Evaluation of the Anti-Aging Effects of a Probiotic Combination Isolated From Centenarians in a SAMP8 Mouse Model.

Population aging is a prominent global problem in today's society. However, there are currently no good methods to treat or prevent aging, so anti-aging research has crucial implications. In this research, we screened bacteria from centenarians, and finally selected four probiotics (Lactobacillus fermentum SX-0718, L. casei SX-1107, Bifidobacterium longum SX-1326, and B. animalis SX-0582) to form a probiotic combination. By using the senescence accelerated mouse prone 8 (SAMP8) model, the anti-aging effects of the probiotic combination were evaluated by using behavioural testing, neuroinflammation, intestinal inflammation, and intestinal microbiota. The results showed that probiotic combination improved the impaired spatial memory, motor dysfunction, and decreased exploratory behavior in aging mice. The probiotic combination inhibited Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NFκB)-induced neuroinflammation and up-regulated the expression of Sirt 1 to protect hippocampal neurons. At the same time, the probiotic combination regulated the intestinal microbiota, reduced the relative abundance of Alistipes and Prevotella in SAMP8 mice, inhibited TLR4/NFκB-induced intestinal inflammation, and increased the expression of intestinal permeability related proteins zonula occludens-1 (ZO-1) and Occuldin. The anti-aging effects of the probiotic combination may be through the regulating intestinal microbiota and inhibiting TLR4/NFκB-induced inflammation. This research provides the basis and technical support for the future production and application of the probiotic combination.

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction.

Cockayne syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sunlight, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limitations of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic gene-corrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display increased susceptibility to DNA damage stress. Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6. We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives (MSCs and NSCs) in the absence or presence of ultraviolet (UV) and replicative stresses, revealing that defects in DNA repair account for CS pathologies. Moreover, we generate autologous GC-MSCs free of pathogenic mutation under a cGMP (Current Good Manufacturing Practice)-compliant condition, which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS. Collectively, our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.

Recent Advances on Reactive Oxygen Species-Responsive Delivery and Diagnosis System.

Reactive oxygen species (ROS) play crucial roles in biological metabolism and intercellular signaling. However, ROS level is dramatically elevated due to abnormal metabolism during multiple pathologies, including neurodegenerative diseases, diabetes, cancer, and premature aging. By taking advantage of the discrepancy of ROS levels between normal and diseased tissues, a variety of ROS-sensitive moieties or linkers have been developed to design ROS-responsive systems for the site-specific delivery of drugs and genes. In this review, we summarized the ROS-responsive chemical structures, mechanisms, and delivery systems, focusing on their current advances for precise drug/gene delivery. In particular, ROS-responsive nanocarriers, prodrugs, and supramolecular hydrogels are summarized in terms of their application for drug/gene delivery, and common strategies to elevate or diminish cellular ROS concentrations, as well as the recent development of ROS-related imaging probes were also discussed.

Hutchinson-Gilford Progeria Syndrome: Challenges at Bench and Bedside.

The structural nuclear proteins known as "lamins" (A-type and B-type) provide a scaffold for the compartmentalization of genome function that is important to maintain genome stability. Mutations in the LMNA gene -encoding for A-type lamins- are associated with over a dozen of degenerative disorders termed laminopathies, which include muscular dystrophies, lipodystrophies, neuropathies, and premature ageing diseases such as Hutchinson Gilford Progeria Syndrome (HGPS). This devastating disease is caused by the expression of a truncated lamin A protein named "progerin". To date, there is no effective treatment for HGPS patients, who die in their teens from cardiovascular disease. At a cellular level, progerin expression impacts nuclear architecture, chromatin organization, response to mechanical stress, and DNA transactions such as transcription, replication and repair. However, the current view is that key mechanisms behind progerin toxicity still remain to be discovered. Here, we discuss new findings about pathological mechanisms in HGPS, especially the contribution of replication stress to cellular decline, and therapeutic strategies to ameliorate progerin toxicity. In particular, we present evidence for retinoids and calcitriol (hormonal vitamin D metabolite) being among the most potent compounds to ameliorate HGPS cellular phenotypes in vitro, providing the rationale for testing these compounds in preclinical models of the disease in the near term, and in patients in the future.

Hepatic manifestations of telomere biology disorders.

