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DNA methylation is one of the epigenetic modifications of the genome, the essence of which is the attachment of a methyl group to nitrogenous bases. In the eukaryote genome, cytosine is methylated in the vast majority of cases. About 98% of cytosines are methylated as part of CpG dinucleotides. They, in turn, form CpG islands, which are clusters of these dinucleotides. Islands located in the regulatory elements of genes are in particular interest. They are assumed to play an important role in the regulation of gene expression in humans. Besides that, cytosine methylation serves the functions of genomic imprinting, transposon suppression, epigenetic memory maintenance, X- chromosome inactivation, and embryonic development. Of particular interest are the enzymatic processes of methylation and demethylation. The methylation process always depends on the work of enzymatic complexes and is very precisely regulated. The methylation process largely depends on the functioning of three groups of enzymes: writers, readers and erasers. Writers include proteins of the DNMT family, readers are proteins containing the MBD, BTB/POZ or SET- and RING-associated domains and erasers are proteins of the TET family. Whereas demethylation can be performed not only by enzymatic complexes, but also passively during DNA replication. Hence, the maintenance of DNA methylation is important. Changes in methylation patterns are observed during embryonic development, aging, and cancers. In both aging and cancer, massive hypomethylation of the genome with local hypermethylation is observed. In this review, we will review the current understanding of the mechanisms of DNA methylation and demethylation in humans, the structure and distribution of CpG islands, the role of methylation in the regulation of gene expression, embryogenesis, aging, and cancer development.

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BACKGROUND: DNA analysis for forensic investigations has a long tradition with important developments and optimizations since its first application. Traditionally, short tandem repeats analysis has been the most powerful method for the identification of individuals. However, in addition, epigenetic changes, i.e., DNA methylation, came into focus of forensic DNA research. Chronological age prediction is one promising application to allow for narrowing the pool of possible individuals who caused a trace, as well as to support the identification of unknown bodies and for age verification of living individuals. OBJECTIVE: This review aims to provide an overview of the current knowledge, possibilities, and (current) limitations about DNA methylation-based chronological age prediction with emphasis on forensic application. METHODS: The development, implementation and application of age prediction tools requires a deep understanding about the biological background, the analysis methods, the age-dependent DNA methylation markers, as well as the mathematical models for age prediction and their evaluation. Furthermore, additional influences can have an impact. Therefore, the literature was evaluated in respect to these diverse topics. CONCLUSION: The numerous research efforts in recent years have led to a rapid change in our understanding of the application of DNA methylation for chronological age prediction, which is now on the way to implementation and validation. Knowledge of the various aspects leads to a better understanding and allows a more informed interpretation of DNAm quantification results, as well as the obtained results by the age prediction tools.

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Most oral health care providers encounter older adults in their practices and can play a critical role in supporting independence and quality of life for this aging cohort. Physiologic and structural oral cavity changes associated with normal aging may affect the presentation and oral health care of older adults. This article reviews the normative aging of dentition and oral structures and physiologic changes associated with normal aging, including cardiovascular, metabolic, and musculoskeletal changes, and how they may affect oral health. Oral health providers should be aware of normal aging processes when they plan care or schedule procedures for older adults.

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Postural control is a complex sensorimotor skill that is fundamental to our daily life. The abilities to maintain and recover balance degrade with age. However, the time decay of balance performance with age is not well understood. In this study, we aim at quantifying the age-dependent changes in standing balance under static and dynamic conditions. We tested 272 healthy subjects with ages ranging from 20 to 90. Subjects maintained the upright posture while standing on the robotic platform hunova®. In the evaluation of static balance, subjects stood on the fixed platform both with eyes open (EO) and eyes closed (EC). In the dynamic condition, subjects stood with eyes open on the moving foot platform that provided three different perturbations: (i) an inclination proportional to the center of pressure displacements, (ii) a pre-defined predictable motion, and (iii) an unpredictable and unexpected tilt. During all these tests, hunova® measured the inclination of the platform and the displacement of the center of pressure, while the trunk movements were recorded with an accelerometer placed on the sternum. To quantify balance performance, we computed spatio-temporal parameters typically used in clinical environments from the acceleration measures: mean velocity, variability of trunk motion, and trunk sway area. All subjects successfully completed all the proposed exercises. Their motor performance in the dynamic balance tasks quadratically changed with age. Also, we found that the reliance on visual feedback is not age-dependent in static conditions. All subjects well-tolerated the proposed protocol independently of their age without experiencing fatigue as we chose the timing of the evaluations based on clinical needs and routines. Thus, this study is a starting point for the definition of robot-based assessment protocols aiming at detecting the onset of age-related standing balance deficits and allowing the planning of tailored rehabilitation protocols to prevent falls in older adults.

