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1.  Elastin Haploinsufficiency Induces Alternative Aging Processes in the Aorta 
Rejuvenation research  2008;11(1):97-112.
Elastin, the main component of elastic fibers, is synthesized only in early life and provides the blood vessels with their elastic properties. With aging, elastin is progressively degraded, leading to arterial enlargement, stiffening, and dysfunction. Also, elastin is a key regulator of vascular smooth muscle cell proliferation and migration during development since heterozygous mutations in its gene (Eln) are responsible for a severe obstructive vascular disease, supravalvular aortic stenosis, isolated or associated to Williams syndrome. Here, we have studied whether early elastin synthesis could also influence the aging processes, by comparing the structure and function of ascending aorta from 6- and 24-month-old Eln+/− and Eln+/+ mice. Eln+/− animals have high blood pressure and arteries with smaller diameters and more rigid walls containing additional although thinner elastic lamellas. Nevertheless, longevity of these animals is unaffected. In young adult Eln+/− mice, some features resemble vascular aging of wild-type animals: cardiac hypertrophy, loss of elasticity of the arterial wall through enhanced fragmentation of the elastic fibers, and extracellular matrix accumulation in the aortic wall, in particular in the intima. In Eln+/− animals, we also observed an age-dependent alteration of endothelial vasorelaxant function. On the contrary, Eln+/− mice were protected from several classical consequences of aging visible in aged Eln+/+ mice, such as arterial wall thickening and alteration of α1-adrenoceptor-mediated vasoconstriction. Our results suggest that early elastin expression and organization modify arterial aging through their impact on both vascular cell physiology and structure and mechanics of blood vessels.
doi:10.1089/rej.2007.0587
PMCID: PMC3729436  PMID: 18173368
2.  Relative Leukocyte Telomere Length and Risk of Incident Ischemic Stroke in Men: A Prospective, Nested Case-Control Approach 
Rejuvenation research  2010;13(4):411-414.
Recent data have implicated telomere-length shortening as potential risk predictor for vascular diseases including stroke. However, to date, prospective, epidemiological data are scarce in relation to ischemic stroke risk. Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of leukocyte telomere repeat copy number to single gene copy number (TSR), using a quantitative polymerase chain reaction protocol, amongst 259 white males who subsequently developed an ischemic stroke and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow-up (controls). The observed TSRs were inversely correlated with age in the controls (p<0.0001). However, the observed TSRs were similar between cases and controls (p=0.92). In a multi-variable adjusted analysis, no evidence was found for an association of the TSRs with ischemic stroke risk (odds ratio=1.100, 95%CI=0.506-2.392, p=0.811). The present investigation has shown no evidence for an association of relative leukocyte telomere length with risk of incident ischemic stroke. More importantly, our present findings require replication/confirmation in future large, prospective studies.
doi:10.1089/rej.2009.0975
PMCID: PMC2914796  PMID: 20426626
relative leukocyte telomere length; ischemic stroke; risk factor
3.  Relative Leukocyte Telomere Length and Risk of Incident Ischemic Stroke in Men: A Prospective, Nested Case-Control Approach 
Rejuvenation Research  2010;13(4):411-414.
Abstract
Recent data have implicated telomere-length shortening as potential risk predictor for vascular diseases, including stroke. However, to date, prospective epidemiological data are scarce in relation to ischemic stroke risk. Using leukocyte DNA samples collected at baseline in a prospective cohort of 14,916 initially healthy American men, we examined the relationship of leukocyte telomere repeat copy number to single gene copy number (TSR), using a quantitative polymerase chain reaction protocol, amongst 259 white males who subsequently developed an ischemic stroke and amongst an equal number of age- and smoking-matched white males who remained free of reported vascular disease during follow up (controls). The observed TSRs were inversely correlated with age in the controls (p < 0.0001). However, the observed TSRs were similar between cases and controls (p = 0.92). In a multivariable adjusted analysis, no evidence was found for an association of the TSRs with ischemic stroke risk (odds ratio [OR] = 1.100, 95% confidence interval [CI], 0.506–2.392, p = 0.811). The present investigation has shown no evidence for an association of relative leukocyte telomere length with risk of incident ischemic stroke. More importantly, our present findings require replication/confirmation in future large, prospective studies.
doi:10.1089/rej.2009.0975
PMCID: PMC2914796  PMID: 20426626
4.  Lifelong Calorie Restriction Alleviates Age-Related Oxidative Damage in Peripheral Nerves 
Rejuvenation Research  2010;13(1):65-74.
