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1.  Successful Aging: Advancing the Science of Physical Independence in Older Adults 
Ageing research reviews  2015;24(0 0):304-327.
The concept of ‘Successful Aging’ has long intrigued the scientific community. Despite this long-standing interest, a consensus definition has proven to be a difficult task, due to the inherent challenge involved in defining such a complex, multi-dimensional phenomenon. The lack of a clear set of defining characteristics for the construct of successful aging has made comparison of findings across studies difficult and has limited advances in aging research. The domain in which consensus on markers of successful aging is furthest developed is the domain of physical functioning. For example, walking speed appears to be an excellent surrogate marker of overall health and predicts the maintenance of physical independence, a cornerstone of successful aging. The purpose of the present article is to provide an overview and discussion of specific health conditions, behavioral factors, and biological mechanisms that mark declining mobility and physical function and promising interventions to counter these effects. With life expectancy continuing to increase in the United States and developed countries throughout the world, there is an increasing public health focus on the maintenance of physical independence among all older adults.
doi:10.1016/j.arr.2015.09.005
PMCID: PMC4661112  PMID: 26462882
age; mobility; obesity; sarcopenia; healthspan; longevity
2.  Intraoperative hemidiaphragm electrical stimulation reduces oxidative stress and upregulates autophagy in surgery patients undergoing mechanical ventilation: exploratory study 
Background
Mechanical ventilation (MV) during a cardio-thoracic surgery contributes to diaphragm muscle dysfunction that impairs weaning and can lead to the ventilator- induced diaphragm dysfunction. Especially, it is critical in older adults who have lower muscle reparative capacity following MV. Reports have shown that the intraoperative intermittent hemidiaphragm electrical stimulation can maintain and/or improve post-surgery diaphragm function. In particular, from a molecular point of view, intermittent ES may reduce oxidative stress and increase regulatory autophagy levels, and therefore improve diaphragm function in animal studies. We have recently shown in humans that intraoperative ES attenuates mitochondrial dysfunction and force decline in single diaphragm muscle fibers. The aim of this study was to investigate an effect of ES on oxidative stress, antioxidant status and autophagy biomarker levels in the human diaphragm during surgery.
Methods
One phrenic nerve was simulated with an external cardiac pacer in operated older subjects (62.4 ± 12.9 years) (n = 8) during the surgery. The patients received 30 pulses per min every 30 min. The muscle biopsy was collected from both hemidiaphragms and frozen for further analyses. 4-hydroxynonenal (4-HNE), an oxidative stress marker, and autophagy marker levels (Beclin-1 and the ratio of microtubule-associated protein light chain 3, I and II-LC3 II/I) protein concentrations were detected by the western blot technique. Antioxidant enzymatic activity copper-zinc (CuZnSOD) and manganese (MnSOD) superoxide dismutase were analyzed.
Results
Levels of lipid peroxidation (4-HNE) were significantly lower in the stimulated side (p < 0.05). The antioxidant enzyme activities (CuZnSOD and MnSOD) in the stimulated side of the diaphragm were not different than in the unstimulated side (p > 0.05). Additionally, the protein concentrations of Beclin-1 and the LC3 II/I ratio were higher in the stimulated side (p < 0.05).
Conclusion
These results suggest that the intraoperative electrical stimulation decreases oxidative stress levels and upregulates autophagy levels in the stimulated hemidiaphragm. These results may contribute future studies and clinical applications on reducing post-operative diaphragm dysfunction.
doi:10.1186/s12967-016-1060-0
PMCID: PMC5080720  PMID: 27784315
3.  Age-related cellular changes in the long-lived bivalve A. islandica 
Age  2015;37(5):90.