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Fish as model objects have found wide applications in biology and fundamental medicine and allow studies of behavioral and physiological responses to various environmental factors. Representatives of the genus Nothobranchius are one of the most convenient objects for such studies. Male fish belonging to the family Nothobranchiidae are characterized by extremely diverse coloration, which constantly changes, depending on the age of the fish, environmental factors, and social hierarchical status. These fish species are characterized by a short life cycle, which allows changes in coloration, an indicator of the ontogenesis stage, to be estimated. Existing methods of fish color assessments do not allow the intensity of coloration of particular body zones to be clearly differentiated. In the present study, we suggest a method of two-factor assessment of specific fish body zones using modified methods of photofixation and image processing software. We describe the protocol of the method and the results of its application to different-aged groups of male Nothobranchius guentheri. The coloration of selected areas (i.e., red spot on the gill cover (RSGC), black border on the caudal fin (BBCF), and white border on the dorsal fin (WBDF)) differed significantly according to the size and age of the fish (p < 0.05). The data obtained suggest that N. guentheri can be a model for studying aging by the intensity of body coloration in males.

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Most oral health care providers encounter older adults in their practices and can play a critical role in supporting independence and quality of life for this aging cohort. Physiologic and structural oral cavity changes associated with normal aging may affect the presentation and oral health care of older adults. This article reviews the normative aging of dentition and oral structures and physiologic changes associated with normal aging, including cardiovascular, metabolic, and musculoskeletal changes, and how they may affect oral health. Oral health providers should be aware of normal aging processes when they plan care or schedule procedures for older adults.

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BACKGROUND: The mortality of nasopharyngeal carcinoma (NPC) is usually lower in females than in males, but the underlying mechanism remains largely unknown. We sought to describe the age-dependent patterns of gender disparities in NPC survival and explore the extent to which the confounder or mediation effects could explain these differences. METHODS: A total of 11,980 patients with NPC were reviewed. The effect of gender on cancer-specific survival (CSS) was assessed using Cox regression analyses. Two propensity score methods were conducted to control the confounding bias between genders. Restricted cubic spline regression was used to model the association of gender and age with mortality flexibly. Multiple mediation analysis was applied to estimate the direct or indirect effect of gender on CSS. RESULTS: Overall, 7026 males and 2320 females were analyzed. The crude CSS was significantly higher for females than males (10-year CSS 78.4% vs 70.3%; P < 0.001). Similar results were observed after adjusting for confounding bias. Gender disparities in NPC-specific mortality were age-dependent, where they would increase with age until peaking at age 55-60 years and decline rapidly afterward. Subgroup analyses revealed that females' survival advantage was observed in the 18-45 age group and was more prominent in the 46-55 age group, but vanished in the > 55 age group. Either confounder or mediation effects only accounted for approximately 20% of the gender differences. CONCLUSIONS: Gender disparities in cancer-specific mortality for patients with NPC were age-dependent. The differences mostly cannot be explained by confounder or mediation effects.

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For the first time proteins are described, reliably increasing and decreasing in urine with age in the range of 20 to 60 years. The combinations of proteins associated with changes in immune processes, violation of blood reology, including the risk of coagulopathy, anticancer defense mechanisms, insulin signaling pathway, changes in cell characteristics are characterized division and quality of the newly formed fabric. Thus, the age dynamics of the main processes triggers a cascade of reactions manifested in the closure of «pathological biochemical circles¼ that form the prerequisites for the development of diseases and, over time, clinical manifestations.

