Patient-Reported Outcomes of Maxillomandibular Surgery for Obstructive Sleep Apnea Treatment: A Scoping Review.

(1) Background: The present scoping review aims to scrutinize all existing patient-reported outcomes and assess the perspectives of obstructive sleep apnea patients after maxillomandibular surgery. (2) Methods: The review was carried out according to the extensions for scoping reviews using the PRISMA-ScR guidelines. Several databases were used to carry out the initial search. This study included randomized controlled trials, cohort studies, cross-sectional and case-control studies. The included studies considered patients with obstructive sleep apnea who were submitted to orthognathic surgery as the main subjects, and the patient's perception of quality of life, satisfaction, treatment experience and side effects were assessed. (3) Results: From 1407 examined articles, a total of 16 were included. Most of the included studies used more than one questionnaire to assess quality of life, except for five articles. The most commonly referred instruments were the Epworth Sleepiness Scale, SF-36, the Functional Outcomes of Sleep and Ottawa Sleep Apnea. The most commonly assessed outcomes were sleep quality, daytime function, facial aesthetics, dental function and emotional health. (4) Conclusions: The number of variables that can be evaluated from a patient's perspective are endless, as are the tools available to assess them. Not all of these tools, which are generally questionnaires, assess all the various outcomes, and some do not compare the pre- and post-surgical situations. Most of them are generic and lack specificity for obstructive sleep apnea.

Reconstruction of Oronasal Fistula with Tongue Flap: A Cleft Palate Report.

Oronasal fistula can persist after conventional secondary alveolar bone graft surgery, which may lead to functional issues, such as regurgitation of fluids from the oral to the nasal cavity. This manuscript describes a clinical case of a patient with a bilateral cleft lip and palate that underwent tongue graft surgery for closure of an oronasal fistula after three failed local mucosa flap surgeries. The multidisciplinary treatment was comprised of orthodontic treatment, mucosa and alveolar grafts for palate closure and aesthetic rehabilitation of the anterior maxillary teeth. Smile aesthetics were noticeably improved, enhancing the patient's self-perception and confidence.

Neuropeptide signaling and SKN-1 orchestrate differential responses of the proteostasis network to dissimilar proteotoxic insults.

The protein homeostasis (proteostasis) network (PN) encompasses mechanisms that maintain proteome integrity by controlling various biological functions. Loss of proteostasis leads to toxic protein aggregation (proteotoxicity), which underlies the manifestation of neurodegeneration. How the PN responds to dissimilar proteotoxic challenges and how these responses are regulated at the organismal level are largely unknown. Here, we report that, while torsin chaperones protect from the toxicity of neurodegeneration-causing polyglutamine stretches, they exacerbate the toxicity of the Alzheimer's disease-causing Aß peptide in neurons and muscles. These opposing effects are accompanied by differential modulations of gene expression, including that of three neuropeptides that are involved in tailoring the organismal response to dissimilar proteotoxic insults. This mechanism is regulated by insulin/IGF signaling and the transcription factor SKN-1/NRF. Our work delineates a mechanism by which the PN orchestrates differential responses to dissimilar proteotoxic challenges and points at potential targets for therapeutic interventions.

Age-related hearing loss, depression and auditory amplification: a randomized clinical trial.

PURPOSE: Our study investigates the effectiveness of aural rehabilitation to decrease depressive symptoms in older adults, and the relationship between hearing loss and depression. METHODS: A randomized controlled study was conducted at a hearing rehabilitation center with people over 65 years old. Participants were randomly allocated to the intervention group who received hearing aids, or to the control group. Data collection included pure-tone audiometry and a Portuguese version of the Geriatric Depression Scale assessed at two time points: baseline (P0) and after 4-week period (P1). RESULTS: The results show that the increase of hearing thresholds in pure-tone audiometry is associated with a significant increase in depressive symptoms (p = 0.001). The effect of aural rehabilitation for improving depressive symptoms was significant in intervention group (p = 0.000) and between groups (p = 0.003) in P1. CONCLUSION: Age-related hearing loss has adverse effects on older adults' mental health, due to reduced hearing inputs that may increase levels of effort to communicate and affect social engagement, which lead to depression. Hearing aid use improves levels of depression and can promote greater quality of life in older adults.

A New Orthodontic-Surgical Approach to Mandibular Retrognathia.