One of the biggest challenges to studying causes and effects of aging is identifying changes in cells that are related to senescence instead of simply the passing of chronological time. We investigated two populations of the longest living non-colonial metazoan, Arctica islandica, with lifespans that differed sixfolds. Of four investigated parameters (nucleic acid oxidation, protein oxidation, lipid oxidation, and protein instability), only nucleic acid oxidation increased with age and correlated with relative lifespan. Nucleic acid oxidation levels increased significantly faster and were significantly higher in the shorter-lived than the longer-lived population. In contrast, neither protein oxidation, lipid oxidation, nor protein stability changed over time. Protein resistance to unfolding stress when treated with urea was significantly lower overall in the shorter-lived population, and lipid peroxidation levels were higher in the longer-lived population. With the exception of nucleic acid oxidation, damage levels of A. islandica do not change with age, indicating excellent cellular maintenance in both populations. Since correlations between nucleic acid oxidation and age have also been shown previously in other organisms, and nucleic acid oxidation accumulation rate correlates with relative age in both investigated populations, nucleic acid oxidation may reflect intrinsic aging mechanisms.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-015-9831-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-015-9831-8
PMCID: PMC5005836  PMID: 26318854
Longevity; Aging marker; Arctica islandica; Oxidation; Cellular maintenance
4.  Walking performance is positively correlated to calf muscle fiber size in peripheral artery disease subjects, but fibers show aberrant mitophagy: an observational study 
Background
Patients with lower extremity peripheral artery disease (PAD) have decreased mobility, which is not fully explained by impaired blood supply to the lower limb. Additionally, reports are conflicted regarding fiber type distribution patterns in PAD, but agree that skeletal muscle mitochondrial respiration is impaired.
Methods
To test the hypothesis that reduced muscle fiber oxidative activity and type I distribution are negatively associated with walking performance in PAD, calf muscle biopsies from non-PAD (n = 7) and PAD participants (n = 26) were analyzed immunohistochemically for fiber type and size, oxidative activity, markers of autophagy, and capillary density. Data were analyzed using analysis of covariance.
Results
There was a wide range in fiber type distribution among subjects with PAD (9–81 % type I fibers) that did not correlate with walking performance. However, mean type I fiber size correlated with 4-min normal- and fastest-paced walk velocity (r = 0.4940, P = 0.010 and r = 0.4944, P = 0.010, respectively). Although intensity of succinate dehydrogenase activity staining was consistent with fiber type, up to 17 % of oxidative fibers were devoid of mitochondria in their cores, and the core showed accumulation of the autophagic marker, LC3, which did not completely co-localize with LAMP2, a lysosome marker.
Conclusions
Calf muscle type I fiber size positively correlates with walking performance in PAD. Accumulation of LC3 and a lack of co-localization of LC3 with LAMP2 in the area depleted of mitochondria in PAD fibers suggests impaired clearance of damaged mitochondria, which may contribute to reduced muscle oxidative capacity. Further study is needed to determine whether defective mitophagy is associated with decline in function over time, and whether interventions aimed at preserving mitochondrial function and improving autophagy can improve walking performance in PAD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-1030-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-016-1030-6
PMCID: PMC5043620  PMID: 27687713
Mitochondria; Mitophagy; Fiber type; Calf muscle; Peripheral artery disease
5.  Dietary Antioxidants as Modifiers of Physiologic Adaptations to Exercise 
Adaptive responses to exercise training (ET) are crucial in maintaining physiological homeostasis and health span. Exercise-induced aerobic bioenergetic reactions in mitochondria and cytosol increase production of reactive oxygen species (ROSs), where excess of ROS can be scavenged by enzymatic as well as non-enzymatic antioxidants to protect against deleterious oxidative stress. Free radicals, however, have recently been recognized as crucial signaling agents that promote adaptive mechanisms to ET, such as mitochondrial biogenesis, antioxidant (AO) enzyme activity defense system upregulation, insulin sensitivity, and glucose uptake in skeletal muscle. Commonly used non-enzymatic AO supplements, such as vitamins C and E, a-lipoic acid, and polyphenols, in combination with ET, have been proposed as ways to prevent exercise-induced oxidative stress and hence improve adaptation responses to endurance training. Preclinical and clinical studies to date have shown inconsistent results indicating either positive or negative effects of endurance training combined with different blends of AO supplements (mostly vitamins C and E and a-lipoic acid) on redox status, mitochondrial biogenesis pathways, and insulin sensitivity. Preclinical reports on ET combined with resveratrol, however, have shown consistent positive effects on exercise performance, mitochondrial biogenesis, and insulin sensitivity, with clinical trials reporting mixed effects. Relevant clinical studies have been few and have used inconsistent results and methodology (types of compounds, combinations, and supplementation time). The future studies would investigate the effects of specific antioxidants and other popular supplements, such as a-lipoic acid and resveratrol, on training effects in humans. Of particular importance are older adults who may be at higher risk of age-related increased oxidative stress, an impaired AO enzyme defense system, and comorbidities such as hypertension, insulin resistance, and diabetes.