Abstract
Aging is associated with protein damage and imbalance in redox status in a variety of cells and tissues, yet little is known about the extent of age-related oxidative stress in the peripheral nervous system. Previously, we showed a drastic decline in the expression of glial and neuronal proteins in myelinated peripheral nerves with age, which is significantly ameliorated by lifelong calorie restriction. The age-related decline in functional molecules is associated with alterations in cellular protein homeostatic mechanisms, which could lead to a buildup of damaged, aggregated proteins. To determine the extent of oxidative damage within myelinated peripheral nerves, we studied sciatic nerves from rats of four different ages (8, 18, 29, and 38 months) maintained on an ad libitum or a 40% calorie-restricted diet. We found a prominent accumulation of polyubiquitinated substrates with age, which are associated with the conglomeration of distended lysosomes and lipofuscin adducts. The occurrence of these structures is notably less frequent within nerves of age-matched rodents kept on a lifelong reduced calorie diet. Markers for lipid peroxidation, inflammation, and immune cell infiltration are all elevated in nerves of ad libitum–fed rats, whereas food restriction is able to attenuate such deleterious processes with age. Together these results show that dietary restriction is an efficient means of defying age-related oxidative damage and maintaining a younger state in peripheral nerves.
doi:10.1089/rej.2009.0892
PMCID: PMC2877262  PMID: 20230280
5.  Association of Apolipoprotein E and Angiotensin Converting Enzyme Gene Polymorphisms with the Multidimensional Impairment in Older Patients 
Rejuvenation research  2009;12(4):239-247.
The role of the apoliprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy–Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of ε4 allele and the ACE D/D genotype was observed. The APOE ε4+ and ACE D/D genotypes were associated with severe MPI grade (APOE ε4+, odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20–2.67; ACE D/D, OR = 1.42, 95% CI 1.05–1.92). The combined APOE ε4+ and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75–4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive.
doi:10.1089/rej.2009.0858
PMCID: PMC2868322  PMID: 19653879
6.  Association of Apolipoprotein E and Angiotensin Converting Enzyme Gene Polymorphisms with the Multidimensional Impairment in Older Patients 
Rejuvenation Research  2009;12(4):239-247.
Abstract
The role of the apoliprotein E (APOE) and the angiotensin converting enzyme (ACE) polymorphisms on health and functional status deterioration in old age is still undefined. Recently, a Multidimensional Prognostic Index (MPI) for 1-year mortality derived from a Comprehensive Geriatric Assessment (CGA) was developed and validated in hospitalized elderly patients. The aim of this study was to investigate the possible association of the APOE and ACE gene polymorphisms with the multidimensional impairment, as evaluated by the MPI, in older patients. These polymorphisms were assessed in 1894 geriatric inpatients divided into three groups according to their MPI values: MPI-1 low risk (n = 988), MPI-2 moderate risk (n = 671), and MPI-3 severe risk of mortality (n = 235). A slight deviation from Hardy–Weinberg equilibrium was observed for the APOE genotypes. With the increasing of the MPI grade, a significant increase in the frequencies of ɛ4 allele and the ACE D/D genotype was observed. The APOE ɛ4+ and ACE D/D genotypes were associated with severe MPI grade (APOE ɛ4+, odds ration [OR] = 1.79, 95% confidence interval [CI] 1.20–2.67; ACE D/D, OR = 1.42, 95% CI 1.05–1.92). The combined APOE ɛ4+ and ACE D/D genetic status was associated with higher MPI grade (OR = 2.85, 95% CI 1.75–4.65), without interaction. No significant associations between APOE and ACE polymorphisms and 2-year mortality were found. APOE and ACE genes might predispose individuals to health and functional status deterioration in old age, and their effect is additive.
doi:10.1089/rej.2009.0858
PMCID: PMC2868322  PMID: 19653879
7.  Lifelong Calorie Restriction Alleviates Age-Related Oxidative Damage in Peripheral Nerves 
Rejuvenation research  2010;13(1):65-74.
