Age-related Biomarkers Research Articles

Are age-related biomarkers of dementia risk accelerated by low educational attainment?

Background: Low education significantly elevates dementia risk but it is not clear whether this is through chronic systemic inflammation, early-onset dementia pathology, or other factors. This project compares biomarkers of inflammation and dementia pathology in a young-old and older cohort. Due to significantly lower education in the young-old cohort, we hypothesized evidence of similar or higher biomarker levels in the young-old cohort compared to the older cohort. 
 Methods: Blood samples were used to measure pro-inflammatory cytokines (C-reactive protein (CRP), tumor necrosis factor (TNF interleukin (IL)-6, and IL-1 anti-inflammatory cytokines (IL-10 and IL-1RA), and the brain biomarkers phosphorylated tau (p-tau) and neurofilament light (NfL). Inflammatory markers were measured at the Considine Lab at the Indiana University School of Medicine using ELISA assays while p-tau and NfL were measured with Simoa assays at the Quanterix lab in Massachusetts. We used the natural logarithm of all biomarker variables to address skewed data. Linear regression was used to investigate race- and gender-adjusted differences in the biomarkers. 
 Results: The young-old cohort (N=42) has a mean age of 62.4, 69.1% are female, and 78.6% are non-Hispanic black (NHB), while the older cohort (N=60) has a mean age of 80.3, 60% are female, and 20% are NHB. Median education in the young-old cohort is 12 vs 16 in the older cohort. Adjusted models showed higher mean CRP (p=0.004) and lower mean IL-10 (p<0.001) in the young-old cohort. TNF- (p <0.001), IL-6 (p=0.021), and IL-1(p=0.017), P-tau (p=0.003), and NfL (p<0.001) were all higher in the older cohort. 
 Conclusion: We found partial support of our hypothesis in that the younger, low education cohort had higher mean CRP and lower mean IL-10 (anti-inflammatory). However, brain biomarkers were higher in the older cohort. More research will be needed to determine if and how low education elevates ADRD risk through systemic inflammation. 

Salivary Biomarkers (Opiorphin, Cortisol, Amylase, and IgA) Related to Age, Sex, and Stress Perception in a Prospective Cohort of Healthy Schoolchildren.

Background The use of easily accessible biomarkers for assessing young patients' health is weighty. This cohort study is aimed at measuring stress/immune biomarkers in the saliva of healthy school-age children and comparing subgroups according to age, sex, and stress perception. Material and Methods. 503 children under 12 years old (8.7 ± 1.3) were included with anthropometric evaluation (height, waist, hip circumference, body weight, and body mass index (BMI)). Levels of opiorphin (OPI), free cortisol, alpha-amylase (sAA), and secreted immunoglobulin (sIgA) were determined by quantitative assays (ELISA) in unstimulated saliva. Unpaired t-test, Welch test, and Mann–Whitney U test were applied for appropriate group comparisons, and the correlation between variables was analyzed with Spearman's rank coefficient. Results were considered significant at p < 0.05. Results sIgA and sAA exhibited significant differences depending on age and sex: IgA (ng/mL): 86 ± 68.6 vs. 104.9 ± 72.1 for (6-7 y.o.) and (8-11 y.o.), respectively, and 108.1 ± 80.1 vs. 94.6 ± 62.2 for male and females, respectively; sAA (U/mL): 78.9 ± 54.4 vs. 100.5 ± 81.2 for (6-7 y.o.) and (8-11 y.o.). No difference related to age or sex between groups was observed for cortisol and OPI. However, OPI levels were higher and correlated to prior stress exposure in children (0.31 ± 0.4 vs. 0.26 ± 0.5 ng/mL, p = 0.031). sAA was negatively correlated to low mood self-declaration in children in the last two weeks (r = −0.10, p = 0.045). Conclusions sIgA and sAA can be used as sex- and age-related biomarkers in children 6-12 y.o., which is not the case for free cortisol and opiorphin. However, OPI reflected previous exposure to stress, suggesting its use for evaluating stress-related changes in children.

