Model Of Premature Aging Research Articles

Characterization of a natural model of adult mice with different rate of aging

Aging is a heterogeneous process, so individuals of the same age may be aging at a different rate. A natural model of premature aging in mice have been proposed based on the poor response to the T-maze. Those that take longer to cross the intersection are known as Prematurely Aging Mice (PAM), while those that show an exceptional response are known as Exceptional non-PAM (E-NPAM), being the rest non-PAM (NPAM). Although many aspects of PAM and E-NPAM have been described, some aspects of their brain aging have not been studied. Similarly, it is known that PAM, NPAM and E-NPAM show a different rate of aging and longevity, but the differences between these three groups in behavior, immune function and oxidative-inflammatory state are unknown. The present study aims to deepen the study of brain aging in PAM and E-NPAM, and to study the differences in behavior, immunity, and oxidative-inflammatory state of peritoneal leukocytes between PAM, NPAM and E-NPAM. Results show deteriorated brains in PAM. Moreover, NPAM show an oxidative state similar to E-NPAM, an anxiety similar to PAM, and an intermediate immunity and lifespan between PAM and E-NPAM. In conclusion, immune function seems to be more associated with the longevity achieved.

The molecular profile people of different ages in «normal» and with dilated cardiomyopathy

Background: Dilated cardiomyopathy (DCMP) is a cardiovascular pathology promising for consideration as a clinical model of premature aging of the body. According to the literature, sirtuins-1, 2, 3, 6; melatonin and its receptors (MT-1 and MT-2); markers of cellular aging (proteins p16, p21) and apoptosis (BAX) may have clinical significance for assessing premature aging of the body on the DCMP model. A comparative study of the expression of these molecules in people of different ages, depending on the presence of DCMP, has not been conducted before. The aim of the study: To identify and compare molecular profiles by the level of expression of the studied signaling molecules in the buccal epithelium and autopsy material of the myocardium in people of different ages with the absence of cardiovascular diseases and the presence of dilated cardiomyopathy. Materials and methods: A study of buccal epithelium (174 people) and autopsy material of myocardium (175 people) in patients aged 45-89 years for the expression of signaling molecules: sirtuins 1, 2, 3, 6, proteins p16, p21 and BAX, was conducted. Methods of immunocytochemical and immunohistochemical studies were used. Groups of middle, elderly and senile age with DCMP and without a history of cardiovascular pathology were identified. Results: Characteristic changes in the molecular profile (the level of the studied signaling molecules) in the buccal epithelium associated with age and the presence of DCMP were revealed: in middle–aged patients – a decrease in the expression of sirtuins 3 and 6 by 2,2-2,3 times, melatonin by 1,8 times and its receptors by 1,4-2,5 times; in elderly patients – a decrease in the expression of sirtuins 1 and 3 by 2,5 times; sirtuin 2 by 2,3 times; melatonin and its receptors by 1,4-1,8 times; in elderly patients – a decrease in the expression of sirtuins 3 and 6 by 3,0-4,7 times; sirtuins 1 and 2 by 6,7-7,3 times; melatonin by 2,8 times; MT-1 – 4,1 times and MT-2 – 23,7 times. An increase in the expression of p16 and BAX proteins by 0,6-0,8 times in the buccal epithelium has additional diagnostic information in the diagnosis of DCMP in individuals of different age groups. There is a correlation between changes in the expression of these molecules in the buccal epithelium and the autopsy material of the myocardium. Conclusion: Molecular profiles in people of different age groups, determined by the level of expression of the studied signaling molecules, significantly differ depending on the presence of DCMP. It is characteristic that the direction of changes in the buccal epithelium is similar to the corresponding molecular profile in the autopsy material of the myocardium.

Initiation phase cellular reprogramming ameliorates DNA damage in the ERCC1 mouse model of premature aging.