doi:10.1249/MSS.0000000000000620
PMCID: PMC4690615  PMID: 25606815
Exercise Training; Dietary Antioxidants; Mitochondrial Biogenesis; Redox Status; Glucose Metabolism
6.  A Detailed Characterization of the Dysfunctional Immunity and Abnormal Myelopoiesis Induced by Severe Shock and Trauma in the Aged 
The elderly are particularly susceptible to trauma, and their outcomes are frequently dismal. Such patients often have complicated clinical courses and ultimately die from infection and sepsis. Recent research has revealed that although elderly subjects have increased baseline inflammation as compared to their younger counterparts, the elderly do not respond to severe infection/injury with an exaggerated inflammatory response. Initial retrospective analysis of clinical data from the Glue Grant trauma database demonstrated that despite a similar frequency, elderly trauma patients have worse outcomes to pneumonia than younger subjects. Subsequent analysis with a murine trauma model also demonstrated that elderly mice had increased mortality after post-trauma Pseudomonas pneumonia. Blood, bone marrow, and bronchoalveolar lavage sample analyses from juvenile and 20–24 month old mice showed that increased mortality to trauma combined with secondary infection in the aged are not due to an exaggerated inflammatory response. Rather, they are due to a failure of bone marrow progenitors, blood neutrophils, and bronchoalveolar lavage cells to initiate and complete an ‘emergency myelopoietic’ response, engendering myeloid cells that fail to clear secondary infection. In addition, the elderly appeared unable to effectively resolve their inflammatory response to severe injury.
doi:10.4049/jimmunol.1500984
PMCID: PMC4546902  PMID: 26246141
7.  Practicality of Intermittent Fasting in Humans and its Effect on Oxidative Stress and Genes Related to Aging and Metabolism 
Rejuvenation Research  2015;18(2):162-172.
Abstract
Caloric restriction has consistently been shown to extend life span and ameliorate aging-related diseases. These effects may be due to diet-induced reactive oxygen species acting to up-regulate sirtuins and related protective pathways, which research suggests may be partially inhibited by dietary anti-oxidant supplementation. Because caloric restriction is not sustainable long term for most humans, we investigated an alternative dietary approach, intermittent fasting (IF), which is proposed to act on similar biological pathways. We hypothesized that a modified IF diet, where participants maintain overall energy balance by alternating between days of fasting (25% of normal caloric intake) and feasting (175% of normal), would increase expression of genes associated with aging and reduce oxidative stress and that these effects would be suppressed by anti-oxidant supplementation. To assess the tolerability of the diet and to explore effects on biological mechanisms related to aging and metabolism, we recruited a cohort of 24 healthy individuals in a double-crossover, double-blinded, randomized clinical trial. Study participants underwent two 3-week treatment periods—IF and IF with anti-oxidant (vitamins C and E) supplementation. We found strict adherence to study-provided diets and that participants found the diet tolerable, with no adverse clinical findings or weight change. We detected a marginal increase (2.7%) in SIRT3 expression due to the IF diet, but no change in expression of other genes or oxidative stress markers analyzed. We also found that IF decreased plasma insulin levels (1.01 μU/mL). Although our study suggests that the IF dieting paradigm is acceptable in healthy individuals, additional research is needed to further assess the potential benefits and risks.
doi:10.1089/rej.2014.1624
PMCID: PMC4403246  PMID: 25546413
8.  Brown Adipose Tissue and the Cold War Against Obesity 
Diabetes  2014;63(12):3998-4000.
doi:10.2337/db14-1373
PMCID: PMC4392919  PMID: 25414014
9.  Amino Acid Homeostasis and Chronological Longevity in Saccharomyces cerevisiae 
Sub-cellular biochemistry  2012;57:161-186.
