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Comparative studies of mortality in the wild are necessary to understand the evolution of aging; yet, ectothermic tetrapods are underrepresented in this comparative landscape, despite their suitability for testing evolutionary hypotheses. We present a study of aging rates and longevity across wild tetrapod ectotherms, using data from 107 populations (77 species) of nonavian reptiles and amphibians. We test hypotheses of how thermoregulatory mode, environmental temperature, protective phenotypes, and pace of life history contribute to demographic aging. Controlling for phylogeny and body size, ectotherms display a higher diversity of aging rates compared with endotherms and include phylogenetically widespread evidence of negligible aging. Protective phenotypes and life-history strategies further explain macroevolutionary patterns of aging. Analyzing ectothermic tetrapods in a comparative context enhances our understanding of the evolution of aging. [ABSTRACT FROM AUTHOR]

People are living longer, but lifespan increase does not coincide with a boost in health-span. Thus, improving the quality of life of older people is a priority. Centenarians reach extreme longevity in a relatively good health status, escaping or delaying fatal or strongly invalidating diseases. Therefore, studying processes involved in longevity is important to explain the biological mechanisms of health and well-being, since knowledge born from this approach can provide valuable information on how to slow aging. We performed the present study in a well characterized very homogeneous sample of 173 people from Western Sicily, to update existing literature on some phenotypic aspects of aging and longevity and to propose a range of values for older people. We classified 5 age groups, from young adults to centenarians, to understand the age and gender-related variations of the different parameters under study. We collected anamnestic data and performed anthropometric, bioimpedance, molecular, haematological, oxidative, and hematochemical tests, adopting a multidimensional analysis approach. An important evidence of the present study is that there are differences related to both age and gender in several biomarkers. Indeed, gender differences seem to be still poorly considered and inadequately investigated in aging as well as in other medical studies. Moreover, we often observed comparable parameters between young and centenarians rather than non-agenarians and centenarians, hypothesizing a sort of slowdown, almost followed by a reversal trend, in the decay of systemic deterioration. The study of centenarians provides important indications on how to slow aging, with benefits for those who are more vulnerable to disease and disability. The identification of the factors that predispose to a long and healthy life is of enormous interest for translational medicine in an aging world. [ABSTRACT FROM AUTHOR]

Could biotechnology stop aging? The answer may be yes, no, or something in between, depending on who is being asked and what it means to “stop” aging. For those at one end of the spectrum— life extension seekers (including some deep-pocketed Silicon Valley investors)—the answer is “yes.” They believe biotechnology will lengthen human life spans to range anywhere from 1,000 years to forever. But for most, the answer is more nuanced and in- volves a dream of extended healthspan, rather than immortality. They imagine a future in which people over the age of 65 years are healthy, active, independent, and not burdened by disease, and that this is the norm rather than the exception. “Healthspanners” believe that one day, science will delay the onset of aging-related conditions and, as a side-effect, modestly extend life. Aging as we know it—and dread it—could become ancient history. [ABSTRACT FROM AUTHOR]

Background: Age-related changes in the sensorimotor system and cognition affect gait adaptation, especially when locomotion is combined with a cognitive task. Performing a dual-task can shift the focus of attention and thus require task prioritization, especially in older adults. To gain a better understanding of the age-related changes in the sensorimotor system, we examined how age and dual-tasking affect adaptive gait and task prioritization while walking on a split-belt treadmill. Methods: Young (21.5 ± 1.0 years, n = 10) and older adults (67.8 ± 5.8 years, n = 12) walked on a split-belt treadmill with a 2:1 belt speed ratio, with and without a cognitive Auditory Stroop task. Symmetry in step length, limb excursion, and double support time, and strategy variables swing time and swing speed were compared between the tied-belt baseline (BL), early (EA) and late split-belt adaptation (LA), and early tied-belt post-adaptation (EP). Results: Both age groups adapted to split-belt walking by re-establishing symmetry in step length and double support time. However, young and older adults differed on adaptation strategy. Older vs. young adults increased swing speed of the fast leg more during EA and LA (0.10–0.13 m/s), while young vs. older adults increased swing time of the fast leg more (2%). Dual-tasking affected limb excursion symmetry during EP. Cognitive task performance was 5–6% lower during EA compared to BL and LA in both age groups. Older vs. young adults had a lower cognitive task performance (max. 11% during EA). Conclusion: Healthy older adults retain the ability to adapt to split-belt perturbations, but interestingly age affects adaptation strategy during split-belt walking. This age-related change in adaptation strategy possibly reflects a need to increase gait stability to prevent falling. The decline in cognitive task performance during early adaptation suggests task prioritization, especially in older adults. Thus, a challenging motor task, like split-belt adaptation, requires prioritization between the motor and cognitive task to prevent adverse outcomes. This suggests that task prioritization and adaptation strategy should be a focus in fall prevention interventions. [ABSTRACT FROM AUTHOR]

A functional protein quality control machinery is crucial to maintain cellular and organismal physiology. Perturbation in the protein homeostasis network can lead to the formation of misfolded and aggregated proteins that are a hallmark of protein conformational disorders and aging. Protein aggregation is counteracted by the action of chaperones that can resolubilize aggregated proteins. An alternative protein aggregation clearance strategy is the elimination by proteolysis employing the ubiquitin proteasome system (UPS) or autophagy. Little is known how these three protein aggregate clearance strategies are regulated and coordinated in an organism with the progression of aging or upon expression of disease-associated proteins. To unravel the crosstalk between the protein aggregate clearance options, we investigated how autophagy and the UPS respond to perturbations in protein disaggregation capacity. We found that autophagy is induced as a potential compensatory mechanism, whereas the UPS exhibits reduced capacity upon depletion of disaggregating chaperones in C. elegans and HEK293 cells. The expression of amyloid proteins Aβ3–42 and Q40 result in an impairment of autophagy as well as the UPS within the same and even across tissues. Our data indicate a tight coordination between the different nodes of the proteostasis network (PN) with the progression of aging and upon imbalances of the capacity of each clearance mechanism. [ABSTRACT FROM AUTHOR]