A 51-year-old Caucasian male was referred for evaluation of variceal bleeding. Laboratory tests were remarkable for mild thrombocytopenia and moderate alkaline phosphatase elevation. Synthetic liver function was well preserved. Abdominal computed tomography scan revealed moderate splenomegaly, gastric varices, and normal hepatic contour. A transjugular liver biopsy was performed revealing findings of nodular regenerative hyperplasia with no significant fibrosis or necroinflammatory activity. Hepatic venous pressure gradient was elevated at 31 mmHg, consistent with clinically significant portal hypertension. The clinical course was complicated by refractory gastric variceal bleeding requiring a surgical portosystemic shunt. Approximately seven years after the initial presentation, the patient developed progressive dyspnoea and a diagnosis of idiopathic pulmonary fibrosis was made. Contrast-enhanced echocardiogram was not suggestive of hepatopulmonary syndrome or portopulmonary hypertension. Given this new diagnosis a telomere biology disorder was suspected. A flow-fluorescence in situ hybridisation analysis for telomere length assessment revealed telomere lengths below the first percentile in both lymphocytes and granulocytes. Next generation sequencing analysis identified a heterozygous mutation involving the hTERT gene (Histidine983Threonine). The lung disease unfortunately progressed in the subsequent two years, leading to the patient's death nine years after his initial presentation with portal hypertension. During those nine years two brothers also developed idiopathic pulmonary fibrosis. The questions that arise from this case include.

The Potential of iPSCs for the Treatment of Premature Aging Disorders.

Premature aging disorders including Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome, are a group of rare monogenic diseases leading to reduced lifespan of the patients. Importantly, these disorders mimic several features of physiological aging. Despite the interest on the study of these diseases, the underlying biological mechanisms remain unknown and no treatment is available. Recent studies on HGPS (due to mutations of the LMNA gene encoding for the nucleoskeletal proteins lamin A/C) have reported disruptions in cellular and molecular mechanisms modulating genomic stability and stem cell populations, thus giving the nuclear lamina a relevant function in nuclear organization, epigenetic regulation and in the maintenance of the stem cell pool. In this context, modeling premature aging with induced pluripotent stem cells (iPSCs) offers the possibility to study these disorders during self-renewal and differentiation into relevant cell types. iPSCs generated by cellular reprogramming from adult somatic cells allows researchers to understand pathophysiological mechanisms and enables the performance of drug screenings. Moreover, the recent development of precision genome editing offers the possibility to study the complex mechanisms underlying senescence and the possibility to correct disease phenotypes, paving the way for future therapeutic interventions.

A High Throughput Phenotypic Screening reveals compounds that counteract premature osteogenic differentiation of HGPS iPS-derived mesenchymal stem cells.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare fatal genetic disorder that causes systemic accelerated aging in children. Thanks to the pluripotency and self-renewal properties of induced pluripotent stem cells (iPSC), HGPS iPSC-based modeling opens up the possibility of access to different relevant cell types for pharmacological approaches. In this study, 2800 small molecules were explored using high-throughput screening, looking for compounds that could potentially reduce the alkaline phosphatase activity of HGPS mesenchymal stem cells (MSCs) committed into osteogenic differentiation. Results revealed seven compounds that normalized the osteogenic differentiation process and, among these, all-trans retinoic acid and 13-cis-retinoic acid, that also decreased progerin expression. This study highlights the potential of high-throughput drug screening using HGPS iPS-derived cells, in order to find therapeutic compounds for HGPS and, potentially, for other aging-related disorders.

Anti-Aging Strategies Based on Cellular Reprogramming.

Aging can be defined as the progressive decline in the ability of a cell or organism to resist stress and disease. Recent advances in cellular reprogramming technologies have enabled detailed analyses of the aging process, often involving cell types derived from aged individuals, or patients with premature aging syndromes. In this review we discuss how cellular reprogramming allows the recapitulation of aging in a dish, describing novel experimental approaches to investigate the aging process. Finally, we explore the role of epigenetic dysregulation as a driver of aging, discussing how epigenetic reprogramming may be harnessed to ameliorate aging hallmarks, both in vitro and in vivo. A better understanding of the reprogramming process may indeed assist the development of novel therapeutic strategies to extend a healthy lifespan.

Anti-aging Effect of Transplanted Amniotic Membrane Mesenchymal Stem Cells in a Premature Aging Model of Bmi-1 Deficiency.

