RESUMEN
Decreased adult neurogenesis, or the gradual depletion of neural stem cells in adult neurogenic niches, is considered a hallmark of brain aging. This review provides a comprehensive overview of the intricate relationship between aging, adult neurogenesis, and the potential neuroregenerative properties of astaxanthin, a carotenoid principally extracted from the microalga Haematococcus pluvialis. The unique chemical structure of astaxanthin enables it to cross the blood-brain barrier and easily reach the brain, where it may positively influence adult neurogenesis. Astaxanthin can affect molecular pathways involved in the homeostasis, through the activation of FOXO3-related genetic pathways, growth, and regeneration of adult brain neurons, enhancing cell proliferation and the potency of stem cells in neural progenitor cells. Furthermore, astaxanthin appears to modulate neuroinflammation by suppressing the NF-κB pathway, reducing the production of pro-inflammatory cytokines, and limiting neuroinflammation associated with aging and chronic microglial activation. By modulating these pathways, along with its potent antioxidant properties, astaxanthin may contribute to the restoration of a healthy neurogenic microenvironment, thereby preserving the activity of neurogenic niches during both normal and pathological aging.
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Antioxidantes , Células-Madre Neurales , Humanos , Antioxidantes/farmacología , Enfermedades Neuroinflamatorias , Neurogénesis , Encéfalo , Antiinflamatorios/farmacologíaRESUMEN
In recent years, the scientific interest in natural compounds with geroprotective activities has grown exponentially. Among the various naturally derived molecules, astaxanthin (ASX) represents a highly promising candidate geroprotector. By virtue of the central polyene chain, ASX acts as a scavenger of free radicals in the internal membrane layer and simultaneously controls oxidation on the membrane surface. Moreover, several studies have highlighted ASX's ability to modulate numerous biological mechanisms at the cellular level, including the modulation of transcription factors and genes directly linked to longevity-related pathways. One of the main relevant evolutionarily-conserved transcription factors modulated by astaxanthin is the forkhead box O3 gene (FOXO3), which has been recognized as a critical controller of cell fate and function. Moreover, FOXO3 is one of only two genes shown to robustly affect human longevity. Due to its tropism in the brain, ASX has recently been studied as a putative neuroprotective molecule capable of delaying or preventing brain aging in different experimental models of brain damage or neurodegenerative diseases. Astaxanthin has been observed to slow down brain aging by increasing brain-derived neurotrophic factor (BDNF) levels in the brain, attenuating oxidative damage to lipids, protein, and DNA and protecting mitochondrial functions. Emerging data now suggest that ASX can modulate Nrf2, FOXO3, Sirt1, and Klotho proteins that are linked to longevity. Together, these mechanisms provide support for a role of ASX as a potential geroneuroprotector.
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Envejecimiento/efectos de los fármacos , Encéfalo/fisiología , Proteína Forkhead Box O3/fisiología , Fármacos Neuroprotectores/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Fármacos Neuroprotectores/farmacología , Xantófilas/metabolismo , Xantófilas/farmacologíaRESUMEN
OBJECTIVE: The G -allele of FOXO3 SNP rs2802292 , which is associated with human resilience and longevity, has been shown to attenuate the impact of hypertension on the risk of intracerebral hemorrhage (ICH). We sought to determine whether the FOXO3 G -allele similarly attenuates the impact of hypertension on the risk of cerebral microinfarcts (CMI). METHODS: From a prospective population-based cohort of American men of Japanese ancestry from the Kuakini Honolulu Heart Program (KHHP) and Kuakini Honolulu-Asia Aging Study (KHAAS) that had brain autopsy data, age-adjusted prevalence of any CMI on brain autopsy was assessed. Logistic regression models, adjusted for age at death, cardiovascular risk factors, FOXO3 and APOE-ε4 genotypes, were utilized to determine the predictors of any CMI. Interaction of FOXO3 genotype and hypertension was analyzed. RESULTS: Among 809 men with complete data, 511 (63.2%) participants had evidence of CMI. A full multivariable model demonstrated that BMI [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14, P â=â0.015) was the only predictor of CMI, while hypertension was a borderline predictor (OR 1.44, 95% CI 1.00-2.08, P â=â0.052). However, a significant interaction between FOXO3 G -allele carriage and hypertension was observed ( P â=â0.020). In the stratified analyses, among the participants without the longevity-associated FOXO3 G -allele, hypertension was a strong predictor of CMI (OR 2.25, 95% CI 1.34-3.77, P â=â0.002), while among those with the longevity-associated FOXO3 G -allele, hypertension was not a predictor of CMI (OR 0.88, 95% CI 0.51-1.54, P â=â0.66). CONCLUSION: The longevity-associated FOXO3 G -allele mitigates the impact of hypertension on the risk of CMI.