Understanding how non-dividing cells remain viable over long periods of time, which may be decades in humans, is of central importance in understanding mechanisms of aging and longevity. The long-term viability of non-dividing cells, known as chronological longevity, relies on cellular processes that degrade old components and replace them with new ones. Key among these processes is amino acid homeostasis. Amino acid homeostasis requires three principal functions: amino acid uptake, de novo synthesis, and recycling. Autophagy plays a key role in recycling amino acids and other metabolic building blocks, while at the same time removing damaged cellular components such as mitochondria and other organelles. Regulation of amino acid homeostasis and autophagy is accomplished by a complex web of pathways that interact because of the functional overlap at the level of recycling. It is becoming increasingly clear that amino acid homeostasis and autophagy play important roles in chronological longevity in yeast and higher organisms. Our goal in this chapter is to focus on mechanisms and pathways that link amino acid homeostasis, autophagy, and chronological longevity in yeast, and explore their relevance to aging and longevity in higher eukaryotes.
doi:10.1007/978-94-007-2561-4_8
PMCID: PMC4603547  PMID: 22094422
Amino acid; Homeostasis; Chronological longevity; Caloric restriction; Autophagy
11.  Calorie restriction for optimal cardiovascular aging: the weight of evidence 
The epidemic of obesity and overweight is spreading worldwide. Excessive adiposity is associated with a myriad of adverse health outcomes, leading to increased healthcare expenditures and shortened life expectancy. In contrast to overeating, calorie restriction (CR), defined as a reduction in food intake without malnutrition, increases both mean and maximum lifespan in a variety of species by reducing the incidence of several chronic degenerative diseases, including cardiovascular disease. The constellation of health benefits brought about by CR results from biological and physiological changes affecting fundamental processes underlying aging and age-related pathologies. Despite the beneficial properties of CR, it is likely that most people will not engage in such a dietary regimen for the long-term. Supplementation with specific compounds mimicking CR may represent a more feasible means to improve health and prolong life. However, evidence on long-term effectiveness and safety of these compounds is not yet available in humans.
PMCID: PMC4573497  PMID: 26388964
obesity; hormesis; stress; inflammation; apoptosis; sirtuins
12.  Mitochondrial Respiration and Passive Stretch of the Diaphragm During Unilateral Phrenic Nerve Stimulation: Authors' Response 
Critical care medicine  2014;42(9):e634.
doi:10.1097/CCM.0000000000000482
PMCID: PMC4262149  PMID: 25126819
mechanical ventilation; phrenic nerve stimulation; diaphragm muscle; mitochondrial respiration
13.  Calorie restriction combined with resveratrol induces autophagy and protects 26-month-old rat hearts from doxorubicin-induced toxicity 
The multiple beneficial effects of calorie restriction (CR) on several organs, including the heart, are widely known. Recently, the plant polyphenol resveratrol has been shown to possess beneficial effects similar to that of CR. Among the host of effects on cardiac muscle, a cellular self-eating process called autophagy has been shown to be induced by both CR and resveratrol. Autophagy is vital in removing dysfunctional organelles and damaged proteins from the cell, thereby maintaining cellular quality control. In this study, we explored whether short-term moderate CR (20%), either alone or in combination with resveratrol, can induce autophagy in the hearts of 26-month old Fischer 344 × Brown Norway (FBN) rats. Autophagy stimulation was investigated by measuring protein expression levels of autophagy proteins Beclin-1, Atg5, p62, and LC3-II/LC3-I ratio. We found that 20% CR or resveratrol alone for 6 weeks could not induce autophagy, but 20% CR in combination with 50 mg/kg/day resveratrol resulted in an induction of autophagy in the hearts of 26 month old rats. Although oxidative stress has been proposed to be an inducer of autophagy, treatment with the chemotherapeutic drug doxorubicin was unable to stimulate autophagy. The enhanced autophagy due to CR + resveratrol was associated with protection from doxorubicin-induced damage, as measured by cardiac apoptotic levels, serum creatine kinase (CK) and lactate dehydrogenase (LDH) activity. We propose that a combinatorial approach of low-dose CR and resveratrol has the potential to be used therapeutically to induce autophagy and provides protection against doxorubicin-mediated toxicity.
doi:10.1016/j.freeradbiomed.2014.06.011
PMCID: PMC4146714  PMID: 24975655
Autophagy; Calorie Restriction; Resveratrol; Heart; Doxorubicin; Oxidative stress
14.  Safety and metabolic outcomes of resveratrol supplementation in older adults: results of a twelve-week, placebo-controlled pilot study 
Experimental gerontology  2014;0:181-187.
