Exercise training is one of the few therapeutic interventions that improves health span by delaying the onset of age-related diseases and preventing early death. The length of telomeres, the 5′-TTAGGGn-3′ tandem repeats at the ends of mammalian chromosomes, is one of the main indicators of biological age. Telomeres undergo shortening with each cellular division. This subsequently leads to alterations in the expression of several genes that encode vital proteins with critical functions in many tissues throughout the body, and ultimately impacts cardiovascular, immune and muscle physiology. The sub-telomeric DNA is comprised of heavily methylated, heterochromatin. Methylation and histone acetylation are two of the most well-studied examples of the epigenetic modifications that occur on histone proteins. DNA methylation is the type of epigenetic modification that alters gene expression without modifying gene sequence. Although diet, genetic predisposition and a healthy lifestyle seem to alter DNA methylation and telomere length (TL), recent evidence suggests that training status or physical fitness are some of the major factors that control DNA structural modifications. In fact, TL is positively associated with cardiorespiratory fitness, physical activity level (sedentary, active, moderately trained, or elite) and training intensity, but is shorter in over-trained athletes. Similarly, somatic cells are vulnerable to exercise-induced epigenetic modification, including DNA methylation. Exercise-training load, however, depends on intensity and volume (duration and frequency). Training load-dependent responses in genomic profiles could underpin the discordant physiological and physical responses to exercise. In the current review, we will discuss the role of various forms of exercise training in the regulation of DNA damage, TL and DNA methylation status in humans, to provide an update on the influence exercise training has on biological aging.

Aging is associated with progressive and site-specific changes in DNA methylation (DNAm). These global changes are captured by DNAm clocks that accurately predict chronological age in humans but relatively little is known about how clocks perform in vitro. Here we culture primary human fibroblasts across the cellular lifespan (∼6 months) and use four different DNAm clocks to show that age-related DNAm signatures are conserved and accelerated in vitro. The Skin & Blood clock shows the best linear correlation with chronological time (r=0.90), including during replicative senescence. Although similar in nature, the rate of epigenetic aging is approximately 62x times faster in cultured cells than in the human body. Consistent with in vivo data, cells aged under hyperglycemic conditions exhibit an approximately three years elevation in baseline DNAm age. Moreover, candidate gene-based analyses further corroborate the conserved but accelerated biological aging process in cultured fibroblasts. Fibroblasts mirror the established DNAm topology of the age-related ELOVL2 gene in human blood and the rapid hypermethylation of its promoter cg16867657, which correlates with a linear decrease in ELOVL2 mRNA levels across the lifespan. Using generalized additive modeling on twelve timepoints across the lifespan, we also show how single CpGs exhibit loci-specific, linear and nonlinear trajectories that reach rates up to −47% (hypomethylation) to +23% (hypermethylation) per month. Together, these high temporal resolution global, gene-specific, and single CpG data highlight the conserved and accelerated nature of epigenetic aging in cultured fibroblasts, which may constitute a system to evaluate age-modifying interventions across the lifespan. Graphical Abstract

The dynamic nature of epigenetic modifications has been leveraged to construct epigenetic clocks that accurately predict an individual’s age based on DNA methylation levels. Here we explore whether the accumulation of epimutations, which can be quantified by Shannon’s entropy, changes reproducibly with age. Using targeted bisulfite sequencing, we analyzed the associations between age, entropy, and methylation levels in human buccal swab samples. We find that epigenetic clocks based on the entropy of methylation states predict chronological age with similar accuracy as common approaches that are based on methylation levels of individual cytosines. Our approach suggests that across many genomic loci, methylation entropy changes reproducibly with age.