Aging is associated with protein damage and imbalance in redox status in a variety of cells and tissues, yet little is known about the extent of age-related oxidative stress in the peripheral nervous system. Previously, we showed a drastic decline in the expression of glial and neuronal proteins in myelinated peripheral nerves with age, which is significantly ameliorated by lifelong calorie restriction. The age-related decline in functional molecules is associated with alterations in cellular protein homeostatic mechanisms, which could lead to a buildup of damaged, aggregated proteins. To determine the extent of oxidative damage within myelinated peripheral nerves, we studied sciatic nerves from rats of four different ages (8, 18, 29, and 38 months) maintained on an ad libitum or a 40% calorie-restricted diet. We found a prominent accumulation of polyubiquitinated substrates with age, which are associated with the conglomeration of distended lysosomes and lipofuscin adducts. The occurrence of these structures is notably less frequent within nerves of age-matched rodents kept on a lifelong reduced calorie diet. Markers for lipid peroxidation, inflammation, and immune cell infiltration are all elevated in nerves of ad libitum–fed rats, whereas food restriction is able to attenuate such deleterious processes with age. Together these results show that dietary restriction is an efficient means of defying age-related oxidative damage and maintaining a younger state in peripheral nerves.
doi:10.1089/rej.2009.0892
PMCID: PMC2877262  PMID: 20230280
8.  Age-Dependent Signature of Metallothionein Expression in Primary CD4 T Cell Responses Is Due to Sustained Zinc Signaling 
Rejuvenation research  2008;11(6):1001-1011.
The ability to mount adaptive immune responses to vaccinations and viral infections declines with increasing age. To identify mechanisms leading to immunosenescence, primary CD4 T cell responses were examined in 60- to 75-year-old individuals lacking overt functional defects. Transcriptome analysis indicated a selective defect in zinc homeostasis. CD4 T cell activation was associated with zinc influx via the zinc transporter Zip6, leading to increased free cytoplasmic zinc and activation of negative feedback loops, including the induction of zinc-binding metallothioneins. In young adults, activation-induced cytoplasmic zinc concentrations declined after 2 days to below prestimulation levels. In contrast, activated naïve CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of old CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of naïve CD4 T cells with age.
doi:10.1089/rej.2008.0747
PMCID: PMC2848531  PMID: 19072254
9.  Plasma Polyunsaturated Fatty Acids and Age-Related Physical Performance Decline 
Rejuvenation research  2009;12(1):25-32.
Due to supporting evidence that dietary patterns may have a significant role in the maintenance of good physical performance with aging, we tested whether plasma fatty acids, saturated fatty acids (SFA), and polyunsaturated (PUFA) fatty acids are cross-sectionally associated with different physical performance and predict changes in physical performance over a 3-year period. Data were from the InCHIANTI study, a population-based study of older Italians. Plasma fatty acids were measured at enrollment (1998–2000), and outcome variables, Summary Physical Performance Battery (SPPB), and time to walk 7 meters (m) were measured at enrollment and after 3 years (2001–2004). At enrollment, 330 participants had significantly impaired lower extremity performance (defined as a SPPB score ≤9). Adjusting for age, participants with a SPPB score >9 had higher levels of total PUFA, n−3 PUFA, and n−6 PUFA, while significantly lower levels of SFA than those with a SPPB score <9. Baseline SPPB scores were also associated with n−3 PUFA (β = 0.148, p = 0.031), whereas the 7-m walk time was associated with total PUFA (β = −0.068, p = 0.008), after adjusting for potential confounders. Of the 884 participants with a SPPB score >9 at baseline, 114 (12.9%) developed impaired lower extremity performance (SPPB ≤9). In fully adjusted logistic models, baseline n−3 PUFA levels were inversely related to the risk of developing a decline in SPPB to ≤9 (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08–0.53), while the n−6/n−3 ratio was associated with a higher risk of SPPB decline to ≤9 (OR = 5.23; 95% CI = 2.02–13.51). In multivariate regression models, the n−6/n−3 ratio was associated with a longer time to walk 7 m (β = 0.396, p = 0.037). n−3 PUFA plasma levels, which most likely reflect dietary intake, seem to protect against accelerated decline of physical performance. A higher n−6/n−3 ratio was associated with higher risk of developing poor physical performance and slower walking speed.
doi:10.1089/rej.2008.0799
PMCID: PMC2674224  PMID: 19196012
10.  Plasma Polyunsaturated Fatty Acids and Age-Related Physical Performance Decline 
Rejuvenation Research  2009;12(1):25-32.