Resveratrol has been found to have potent antioxidant, anti-inflammatory, and anticarcinogenic effects. The safety and efficacy of resveratrol supplementation in older adults are currently unknown. We conducted a double-blind, randomized, placebo-controlled trial to examine the safety and metabolic outcomes in 32 overweight, older adults (mean age, 73 ± 7 years). Participants were randomized into one of three treatment groups: (1) placebo, (2) moderate dose resveratrol (300 mg/day), and (3) high dose resveratrol (1000 mg/day). Both resveratrol and placebo were orally ingested in capsule form twice daily for 90 days. Blood chemistry values remained within the normal range, and there were no significant differences in the number of participants reporting adverse events across conditions. Compared to placebo, glucose levels were significantly lower at post-treatment among participants randomized to both resveratrol conditions, with and without adjustment for the corresponding baseline values (ps < 0.05). Glucose values of participants in the treatment groups, however, were not significantly different from baseline levels. These findings suggest that short-term resveratrol supplementation at doses of 300 mg/day and 1000 mg/day does not adversely affect blood chemistries and is well tolerated in overweight, older individuals. These findings support the study of resveratrol for improving cardio-metabolic health in older adults in larger clinical trials.
doi:10.1016/j.exger.2014.05.015
PMCID: PMC4149922  PMID: 24866496
Resveratrol; Safety; Metabolism; Glucose; Blood pressure
15.  Short-term caloric restriction, resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber-type specific manner in aged animals 
Experimental gerontology  2013;48(9):858-868.
Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR + RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 × Brown Norway rats. CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR + RSV) paradigms showed a protective effect in the soleus and plantaris muscle (P < 0.05). Sirt1 protein content was increased by 2.6-fold (P < 0.05) in WG but not RG muscle with RSV treatment, while CR or CR + RSV had no effect. PGC-1α levels were higher (2-fold) in the WG from CR-treated animals (P < 0.05) when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment. Levels of the anti-apoptotic protein Bcl-2 were significantly higher (1.6-fold) in the WG muscle of RSV and CR + RSV groups compared to AL (P < 0.05) but tended to occur coincident with elevations in the pro-apoptotic protein Bax so that the apoptotic susceptibility as indicated by the Bax to Bcl-2 ratio was unchanged. There were no alterations in DNA fragmentation with any treatment in muscle from older animals. Additionally, mitochondrial respiration measured in permeabilized muscle fibers was unchanged in any treatment group and this paralleled the lack of change in cytochrome c oxidase (COX) activity. These data suggest that short-term moderate CR, RSV, or CR + RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study.
doi:10.1016/j.exger.2013.05.061
PMCID: PMC4550205  PMID: 23747682
Aging; Caloric restriction; Sarcopenia; Apoptosis; Biogenesis; Sirtuins
16.  Long-term perturbation of muscle iron homeostasis following hindlimb suspension in old rats is associated with high levels of oxidative stress and impaired recovery from atrophy 
Experimental gerontology  2011;47(1):100-108.