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Mutations in LRRK2 cause familial Parkinson's disease and common variants increase disease risk. LRRK2 kinase activity and cellular localization are tightly regulated by phosphorylation of key residues, primarily Ser1292 and Ser935, which impacts downstream phosphorylation of its substrates, among which Rab10. A comprehensive characterization of LRRK2 activity and phosphorylation in brain as a function of age and mutations is missing. Here, we monitored Ser935 and Ser1292 phosphorylation in midbrain, striatum, and cortex of 1, 6, and 12 months-old mice carrying G2019S and R1441C mutations or murine bacterial artificial chromosome (BAC)-Lrrk2-G2019S. We observed that G2019S and, at a greater extent, R1441C brains display decreased phospho-Ser935, while Ser1292 autophosphorylation increased in G2019S but not in R1441C brain, lung, and kidney compared to wild-type. Further, Rab10 phosphorylation, is elevated in R1441C carrying mice, indicating that the effect of LRRK2 mutations on substrate phosphorylation is not generalizable. In BAC-Lrrk2-G2019S striatum and midbrain, Rab10 phosphorylation, but not Ser1292 autophosphorylation, decreases at 12-months, pointing to autophosphorylation and substrate phosphorylation as uncoupled events. Taken together, our study provides novel evidence that LRRK2 phosphorylation in mouse brain is differentially impacted by mutations, brain area, and age, with important implications as diagnostic markers of disease progression and stratification.

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OBJECTIVES: To quantify the morphological correlation between the posterior cruciate ligament (PCL) and the meniscofemoral ligaments (MFLs), to propose normal ranges for different age populations, and to define guidelines for correct identification and differentiation of MFLs in routine MRI. METHODS: Three hundred forty-two subjects were included retrospectively and subdivided into five age groups. Morphometrics of the PCL and the MFLs were measured on standard MRI in the sagittal, coronal, and axial planes. Student's t test, Mann-Whitney U test, and ANOVA and Kruskal-Wallis tests with Bonferroni correction were used for comparison. RESULTS: The MFLs did not vary significantly between sexes (p > 0.05) or in those older than 10 years (p > 0.05). Longitudinal MFL growth is completed before age 11 years, with cross-sectional area (CSA) increasing until age 20. The CSA of the PCL was significantly (p = 0.028) larger in knees without a pMFL (Mdn = 39.7 mm2) than with a pMFL (Mdn = 35.4 mm2). MFLs were more often detected on sagittal than coronal images. CONCLUSIONS: This study describes the morphometric relation between the PCL and the MFLs on routine MRI. When reporting imaging findings in preparation for arthroscopic knee surgery, evaluation of MFLs, first in the sagittal and then the coronal plane, will achieve the best results. KEY POINTS: • The MFLs and the PCL have distinct morphological patterns throughout life. • These patterns show intimate anatomical relationships and a potential biomechanical impact. • Those patterns and relationships can be quantified with MRI. • A correlation exists between age and morphometrics of the MFLs. • Recommendations for correct identification of the MFLs are provided.

