Mitochondria are critical regulators of cellular function and survival. We have previously demons... more Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker—Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.
Chronic inflammation is associated with muscle weakness and frailty in older adults. The antagoni... more Chronic inflammation is associated with muscle weakness and frailty in older adults. The antagonistic cross-talk between macrophage migration inhibitory factor (Mif), an anti-apoptotic cytokine and NIP3-like protein X (Nix), a pro-apoptotic mitochondrial protein, may play a role in mitochondrial free radical homeostasis and inflammatory myopathies. We examined Nix-Mif interaction in inflammation and aging using young and old, IL-10tm/tm (a rodent model of chronic inflammation) and C57BL/6 mice. In this study, we observed that Nix and Mif were co-localized in skeletal muscles of aged and inflamed mice. We show an inflammation- and age-related association between Nix and Mif gene expression, with the strongest positive correlation observed in old IL-10tm/tm skeletal muscles. The IL-10tm/tm skeletal muscles also had the highest levels of oxidative stress damage. These observations suggest that Nix-Mif cross-talk may play a role in the interface between chronic inflammation and oxidative stress in aging skeletal muscles.
Dysregulation of energy producing metabolic pathways has been observed in older adults with frail... more Dysregulation of energy producing metabolic pathways has been observed in older adults with frailty. In this study, we used liquid chromatography–mass spectrometry technology to identify aging- and frailty-related differences in metabolites involved in glycolysis, the tricarboxylic (TCA) cycle, and other energy metabolism-related pathways in the serum of a cohort of community-dwelling adults aged 20–97 (n = 146). We also examined the relationship between serum levels of metabolites and functional measures, physical frailty, and risk status for adverse health outcomes. We observed elevated levels of TCA cycle and glycolytic intermediates in frail subjects; however, the differences in the levels of ATP and other energy metabolites between young, nonfrail, and frail adults were not significant. Instead, we found that serum levels of neurotransmitters N-acetyl-aspartyl-glutamate, glutamate, and γ-aminobutyric acid were significantly elevated in older adults with frailty. These elevations of glycolytic and TCA cycle intermediates, and neurotransmitters may be part of the biological signature of frailty.
Chronic inflammation (CI) in older adults is associated with reduced health span and life span. I... more Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty.
Coexistence of complex multiple chronic conditions is rather a norm than exception in older adult... more Coexistence of complex multiple chronic conditions is rather a norm than exception in older adults. As such, interventional strategies that improve overall health and function, or healthspan, above and beyond diseasespecific benefit and longevity have become critically important for this growing and yet vulnerable population as well as for the society [1, 2]. Animal models with diverse genetic background suitable for the study of complex disease risks and aging may facilitate developing such strategies and are of immediate interest to the field of gerontology. While such ideal model Research Paper systems with no genomic manipulation are scarce, a rat model of intrinsic aerobic exercise capacity can serve at least to some extent, as one. This rat model was developed from the genetically heterogeneous N:NIH out-crossed stock [3] through 2-way selective breeding using a rotational breeding scheme on the trait of running capacity measured by maximal distance run to exhaustion on a speed-ramped treadmill [4]. Low capacity runner (LCR) rats derived from generations 14, 15, and 17 demonstrated 7-fold lower average aerobic running capacity, up to 45% shorter lifespan than high capacity runners (HCRs) [5]. LCRs also display increased complex metabolic and cardiovascular
BACKGROUND: Agonistic angiotensin II type 1 receptor autoantibodies (AT1RaAbs) have not been asso... more BACKGROUND: Agonistic angiotensin II type 1 receptor autoantibodies (AT1RaAbs) have not been associated with functional measures or risk for adverse health outcomes. AT1RaAbs could be used to stratify patient risk and to identify patients who can benefit from angiotensin receptor blocker treatment. METHODS: Demographic and physiological covariates were measured in a discovery set of community-dwelling adults from Baltimore (N=255) and AT1RaAb associations with physical function tests and outcomes assessed. A group from Chicago (N=60) was used for validation of associations and to explore the impact of angiotensin receptor blocker treatment. RESULTS: The Baltimore group had 28 subjects with falls, 32 frail subjects, and 5 deaths. Higher AT1RaAbs correlated significantly with interleukin-6 (Spearman r=0.33, P<0.0001), systolic blood pressure (Spearman r=0.28, P<0.0001), body mass index (Spearman r=0.28, P<0.0001), weaker grip strength (Spearman r=-0.34, P<0.01), and slower walking speed (Spearman r=-0.30, P<0.05). Individuals with high AT1RaAbs were 3.9 (95% confidence interval, 1.38-11.0) times more likely to be at high risk after adjusting for age (P<0.05). Every 1 µg/mL increase in AT1RaAbs increased the odds of falling 30% after adjusting for age, sex, body mass index, and blood pressure. The Chicago group had 46 subjects with falls and 60 deaths. Serum AT1RaAb levels were significantly correlated with grip strength (Spearman r=-0.57, P<0.005), walking speed (Spearman r=-0.47, P<0.005), and falls (Spearman r=0.30, P<0.05). Every 1 µg/mL increase in AT1RaAbs, decreased time to death by 9% after adjusting for age, sex, body mass index, and blood pressure. Chronic treatment with angiotensin receptor blockers was associated with better control of systolic blood pressure and attenuation of decline in both grip strength and time to death. CONCLUSIONS: In older individuals, higher AT1RaAb levels were associated with inflammation, hypertension, and adverse outcomes. Angiotensin receptor blocker treatment may blunt the harm associated with high levels of AT1RaAb.