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Hipertensión , Longevidad , Masculino , Humanos , Longevidad/genética , Estudios Prospectivos , Genotipo , Hipertensión/complicaciones , Hipertensión/genética , Alelos , Proteína Forkhead Box O3/genéticaRESUMEN
Nonagenarians and centenarians serve as successful examples of aging and extended longevity, showcasing robust regulation of biological mechanisms and homeostasis. Given that human longevity is a complex field of study that navigates molecular and biological mechanisms influencing aging, we hypothesized that microRNAs, a class of small noncoding RNAs implicated in regulating gene expression at the post-transcriptional level, are differentially regulated in the circulatory system of young, middle-aged, and nonagenarian individuals. We sequenced circulating microRNAs in Okinawan males and females <40, 50-80, and >90 years of age accounting for FOXO3 genetic variations of single nucleotide polymorphism (SNP) rs2802292 (TT - common vs. GT - longevity) and validated the findings through RT-qPCR. We report five microRNAs exclusively upregulated in both male and female nonagenarians with the longevity genotype, play predictive functional roles in TGF-ß, FoxO, AMPK, Pi3K-Akt, and MAPK signaling pathways. Our findings suggest that these microRNAs upregulated in nonagenarians may provide novel insight into enhanced lifespan and health span. This discovery warrants further exploration into their roles in human aging and longevity.
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Longevidad , Humanos , Longevidad/genética , Masculino , Femenino , Anciano de 80 o más Años , Persona de Mediana Edad , Adulto , MicroARN Circulante/genética , MicroARN Circulante/sangre , Japón , Anciano , Polimorfismo de Nucleótido Simple/genética , MicroARNs/genética , MicroARNs/sangre , Envejecimiento/genética , Envejecimiento/sangreRESUMEN
The genetic association of FOXO3 genotypes with human longevity is well established, although the mechanism is not fully understood. We now report on the relationship of the FOXO3 longevity variant rs2802292 with telomere length, telomerase activity, FOXO3 expression, and inflammatory cytokine levels in men and women. In agreement with earlier work, the FOXO3 longevity variant conferred protection against telomere shortening of peripheral blood mononuclear cells from adults aged 55 years and older. This was accompanied by higher levels of telomerase activity in mononuclear cells for carriers of the longevity-associated FOXO3 G-allele of SNP rs2802292 (P = 0.015). FOXO3 mRNA expression increased slightly with age in both young (P = 0.02) and old (P = 0.08) G-allele carriers. Older female G-allele carriers displayed a modest decline in levels of pro-inflammatory cytokine IL-6 with age (P = 0.07). In contrast, older male G-allele carriers displayed an age-dependent increase in levels of anti-inflammatory cytokine IL-10 with age (P = 0.04). Thus, FOXO3 may act through several different pro-longevity mechanisms, which may differ by age and sex.
RESUMEN
In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 ± 520 (9) ppm and Mec at 544 ± 48 (9) ppm, stated as mean ± SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging.
