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Reactivation of retroelements in the human genome has been linked to aging. However, whether the epigenetic state of specific retroelements can predict chronological age remains unknown. We provide evidence that locus‐specific retroelement DNA methylation can be used to create retroelement‐based epigenetic clocks that accurately measure chronological age in the immune system, across human tissues, and pan‐mammalian species. We also developed a highly accurate retroelement epigenetic clock compatible with EPICv.2.0 data that was constructed from CpGs that did not overlap with existing first‐ and second‐generation epigenetic clocks, suggesting a unique signal for epigenetic clocks not previously captured. We found retroelement‐based epigenetic clocks were reversed during transient epigenetic reprogramming, accelerated in people living with HIV‐1, and responsive to antiretroviral therapy. Our findings highlight the utility of retroelement‐based biomarkers of aging and support a renewed emphasis on the role of retroelements in geroscience. [ABSTRACT FROM AUTHOR]

Background : Geroscience focuses on interventions to mitigate molecular changes associated with aging. Lifestyle modifications, medications, and social factors influence the aging process, yet the complex molecular mechanisms require an in-depth exploration of the epigenetic landscape. The specific epigenetic clock and predictor effects of a vegan diet, compared to an omnivorous diet, remain underexplored despite potential impacts on aging-related outcomes. Methods: This study examined the impact of an entirely plant-based or healthy omnivorous diet over 8 weeks on blood DNA methylation in paired twins. Various measures of epigenetic age acceleration (PC GrimAge, PC PhenoAge, DunedinPACE) were assessed, along with system-specific effects (Inflammation, Heart, Hormone, Liver, and Metabolic). Methylation surrogates of clinical, metabolite, and protein markers were analyzed to observe diet-specific shifts. Results: Distinct responses were observed, with the vegan cohort exhibiting significant decreases in overall epigenetic age acceleration, aligning with anti-aging effects of plant-based diets. Diet-specific shifts were noted in the analysis of methylation surrogates, demonstrating the influence of diet on complex trait prediction through DNA methylation markers. An epigenome-wide analysis revealed differentially methylated loci specific to each diet, providing insights into the affected pathways. Conclusions: This study suggests that a short-term vegan diet is associated with epigenetic age benefits and reduced calorie intake. The use of epigenetic biomarker proxies (EBPs) highlights their potential for assessing dietary impacts and facilitating personalized nutrition strategies for healthy aging. Future research should explore the long-term effects of vegan diets on epigenetic health and overall well-being, considering the importance of proper nutrient supplementation. Trial registration: Clinicaltrials.gov identifier: NCT05297825 [ABSTRACT FROM AUTHOR]

Background: Histone deacetylases (HDACs) regulate transcriptional responses to injury stimuli that are critical for successful tissue regeneration. Previously we showed that HDAC inhibitor romidepsin potently inhibits axolotl tail regeneration when applied for only 1‐minute postamputation (MPA). Results: Here we tested CoCl2, a chemical that induces hypoxia and cellular stress, for potential to reverse romidepsin inhibition of tail regeneration. Partial rescue of regeneration was observed among embryos co‐treated with romidepsin and CoCl2 for 1 MPA, however, extending the CoCl2 dosage window either inhibited regeneration (CoCl2:0 to 30 MPA) or was lethal (CoCl2:0 to 24 hours postamputation; HPA). CoCl2:0 to 30 MPA caused tissue damage, tissue loss, and cell death at the distal tail tip, while CoCl2 treatment of non‐amputated embryos or CoCl2:60 to 90 MPA treatment after re‐epithelialization did not inhibit tail regeneration. CoCl2‐romidepsin:1 MPA treatment partially restored expression of transcription factors that are typical of appendage regeneration, while CoCl2:0 to 30 MPA significantly increased expression of genes associated with cell stress and inflammation. Additional experiments showed that CoCl2:0 to 1 MPA and CoCl2:0 to 30 MPA significantly increased levels of glutathione and reactive oxygen species, respectively. Conclusion: Our study identifies a temporal window from tail amputation to re‐epithelialization, within which injury activated cells are highly sensitive to CoCl2 perturbation of redox homeostasis. Key Findings: HDACi inhibit axolotl tail regeneration.Acute CoCl2 treatment partially rescues HDACi mediated inhibition of axolotl tail regeneration.CoCl2 rescue of regeneration is associated with rescue of regeneration specific, transcription factor gene expression.Chronic CoCl2 treatment impairs wound healing and inhibits axolotl tail regeneration.Strategic application of chemical inhibitors can reveal critical windows and biological processes that are essential for wound healing and regeneration. [ABSTRACT FROM AUTHOR]

