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1.  Effects of Long-Term Dharma-Chan Meditation on Cardiorespiratory Synchronization and Heart Rate Variability Behavior 
Rejuvenation Research  2013;16(2):115-123.
Abstract
Remarkable changes in cardiorespiratory interactions are frequently experienced by Chan meditation practitioners following years of practice. This study compares the results of our study on cardiorespiratory interactions for novice (control group) and experienced (experimental group) Chan meditation practitioners. The effectual co-action between the cardiac and respiratory systems was evaluated by the degree of cardiorespiratory phase synchronization (CRPS). In addition, an adaptive-frequency-range (AFR) scheme to reliably quantify heart rate variability (HRV) was developed for assessing the regulation of sympathetic–parasympathetic activity and the efficiency of pulmonary gas exchange. The enhanced HRV method, named HRVAFR, can resolve the issue of overestimating HRV under the condition of slow respiration rates, which is frequently encountered in studies on Chan meditation practitioners. In the comparison of the three data sets collected from the two groups, our findings resulted in innovative hypotheses to interpret the extraordinary process of the rejuvenation of cardiorespiratory functions through long-term Dharma-Chan meditation practice. Particularly, advanced practitioners exhibit a continuously high degree of cardiorespiratory phase synchronization, even during rapid breathing. Based on our post-experimental interview with advanced practitioners, the activation of inner Chakra energy, during the course of Chan-detachment practice, frequently induces perceptible physiological-mental reformation, including an efficient mechanism for regulating cardiorespiratory interactions.
doi:10.1089/rej.2012.1363
PMCID: PMC3634153  PMID: 23323597
2.  Effects of Different Exercise Interventions on Risk of Falls, Gait Ability, and Balance in Physically Frail Older Adults: A Systematic Review 
Rejuvenation Research  2013;16(2):105-114.
Abstract
The aim of this review was to recommend training strategies that improve the functional capacity in physically frail older adults based on scientific literature, focusing specially in supervised exercise programs that improved muscle strength, fall risk, balance, and gait ability. Scielo, Science Citation Index, MEDLINE, Scopus, Sport Discus, and ScienceDirect databases were searched from 1990 to 2012. Studies must have mentioned the effects of exercise training on at least one of the following four parameters: Incidence of falls, gait, balance, and lower-body strength. Twenty studies that investigated the effects of multi-component exercise training (10), resistance training (6), endurance training (1), and balance training (3) were included in the present revision. Ten trials investigated the effects of exercise on the incidence of falls in elderly with physical frailty. Seven of them have found a fewer falls incidence after physical training when compared with the control group. Eleven trials investigated the effects of exercise intervention on the gait ability. Six of them showed enhancements in the gait ability. Ten trials investigated the effects of exercise intervention on the balance performance and seven of them demonstrated enhanced balance. Thirteen trials investigated the effects of exercise intervention on the muscle strength and nine of them showed increases in the muscle strength. The multi-component exercise intervention composed by strength, endurance and balance training seems to be the best strategy to improve rate of falls, gait ability, balance, and strength performance in physically frail older adults.
doi:10.1089/rej.2012.1397
PMCID: PMC3634155  PMID: 23327448
3.  Trade-Off in the Effect of the APOE Gene on the Ages at Onset of Cardiocascular Disease and Cancer across Ages, Gender, and Human Generations* 
Rejuvenation Research  2013;16(1):28-34.
Abstract
Decades of studies of candidate genes show their complex role in aging-related traits. We focus on apolipoprotein E e2/3/4 polymorphism and ages at onset of cardiovascular diseases (CVD) and cancer in the parental and offspring generations of the Framingham Heart Study participants to gain insights on the role of age and gender across generations in genetic trade-offs. The analyses show that the apolipoprotein E e4 allele carriers live longer lives without cancer than the non-e4 allele carriers in each generation. The role of the e4 allele in onset of CVD is age- and generation-specific, constituting two modes of sexually dimorphic genetic trade-offs. In offspring, the e4 allele confers risk of CVD primarily in women and can protect against cancer primarily in men of the same age. In the parental generation, genetic trade-off is seen in different age groups, with a protective role of the e4 allele against cancer in older men and its detrimental role in CVD in younger women. The puzzling complexity of genetic mechanisms working in different genders, ages, and environments calls for more detail and systemic analyses beyond those adapted in current large-scale genetic association studies.
doi:10.1089/rej.2012.1362
PMCID: PMC3582279  PMID: 23094790
4.  Linkage Disequilibrium and Haplotype Analysis of the ATP7B Gene in Alzheimer's Disease 
Rejuvenation Research  2013;16(1):3-10.