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Flavonoles , Sulfuro de Hidrógeno , Longevidad , Fenilbutiratos , Femenino , Ratones , Masculino , Animales , Meclizina/farmacología , Sulfuro de Hidrógeno/farmacología , Dimetilfumarato/farmacología , Ácido Micofenólico/farmacología , XantófilasRESUMEN
In various types of stem cells, including embryonic stem (ES) cells and hematopoietic stem cells, telomerase functions to ensure long-term self-renewal capacity via maintenance of telomere reserve. Expression of the catalytic component of telomerase, telomerase reverse transcriptase (Tert), which is essential for telomerase activity, is limiting in many types of cells and therefore plays an important role in establishing telomerase activity levels. However, the mechanisms regulating expression of Tert in cells, including stem cells, are presently poorly understood. In the present study, we sought to identify genes involved in the regulation of Tert expression in stem cells by performing a screen in murine ES (mES) cells using a shRNA expression library targeting murine transcriptional regulators. Of 18 candidate transcriptional regulators of Tert expression identified in this screen, only one candidate, hypoxia inducible factor 1 alpha (Hif1alpha), did not have a significant effect on mES cell morphology, survival, or growth rate. Direct shRNA-mediated knockdown of Hif1alpha expression confirmed that suppression of Hif1alpha levels was accompanied by a reduction in both Tert mRNA and telomerase activity levels. Furthermore, gradual telomere attrition was observed during extensive proliferation of Hif1alpha-targeted mES cells. Switching Hif1alpha-targeted mES cells to a hypoxic environment largely restored Hif1alpha levels, as well as Tert expression, telomerase activity levels, and telomere length. Together, these findings suggest a direct effect of Hif1alpha on telomerase regulation in mES cells, and imply that Hif1alpha may have a physiologically relevant role in maintenance of functional levels of telomerase in stem cells.
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Células Madre Embrionarias/metabolismo , Regulación de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Interferencia de ARN , Telomerasa/metabolismo , Transcripción Genética , Animales , Secuencia de Bases , Hipoxia de la Célula , Línea Celular , Homeostasis , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Telomerasa/genéticaRESUMEN
BACKGROUND: We assessed 10-year longitudinal associations between late-life social networks and incidence of all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) in Japanese-American men. METHODS: We prospectively analyzed, from baseline (1991-1993) through 1999-2000, 2636 initially nondemented Kuakini Honolulu-Asia Aging Study participants who remained dementia-free during the first 3 years of follow-up. Global cognition was evaluated by the Cognitive Abilities Screening Instrument (CASI); depressive symptoms by the 11-item Center for Epidemiologic Studies Depression (CES-D) Scale; and social networks by the Lubben Social Network Scale (LSNS). Median split of LSNS scores defined weak/strong social network groups. A panel of neurologists and geriatricians diagnosed and classified dementia; AD and VaD diagnoses comprised cases in which AD or VaD, respectively, were considered the primary cause of dementia. RESULTS: Median (range) baseline age was 77 (71-93) years. Participants with weak (LSNS score ≤29) versus strong (>29) social networks had higher age-adjusted incidence (in person-years) of ACD (12.6 vs. 8.7; p = .014) and AD (6.7 vs. 4.0; p = .007) but not VaD (2.4 vs. 1.4; p = .15). Kaplan-Meier curves showed a lower likelihood of survival free of ACD (log-rank p < .0001) and AD (p = .0006) for men with weak networks. In Cox proportional hazards models adjusting for age, education, APOE É4, prevalent stroke, depressive symptoms, and CASI score (all at baseline), weak networks predicted increased incidence of ACD (hazard ratio [HR] = 1.52, p = .009) and AD (HR = 1.67, p = .014) but not VaD (p > .2). CONCLUSION: Weak social networks may heighten the risk of dementia and AD, underscoring the need to promote social connectedness in older adults.