In the present study, we investigated the effects of 7 and 14 days of re-loading following 14-day muscle unweighting (hindlimb suspension, HS) on iron transport, non-heme iron levels and oxidative damage in the gastrocnemius muscle of young (6 months) and old (32 months) male Fischer 344×Brown Norway rats. Our results demonstrated that old rats had lower muscle mass, higher levels of total non-heme iron and oxidative damage in skeletal muscle in comparison with young rats. Non-heme iron concentrations and total non-heme iron amounts were 3.4- and 2.3-fold higher in aged rats as compared with their young counterparts, respectively. Seven and 14 days of re-loading was associated with higher muscle weights in young animals as compared with age-matched HS rats, but there was no difference in muscle weights among aged HS, 7 and 14 days of re-loading rats, indicating that aged rats may have a lower adaptability to muscle disuse and a lower capacity to recover from muscle atrophy. Protein levels of cellular iron transporters, such as divalent metal transport-1 (DMT1), transferrin receptor-1 (TfR1), Zip14, and ferroportin (FPN), and their mRNA abundance were determined. TfR1 protein and mRNA levels were significantly lower in aged muscle. Seven and 14 days of re-loading were associated with higher TfR1 mRNA and protein levels in young animals in comparison with their age-matched HS counterparts, but there was no difference between cohorts in aged animals, suggesting adaptive responses in the old to cope with iron deregulation. The extremely low expression of FPN in skeletal muscle might lead to inefficient iron export in the presence of iron overload and play a critical role in age-related iron accumulation in skeletal muscle. Moreover, oxidative stress was much greater in the muscles of the older animals measured as 4-hydroxy-2-nonhenal (HNE)-modified proteins and 8-oxo-7,8-dihydroguanosine levels. These markers remained fairly constant with either HS or re-loading in young rats. In old rats, HNE-modified proteins and 8-oxo-7,8-dihydroguanosine levels were markedly higher in HS and were lower after 7 days of recovery. However, no difference was observed following 14 days of recovery between control and re-loading animals. In conclusion, advanced age is associated with disruption of muscle iron metabolism which is further perturbed by disuse and persists over a longer time period.
doi:10.1016/j.exger.2011.10.011
PMCID: PMC4545509  PMID: 22085543
Aging; Sarcopenia; Iron metabolism; Hindlimb unloading and re-loading; Skeletal muscle atrophy
17.  Hydrogen Sulfide Induces Oxidative Damage to RNA and DNA in a Sulfide-Tolerant Marine Invertebrate 
Hydrogen sulfide acts as an environmental toxin across a range of concentrations and as a cellular signaling molecule at very low concentrations. Despite its toxicity, many animals, including the mudflat polychaete Glycera dibranchiata, are periodically or continuously exposed to sulfide in their environment. We tested the hypothesis that a broad range of ecologically relevant sulfide concentrations induces oxidative stress and oxidative damage to RNA and DNA in G. dibranchiata. Coelomocytes exposed in vitro to sulfide (0–3 mmol L−1 for 1 h) showed dose-dependent increases in oxidative stress (as 2′,7′-dichlorofluorescein fluorescence) and superoxide production (as dihydroethidine fluorescence). Coelomocytes exposed in vitro to sulfide (up to 0.73 mmol L−1 for 2 h) also acquired increased oxidative damage to RNA (detected as 8-oxo-7,8-dihydroguanosine) and DNA (detected as 8-oxo-7,8-dihydro-2′-deoxyguanosine). Worms exposed in vivo to sulfide (0–10 mmol L−1 for 24 h) acquired elevated oxidative damage to RNA and DNA in both coelomocytes and body wall tissue. While the consequences of RNA and DNA oxidative damage are poorly understood, oxidatively damaged deoxyguanosine bases preferentially bind thymine, causing G-T transversions and potentially causing heritable point mutations. This suggests that sulfide can be an environmental mutagen in sulfide-tolerant invertebrates.
doi:10.1086/597529
PMCID: PMC4542154  PMID: 19327040
18.  Increased inflammation but similar physical composition and function in older-aged, HIV-1 infected subjects 
BMC Immunology  2015;16:43.
Background
Systemic immune activation (inflammation) and immunosenescence develop in some people with advancing age. This process, known as “inflamm-aging,” is associated with physical frailty and sarcopenia. Meanwhile, successful antiretroviral therapy has led to a growing number of older HIV-1-infected individuals who face both age-related and HIV-1-related inflammation, which may synergistically promote physical decline, including frailty and sarcopenia. The purpose of our study was to determine if inflammation during treated HIV-1 infection worsens physical impairment in older individuals.