Abstract
Due to supporting evidence that dietary patterns may have a significant role in the maintenance of good physical performance with aging, we tested whether plasma fatty acids, saturated fatty acids (SFA), and polyunsaturated (PUFA) fatty acids are cross-sectionally associated with different physical performance and predict changes in physical performance over a 3-year period. Data were from the InCHIANTI study, a population-based study of older Italians. Plasma fatty acids were measured at enrollment (1998–2000), and outcome variables, Summary Physical Performance Battery (SPPB), and time to walk 7 meters (m) were measured at enrollment and after 3 years (2001–2004). At enrollment, 330 participants had significantly impaired lower extremity performance (defined as a SPPB score ≤9). Adjusting for age, participants with a SPPB score >9 had higher levels of total PUFA, n-3 PUFA, and n-6 PUFA, while significantly lower levels of SFA than those with a SPPB score <9. Baseline SPPB scores were also associated with n-3 PUFA (β = 0.148, p = 0.031), whereas the 7-m walk time was associated with total PUFA (β = −0.068, p = 0.008), after adjusting for potential confounders. Of the 884 participants with a SPPB score >9 at baseline, 114 (12.9%) developed impaired lower extremity performance (SPPB ≤9). In fully adjusted logistic models, baseline n-3 PUFA levels were inversely related to the risk of developing a decline in SPPB to ≤9 (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.08–0.53), while the n-6/n-3 ratio was associated with a higher risk of SPPB decline to ≤9 (OR = 5.23; 95% CI = 2.02–13.51). In multivariate regression models, the n-6/n-3 ratio was associated with a longer time to walk 7 m (β = 0.396, p = 0.037). n-3 PUFA plasma levels, which most likely reflect dietary intake, seem to protect against accelerated decline of physical performance. A higher n-6/n-3 ratio was associated with higher risk of developing poor physical performance and slower walking speed.
doi:10.1089/rej.2008.0799
PMCID: PMC2674224  PMID: 19196012
11.  Age-Dependent Signature of Metallothionein Expression in Primary CD4 T Cell Responses Is Due to Sustained Zinc Signaling 
Rejuvenation Research  2008;11(6):1001-1011.
Abstract
The ability to mount adaptive immune responses to vaccinations and viral infections declines with increasing age. To identify mechanisms leading to immunosenescence, primary CD4 T cell responses were examined in 60- to 75-year-old individuals lacking overt functional defects. Transcriptome analysis indicated a selective defect in zinc homeostasis. CD4 T cell activation was associated with zinc influx via the zinc transporter Zip6, leading to increased free cytoplasmic zinc and activation of negative feedback loops, including the induction of zinc-binding metallothioneins. In young adults, activation-induced cytoplasmic zinc concentrations declined after 2 days to below prestimulation levels. In contrast, activated naïve CD4 T cells from older individuals failed to downregulate cytoplasmic zinc, resulting in excessive induction of metallothioneins. Activation-induced metallothioneins regulated the redox state in activated T cells and accounted for an increased proliferation of old CD4 T cells, suggesting that regulation of T cell zinc homeostasis functions as a compensatory mechanism to preserve the replicative potential of naïve CD4 T cells with age.
doi:10.1089/rej.2008.0747
PMCID: PMC2848531  PMID: 19072254
12.  Blueberry Opposes β-Amyloid Peptide-Induced Microglial Activation Via Inhibition of p44/42 Mitogen-Activation Protein Kinase 
Rejuvenation Research  2008;11(5):891-901.
Abstract
Alzheimer's Disease (AD) is the most common age-related dementia, with a current prevalence in excess of five million individuals in the United States. The aggregation of amyloid-beta (Aβ) into fibrillar amyloid plaques is a key pathological event in the development of the disease. Microglial proinflammatory activation is widely known to cause neuronal and synaptic damage that correlates with cognitive impairment in AD. However, current pharmacological attempts at reducing neuroinflammation mediated via microglial activation have been largely negative in terms of slowing AD progression. Previously, we have shown that microglia express proinflammatory cytokines and a reduced capacity to phagocytose Aβ in the context of CD40, Aβ peptides and/or lipopolysaccharide (LPS) stimulation, a phenomenon that can be opposed by attenuation of p44/42 mitogen-activated protein kinase (MAPK) signaling. Other groups have found that blueberry (BB) extract both inhibits phosphorylation of this MAPK module and also improves cognitive deficits in AD model mice. Given these considerations and the lack of reduced Aβ quantities in behaviorally improved BB-fed mice, we wished to determine whether BB supplementation would alter the microglial proinflammatory activation state in response to Aβ. We found that BB significantly enhances microglial clearance of Aβ, inhibits aggregation of Aβ1–42, and suppresses microglial activation, all via suppression of the p44/42 MAPK module. Thus, these data may explain the previously observed behavioral recovery in PSAPP mice and suggest a means by which dietary supplementation could mitigate an undesirable microglial response toward fibrillar Aβ.
doi:10.1089/rej.2008.0757
PMCID: PMC2751806  PMID: 18789000
13.  Blueberry Opposes β-Amyloid Peptide-Induced Microglial Activation Via Inhibition of p44/42 Mitogen-Activation Protein Kinase 
Rejuvenation research  2008;11(5):891-901.
Alzheimer’s Disease (AD) is the most common age-related dementia, with a current prevalence in excess of five million individuals in the United States. The aggregation of amyloid-beta (Aβ) into fibrillar amyloid plaques is a key pathological event in the development of the disease. Microglial proinflammatory activation is widely known to cause neuronal and synaptic damage that correlates with cognitive impairment in AD. However, current pharmacological attempts at reducing neuroinflammation mediated via microglial activation have been largely negative in terms of slowing AD progression. Previously, we have shown that microglia express proinflammatory cytokines and a reduced capacity to phagocytose Aβ in the context of CD40, Aβ peptides and/or lipopolysaccharide (LPS) stimulation, a phenomenon that can be opposed by attenuation of p44/42 mitogen-activated protein kinase (MAPK) signaling. Other groups have found that blueberry (BB) extract both inhibits phosphorylation of this MAPK module and also improves cognitive deficits in AD model mice. Given these considerations and the lack of reduced Aβ quantities in behaviorally improved BB-fed mice, we wished to determine whether BB supplementation would alter the microglial proinflammatory activation state in response to Aβ. We found that BB significantly enhances microglial clearance of Aβ, inhibits aggregation of Aβ1–42, and suppresses microglial activation, all via suppression of the p44/42 MAPK module. Thus, these data may explain the previously observed behavioral recovery in PSAPP mice and suggest a means by which dietary supplementation could mitigate an undesirable microglial response toward fibrillar Aβ.
doi:10.1089/rej.2008.0757
PMCID: PMC2751806  PMID: 18789000
14.  Carotenoids as Protection Against Disability in Older Persons 
Rejuvenation research  2008;11(3):557-563.
The purpose was to examine the relationship of total plasma carotenoids, an indicator of fruit and vegetable intake, with walking speed and severe walking disability in older adults. Nine hundred twenty-eight men and women aged 65 to 102 years from the Invecchiare in Chianti (Aging in the Chianti Area [InCHIANTI]) study, a population-based cohort in Tuscany, Italy, were studied. Plasma carotenoids were measured at enrollment (1998–2000), and walking speed over 4 meters and 400 meters distance were assessed at enrollment and 6 years later (2004–2006). At enrollment, 85 of 928 (9.2%) participants had severe walking disability (defined as being unable to walk or having a walking speed at the 4-meter walking test < 0.4 m/sec). After adjusting for potential confounders, participants with high total plasma carotenoids were significantly less likely to have prevalent severe walking disability (odds ration [OR] 0.59, 95% confidence interval [CI] 0.38–0.90, p = 0.01) and had higher walking speed over 4 meters (β = 0.024, standard error [SE] = 0.011, p = 0.03) and over 400 meters (β = 0.019, SE = 0.010, p = 0.04). Of 621 participants without severe walking disability at enrollment who were seen 6 years later, 68 (11.0%) developed severe walking disability. After adjusting for potential confounders, higher total plasma carotenoids were associated with a significantly lower risk of developing severe walking disability (OR 0.51, 95% CI 0.30–0.86, p = 0.01) and were associated with a less steep decline in 4-meter walking speed over a 6-year follow-up (n = 579; β = 0.026, SE = 0.012, p = 0.03) and with lower incidence rates of being unable to successfully complete the 400-meter walking test at the 6-year follow-up visit (β = −0.054, SE = 0.03, p = 0.04). High plasma carotenoids concentrations may be protective against the decline in walking speed and the development of severe walking disability in older adults.
doi:10.1089/rej.2007.0581
PMCID: PMC2734103  PMID: 18593275
15.  Long-Term Effects of Caloric Restriction or Exercise on DNA and RNA Oxidation Levels in White Blood Cells and Urine in Humans 
Rejuvenation research  2008;11(4):793-799.
Excessive adiposity is associated with increased oxidative stress and accelerated aging. Weight loss induced by negative energy balance reduces markers of oxidation in experimental animals and humans. The long-term effects of weight loss induced by calorie restriction or increased energy expenditure induced by exercise on measures of oxidative stress and damage have not been studied in humans. The objective of the present study was to compare the effects of 20% caloric restriction or 20% exercise alone over 1 year on oxidative damage to DNA and RNA, as assessed through white blood cell and urine analyses. Eighteen men and women aged 50 to 60 years with a body mass index (BMI) between 23.5 to 29.9 kg/m2 were assigned to one of two conditions — 20% CR (n = 9) or 20% EX (n = 9) — which was designed to produce an identical energy deficit through increased energy expenditure. Compared to baseline, both interventions significantly reduced oxidative damage to both DNA (48.5% and 49.6% reduction for the CR and EX groups, respectively) and RNA (35.7% and 52.1% reduction for the CR and EX groups, respectively) measured in white blood cells. However, urinary levels of DNA and RNA oxidation products did not differ from baseline values following either 12-month intervention program. Data from the present study provide evidence that negative energy balances induced through either CR or EX result in substantial and similar improvements in markers of DNA and RNA damage to white blood cells, potentially by reducing systemic oxidative stress.
doi:10.1089/rej.2008.0712
PMCID: PMC2724865  PMID: 18729811
16.  Long-Term Effects of Caloric Restriction or Exercise on DNA and RNA Oxidation Levels in White Blood Cells and Urine in Humans 
Rejuvenation Research  2008;11(4):793-799.
Abstract
Excessive adiposity is associated with increased oxidative stress and accelerated aging. Weight loss induced by negative energy balance reduces markers of oxidation in experimental animals and humans. The long-term effects of weight loss induced by calorie restriction or increased energy expenditure induced by exercise on measures of oxidative stress and damage have not been studied in humans. The objective of the present study was to compare the effects of 20% caloric restriction or 20% exercise alone over 1 year on oxidative damage to DNA and RNA, as assessed through white blood cell and urine analyses. Eighteen men and women aged 50 to 60 years with a body mass index (BMI) between 23.5 to 29.9 kg/m2 were assigned to one of two conditions — 20% CR (n = 9) or 20% EX (n = 9) — which was designed to produce an identical energy deficit through increased energy expenditure. Compared to baseline, both interventions significantly reduced oxidative damage to both DNA (48.5% and 49.6% reduction for the CR and EX groups, respectively) and RNA (35.7% and 52.1% reduction for the CR and EX groups, respectively) measured in white blood cells. However, urinary levels of DNA and RNA oxidation products did not differ from baseline values following either 12-month intervention program. Data from the present study provide evidence that negative energy balances induced through either CR or EX result in substantial and similar improvements in markers of DNA and RNA damage to white blood cells, potentially by reducing systemic oxidative stress.
doi:10.1089/rej.2008.0712
PMCID: PMC2724865  PMID: 18729811
17.  AN INVERSE ASSOCIATION BETWEEN SELF-REPORTED ARTHRITIS AND MORTALITY IN THE ELDERLY: FINDINGS FROM THE NATIONAL LONG TERM CARE SURVEY 
Rejuvenation research  2008;11(1):251-257.
Major musculoskeletal conditions including arthritis represent an increasing burden on individuals and societies. We analyze the association between self-reported arthritis and mortality in the U.S. elderly disabled and non-disabled individuals using unique disability-focused data from the large-scale population-based National Long Term Care Survey. It is found that males and females who reported arthritis/rheumatism have, generally, smaller risks of death than those who did not report those conditions. This inverse relationship is more pronounced in disabled individuals. This finding holds for both short- (Relative Risk [RR]=0.81; 95% Confidence Interval [CI]:0.75–0.88 for males and RR=0.76; CI:0.71–0.82 for females) and long- (RR=0.82; CI:0.78–0.87 for males and RR=0.83; CI:0.79–0.87 for females) term follow-ups. For females, this effect is age insensitive, while for males it is limited to ages below 85. Demographic and 19 major geriatric conditions have trivial effect on these risks supporting the view that a better survival of diseased individuals can be attributed to the effects of medical treatment. Given the widespread prevalence of arthritis/rheumatism and disability in elderly populations and the increasing population of the elderly, these findings call for comprehensive analyses of factors driving better survival and medical costs associated with extended lives.
doi:10.1089/rej.2007.0611
PMCID: PMC2710617  PMID: 18240974
Aging; disease; longevity; mortality
18.  Caloric Restriction But Not Exercise-Induced Reductions in Fat Mass Decrease Plasma Triiodothyronine Concentrations 
Rejuvenation research  2008;11(3):605-609.