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Enfermedad de Alzheimer , Demencia Vascular , Masculino , Humanos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/diagnóstico , Envejecimiento , Asia , Escolaridad , Factores de RiesgoRESUMEN
BACKGROUND: It is well established that mid-life hypertension increases risk of dementia, whereas the association of late-life hypertension with dementia is unclear. OBJECTIVE: To determine whether FOXO3 longevity-associated genotype influences the association between late-life hypertension and incident dementia. METHODS: Subjects were 2,688 American men of Japanese ancestry (baseline age: 77.0±4.1 years, range 71-93 years) from the Kuakini Honolulu Heart Program. Status was known for FOXO3 rs2802292 genotype, hypertension, and diagnosis of incident dementia to 2012. Association of FOXO3 genotype with late-life hypertension and incident dementia, vascular dementia (VaD) and Alzheimer's disease (AD) was assessed using Cox proportional hazards models. RESULTS: During 21 years of follow-up, 725 men were diagnosed with all-cause dementia, 513 with AD, and 104 with VaD. A multivariable Cox model, adjusting for age, education, APOEÉ4, and cardiovascular risk factors, showed late-life hypertension increased VaD risk only (HRâ=â1.71, 95% CIâ=â1.08-2.71, pâ=â0.022). We found no significant protective effect of FOXO3 longevity genotype on any type of dementia at the population level. However, in a full Cox model adjusting for age, education, APOEÉ4, and other cardiovascular risk factors, there was a significant interaction effect of late-life hypertension and FOXO3 longevity genotype on incident AD (ß=â-0.52, pâ=â0.0061). In men with FOXO3 rs2802292 longevity genotype (TG/GG), late-life hypertension showed protection against AD (HRâ=â0.72; 95% CIâ=â0.55-0.95, pâ=â0.021). The non-longevity genotype (TT) (HRâ=â1.16; 95% CIâ=â0.90-1.51, pâ=â0.25) had no protective effect. CONCLUSION: This longitudinal study found late-life hypertension was associated with lower incident AD in subjects with FOXO3 genotype.
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Enfermedad de Alzheimer , Demencia Vascular , Hipertensión , Masculino , Humanos , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Estudios Longitudinales , Incidencia , Demencia Vascular/epidemiología , Genotipo , Hipertensión/epidemiología , Hipertensión/genética , Factores de Riesgo , Proteína Forkhead Box O3/genéticaRESUMEN
The use of nonstandardized and inadequately validated outcome measures in atopic eczema trials is a major obstacle to practising evidence-based dermatology. The Harmonising Outcome Measures for Eczema (HOME) initiative is an international multiprofessional group dedicated to atopic eczema outcomes research. In June 2011, the HOME initiative conducted a consensus study involving 43 individuals from 10 countries, representing different stakeholders (patients, clinicians, methodologists, pharmaceutical industry) to determine core outcome domains for atopic eczema trials, to define quality criteria for atopic eczema outcome measures and to prioritize topics for atopic eczema outcomes research. Delegates were given evidence-based information, followed by structured group discussion and anonymous consensus voting. Consensus was achieved to include clinical signs, symptoms, long-term control of flares and quality of life into the core set of outcome domains for atopic eczema trials. The HOME initiative strongly recommends including and reporting these core outcome domains as primary or secondary endpoints in all future atopic eczema trials. Measures of these core outcome domains need to be valid, sensitive to change and feasible. Prioritized topics of the HOME initiative are the identification/development of the most appropriate instruments for the four core outcome domains. HOME is open to anyone with an interest in atopic eczema outcomes research.