(1) Background: Mandibular deficiency is one of the most common growth disorders of the facial skeleton. Recently, distraction osteogenesis has been suggested as the treatment of choice for overcoming the limitations of conventional orthognathic surgery; (2) Methods: A new custom-manufactured dental-anchored distractor was built and anchored in the first molar and lower canine. It consists of a stainless-steel disjunction screw, adapted and welded to the orthodontic bands through two 1.2 mm diameter connector bars with a universal silver-based and cadmium-free solder; (3) Results: The distractor described can be a useful tool to correct mandibular retrognathia and is better tolerated by patients, especially in severe cases; (4) Conclusions: The dental-anchored distractor increases the anterior mandibular bone segment without affecting the gonial angle or transverse angulation of the segments and avoids posterior mandibular rotation, overcoming the limitations of conventional surgical treatment.

Low doses of ionizing radiation activate endothelial cells and induce angiogenesis in peritumoral tissues.

PURPOSE: During radiotherapy the peritumoral tissues are daily exposed to subtherapeutic doses of ionizing radiation. Herein, the biological and molecular effects of doses lower than 0.8 Gy per fraction (LDIR), previously described as angiogenesis inducers, were assessed in human peritumoral tissues. MATERIAL AND METHODS: Paired biopsies of preperitoneal adipose tissue were surgically collected from 16 patients diagnosed with locally advanced rectal cancer who underwent neo-adjuvant radiotherapy. One of the biopsies is located in the vicinity of the region where the tumor received the prescribed dose of radiation, and thus exposed to LDIR; the other specimen, outside all beam apertures, was used as an internal calibrator (IC). Microvessel density (MDV) was quantified by immunohistochemistry and the expression of angiogenic, pro-inflammatory, adhesion and oxidative stress genes was assessed by quantitative RT-PCR using exclusively endothelial cells (ECs) isolated by laser capture microdissection microscopy. RESULTS: LDIR activated peritumoral ECs by significantly up-regulating the expression of several pro-angiogenic genes such as VEGFR1, VEGFR2, ANGPT2, TGFB2, VWF, FGF2, HGF and PDGFC and down-regulating the pro-inflammatory IL8 marker. Accordingly, the MVD was significantly increased in peritumoral tissues exposed to LDIR, compared to the IC. The patients that yielded a larger pro-angiogenic response, also showed the highest MVD. CONCLUSIONS: LDIR activate ECs in peritumoral tissues that are associated with increased MVD. Although the technological advances in radiotherapy have contributed to reduce the damage to healthy tissues over the past years, the anatomical regions receiving LDIR should be taken into account in the treatment plan report for patient follow-up and in future studies to correlate these doses with tumor dissemination.

Screening for Anemia and Iron Deficiency in the Adult Portuguese Population.

Anemia and iron deficiency (ID) can impair quality of life and socioeconomic development. We evaluated the prevalence of anemia and ID in the adult Portuguese population in real-life contexts by gender, age, and pregnancy status. We performed a cross-sectional screening in adult individuals in mainland Portugal from 2013 to 2017. Participants completed a survey about demographics and signs or symptoms compatible with anemia, and ID and hemoglobin and ferritin concentrations were determined by point-of-care tests. We estimated and compared prevalence ratios (PR) of anemia and ID using Poisson regression with robust variance and the Wald chi-square test. We collected data from 11,030 individuals (26% men, 64% nonpregnant women, and 10% pregnant women). We found anemia in 51.8% (95% CI 50.1-53.4%) of nonpregnant women in fertile age, 46.6% (95% CI 44.7-48.6%) of nonpregnant women >51 years, 38.2% (95% CI 35.4-41.1%) of pregnant women, and 33.3% (95% CI 31.6-35.1%) of men. The prevalence of ID was 72.9% (95% CI 71.4-74.4%) in nonpregnant women in fertile age, 50.5% (95% CI 48.5-52.4%) in nonpregnant women >51 years, 94.8% (95% CI 93.3-96.0%) in pregnant women, and 28.9% (95% CI 27.3-30.6%) in men. We found significant associations between the prevalence of anemia or ID and nonpregnant women (PR: 1.50, 95% CI 1.42-1.59 or PR: 2.21, 95% CI 2.09-2.35, respectively), manifestation of signs or symptoms (PR: 1.19, 95% CI 1.53-1.23 or PR: 1.22, 95% CI 1.18-1.26), pregnant women (PR: 0.74, 95% CI 0.68-0.80 or PR: 1.30, 95% CI 1.27-1.33), and nonpregnant women ≤51 years (PR: 1.11, 95% CI 1.06-1.17 or PR: 1.42, 95% CI 1.36-1.48). In conclusion, anemia and ID represent moderate to severe public health problems, particularly among women in fertile age and in 3rd trimester, of pregnancy emphasizing the need to raise the public and health professionals' awareness of these problems and their prevention, diagnosis, and treatment.