Aging is associated with the accumulation of various deleterious changes in cells. According to t... more Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox) homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS). A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II binds with equal affinity to two main angiotensin receptors-type 1 (AT 1 R) and type 2 (AT 2 R). The binding of Ang II to AT 1 R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS). This Ang II-AT 1 R-NADPH-ROS signal triggers the opening of mitochondrial K ATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell. AT 2 R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT 2 R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a) report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b) discuss the effect of age-related activation of RAS on generation of free radicals.
Burden is a significant negative outcome for caregivers of individuals with dementia. Guided by t... more Burden is a significant negative outcome for caregivers of individuals with dementia. Guided by the Stress Process Model, the following study examined the impact of several novel constructs on burden including: compassion for others, family functioning, coping styles, and positive and negative affect. Data were gathered through Amazon Mechanical Turk from 102 dementia caregivers. Participants were 62% female, 72% Caucasian with a mean age of 39.5 years old. Burden was significantly related to positive affect (r =-.31, p =.01), negative affect (r =.56, p =<.01), family functioning (r =.43, p <.01), and dysfunctional coping (r =.37, p <.01). Compassion for others was not correlated with burden. Multiple regression analysis results found the set of predictors accounted for 65.0% of the total variance in burden (F(5,96) = 14.17, p < .01, R2= .65), with positive affect (β =-.26, p = .01), negative affect (β = .19, p= .05), and dysfunctional coping (β = .31, p= .01) predicting significant and unique variance. Results from mediation analyses indicated dysfunctional coping mediated the relationship between positive affect and burden (effect=-.14 95% bootstrap CI=-.26,-.04) as well as the relationship between negative affect and burden (effect= .24, 95% bootstrap CI= .07, .48). A mediating relationship between dysfunctional coping and family functioning and burden was not supported. Discussion will highlight the implications of the study findings in developing innovative caregiver programs aimed at reducing dysfunctional coping and the broader theoretical implications of the role of affect in family caregivers of individuals with dementia.
Background:Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death a... more Background:Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA).Objective:The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults.Methods:We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education.Results:Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up.Conclusion:This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.
Resiliency is the ability to respond to, adapt to and recover from stressors. Deterioration of re... more Resiliency is the ability to respond to, adapt to and recover from stressors. Deterioration of resiliency in older adults has been hypothesized to be regulated by age-related changes in stress response systems, including the Hypothalamic Pituitary Adrenal (HPA) axis and the innate immune system response. Although age-related chronic inflammation is strongly related to lack of resiliency, the impact of chronic inflammation on acute stress response is unclear. Here we describe the impact of a five-hour exposure to cold temperature acute stressor, on immune and corticosterone response using older and younger IL-10tm/tm mice, a mouse model with chronic inflammatory pathway activation, and age and gender matched C57/Bl6 background control (WT) mice. Overall, mice exposed to 4°C for 5 hours had significantly higher plasma corticosterone levels compared to those that remained at room temperature (25°C), with the exception of the WT females. Cold stressed mice had lower plasma tumor necrosis factor receptor 1 (TNFR1) levels with varying significance, in all ages and phenotypes, with the exception of the old female WT mice. In contrast, the effects of cold stress on pro-inflammatory cytokine interleukin 6 (IL-6) levels were inconsistent and not significant, with the exception of the female IL-10tm/tm mice. In conclusion, these findings demonstrate that sex, age and chronic inflammatory pathway activation all influence corticosterone secretion and inflammatory processes in the face of acute cold stress.
Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondria... more Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondrial clearance is a process to dampen inflammation and is a critical prerequisite to mitobiogenesis. The combined effect of aging and chronic inflammation on mitochondrial degradation by autophagy is understudied. In interleukin 10 null mouse (IL-10 tm/tm), a rodent model of chronic inflammation, we studied the effects of aging and inflammation on mitochondrial clearance. We show that aging in IL-10 tm/tm is associated with reduced skeletal muscle mitochondrial death signaling and altered formation of autophagosomes, compared to agematched C57BL/6 controls. Moreover, skeletal muscles of old IL-10 tm/tm mice have the highest levels of damaged mitochondria with disrupted mitochondrial ultrastructure and autophagosomes compared to all other groups. These observations highlight the interface between chronic inflammation and aging on altered mitochondrial biology in skeletal muscles.
Background Dementia and frailty are common age-related syndromes often linked to chronic inflamma... more Background Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. Results Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. Conclusion In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.
Physical frailty has a complex and heterogenous biological basis that likely includes genetic inf... more Physical frailty has a complex and heterogenous biological basis that likely includes genetic influences, age-related biological changes to metabolic processes and stress response systems, and mitochondrial decline. Although it is at present not possible to assign causality to specific biological processes, progress has been made in understanding the contributions of a variety of biological processes that influence frailty. In this symposium, we will provide new information on the role of genetic variants related to iron metabolism in the role of muscle weakness in older adults, on the potential role of mitochondrial DNA in driving frailty and inflammation, and the role of altered metabolic processes as measured by metabolomic variables. Each of these biological domains provide measureable variables that can potentially be used for diagnostic or therapeutic purposes. At the end of this symposium, the audience should be able to better understand the processes that potentially drive frailty in older adults, and the possibilities for future diagnostic and treatment modalities for frailty in older adults.
The renin-angio tensin system (RAS) is now regarded as an integral component in not only the deve... more The renin-angio tensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems.
Chronic wounds are a common and debilitating condition associated with aging populations that imp... more Chronic wounds are a common and debilitating condition associated with aging populations that impact more than 6.5 million patients in the United States. We have previously demonstrated the efficacy of daily topical 1% valsartan in treating wounds in diabetic mouse and pig models. Despite these promising results, there remains a need to develop an extended‐release formulation that would reduce patient burden by decreasing the frequency of daily applications. Here, we used nanotechnology to self‐assemble valsartan amphiphiles into a filamentous structure (val‐filaments) that would serve as a scaffold in wound beds and allow for steady, localised and tunable release of valsartan amphiphiles over 24 days. Two topical treatments of this peptide‐based hydrogel on full‐thickness wounds in Zucker Diabetic Fatty rats resulted in faster rates of wound closure. By day 23, all val‐filament treated wounds were completely closed, as compared to one wound closed in the placebo group. Mechanistically, we observed enrichment of proteins involved in cell adhesion and energetics pathways, downregulation of Tgf‐β signalling pathway mediators (pSmad2, pSmad3 and Smad4) and increased mitochondrial metabolic pathway intermediates. This study demonstrates the successful synthesis of a sustained‐release valsartan filament hydrogel, its impact on mitochondrial energetics and efficacy in treating diabetic wounds.
