RESUMO
The exceptional longevity of Ames dwarf (DF) mice can be abrogated by a brief course of growth hormone (GH) injections started at 2 weeks of age. This transient GH exposure also prevents the increase in cellular stress resistance and decline in hypothalamic inflammation characteristic of DF mice. Here, we show that transient early-life GH treatment leads to permanent alteration of pertinent changes in adipocytes, fat-associated macrophages, liver, muscle, and brain that are seen in DF mice. Ames DF mice, like Snell dwarf and GHRKO mice, show elevation of glycosylphosphatidylinositol specific phospholipase D1 in liver, neurogenesis in brain as indicated by BDNF and DCX proteins, muscle production of fibronectin type III domain-containing protein 5 (a precursor of irisin), uncoupling protein 1 as an index of thermogenic capacity in brown and white fat, and increase in fat-associated anti-inflammatory macrophages. In each case, transient exposure to GH early in life reverts the DF mice to the levels of each protein seen in littermate control animals, in animals evaluated at 15-18 months of age. Thus, many of the traits seen in long-lived mutant mice, pertinent to age-related changes in inflammation, neurogenesis, and metabolic control, are permanently set by early-life GH levels.
Assuntos
Hormônio do Crescimento , Hormônio do Crescimento Humano , Adipócitos/metabolismo , Animais , Encéfalo/metabolismo , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento Humano/metabolismo , Inflamação/metabolismo , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Mutantes , Músculos/metabolismoRESUMO
The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP3) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered "aging rate indicators" in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics.
Assuntos
Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Envelhecimento , Fibronectinas/metabolismo , Lipídeos , Fenótipo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
Average and maximal lifespan can be increased in mice, in one or both sexes, by four drugs: rapamycin, acarbose, 17a-estradiol, and canagliflozin. We show here that these four drugs, as well as a calorie-restricted diet, can induce a common set of changes in fat, macrophages, plasma, muscle, and brain when evaluated in young adults at 12 months of age. These shared traits include an increase in uncoupling protein UCP1 in brown fat and in subcutaneous and intra-abdominal white fat, a decline in proinflammatory M1 macrophages and corresponding increase in anti-inflammatory M2 macrophages, an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product irisin, and higher levels of doublecortin (DCX) and brain-derived neurotrophic factor (BDNF) in brain. Each of these proteins is thought to play a role in one or more age-related diseases, including metabolic, inflammatory, and neurodegenerative diseases. We have previously shown that the same suite of changes is seen in each of four varieties of slow-aging single-gene mutant mice. We propose that these changes may be a part of a shared common pathway that is seen in slow-aging mice whether the delayed aging is due to a mutation, a low-calorie diet, or a drug.
Assuntos
Restrição Calórica , Músculo Esquelético , Masculino , Feminino , Camundongos , Animais , Músculo Esquelético/metabolismo , Encéfalo/metabolismo , Envelhecimento , Macrófagos/metabolismo , Fibronectinas/metabolismoRESUMO
Deletion of pregnancy-associated plasma protein-A (PAPP-A), a protease that cleaves some but not all IGF1 binding proteins, postpones late-life diseases and extends lifespan in mice, but the mechanism of this effect is unknown. Here we show that PAPP-A knockout (PKO) mice display a set of changes, in multiple tissues, that are characteristic of other varieties of slow-aging mice with alterations in GH production or GH responsiveness, including Ames dwarf, Snell dwarf, and GHRKO mice. PKO mice have elevated UCP1 in brown and white adipose tissues (WAT), and a change in fat-associated macrophage subsets that leads to diminished production of inflammatory cytokines. PKO mice also show increased levels of muscle FNDC5 and its cleavage product, the myokine irisin, thought to cause changes in fat cell differentiation. PKO mice have elevated production of hepatic GPLD1 and plasma GPLD1, consistent with their elevation of hippocampal BDNF and DCX, used as indices of neurogenesis. In contrast, disruption of PAPP-A limited to muscle ("muPKO" mice) produces an unexpectedly complex set of changes, in most cases opposite in direction from those seen in PKO mice. These include declines in WAT UCP1, increases in inflammatory macrophages and cytokines in WAT, and a decline in muscle FNDC5 and plasma irisin. muPKO mice do, however, resemble global PKO mice in their elevation of hippocampal BDNF and DCX. The data for the PKO mice support the idea that these changes in fat, macrophages, liver, muscle, plasma, and brain are consistent and biologically significant features of the slow-aging phenotype in mice. The results on the muPKO mice provide a foundation for further investigation of the complex, local, and global circuits by which PAPP-A modulates signals ordinarily controlled by GH and/or IGF1.