Low doses of ionizing radiation enhance angiogenesis and consequently accelerate post-embryonic development but not regeneration in zebrafish.

Low doses of ionizing radiation (LDIR) activate endothelial cells inducing angiogenesis. In zebrafish, LDIR induce vessel formation in the sub-intestinal vessels during post-embryonic development and enhance the inter-ray vessel density in adult fin regeneration. Since angiogenesis is a crucial process involved in both post-embryonic development and regeneration, herein we aimed to understand whether LDIR accelerate these physiological conditions. Our data show that LDIR upregulate the gene expression of several pro-angiogenic molecules, such as flt1, kdr, angpt2a, tgfb2, fgf2 and cyr61in sorted endothelial cells from zebrafish larvae and this effect was abrogated by using a vascular endothelial growth factor receptor (VEGFR)-2 tyrosine kinase inhibitor. Irradiated zebrafish present normal indicators of developmental progress but, importantly LDIR accelerate post-embryonic development in a VEGFR-2 dependent signaling. Furthermore, our data show that LDIR do not accelerate regeneration after caudal fin amputation and the gene expression of the early stages markers of regeneration are not modulated by LDIR. Even though regeneration is considered as a recapitulation of embryonic development and LDIR induce angiogenesis in both conditions, our findings show that LDIR accelerate post-embryonic development but not regeneration. This highlights the importance of the physiological context for a specific phenotype promoted by LDIR.

Qualidade de Vida e Participação em Iniciativas de Base Comunitária: Um estudo num município da zona centro de Portugal / Quality of Life and Participation in Community-Based Programs: A study with a municipality in central Portugal / Calidad de vida y participación en iniciativas comunitarias: un estudio en un municipio del centro de Portugal

Face ao reconhecimento da importância da participação social como fator promotor de envelhecimento bem-sucedido, procura-se, através de um estudo de natureza quantitativo, analisar os efeitos de variáveis sociodemográficas e da participação social em atividades/programas de base comunitária, promovidas por um município da zona centro de Portugal, ao nível da qualidade de vida de pessoas com mais de 56 anos, residentes no concelho.

Dado el reconocimiento de la importancia de la participación social como un factor que promueve el envejecimiento exitoso, un estudio cuantitativo busca analizar los efectos de las variables sociodemográficas y la participación social en actividades / programas basados en la comunidad promovidos. por un municipio del centro de Portugal, en términos de calidad de vida de las personas mayores de 56 años, residentes en el municipio.

Considering the recognition of social participation as a relevant factor for promoting successful ageing, a study of quantitative nature was conducted in order to analyze the effects of sociodemographic variables and of social participation in community-based activities/ programs, promoted by a municipality in central Portugal, into the level of quality of life of its habitants, over 56 years of age.

Low doses of ionizing radiation activate endothelial cells and induce angiogenesis in peritumoral tissues.

PURPOSE: During radiotherapy the peritumoral tissues are daily exposed to subtherapeutic doses of ionizing radiation. Herein, the biological and molecular effects of doses lower than 0.8 Gy per fraction (LDIR), previously described as angiogenesis inducers, were assessed in human peritumoral tissues. MATERIAL AND METHODS: Paired biopsies of preperitoneal adipose tissue were surgically collected from 16 patients diagnosed with locally advanced rectal cancer who underwent neo-adjuvant radiotherapy. One of the biopsies is located in the vicinity of the region where the tumor received the prescribed dose of radiation, and thus exposed to LDIR; the other specimen, outside all beam apertures, was used as an internal calibrator (IC). Microvessel density (MDV) was quantified by immunohistochemistry and the expression of several pro-angiogenic genes was assessed by quantitative RT-PCR using exclusively endothelial cells (ECs) isolated by laser capture microdissection microscopy. RESULTS: LDIR activated peritumoral ECs by significantly up-regulating the expression of several pro-angiogenic genes such as VEGFR1, VEGFR2, ANGPT2, TGFB2, VWF, FGF2, HGF and PDGFC. Accordingly, the MVD was significantly increased in peritumoral tissues exposed to LDIR, compared to the IC. The patients that yielded a larger pro-angiogenic response, also showed the highest MVD. CONCLUSIONS: LDIR activate ECs in peritumoral tissues that are associated with increased MVD. Although the technological advances in radiotherapy have contributed to reduce the damage to healthy tissues over the past years, the anatomical regions receiving LDIR should be taken into account in the treatment plan report for patient follow-up and in future studies to correlate these doses with tumor dissemination.