Unlike aged somatic cells, which exhibit a decline in molecular fidelity and eventually reach a state of replicative senescence, pluripotent stem cells can indefinitely replenish themselves while retaining full homeostatic capacity. The conferment of beneficial-pluripotency related traits via in vivo partial cellular reprogramming in vivo partial reprogramming significantly extends lifespan and restores aging phenotypes in mouse models. Although the phases of cellular reprogramming are well characterized, details of the rejuvenation processes are poorly defined. To understand whether cellular reprogramming can ameliorate DNA damage, we created a reprogrammable accelerated aging mouse model with an ERCC1 mutation. Importantly, using enhanced partial reprogramming by combining small molecules with the Yamanaka factors, we observed potent reversion of DNA damage, significant upregulation of multiple DNA damage repair processes, and restoration of the epigenetic clock. In addition, we present evidence that pharmacological inhibition of ALK5 and ALK2 receptors in the TGFb pathway are able to phenocopy some benefits including epigenetic clock restoration suggesting a role in the mechanism of rejuvenation by partial reprogramming.

Dilated cardiomyopathy as a clinical model of premature aging in humans

The compliance of dilated cardiomyopathy (DCM) with the requirements of a clinical model of premature aging in humans is substantiated. The pathogenetic basis of the formation of DCM and their relationship with changes associated with myocardial aging are considered. The study complements and clarifies the understanding of the pathogenetic mechanisms of premature aging of the human body and its clinical models, and also provides the basis for further research into the problem of premature aging of the body and age-related diseases.

#5489 CROSS-TALK BETWEEN FRAILTY AND IMMUNOSENESCENCE IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Chronic kidney disease (CKD) has been proposed as a model of premature ageing. The immune system is an important factor in the ageing process and can modulate the rate of ageing. The uremic environment highly affects this system, deteriorating its functionality and increasing susceptibility to infections, cancer, and pathologies like cardiovascular disease. Also, CKD patients are highly predisposed to frailty, which increases the organism's vulnerability to disease. This premature ageing, partially caused by the immune disorder and increased frailty, is responsible for these patients' high morbidity and mortality. Understanding these processes and how they are affected by different treatments will help generate better nutritional, pharmacological and lifestyle strategies. For this, the aim of this study was to determine the immune and frailty status of patients with CKD and their therapies. Method We performed a cross-sectional study involving 18 healthy subjects (HS) and 156 patients from the Nephrology Department of the Hospital Universitario “12 de Octubre” (Madrid, Spain). The distribution of patients was as follows: 40 with end-stage renal disease (ESRD), 40 on haemodialysis (HD), 36 on peritoneal dialysis (PD) and 40 patients who had received initial kidney transplantation (KT). The frailty status of the patients was assessed by the Edmonton Frail Scale test. Lymphocyte populations (T lymphocytes, T-helper lymphocytes, T-cytotoxic lymphocytes, and B lymphocytes) and monocytes (classical, intermediate, non-classical, and the expression of the adhesion molecule ICAM-1 and co-stimulatory B7.2) were determined in peripheral blood samples. Results The patients were similar in age and sex. The number of frail individuals was higher in patients (ESRD p<0.001, PD p<0.001, KT p = 0.004) than in HS, particularly in HD (p<0.001) (Figure 1). Regarding immune phenotype (Figure 2), HD patients showed a lower number of T-cells (p<0.001), particularly T-helper cells (p<0.001), than the other groups. Also, DP patients presented fewer T and T-cytotoxic cells than HS (p = 0.029, p = 0.05). Also, HD showed lower T-cytotoxic and helper/cytotoxic ratios than HS (p = 0.022; p = 0.011) and ESRD (p = 0.017; p = 0.008). The proportion of classical monocytes decreased, and the proportion of intermediate and non-classical monocytes increased in HD with respect to the other groups (p<0.001). The expression of the costimulatory molecule B7.2 was increased in the patients with respect to HS in all monocyte subsets (Classical: ESRD p = 0.002, HD p<0.001, PD p<0.001, KT p<0.001; Intermediate: ESRD p = 0.014, HD p<0.001, PD p<0.001, KT p = 0.002; Non-classical: ESRD p = 0.006, HD p<0.001, PD p<0.001, KT p = 0.013), while adhesion molecules were only elevated in HD with respect to HS in all subsets (classical p<0.001, intermediate p<0.001, non-classical p = 0.023). Conclusion The CKD patients, regardless of the treatment, showed, in general, an alteration in the lymphocyte subsets. These alterations were more significant in dialysis patients, particularly in HD patients. This group also presented the most significant alterations in monocyte subsets and higher frailty. This may explain why haemodialysis patients show major adverse outcomes compared to other treatments. Determining immune profiles can help us to relate these alterations to adverse events to carry out preventive and personalised medicine.