Journal of Interferon and Cytokine Research, Jun 1, 2011
Angiotensin subtype-1 receptor (AT 1 R) influences inflammatory processes through enhancing signa... more Angiotensin subtype-1 receptor (AT 1 R) influences inflammatory processes through enhancing signal transducer and activator of transcription proteins 3 (STAT3) signal transduction, resulting in increased tumor necrosis factor-a (TNF-a) production. Although angiotensin subtype-2 receptor (AT 2 R), in general, antagonizes AT 1 Rstimulated activity, it is not known if AT 2 R has any anti-inflammatory effects. In this study, we tested the hypothesis that AT 2 R activation plays an anti-inflammatory role by reducing STAT3 phosphorylation and TNFa production. Changes in AT 2 R expression, TNF-a production, and STAT3 phosphorylation were quantified by Western blotting, Bio-Plex cytokine, and phosphoprotein cellular signaling assays in PC12W cells that express AT 2 R but not AT 1 R, in response to the AT 2 R agonist, CGP-42112 (CGP, 100 nm), or AT 2 R antagonist PD-123319 (PD, 1 mm). A 100% increase in AT 2 R expression in response to stimulation with its agonist CGP was observed. Further, AT 2 R activation reduced TNF-a production by 39% and STAT3 phosphorylation by 83%. In contrast, PD decreased AT 2 R expression by 76%, increased TNF-a production by 84%, and increased STAT3 phosphorylation by 67%. These findings suggest that increased AT 2 R expression may play a role in the observed decrease in inflammatory pathway activation through decreased TNF-a production and STAT3 signaling. Restoration of AT 2 R expression and/or its activation constitute a potentially novel therapeutic target for the management of inflammatory processes.
Sarcopenia is an age-related decline in skeletal muscle mass and function that is multifactorial ... more Sarcopenia is an age-related decline in skeletal muscle mass and function that is multifactorial in etiology. Age-related changes in the renin-angiotensin system (RAS), increased oxidative stress, and chronic inflammation likely all contribute to its development. Losartan, an angiotensin II type I receptor blocker (ARB) decreases RAS activity and likely influences oxidative stress and inflammation. Given this, we hypothesized that losartan would improve activity levels and parameters related to inflammation and oxidative stress in older mice. We sought to test this hypothesis by comparing functional and molecular parameters between 18-month-old C57BL/6 mice treated with 50-70 mg/kg/day of losartan over a 4 month-period and age-and gendermatched mice receiving placebo. Losartan treatment significantly improved several activity measurements during treatment period compared to placebo controlled group, including increased time on treadmill, traveling activity, standing activity, and decreased grid contacts (p-values < 0.05, 0.001, 0.01; and 0.04 respectively). Grip strength did not improve in treatment group relative to control group over time. Serum IL-6 level in the treated group was significantly lower than that in the control group at the end of treatment, (30.3±12.9 vs. 173.0±59.5 pg/ml, p< 0.04), and mRNA expression of antioxidant enzymes catalase (3.9±0.9 vs. 1.0±0.4) and glutathione peroxidase (4.7±1.1 vs. 1.0±0.4) was significantly higher, P-value: 0.02, and 0.03 respectively) in quadriceps muscle after 4 months of treatment in treated and control groups. These results support the hypothesis that chronic losartan treatment improves skeletal muscle related activity measures in older mice, and that it is associated with more favorable relevant biological profiles in the treatment group. Additional studies are needed to 1) further quantify this functional improvement,
Mitochondria are critical regulators of cellular function and survival. We have previously demons... more Mitochondria are critical regulators of cellular function and survival. We have previously demonstrated that functional angiotensin receptors embedded within the inner mitochondrial membrane modulate mitochondrial energy production and free radical generation. The expression of mitochondrial angiotensin II type-1 receptors increases during aging, with a complementary decrease in angiotensin II type-2 receptor density. To address this age-associated mitochondrial dysfunction, we have developed a mitochondria-targeted delivery system to effectively transport angiotensin type-1 receptor blocker—Losartan (mtLOS) into the inner mitochondrial membrane. We engineered mtLOS to become active within the mitochondria after cleavage by mitochondrial peptidases. Our data demonstrate effective and targeted delivery of mtLOS into the mitochondria, compared to a free Losartan, or Losartan conjugated to a scrambled mitochondrial target signal peptide, with significant shifts in mitochondrial membrane potential upon mtLOS treatment. Furthermore, engineered mitochondrial-targeting modalities could open new avenues to transport nonmitochondrial proteins into the mitochondria, such as other macromolecules and therapeutic agents.