Background: Aging is affected by genetic and environmental factors, and cigarette smoking is strongly associated with accumulation of senescent cells. In this study, we wanted to identify genes that may potentially be beneficial for cell survival in response to cigarette smoke and thereby may contribute to development of cellular senescence. Results: Primary human bronchial epithelial cells from five healthy donors were cultured, treated with or without 1.5% cigarette smoke extract (CSE) for 24 h or were passaged into replicative senescence. Transcriptome changes were monitored using RNA-seq in CSE and non-CSE exposed cells and those passaged into replicative senescence. We found that, among 1534 genes differentially regulated during senescence and 599 after CSE exposure, 243 were altered in both conditions, representing strong enrichment. Pathways and gene sets overrepresented in both conditions belonged to cellular processes that regulate reactive oxygen species, proteasome degradation, and NF-κB signaling. Conclusions: Our results offer insights into gene expression responses during cellular aging and cigarette smoke exposure, and identify potential molecular pathways that are altered by cigarette smoke and may also promote airway epithelial cell senescence. [ABSTRACT FROM AUTHOR]

Highlights • We review the evidence that major traumatic injury influences long term morbidity and mortality. • We propose that physical trauma may be accelerating ageing. • If ageing is accelerated, these patients could benefit from novel anti-ageing therapies. Abstract It is well established that numerous factors can affect the rate at which we age biologically. Diet, physical activity, lifestyle and our genes all play a major role in influencing the ageing trajectory and longevity. Major trauma affects millions globally, is the major cause of death in young adults and could influence ageing processes but has largely been ignored by biogenterologists. The long-term health consequences of physical trauma are well known in the medical community, how trauma effects the ageing process at a molecular level is not. It has long been difficult to assess ageing trajectories due to the absence of a biomarker of biological rather than chronological age. Recent advances in epigenetics have helped by identifying specific DNA methylation sites as good indicators of biological age. Recent investigations into the impact of psychological trauma and the associated physical stress on accelerating ageing as measured by epigenetic drift are promising. The physical and metabolic stress which is synonymous with physical trauma may also accelerate the ageing process. We suggest that long term epigenetic profiling is required to understand to what degree the ageing trajectory is altered by trauma, which will in turn add support for the development of novel therapies to improve health outcomes for survivors of traumatic injury. [ABSTRACT FROM AUTHOR]

The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors(age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80%and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging [ABSTRACT FROM AUTHOR]

While average human life expectancy has increased dramatically in the last century, the maximum life span has only modestly increased. These observations prompted the notion that human life span might have reached its maximal natural limit of ~115 years. To evaluate this hypothesis, we conducted a systematic analysis of all-cause human mortality throughout the 20th century. Our analyses revealed that, once cause of death is accounted for, there is a proportional increase in both median age of death and maximum life span. To examine whether pathway targeted aging interventions affected both median and maximum life span, we analyzed hundreds of interventions performed in multiple organisms (yeast, worms, flies, and rodents). Three criteria: median, maximum, and last survivor life spans were all significantly extended, and to a similar extent. Altogether, these findings suggest that targeting the biological/genetic causes of aging can allow breaking the currently observed ceiling of human maximal life span. [ABSTRACT FROM AUTHOR]

Gene expression in the aging brain depends on transcription signals generated by senescent physiology, interacting with genetic and epigenetic programs. In turn, environmental factors influence epigenetic mechanisms, such that an epigenetic–environmental link may contribute to the accumulation of cellular damage, susceptibility or resilience to stressors, and variability in the trajectory of age-related cognitive decline. Epigenetic mechanisms, DNA methylation and histone modifications, alter chromatin structure and the accessibility of DNA. Furthermore, small non-coding RNA, termed microRNA (miRNA) bind to messenger RNA (mRNA) to regulate translation. In this review, we examine key questions concerning epigenetic mechanisms in regulating the expression of genes associated with brain aging and age-related cognitive decline. In addition, we highlight the interaction of epigenetics with senescent physiology and environmental factors in regulating transcription. [ABSTRACT FROM AUTHOR]

Purpose: Insulin-like growth factor-1 (IGF-1) regulates protein synthesis and cell cycle kinetics. Given that aging is associated with anabolic resistance, we sought to determine if the attenuated exercise-induced satellite cell (SC) expression in older muscle is associated with a blunted IGF-1 response.Methods: SC expression (Pax7+ cells) and protein (Western blot) and mRNA (RT-PCR) expression of IGF-1 splice variants and ubiquitous (IGFBP4) and muscle-specific (IGFBP3 and -5) IGF-1 binding proteins were measured in skeletal muscle of young (Y: 22 ± 2, n = 7) and older (O: 70 ± 2, n = 7) adults up to 48 h after an acute bout of resistance exercise.Results: SC expression was greater in Y compared to O (age; P < 0.01) and increased (interaction; P < 0.05) by 24 h after exercise in Y only. IGF-1Ea and IGF-1Eb mRNA tended to be greater in O (age; P < 0.06-0.09). IGF-1Eb mRNA increased at 48 h (time; P < 0.05), whereas IGF-1Ec mRNA increased (interaction; P < 0.05) at 24 and 48 h in O only. IGF binding protein (IGFBP)4 mRNA was greater (age; P < 0.01) in O with the increase at 24 h and 48 h (time; P < 0.01) primarily driven by changes in O (interaction; P < 0.01). Despite IGFBP3 mRNA being greater in O (age; P < 0.01) and increasing at 48 h (time; P < 0.01), there was no effect of age or exercise on IGFBP3 protein expression. In contrast, IGFBP5 mRNA was greater (age; P < 0.01) despite IGFBP5 protein expression being lower (age; P < 0.01) in O compared to Y.Conclusions: The greater muscle-specific expression of IGF-1 family members with a blunted post-exercise SC expression may be a compensatory attempt to rescue age-related anabolic resistance. [ABSTRACT FROM AUTHOR]