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Most infant deaths occur in the first year of life. Yet, our knowledge of immune development during this period is scarce and derived from cord blood (CB) only. To more effectively combat pediatric diseases, a deeper understanding of the kinetics and the factors that regulate the maturation of immune functions in early life is needed. Increased disease susceptibility of infants is generally attributed to T helper 2-biased immune responses. The differentiation of CD4+ T cells along a specific T helper cell lineage is dependent on the pathogen type, and on costimulatory and cytokine signals provided by antigen-presenting cells. Cytokines also regulate many other aspects of the host immune response. Therefore, toward the goal of increasing our knowledge of early immune development, we defined the temporal development of the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signaling function of CD4+ T cells using cross-sectional blood samples from healthy infants ages 0 (birth) to 14 months. We specifically focused on cytokines important in T cell differentiation (IFN-γ, IL-12, and IL-4) or in T cell survival and expansion (IL-2 and IL-7) in infant CD4+ T cells. Independent of the cytokine tested, JAK/STAT signaling in infant compared to adult CD4+ T cells was impaired at birth, but increased during the first year, with the most pronounced changes occurring in the first 6 months. The relative change in JAK/STAT signaling of infant CD4+ T cells with age was distinct for each cytokine tested. Thus, while about 60% of CB CD4+ T cells could efficiently activate STAT6 in response to IL-4, less than 5% of CB CD4+ T cells were able to activate the JAK/STAT pathway in response to IFN-γ, IL-12 or IL-2. By 4-6 months of age, the activation of the cytokine-specific STAT molecules was comparable to adults in response to IL-4 and IFN-γ, while IL-2- and IL-12-induced STAT activation remained below adult levels even at 1 year. These results suggest that common developmental and cytokine-specific factors regulate the maturation of the JAK/STAT signaling function in CD4+ T cells during the first year of life.

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We compared the calling and mating behavior and volatile release of wild males Anastrepha ludens (Loew) with males from 4 mass-reared strains: (i) a standard mass-reared colony (control), (ii) a genetic sexing strain (Tap-7), (iii) a colony started from males selected on their survival and mating competitiveness abilities (selected), and (iv) a hybrid colony started by crossing wild males with control females. Selected and wild males were more competitive, achieving more matings under field cage conditions. Mass-reared strains showed higher percentages of pheromone calling males under field conditions except for Tap-7 males, which showed the highest percentages of pheromone calling males under laboratory cage conditions. For mature males of all strains, field-cage calling behavior increased during the last hour before sunset, with almost a 2 fold increase exhibited by wild males during the last half hour. The highest peak mating activity of the 4 mass-reared strains occurred 30 min earlier than for wild males. By means of solid phase microextraction (SPME) plus gas chromatography-mass spectrometry (GC-MS), the composition of volatiles released by males was analyzed and quantified. Wild males emitted significantly less amounts of (E,E)-α-farnesene but emitted significantly more amounts of (E,E)-suspensolide as they aged than mass-reared males. Within the 4 mass-reared strains, Tap-7 released significantly more amounts of (E,E)-α-farnesene and hybrid more of (E,E)-suspensolide. Differences in chemical composition could be explained by the intrinsic characteristics of the strains and the colony management regimes. Characterization of calling behavior and age changes of volatile composition between wild and mass-reared strains could explain the differences in mating competitiveness and may be useful for optimizing the sterile insect technique in A. ludens.

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Aging is accompanied by progressive dysfunction of mitochondria associated with a continuous decrease of their capacity to produce ATP. Mitochondria isolated from brain of aged animals show an increased mitochondrial permeability transition pore (mPTP) opening. We recently detected new regulators of mPTP function in brain mitochondria, the enzyme 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) and its substrates 2', 3'-cAMP and 2', 3'-cNADP, and the neuronal protein p42(IP4). Here, we compared parameters of mPTP opening in non-synaptic brain mitochondria isolated from young and old rats. In mitochondria from old rats (>18 months), mPTP opening occurred at a lower threshold of Ca(2+) concentration than in mitochondria from young rats (<3 months). mPTP opening in mitochondria from old rats was accelerated by 2', 3'-cAMP, which further lowered the threshold Ca(2+) concentration. In non-synaptic mitochondria from old rats, the CNP level was decreased by 34%. Lowering of the CNP level in non-synaptic mitochondria with aging was accompanied by decreased levels of voltage-dependent anion channel (VDAC; by 69%) and of p42(IP4) (by 59%). Thus, reduced levels of CNP in mitochondria could lead to a rise in the concentration of the mPTP promoter 2', 3'-cAMP. The level of CNP and p42(IP4) and, probably VDAC, might be essential for myelination and electrical activity of axons. We propose that in aging the reduction in the level of these proteins leads to mitochondrial dysfunction, in particular, to a decreased threshold Ca(2+) concentration to induce mPTP opening. This might represent initial steps of age-related mitochondrial dysfunction, resulting in myelin and axonal pathology.