To determine whether transplanted amniotic membrane mesenchymal stem cells (AMSCs) ameliorated the premature senescent phenotype of Bmi-1-deficient mice, postnatal 2-day-old Bmi-1(-/-) mice were injected intraperitoneally with the second-passage AMSCs from amniotic membranes of ß-galactosidase (ß-gal) transgenic mice or wild-type (WT) mice labeled with DiI. Three reinjections were given, once every seven days. Phenotypes of 5-week-old ß-gal(+) AMSC-transplanted or 6-week-old DiI(+) AMSC-transplanted Bmi-1(-/-) mice were compared with vehicle-transplanted Bmi-1(-/-) and WT mice. Vehicle-transplanted Bmi-1(-/-) mice displayed growth retardation and premature aging with decreased cell proliferation and increased cell apoptosis; a decreased ratio and dysmaturity of lymphocytic series; premature osteoporosis with reduced osteogenesis and increased adipogenesis; redox imbalance and DNA damage in multiple organs. Transplanted AMSCs carried Bmi-1 migrated into multiple organs, proliferated and differentiated into multiple tissue cells, promoted growth and delayed senescence in Bmi-1(-/-) transplant recipients. The dysmaturity of lymphocytic series were ameliorated, premature osteoporosis were rescued by promoting osteogenesis and inhibiting adipogenesis, the oxidative stress and DNA damage in multiple organs were inhibited by the AMSC transplantation in Bmi-1(-/-) mice. These findings indicate that AMSC transplantation ameliorated the premature senescent phenotype of Bmi-1-deficient mice and could be a novel therapy to delay aging and prevent aging-associated degenerative diseases.

Emerging therapeutic approaches based on nanotechnology for the treatment of diseases associated with telomere dysfunction.

Telomeric diseases are a group of rare progeroid genetic syndromes, presenting premature aging phenotypes, characterized for defects on telomere maintenance. In humans, telomeres are heterochromatic structures consisting of long TTAGGG repeats located at the chromosomal ends, which shorten progressively after each DNA replication because of the 'end replication problem'. Critically short telomeres activate a DNA damage response that leads to the arrest of the cell cycle and resulting in cellular senescence or apoptosis. Furthermore, excessively short telomeres are prone to create telomeric fusions, causing genomic instability and malignant transformation. In order to counteract this process, there are two enzymatic complexes, the telomerase complex, with the capacity to elongate telomeres; and the shelterin complex, which protects them from being recognized as DNA breaks. Over the last few decades, several studies have confirmed that critically short telomeres and defects in telomere-associated enzymatic complexes are involved in the development of a group of rare human genetic diseases, with the accumulation of excessive telomere attrition as the underlying cause of these pathologies. Despite the severity of these disorders, there is no curative treatment for any of them. In light of this, this review summarizes the most important defective telomere diseases, their current management, and it presents possible therapeutic strategies based on nanotechnology which may open up new possibilities for their treatment.

Is aging a barrier to reprogramming? Lessons from induced pluripotent stem cells.

The discovery of induced pluripotent stem cells (iPSCs) has the potential to revolutionize the field of regenerative medicine. In the past few years, iPSCs have been the subject of intensive research towards their application in disease modeling and drug screening. In the future, these cells may be applied in cell therapy to replace or regenerate tissues by autologous transplantation. However, two major hurdles need to be resolved in order to reach the later goal: the low reprogramming efficiency and the safety risks, such as the integration of foreign DNA into the genome of the cells and the tumor formation potential arising from transplantation of residual undifferentiated cells. Recently, aging emerged as one of the barriers that accounts, at least in part, for the low reprogramming efficiency of bona fide iPSCs. Here, we review the molecular pathways linking aging and reprogramming along with the unanswered questions in the field. We discuss whether reprogramming rejuvenates the molecular and cellular features associated with age, and present the recent advances with iPSC-based models, contributing to our understanding of physiological and premature aging.

Psychoneuroendocrine interventions aimed at attenuating immunosenescence: a review.