Abstract Aims The aim of this study was to evaluate the effects of aging on intracellular adiponectin signaling and the possible therapeutic effect of physical exercise. Main methods Fischer 344 rats were distributed in the following groups: Young (3 months old); Sedentary Old (Old, 27 months old); and Old Exercised (Old-Exe, 27 months old), which were subjected to a short-term exercise training protocol. Key findings The results showed that the old rats presented glucose intolerance without increased adiposity. However, short-term exercise training reversed this disorder, which was associated with a decrease in the pleckstrin homology domain, phosphotyrosine-binding domain, and leucine zipper motif (APPL) isoform 2 (APPL2) content. The APPL isoform 1 (APPL1) and TRB3 (Tribbles homolog 3) contents were not altered. Akt phosphorylation was only increased in the old exercised rats. There was a reduction in the content of adiponectin receptor 1 in the old rats. Significance The short-term exercise training protocol was able to decrease APPL2 content in the skeletal muscle, which was accompanied by an improvement in the glucose tolerance of the old Fischer 344 rats. These findings provide new evidence supporting the role of physical exercise as a non-pharmacological therapeutic intervention to attenuate age-related deficits. [ABSTRACT FROM AUTHOR]

During evolution, Muller's ratchet permanently generates deleterious germline mutations that eventually must be defused by selection. It seems widely held that cancer and aging-related diseases (ARDs) cannot contribute to this germline gene selection because they tail reproduction and thus occur too late, at the end of the life cycle. Here we posit however that by lessening the offspring's survival by proxy through diminishing parental care, they can still contribute to the selection. The hypothesis in detail: The widespread occurrence of aging in animals suggests that it is an adaptation. But to what benefit? Aging seems to have only drawbacks. In humans, ARDs cause today almost all mortality; they include heart disease, cerebrovascular disease, Alzheimer's disease, kidney disease and cancer. Compensation seems unthinkable. For cancer, the author proposed in a previous study a benefit to the species: purifying selection against deleterious germline genes that when expressed enhance intracellular energy dissipation. This multicausal energy dissipation, posited as the universal origin of cancer initiation, relates to cellular heat generation, disrupted metabolism, and inflammation. The organism reproduces during cancer's dormancy, and when approaching its end of life, the onset of cancer is accelerated in proportion to the cancer-initiating signal. Through cancer, the organism, now a parent, implements the self-actuated programmed death of Skulachev's phenoptosis. This "first death" enhances by proxy the offspring's chance of "second death" (or "double death") through diminished parental care. Repetition over generations realizes a purifying selection against genes causing energy dissipation. The removal of the deleterious germline gene mutations permanently generated by Muller's ratchet gives a benefit. We generalize, motivated by the parallels between cancer and aging, the purifying selection posited for cancer to aging. An ARD would be initiated in the organ by multicausal disruption of homeostasis, and be followed by dormancy and senescence until its onset near the end of the life cycle. Just as for cancer, the ARD eventually enhances double death, and the realized permanent selection gives a benefit to the species through the selection against germ line genes that disrupt homeostasis. Given their similarities, cancer and aging are combined in the posited Unified Cancer-Aging Adaptation (UCAA) model, which may be confirmed by next-generation sequencing data. Also because of the emerging important role of cellular senescence, the hypothesis may guide the development of therapies against both cancer and aging. [ABSTRACT FROM AUTHOR]

Natural honey has many biological activities including increase serum testosterone level. The aim of this study was to evaluate the effect of three types of honey on the levels of testosterone in the serum of healthy aging men. About 60 healthy men were selected (aged 42-60 years) and divided into three groups, as a group of 20 men who were given honey daily orally for 30 days and tested before and after treatment, group I (50gm clover honey), group II (50gm Eucalyptus honey) and group III (50 gm Sidr honey). Oral administration of natural honey increased testosterone level in serum after 30 days treatment, in three groups. It might be concluded that honey has an effect in increasing serum testosterone level. [ABSTRACT FROM AUTHOR]

Aging is a complex process and is associated with various molecular regulations on DNA or RNA levels. In forensic science, accurate age estimation of an unknown individual can be of extremely important. Recent years, age-related molecular biomarkers have been proposed as indicators of chronological age. There were studies showing that circular RNAs (circRNAs) change significantly during aging. Here, the correlation of circRNAs expression levels and age was investigated by detecting circRNA levels in peripheral whole blood utilizing next-generation RNA sequencing (RNA-seq). We suggest that circRNA can be a novel biomarker for forensic age estimation. [ABSTRACT FROM AUTHOR]