Caloric restriction (CR) decreases circulating triiodothyronine (T3) concentration. However, it is not known if this effect is due to body fat mass reductions or due to CR, per se. The purpose of this study was to test the hypothesis that plasma T3 concentration decreases with CR-induced reductions in fat mass but not in response to similar decreases in fat mass that are induced by exercise. Sedentary, nonobese 50- to 60-year-old men and women with no clinical evidence of cardiovascular or metabolic disease and not taking thyroid medications were randomly assigned to 12 months of caloric restriction (n = 18) or exercise-induced weight loss (n = 17) or to a control group (n = 9). Body weight and composition and plasma concentrations of the thyroid hormones T3, thyrotropin (TSH), thyroxine (T4), and free thyroxine (FT4) were measured at baseline and 12 months. Fat mass changed significantly in the CR (-6.3 ± 1.0 kg) and exercise (-5.5 ± 1.0 kg) groups but not in the control group (-0.6 ± 1.4 kg). The changes were not significantly different between the CR and exercise groups. Plasma T3 concentration decreased in the CR group (-9.8 ± 2.0 ng/dL, p <0.0001) but not in the exercise (-3.8 ± 2.1 ng/dL, p = 0.07) or control (-1.3 ± 2.8 ng/dL, p = 0.65) groups. TSH, T4, and FT4 did not change in any of the study groups. Twelve months of CR decreased circulating T3 concentrations in middle-aged adults. This effect does not appear to be attributable to changes in body fat mass because a comparable decrease in T3 concentration was not observed in response to an exercise-induced fat mass reduction.
doi:10.1089/rej.2007.0622
PMCID: PMC2649744  PMID: 18593278
19.  Caloric Restriction But Not Exercise-Induced Reductions in Fat Mass Decrease Plasma Triiodothyronine Concentrations: A Randomized Controlled Trial 
Rejuvenation Research  2008;11(3):605-609.
Abstract
Caloric restriction (CR) decreases circulating triiodothyronine (T3) concentration. However, it is not known if this effect is due to body fat mass reductions or due to CR, per se. The purpose of this study was to test the hypothesis that plasma T3 concentration decreases with CR-induced reductions in fat mass but not in response to similar decreases in fat mass that are induced by exercise. Sedentary, nonobese 50- to 60-year-old men and women with no clinical evidence of cardiovascular or metabolic disease and not taking thyroid medications were randomly assigned to 12 months of caloric restriction (n = 18) or exercise-induced weight loss (n = 17) or to a control group (n = 9). Body weight and composition and plasma concentrations of the thyroid hormones T3, thyrotropin (TSH), thyroxine (T4), and free thyroxine (FT4) were measured at baseline and 12 months. Fat mass changed significantly in the CR (−6.3 ± 1.0 kg) and exercise (−5.5 ± 1.0 kg) groups but not in the control group (−0.6 ± 1.4 kg). The changes were not significantly different between the CR and exercise groups. Plasma T3 concentration decreased in the CR group (−9.8 ± 2.0 ng/dL, p < 0.0001) but not in the exercise (−3.8 ± 2.1 ng/dL, p = 0.07) or control (− 1.3 ± 2.8 ng/dL, p = 0.65) groups. TSH, T4, and FT4 did not change in any of the study groups. Twelve months of CR decreased circulating T3 concentrations in middle-aged adults. This effect does not appear to be attributable to changes in body fat mass because a comparable decrease in T3 concentration was not observed in response to an exercise-induced fat mass reduction.
doi:10.1089/rej.2007.0622
PMCID: PMC2649744  PMID: 18593278
20.  Carotenoids as Protection Against Disability in Older Persons 
Rejuvenation Research  2008;11(3):557-563.
Abstract
The purpose was to examine the relationship of total plasma carotenoids, an indicator of fruit and vegetable intake, with walking speed and severe walking disability in older adults. Nine hundred twenty-eight men and women aged 65 to 102 years from the Invecchiare in Chianti (Aging in the Chianti Area [InCHIANTI]) study, a population-based cohort in Tuscany, Italy, were studied. Plasma carotenoids were measured at enrollment (1998–2000), and walking speed over 4 meters and 400 meters distance were assessed at enrollment and 6 years later (2004–2006). At enrollment, 85 of 928 (9.2%) participants had severe walking disability (defined as being unable to walk or having a walking speed at the 4-meter walking test < 0.4 m/sec). After adjusting for potential confounders, participants with high total plasma carotenoids were significantly less likely to have prevalent severe walking disability (odds ration [OR] 0.59, 95% confidence interval [CI] 0.38–0.90, p = 0.01) and had higher walking speed over 4 meters (β = 0.024, standard error [SE] = 0.011, p = 0.03) and over 400 meters (β = 0.019, SE = 0.010, p = 0.04). Of 621 participants without severe walking disability at enrollment who were seen 6 years later, 68 (11.0%) developed severe walking disability. After adjusting for potential confounders, higher total plasma carotenoids were associated with a significantly lower risk of developing severe walking disability (OR 0.51, 95% CI 0.30–0.86, p = 0.01) and were associated with a less steep decline in 4-meter walking speed over a 6-year follow-up (n = 579; β = 0.026, SE = 0.012, p = 0.03) and with lower incidence rates of being unable to successfully complete the 400-meter walking test at the 6-year follow-up visit (β = − 0.054, SE = 0.03, p = 0.04). High plasma carotenoids concentrations may be protective against the decline in walking speed and the development of severe walking disability in older adults.