Abstract
Copper dyshomeostasis leading to a labile Cu2+ not bound to ceruloplasmin (“free” copper) may influence Alzheimer's disease (AD) onset or progression. To investigate this hypothesis, we investigated ATP7B, the gene that controls copper excretion through the bile and concentrations of free copper in systemic circulation. Our study analyzed informative ATP7B single-nucleotide polymorphisms (SNPs) in a case–control population (n=515). In particular, we evaluated the genetic structure of the ATP7B gene using the HapMap database and carried out a genetic association investigation. Linkage disequilibrium (LD) analysis highlighted that our informative SNPs and their LD SNPs covered 96% of the ATP7B gene sequence, distinguishing two “strong LD” blocks. The first LD block contains the gene region encoding for transmembrane and copper-binding, whereas the second LD block encodes for copper-binding domains. The genetic association analysis showed significant results after multiple testing correction for all investigated variants (rs1801243, odds ratio [OR]=1.52, 95% confidence interval [CI]=1.10–2.09, p=0.010; rs2147363, OR=1.58, 95% CI=1.11–2.25, p=0.010; rs1061472, OR=1.73, 95% CI=1.23–2.43, p=0.002; rs732774, OR=2.31, 95% CI=1.41–3.77, p<0.001), indicating that SNPs in transmembrane domains may have a stronger association with AD risk than variants in copper-binding domains. Our study provides novel insights that confirm the role of ATP7B as a potential genetic risk factor for AD. The analysis of ATP7B informative SNPs confirms our previous hypothesis about the absence of ATP7B in the significant loci of genome-wide association studies of AD and the genetic association study suggests that transmembrane and adenosine triphosphate (ATP) domains in the ATP7B gene may harbor variants/haplotypes associated with AD risk.
doi:10.1089/rej.2012.1357
PMCID: PMC3582274  PMID: 22950421
5.  Antioxidant Status and APOE Genotype As Susceptibility Factors for Neurodegeneration in Alzheimer's Disease and Vascular Dementia 
Rejuvenation Research  2013;16(1):51-56.
Abstract
Different factors interact to develop neurodegeneration in patients with dementia and other neurodegenerative disorders. Oxidative stress and the ε4 allele of apolipoprotein E (ApoE) are associated with significant alteration in lipid metabolism, in turn connected to a variety of neurodegenerative diseases and aging. Thus, a better understanding of the pathogenetic pathways associated with lipid dyshomeostasis may elucidate the causes of neurodegenerative processes. To address this issue, we evaluated the effects of antioxidant status and APOE genotype on neurodegeneration in patients with dementia of the Alzheimer type (AD), with vascular dementia (VaD), and in elderly healthy controls. Eighty-two AD, 42 VaD patients, and 26 healthy controls were recruited and underwent medial temporal lobe atrophy (MTA) assessment, white matter hyperintensities rating (WMH), serum total antioxidant status assaying (TAS), and APOE genotyping. A logistic regression algorithm applied to our data revealed that a 0.01 mmol/L decrease of TAS concentration increased the probability of MTA by 24% (p=0.038) and that carriers of the APOE ε4 allele showed higher WMH scores (p=0.018), confirming that small variations in antioxidant systems homeostasis are associated with relevant modifications of disease risk. Furthermore, in individuals with analogous TAS values, the presence of the ε4 allele increased the predicted probability of having MTA. These outcomes further sustain the interaction of oxidative stress and APOE genotype to neurodegeneration.
doi:10.1089/rej.2012.1383
PMCID: PMC3582293  PMID: 23216585
6.  Relationship Between Renal Function and Physical Performance in Elderly Hospitalized Patients 
Rejuvenation Research  2012;15(6):545-552.