Exploring biomarkers of age in routine diagnostics for the risk stratification of older patients in the emergency department

Abstract Objectives To estimate the association of the routinely applied biological age-related biomarkers hs-TnT, CRP and Hemoglobin (Hb) with mortality for the purpose of older patient's risk stratification in the emergency department (ED). Design Exploratory, prospective cohort study with a follow-up at 2.5 years after recruitment start. Setting and participants A cardiological emergency department (ED), chest pain unit, of our University Hospital. N=256 cardiological ED patients with a minimum age of 70 years and with an expected life-expectancy above 24h. Methods Data from the hospital files were supplemented by a questionnaire. Patients were followed-up for mortality by requesting registry office information. Results Among N=256 patients 63 died over the follow-up period. Positive results in each of the three biomarkers alone as well as the combination were associated with increased all-cause mortality at follow-up. The number of positive age-related biomarkers appeared to be strongly indicative of the risk of mortality, even when controlled for major confounders (age, sex, BMI, creatinine clearance, and comorbidity). Conclusion and implications In older ED patients, biomarkers explicitly related to biological aging processes such as hs-TnT, CRP and Hb were independently of each other as well as combined associated with an increased risk of all-cause mortality. Thus, they may have the potential to be used to supplement the general risk stratification of older patients in the ED. Validation of the results in a large dataset is needed. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Robert Bosch Foundation, Stuttgart, Germany Kaplan-Meier curves with 95% CIKaplan-Meier curves for patients grouped

Chemotyping of three Morchella species reveals species- and age-related aroma volatile biomarkers

The desirable aroma of morels is ascribed to volatiles from various metabolic pathways. Mushrooms' volatile composition varies with genetic background, age, and cultivation conditions. We aimed to differentiate mushrooms based on their aroma profiles, and identify biomarkers for chemotyping. The aroma volatile composition of Morchella rufobrunnea, Morchella importuna, and Morchella dunalii was described using headspace GC/MS. Eighty six aroma compounds were identified, comprised of alcohols, aldehydes, hydrocarbons, esters, furans, ketones, phenolic compounds, pyrazines, and terpenes. 1-Octanol, heptanal, 3-ethyl-3-methylheptane, 4,6-dimethylundecane, and 1,3-bis(1,1-dimethylethyl) benzene were identified as key species-specific biomarkers; and octanal, heptanal, 3-octen-2-one, and benzeneacetaldehyde as key age-related (young vs. mature mushroom) biomarkers. 4,6-Dimethylundecane and 1,3-bis(1,1-dimethylethyl) benzene were in accordance with the saprophytic origin of M. rufobrunnea and M. importuna. Thus, specific Morchella volatiles can serve as biomarkers in chemotyping Morchella species, indicating their age, and hinting at their saprophytic nature.

Icariin enhances youth-like features by attenuating the declined gut microbiota in the aged mice

We previously reported the neuroprotective effects of icariin in rat cortical neurons. Here, we present a study on icariin's anti-aging effect in 24-month aged mice by treating them with a single daily dose of 100 mg/kg of icariin for 15 consecutive days. Icariin treatment improved motor coordination and learning skills while lowered oxidative stress biomarkers in the serum, brain, kidney, and liver of the aged mice. In addition, icariin improved the intestinal integrity of the aged mice by upregulating tight junction adhesion molecules and the Paneth and goblet cells, along with the reduction of iNOS and pro-inflammatory cytokines (IL-1β, TNF-α, IL-2 and IL-6, and IL-12). Icariin treatments also significantly upregulated aging-related signaling molecules, Sirt 1, 3 & 6, Pot1α, BUB1b, FOXO1, Ep300, ANXA3, Calb1, SNAP25, and BDNF in old mice. Through gut microbiota (GM) analysis, we observed icariin-associated improvements in GM composition of aged mice by reinstating bacteria found in the young mice, while suppressing some bacteria found in the untreated old mice. To clarify whether icariin's anti-aging effect is rooted in the GM, we performed fecal microbiota transfer (FMT) from icariin-treated old mice to the old mice. FMT-recipients exhibited similar improvements in the rotarod score and age-related biomarkers as observed in the icariin-treated old mice. Equal or better improvement on the youth-like features was noticed when aged mice were FMT with feces from young mice. Our study shows that both direct treatments with icariin and fecal transplant from the icariin-treated aged mice produce similar anti-aging phenotypes in the aged mice. We prove that GM plays a pivotal role in the healing abilities of icariin. Icariin has the potentials to be developed as a medicine for the wellness of the aged adults.