Low Doses of Ionizing Radiation Enhance the Angiogenic Potential of Adipocyte Conditioned Medium.

At low doses, ionizing radiation activates endothelial cells and promotes angiogenesis. However, it is still unknown if other cells may contribute to this process. In this study, the effect of low-dose ionizing radiation (LDIR) in modulating the pro-angiogenic potential of adipocytes was investigated. Adipocytes are known to secrete multiple angiogenic factors and adipokines that induce angiogenesis. In this work, a confluent monolayer of 3T3-L1 pre-adipocytes was exposed to low doses (0.1 and 0.3 Gy) and to higher doses (0.5, 0.8 and 1.0 Gy), as control. Our data show that the adipocyte-conditioned media (A-CM) from mature adipocytes differentiated from low-dose irradiated pre-adipocytes presented a higher angiogenic potential, compared to mature adipocytes differentiated from sham-irradiated control preadipocytes. The vascular endothelial growth factor (VEGF)-A levels were significantly increased in A-CM from the 0.1 Gy (P < 0.05) and 0.3 Gy (P < 0.01) experimental conditions and a significant increase was found in response to 0.3 Gy dose of radiation for VEGF-C, angiopoietin-2 (ANG-2) and hepatocyte growth factor (HGF). Moreover, 0.3 Gy dose of radiation significantly increased the expression of matrix metalloproteinase (MMP)-2 active forms. In vitro, the A-CM from the 0.1 and 0.3 Gy doses experimental conditions significantly accelerated endothelial cell migration after an in vitro wound healing assay. Importantly, in vivo, the A-CM corresponding to the 0.3 Gy experimental condition significantly induced the growth of more blood vessels towards the inoculation area in the chick embryo chorioallantoic membrane (CAM). In conclusion, this work reveals a new mechanism by which low-dose radiation might promote angiogenesis, enhancing the angiogenic potential of A-CM.

Prevalence and prognostic impact of anemia and iron deficiency in patients hospitalized in an internal medicine ward: The PRO-IRON study.

OBJECTIVES: To assess prevalence, predictive factors, and prognostic impact on in-hospital mortality of anemia, iron deficiency anemia (IDA), iron deficiency with or without anemia (ID), and iron deficiency without anemia (IDWA) in patients admitted to an internal medicine ward. METHODS: This 1-year prospective study collected data on demographics, medical history, and blood tests in 771 consecutive patients on admission. RESULTS: Most patients were ≥65 years old (80%) and had hypertension (63%), moderate chronic kidney disease (CKD) (43%), and heart failure (41%). Prevalence of anemia, IDA, ID, and IDWA was 67%, 41%, 58%, and 18%, respectively. Anemia was independently associated with age ≥65 years (OR 1.76, 95% CI 1.15-2.70), active cancer (OR 2.44, 95% CI 1.42-4.39), and moderate CKD (OR 1.65, 95% CI 1.12-2.43). ID was independently associated with female gender (OR 2.29, 95% CI 1.64-3.22), heart failure (OR 1.65, 95% CI 1.16-2.37), and moderate CKD (OR 2.95, 95% CI 2.04-4.30). Incidence of in-hospital mortality was 21% and independently associated with anemia (RR 1.82, 95% CI 1.21-2.74). CONCLUSIONS: Anemia and iron deficiency were highly prevalent in internal medicine patients. As anemia negatively impacts on in-hospital mortality, awareness should be raised for effective diagnosis and management of these comorbidities in hospitalized patients.

A case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient.

Programmed cell death-1 protein (PD-1) is an immune checkpoint that has gained popularity in the treatment of several advanced cancers. Inhibiting this checkpoint is known to enhance immune response, but is also known to diminish immune tolerance and to increase autoimmune toxicity. We discuss a case of rapid onset fulminant Type 1 diabetes induced by treatment with anti-programmed cell death-1 monoclonal antibody, nivolumab, in a patient with late-stage non-small-cell lung adenocarcinoma. The patient had no history of previous diabetes but did reveal a high-risk genotype for Type 1 diabetes development (DR3-DQ2; DR4-DQ8). This finding supports that acute Type 1 diabetes can be an important adverse effect of immunotherapies targeting T-cell activation regulation. Because of the severity of this adverse effect, physicians should be aware of it, and studies directed to the detection of new biomarkers for early risk stratification (e.g., HLA) should be sought.