Assuntos
Músculo Esquelético , Proteína Plasmática A Associada à Gravidez , Camundongos , Animais , Proteína Plasmática A Associada à Gravidez/genética , Proteína Plasmática A Associada à Gravidez/metabolismo , Músculo Esquelético/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Fibronectinas/metabolismo , Fenótipo , Fatores de Transcrição/genética , Citocinas/metabolismo , EnvelhecimentoRESUMO
Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) hydrolyzes inositol phosphate linkages in proteins anchored to the cell membrane. Mice overexpressing GPLD1 show enhanced neurogenesis and cognition. Snell dwarf (DW) and growth hormone receptor knockout (GKO) mice show delays in age-dependent cognitive decline. We hypothesized that augmented GPLD1 might contribute to retained cognitive function in these mice. We report that DW and GKO show higher GPLD1 levels in the liver and plasma. These mice also have elevated levels of hippocampal brain-derived neurotrophic factor (BDNF) and of doublecortin (DCX), suggesting a mechanism for maintenance of cognitive function at older ages. GPLD1 was not increased in the hippocampus of DW or GKO mice, suggesting that plasma GPLD1 increases elevated these brain proteins. Alteration of the liver and plasma GPLD1 was unaltered in mice with liver-specific GHR deletion, suggesting that the GH effect was not intrinsic to the liver. GPLD1 was also induced by caloric restriction and by each of four drugs that extend lifespan. The proteome of DW and GKO mice is molded by selective translation of mRNAs, involving cap-independent translation (CIT) of mRNAs marked by N6 methyladenosine. Because GPLD1 protein increases were independent of the mRNA level, we tested the idea that GPLD1 might be regulated by CIT. 4EGI-1, which enhances CIT, increased GPLD1 protein without changes in GPLD1 mRNA in cultured fibroblasts and mice. Furthermore, transgenic overexpression of YTHDF1, which promotes CIT by reading m6A signals, also led to increased GPLD1 protein, showing that elevation of GPLD1 reflects selective mRNA translation.
Assuntos
Encéfalo , Fosfolipase D , Animais , Encéfalo/metabolismo , Fígado/metabolismo , Longevidade/genética , Camundongos , Fosfolipase D/genética , RNA Mensageiro/metabolismo , Receptores da Somatotropina/metabolismoRESUMO
OBJECTIVE: We sought to determine what information should be included on the nutrition facts label (NFL) to improve its usefulness for individuals with chronic kidney disease (CKD). DESIGN: Our survey asked for frequency of food-label reading, use of information on the label related to specific nutrients, and perceived needs. SETTING: Our survey was internet-based. SUBJECTS: Our subjects included 317 individuals with CKD and caregivers who self-subscribed to electronic mailing lists maintained by nationally based groups providing education and/or support for individuals with CKD. INTERVENTION: The intervention consisted of an analysis of survey results. MAIN OUTCOME MEASURES: Main outcome measures included respondent self-reported behaviors, opinions, attitudes, knowledge, and perceived needs related to the NFL in terms of foods and beverages. RESULTS: Survey respondents (81.8%) rated nutrition as important (39.2%) or very important (42.6%) when making food choices. A roughly equal number (82.6%) indicated reading the NFL often for the amounts of nutrients in a food. However, less than one fourth of the respondents (24.0%) were able to determine the amount of calcium in a food correctly, based on percent daily value (%DV), and many (64.6%) indicated they did not know how to convert the %DV to an absolute amount (the 100% daily value for calcium is 1000 mg). Respondents indicated that they decided not to purchase foods that did not list absolute amounts of nutrients of concern (58.4% for potassium, and 53.9% for phosphorus) on the NFL. CONCLUSIONS: Individuals with CKD would prefer, or find it more useful, to see nutrients of concern listed in absolute amounts on the NFL. They also indicated that potassium and phosphorus should be required on the label, to allow the option of determining whether to include a food in their diet.