Abstract
Chronic kidney disease (CKD) is increasingly recognized as a cause of worsening physical functioning in older patients. The Short Physical Performance Battery (SPPB) is highly reliable in older populations, but no data on older hospitalized patients with different degrees of kidney function are available. We aimed at testing the association between estimated glomerular filtration rate (eGFR) and SPPB, either global score (range 0–12) or its individual components (muscle strength, balance, and walking speed, each ranging from 0 to 4), in a sample of older hospitalized patients. Our series consisted of 486 patients aged 65 or more consecutively enrolled in 11 acute care medical wards participating to a multicenter observational study. eGFR was obtained by the Chronic Kidney Disease Epidemiological Collaboration (CKD-EPI) equation. Physical performance was objectively measured by the SPPB. The relationship between eGFR and SPPB was investigated by multiple linear regression analysis. Physically impaired patients (SPPB total score<5) were older, had lower serum albumin and Mini-Mental State Examination (MMSE) scores as well as higher overall co-morbidity, prevalence of stroke, cancer, and anemia compared to those with intermediate (SPPB=5–8) and good physical performance (SPPB=9–12). Fully adjusted multivariate models showed that eGFR (modeled as 10 mL/min per 1.73 m2 intervals) was independently associated with the SPPB total score (B=0.49; 95% confidence interval [CI]=0.18–0.66; p=0.003), balance (B=0.30; 95% CI=0.10–0.49; p=0.005), and muscle strength (B=0.06; 95% CI=0.01–0.10; p=0.043), but not with walking speed (B=−0.04; 95% CI=−0.09–0.11; p=0.107). In conclusion, reduced renal function is associated with poorer physical performance in older hospitalized patients. SPPB is worthy of testing to monitor changes in physical performance in elderly CKD patients.
doi:10.1089/rej.2012.1329
PMCID: PMC3549205  PMID: 22950422
7.  Quinic Acid Could Be a Potential Rejuvenating Natural Compound by Improving Survival of Caenorhabditis elegans under Deleterious Conditions 
Rejuvenation Research  2012;15(6):573-583.
Abstract
Quinic acid (QA) is an active ingredient of Cat's Claw (Uncaria tomentosa), which is found to be active in enhancing DNA repair and immunity in model systems and able to generate neuroprotective effects in neurons. However, QA's role in improving survival is not well studied. Here we report that QA can provide protection in Caenorhabidits elegans and improve worm survival under stress. Under heat stress and oxidative stress, QA-treated wild-type C. elegans N2 (N2) survived 17.8% and 29.7% longer, respectively, than the control worms. Our data suggest that under heat stress, QA can upregulate the expression of the small heat shock protein hsp-16.2 gene, which could help the worms survive a longer time. We also found that QA extended the C. elegans mutant VC475 [hsp-16.2 (gk249)] life span by 15.7% under normal culture conditions. However, under normal culture conditions, QA did not affect hsp-16.2 expression, but upregulated the expression of daf-16 and sod-3 in a DAF-16–dependent manner, and downregulated the level of reactive oxygen species (ROS), suggesting that under normal conditions QA acts in different pathways. As a natural product, QA demonstrates great potential as a rejuvenating compound.
doi:10.1089/rej.2012.1342
PMCID: PMC3549210  PMID: 22950425
8.  The Decay of Stem Cell Nourishment at the Niche 
Rejuvenation Research  2013;16(6):487-494.
Abstract
One of the main features of human aging is the loss of adult stem cell homeostasis. Organs that are very dependent on adult stem cells show increased susceptibility to aging, particularly organs that present a vascular stem cell niche. Reduced regenerative capacity in tissues correlates with reduced stem cell function, which parallels a loss of microvascular density (rarefraction) and plasticity. Moreover, the age-related loss of microvascular plasticity and rarefaction has significance beyond metabolic support for tissues because stem cell niches are regulated co-ordinately with the vascular cells. In addition, microvascular rarefaction is related to increased inflammatory signals that may negatively regulate the stem cell population. Thus, the processes of microvascular rarefaction, adult stem cell dysfunction, and inflammation underlie the cycle of physiological decline that we call aging. Observations from new mouse models and humans are discussed here to support the vascular aging theory. We develop a novel theory to explain the complexity of aging in mammals and perhaps in other organisms. The connection between vascular endothelial tissue and organismal aging provides a potential evolutionary conserved mechanism that is an ideal target for the development of therapies to prevent or delay age-related processes in humans.
doi:10.1089/rej.2013.1440
PMCID: PMC3869415  PMID: 23937078
9.  Inflammation, Adiposity, and Mortality in the Oldest Old 
Rejuvenation Research  2012;15(5):445-452.
Abstract
Background
Increased proinflammatory status is associated with both increased adiposity and higher mortality risk. Thus, it is paradoxical that mild obesity does not predict increased mortality in older adults. We investigated the association of inflammatory markers with body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) in nonagenarians, and the combined effects of BMI, WC, WHR, and inflammatory status on mortality.
Methods
This study was based on a prospective population-based study, Vitality 90+, carried out in Tampere, Finland. Altogether, 157 women and 53 men aged 90 years were subjected to anthropometric measurements, blood samples, and a 4-year mortality follow-up. Inflammatory status was based on sex-specific median levels of interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α).