Methods
We determined the severity of HIV-associated inflammation and physical performance (strength and endurance) in 21 older HIV-infected individuals (54–69 years) receiving suppressive antiretroviral therapy, balanced for confounding variables including age, anthropometrics, and co-morbidities with 10 uninfected control individuals. Biomarkers for microbial translocation (lipopolysaccharide [LPS]), inflammation (soluble CD14 [sCD14], osteopontin, C-reactive protein [CRP], interleukin-6 [IL-6], soluble ICAM-1 [sICAM-1] and soluble VCAM-1 [sVCAM-1]), and coagulopathy (D-dimer) were assayed in plasma. Activation phenotypes of CD4+T cells, CD8+ T cells and monocytes were measured by flow cytometry. Physical performance was measured by 400 m walking speed, a short physical performance battery [SPPB], and lower extremity muscle strength and fatigue.
Results
Overall physical function was similar in the uninfected and HIV-infected groups. Compared to uninfected individuals, the HIV-infected group had elevated levels of sCD14 (P < 0.001), CRP (P < 0.001) and IL-6 (P = 0.003) and an increased frequency of CD4+ and CD8+ T cells with an immunosenescent CD57+ phenotype (P = 0.004 and P = 0.043, respectively). Neither plasma inflammatory biomarkers nor CD57+ T cells correlated with CD4+ T cell counts. Furthermore, none of the elevated inflammatory biomarkers in the HIV-infected subjects were associated with any of the physical performance results.
Conclusions
When age-related co-morbidities were carefully balanced between the uninfected and HIV-infected groups, no evidence of inflammation-associated physical impairment was detected. Despite careful balancing for age, BMI, medications and co-morbidities, the HIV-infected group still displayed evidence of significant chronic inflammation, including elevated sCD14, CRP, IL-6 and CD57+ T cells, although the magnitude of this inflammation was unrelated to physical impairment.
doi:10.1186/s12865-015-0106-z
PMCID: PMC4513956  PMID: 26204934
19.  Current nutritional recommendations and novel dietary strategies to manage sarcopenia 
Sarcopenia, the loss of skeletal muscle mass and function that occurs with aging, is associated with increased risk for several adverse health outcomes, including frailty, disability, falls, loss of independent living, and mortality. At present, no pharmacological treatment exists that is able to definitely halt the progression of sarcopenia. Likewise, no pharmacological remedies are yet available to prevent the onset of age-related muscle wasting. In this scenario, the combination of nutritional interventions and physical exercise appears to be the most effective strategy presently available for the management of sarcopenia. The purposes of this review are to summarize the current knowledge on the role of nutrition as a countermeasure for sarcopenia, illustrate the mechanisms of action of relevant dietary agents on the aging muscle, and introduce novel nutritional strategies that may help preserve muscle mass and function into old age. Issues related to the identification of the optimal timing of nutritional interventions in the context of primary and secondary prevention are also discussed. Finally, the prospect of elaborating personalized dietary and physical exercise recommendations through the implementation of integrated, high-throughput analytic approaches is illustrated.
PMCID: PMC4465574  PMID: 26082911
aging; protein; vitamin D; creatine; omics; personalized diet; Pachinko model
20.  Protective Immunity and Defects in the Neonatal and Elderly Immune Response to Sepsis 
Populations encompassing extremes of age, including neonates and elderly, have greater mortality from sepsis. We propose that the increased mortality observed in the neonatal and elderly populations after sepsis is due to fundamental differences in host protective immunity, and are manifested at the level of the leukocyte transcriptome. Neonatal (5–7 days), young adult (6–12 weeks), or elderly (20–24 months) mice underwent a cecal slurry model of intra-abdominal sepsis. Both neonatal and elderly mice exhibited significantly greater mortality to sepsis (p<0.05). Neonates in particular exhibited significant attenuation of their inflammatory response (p<0.05), as well as reductions in cell recruitment and reactive oxygen species production (both p<0.05), all of which could be confirmed at the level of the leukocyte transcriptome. In contrast elderly mice were also more susceptible to abdominal peritonitis, but this was associated with no significant differences in the magnitude of the inflammatory response, reduced bacterial killing (p<0.05), reduced early myeloid cell activation (p<0.05) and a persistent inflammatory response that failed to resolve. Interestingly, elderly mice expressed a persistent inflammatory and immunosuppressive response at the level of the leukocyte transcriptome, with failure to return to baseline by three days. This study reveals that neonatal and elderly mice have profoundly different responses to sepsis that are manifested at the level of their circulating leukocyte transcriptome, although the net result of increased mortality, is similar. Considering these differences are fundamental aspects of the genomic response to sepsis, interventional therapies will require individualization based on the age of the population.
doi:10.4049/jimmunol.1301726
PMCID: PMC3967513  PMID: 24591376
21.  Advanced age is associated with worsened outcomes and a unique genomic response in severely injured patients with hemorrhagic shock 
Critical Care  2015;19(1):77.