Mutation-based clustering and classification analysis reveals distinctive age groups and age-related biomarkers for glioma

BackgroundMalignant brain tumor diseases exhibit differences within molecular features depending on the patient’s age.MethodsIn this work, we use gene mutation data from public resources to explore age specifics about glioma. We use both an explainable clustering as well as classification approach to find and interpret age-based differences in brain tumor diseases. We estimate age clusters and correlate age specific biomarkers.ResultsAge group classification shows known age specifics but also points out several genes which, so far, have not been associated with glioma classification.ConclusionsWe highlight mutated genes to be characteristic for certain age groups and suggest novel age-based biomarkers and targets.

Changes in Peripheral Blood Biomarkers with Aging and Neurodegenerative Disorders.

Aging is associated with most neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. Determination of peripheral blood biomarkers represents a low invasive approach for tracking early changes in body metabolism during aging. This study addresses a cross-sectional analysis to identify changes in lipid, minerals, and antioxidant capacity as potential biomarkers to the onset of neurodegenerative diseases during aging. A retrospective analysis was performed to determine age-related biomarkers from a clinical sample database. Next, one hundred volunteers between 20-59 (adult) and over 60 years (elderly) were selected for the motor and cognitive tests according to Unified Parkinson's Disease Rating Scale (UPDRS) and Mini-Mental State Examination (MMSE), respectively. Peripheral blood samples were also collected to determine circulating lipids, minerals, and antioxidant capacity. Lipid profile revealed an increase in triglycerides, total, and VLDL Cholesterol. Among the elderlies, HDL was lower than the adult group, particularly in volunteers with severe cognitive decline. Minerals involved in antioxidant defense such as iron, selenium, and manganese were lower in elderly people compared to adults. Catalase activity was also reduced among elderlies with mild cognitive impairment. Here, we show changes in key serum biomarkers correlate with aging and clinical cognitive decline among elderly people. These findings may contribute to the understanding of how biomarkers can be useful for early diagnosis and treatment of aging-related diseases.

Resting-state functional connectivity and quantitation of glutamate and GABA of the PCC/precuneus by magnetic resonance spectroscopy at 7T in healthy individuals.

The default mode network (DMN) is the main large-scale network of the resting brain and the PCC/precuneus is a major hub of this network. Glutamate and GABA (γ-amino butyric acid) are the main excitatory and inhibitory neurotransmitters in the CNS, respectively. We studied glutamate and GABA concentrations in the PCC/precuneus via magnetic resonance spectroscopy (MRS) at 7T in relation to age and correlated them with functional connectivity between this region and other DMN nodes in ten healthy right-handed volunteers ranging in age between 23–68 years. Mean functional connectivity of the PCC/precuneus to the other DMN nodes and the glutamate/GABA ratio significantly correlated with age (r = 0.802, p = 0.005 and r = 0.793, p = 0.006, respectively) but not with each other. Glutamate and GABA alone did not significantly correlate with age nor with functional connectivity within the DMN. The glutamate/GABA ratio and functional connectivity of the PCC/precuneus are, therefore, independent age-related biomarkers of the DMN and may be combined in a multimodal pipeline to study DMN alterations in various disease states.

Age-Dependent Changes in the Plasma Proteome of Healthy Adults.