Among tetrapods, only salamanders can regenerate their limbs and tails throughout life. This amazing regenerative ability has attracted the attention of scientists for hundreds of years. Now that large, salamander genomes are beginning to be sequenced for the first time, omics tools and approaches can be used to integrate new perspectives into the study of tissue regeneration. Here we argue the need to move beyond the primary salamander models to investigate regeneration in other species. Salamanders at first glance come across as a phylogenetically conservative group that has not diverged greatly from their ancestors. While salamanders do present ancestral characteristics of basal tetrapods, including the ability to regenerate limbs, data from fossils and data from studies that have tested for species differences suggest there may be considerable variation in how salamanders develop and regenerate their limbs. We review the case for expanded studies of salamander tissue regeneration and identify questions and approaches that are most likely to reveal commonalities and differences in regeneration among species. We also address challenges that confront such an initiative, some of which are regulatory and not scientific. The time is right to gain evolutionary perspective about mechanisms of tissue regeneration from comparative studies of salamander species. Research Highlights: Salamander limb regeneration has been studied using relatively few species.Salamanders as a group present many examples of homoplasy.Studies of additional species will likely identify mechanistic variations in limb regeneration. [ABSTRACT FROM AUTHOR]

Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention, without the need for decade-spanning trials, by acting as surrogate endpoints. Prior to testing whether aging biomarkers may be useful as surrogate endpoints, it is first necessary to determine whether they are responsive to interventions that target aging. Epigenetic clocks are aging biomarkers based on DNA methylation with prognostic value for many aging outcomes. Many individual studies are beginning to explore whether epigenetic clocks are responsive to interventions. However, the diversity of both interventions and epigenetic clocks in different studies make them difficult to compare systematically. Here, we curate TranslAGE-Response, a harmonized database of 51 public and private longitudinal interventional studies and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 95 other DNAm biomarkers that help explain changes in each clock. With this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging have the strongest response across all interventions and show consistent agreement with each other, pharmacological and lifestyle interventions drive the strongest response from DNAm biomarkers, and study population and study duration are key factors in driving responsiveness of DNAm biomarkers in an intervention. Some classes of interventions such as TNF-alpha inhibitors have strong, consistent effects across multiple studies, while others such as senolytic drugs have inconsistent effects. Clocks with multiple sub-scores (i.e. "explainable clocks") provide specificity and greater mechanistic insight into responsiveness of interventions than single-score clocks. Our work can help the geroscience field design future clinical trials, by guiding the choice of interventions, specific subsets of epigenetic clocks to minimize multiple testing, study duration, study population, and sample size, with the eventual aim of determining whether epigenetic clocks can be used as surrogate endpoints.

The recent unprecedented progress in ageing research and drug discovery brings together fundamental research and clinical applications to advance the goal of promoting healthy longevity in the human population. We, from the gathering at the Aging Research and Drug Discovery Meeting in 2023, summarised the latest developments in healthspan biotechnology, with a particular emphasis on artificial intelligence (AI), biomarkers and clocks, geroscience, and clinical trials and interventions for healthy longevity. Moreover, we provide an overview of academic research and the biotech industry focused on targeting ageing as the root of age-related diseases to combat multimorbidity and extend healthspan. We propose that the integration of generative AI, cutting-edge biological technology, and longevity medicine is essential for extending the productive and healthy human lifespan.