Results
In the unadjusted linear regression analyses, IL-1RA, CRP, and TNF-α were positively associated with BMI and WC in women, whereas in men IL-1RA was positively associated with BMI and IL-6 positively with WC. In the models adjusted for diseases, functional status, and smoking, IL-1RA and CRP were positively associated with BMI and WC in women. Low WC and WHR combined with low inflammation protected from mortality in women and high BMI and WC regardless of inflammation protected from mortality in men in the adjusted Cox regression analysis.
Conclusions
In the oldest old, the effect of adiposity in combination with inflammatory status on mortality differs between men and women. More research is needed to disentangle the role of adiposity among the oldest old.
doi:10.1089/rej.2011.1310
PMCID: PMC3482839  PMID: 22998329
10.  Dietary Intake of Resveratrol Enhances the Adaptive Immunity of Aged Rats 
Rejuvenation Research  2012;15(5):507-515.
Abstract
It is well known that immune response declines with aging. Resveratrol, a polyphenol that occurs naturally in several plant species including grapevines and berries, has been shown to have potent antiaging and health-promoting activities. However, the mechanism underlying these activities remains largely unknown. Here we clearly demonstrate that: (1) Dietary intake of resveratrol induced a significant increase in T helper cells (CD4+) in middle-aged (12 months old) and aged (21 months old) Wistar male rats; (2) resveratrol supplementation considerably increased the delayed-type hypersensitivity response, a T cell–mediated immune response, in aged rats; and (3) reveratrol supplementation remarkably promoted the production of total anti-keyhole limpet hemocyanin (KLH) immunoglobulin G (IgG), anti-KLH IgG1, and anti-KLH IgG2α in aged rats without disturbing immune homeostasis. These data together indicate that resveratrol is capable of counteracting immunosenescence, thereby leading to rejuvenation. In practice, resveratrol can be useful to help the elderly generate an improved response to vaccine with stronger humoral and cell-mediated immune responses.
doi:10.1089/rej.2012.1321
PMCID: PMC3482841  PMID: 22950432
11.  Luteolin Prevents Solar Radiation-Induced Matrix Metalloproteinase-1 Activation in Human Fibroblasts: A Role for p38 Mitogen-Activated Protein Kinase and Interleukin-20 Released from Keratinocytes 
Rejuvenation Research  2012;15(5):466-475.
Abstract
Human skin is continuously exposed to solar radiation, which can result in photoaging, a process involving both dermal and, to a lesser extent, epidermal structures. Previously, we have shown that the flavonoid luteolin protects the epidermis from ultraviolet (UV)-induced damage by a combination of UV-absorbing, antioxidant, and antiinflammatory properties. The aim of the present study was to determine direct and indirect effects of luteolin on dermal fibroblasts as major targets of photoaging. Stimulation of fibroblasts with UVA light or the proinflammatory cytokine interleukin-20 (IL-20) is associated with wrinkled skin, increased IL-6 secretion, matrix metalloproteinase (MMP-1) expression, and hyaluronidase activity. All of these targets were inhibited by luteolin via interference with the p38 mitogen-activated protein kinase (MAPK) pathway. Next, we assessed the role of conditioned supernatants from keratinocytes irradiated with solar-simulated radiation (SSR) on nonirradiated dermal fibroblasts. In keratinocytes, luteolin inhibited SSR-induced production of IL-20, also via interference with the p38 MAPK pathway. Similarly, keratinocyte supernatant-induced IL-6 and MMP-1 expression in fibroblasts was reduced by pretreatment of keratinocytes with luteolin. Finally, these results were confirmed ex vivo on skin explants treated with luteolin before UV irradiation. Our results suggest that SSR-mediated production of soluble factors in keratinocytes is modulated by luteolin and may attenuate photoaging in dermal fibroblasts.
doi:10.1089/rej.2011.1309
PMCID: PMC3482844  PMID: 23004935
12.  The Role of DNA Methylation in Aging, Rejuvenation, and Age-Related Disease 
Rejuvenation Research  2012;15(5):483-494.
Abstract
DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-l-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.
doi:10.1089/rej.2012.1324
PMCID: PMC3482848  PMID: 23098078
13.  Tissue Inhibitor of Matrix Metalloproteinase-3 or Vascular Endothelial Growth Factor Transfection of Aged Human Mesenchymal Stem Cells Enhances Cell Therapy after Myocardial Infarction 
Rejuvenation Research  2012;15(5):495-506.
Abstract
Mesenchymal stem cell (MSC) transplantation has been proposed as a potential therapeutic approach for ischemic heart disease, but the regenerative capacity of these cells decreases with age. In this study, we genetically engineered old human MSCs (O-hMSCs) with tissue inhibitor of matrix metalloproteinase-3 (TIMP3) and vascular endothelial growth factor (VEGF) and evaluated the effects on the efficacy of cell-based gene therapy in a rat myocardial infarction (MI) model. Cultured O-hMSCs were transfected with TIMP3 (O-TIMP3) or VEGF (O-VEGF) and compared with young hMSCs (Y-hMSCs) and non-transfected O-hMSCs for growth, clonogenic capacity, and differentiation potential. In vivo, rats were subjected to left coronary artery ligation with subsequent injection of Y-hMSCs, O-hMSCs, O-TIMP3, O-VEGF, or medium. Echocardiography was performed prior to and at 1, 2, and 4 weeks after MI. Myocardial levels of matrix metalloproteinase-2 (MMP2), MMP9, TIMP3, and VEGF were assessed at 1 week. Hemodynamics, morphology, and histology were measured at 4 weeks. In vitro, genetically modified O-hMSCs showed no changes in growth, colony formation, or multi-differentiation capacity. In vivo, transplantation with O-TIMP3, O-VEGF, or Y-hMSCs increased capillary density, preserved cardiac function, and reduced infarct size compared to O-hMSCs and medium control. O-TIMP3 and O-VEGF transplantation enhanced TIMP3 and VEGF expression, respectively, in the treated animals. O-hMSCs genetically modified with TIMP3 or VEGF can increase angiogenesis, prevent adverse matrix remodeling, and restore cardiac function to a degree similar to Y-hMSCs. This gene-modified cell therapy strategy may be a promising clinical treatment to rejuvenate stem cells in elderly patients.
doi:10.1089/rej.2012.1325
PMCID: PMC3482878  PMID: 22950427
14.  Polygenic Effects of Common Single-Nucleotide Polymorphisms on Life Span: When Association Meets Causality 
Rejuvenation Research  2012;15(4):381-394.
Abstract
Recently we have shown that the human life span is influenced jointly by many common single-nucleotide polymorphisms (SNPs), each with a small individual effect. Here we investigate further the polygenic influence on life span and discuss its possible biological mechanisms. First we identified six sets of prolongevity SNP alleles in the Framingham Heart Study 550K SNPs data, using six different statistical procedures (normal linear, Cox, and logistic regressions; generalized estimation equation; mixed model; gene frequency method). We then estimated joint effects of these SNPs on human survival. We found that alleles in each set show significant additive influence on life span. Twenty-seven SNPs comprised the overlapping set of SNPs that influenced life span, regardless of the statistical procedure. The majority of these SNPs (74%) were within genes, compared to 40% of SNPs in the original 550K set. We then performed a review of current literature on functions of genes closest to these 27 SNPs. The review showed that the respective genes are largely involved in aging, cancer, and brain disorders. We concluded that polygenic effects can explain a substantial portion of genetic influence on life span. Composition of the set of prolongevity alleles depends on the statistical procedure used for the allele selection. At the same time, there is a core set of longevity alleles that are selected with all statistical procedures. Functional relevance of respective genes to aging and major diseases supports causal relationships between the identified SNPs and life span. The fact that genes found in our and other genetic association studies of aging/longevity have similar functions indicates high chances of true positive associations for corresponding genetic variants.
doi:10.1089/rej.2011.1257
PMCID: PMC3419841  PMID: 22533364
15.  Pulmonary Delivery of Interleukin-7 Provides Efficient and Safe Delivery to the Aging Immune System 
Rejuvenation Research  2012;15(4):414-422.
Abstract
Age-associated atrophy of the thymus with coincident reduction in thymopoeisis, decline in thymic output, and subsequent immune dysfunction has been reversed by the use of interleukin-7 (IL-7). In the earlier studies and in clinical trials, delivery of IL-7 has been by multiple injections over several days to maintain effective activity levels in the tissues. This is unlikely to meet with high compliance rates in future clinical use, and so we tested alternate routes of delivery using a technique involving tagging IL-7 with fluorescent dye that emits in the near-infrared region and whose fluorescence can be visualized within the tissues of live animals. We have shown that intratracheal instillation, enabling transfer through the lungs, provides an effective route for delivering IL-7 into the bloodstream and from there into the tissues in older animals. Delivery is rapid and widespread tissue distribution is seen. Comparison of administration either subcutaneously or by instillation reveals that IL-7 delivery by the pulmonary route provides significantly greater transmission to lymphoid tissues when compared with injection. In functional assessment studies, pulmonary administration led to significantly improved intrathymic T cell development in older animals when compared with IL-7 delivered by injection. Furthermore, in these older animals, delivery of IL-7 by intratracheal instillation was not accompanied by any apparent adverse events when compared with controls receiving saline vehicle by instillation or animals receiving IL-7 by subcutaneous injection.
doi:10.1089/rej.2011.1258
PMCID: PMC3419844  PMID: 22663183
16.  How Genes Influence Life Span: The Biodemography of Human Survival 
Rejuvenation Research  2012;15(4):374-380.
Abstract
Background
In genome-wide association studies (GWAS) of human life span, none of the genetic variants has reached the level of genome-wide statistical significance. The roles of such variants in life span regulation remain unclear.
Data and Method
A biodemographic analyses was done of genetic regulation of life span using data on low-significance longevity alleles selected in the earlier GWAS of the original Framingham cohort.
Results
Age-specific survival curves considered as functions of the number of longevity alleles exhibit regularities known in demography as “rectangularization” of survival curves. The presence of such pattern confirms observations from experimental studies that regulation of life span involves genes responsible for stress resistance.
Conclusion
Biodemographic analyses could provide important information about the properties of genes affecting phenotypic traits.
doi:10.1089/rej.2011.1290
PMCID: PMC3419845  PMID: 22607627
17.  Data Mining Identifies Digit Symbol Substitution Test Score and Serum Cystatin C as Dominant Predictors of Mortality in Older Men and Women 
Rejuvenation Research  2012;15(4):405-413.
Abstract
Background
Characterization of long-term health trajectory in older individuals is important for proactive health management. However, the relative prognostic value of information contained in clinical profiles of nonfrail older adults is often unclear.
Methods
We screened 825 phenotypic and genetic measures evaluated during the Health, Aging, and Body Composition Study (Health ABC) baseline visit (3,067 men and women aged 70–79). Variables that best predicted mortality over 13 years of follow-up were identified using 10-fold cross-validation.
Results
Mortality was most strongly associated with low Digit Symbol Substitution Test (DSST) score (DSST<25; 21.9% of cohort; hazard ratio [HR]=1.87±0.06) and elevated serum cystatin C (≥1.30 mg/mL; 12.1% of cohort; HR=2.25±0.07). These variables predicted mortality better than 823 other measures, including baseline age and a 45-variable health deficit index. Given elevated cystatin C (≥1.30 mg/mL), mortality risk was further increased by high serum creatinine, high abdominal visceral fat density, and smoking history (2.52≤HR ≤3.73). Given a low DSST score (<25) combined with low-to-moderate cystatin C (<1.30 mg/mL), mortality risk was highest among those with elevated plasma resistin and smoking history (1.90≤HR≤2.02).
Conclusions
DSST score and serum cystatin C warrant priority consideration for the evaluation of mortality risk in older individuals. Both variables, taken individually, predict mortality better than chronological age or a health deficit index in well-functioning older adults (ages 70–79). DSST score and serum cystatin C can thus provide evidence-based tools for geriatric assessment.
doi:10.1089/rej.2011.1297
PMCID: PMC3419847  PMID: 22607624
18.  Leukocyte CCR2 Expression Is Associated with Mini-Mental State Examination Score in Older Adults 
Rejuvenation Research  2012;15(4):395-404.
Abstract
Introduction
Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample.
Methods
We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models.
Results
In genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta=−0.16, p=5.1×10−6, false discovery rate (FDR; q=0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta=−0.16, p=5.1×10−6, q=0.003; and beta=−0.13, p=5.5×10−5, q=0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype.
Conclusions
We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated β-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.
doi:10.1089/rej.2011.1302
PMCID: PMC3419848  PMID: 22607625
19.  Association Between Age-Related Decline of Kidney Function and Plasma Malondialdehyde 
Rejuvenation Research  2012;15(3):257-264.
Abstract
Oxidative stress is a key factor linked renal function decline with age. However, there is still no large cohort study exploring the potential role of oxidative stress in mild insufficiency of kidney function (MIKF) and chronic kidney disease (CKD) after adjusting for confounding factors. This study tested the hypothesis that oxidative stress, indicated by plasma malondialdehyde (MDA), is associated with the prevalence of MIKF and CKD after controlling the effects of confounding factors.
Plasma levels of MDA and serum levels of fasting glucose, cholesterol, triglycerides, creatinine, alanine aminotransferase, and aspartate aminotransferase were analyzed from 2,169 Chinese Han adults. A questionnaire and physical examination were performed to identify and suspect risk factors of renal function decline with age. Kidney function, as indicated by estimated glomerular filtration rate, showed a significant decline with age in both male and female. Although the association between age and plasma MDA levels was nonlinear, MDA was negatively related to kidney function. The multivariate-adjusted odds ratios showed that plasma MDA had a significantly graded relation to the prevalence of MIKF and CKD with or without adjustment for covariates. By comparison with the lowest quartile, individuals with the highest quartile of MDA level had a 99% and 223% increased risk of developing MIKF and CKD, respectively. Further results from multiinteraction analysis demonstrated that plasma MDA may be the mediator linking different covariates with renal function decline. The most striking finding of this study was that oxidative stress, as indicated by plasma MDA levels, is associated with the prevalence of MIKF and/or CKD. Although imposing an increasing burden on the kidney and/or promoting a cyclical process of oxidative stress in the body, high levels of MDA in plasma may link the decline of kidney function with age.
doi:10.1089/rej.2011.1259
PMCID: PMC3388493  PMID: 22530729
20.  Relationship of Low-Circulating “Anti-Aging” Klotho Hormone with Disability in Activities of Daily Living among Older Community-Dwelling Adults 
Rejuvenation Research  2012;15(3):295-301.
Abstract
The aging suppressor gene klotho encodes a single-pass transmembrane protein klotho that in mice is known to extend life span when overexpressed and to resemble accelerated aging, with skeletal muscle atrophy and decreased bone mineral density, when expression is disrupted. We sought to examine the relationship between plasma klotho and disability in activities of daily living (ADL) in older community-dwelling adults. In a cross-sectional study, plasma klotho was measured in a population-based sample of 802 adults, ≥65 years, who participated in the “Invecchiare in Chianti” (Aging in the Chianti Area) (InCHIANTI) study in Tuscany, Italy. The overall proportion of adults with ADL disability was 11.9%. Mean (standard deviation) klotho concentrations were 689 (238) pg/mL. From the lowest to the highest tertile of plasma klotho, 16.1%, 9.7%, and 5.6% of participants, respectively, had ADL disability (p=0.0004). Plasma klotho, per 1 standard deviation increase, was associated with ADL disability (odds ratio=0.57, 95% confidence interval 0.35–0.93, p=0.02) in a multivariate logistic regression model adjusting for age, education, cognition, physical activity, physical performance, total cholesterol, alcohol and tobacco use, and chronic diseases. Low plasma klotho concentrations were independently associated with ADL disability among older community-dwelling men and women.
doi:10.1089/rej.2011.1268
PMCID: PMC3388499  PMID: 22530731
21.  Positive Lysosomal Modulation As a Unique Strategy to Treat Age-Related Protein Accumulation Diseases 
Rejuvenation Research  2012;15(2):189-197.
Abstract
Lysosomes are involved in degrading and recycling cellular ingredients, and their disruption with age may contribute to amyloidogenesis, paired helical filaments (PHFs), and α-synuclein and mutant huntingtin aggregation. Lysosomal cathepsins are upregulated by accumulating proteins and more so by the modulator Z-Phe-Ala-diazomethylketone (PADK). Such positive modulators of the lysosomal system have been studied in the well-characterized hippocampal slice model of protein accumulation that exhibits the pathogenic cascade of tau aggregation, tubulin breakdown, microtubule destabilization, transport failure, and synaptic decline. Active cathepsins were upregulated by PADK; Rab proteins were modified as well, indicating enhanced trafficking, whereas lysosome-associated membrane protein and proteasome markers were unchanged. Lysosomal modulation reduced the pre-existing PHF deposits, restored tubulin structure and transport, and recovered synaptic components. Further proof-of-principle studies used Alzheimer disease mouse models. It was recently reported that systemic PADK administration caused dramatic increases in cathepsin B protein and activity levels, whereas neprilysin, insulin-degrading enzyme, α-secretase, and β-secretase were unaffected by PADK. In the transgenic models, PADK treatment resulted in clearance of intracellular amyloid beta (Aβ) peptide and concomitant reduction of extracellular deposits. Production of the less pathogenic Aβ1–38 peptide corresponded with decreased levels of Aβ1–42, supporting the lysosome's antiamyloidogenic role through intracellular truncation. Amelioration of synaptic and behavioral deficits also indicates a neuroprotective function of the lysosomal system, identifying lysosomal modulation as an avenue for disease-modifying therapies. From the in vitro and in vivo findings, unique lysosomal modulators represent a minimally invasive, pharmacologically controlled strategy against protein accumulation disorders to enhance protein clearance, promote synaptic integrity, and slow the progression of dementia.
doi:10.1089/rej.2011.1282
PMCID: PMC3332372  PMID: 22533430
22.  Early Impairment of Long-Term Depression in the Perirhinal Cortex of a Mouse Model of Alzheimer's Disease 
Rejuvenation Research  2012;15(2):231-234.