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Ensayos Clínicos como Asunto/normas , Dermatitis Atópica/terapia , Cooperación Internacional , Evaluación de Resultado en la Atención de Salud , Dermatitis Atópica/fisiopatología , Femenino , Humanos , Masculino , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: Since the G allele of forkhead box O3 ( FOXO3 ) single nucleotide polymorphism (SNP) rs2802292 is associated with resilience and longevity, ostensibly by mitigating the adverse effects of chronic cardiometabolic stress on mortality, our aim was to determine the association between the FOXO3 SNP rs2802292 genotype and risk of hypertension-mediated intracerebral haemorrhage (ICH). METHODS: From a prospective population-based cohort of Japanese American men from the Kuakini Honolulu Heart Program (KHHP), age-adjusted prevalence of ICH by hypertension was assessed for the whole cohort after stratifying by FOXO3 genotype. Cox regression models, adjusted for age, cardiovascular risk factors and, FOXO3 and APOE genotypes, were utilized to determine relative risk of hypertension's effect on ICH. All models were created for the whole cohort and stratified by FOXO3 G -allele carriage vs. TT genotype. RESULTS: Among 6469 men free of baseline stroke, FOXO3 G -allele carriage was seen in 3009 (46.5%) participants. Overall, 183 participants developed ICH over the 34-year follow-up period. Age-adjusted ICH incidence was 0.90 vs. 1.32 per 1000 person-years follow-up in those without and with hypertension, respectively ( P â=â0.002). After stratifying by FOXO3 genotype, this association was no longer significant in G allele carriers. In the whole cohort, hypertension was an independent predictor of ICH (relative risk [RR]â=â1.70, 95% confidence interval [CI] 1.25, 2.32; P â=â0.0007). In stratified analyses, hypertension remained an independent predictor of ICH among the FOXO3 TT -genotype group (RRâ=â2.02, 95% CI 1.33, 3.07; P â=â0.001), but not in FOXO3 G -allele carriers (RRâ=â1.39, 95% CI 0.88, 2.19; P â=â0.15). CONCLUSIONS: The longevity-associated FOXO3 â G allele may attenuate the impact of hypertension on ICH risk.
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Hemorragia Cerebral , Proteína Forkhead Box O3 , Hipertensión , Longevidad , Apolipoproteínas E/genética , Asiático , Hemorragia Cerebral/genética , Proteína Forkhead Box O3/genética , Genotipo , Humanos , Hipertensión/genética , Longevidad/genética , Masculino , Polimorfismo de Nucleótido Simple , Estudios ProspectivosRESUMEN
The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5' truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5' truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality.
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Longevidad , Polimorfismo de Nucleótido Simple , Alelos , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Humanos , Longevidad/genética , Polimorfismo de Nucleótido Simple/genética , Isoformas de Proteínas/genéticaRESUMEN
The G allele of FOXO3 gene (single-nucleotide polymorphism; rs2802292) is strongly associated with human longevity. However, knowledge of the effect of FOXO3 in older populations, men or women, with heart disease is limited. This cross-sectional study in Japan included 1836 older adults in the 70- and 80-year-old groups. DNA samples isolated from buffy coat samples of peripheral blood were used to genotype FOXO3 (rs2802292). Self-reports were used to obtain heart disease data according to physician diagnosis. Multiple logistic regression was used to test the association by adjusting for the traditional risk factor of heart disease. The prevalence of heart disease in women FOXO3 G-allele carriers was higher than noncarriers (16.7% vs 11.6%, p = .022). The prevalence of coronary heart disease was lower for FOXO3 G carriers in the 70-year-old group for both sexes (men: 9.3% vs 4.3%, p = .042 and women: 10% vs 9%, p = .079, respectively). The G allele was negatively associated with heart disease after adjusting for diabetes, hypertension, dyslipidemia, and smoking in men (odds ratio [OR] = 0.70, 95% confidence intervals [CIs], 0.49-0.99, p = .046), although the association was weaker after full adjustment. In contrast, women carriers of the FOXO3 G allele showed a positive association with heart disease after total adjustment (OR = 1.49, 95% CI, 1.00-2.21, p = .049). In conclusion, the longevity-associated G allele of FOXO3 was observed to have contrasting associations with heart disease prevalence according to sex in older Japanese. To further confirm this association, a longitudinal study and a large sample size will be required.