Background: The dramatic increase in exposure to non-native sources of electromagnetic fields (EMF) in recent years has given rise to numerous human health concerns. The near pervasive exposure to radiofrequency (RF) emanating from wireless technologies inside the home (e.g., cell phones, wireless routers, "Smart" devices) and outside of the home (e.g., cell towers, automobiles, computers at work, tablets at school) is particularly troubling. While epidemiological studies are somewhat conflicting to date, RF exposure is currently classified by the World Health Organization as a Class 2B carcinogen. Mechanisms of activity of the deleterious effects of RF exposure on human health include the generation of excessive oxidative stress, chronic inflammation, and disruption of the production of melatonin and other hormones, all of which are believed to be due largely to the activation of voltage-gated calcium channels (VGCC). Mitigation strategies are currently generally limited to wireless device hygiene (e.g., hard-wired ethernet, turning off wireless routers at night, keeping cellphones away from the body) and metal-based shielding in the home, which can be expensive and not feasible for many. The goal of this pilot and feasibility trial was to evaluate the feasibility and preliminary signs of efficacy of an in-home resonance-based electromagnetic field protection device (BluShield) on various physiological and patient-reported outcomes commonly affected by excessive RF exposure., Methods: A sample of relatively healthy adults was enrolled in a single arm, 12-week pilot and feasibility study. The intervention consisted of plugging in the BluShield device at home or at the participant's residence when traveling. Outcomes included laboratory panels assessing overall physiological health (CBC & CMP), blood markers related to inflammation, oxidative stress, DNA damage, and cellular senescence (Jinfiniti), a high-resolution genome-wide assessment of DNA methylation (TruDiagnostic), a validated questionnaire to assess cognitive function (CNS - Vital Signs), a wearable device to assess sleep and other physiological parameters (Oura ring), and a single-item assessment of overall health. Outcomes were compared before and after the intervention with paired t tests or Wilcoxon signed rank tests, depending upon the distribution of data., Results: 25 participants enrolled in the study. All participants reported compliance with the EMF mitigation device throughout the course of the study, and no adverse events were reported. There were limited changes in conventional labs (decrease in glucose, increase in monocytes; P < .04]), but modest improvement in self-reported health ( P = .02), improvements on numerous domains of the CNS - Vital Signs questionnaire (Composite Memory, Cognitive Flexibility, Executive Function, and Processing Speed; P < .02), wearable device parameters (deep sleep, heart rate variability, resting heart rate, and body temperature; P < .04), and perhaps most interestingly, hypermethylation of genes involved in RF exposure (including a key VGCC gene [ CACNA1G ]; P = .000045)., Discussion: The use of the BluShield is feasible and revealed improvements in some markers of sleep, cognitive function, and overall health. These improvements may be due in part to suppression of VGCC activity, which previous literature has demonstrated is activated by RF exposure and can generate oxidative stress and inflammation. An RF mitigation strategy should focus primarily on limiting modifiable exposures within the home, and the device appears to be a promising component of a comprehensive approach.. Controlled studies are needed to mitigate potential sources of confounding in this single-arm pilot study. A specific focus among populations with excessive RF exposures that are not modifiable within the home, such as those living in high-density urban settings, in close proximity to cell towers, or certain occupational hazards, also appears warranted., (Copyright © 2024 InnoVision Professional Media Inc.)

Genome-wide association studies (GWAS) with proteomics are essential tools for drug discovery. To date, most studies have used affinity proteomics platforms, which have limited discovery to protein panels covered by the available affinity binders. Furthermore, it is not clear to which extent protein epitope changing variants interfere with the detection of protein quantitative trait loci (pQTLs). Mass spectrometry-based (MS) proteomics can overcome some of these limitations. Here we report a GWAS using the MS-based Seer Proteograph ™ platform with blood samples from a discovery cohort of 1,260 American participants and a replication in 325 individuals from Asia, with diverse ethnic backgrounds. We analysed 1,980 proteins quantified in at least 80% of the samples, out of 5,753 proteins quantified across the discovery cohort. We identified 252 and replicated 90 pQTLs, where 30 of the replicated pQTLs have not been reported before. We further investigated 200 of the strongest associated cis-pQTLs previously identified using the SOMAscan and the Olink platforms and found that up to one third of the affinity proteomics pQTLs may be affected by epitope effects, while another third were confirmed by MS proteomics to be consistent with the hypothesis that genetic variants induce changes in protein expression. The present study demonstrates the complementarity of the different proteomics approaches and reports pQTLs not accessible to affinity proteomics, suggesting that many more pQTLs remain to be discovered using MS-based platforms., Competing Interests: COMPETING INTERESTS STATEMENT H.G. and S.B. are employees and/or stockholders of Seer, Inc.; J.L-S. is a scientific advisor to Precion Inc. and TruDiagnostic; J.L-S. has a sponsored research agreement with TruDiagnostic. J.L-S. previously consulted for Cambrian and Ahara. The other authors declare no competing interests.