The role of DNA methylation patterns in complex phenotypes remains unclear. To explore this question, we adapted our methods for rare variant analysis to characterize genome-wide murine DNA hybridization array to investigate methylation at CpG islands, shores, and regulatory elements. We have applied this platform to compare age and tissue- specific methylation differences in the brain and spleen of young and aged mice. As expected from prior studies, there are clear global differences in organ-specific, but not age-specific, methylation due mostly to changes at repetitive elements. Surprisingly, out of 200,000 loci there were only 946 differentially methylated cytosines (DMCs) between young and old samples (529 hypermethylated, 417 hypomethylated in aged mice) compared to thousands of tissue-specific DMCs. Hypermethylated loci were clustered around the promoter region of Sfi1, exon 2 of Slc11a2, Drg1, Esr1 and Foxa2 transcription factor binding sites. In particular, there were 75 hypermethylated Foxa2 binding sites across a 2.7 Mb region of chromosome 11. Hypomethylated loci were clustered around Mid1, Isoc2b and genome-wide loci with binding sites for Foxa2 and Esr1, which are known to play important roles in development and aging. These data suggest discreet tissue-independent methylation changes associated with aging processes such as cell division (Sfi1, Mid1), energy production (Drg1, Isoc2b) and cell death (Foxa2, Esr1). [ABSTRACT FROM AUTHOR]

Pathological changes underlying Alzheimer's disease (AD) begin decades before the classical symptoms of memory loss become evident. As microRNAs are released from neurons and enter the bloodstream, circulating microRNAs may be reflective of AD progression and are ideal candidates as biomarkers for early-stage disease detection. Here, we provide a novel, in-depth analysis of how plasma microRNAs alter with aging, the most prominent risk factor for AD, and with development of amyloid-β (Aβ) plaque deposition. We assessed the circulating microRNAs in APPswe/PSEN1dE9 transgenic mice and wild-type controls at 4, 8 and 15 m (n = 8-10) using custom designed Taqman arrays representing 185 neuropathology-related microRNAs. We performed a linear mixed-effects model to investigate the effects of age and genotype on plasma microRNAs expression. Following this analysis, we found 8 microRNAs were significantly affected by age alone in wild-type animals and 12 microRNAs altered in APPswe/PSEN1dE9 mice, either prior to Aβ plaque deposition (4 m) or during the development of AD-like pathogenesis (8 m or 15 m). Importantly, we found that differing sets of microRNAs were identified at each time point. Functional analysis of these data revealed that while common biological pathways, such as Inflammatory Response, were enriched throughout the disease process, Free Radical Scavenging, Immunological Disease, and Apoptosis Signaling were specifically enriched later in the disease process. Overall, this study reinforces that distinct biological processes underpin the early versus late stages of AD-like pathogenesis and highlights potential pre-symptomatic microRNAs biomarkers of neurodegeneration. [ABSTRACT FROM AUTHOR]

Age-associated changes in natural killer (NK) cell population, phenotype, and functions are directly attributed to the risk of several diseases and infections. It is predicted to be the major cause of the increase in mortality. Based on the surface density of CD56, NK cells are subdivided into two types, such as CD56bright and CD56dim cells, which represent cytokine production and cytotoxicity. In our study, we have examined the age-associated changes in the NK cell population and their subsets at different age groups of males and females (at a range from 41 to 80 years). We found that the total lymphocyte count significantly dropped upon aging in both genders. Although, the level of total immune cells also dropped on aging, and surprisingly the total NK cell population was remarkably increased with the majority of NK cells being CD56dim. Subsequently, we evaluated the proliferation potential of NK cells and our results showed that the NK cell proliferation ability declines with age. Overall, our findings prove that there is an increase in the circulating NK cell population upon aging. However, the proliferation rate upon aging declines when compared to the young age group (<41 yrs). [ABSTRACT FROM AUTHOR]

While the questions of “What causes aging?” and “Why do we age?” and “How can we stop it?” remain unanswered, recent advances in aging research have continued to increase our understanding of the aging process. Until the last couple of decades, aging was viewed as an inevitable process of damage accumulation and not a subject for scientific pursuit. This view changed when it was demonstrated that the aging process is in fact malleable and genetically determined: mutations in single genes can have dramatic effects on longevity. Despite the rapid advancement of our knowledge about aging, the cause of aging remains unclear. In this paper, experiments demonstrating the roles of genetics and epigenetics in modulating longevity are reviewed, concluding with a new model of aging. This genetic switch model of aging proposes that aging is caused by a genetically-programmed turning off of survival and maintenance pathways after reproduction finishes leading to a progressive functional decline. If this model is correct, it may be possible to extend lifespan and healthspan by identifying the molecular pathways involved and simply turning the switch back on. [ABSTRACT FROM AUTHOR]

Rapalogs, inhibitors of mTORC1 (mammalian target of rapamycin complex 1), increase life span and delay age-related phenotypes in many species. However, the molecular mechanisms have not been fully elucidated. We determined gene expression changes comparing 6- and 24-month-old rats in the kidney, liver, and skeletal muscle, and asked which of these changes were counter-regulated by a clinically-translatable (short-term and low-concentration) treatment, with a rapalog (RAD001). Surprisingly, RAD001 had a more pronounced effect on the kidney under this regimen in comparison to the liver or skeletal muscle. Histologic evaluation of kidneys revealed that the severity of chronic progressive nephropathy lesions was lower in kidneys from 24-month-old rats treated with RAD001 compared with vehicle. In addition to other gene expression changes, c-Myc, which has been shown to regulate aging, was induced by aging in the kidney and counter-regulated by RAD001. RAD001 caused a decrease in c-Myc protein, which could be rescued by a proteasome inhibitor. These findings point to settings for use of mTORC1 inhibitors to treat age-related disorders, and highlight c-Myc regulation as one of the potential mechanisms by which mTORC1 inhibition is perturbing age-related phenotypes. [ABSTRACT FROM AUTHOR]