Prevalence of anemia and iron deficiency in older Portuguese adults: An EMPIRE substudy.

AIM: The present study aimed to characterize the prevalence of anemia and iron deficiency in older Portuguese adults, and to compare it with the prevalence in younger individuals. METHODS: A population-based, cross-sectional study (EMPIRE study) enrolling a representative sample of 6267 adults aged <65 years and 1617 adults aged ≥65 years was carried out. Hemoglobin, ferritin, creatinine and C-reactive protein levels were measured by Point-of-Care tests. RESULTS: Anemia was more prevalent (P < 0.001) in participants aged ≥80 years (31.4%) compared with participants aged <65 years (19.6%) and 65-79 years (17.3%). At a 30-ng/mL ferritin cut-off, iron deficiency was more prevalent in participants aged ≥80 years (42.8%) compared with participants aged <65 years (31.5%) and 65-79 years (30.2%). Alternative ferritin cut-offs showed overall similar patterns. Anemia and iron deficiency were significantly more prevalent in older individuals who self-reported heart failure, coronary heart disease and gastritis. Anemia was more prevalent in participants aged <65 years in the north of Portugal and participants aged ≥65 years in central Portugal, following the prevalence of iron deficiency in the regions. In all regions, anemia was more prevalent in participants aged ≥80 years (reaching 39.0% in Lisbon and Tagus Valley, and 51.0% in the south). CONCLUSIONS: Anemia and iron deficiency are highly prevalent in older Portuguese adults, particularly among those aged ≥80 years. Better diagnosis, prevention and treatment strategies should be implemented taking into account the outstanding role of iron deficiency in older Portuguese adults, the differences between regions and the intrinsic characteristics of this population. Geriatr Gerontol Int 2017; 17: 1814-1822.

Portuguese older gay men: pathways to family integrity / Homens idosos homossexuais portugueses: caminhos para a integridade familiar / Hombres gay mayores portugueses: vías para acceder a la integridad familiar

Research in the field of older gay men remains scarce. This exploratory study examines older gay men's experiences in the construction of family integrity (versus disconnection and alienation). The family integrity approach is a developmental perspective that links ego integrity to a larger process of constructing meaning within the family system. The sample comprises ten participants (from 60 to 88 years old). A semi-structured interview was conducted and submitted to content analysis. The main findings suggest three experiences in older gay men's construction of family integrity: (i) influence of homosexuality throughout life; (ii) establishing a family of choice; (iii) creating a legacy associated with homosexuality. Family integrity in older gay men seems to evolve from disclosure at a young age to making homosexuality a legacy in old age.

A investigação centrada em homens idosos homossexuais ainda é escassa. Este estudo exploratório analisa especificidades da homossexualidade na construção da integridade familiar(versus desconexão ou alienação). A integridade familiar é uma perspectiva de desenvolvimento que associa a integridade do ego a um processo maisvasto de construção de significado dentro do sistema familiar. A amostra reúne 10 participantes (60-88 anos). A entrevista semi-estruturada foi administrada e submetida à análise de conteúdo. Os principais resultados sugerem três especificidades na construção da integridade familiar: (i) influência da homossexualidade ao longo da vida; (ii) formar uma família de escolha; (iii) formarum legado associado à homossexualidade. A integridade familiar em idosos homossexuais parece evoluir da divulgação (da homossexualidade) na juventude,ganhando ascendência na velhice quando a homossexualidade se torna um legado.

La investigación cuanto a los hombres gay mayores sigue escasa. Este estudio exploratorio examina especificidades de la homosexualidad en la construcción de la integridad familiar (vs desconexión o alienación). La integridad familiar es una perspectiva de desarrollo que vincula la integridad del yo con el amplio proceso de construcción de significado dentro del sistema familiar. La muestra reúne 10 participantes (60 a 88 años). Una entrevista semiestructurada fue administrada y sometida al análisis de contenido. Los hallazgos sugieren tres especificidades enla construcción de la integridad familiar: (i) influencia de la homosexualidad durante la vida; (ii) formar una familia de elección; (iii) formarun legado asociado con la homosexualidad. La integridad familiar en los hombres gay mayores parece evolucionar de la divulgación (homosexualidad) enla juventud para convertirse en un legado en la vejez.