Abstract
Visual recognition memory is early impaired in Alzheimer's disease. Long-term depression of synaptic transmission in the perirhinal cortex is critically involved in this form of memory. We found that synaptic transmission was impaired in perirhinal cortex slices obtained from 3-month-old Tg2576 mice, and that 3,000 pulses at 5 Hz induced long-term depression in perirhinal cortex slices from age-matched control mice, but not in those from Tg2576 mice. To our knowledge, these data provide the first evidence of synaptic transmission and long-term depression impairment in the perirhinal cortex in an animal model of Alzheimer's disease, and the earliest synaptic deficit in Tg2576 mice.
doi:10.1089/rej.2011.1311
PMCID: PMC3332373  PMID: 22533438
23.  Impairments of Synaptic Plasticity in Aged Animals and in Animal Models of Alzheimer's Disease 
Rejuvenation Research  2012;15(2):235-238.
Abstract
Aging is associated with a gradual decline in cognitive functions, and more dramatic cognitive impairments occur in patients affected by Alzheimer's disease (AD). Electrophysiological and molecular studies performed in aged animals and in animal models of AD have shown that cognitive decline is associated with significant modifications in synaptic plasticity (i.e., activity-dependent changes in synaptic strength) and have elucidated some of the cellular mechanisms underlying this process. Morphological studies have revealed a correlation between the quality of memory performance and the extent of structural changes of synaptic contacts occurring during memory consolidation. We briefly review recent experimental evidence here.
doi:10.1089/rej.2012.1318
PMCID: PMC3332390  PMID: 22533439
24.  Hormone Supplementation During Aging: How Much and When? 
Rejuvenation Research  2012;15(2):128-131.
Abstract
Circulating levels of dehydroepiandrosterone, a major adrenal steroid, show a marked age-related decrease in both humans and nonhuman primates. Because this decrease has been implicated in age-related cognitive decline, we administered supplementary dehydroepiandrosterone to perimenopausal rhesus macaques (Macaca mulatta) to test for cognitive benefits. Although recognition memory improved, there was no benefit to spatial working memory. To address the limitations of this study we developed a hormone supplementation regimen in aged male macaques that more accurately replicates the 24-hr androgen profiles of young animals. We hypothesize that this more comprehensive physiological hormone replacement paradigm will enhance cognitive function in the elderly.
doi:10.1089/rej.2011.1251
PMCID: PMC3332522  PMID: 22533414
25.  Prognostic Significance of the Short Physical Performance Battery in Older Patients Discharged from Acute Care Hospitals 
Rejuvenation Research  2012;15(1):41-48.
Abstract
We investigated the prognostic role of the Short Physical Performance Battery (SPPB) in elderly patients discharged from the acute care hospital. Our series consisted of 506 patients aged 70 years or more enrolled in a multicenter collaborative observational study. We considered three main outcomes: 1-year survival after discharge, functional decline, and hospitalization during follow-up. Independent predictors/correlates of the outcomes were investigated by Cox regression or logistic regression analysis when appropriate. The diagnostic accuracy of SPPB in relation to study outcomes was investigated by receiver operating characteristic (ROC) curve. SPPB score was associated with reduced mortality (hazard ratio [HR]=0.86, 95% confidence interval [CI] 0.78–0.95). When the analysis was adjusted for functional status at discharge, such an association was still near significant only for SPPB values >8 (HR=0.51; 95% CI 0.30–1.05). An SPPB score<5 could identify patients who died during follow-up with fair sensitivity (0.66), specificity (0.62), and area under the ROC curve (0.66). SPPB also qualified as independent correlate of functional decline (odds ratio [OR]=0.82; 95% CI 0.70–0.96), but not of rehospitalization or combined end-point death or rehospitalization. An SPPB score <5 could identify patients experiencing functional decline during follow-up with lower sensitivity (0.60), but higher specificity (0.69), and area under the ROC curve (0.69) with respect to mortality. In conclusion, SPPB can be considered a valid instrument to identify patients at major risk of functional decline and death after discharge from acute care hospital. However, it could more efficiently target patients at risk of functional decline than those at risk of death.
doi:10.1089/rej.2011.1215
PMCID: PMC3283437  PMID: 22004280

Results 1-25 (62)