Chronic inflammation is associated with muscle weakness and frailty in older adults. The antagoni... more Chronic inflammation is associated with muscle weakness and frailty in older adults. The antagonistic cross-talk between macrophage migration inhibitory factor (Mif), an anti-apoptotic cytokine and NIP3-like protein X (Nix), a pro-apoptotic mitochondrial protein, may play a role in mitochondrial free radical homeostasis and inflammatory myopathies. We examined Nix-Mif interaction in inflammation and aging using young and old, IL-10tm/tm (a rodent model of chronic inflammation) and C57BL/6 mice. In this study, we observed that Nix and Mif were co-localized in skeletal muscles of aged and inflamed mice. We show an inflammation- and age-related association between Nix and Mif gene expression, with the strongest positive correlation observed in old IL-10tm/tm skeletal muscles. The IL-10tm/tm skeletal muscles also had the highest levels of oxidative stress damage. These observations suggest that Nix-Mif cross-talk may play a role in the interface between chronic inflammation and oxidative stress in aging skeletal muscles.
Dysregulation of energy producing metabolic pathways has been observed in older adults with frail... more Dysregulation of energy producing metabolic pathways has been observed in older adults with frailty. In this study, we used liquid chromatography–mass spectrometry technology to identify aging- and frailty-related differences in metabolites involved in glycolysis, the tricarboxylic (TCA) cycle, and other energy metabolism-related pathways in the serum of a cohort of community-dwelling adults aged 20–97 (n = 146). We also examined the relationship between serum levels of metabolites and functional measures, physical frailty, and risk status for adverse health outcomes. We observed elevated levels of TCA cycle and glycolytic intermediates in frail subjects; however, the differences in the levels of ATP and other energy metabolites between young, nonfrail, and frail adults were not significant. Instead, we found that serum levels of neurotransmitters N-acetyl-aspartyl-glutamate, glutamate, and γ-aminobutyric acid were significantly elevated in older adults with frailty. These elevations of glycolytic and TCA cycle intermediates, and neurotransmitters may be part of the biological signature of frailty.
Chronic inflammation (CI) in older adults is associated with reduced health span and life span. I... more Chronic inflammation (CI) in older adults is associated with reduced health span and life span. Interleukin-6 (IL-6) is one CI marker that is strongly associated with adverse health outcomes and mortality in aging. We have previously characterized a mouse model of frailty and chronic inflammatory pathway activation (IL-10tm/tm, IL-10 KO) that demonstrates the upregulation of numerous proinflammatory cytokines, including IL-6. We sought to identify a more specific role for IL-6 within the context of CI and aging and developed a mouse with targeted deletion of both IL-10 and IL-6 (IL-10tm/tm/IL-6tm/tm, DKO). Phenotypic characteristics, cytokine measurements, cardiac myocardial oxygen consumption, physical function, and survival were measured in DKO mice and compared to age- and gender-matched IL-10 KO and wild-type mice. Our findings demonstrate that selective knockdown of IL-6 in a frail mouse with CI resulted in the reversal of some of the CI-associated changes. We observed increased protective mitochondrial-associated lipid metabolites, decreased cardiac oxaloacetic acid, improved myocardial oxidative metabolism, and better short-term functional performance in DKO mice. However, the DKO mice also demonstrated higher mortality. This work shows the pleiotropic effects of IL-6 on aging and frailty.
Coexistence of complex multiple chronic conditions is rather a norm than exception in older adult... more Coexistence of complex multiple chronic conditions is rather a norm than exception in older adults. As such, interventional strategies that improve overall health and function, or healthspan, above and beyond diseasespecific benefit and longevity have become critically important for this growing and yet vulnerable population as well as for the society [1, 2]. Animal models with diverse genetic background suitable for the study of complex disease risks and aging may facilitate developing such strategies and are of immediate interest to the field of gerontology. While such ideal model Research Paper systems with no genomic manipulation are scarce, a rat model of intrinsic aerobic exercise capacity can serve at least to some extent, as one. This rat model was developed from the genetically heterogeneous N:NIH out-crossed stock [3] through 2-way selective breeding using a rotational breeding scheme on the trait of running capacity measured by maximal distance run to exhaustion on a speed-ramped treadmill [4]. Low capacity runner (LCR) rats derived from generations 14, 15, and 17 demonstrated 7-fold lower average aerobic running capacity, up to 45% shorter lifespan than high capacity runners (HCRs) [5]. LCRs also display increased complex metabolic and cardiovascular