Human blood plasma is a complex that communicates with most parts of the body and reflects the changes in the state of an organism. Identifying age-related biomarkers can help predict and monitor age-related physiological decline and diseases and identify new treatments for diseases. In this study, TMT-LC-MS/MS was utilized to screen differentially expressed plasma proteins in 118 healthy adults of different ages. Participants were divided into three groups: 21-30 years of age (Young), 41-50 years of age (Middle) and ≥60 years of age (Old). The number of differentially expressed proteins in the comparisons of Young vs Middle, Middle vs Old and Young vs Old were 82, 22 and 99, respectively. These proteins were involved in numerous physiological processes, such as "negative regulation of smooth muscle cell proliferation" and "blood coagulation". Moreover, when Young was compared with Middle or Old, "complement and coagulation cascades" was the top enriched pathway by KEGG pathway enrichment analysis. Functional phenotyping of the proteome demonstrated that the plasma proteomic profiles of young adults were strikingly dissimilar to those of the middle-aged or older adults. The results of this study mapped the variation in the expression of plasma proteins and provided information about possible biomarkers/treatments for different age-related functional disorders.

Age-Related Biomarkers to Predict Acute Kidney Injury in Children Undergoing Cardiac Surgery

Age-Related Biomarkers to Predict Acute Kidney Injury in Children Undergoing Cardiac Surgery

NOVEL BIOMARKERS OF BIOLOGICAL AGE IN THE HEALTH AND RETIREMENT STUDY

This symposium presents early results on epigenetic, transcriptomic and other aging biomarkers such as telomere length and mitochondrial DNA copy number from the Health and Retirement Study that allows a detailed examination of the biological pathways through which socioeconomic conditions influence the human aging process. In 2016 HRS collected 6 tubes of blood from people who completed the 2016 interview, had been in the sample at the prior wave and were not in a nursing home (n=9,973) to maintain a nationally-representative sample. These blood samples were analyzed for novel biomarkers of aging that included global methylation arrays, whole transcriptome sequencing, telomere length and mitochondrial DNA copy number among other biomarkers that were shown to be related to both social and economic circumstances and health outcomes at older ages. This level of integration of biological data to address social disparities hasn’t been accomplished before on a large nationally-representative sample of Americans and will provide a unique opportunity to understand the biological mechanisms through which social disparities affect human health. The symposium will describe the utility of measuring novel age related biomarkers in a nationally representative population study such as HRS and the potential research opportunities that can be pursued using this publicly available resource. It will provide an overview of the measurement and distribution of epigenetic, transcriptomic and telomere length and mitochondrial DNA copy number as novel aging biomarkers. It will also describe the utility of these biomarkers in further understanding the biological underpinnings of socioeconomic differences in health and mortality.

Early life exposure to di(2-ethylhexyl)phthalate causes age-related declines associated with insulin/IGF-1-like signaling pathway and SKN-1 in Caenorhabditis elegans

Di(2-ethylhexyl)phthalate (DEHP) is an ubiquitous and emerging contaminant that is widely present in food, agricultural crop, and the environment, posing a potential risk to human health. This study utilized the nematode Caenorhabditis elegans to decipher the toxic effects of early life exposure to DEHP on aging and its underlying mechanisms. The results showed that exposure to DEHP at 0.1 and 1.5 mg/L inhibited locomotive behaviors. In addition, DEHP exposure significantly shortened the mean lifespan of the worms and further adversely affected pharyngeal pumping rate and defecation cycle in aged worms. Moreover, DEHP exposure also further enhanced accumulation of age-related biomarkers including lipofuscin, lipid peroxidation, and intracellular reactive oxygen species in aged worms. In addition, exposure to DEHP significantly suppressed gene expression of hsp-16.1, hsp-16.49, and hsp-70 in aged worms. Further evidences showed that mutation of genes involved in insulin/IGF-1-like signaling (IIS) pathway (daf-2, age-1, pdk-1, akt-1, akt-2, and daf-16) restored lipid peroxidation accumulation upon DEHP exposure in aged worms, whereas skn-1 mutation resulted in enhanced lipid peroxidation accumulation. Therefore, IIS and SKN-1 may serve as an important molecular basis for DEHP-induced age-related declines in C. elegans. Since IIS and SKN-1 are highly conserved among species, the age-related declines caused by DEHP exposure may not be exclusive in C. elegans, leading to adverse human health consequences due to widespread and persistent DEHP contamination in the environment.