There is evidence suggesting that immunosenescence can be accelerated by external factors such as chronic stress. Here we review potential psychoneuroendocrine determinants of premature aging of the immune system and discuss available interventions aimed at attenuating immunosenescence. Chronic stress may accelerate various features of immunosenescence by activating key allostatic systems, notably the hypothalamic-pituitary-adrenal axis. The immunological impact of such neuroendocrine dysregulation may be further amplified by a dramatic decline in dehydroepiandrosterone (DHEA) levels, acting in part as an endogenous glucocorticoid antagonist. Stress-buffering strategies show beneficial effects on various biomarkers in elderly populations. Likewise, supplementation of DHEA, melatonin or growth hormone has yielded significant beneficial effects in a number of studies, including: increased well-being, memory performance, bone mineral density and improved immunocompetence as evidenced by results of in vitro (T cell proliferation, cytotoxicity, cytokine production), and in vivo immune challenges. However, the side-effects of hormonal supplementation are also discussed. Finally, moderate exercise via the promotion of cortisol/DHEA balance or epigenetic modifications, is associated with lower serum pro-inflammatory cytokines, greater lymphoproliferative responses and lower counts of senescent T cells. Taken together, these data suggest that immune system is plastic and immunosenescence can be attenuated psychoneuroendocrine interventions.

Loss of renal function causes premature aging of the immune system.

BACKGROUND: Uremia-associated immune deficiency is a well-known complication of loss of renal function and contributes significantly to the overall mortality and morbidity of patients with end-stage renal disease. Chronic inflammation and increased oxidative stress are underlying the uremia-associated immune deficiency. SUMMARY: In this review, the differential impact of uremia on the cellular immune system is summarized. Virtually all immune cells studied show a combination of an activated status and loss of function. However, uremia preferentially decreases the number and function of lymphoid cells while myeloid cells show normal and/or elevated cell numbers with increased production of inflammatory cytokines and reactive oxygen species. These particular changes are compatible with immunological aging, which is characterized by loss of thymic function, attrition of telomeres and an expanded memory T cell population. Similar to aging in healthy individuals, the proinflammatory and potential cardiotoxic subsets of CD28(null) T cells and CD16(+) monocytes are increased. Epigenetically changed hematopoietic stem cells may be involved in immunological aging as specific DNA regions become hypermethylated. Proinflammatory T cells and monocytes persist after kidney transplantation, which constitutes a persistent cardiovascular risk factor. Possible therapeutic options to reverse or halt uremia-associated immunological aging are discussed. KEY MESSAGES: Premature aging of the immune system is a dominant feature in patients with end-stage renal failure, which corresponds to immunological aging in elderly healthy individuals, which is characterized by preferential loss of cells belonging to the lymphoid cell lineage, inflammation and expansion of proinflammatory immune cells.

[The method of cryotherapeutic correction for premature aging and permeability of the blood-brain barrier in Afghanistan veterans with initial manifestations of insufficient blood supply to the brain].

The levels of neurospecific peptides in the systemic circulation and the rate of biological aging of veterans of war in Afghanistan were studied. A significant increase in the level of matrix metalloproteinase-9 reflecting the increased permeability of the blood-brain barrier in the initial manifestations of insufficient blood supply to the brain was found. After a course of general aerocryotherapy the optimization of biological and cardiopulmonary age were marked, which indicates a slowing of the biological aging.

[The influence of different massage techniques on the characteristics of biological age in the subjects above the age of 30 years].

This paper is designed to demonstrate the efficacy of different massage modalities used to decrease the biological age in relatively healthy subjects between 30 and 69 years of life. The study involved 78 subjects (67 women and 11 men). Each of them underwent a course of 10 sessions of massage of the collar and upper back regions for the prevention of premature ageing and the reduction of the biological age. Cryomassage was performed with the use of cryocare packs and vacuum massage on the Cerri apparatus (Italy). The control group was comprised of the subjects given no treatment. The main characteristics measured before and after therapy included biomarkers of ageing and biological age. The results of the study indicate that both cryogenic and vacuum massage effectively improves certain biomarkers of ageing; namely, such treatment reduces systolic, diastolic, and pulse pressure, increase pulmonary vital capacity and breath holding time in expiration, improves the sense of equilibrium, self-assessment of health condition, and concentration of attention. Taken together, these effects contribute to the reduction of the biological age of the subjects and prevent their premature ageing to a greater extent than in the untreated persons.

[Caloric restriction in primates: how efficient as an anti-aging approach?]. / La restriction calorique chez les primates.

Caloric restriction (CR) is the only non-genetic intervention known to date to slow the onset of age-related diseases and increase average and maximum lifespan in several species. Its interest is continually growing, particularly for the identification of mechanisms involved in increasing longevity. Unlike studies in invertebrate and rodent models have provided some indication about the mechanisms of the CR, the efficacy of CR as an anti-aging protocol in primates has not yet been fully established. In this review we present the advantages of using non human primates as relevant models to the study of human aging in general and specifically in the context of therapeutic interventions applicable to humans, such as CR. Through the longitudinal findings in the Grey Mouse Lemur (Microcebus murinus), we stress the importance of primate studies in the context of research on aging and their potential to advance the development of molecules which can mimic the beneficial effects of CR, already observed in some species, without imposing a reduced calorie diet.

Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: molecules to patients.

A workshop(1) to share, consider and discuss the latest developments in understanding xeroderma pigmentosum and other human diseases caused by defects in nucleotide excision repair (NER) of DNA damage was held on September 21-24, 2010 in Virginia. It was attended by approximately 100 researchers and clinicians, as well as several patients and representatives of patient support groups. This was the third in a series of workshops with similar design and goals: to emphasize discussion and interaction among participants as well as open exchange of information and ideas. The participation of patients, their parents and physicians was an important feature of this and the preceding two workshops. Topics discussed included the natural history and clinical features of the diseases, clinical and laboratory diagnosis of these rare diseases, therapeutic strategies, mouse models of neurodegeneration, molecular analysis of accelerated aging, impact of transcriptional defects and mitochondrial dysfunction on neurodegeneration, and biochemical insights into mechanisms of NER and base excision repair.

Early onset ageing and service preparation in people with intellectual disabilities: institutional managers' perspective.

Although longevity among older adults with intellectual disabilities is increasing, there is limited information on their premature aging related health characteristics and how it may change with increasing age. The present paper provides information of the institutional manager's perception on early onset aging and service preparation for this population. We used purposive sampling to recruit 54 institutional managers who care for people with intellectual disabilities in Taiwan. The present study employed a cross-sectional design using a self-administrative structured questionnaire that was completed by the respondents in November 2009. The results showed that more than 90% of the respondents agreed with earlier onset aging characteristics of people with ID. However, nearly all of the respondents expressed that the government policies were inadequate and the institution is not capable of caring for aging people with ID, and more than half of them did not satisfy to their provisional care for this group of people. With regard to the service priority of government aging policy for people with ID, the respondent expressed that medical care, financial support, daily living care were the main areas in the future policy development for them. The factors of institutional type, expressed adequacy of government's service, respondent's job position, age, and working years in disability service were variables that can significantly predict the positive perceptions toward future governmental aging services for people with ID (adjusted R(2) = 0.563). We suggest that the future study strategy should underpin the aging characteristics of people with intellectual disabilities and its differences with general population to provide the useful information for the institutional caregivers.

Adults with cerebral palsy: a workshop to define the challenges of treating and preventing secondary musculoskeletal and neuromuscular complications in this rapidly growing population.

Although the neurological injury associated with cerebral palsy (CP) is non-progressive, adults with the disorder often develop musculoskeletal and neurological symptoms, such as severe pain, chronic fatigue, and a premature decline in mobility and function, as they age. Little is known about how to manage, much less prevent, these symptoms. This paper summarizes the findings of a multi-disciplinary workshop, sponsored by the Cerebral Palsy International Research Foundation, the American Academy for Cerebral Palsy and Developmental Medicine, and Reaching for the Stars, convened to review current knowledge and begin to develop a blueprint for future research. The goals of the workshop were to (1) define the current incidence and prevalence of CP, (2) review the known complications for persons aging with CP, (3) review current understanding of physiological processes that may contribute to loss of function and premature aging in CP, (4) evaluate current treatment interventions in terms of long-term outcomes, (5) identify cutting-edge technologies in neurorehabilitation that may help prevent or treat the effects of accelerated aging for persons diagnosed with CP, and (6) identify strategies to ensure that individuals with CP receive evidence-based care as they transition from pediatric to adult-care services.

HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches.

Progeroid syndromes are heritable human disorders displaying features that recall premature ageing. In these syndromes, premature aging is defined as "segmental" since only some of its features are accelerated. A number of cellular biological pathways have been linked to aging, including regulation of the insulin/growth hormone axis, pathways involving ROS metabolism, caloric restriction, and DNA repair. The number of identified genes associated with progeroid syndromes has increased in recent years, possibly shedding light as well on mechanisms underlying ageing in general. Among these, premature aging syndromes related to alterations of the LMNA gene have recently been identified. This review focuses on Hutchinson-Gilford Progeria syndrome and Restrictive Dermopathy, two well-characterized Lamin-associated premature aging syndromes, pointing out the current knowledge concerning their pathophysiology and the development of possible therapeutic approaches.