Trabecular bone remodeling in the aging mouse: A micro-multiphysics agent-based in silico model using single-cell mechanomics.

Bone remodeling is regulated by the interaction between different cells and tissues across many spatial and temporal scales. Notably, in silico models are regarded as powerful tools to further understand the signaling pathways that regulate this intricate spatial cellular interplay. To this end, we have established a 3D multiscale micro-multiphysics agent-based (micro-MPA) in silico model of trabecular bone remodeling using longitudinal in vivo data from the sixth caudal vertebra (CV6) of PolgA(D257A/D257A) mice, a mouse model of premature aging. Our in silico model includes a variety of cells as single agents and receptor-ligand kinetics, mechanomics, diffusion and decay of cytokines which regulate the cells' behavior. We highlighted its capabilities by simulating trabecular bone remodeling in the CV6 of five mice over 4weeks and we evaluated the static and dynamic morphometry of the trabecular bone microarchitecture. Based on the progression of the average trabecular bone volume fraction (BV/TV), we identified a configuration of the model parameters to simulate homeostatic trabecular bone remodeling, here named basal. Crucially, we also produced anabolic, anti-anabolic, catabolic and anti-catabolic responses with an increase or decrease by one standard deviation in the levels of osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), and sclerostin (Scl) produced by the osteocytes. Our results showed that changes in the levels of OPG and RANKL were positively and negatively correlated with the BV/TV values after 4weeks in comparison to basal levels, respectively. Conversely, changes in Scl levels produced small fluctuations in BV/TV in comparison to the basal state. From these results, Scl was deemed to be the main driver of equilibrium while RANKL and OPG were shown to be involved in changes in bone volume fraction with potential relevance for age-related bone features. Ultimately, this micro-MPA model provides valuable insights into how cells respond to their local mechanical environment and can help to identify critical pathways affected by degenerative conditions and ageing.

Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle

We investigate the age-related metabolic changes that occur in aged and rejuvenated myoblasts using in vitro and in vivo models of aging. Metabolic and signaling experiments reveal that human senescent myoblasts and myoblasts from a mouse model of premature aging suffer from impaired glycolysis, insulin resistance, and generate Adenosine triphosphate by catabolizing methionine via a methionine adenosyl-transferase 2A-dependant mechanism, producing significant levels of ammonium that may further contribute to cellular senescence. Expression of the pluripotency factor NANOG downregulates methionine adenosyltransferase 2 A, decreases ammonium, restores insulin sensitivity, increases glucose uptake, and enhances muscle regeneration post-injury. Similarly, selective inhibition of methionine adenosyltransferase 2 A activates Akt2 signaling, repairs pyruvate kinase, restores glycolysis, and enhances regeneration, which leads to significant enhancement of muscle strength in a mouse model of premature aging. Collectively, our investigation indicates that inhibiting methionine metabolism may restore age-associated impairments with significant gain in muscle function.