Diesel exhaust exposure intensifies inflammatory and structural changes associated with lung aging in mice

Life expectancy is increasing worldwide. Lung aging is a process marked by changes in multiple morphological, physiological and age-related biomarkers (e.g., sirtuins) and is influenced by external factors, such as air pollution. Hence, the elderly are considered more vulnerable to the air pollution hazards. We hypothesized that diesel exhaust (DE) exposure intensifies changes in lung inflammatory and structural parameters in aging subjects. Two- and fifteen-month-old mice were exposed to DE for 30 days. Lung function was measured using the forced oscillation method. The inflammatory profile was evaluated in the bronchoalveolar lavage fluid (BALF) and blood, and lung volumes were estimated by stereology. Antioxidant enzyme activity was evaluated by spectrophotometry, sirtuin 1 (SIRT1), sirtuin 2 (SIRT2) and sirtuin 6 (SIRT6) expression was assessed by reverse transcription polymerase chain reaction (RT-PCR), and levels of the sirtuin proteins were evaluated by immunohistochemical staining in lung tissues. Older mice presented decreased pulmonary resistance and elastance, increased macrophage infiltration and decreased tumor necrosis factor (TNF) and interleukin 10 (IL-10) levels in the BALF, reduced activities of the antioxidant enzymes glutathione peroxidase (GPx) and glutathione reductase (GR), and increased activity glutathione S-transferase (GST); increased lung volumes with decreased elastic fiber and increased airway collagen content. SIRT1 gene expression was decreased in older animals, but protein levels were increased. DE exposure increased macrophage infiltration and oxidative stress in the lungs of animals of both ages. SIRT6 gene expression was decreased by DE exposure, with increased protein levels. In older animals, DE affected lung structure and collagen content. Lung aging features, such as decreased antioxidant reserves, lower IL-10 expression, and decreased SIRT1 levels may predispose subjects to exacerbated responses after DE exposure. Our data support the hypothesis that strategies designed to reduce ambient air pollution are an important step towards healthy aging.

Late-onset administration of GDF11 extends life span and delays development of age-related markers in the annual fish Nothobranchius guentheri.

Current studies have generated disputes on the age-related change in the concentration of growth differentiation factor 11 (GDF11) and its role in the genesis of rejuvenation conditions. In this study we showed for the first time that both GDF11 gene expression and its protein abundance decreased with age in the fish Nothobranchius guentheri. We also showed that rGDF11 fed was indeed absorbed by the fish. Importantly, we demonstrated that dietary intake of recombinant GDF11 had little influences on the body weight and length of aging N. guentheri, but it delayed the development of age-related biomarkers and extended both the median and maximum life span of the fish. Our results clearly demonstrate that piscine GDF11 has rejuvenation and anti-aging capacity, the first data as such in non-mammalian vertebrates.

Inhibitory effect of naringenin on LPS-induced skin senescence by SIRT1 regulation in HDFs

BackgroundThis study aims to investigate the ability of naringenin to regulate the expression of nuclear factor-кB, the upper gene of lipopolysaccharide-induced SIRT1; regulate signal transduction in the extracellular matrix, which plays an important role in the dermis; and alter the matrix metalloproteinase 1 and matrix metalloproteinase 3 gene expression, therefore having suppressing effect on skin cell senescence and deoxyribonucleic acid protection and cell protection effects and confirm naringenin’s potential as an important cosmetic ingredient.MethodsThe efficacy of naringenin was assessed through reactive oxygen species assay, water-soluble tetrazolium salt assay, nuclear factor-кB luciferase assay, enzyme-linked immunosorbent assay, nicotinamide adenine dinucleotide phosphate oxidase activity assay, and quantitative real-time polymerase chain reaction.ResultsSirt1, which regulates naringenin upstream of the nuclear factor-кB pathway, inhibits nuclear factor-кB activity and decreases matrix metalloproteinase expression level and SIRT1 gene dose-dependently. The results confirmed naringenin had an anti-aging effect on lipopolysaccharide-induced skin senescence. Various age-related biomarkers were used to analyze the inhibitory effect naringenin had on cell senescence progress and oxidative activity. Further experiments also showed naringenin also acted on NADPH oxidase, which produces superoxide (O2-), resulting in inhibiting NADPH oxidase activity. Experimental results reported that naringenin regulated the activity of SIRT1, which is the cause of modern skin cell aging, and in turn had a regenerative effect on reactive oxygen species-induced skin cellular senescence which affects skin elasticity and wrinkles.ConclusionsThis study confirmed that naringenin inhibits cellular senescence and regenerates human dermal fibroblasts damaged by lipopolysaccharide, and suggests that naringenin will be a cosmetic ingredient that has cell regenerative effects and anti-aging effects.