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Proteína Forkhead Box O3 , Cardiopatías , Longevidad , Anciano , Anciano de 80 o más Años , Alelos , Estudios Transversales , Femenino , Proteína Forkhead Box O3/genética , Genotipo , Cardiopatías/epidemiología , Cardiopatías/genética , Humanos , Longevidad/genética , Estudios Longitudinales , Masculino , Octogenarios , Polimorfismo de Nucleótido SimpleRESUMEN
The single nucleotide polymorphism (SNP) rs4130113 of the growth hormone receptor gene (GHR) is associated with longevity. Here we explored whether longevity-associated genotypes protect against mortality in all individuals, or only in individuals with aging-related diseases. Rs4130113 genotypes were tested for association with mortality in 3,557 elderly American men of Japanese ancestry. At baseline (1991-1993), 1,000 had diabetes, 730 had coronary heart disease (CHD), 1,901 had hypertension, 485 had cancer, and 919 lacked these diseases. The men were followed from baseline until Dec 31, 2019 or death (mean 10.8 ± 6.5 SD years, range 0.01-28.8 years; 99.0% deceased by that date). In a heterozygote disadvantage model, longevity-associated genotypes were associated with significantly lower mortality risk in individuals having hypertension (covariate-adjusted hazard ratio [HR] 0.83 [95% CI: 0.76-0.93, p = 4.3 x10-4]. But in individuals with diabetes, CHD, and cancer there was no genotypic difference in lifespan. As expected, normotensive men outlived men with hypertension (p = 0.036). There was no effect, however, of genotypic difference on lifespan in normotensive men (p = 0.11). We found that SNP rs4130113 potentially influenced the binding of transcription factors E2A, MYF, NRSF, TAL1, and TCF12 so as to alter GHR expression. We propose that in individuals with hypertension, longevity-associated genetic variation in GHR enhances cell resilience mechanisms to help protect against cellular stress caused by hypertension. As a result, hypertension-affected men who possess the longevity-associated genetic variant of GHR live as long as normotensive men.
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Variación Genética , Hipertensión/genética , Hipertensión/mortalidad , Longevidad/genética , Receptores de Somatotropina/genética , Anciano , Glucemia/metabolismo , Índice de Masa Corporal , Genotipo , Humanos , Hipertensión/sangre , Masculino , Anotación de Secuencia Molecular , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
Genetic variants of the kinase signaling gene MAP3K5 are associated with longevity. Here we explore whether the longevity-association involves protection against mortality in all individuals, or only in individuals with aging-related diseases. We tested the strongest longevity associated single nucleotide polymorphism (SNP), rs2076260, for association with mortality in 3,516 elderly American men of Japanese ancestry. At baseline (1991-1993), 2,461 had either diabetes (n=990), coronary heart disease (CHD; n=724), or hypertension (n=1,877), and 1,055 lacked any of these cardiometabolic diseases (CMDs). The men were followed from baseline until Dec 31, 2019. Longevity-associated genotype CC in a major allele homozygote model, and CC+TT in a heterozygote disadvantage model were associated with longer lifespan in individuals having a CMD (covariate-adjusted hazard ratio [HR] 1.23 [95% CI: 1.12-1.35, p=2.5x10-5] in major allele homozygote model, and 1.22 [95% CI: 1.11-1.33, p=1.10x10-5] in heterozygote disadvantage model). For diabetes, hypertension and CHD, HR p-values were 0.019, 0.00048, 0.093, and 0.0024, 0.00040, 0.0014, in each respective genetic model. As expected, men without a CMD outlived men with a CMD (p=1.9x10-6). There was, however, no difference in lifespan by genotype in men without a CMD (p=0.21 and 0.86, respectively, in each genetic model). In conclusion, we propose that in individuals with a cardiometabolic disease, longevity-associated genetic variation in MAP3K5 enhances resilience mechanisms in cells and tissues to help protect against cardiometabolic stress caused by CMDs. As a result, men with CMD having longevity genotype live as long as all men without a CMD.