BACKGROUND: Agonistic angiotensin II type 1 receptor autoantibodies (AT1RaAbs) have not been asso... more BACKGROUND: Agonistic angiotensin II type 1 receptor autoantibodies (AT1RaAbs) have not been associated with functional measures or risk for adverse health outcomes. AT1RaAbs could be used to stratify patient risk and to identify patients who can benefit from angiotensin receptor blocker treatment. METHODS: Demographic and physiological covariates were measured in a discovery set of community-dwelling adults from Baltimore (N=255) and AT1RaAb associations with physical function tests and outcomes assessed. A group from Chicago (N=60) was used for validation of associations and to explore the impact of angiotensin receptor blocker treatment. RESULTS: The Baltimore group had 28 subjects with falls, 32 frail subjects, and 5 deaths. Higher AT1RaAbs correlated significantly with interleukin-6 (Spearman r=0.33, P<0.0001), systolic blood pressure (Spearman r=0.28, P<0.0001), body mass index (Spearman r=0.28, P<0.0001), weaker grip strength (Spearman r=-0.34, P<0.01), and slower walking speed (Spearman r=-0.30, P<0.05). Individuals with high AT1RaAbs were 3.9 (95% confidence interval, 1.38-11.0) times more likely to be at high risk after adjusting for age (P<0.05). Every 1 µg/mL increase in AT1RaAbs increased the odds of falling 30% after adjusting for age, sex, body mass index, and blood pressure. The Chicago group had 46 subjects with falls and 60 deaths. Serum AT1RaAb levels were significantly correlated with grip strength (Spearman r=-0.57, P<0.005), walking speed (Spearman r=-0.47, P<0.005), and falls (Spearman r=0.30, P<0.05). Every 1 µg/mL increase in AT1RaAbs, decreased time to death by 9% after adjusting for age, sex, body mass index, and blood pressure. Chronic treatment with angiotensin receptor blockers was associated with better control of systolic blood pressure and attenuation of decline in both grip strength and time to death. CONCLUSIONS: In older individuals, higher AT1RaAb levels were associated with inflammation, hypertension, and adverse outcomes. Angiotensin receptor blocker treatment may blunt the harm associated with high levels of AT1RaAb.
Aging is associated with the accumulation of various deleterious changes in cells. According to t... more Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox) homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS). A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II) by angiotensin-converting enzyme (ACE). Ang II binds with equal affinity to two main angiotensin receptors-type 1 (AT 1 R) and type 2 (AT 2 R). The binding of Ang II to AT 1 R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS). This Ang II-AT 1 R-NADPH-ROS signal triggers the opening of mitochondrial K ATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell. AT 2 R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT 2 R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a) report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b) discuss the effect of age-related activation of RAS on generation of free radicals.
Burden is a significant negative outcome for caregivers of individuals with dementia. Guided by t... more Burden is a significant negative outcome for caregivers of individuals with dementia. Guided by the Stress Process Model, the following study examined the impact of several novel constructs on burden including: compassion for others, family functioning, coping styles, and positive and negative affect. Data were gathered through Amazon Mechanical Turk from 102 dementia caregivers. Participants were 62% female, 72% Caucasian with a mean age of 39.5 years old. Burden was significantly related to positive affect (r =-.31, p =.01), negative affect (r =.56, p =<.01), family functioning (r =.43, p <.01), and dysfunctional coping (r =.37, p <.01). Compassion for others was not correlated with burden. Multiple regression analysis results found the set of predictors accounted for 65.0% of the total variance in burden (F(5,96) = 14.17, p < .01, R2= .65), with positive affect (β =-.26, p = .01), negative affect (β = .19, p= .05), and dysfunctional coping (β = .31, p= .01) predicting significant and unique variance. Results from mediation analyses indicated dysfunctional coping mediated the relationship between positive affect and burden (effect=-.14 95% bootstrap CI=-.26,-.04) as well as the relationship between negative affect and burden (effect= .24, 95% bootstrap CI= .07, .48). A mediating relationship between dysfunctional coping and family functioning and burden was not supported. Discussion will highlight the implications of the study findings in developing innovative caregiver programs aimed at reducing dysfunctional coping and the broader theoretical implications of the role of affect in family caregivers of individuals with dementia.
Background:Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death a... more Background:Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA).Objective:The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults.Methods:We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education.Results:Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up.Conclusion:This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.