ITRAQ-based quantitative analysis of age-specific variations in salivary proteome of caries-susceptible individuals

BackgroundHuman saliva is a protein-rich, easily accessible source of potential biomarkers for the diagnosis of oral and systemic diseases. However, little is known about the changes in salivary proteome associated with aging of patients with dental caries. Here, we applied isobaric tags for relative and absolute quantitation (iTRAQ) in combination with multiple reaction monitoring mass spectrometry (MRM-MS) to characterize the salivary proteome profiles of subjects of different ages, presenting with and without caries, with the aim of identifying age-related biomarkers for dental caries.MethodsUnstimulated whole saliva samples were collected from 40 caries-free and caries-susceptible young adults and elderly individuals. Salivary proteins were extracted, reduced, alkylated, digested with trypsin and then analyzed using iTRAQ-coupled LC–MS/MS, followed by GO annotation, biological pathway analysis, hierarchical clustering analysis, and protein–protein interaction analysis. Candidate verification was then conducted using MRM-MS.ResultsAmong 658 salivary proteins identified using tandem mass spectrometry, 435 proteins exhibited altered expression patterns in different age groups with and without caries. Of these proteins, 96 displayed age-specific changes among caries-susceptible adults and elderly individuals, and were mainly associated with salivary secretion pathway, while 110 age-specific proteins were identified among healthy individuals. It was found that the age factor caused significant variations and played an important role in both healthy and cariogenic salivary proteomes. Subsequently, a total of 136 target proteins with complex protein–protein interactions, including 14 age-specific proteins associated with caries, were further successfully validated using MRM analysis. Moreover, non-age-specific proteins (histatin-1 and BPI fold-containing family B member 1) were verified to be important candidate biomarkers for common dental caries.ConclusionsOur proteomic analysis performed using the discovery-through-verification pipeline revealed distinct variations caused by age factor in both healthy and cariogenic salivary proteomes, highlighting the significance of age in the great potential of saliva for caries diagnosis and biomarker discovery.

Identification and expression of carbonic anhydrase 2, myosin regulatory light chain 2 and selenium-binding protein 1 in zebrafish Danio rerio: Implication for age-related biomarkers

Proteomic study has determined age-related changes in synthesis of carbonic anhydrase 2, myosin regulatory light chain 2 and selenium-binding protein 1 in muscle of post-menopausal women. However, little information is available regarding the expression and role of these proteins in early development and life span. In this study we showed that zebrafish ca2, myl2a, myl2b and selenbp1 were highly identical to their mammalian counterparts in primary and tertiary structures as well as genomic organization and syntenic map. They displayed distinct spatiotemporal expression patterns in embryos and larvae of zebrafish. Moreover, their transcription levels in the respective tissues were obviously remodeled in an age-dependent fashion, i.e. some mRNA levels were increased, while others remained unchanged or even decreased, suggesting that CA2, MYL2a, MYL2b and SELENBP1 can be used as aging biomarkers. Our study also lays a foundation for further illumination of the functions of these genes in early development and aging processes.