Senolytics, small molecules targeting cellular senescence, have emerged as potential therapeutics to enhance health span. However, their impact on epigenetic age remains unstudied. This study aimed to assess the effects of Dasatinib and Quercetin (DQ) senolytic treatment on DNA methylation (DNAm), epigenetic age, and immune cell subsets. In a Phase I pilot study, 19 participants received DQ for 6 months, with DNAm measured at baseline, 3 months, and 6 months. Significant increases in epigenetic age acceleration were observed in first-generation epigenetic clocks and mitotic clocks at 3 and 6 months, along with a notable decrease in telomere length. However, no significant differences were observed in second and third-generation clocks. Building upon these findings, a subsequent investigation evaluated the combination of DQ with Fisetin (DQF), a well-known antioxidant and antiaging senolytic molecule. After one year, 19 participants (including 10 from the initial study) received DQF for 6 months, with DNAm assessed at baseline and 6 months. Remarkably, the addition of Fisetin to the treatment resulted in non-significant increases in epigenetic age acceleration, suggesting a potential mitigating effect of Fisetin on the impact of DQ on epigenetic aging. Furthermore, our analyses unveiled notable differences in immune cell proportions between the DQ and DQF treatment groups, providing a biological basis for the divergent patterns observed in the evolution of epigenetic clocks. These findings warrant further research to validate and comprehensively understand the implications of these combined interventions.

Objective: Surgery for spinal deformity has the potential to improve pain, disability, function, self-image, and mental health. These surgical procedures carry significant risk and require careful selection, optimization, and risk assessment. Epigenetic clocks are age estimation tools derived by measuring the methylation patterns of specific DNA regions. The study of biological age in the adult deformity population has the potential to shed insight onto the molecular basis of frailty and to improve current risk assessment tools., Methods: Adult patients who underwent deformity surgery were prospectively enrolled. Preoperative whole blood samples were used to assess epigenetic age and telomere length. DNA methylation patterns were quantified and processed to extract 4 principal component (PC)-based epigenetic age clocks (PC Horvath, PC Hannum, PC PhenoAge, and PC GrimAge) and the instantaneous pace of aging (DunedinPACE). Telomere length was assessed using both quantitative polymerase chain reaction (telomere to single gene [T/S] ratio) and a methylation-based telomere estimator (PC DNAmTL). Patient demographic and surgical data included age, BMI, American Society of Anesthesiologists Physical Status Classification System class, and scores on the Charlson Comorbidity Index, adult spinal deformity frailty index (ASD-FI), Edmonton Frail Scale (EFS), Oswestry Disability Index, and Scoliosis Research Society-22r questionnaire (SRS-22r). Medical or surgical complications within 90 days of surgery were collected. Spearman correlations and beta coefficients (β) from linear regression, adjusted for BMI and sex, were calculated., Results: Eighty-three patients were enrolled with a mean age of 65 years, and 45 were women (54%). All patients underwent posterior fusion with a mean of 11 levels fused and 33 (40%) 3-column osteotomies were performed. Among the epigenetic clocks adjusted for BMI and sex, DunedinPACE showed a significant association with ASD-FI (β = 0.041, p = 0.002), EFS (β = 0.696, p = 0.026), and SRS-22r (β = 0.174, p = 0.013) scores. PC PhenoAge showed associations with ASD-FI (β = 0.029, p = 0.028) and SRS-22r (β = 0.159, p = 0.018) scores. PC GrimAge showed associations with ASD-FI (β = 0.029, p = 0.037) and SRS-22r (β = 0.161, p = 0.025) scores. Patients with postoperative complications were noted to have shorter telomere length (T/S 0.790 vs 0.858, p = 0.049), even when the analysis controlled for BMI and sex (OR = 1.71, 95% CI 1.07-2.87, p = 0.031)., Conclusions: Epigenetic clocks showed significant associations with markers of frailty and disability, while patients with postoperative complications had shorter telomere length. These data suggest a potential role for aging biomarkers as components of surgical risk assessment. Integrating biological age into current risk calculators may improve their accuracy and provide valuable information for patients, surgeons, and payers.