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Alelos , Genotipo , Longevidad/genética , Síndrome Metabólico/genética , Polimorfismo de Nucleótido Simple , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Asociación Genética , Humanos , MAP Quinasa Quinasa Quinasa 5 , MasculinoRESUMEN
Purpose: Regional differences in dietary patterns in Asian countries might affect the balance of insulin response and sensitivity. However, this notion is yet to be validated. To clarify the regional differences in the insulin response and sensitivity and their relationship to nutrients, we compared the insulin secretory response during an oral glucose tolerance test in Japanese participants. Methods: This observational retrospective cohort study analyzed the data from participants with normal glucose tolerance (NGT) from four distinct areas of Japan with regard to the food environment: Fukushima, Nagano, Tokushima, and Okinawa based on data available in the Japanese National Health Insurance database. Results: Although the glucose levels were comparable among the four regions, the insulin responses were significantly different among the regions. This difference was observed even within the same BMI category. The plot between the insulin sensitivity index (Matsuda index) and insulinAUC/glucoseAUC or the insulinogenic index showed hyperbolic relationships with variations in regions. The indices of insulin secretion correlated positively with fat intake and negatively with the intake of fish, carbohydrate calories, and dietary fiber. Conclusions: We found that significant regional differences in insulin response and insulin sensitivity in Japanese participants and that nutritional factors may be linked to these differences independently of body size/adiposity. Insulin response and insulin sensitivity can vary among adult individuals, even within the same race and the same country, and are likely affected by environmental/lifestyle factors as well as genetic traits.
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Telomeres shorten in hematopoietic cells, including hematopoietic stem cells (HSCs), during aging and after transplantation, despite the presence of readily detectable levels of telomerase in these cells. In T cells, antigenic stimulation has been shown to result in a marked increase in the level of telomerase activity. We now show that stimulation of T cells derived from serially transplanted HSC results in a telomerase-dependent elongation of telomere length to a size similar to that observed in T cells isolated directly from young mice. Southern analysis of telomere length in resting and anti-CD3/CD28 stimulated donor-derived splenic T cells revealed an increase in telomere size by approximately 7 kb for the population as a whole. Stimulation of donor-derived T cells from recipients of HSCs from telomerase-deficient mice did not result in regeneration of telomere length, demonstrating a dependence on telomerase. Furthermore, clonal anti-CD3/CD28 stimulation of donor-derived T cells followed by fluorescent in situ hybridization (FISH) analysis of telomeric signal intensity showed that telomeres had increased in size by approximately 50% for all clonal expansions. Together, these results imply that one role for telomerase in T cells may be to renew or extend replicative potential via the rejuvenation of telomere length.
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Trasplante de Células Madre Hematopoyéticas , Linfocitos T/fisiología , Telomerasa/fisiología , Telómero , Animales , Southern Blotting , Proteínas de Unión al ADN , Activación Enzimática , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 de Unión a Repeticiones Teloméricas/fisiologíaRESUMEN
FOXO3 is a prominent longevity gene. To date, no-one has examined whether longevity-associated FOXO3 genetic variants protect against mortality in all individuals, or only in those with aging-related diseases. We therefore tested longevity-associated FOXO3 single nucleotide polymorphisms in a haplotype block for association with mortality in 3,584 elderly American men of Japanese ancestry, 2,512 with and 1,072 without a cardiometabolic disease (CMD). At baseline (1991-1993), 1,010 CMD subjects had diabetes, 1,919 had hypertension, and 738 had coronary heart disease (CHD). Follow-up until Dec 31, 2019 found that in CMD-affected individuals, longevity-associated alleles of FOXO3 were associated with significantly longer lifespan: haplotype hazard ratio 0.81 (95% CI 0.72-0.91; diabetes 0.77, hypertension 0.82, CHD 0.83). Overall, men with a CMD had higher mortality than men without a CMD (P=6x10-7). However, those men with a CMD who had the FOXO3 longevity genotype had similar survival as men without a CMD. In men without a CMD there was no association of longevity-associated alleles of FOXO3 with lifespan. Our study provides novel insights into the basis for the long-established role of FOXO3 as a longevity gene. We suggest that the FOXO3 longevity genotype increases lifespan only in at-risk individuals by protection against cardiometabolic stress.