Catatonia as an internal medicine disease: infrequent or still underdiagnosed?

Catatonia is a motor and behavioural syndrome with multiple psychiatric, general medical and neurological aetiologies that might be simultaneously present. B12 deficiency is a rare, treatable cause of catatonia, not always easy to rule out. The authors present a case of a woman with catatonia associated with severe cyanocobalamin deficiency, admitted to an internal medicine ward. The benign course was related to an adequate and early diagnosis.

A VIVÊNCIA DOS MAIS VELHOS EM UMA COMUNIDADE INDÍGENA GUARANI MBYÁ / LA EXPERIENCIA DE LAS PERSONAS MAYORES EN UNA COMUNIDAD INDÍGENA 'GUARANÍ MBYÁ' / THE EXPERIENCE OF OLDER AMONG THE INDIGENOUS GUARANI MBYÁ

É possível entender que o aumento de pessoas idosas no mundo requer uma perspectiva transcultural da adultez e da velhice. Assim, este estudo exploratório procurou compreender a dinâmica cultural de uma comunidade indígena, destacando o papel da pessoa mais velha. Para tal foram realizadas entrevistas abertas com roteiro semi-estrurado com seis interlocutores do Conselho de Anciãos do povo Guarani-Mbyá, de uma tradicional aldeia de São Paulo que se dispuseram a participar; e outras informações e impressões foram registradas ao longo da pesquisa num diário de campo. A análise do conteúdo sugeriu que "ser Guarani-Mbyá" é um modo de viver e estar, orientado para a preservação da tradição através da educação e religião; o papel dos mais velhos como guardiões e transmissores das tradições. Os resultados contribuem para olhar o envelhecimento sob outras perspectivas culturais...

El aumento de las personas mayores en el mundo requiere de una perspectiva transcultural de la edad adulta y la vejez. Por lo tanto, este estudio exploratorio trató de comprender la dinámica cultural de una comunidad indígena, destacando el papel de la persona de edad. Para ello se realizaron entrevistas abiertas con seis miembros del Consejo de Ancianos del pueblo Guaraní-Mbyá, un pueblo tradicional de São Paulo, Brasil, que estaban dispuestos a participar; otras informaciones, observaciones e impresiones fueron grabadas durante la investigación en un diario de campo. Los resultados sugieren que "ser guaraní mbyá" es una forma de vivir y de ser, orientada a la preservación de la tradición a través de la educación y la religión; el papel de los ancianos como guardianes y transmisores de tradiciones. Estos resultados pueden contribuir a la comprensión del envejecimiento en otras perspectivas culturales...

The world increase of older persons requires a transcultural perspective on adulthood and ageing. This exploratory study aims to better understand the cultural dynamics on the indigenous community Guarani Mbya, living in the Krukutu village, highlighting the role of the older persons. The sample comprises six members of the elders' council (Conselho de anciãos). Data collection was carried out through an open interview and a board diary. Data were submitted to content analysis. Main findings suggest that being Guarani is a way of being oriented to the traditions preservation through education and religion; older persons are the main guardians and transmit those traditions. Results contribute to a cultural perspective on old age and aging...

The roles of cellular and organismal aging in the development of late-onset maladies.

Numerous disorders, including neurodegenerative diseases and certain types of cancer, manifest late in life. This common feature raises the prospect that an aging-associated decline in the activity of cellular and organismal maintenance mechanisms enables the emergence of these maladies in late life stages. Accordingly, the alteration of aging bears the promise of harnessing the mechanisms that protect the young organism to prevent illness in the elderly. The identification of aging-regulatory pathways has enabled scrutiny of this hypothesis and revealed that the alteration of aging protects invertebrates and mammals from toxic protein aggregation linked to neurodegeneration and from cancer. Here we review the current knowledge on the regulation of aging at the cellular and organismal levels, delineate the mechanistic links between aging and late-onset disorders, describe efforts to develop compounds that protect from these maladies by selectively manipulating aging, and discuss future research directions and possible therapeutic implications of this approach.

A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity.

Aging manipulation is an emerging strategy aimed to postpone the manifestation of late-onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the insulin/IGF signaling cascade (IIS), a prominent aging-regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD-associated peptide, Aß- and the HD-linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD-like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Here, we report that NT219, a novel IIS inhibitor, mediates a long-lasting, highly efficient inhibition of this signaling cascade by a dual mechanism; it reduces the autophosphorylation of the IGF1 receptor and directs the insulin receptor substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD- and HD-associated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging.