging effects.

Apart from the AP-1 complex, our analysis revealed the transcriptional stress response TFs NFE2L2 and MAF as master regulators of certain rejuvenation interventions in different cell types. Indeed, MAF and NFE2L2 have been shown to dimerize and regulate gene expression programs that protect against oxidative stress, which are lost with age. Moreover, over-expressing MAF has been shown to rescue these protective expression programs and preserve fitness in an animal aging model. Conversely, the reduced activity of NFE2L2 leads to increased cellular senescence and inflammation.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Despite the undetermined pathogenesis of PD, serum uric acid (UA) levels are decreased in patients with PD. A meta-analysis of dose-response studies established a correlation between a 6% increased risk of PD and every 1 mg/dL decrement in serum UA level. Although there is evidence of decreased UA levels in patients with PD, the causal relationship between UA levels and PD onset or progression remains unclear. Findings suggest that the reduction in serum UA levels in PD is not a causative factor in the onset or progression of the disease but rather a consequence of impaired mitochondrial function, altered gastrointestinal function, and impaired motor function, which may also influence the onset and progression of PD (reverse causation).

Alterations in purine metabolism are also key to understanding the pathophysiology behind lower UA levels in PD patients. UA production follows this pathway: inosine monophosphate (IMP) → inosine → hypoxanthine → xanthine → UA. Although the levels of inosine, hypoxanthine, and xanthine, which are "upstream" in the purine metabolic pathway, may affect UA levels, the "downstream" product in patients with PD, no past studies have explored upstream purine metabolism in the CSF and blood of patients with PD.

Our study compared serum and cerebrospinal fluid (CSF) levels of inosine, hypoxanthine, xanthine, and UA in PD patients and healthy controls. We analyzed 132 samples using liquid chromatography-tandem mass spectrometry. Results showed significantly lower serum and CSF UA levels in PD patients than in controls. Decreased serum hypoxanthine levels were observed in PD patients compared to controls with decreased CSF inosine and hypoxanthine levels. Our findings suggest that decreased UA levels in PD patients are influenced by factors beyond purine metabolism, including external factors such as sex, weight, and age. The observed reductions in serum and CSF hypoxanthine and CSF inosine highlight potential impairments in purine recycling pathways, warranting further research into alternative therapeutic strategies.

Inadequate sleep duration and poor sleep quality are becoming significant public health issues linked to cardiometabolic risk factors like obesity, particularly with an aging population. Approximately 20% of adults are impacted by health issues associated with substandard sleep quality or insufficient sleep durations. Research has demonstrated that the occurrence of dementia is indicative of a greater risk of future all-cause mortality . Furthermore, there is increasing evidence suggesting that both short and lengthy sleep durations, as well as other disturbances, are associated with higher risks of mortality from all causes. Limited attempts to assess the connection between sleep and neurodegenerative illnesses usually found that insufficient sleep length, low sleep quality, and sleep disorders were associated with negative outcomes that included dementia.

Considering the interconnection between sleep, dementia, and the rate of mortality, it is important to investigate the pathways and potential interactions among them. This study aims to investigate the relationship between poor sleep quality and dementia status with mortality risk. We examine this relationship independently of potential confounding factors, while also considering the influence of sex and race. The study is conducted using a sub-sample of the Health and Retirement Study (HRS) with complete algorithmically defined dementia status and probability outcomes. The participants in this sub-sample have a mean age of approximately 78 years. Furthermore, we conduct a simultaneous examination to assess the potential interaction between poor sleep quality and dementia outcomes in determining the risk of mortality.

Poor sleep quality was only directly related to mortality risk before adjustment for lifestyle and health-related factors. Therefore, the potential causal effect of poor sleep quality on mortality risk appears to be confounded by other lifestyle and health-related factors. Dementia was positively associated with mortality risk, particularly among individuals with better sleep quality and among males.

Experts have long observed that those with poor oral health are statistically more vulnerable than those with healthier mouths to head and neck squamous cell carcinoma (HNSCC), a group that includes the most common cancers of the mouth and throat. While small studies have tied some bacteria in these regions (the oral microbiome) to the cancers, the exact bacterial types most involved had until now remained unclear.

Researchers analyzed data from three ongoing investigations tracking 159,840 Americans from across the country to better understand how diet, lifestyle, medical history, and many other factors are involved in cancer. Shortly after enrolling, participants rinsed with mouthwash, providing saliva samples that preserved the numbers and species of microbes for testing. Researchers then followed up for roughly 10 to 15 years to record any presence of tumors. The investigators analyzed bacterial and fungal DNA from the saliva samples. Then, they identified 236 patients who were diagnosed with HNSCC and compared the DNA of their oral microbes with that of 458 randomly selected study subjects who had remained cancer-free.

Of the hundreds of different bacteria that are routinely found in the mouth, 13 species were shown to either raise or lower risk of HNSCC. Overall, this group was linked to a 30% greater likelihood of developing the cancers. In combination with five other species that are often seen in gum disease, the overall risk was increased by 50%. This is the largest and most detailed analysis of its kind to date. It is also among the first to examine whether common fungi, organisms like yeast and mold that, along with bacteria, make up the oral microbiome, might play a role in HNSCC. The new experiments found no such role for fungal organisms.

An ovarian follicle is a basic functional unit in the mammalian ovary, composed of somatic cells (granulosa cells) that surround and support an oocyte (an immature egg cell) as it grows and matures before ovulation. The granulosa cells communicate with the oocyte to provide essential nutrients and components through channels known as transzonal projections. In turn, the oocyte provides key components that signal the growth and development of granulosa cells. Researchers tapped on this understanding of the relationship between somatic cells of the ovarian follicle and the oocyte to create hybrid ovarian follicles through an ex-vivo 3D culturing platform, building upon previous methods. The team then extracted the oocyte from its original follicular environment and transplanted it to a new follicular environment, whose own oocyte had been removed, to construct the hybrid ovarian follicle.

The researchers confirmed that aged granulosa cells, compared to young granulosa cells, exhibited an increase in the hallmarks of ageing, such as an increase in indicators of DNA damage and other factors linked to programmed cell death. They showed that this aged follicular environment can reduce the quality and developmental potential of a young oocyte.

The research team then created hybrid ovarian follicles containing an aged oocyte (i.e. an immature egg cell from an aged follicular environment) in a young follicular environment. The researchers demonstrated that the quality and developmental competence of the aged oocyte can be substantially, though not fully, restored through "nurturing" in a young follicular environment. The team found that the restoration of the quality of the aged oocyte was attributed to the reshaping of its metabolism and gene expression. The researchers discovered that the young granulosa cells, which were much better at establishing transzonal projections toward the aged oocyte, helped to facilitate this restoration. In addition, there was an improvement in the function and health of oocyte mitochondria, crucial organelles for energy production and cellular metabolism.