Assuntos
Coleta de Dados/métodos , Rotulagem de Alimentos/métodos , Conhecimentos, Atitudes e Prática em Saúde , Falência Renal Crônica/complicações , Distúrbios Nutricionais/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Coleta de Dados/estatística & dados numéricos , Feminino , Rotulagem de Alimentos/estatística & dados numéricos , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Distúrbios Nutricionais/complicações , Inquéritos e Questionários , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Current end-of-life hospital care can be of poor quality and high cost. High volume and/or specialist care, and standardized care with clinical practice guidelines, has improved outcomes and costs in other areas of cancer care. METHODS: The objective of this study was to measure the impact of the palliative care unit (PCU) on the cost of care. The PCU is a dedicated 11-bed inpatient (PCU) staffed by a high-volume specialist team using standardized care. We compared daily charges and costs of the days prior to PCU transfer to the stay in the PCU, for patients who died in the first 6 months after the PCU opened May 2000. We performed a case-control study by matching 38 PCU patients by diagnosis and age to contemporary patients who died outside the PCU cared for by other medical or surgical teams, to adjust for potential differences in the patients or goals of care. RESULTS: The unit admitted 237 patients from May to December 2000. Fifty-two percent had cancer followed by vascular events, immunodeficiency, or organ failure. For the 123 patients with both non-PCU and PCU days, daily charges and costs were reduced by 66% overall and 74% in "other" (medications, diagnostics, etc.) after transfer to the PCU (p < 0.0001 for all). Comparing the 38 contemporary control patients who died outside the PCU to similar patients who died in the PCU, daily charges were 59% lower (US dollars 5304 +/- 5850 to US dollars 2172 +/- 2250, p = 0.005), direct costs 56% lower (US dollars 1441 +/- 1438 to US dollars 632 +/- 690, p = 0.004), and total costs 57% lower (US dollars 2538 +/- 2918 to US dollars 1095 +/- 1153, p = 0.009). CONCLUSIONS: Appropriate standardized care of medically complex terminally ill patients in a high-volume, specialized unit may significantly lower cost. These results should be confirmed in a randomized study but such studies are difficult to perform.
Assuntos
Custos Hospitalares , Cuidados Paliativos/economia , Equipe de Assistência ao Paciente/economia , Assistência Terminal/economia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Medicina , Medição da Dor , Cuidados Paliativos/normas , Equipe de Assistência ao Paciente/normas , Qualidade da Assistência à Saúde , Especialização , Assistência Terminal/normasAssuntos
Dietética/legislação & jurisprudência , Dietética/normas , Licenciamento Hospitalar/normas , Terapia Nutricional/normas , Política Pública , Acreditação , Serviços de Dietética/normas , Serviço Hospitalar de Nutrição/normas , Humanos , Joint Commission on Accreditation of Healthcare Organizations , Licenciamento , Estados UnidosAssuntos
Dietética/economia , Medicaid , Medicare , Terapia Nutricional , Telemedicina/economia , Telemedicina/estatística & dados numéricos , Centers for Medicare and Medicaid Services, U.S. , Dietética/legislação & jurisprudência , Humanos , Cobertura do Seguro , Terapia Nutricional/economia , Terapia Nutricional/estatística & dados numéricos , Estados UnidosAssuntos
Dietoterapia/normas , Dietética/normas , Serviço Hospitalar de Nutrição/legislação & jurisprudência , Medicaid/legislação & jurisprudência , Medicare/legislação & jurisprudência , Centers for Medicare and Medicaid Services, U.S. , Fiscalização e Controle de Instalações , Serviço Hospitalar de Nutrição/normas , Humanos , Medicare Part A/legislação & jurisprudência , Medicare Part A/normas , Qualidade da Assistência à Saúde , Estados UnidosAssuntos
Dietética/legislação & jurisprudência , Dietética/normas , Internato não Médico/normas , Legislação Hospitalar , Prontuários Médicos/legislação & jurisprudência , Prática Profissional/legislação & jurisprudência , Humanos , Internato não Médico/legislação & jurisprudência , Prontuários Médicos/normas , Estados UnidosRESUMO
The United States government has published official Dietary Guidelines for Americans (DGA) since 1980 and has recently released the 2010 version. Serving as a foundational cornerstone for federal nutrition policy, the DGA embrace current nutritional science and translate it into practical guidance to enhance the overall health of Americans. This article reviews the history and process for developing the DGA, including the incorporation of sophisticated and systematic techniques for reviewing emerging evidence. It also explores issues related to implementation of the guidelines through federal policy, the food supply, and consumer knowledge and behavior.