МОРФОФУНКЦИОНАЛЬНЫЕ ИЗМЕНЕНИЯ СЕМЕННИКОВ КРЫСПРИ ПРЕЖДЕВРЕМЕННОМ СТАРЕНИИ, ВЫЗВАННОМ ТЕМНОВОЙ ДЕПРИВАЦИЕЙ

The rapid development of technology has a significant impact on the daily life of a person. Light, sound, information pollution leads to sleep disturbance, which has a negative impact on the physical condition. Even short-term sleep disturbance caused by dark deprivation leads to a decrease in serum testosterone levels. The imbalance of male sex hormones, the synthesis of which is under the control of the hypothalamic-pituitary system, negatively affects the morphofunctional state of the testes. The effect of exogenous melatonin on the morphological and functional state of the spermatogenic epithelium of the testes, Leydig cells in white outbred male rats of 4 months of age was studied on the model of premature aging caused by 30-day dark deprivation, and the Klotho protein level in blood serum was assessed by enzyme immunoassay. It was found that the morphological changes in the testes were characterized by a decrease in the thickness of the spermatogenic epithelium by 30 days after darkdeprivation and a decrease in the level of the Klotho protein, which is a marker of premature aging. The introduction of exogenous melatonin had a protective effect on the morphological and functional status of the testes of animals, accompanied by the restorationof the spermatogenic epithelium, an increase in the Klotho protein to the level of thenegative control group

ВЛИЯНИЕ МЕЛАТОНИНА НА ДИНАМИКУ МАССЫ ТЕЛА И УРОВЕНЬ БЕЛКА КЛОТО В КРОВИ У ЖИВОТНЫХС ПРЕЖДЕВРЕМЕННЫМ СТАРЕНИЕМ, ВЫЗВАННЫМТЕМНОВОЙ ДЕПРИВАЦИЕЙ

On the model of premature aging induced by 30-day dark deprivation (light-dark cycle 24/0 h, artificial illumination 300 Lux), the effect of exogenous melatonin (0.3 mg/kg, 14 days after the cancellation of dark deprivation, intragastric dailyin 2 % starch mucus) on the dynamics of body weight and the level of Klotho protein in the blood was studied in outbred white male rats of 4 months of age. It has been shown that prolonged dark deprivation is accompanied by a statistically significantdecrease in the content of the Klotho protein in the blood serum, which is a marker of premature aging. Metabolic disorders associated with a statistically significant decrease in the level of melatonin and Klotho protein in the blood were expressedin fluctuations in the dynamics and rate of body weight gain in animals. At the same time, exogenous melatonin had a protective effect on the condition of animals –it contributed to an increase in the content of Klotho protein in the blood serum and restoredthe level of melatonin to the values of the negative control indicator.

520 The protective effects of Apocynin against ultraviolet B-induced cellular senescence in human keratinocytes

Cellular senescence is an irreversible growth arrest caused by oxidative stress and DNA damage and ultraviolet (UV) radiation mediated cellular damage is responsible for skin photoaging. Type 17 collagen (COL17) is crucial for preventing skin aging. Apocynin, a NADPH oxidase inhibitor can chemically induce COL17 protein synthesis and promote stem cell survival. Our unpublished data showed that klotho mutant (kl/kl) mice, which is a premature aging model, displayed increased senescence-associated-β-galactosidase (Sa-β-Gal) activity, increased production of p16, phosphorylated histone H2AX (γH2AX), matrix metallopeptidase 9 and 1 (MMP-9, MMP-1), increased activation of mitogen-activated kinase (MAPK) along with deceased COL17 production in the skin.

The Absence of Parkin Does Not Promote Dopamine or Mitochondrial Dysfunction in PolgAD257A/D257A Mitochondrial Mutator Mice.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). In this study, we generated a transgenic model by crossing germline Parkin-/- mice with PolgAD257A mice, an established model of premature aging and mitochondrial stress. We hypothesized that loss of Parkin-/- in PolgAD257A/D257A mice would exacerbate mitochondrial dysfunction, leading to loss of dopamine neurons and nigral-striatal specific neurobehavioral motor dysfunction. We found that aged Parkin-/-/PolgAD257A/D257A male and female mice exhibited severe behavioral deficits, nonspecific to the nigral-striatal pathway, with neither dopaminergic neurodegeneration nor reductions in striatal dopamine. We saw no difference in expression levels of nuclear-encoded subunits of mitochondrial markers and mitochondrial Complex I and IV activities, although we did observe substantial reductions in mitochondrial-encoded COX41I, indicating mitochondrial dysfunction as a result of PolgAD257A/D257A mtDNA mutations. Expression levels of mitophagy markers LC3I/LC3II remained unchanged between cohorts, suggesting no overt mitophagy defects. Expression levels of the parkin substrates, VDAC, NLRP3, and AIMP2 remained unchanged, suggesting no parkin dysfunction. In summary, we were unable to observe dopaminergic neurodegeneration with corresponding nigral-striatal neurobehavioral deficits, nor Parkin or mitochondrial dysfunction in Parkin-/-/PolgAD257A/D257A mice. These findings support a lack of synergism of Parkin loss on mitochondrial dysfunction in mouse models of mitochondrial deficits.SIGNIFICANCE STATEMENT Producing a mouse model of Parkinson's disease (PD) that is etiologically relevant, recapitulates clinical hallmarks, and exhibits reproducible results is crucial to understanding the underlying pathology and in developing disease-modifying therapies. Here, we show that Parkin-/-/PolgAD257A/D257A mice, a previously reported PD mouse model, fails to reproduce a Parkinsonian phenotype. We show that these mice do not display dopaminergic neurodegeneration nor nigral-striatal-dependent motor deficits. Furthermore, we report that Parkin loss does not synergize with mitochondrial dysfunction. Our results demonstrate that Parkin-/-/PolgAD257A/D257A mice are not a reliable model for PD and adds to a growing body of work demonstrating that Parkin loss does not synergize with mitochondrial dysfunction in mouse models of mitochondrial deficits.

583 Induction of type 17 collagen decreases ultraviolet b-induced cellular senescence in human htert/ker-ct keratinocytes

Cellular senescence is an irreversible growth arrest caused by oxidative stress and DNA damage and ultraviolet radiation mediated cellular damage is responsible for skin photoaging. The Type 17 collagen (COL17A1) expressed in epithelial hemidesmosomes plays a crucial role in maintaining hair follicle stem cells. Apocynin, (1-(4-Hydroxy-3-methoxyphenyl)ethan-1-one)) is a chemical inducer of Collagen 17A1 which promotes the Collagen 17A1 protein synthesis. Our unpublished data showed that klotho mutant (kl/kl) mice, which is a premature aging model, display increased senescence associated-β-galactosidase (Sa-β-Gal) activity, p16 and phosphorylated histone H2AX (γH2AX) expression along with deceased Collagen 17A1 expression.

Evaluation of a CRISPR/Cas9-based dual-fluorescent reporter mouse model of premature aging to investigate the mechanobiology of bone regeneration

Evaluation of a CRISPR/Cas9-based dual-fluorescent reporter mouse model of premature aging to investigate the mechanobiology of bone regeneration

Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation

ObjectiveThere is strong evidence that mitochondrial DNA mutations and mitochondrial dysfunction play a role in diabetes pathogenesis. The homozygous knock-in mtDNA mutator mouse is a model of premature aging due to the accumulation of mitochondrial DNA mutations. We used this mouse model to investigate the relationship between mitochondrial subunit expression and pancreatic islet cell composition. MethodsQuadruple immunofluorescence was used to quantify mitochondrial subunit expression (complex I and IV) and cell composition in pancreatic islets from mitochondrial DNA mutator mice (PolgAmut/mut) and control C57BL/6 mice at 12 and 44 weeks of age. ResultsMitochondrial complex I subunit expression was decreased in islets from 12 week PolgAmut/mut mice. This complex I deficiency persisted with age and was associated with decreased insulin staining intensity at 44 weeks. Complex I deficiency was greater in α-cells compared with β-cells in islets from 44 week PolgAmut/mut mice. Islet cell composition was normal in 12 week PolgAmut/mut mice, but the β: α cell ratio was decreased in islets from 44 week PolgAmut/mut mice. This was due to an increase in α-cell number linked to an increase in α-cell proliferation. ConclusionComplex I deficiency promotes α-cell proliferation and alters islet cell composition.

Invivo partial cellular reprogramming enhances liver plasticity and regeneration.

Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in hepatocytes. Transient invivo 4F expression induces partial reprogramming of adult hepatocytes to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liver-specific 4F expression invivo induces cellular plasticity and counteracts liver failure, suggesting that partial reprogramming may represent an avenue for enhancing tissue regeneration.

Oxidative Stress and Cellular Senescence Are Involved in the Aging Kidney.

Chronic kidney disease (CKD) can be considered as a clinical model for premature aging. However, non-invasive biomarkers to detect early kidney damage and the onset of a senescent phenotype are lacking. Most of the preclinical senescence studies in aging have been done in very old mice. Furthermore, the precise characterization and over-time development of age-related senescence in the kidney remain unclear. To address these limitations, the age-related activation of cellular senescence-associated mechanisms and their correlation with early structural changes in the kidney were investigated in 3- to 18-month-old C57BL6 mice. Inflammatory cell infiltration was observed by 12 months, whereas tubular damage and collagen accumulation occurred later. Early activation of cellular-senescence-associated mechanisms was found in 12-month-old mice, characterized by activation of the DNA-damage-response (DDR), mainly in tubular cells; activation of the antioxidant NRF2 pathway; and klotho downregulation. However, induction of tubular-cell-cycle-arrest (CCA) and overexpression of renal senescent-associated secretory phenotype (SASP) components was only found in 18-month-old mice. In aging mice, both inflammation and oxidative stress (marked by elevated lipid peroxidation and NRF2 inactivation) remained increased. These findings support the hypothesis that prolonged DDR and CCA, loss of nephroprotective factors (klotho), and dysfunctional redox regulatory mechanisms (NRF2/antioxidant defense) can be early drivers of age-related kidney-damage progression.

Bifidobacterium adolescentis regulates catalase activity and host metabolism and improves healthspan and lifespan in multiple species.

To identify candidate bacteria associated with aging, we performed fecal microbiota sequencing in young, middle-aged and older adults, and found lower Bifidobacterium adolescentis abundance in older individuals aged ≥60 years. Dietary supplementation of B. adolescentis improved osteoporosis and neurodegeneration in a mouse model of premature aging (Terc-/-) and increased healthspan and lifespan in Drosophila melanogaster and Caenorhabditis elegans. B. adolescentis supplementation increased the activity of the catalase (CAT) enzyme in skeletal muscle and brain tissue from Terc-/- mice, and suppressed cellular senescence in mouse embryonic fibroblasts. Transgenic deletion of catalase (ctl-2) in C. elegans abolished the effects of B. adolescentis on the lifespan and healthspan. B. adolescentis feeding also led to changes in oxidative stress-associated metabolites in Terc-/- mouse feces. These results suggest a role for B. adolescentis in improving the healthspan and lifespan through the regulation of CAT activity and host metabolism.

Ameliorating the hallmarks of cellular senescence in skeletal muscle myogenic progenitors in vitro and in vivo.

Senescence of myogenic progenitors impedes skeletal muscle regeneration. Here, we show that overexpression of the transcription factor NANOG in senescent myoblasts can overcome the effects of cellular senescence and confer a youthful phenotype to senescent cells. NANOG ameliorated primary hallmarks of cellular senescence including genomic instability, loss of proteostasis, and mitochondrial dysfunction. The rejuvenating effects of NANOG included restoration of DNA damage response via up-regulation of DNA repair proteins, recovery of heterochromatin marks via up-regulation of histones, and reactivation of autophagy and mitochondrial energetics via up-regulation of AMP-activated protein kinase (AMPK). Expression of NANOG in the skeletal muscle of a mouse model of premature aging restored the number of myogenic progenitors and induced formation of eMyHC+ myofibers. This work demonstrates the feasibility of reversing the effects of cellular senescence in vitro and in vivo, with no need for reprogramming to the pluripotent state.

Transcriptome Analysis in a Mouse Model of Premature Aging of Dentate Gyrus: Rescue of Alpha-Synuclein Deficit by Virus-Driven Expression or by Running Restores the Defective Neurogenesis.

The dentate gyrus of the hippocampus and the subventricular zone are neurogenic niches where neural stem and progenitor cells replicate throughout life to generate new neurons. The Btg1 gene maintains the stem cells of the neurogenic niches in quiescence. The deletion of Btg1 leads to an early transient increase of stem/progenitor cells division, followed, however, by a decrease during adulthood of their proliferative capability, accompanied by apoptosis. Since a physiological decrease of neurogenesis occurs during aging, the Btg1 knockout mouse may represent a model of neural aging. We have previously observed that the defective neurogenesis of the Btg1 knockout model is rescued by the powerful neurogenic stimulus of physical exercise (running). To identify genes responsible for stem and progenitor cells maintenance, we sought here to find genes underlying this premature neural aging, and whose deregulated expression could be rescued by running. Through RNA sequencing we analyzed the transcriptomic profiles of the dentate gyrus isolated from Btg1 wild-type or Btg1 knockout adult (2-month-old) mice submitted to physical exercise or sedentary. In Btg1 knockout mice, 545 genes were deregulated, relative to wild-type, while 2081 genes were deregulated by running. We identified 42 genes whose expression was not only down-regulated in the dentate gyrus of Btg1 knockout, but was also counter-regulated to control levels by running in Btg1 knockout mice, vs. sedentary. Among these 42 counter-regulated genes, alpha-synuclein (Snca), Fos, Arc and Npas4 showed significantly greater differential regulation. These genes control neural proliferation, apoptosis, plasticity and memory and are involved in aging. In particular, Snca expression decreases during aging. We tested, therefore, whether an Snca-expressing lentivirus, by rescuing the defective Snca levels in the dentate gyrus of Btg1 knockout mice, could also reverse the aging phenotype, in particular the defective neurogenesis. We found that the exogenous expression of Snca reversed the Btg1 knockout-dependent decrease of stem cell proliferation as well as the increase of progenitor cell apoptosis. This indicates that Snca has a functional role in the process of neural aging observed in this model, and also suggests that Snca acts as a positive regulator of stem cell maintenance.

Loss of \u03b1klotho causes reduced motor ability and short lifespan in zebrafish

The klotho gene encodes a transmembrane protein αKlotho that interacts with a fibroblast growth factor (FGF) receptor in renal tubular epithelial cells and functions as a co-receptor for FGF23, which is an osteocytes-derived hormone. This bone-to-kidney signal promotes urinary phosphate excretion. Interestingly, αKlotho knockout mice show an accelerated aging and a shortened life span. Similarly, C. elegans lacking the αklotho homologue showed a short life span. However, the physiological basis of aging-related function of αklotho remain unclear. The αklotho-deficient vertebrate animals other than mice have been awaited as an alternative model of premature aging. We here employed zebrafish in our study and revealed that αklotho mutant zebrafish appeared to be normal at 3 months postfertilization (mpf) but eventually underwent premature death by 9 mpf, while normal zebrafish is known to survive for 42 months. We also assessed the motor ability of zebrafish in a forced swimming assay and found that αklotho mutant zebrafish displayed reduced swimming performance before their survival declined. A recent study also reported a similar finding that αklotho-deficient zebrafish exhibited a short life span and reduced spontaneous movements. Taken together, these results suggest that αKlotho mutant zebrafish show premature aging and are useful to investigate aging in vertebrates.