Aging involves widespread epigenetic remodeling across tissues, yet the nature and consistency of these changes remain unclear. We conducted a meta-analysis of more than 15,000 human methylomes spanning 17 tissues, identifying both conserved and tissue-specific aging signatures. We examined linear changes via differentially methylated positions, variability shifts via variably methylated positions, and Shannon-entropy to capture methylation disorder. Network analysis revealed fragile co-methylation modules largely resistant to beneficial perturbation. Key disruptors, including PCDHGA1, MEST, HDAC4, and HOX genes, exacerbated aging signals across tissues. Notably, a resilient module enriched for NAD□ salvage metabolism supports therapeutic targeting of NAD□ in aging. PCDHGA1 emerged as a conserved cross-tissue driver, suggesting protocadherin-mediated adhesion plays a broader role in maintaining structural and signaling stability in multiple organ systems. Our open-access atlas provides a foundational resource for dissecting the molecular architecture of human aging and identifying testable targets for intervention, biomarkers, and translational epigenetic therapies.

Objective: To review somatic genetic changes in nephrogenic rests (NR), which are considered to be precursor lesions of Wilms tumors (WT). Methods: This systematic review is written according to the PRISMA statement. PubMed and EMBASE were systematically searched for articles in the English language studying somatic genetic changes in NR between 1990 and 2022. Results: Twenty-three studies were included in this review, describing 221 NR of which 119 were pairs of NR and WT. Single gene studies showed mutations in WT1 and WTX, but not CTNNB1 to occur in both NR and WT. Studies investigating chromosomal changes showed loss of heterozygosity of 11p13 and 11p15 to occur in both NR and WT, but loss of 7p and 16q occurred in WT only. Methylome-based studies found differential methylation patterns between NR, WT, and normal kidney (NK). Conclusions: Over a 30-year time frame, few studies have addressed genetic changes in NR, likely hampered by technical and practical limitations. A limited number of genes and chromosomal regions have been implicated in the early pathogenesis of WT, exemplified by their occurrence in NR, including WT1, WTX, and genes located at 11p15. Further studies of NR and corresponding WT are urgently needed.

Hepatic xenobiotic metabolism and transport decline with age, while intact xenobiotic metabolism is associated with longevity. However, few studies have examined the genome-wide impact of epigenetic aging on these processes. We used reduced representation bisulfite sequencing (RRBS) to map DNA methylation changes in liver DNA from mice ages 4 and 24 months. We identified several thousand age-associated differentially methylated sites (a-DMS), many of which overlapped genes encoding Phase I and Phase II drug metabolizing enzymes, in addition to ABC and SLC classes of transporters. Notable genes harboring a-DMS were Cyp1a2, Cyp2d9, and Abcc2 that encode orthologs of the human drug metabolizing enzymes CYP1A2 and CYP2D6, and the multidrug resistance protein 2 (MRP2) transporter. Cyp2d9 hypermethylation with age was significantly associated with reduced gene expression, while Abcc2 expression was unchanged with age. Cyp1a2 lost methylation with age while, counterintuitively, its expression also reduced with age. We hypothesized that age-related dysregulation of the hepatic transcriptional machinery caused down-regulation of genes despite age-related hypomethylation. Bioinformatic analysis of hypomethylated a-DMS in our sample found them to be highly enriched for hepatic nuclear factor 4 alpha (HNF4α) binding sites. HNF4α promotes Cyp1a2 expression and is downregulated with age, which could explain the reduction in Cyp1a2 expression. Overall, our study supports the broad impact of epigenetic aging on xenobiotic metabolism and transport. Future work should evaluate the interplay between hepatic nuclear receptor function and epigenetic aging. These results may have implications for studies of longevity and healthy aging.

Abstract This study is the first systematic meta-analysis of epigenetic age acceleration of the largest publicly available DNA methylation data for healthy samples (93 datasets, 23K samples), focusing on geographic and ethnic aspects of different countries (25 countries) and populations (31 ethnicities) around the world. The most popular epigenetic tools for assessing age acceleration were examined in detail, their quality metrics were analyzed, and their ability to extrapolate to epigenetic data from different tissue types and age ranges different from the training data of these models was explored. In most cases, the models are not consistent with each other and show different signs of age acceleration, with the PhenoAge model tending to systematically underestimate and different versions of the GrimAge model tending to systematically overestimate the age prediction of healthy subjects. Although GEO is the largest open-access epigenetic database, most countries and populations are not represented, and different datasets use different criteria for determining healthy controls. Because of this, it is difficult to fully isolate the contribution of “geography/environment”, “ethnicity” and “healthiness” to epigenetic age acceleration. However, the DunedinPACE metric, which measures aging rate, adequately reflects the standard of living and socioeconomic indicators in countries, although it can be applied only to blood methylation data. When comparing epigenetic age acceleration, males age faster than females in most of the countries and populations considered.