Frailty, a condition involving increased risk of disability and mortality in older adults, has emerged as a reliable way to predict the effect of aging. Genomic instability may help to anticipate recognition of frail individuals and improving frailty outcomes. Our objective was to evaluate the potential of the micronucleus frequency, evaluated in lymphocytes and buccal cells, to anticipate frailty identification and improve diagnosis reliability. Our results, from a group of older adults over 65, showed that frail individuals had significantly higher frequencies of micronucleus in lymphocytes (19.16 ± 0.66 vs. 13.07 ± 0.78, p < .001) and of binucleated buccal cells (82.65 ± 3.42 vs. 37.16 ± 2.85, p < .001) and lower frequencies of pyknotic and condensed chromatin buccal cells, than nonfrail subjects. When cognitive status was considered, similar results were obtained. Moreover, the presence of frailty and cognitive impairment were independently related to increases in frequencies of lymphocyte micronucleus and binucleated buccal cells. Our results encourage the use of micronucleus frequency in lymphocytes as a complement to clinical parameters in frailty identification. However, these results have to be further evaluated in prefrail patients, to better understand the connection between genomic instability and frailty and to establish these parameters as actual biomarkers of frailty in clinical practice. [ABSTRACT FROM AUTHOR]

DNA is constantly being damaged, either by endogenous or exogenous genotoxins. In that regard, DNA repair activities are essential for maintaining genomic stability and to life itself. Mutations in genes encoding DNA repair proteins cause severe human syndromes, butDNA repair defects have also been linked to several other diseases, notably to cancer and normal aging. Recently, new evidence has emerged indicating that some DNA repair diseases display mitochondrial and metabolic dysfunction through mechanisms that are yet being uncovered. These results suggest that mitochondria play an import role in the DNA damage response pathways and that damage accumulation may lead to mitochondrial dysfunction via metabolic imbalance and mitophagy impairment. Here we review the recent findings linking mitochondrial impairment and cell death to DNA damage accumulation in the context of DNA repair defects. In addition, the general involvement of DNA damage in cellular dysfunction suggests that these phenomena may be also involved in other human pathologies in which mitochondrial dysfunction and metabolic disruption play causative roles. [ABSTRACT FROM AUTHOR]

Fighting diseases and controlling the signs of ageing are the major goals of biomedicine. Sirtuins, enzymes with mainly deacetylating activity, could be pivotal targets of novel preventive and therapeutic strategies to reach such aims. Scientific proofs are accumulating in experimental models, but, to a minor extent, also in humans, that the ancient practice of calorie restriction could prove an effective way to prevent several degenerative diseases and to postpone the detrimental signs of ageing. In the present review, we summarize the evidence about the central role of sirtuins in mediating the beneficial effects of calorie restriction in skeletal and cardiac muscle since these tissues are greatly damaged by diseases and advancing years. Moreover, we entertain the possibility that the identification of sirtuin activators that mimic calorie restriction could provide the benefits without the inconvenience of this dietary style. [ABSTRACT FROM AUTHOR]

In the adult brain, the neural stem cell (NSC) pool comprises quiescent and activated populations with distinct roles. Transcriptomic analysis revealed that quiescent and activated NSCs exhibited differences in their protein homeostasis network. Whereas activated NSCs had active proteasomes, quiescent NSCs contained large lysosomes. Quiescent NSCs from young mice accumulated protein aggregates, and many of these aggregates were stored in large lysosomes. Perturbation of lysosomal activity in quiescent NSCs affected protein-aggregate accumulation and the ability of quiescent NSCs to activate. During aging, quiescent NSCs displayed defects in their lysosomes, increased accumulation of protein aggregates, and reduced ability to activate. Enhancement of the lysosome pathway in old quiescent NSCs cleared protein aggregates and ameliorated the ability of quiescent NSCs to activate, allowing them to regain a more youthful state. [ABSTRACT FROM AUTHOR]

Understanding the control of epigenetic regulation is key to explain and modify the aging process. Because histone-modifying enzymes are sensitive to shifts in availability of cofactors (e.g. metabolites), cellular epigenetic states may be tied to changing conditions associated with cofactor variability. The aim of this study is to analyse the relationships between cofactor fluctuations, epigenetic landscapes, and cell state transitions. Using Approximate Bayesian Computation, we generate an ensemble of epigenetic regulation (ER) systems whose heterogeneity reflects variability in cofactor pools used by histone modifiers. The heterogeneity of epigenetic metabolites, which operates as regulator of the kinetic parameters promoting/preventing histone modifications, stochastically drives phenotypic variability. The ensemble of ER configurations reveals the occurrence of distinct epi-states within the ensemble. Whereas resilient states maintain large epigenetic barriers refractory to reprogramming cellular identity, plastic states lower these barriers, and increase the sensitivity to reprogramming. Moreover, fine-tuning of cofactor levels redirects plastic epigenetic states to re-enter epigenetic resilience, and vice versa. Our ensemble model agrees with a model of metabolism-responsive loss of epigenetic resilience as a cellular aging mechanism. Our findings support the notion that cellular aging, and its reversal, might result from stochastic translation of metabolic inputs into resilient/plastic cell states via ER systems. [ABSTRACT FROM AUTHOR]