Resiliency is the ability to respond to, adapt to and recover from stressors. Deterioration of re... more Resiliency is the ability to respond to, adapt to and recover from stressors. Deterioration of resiliency in older adults has been hypothesized to be regulated by age-related changes in stress response systems, including the Hypothalamic Pituitary Adrenal (HPA) axis and the innate immune system response. Although age-related chronic inflammation is strongly related to lack of resiliency, the impact of chronic inflammation on acute stress response is unclear. Here we describe the impact of a five-hour exposure to cold temperature acute stressor, on immune and corticosterone response using older and younger IL-10tm/tm mice, a mouse model with chronic inflammatory pathway activation, and age and gender matched C57/Bl6 background control (WT) mice. Overall, mice exposed to 4°C for 5 hours had significantly higher plasma corticosterone levels compared to those that remained at room temperature (25°C), with the exception of the WT females. Cold stressed mice had lower plasma tumor necrosis factor receptor 1 (TNFR1) levels with varying significance, in all ages and phenotypes, with the exception of the old female WT mice. In contrast, the effects of cold stress on pro-inflammatory cytokine interleukin 6 (IL-6) levels were inconsistent and not significant, with the exception of the female IL-10tm/tm mice. In conclusion, these findings demonstrate that sex, age and chronic inflammatory pathway activation all influence corticosterone secretion and inflammatory processes in the face of acute cold stress.
Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondria... more Mitochondrial dysfunction, chronic inflammation and muscle aging are closely linked. Mitochondrial clearance is a process to dampen inflammation and is a critical prerequisite to mitobiogenesis. The combined effect of aging and chronic inflammation on mitochondrial degradation by autophagy is understudied. In interleukin 10 null mouse (IL-10 tm/tm), a rodent model of chronic inflammation, we studied the effects of aging and inflammation on mitochondrial clearance. We show that aging in IL-10 tm/tm is associated with reduced skeletal muscle mitochondrial death signaling and altered formation of autophagosomes, compared to agematched C57BL/6 controls. Moreover, skeletal muscles of old IL-10 tm/tm mice have the highest levels of damaged mitochondria with disrupted mitochondrial ultrastructure and autophagosomes compared to all other groups. These observations highlight the interface between chronic inflammation and aging on altered mitochondrial biology in skeletal muscles.
Background Dementia and frailty are common age-related syndromes often linked to chronic inflamma... more Background Dementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk. Results Our study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels. Conclusion In a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.
Physical frailty has a complex and heterogenous biological basis that likely includes genetic inf... more Physical frailty has a complex and heterogenous biological basis that likely includes genetic influences, age-related biological changes to metabolic processes and stress response systems, and mitochondrial decline. Although it is at present not possible to assign causality to specific biological processes, progress has been made in understanding the contributions of a variety of biological processes that influence frailty. In this symposium, we will provide new information on the role of genetic variants related to iron metabolism in the role of muscle weakness in older adults, on the potential role of mitochondrial DNA in driving frailty and inflammation, and the role of altered metabolic processes as measured by metabolomic variables. Each of these biological domains provide measureable variables that can potentially be used for diagnostic or therapeutic purposes. At the end of this symposium, the audience should be able to better understand the processes that potentially drive frailty in older adults, and the possibilities for future diagnostic and treatment modalities for frailty in older adults.
The renin-angio tensin system (RAS) is now regarded as an integral component in not only the deve... more The renin-angio tensin system (RAS) is now regarded as an integral component in not only the development of hypertension, but also in physiologic and pathophysiologic mechanisms in multiple tissues and chronic disease states. While many of the endocrine (circulating), paracrine (cell-to-different cell) and autacrine (cell-to-same cell) effects of the RAS are believed to be mediated through the canonical extracellular RAS, a complete, independent and differentially regulated intracellular RAS (iRAS) has also been proposed. Angiotensinogen, the enzymes renin and angiotensin-converting enzyme (ACE) and the angiotensin peptides can all be synthesized and retained intracellularly. Angiotensin receptors (types I and 2) are also abundant intracellularly mainly at the nuclear and mitochondrial levels. The aim of this review is to focus on the most recent information concerning the subcellular localization, distribution and functions of the iRAS and to discuss the potential consequences of activation of the subcellular RAS on different organ systems.