Ageing is a crucial factor in the development of chronic lung diseases, including COPD, idiopathic pulmonary fibrosis, and lung cancer. Marking the 10th anniversary of the original "Hallmarks of the ageing lung" published in this journal, we present an updated review highlighting key cellular and molecular features of ageing that drive the onset and progression of these conditions. Ageing stands as the most significant risk factor for chronic lung diseases, which are characterised by structural and functional changes such as reduced elasticity, persistent inflammation, and impaired repair capacity. Recent evidence confirms that nearly all recognised hallmarks of ageing play a role in the pathogenesis of these diseases. Notably, extracellular matrix dysregulation, first proposed as a lung ageing hallmark in 2015, has become an integral aspect of ageing in lung disease. Environmental exposures, such as cigarette or wildfire smoke, accelerate age-related changes by increasing oxidative stress, promoting cellular senescence, and disrupting tissue homeostasis. In lung cancer, ageing contributes to genomic alterations, epigenetic dysregulation, immune evasion and therapeutic resistance. Additionally, the roles of extracellular vesicles and microbiome changes in shaping these ageing phenotypes are emerging areas of research. Early clinical studies are now targeting specific ageing hallmarks, such as cellular senescence, with the goal of reducing age-related pathology and improving outcomes. Overall, integrating ageing biology into lung disease research paves the way for innovative diagnostic and therapeutic strategies that address common molecular mechanisms across multiple chronic lung conditions.

Summary Induced pluripotent stem cells (IPSCs), with their unlimited regenerative capacity, carry the promise for tissue replacement to counter age-related decline. However, attempts to realise in vivo iPSC have invariably resulted in the formation of teratomas. Partial reprogramming in prematurely aged mice has shown promising results in alleviating age-related symptoms without teratoma formation. Does partial reprogramming lead to rejuvenation (i.e. “younger” cells), rather than dedifferentiation, which bears the risk of cancer? Here we analyse the dynamics of cellular age during human iPSC reprogramming and find that partial reprogramming leads to a reduction in the epigenetic age of cells. We also find that the loss of somatic gene expression and epigenetic age follow different kinetics, suggesting that they can be uncoupled and there could be a safe window where rejuvenation can be achieved with a minimised risk of cancer.

cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance betwe Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abnormal cell division. Cell division is a physiological process that occurs in almost all tissues and under a variety of circumstances. Normally, the balance between proliferation and programmed cell death, in the form of apoptosis, is maintained to ensure the integrity of tissues and organs. According to the prevailing accepted theory of carcinogenesis, the somatic mutation theory, mutations in DNA and epimutations that lead to cancer disrupt these orderly processes by interfering with the programming regulating the processes, upsetting the normal balance between proliferation and cell death. This results in uncontrolled cell division and… J… While genetic and epigenetic alterations in tumor suppressor genes and oncogenes change the behavior of cells, those alterations, in the end, result in cancer through their effects on the population of neoplastic cells and their microenvironment. Mutant cells in neoplasms compete for space and resources. Thus, a clone with a mutation in a tumor suppressor gene or oncogene will expand only in a neoplasm if that mutation gives the clone a competitive advantage over the other clones and normal cells in its microenvironment. Thus, the process of carcinogenesis is formally a process of Darwinian evolution, known as somatic or clonal evolution. Furthermore, in light of the Darwinistic mechanisms of carcinogenesis, it has been theorized that the various forms of cancer can be categorized as pubertal and gerontological. Anthropological research is currently being conducted on cancer as a natural evolutionary process through which natural selection destroys environmentally inferior phenotypes while supporting others. According to this theory, cancer comes in two separate types: from birth to the end of puberty (approximately age 20) teleologically inclined toward supportive group dynamics, and from mid-life to death (approximately age 40+) teleologically inclined away from overpopulated group dynamics.