Evolutionary biology and biomedicine have seen a surge of recent interest in the possibility that telomeres play a role in life-history trade-offs and ageing. Here, I evaluate alternative hypotheses for the role of telomeres in the mechanisms and evolution of life-history trade-offs and ageing, and highlight outstanding challenges. First, while recent findings underscore the possibility of a proximate causal role for telomeres in current-future trade-offs and ageing, it is currently unclear (i) whether telomeres ever play a causal role in either and (ii) whether any causal role for telomeres arises via shortening or length-independent mechanisms. Second, I consider why, if telomeres do play a proximate causal role, selection has not decoupled such a telomeremediated trade-off between current and future performance. Evidence suggests that evolutionary constraints have not rendered such decoupling impossible. Instead, a causal role for telomeres would more plausibly reflect an adaptive strategy, born of telomere maintenance costs and/or a function for telomere attrition (e.g. in countering cancer), the relative importance of which is currently unclear. Finally, I consider the potential for telomere biology to clarify the constraints at play in life-history evolution, and to explain the form of the current-future trade-offs and ageing trajectories that we observe today. This article is part of the theme issue 'Understanding diversity in telomere dynamics'. [ABSTRACT FROM AUTHOR]

Considerable evidence suggests that circadian rhythmicity is progressively disrupted in senescence. Among clock genes, Period3 (PER3) has been associated with circadian phenotypes, homeostatic regulation of sleep, and cognitive performance in young adults. However, the effects of PER3 genotype on aging-related changes in both cognitive function and cortical integrity remain largely unknown. To shed light into this issue, we have investigated differences in cognitive performance, patterns of cortical thickness, and cortical glucose consumption in normal elderly subjects homozygous carriers of the short (PER34/4, n = 32) and long repeat alleles (PER35/5, n = 32). Relationships between cognitive performance and cortical thickness/metabolism were further explored for each PER3 genotype. We found that PER35/5 carriers had poorer cognitive performance (attention, executive function, semantic memory, and verbal fluency) and lower cortical integrity (structural and functional) than PER34/4. PER35/5 further showed thinning of temporo–parietal areas, and reductions of glucose consumption in fronto–temporo–parietal regions bilaterally. Moreover, PER35/5 subjects exhibited significant correlations between decreased glucose metabolism in fronto–parietal regions and poorer cognitive flexibility, though only correlations with lower glucose consumption of the supramarginal gyrus distinguished PER35/5 from PER34/4 groups. Overall, these findings enhance our understanding on the gene–brain interaction in aging, and may have further implications for the detection of subclinical cognitive decline associated with PER3 genotypes in late life. [ABSTRACT FROM AUTHOR]

Aging-related declines in vision can decrease well-being of the elderly. Concerning early sensory changes as in the primary visual cortex, physiological and behavioral reports seem contradictory. Neurophysiological studies on orientation tuning properties suggested that neuronal changes might come from decreased cortical local inhibition. However, behavioral results either showed no clear deficits in orientation processing in older adults, or proposed stronger surround suppression. Through psychophysical experiments and computational modeling, we resolved these discrepancies by suggesting that lateral inhibition increased in older adults while neuronal orientation tuning widths, related to local inhibition, stayed globally intact across age. We confirmed this later result by re-analyzing published neurophysiological data, which showed no systematic tuning width changes, but instead displayed a higher neuronal noise with aging. These results suggest a stronger lateral inhibition and mixed effects on local inhibition during aging, revealing a more complex picture of age-related effects in the central visual system than people previously thought. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are involved in the regulation of important biological processes. Here, we describe a novel Drosophila miRNAs involved in aging. We selected eight Drosophila miRNAs, displaying high homology with seed sequences of aging‐related miRNAs characterized in other species, and investigated whether the over‐expression of these miRNAs affected aging in Drosophila adult flies. The lifespan of adults over‐expressing miR‐305, a miRNA showing high homology with miR‐239 in C. elegans, was significantly shorter. Conversely, a reduction in miR‐305 expression led to a longer lifespan than that in control flies. miR‐305 over‐expression accelerated the impairment of locomotor activity and promoted the age‐dependent accumulation of poly‐ubiquitinated protein aggregates in the muscle, as flies aged. Thus, we show that the ectopic expression of miR‐305 has a deleterious effect on aging in Drosophila. To identify the targets of miR‐305, we performed RNA‐Seq. We discovered several mRNAs encoding antimicrobial peptides and insulin‐like peptides, whose expression changed in adults upon miR‐305 over‐expression. We further confirmed, by qRT‐PCR, that miR‐305 over‐expression significantly decreases the mRNA levels of four antimicrobial peptides. As these mRNAs contain multiple sequences matching the seed sequence of miR‐305, we speculate that a reduction in target mRNA levels, caused by ectopic miRNA expression, promotes aging. [ABSTRACT FROM AUTHOR]

Aging impacts diseases and lifespan. With current knowledge of stem cells, it is feasible to design and test interventions that delay aging and improve both health and lifespan. Stem cells, together with antiaging genes such as Klotho, play a crucial role in delaying the aging process. Stem cells in combination with anti-aging genes make a complex and protective shield, which stand against the eroding effects of aging. Increased wear and tear of the stem cells, as well as Klotho deficiency, is expected to heavily increase cellular damage and accelerate the process of aging. Stem cells in conjugation with anti-aging genes probably receive and neutralize most of the devastating signaling effects which are known to cause premature aging. The shield of stem cells combined with anti-aging genes is a primary target for absorbing the shock of aging. If this shield neutralizes the shocks, it could lead to a youthful state, but if not it will accelerate the aging journey. In this review, we concisely discuss the neutralizing ability, operated and regulated by stem cells and other life-extension factors. We suggest that stem cell interventions that increase rejuvenation and keep in balance the expression of anti-aging genes could delay the aging phenotypes and result in prolonged lifespan. [ABSTRACT FROM AUTHOR]