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This article reviews the concepts of physiologic reserve, the principles of the normative aging process as exemplified by the cardiovascular, neurologic, and musculoskeletal systems. How these principles apply to oral health, and age-related changes in the oral cavity itself, is reviewed and suggests how they may affect disease management by oral health care providers. It does not focus on diseases related to aging, but rather aims to explore the normal physiologic changes associated with aging dentition and systemic changes related to age, thus enabling clinicians to obtain a better understanding of the presentation of older adults and how it may change their approach to diagnosis and treatment.

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OBJECTIVE: This study has assessed age-related changes of foot morphology for developing appropriate footwear with particular reference to the elderly. METHODS: Anatomical parameters such as foot length, circumference and height and ankle length, circumference and height were assessed in a sample of males (n=577) and females (n=528) divided into three age groups. The groups included young-adult, aged between 20 and 25 years; adult, aged between 35 and 55 years; and old, aged between 65 and 70 years individuals. RESULTS: In terms of gender differences, in young-adult individuals the sex-related morphological differences observed, are just related to a significantly lower length of foot in females. In adult subjects morphological parameters investigated were significantly lower in females even after normalization for foot length. In old individuals, no differences of the parameters were found after normalization for foot length. Comparative analysis of morphometric data between young-adult and adult individuals revealed that the instep length was smaller in adults. The opposite was observed for the great toe and medial foot arch height. Length of ankle was higher in adult than in young-adult individuals, whereas ankle circumference and height were smaller. In old vs adult individuals foot circumference showed the most relevant age-related differences. CONCLUSIONS: Feet anatomy presents specific characteristics in different ages of life. The ideal footwear should take into account these characteristics. This is true primarily for the elderly for minimizing the risk of falls or of other problems related to inappropriate footwear.

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OBJECTIVE: This study examined the temporal congruency between real and imagined movements and explored intermanual transfer effects in healthy subjects. METHODS: Seventy-six right-handed healthy subjects were allocated to three age groups and tested with a modified version of the Box and Block Test (BBT). We focussed on two aspects. First, the BBT was evaluated with respect to its ability to assess MC. Second, we were interested whether performance of motor imagery (MI) and real execution with one hand would modify performance with the other hand. To explore MC, we measured motor execution (ME) time as the time needed to perform the BBT, and MC time as the time difference between ME and the time needed for imagination of task execution. The BBT was performed with both hands consecutively to study transfer effects from one hand to the other and then repeated with the first hand for practice effects. RESULTS: The age group with the oldest subjects exhibited a slower BBT performance and a less precise MC than the other 2 age groups. Irrespective of the age, MC abilities could be transferred to the other hand, whereas ME only improved when repeating the task with the same hand. CONCLUSIONS: The BBT was able to demonstrate an age-related decline of dexterity and MC. Intermanual transfer of MI abilities occurred even after a single run.

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It is still widely believed that exaggerated stretch reflexes and increased muscle tone in ankle plantar flexors contribute to reduced ankle joint movement during gait in children with cerebral palsy (CP). However, no study has directly measured stretch reflex activity during gait in these children. We investigated sensory feedback mechanisms during walking in 20 CP children and 41 control children. Stretch responses in plantar flexor muscles evoked in stance showed an age-related decline in control but not CP children. In swing the responses were abolished in control children, but significant responses were observed in 14 CP children. This was related to reduced activation of dorsiflexors in swing. Removal of sensory feedback in stance produced a drop in soleus activity of a similar size in control and CP children. Soleus activity was observed in swing to the same extent in control and CP children. Removal of sensory feedback in swing caused a larger drop in soleus activity in control children than in CP children. The lack of age-related decline in stretch reflexes and the inability to suppress reflexes in swing is likely related to lack of maturation of corticospinal control in CP children. Since soleus activity was not seen more frequently than in control children in swing and since sensory feedback did not contribute more to their soleus activity, spasticity is unlikely to contribute to foot drop and toe walking. We propose that altered central drive to the ankle muscles and increased passive muscle stiffness are the main causes of foot drop and toe walking.

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