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Enfermedad Coronaria/genética , Diabetes Mellitus Tipo 2/genética , Proteína Forkhead Box O3/genética , Hipertensión/genética , Longevidad/genética , Síndrome Metabólico/genética , Polimorfismo de Nucleótido Simple , Factores de Edad , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Factores de Riesgo Cardiometabólico , Estudios de Casos y Controles , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/etnología , Enfermedad Coronaria/mortalidad , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnología , Diabetes Mellitus Tipo 2/mortalidad , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Hawaii/epidemiología , Humanos , Hipertensión/diagnóstico , Hipertensión/etnología , Hipertensión/mortalidad , Japón/etnología , Estudios Longitudinales , Masculino , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/etnología , Síndrome Metabólico/mortalidad , Fenotipo , Prevalencia , Medición de Riesgo , Factores SexualesRESUMEN
OBJECTIVE: To examine whether cognitive impairment, deep white matter hyperintensity (DWMH) on brain MRI, and shorter telomere length would be predictors of mortality in community-dwelling Japanese elderly. METHODS: We followed 259 individuals (74% of all the residents at age 70) from age 70 to 83â¯years. The mean observation period was 133⯱â¯34â¯months. The key clinical characteristics examined included DWMH on brain MRI and cognitive function. Telomere length was also measured in 81 subjects. Both univariate and multivariate analyses were performed. RESULTS: Of the 259 subjects, 69 subjects (30 men, 39 women; 26.6%) died during the follow-up period. Cognitive impairment, smoking habits, diabetes mellitus, and moderate to severe DWMH were significant predictors of total mortality in univariate analysis. However, only cognitive impairment and moderate to severe DWMH remained as significant independent predictors of death in multivariate analysis. The rate of mortality increased with additional number of risk factors (cognitive impairment and DWMH). The total mortality of subjects with both cognitive impairment and DWMH was 71.4%. The median telomere length was 7.8â¯kb in the deceased and 8.2â¯kb in the living subjects. The deceased subjects had significantly shorter telomere length (Pâ¯=â¯.0025) than the living subjects. Telomere length with moderate to severe DWMH was higher than without moderate to severe DWMH on brain MRI (Pâ¯=â¯.017). CONCLUSIONS: The present study revealed that cognitive impairment, DWMH, and shorter telomere length were significant predictors of total mortality in the community-dwelling Japanese elderly. Furthermore, the combination of cognitive impairment and DWMH increased the mortality rate, as compared with a single risk factor. It is also clarified that a significant difference was present in telomere length by severity of DWMH.
Asunto(s)
Isquemia Encefálica/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico , Telómero , Anciano , Anciano de 80 o más Años , Isquemia Encefálica/mortalidad , Cognición/fisiología , Disfunción Cognitiva/mortalidad , Femenino , Humanos , Vida Independiente , Japón/epidemiología , Imagen por Resonancia Magnética , Masculino , Estudios Prospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Aging is a complex, multifactorial process with significant plasticity. While several biological pathways appear to influence aging, few genes have been identified that are both evolutionarily conserved and have a strong impact on aging and age-related phenotypes. The FoxO3 gene (FOXO3), and its homologs in model organisms, appears especially important, forming a key gene in the insulin/insulin-like growth factor-signaling pathway, and influencing life span across diverse species. We highlight some of the key findings that are associated with FoxO3 protein, its gene and homologs in relation to lifespan in different species, and the insights these findings might provide about the molecular, cellular, and physiological processes that modulate aging and longevity in humans.