Probabilistic category learning involves complex interactions between the hippocampus and striatum that may depend on whether acquisition occurs via feedback or observation. Little is known about how healthy aging affects these processes. We tested whether age-related behavioral differences in probabilistic category learning from feedback or observation depend on a genetic factor known to influence individual differences in hippocampal function, the KIBRA gene (single nucleotide polymorphism rs17070145). Results showed comparable age-related performance impairments in observational as well as feedback-based learning. Moreover, genetic analyses indicated an age-related interactive effect of KIBRA on learning: among older adults, the beneficial T-allele was positively associated with learning from feedback, but negatively with learning from observation. In younger adults, no effects of KIBRA were found. Our results add behavioral genetic evidence to emerging data showing age-related differences in how neural resources relate to memory functions, namely that hippocampal and striatal contributions to probabilistic category learning may vary with age. Our findings highlight the effects genetic factors can have on differential age-related decline of different memory functions. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are able to regulate adjacent genes and thus participate in the incidence in the present study has identified lncRNA AP003419.16, adjacent to the protein-coding gene ribosomal protein S6 kinase B-2 (RPS6KB2). RPS6KB2 is believed to be involved in the process of aging and idiopathic pulmonary fibrosis (IPF), due to its activation by growth factors and regulation by the protein kinase mTOR signaling pathway. The results of the present study indicated that the expression of AP003419.16 increased significantly in patients with IPF, whereas its adjacent gene ribosomal protein S6 kinase B-2 increased simultaneously. AP003419.16 expression may be used to predict an increased risk of aging-associated IPF. The present study provided a molecular hypothesis of IPF occurrence in the aging process, in addition to novel molecular targets for the clinical treatment of IPF. [ABSTRACT FROM AUTHOR]

Context:γ-Linolenic acid (GLA) is an important constituent of anti-ageing supplements. Objective:The current study investigates the anti-ageing effect of GLA in Sprague-Dawley rats. Materials and methods:GLA (0.1, 0.2, 0.4, 2, 10, 20 and 24 μM) was initially evaluated for its effect on the formation of advanced glycation end products (AGEs)in vitro. Forin vivoassessment (1, 5 or 15 mg/kg), the rat model of accelerated ageing was developed usingd-fructose (1000 mg/kg (i.p.) plus 10% in drinking water for 40 days). Morris water maze was used to evaluate impairment in learning and memory. The blood of treated animals was used to measure glycosylated haemoglobin (HbA1c) levels. The interaction of GLA with active residues of receptor of AGE (RAGE) was analyzed using AutoDock Vina. Results:Our data showed that GLA inhibited the production of AGEs (IC50 = 1.12 ± 0.05 μM). However, this effect was more significant at lower tested doses. A similar pattern was also observed inin vivoexperiments, where the effect of fructose was reversed by GLA only at lowest tested dose of 1 mg/kg. The HbA1c levels also revealed significant reduction at lower doses (1 and 5 mg/kg). Thein silicodata exhibited promising interaction of GLA with active residues (Try72, Arg77 and Gln67) of RAGE. Conclusion:The GLA, at lower doses, possesses therapeutic potential against glycation-induced memory decline. [ABSTRACT FROM PUBLISHER]

Gene plays a significant role in aging. all aging process can depend on just the mutation of a single gene. Longevity of life is heritable and shows at old age, at some points in time the rate at which human and other animals' age increase rapidly as a result of certain mutation. It has been observed that some living organisms show sign of aging at a very tender age due to some set of syndromes that are known as progeroid syndromes. Aging is not really characterised by brain aging but by old skin, early cataract and some other signs. It was discovered by some scientist that aging can be delayed in living organisms using Calorie Restriction, hundreds of genes identified to regulate aging provide strong evidence that aging has a strong genetic basis and that indeed a basic aging process exists. Although daf-2 can limit expansion of life when not mutated, Daf-2 and daf-16 are two types of gene that plays the major role of life expansion and aging. The gene helps to interfere with life span by controlling other gene that coordiate the survival system. [ABSTRACT FROM AUTHOR]

Aging is a progressive internal physiological deterioration of the organism, leading to the occurrence of age-related lethal diseases. It has become a major societal challenge to understand the processes that drive aging and to develop rational pharmacological agents and dietary approaches to fight against age-related deterioration and diseases. Interestingly, several lines of evidence highlight an influence of the developmental period on the risk of age-related diseases later in life. This field is known as the developmental origins of health and disease. Following this logic, studying the modification of maternal diet during early life may provide innovative new anti-aging approaches. Nutritional and psychological stresses during gestation are associated with poorer offspring health conditions in late life, and must be avoided during pregnancy. Besides these recommendations, very little has been published about the possible use of maternal diet to program offspring for healthy aging and an extended lifespan. Such health benefits may be provided by different foreign molecules, and particularly the phytochemicals produced by stressed plants, or xenohormetins. The xenohormesis hypothesis proposes that xenohormetins are signals of environmental change and trigger a beneficial adaptive response in individuals who consume them. No studies to date have investigated whether the consumption of stressed plants during pregnancy and lactation could provide chemical cues that impact early life programming and thus influence the future health and lifespan of offspring. Investigating the effect of xenohormesis in early life will involve adding edible plants exposed to different stressors (i.e. UV light, heat, ozone, etc.) to maternal diet and the exposure of offspring to this xenohormetin-enriched maternal diet at different periods of their prenatal life. The hypothesis proposed in this article is a potential tool to decipher the possible impact of xenohormesis during early life, and paving the way toward an innovative maternal diet that ensures the healthy aging of the progeny. [ABSTRACT FROM AUTHOR]

Skeletal muscle is a highly oxygen-consuming tissue that ensures body support and movement, as well as nutrient and temperature regulation. DNA damage induced by reactive oxygen species is present in muscles and tends to accumulate with age. Here, we present a summary of data obtained on DNA damage and its implication in muscle homeostasis, myogenic differentiation and neuromuscular disorders. Controlled and transient DNA damage appears to be essential for muscular homeostasis and differentiation while uncontrolled and chronic DNA damage negatively affects muscle health. [ABSTRACT FROM AUTHOR]

Background: Identification of genes or fundamental biological pathways that regulate aging phenotypes and longevity could lead to possible interventions to increase healthy longevity.Methods: Using data from the Long Life Family Study, we performed genomewide association analyses on an endophenotype construct, LF1, comprising a linear combination of traits across health domains. LF1 primarily reflected traits from the pulmonary and physical activity domains.Results: We detected a significant association between LF1 and a locus on chromosome 10p15 (p-value = 4.65 × 10-8) and suggestive evidence (p-value < 5 × 10-6) for association on chromosomes 1, 2, 8, 12, 15, 18, and 22. Using data from the Health, Aging and Body Composition Study, we subsequently replicated the association for the 1p13 region near the NBPF6 locus (p-value = 3.65 × 10-4).Conclusions: Our analyses indicate that loci influencing a healthy aging endophenotype construct predominantly comprised of pulmonary and physical function domains may be located on chromosome 1p13 near the NBPF6 locus. Further investigation of this possible locus and other suggestive loci may reveal novel biological pathways that influence healthy aging. [ABSTRACT FROM AUTHOR]

Definitive quantitation of mitochondrial DNA (mtDNA) and mtDNA deletion mutation abundances would help clarify the role of mtDNA instability in aging. To more accurately quantify mtDNA, we applied the emerging technique of digital polymerase chain reaction to individual muscle fibers and muscle homogenates from aged rodents. Individual fiber mtDNA content correlated with fiber type and decreased with age. We adapted a digital polymerase chain reaction deletion assay that was accurate in mixing experiments to a mutation frequency of 0.03% and quantitated an age-induced increase in deletion frequency from rat muscle homogenates. Importantly, the deletion frequency measured in muscle homogenates strongly correlated with electron transport chain-deficient fiber abundance determined by histochemical analyses. These data clarify the temporal accumulation of mtDNA deletions that lead to electron chain-deficient fibers, a process culminating in muscle fiber loss. [ABSTRACT FROM AUTHOR]

Background and aims Cross-sectional twin and family studies report a moderate heritability of baseline levels of C-reactive protein (CRP), ranging from 0.10 to 0.65 for different age ranges. Here, we investigated the stability and relative impact of genetic and environmental factors underlying serum levels of CRP, using a longitudinal classical twin design. Methods A maximum of 6201 female twins from the TwinsUK registry with up to three CRP measurements (i.e. visit 1 [V1], visit 2 [V2] and visit 3 [V3]) over a 10-year follow-up period were included in this study. Structural equation modeling was applied to dissect the observed phenotypic variance into its genetic and environmental components. To estimate the heritability of CRP as well as its genetic and environmental correlations across different time points, a trivariate model was used. Results Natural log (ln) CRP levels significantly increased from V1 to V2 ( p =4.4 × 10 −25 ) and between V1 and V3 ( p =1.2 × 10 −15 ), but not between V2 and V3. The median (IQR) follow-up time between V1 and V3 was 9.58 (8.00–10.46) years. Heritability estimates for CRP were around 50% and constant over time (0.46–0.52). Additionally, adjustment for BMI did not meaningfully change the heritability estimates (0.49–0.51). The genetic correlations between visits were significantly smaller than one, ranging from 0.66 to 0.85. Conclusions The present study provides evidence for stable heritability estimates of CRP of around 50% with advancing age. However, between-visit genetic correlations are significantly lower than 1, indicating emergence of new genetic effects on CRP levels with age. [ABSTRACT FROM AUTHOR]

The mitochondrial arginase type II (Arg-II) has been shown to interact with ribosomal protein S6 kinase 1 (S6K1) and mitochondrial p66Shc and to promote cell senescence, apoptosis and inflammation under pathological conditions. However, the impact of Arg-II on organismal lifespan is not known. In this study, we demonstrate a significant lifespan extension in mice with Arg-II gene deficiency (Arg-II-/-) as compared to wild type (WT) control animals. This effect is more pronounced in the females than in the males. The gender difference is associated with higher Arg-II expression levels in the females than in the males in skin and heart at both young and old age. Ablation of Arg-II gene significantly reduces the aging marker p16INK4a levels in these tissues of old female mice, whereas in the male mice this effect of Arg-II deficiency is weaker. In line with this observation, age-associated increases in S6K1 signaling and p66Shc levels in heart are significantly attenuated in the female Arg-II-/- mice. In the male mice, only p66Shc but not S6K1 signaling is reduced. In summary, our study demonstrates that Arg-II may play an important role in the acceleration of aging in mice. Genetic disruption of Arg-II in mouse extends lifespan predominantly in females, which relates to inhibition of S6K1, p66Shc, and p16INK4a. Thus, Arg-II may represent a promising target to decelerate aging process and extend lifespan as well as to treat age-related diseases. [ABSTRACT FROM AUTHOR]

Aging is a multifactorial process involving an accumulation of alterations on various organizational levels, which finally compromises viability and limits the lifespan of organisms. It is now well-established that many aspects of aging can be positively affected by (macro)autophagy, a mechanism of self-digestion found in virtually all eukaryotic cells. A comprehensive understanding of autophagy is thus expected to not only deepen our insight into the mechanisms of aging but to also open up new avenues toward increasing the healthy lifespan in humans. In this review, we focus on the Atg8 family of ubiquitin-like proteins, which play a crucial role in the autophagy process by virtue of their unique mode of reversible membrane association. [ABSTRACT FROM AUTHOR]