Metabolic Biomarkers of Ageing in C57BL/6J Wild-Type and Flavin-Containing Monooxygenase 5 (FMO5)-Knockout Mice

It was recently demonstrated in mice that knockout of the flavin-containing monooxygenase 5 gene, Fmo5, slows metabolic ageing via pleiotropic effects. We have now used an NMR-based metabonomics approach to study the effects of ageing directly on the metabolic profiles of urine and plasma from male, wild-type C57BL/6J and Fmo5−/− (FMO5 KO) mice back-crossed onto the C57BL/6J background. The aim of this study was to identify metabolic signatures that are associated with ageing in both these mouse lines and to characterize the age-related differences in the metabolite profiles between the FMO5 KO mice and their wild-type counterparts at equivalent time points. We identified a range of age-related biomarkers in both urine and plasma. Some metabolites, including urinary 6-hydroxy-6-methylheptan-3-one (6H6MH3O), a mouse sex pheromone, showed similar patterns of changes with age, regardless of genetic background. Others, however, were altered only in the FMO5 KO, or only in the wild-type mice, indicating the impact of genetic modifications on mouse ageing. Elevated concentrations of urinary taurine represent a distinctive, ageing-related change observed only in wild-type mice.

Role of phospholipase D in the lifespan of Caenorhabditis elegans

We have previously shown that phospholipase D (PLD) downregulation accelerates cellular senescence, which is widely believed to play an important role in aging, by stimulating reactive oxygen species (ROS) accumulation in human cells. In this study, we examined the role of PLD in aging using the nematode Caenorhabditis elegans. The mRNA level of pld-1 was found to be inversely correlated with aging. RNAi-mediated knockdown of pld-1 expression in nematodes enhanced ROS and lipofuscin accumulation and decreased lifespan, motility, and resistance to stress compared to that in nematodes treated with control RNAi. Pld-1 knockdown repressed the long lifespan of age-1 and akt-1 mutants but did not further reduce the short lifespan of daf-16 mutants, suggesting that PLD functions between AKT-1 and DAF-16. The ROS scavenger N-acetyl-L-cysteine, a PLD effector phosphatidic acid and a possible CK2 activator spermidine attenuated the lifespan shortening and age-related biomarkers triggered by pld-1 knockdown. Pld-1 RNAi downregulated the expression of DAF-16 target genes such as sod-3, dod-11, and mtl-1 in nematodes. In human cells, furthermore, PLD2 downregulation decreased the transcription of FoxO3a target genes (Cu/ZnSOD, MnSOD, catalase, thioredoxin-2, and peroxiredoxin-5), whereas ectopic PLD2 expression elevated the mRNA levels of these antioxidant genes. Taken together, these results indicated that PLD downregulation shortens longevity and induces age-related biomarkers through ROS accumulation by inhibiting the DAF-16/FoxO3a pathway in nematodes.

Time-dependent effects of late-onset dietary intake of salidroside on lifespan and age-related biomarkers of the annual fish Nothobranchius guentheri.

One of the most studied and widely accepted conjectures of aging process is the oxidative stress theory. Previous studies have shown that salidroside can protect D-galactose-induced mouse model against aging and a formulation of Rhodiola rosea extracts (SHR-5) containing salidroside increases lifespan of fruit fly. However, direct evidence linking salidroside itself with the observed anti-aging effect in vivo and relevant molecular mechanisms are poorly defined. In this study, we first demonstrated that salidroside exhibited a time-dependent effect, and late-onset long-term salidroside dietary intake extended the lifespan in the annual fish Nothobranchius guentheri. We then showed that salidroside reduced the accumulation of lipofuscin in the gills as well as the levels of protein oxidation, lipid peroxidation and reactive oxygen species in the muscles; enhanced the activities of catalase, glutathione peroxidase, and superoxide dismutase in the fish; and decelerated the increase of P66shc, a critical factor for regulation of intracellular reactive oxygen species contents. Collectively, these data indicate that salidroside can prolong the lifespan and retard the onset of age-related biomarkers via the antioxidant system in aging fish. It also suggests that salidroside may have a potential usefulness in prolonging the lifespan of the elderly.