doi:10.1089/rej.2007.0581
PMCID: PMC2734103  PMID: 18593275
21.  Development and Validation of a Multidimensional Prognostic Index for One-Year Mortality from Comprehensive Geriatric Assessment in Hospitalized Older Patients 
Rejuvenation research  2008;11(1):151-161.
Our objective was to construct and validate a Multidimensional Prognostic Index (MPI) for 1-year mortality from a Comprehensive Geriatric Assessment (CGA) routinely carried out in elderly patients in a geriatric acute ward. The CGA included clinical, cognitive, functional, nutritional, and social parameters and was carried out using six standardized scales and information on medications and social support network, for a total of 63 items in eight domains. A MPI was developed from CGA data by aggregating the total scores of the eight domains and expressing it as a score from 0 to 1. Three grades of MPI were identified: low risk, 0.0–0.33; moderate risk, 0.34–0.66; and severe risk, 0.67–1.0. Using the proportional hazard models, we studied the predictive value of the MPI for all causes of mortality over a 12-month follow-up period. MPI was then validated in a different cohort of consecutively hospitalized patients. The development cohort included 838 and the validation cohort 857 elderly hospitalized patients. Of the patients in the two cohorts, 53.3 and 54.9% were classified in the low-risk group, respectively (MPI mean value, 0.18 ± 0.09 and 0.18 ± 0.09); 31.2 and 30.6% in the moderate-risk group (0.48 ± 0.09 and 0.49 ± 0.09); 15.4 and 14.2% in the severe-risk group (0.77 ± 0.08 and 0.75 ± 0.07). In both cohorts, higher MPI scores were significantly associated with older age (p = 0.0001), female sex (p = 0.0001), lower educational level (p = 0.0001), and higher mortality (p = 0.0001). In both cohorts, a close agreement was found between the estimated mortality and the observed mortality after both 6 months and 1 year of follow-up. The discrimination of the MPI was also good, with a ROC area of 0.751 (95%CI, 0.70–0.80) at 6 months and 0.751 (95%CI, 0.71–0.80) at 1 year of follow-up. We conclude that this MPI, calculated from information collected in a standardized CGA, accurately stratifies hospitalized elderly patients into groups at varying risk of mortality.
doi:10.1089/rej.2007.0569
PMCID: PMC2668166  PMID: 18173367
22.  Examination of Cognitive Function During Six Months of Calorie Restriction: Results of a Randomized Controlled Trial 
Rejuvenation research  2007;10(2):179-190.
Background
Calorie restriction increases longevity in many organisms, and calorie restriction or its mimetic might increase longevity in humans. It is unclear if calorie restriction/dieting contributes to cognitive impairment. During this randomized controlled trial, the effect of 6 months of calorie restriction on cognitive functioning was tested.
Methods
Participants (n = 48) were randomized to one of four groups: (1) control (weight maintenance), (2) calorie restriction (CR; 25% restriction), (3) CR plus structured exercise (CR + EX, 12.5% restriction plus 12.5% increased energy expenditure via exercise), or (4) low-calorie diet (LCD; 890 kcal/d diet until 15% weight loss, followed by weight maintenance). Cognitive tests (verbal memory, visual memory, attention/concentration) were conducted at baseline and months 3 and 6. Mixed linear models tested if cognitive function changed significantly from baseline to months 3 and 6, and if this change differed by group. Correlation analysis was used to determine if average daily energy deficit (quantified from change in body energy stores) was associated with change in cognitive test performance for the three dieting groups combined.
Results
No consistent pattern of verbal memory, visual retention/memory, or attention/concentration deficits emerged during the trial. Daily energy deficit was not significantly associated with change in cognitive test performance.
Conclusions
This randomized controlled trial suggests that calorie restriction/dieting was not associated with a consistent pattern of cognitive impairment. These conclusions must be interpreted in the context of study limitations, namely small sample size and limited statistical power. Previous reports of cognitive impairment might reflect sampling biases or information processing biases.
doi:10.1089/rej.2006.0502
PMCID: PMC2664681  PMID: 17518698

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