Chronic wounds are a common and debilitating condition associated with aging populations that imp... more Chronic wounds are a common and debilitating condition associated with aging populations that impact more than 6.5 million patients in the United States. We have previously demonstrated the efficacy of daily topical 1% valsartan in treating wounds in diabetic mouse and pig models. Despite these promising results, there remains a need to develop an extended‐release formulation that would reduce patient burden by decreasing the frequency of daily applications. Here, we used nanotechnology to self‐assemble valsartan amphiphiles into a filamentous structure (val‐filaments) that would serve as a scaffold in wound beds and allow for steady, localised and tunable release of valsartan amphiphiles over 24 days. Two topical treatments of this peptide‐based hydrogel on full‐thickness wounds in Zucker Diabetic Fatty rats resulted in faster rates of wound closure. By day 23, all val‐filament treated wounds were completely closed, as compared to one wound closed in the placebo group. Mechanistically, we observed enrichment of proteins involved in cell adhesion and energetics pathways, downregulation of Tgf‐β signalling pathway mediators (pSmad2, pSmad3 and Smad4) and increased mitochondrial metabolic pathway intermediates. This study demonstrates the successful synthesis of a sustained‐release valsartan filament hydrogel, its impact on mitochondrial energetics and efficacy in treating diabetic wounds.
Journal of Interferon and Cytokine Research, Jun 1, 2011
Angiotensin subtype-1 receptor (AT 1 R) influences inflammatory processes through enhancing signa... more Angiotensin subtype-1 receptor (AT 1 R) influences inflammatory processes through enhancing signal transducer and activator of transcription proteins 3 (STAT3) signal transduction, resulting in increased tumor necrosis factor-a (TNF-a) production. Although angiotensin subtype-2 receptor (AT 2 R), in general, antagonizes AT 1 Rstimulated activity, it is not known if AT 2 R has any anti-inflammatory effects. In this study, we tested the hypothesis that AT 2 R activation plays an anti-inflammatory role by reducing STAT3 phosphorylation and TNFa production. Changes in AT 2 R expression, TNF-a production, and STAT3 phosphorylation were quantified by Western blotting, Bio-Plex cytokine, and phosphoprotein cellular signaling assays in PC12W cells that express AT 2 R but not AT 1 R, in response to the AT 2 R agonist, CGP-42112 (CGP, 100 nm), or AT 2 R antagonist PD-123319 (PD, 1 mm). A 100% increase in AT 2 R expression in response to stimulation with its agonist CGP was observed. Further, AT 2 R activation reduced TNF-a production by 39% and STAT3 phosphorylation by 83%. In contrast, PD decreased AT 2 R expression by 76%, increased TNF-a production by 84%, and increased STAT3 phosphorylation by 67%. These findings suggest that increased AT 2 R expression may play a role in the observed decrease in inflammatory pathway activation through decreased TNF-a production and STAT3 signaling. Restoration of AT 2 R expression and/or its activation constitute a potentially novel therapeutic target for the management of inflammatory processes.
Sarcopenia is an age-related decline in skeletal muscle mass and function that is multifactorial ... more Sarcopenia is an age-related decline in skeletal muscle mass and function that is multifactorial in etiology. Age-related changes in the renin-angiotensin system (RAS), increased oxidative stress, and chronic inflammation likely all contribute to its development. Losartan, an angiotensin II type I receptor blocker (ARB) decreases RAS activity and likely influences oxidative stress and inflammation. Given this, we hypothesized that losartan would improve activity levels and parameters related to inflammation and oxidative stress in older mice. We sought to test this hypothesis by comparing functional and molecular parameters between 18-month-old C57BL/6 mice treated with 50-70 mg/kg/day of losartan over a 4 month-period and age-and gendermatched mice receiving placebo. Losartan treatment significantly improved several activity measurements during treatment period compared to placebo controlled group, including increased time on treadmill, traveling activity, standing activity, and decreased grid contacts (p-values < 0.05, 0.001, 0.01; and 0.04 respectively). Grip strength did not improve in treatment group relative to control group over time. Serum IL-6 level in the treated group was significantly lower than that in the control group at the end of treatment, (30.3±12.9 vs. 173.0±59.5 pg/ml, p< 0.04), and mRNA expression of antioxidant enzymes catalase (3.9±0.9 vs. 1.0±0.4) and glutathione peroxidase (4.7±1.1 vs. 1.0±0.4) was significantly higher, P-value: 0.02, and 0.03 respectively) in quadriceps muscle after 4 months of treatment in treated and control groups. These results support the hypothesis that chronic losartan treatment improves skeletal muscle related activity measures in older mice, and that it is associated with more favorable relevant biological profiles in the treatment group. Additional studies are needed to 1) further quantify this functional improvement,
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Papers by Peter Abadir