Introduction
We wished to characterize the relationship of advanced age to clinical outcomes and to transcriptomic responses after severe blunt traumatic injury with hemorrhagic shock.
Methods
We performed epidemiological, cytokine, and transcriptomic analyses on a prospective, multi-center cohort of 1,928 severely injured patients.
Results
We found that there was no difference in injury severity between the aged (age ≥55, n = 533) and young (age <55, n = 1395) cohorts. However, aged patients had more comorbidities. Advanced age was associated with more severe organ failure, infectious complications, ventilator days, and intensive care unit length of stay, as well as, an increased likelihood of being discharged to skilled nursing or long-term care facilities. Additionally, advanced age was an independent predictor of a complicated recovery and 28-day mortality. Acutely after trauma, blood neutrophil genome-wide expression analysis revealed an attenuated transcriptomic response as compared to the young; this attenuated response was supported by the patients’ plasma cytokine and chemokine concentrations. Later, these patients demonstrated gene expression changes consistent with simultaneous, persistent pro-inflammatory and immunosuppressive states.
Conclusions
We concluded that advanced age is one of the strongest non-injury related risk factors for poor outcomes after severe trauma with hemorrhagic shock and is associated with an altered and unique peripheral leukocyte genomic response. As the general population’s age increases, it will be important to individualize prediction models and therapeutic targets to this high risk cohort.
doi:10.1186/s13054-015-0788-x
PMCID: PMC4404112  PMID: 25880307
22.  A comparison among the tissue-specific effects of aging and calorie restriction on TFAM amount and TFAM-binding activity to mtDNA in rat 
Biochimica et biophysica acta  2014;1840(7):2184-2191.
Background
Mitochondrial Transcription Factor A (TFAM) is regarded as a histone-like protein of mitochondrial DNA (mtDNA), performing multiple functions for this genome. Aging affects mitochondria in a tissue-specific manner and only calorie restriction (CR) is able to delay or prevent the onset of several age-related changes also in mitochondria.
Methods
Samples of the frontal cortex and soleus skeletal muscle from 6- and 26-month-old ad libitum-fed and 26-month-old calorie-restricted rats and of the livers from 18- and 28-month-old ad libitum-fed and 28-month-old calorie-restricted rats were used to detect TFAM amount, TFAM-binding to mtDNA and mtDNA content.
Results
We found an age-related increase in TFAM amount in the frontal cortex, not affected by CR, versus an age-related decrease in the soleus and liver, fully prevented by CR. The semi-quantitative analysis of in vivo binding of TFAM to specific mtDNA regions, by mtDNA immunoprecipitation assay and following PCR, showed a marked age-dependent decrease in TFAM-binding activity in the frontal cortex, partially prevented by CR. An age-related increase in TFAM-binding to mtDNA, fully prevented by CR, was found in the soleus and liver. MtDNA content presented a common age-related decrease, completely prevented by CR in the soleus and liver, but not in the frontal cortex.
Conclusions
The modulation of TFAM expression, TFAM-binding to mtDNA and mtDNA content with aging and CR showed a trend shared by the skeletal muscle and liver, but not by the frontal cortex counterpart.
General significance: Aging and CR appear to induce similar mitochondrial molecular mechanisms in the skeletal muscle and liver, different from those elicited in the frontal cortex.
doi:10.1016/j.bbagen.2014.03.004
PMCID: PMC4335656  PMID: 24631828
Mitochondrial Transcription Factor A; Mitochondrial Transcription Factor; A–mitochondrial deoxyribonucleic acid binding; Tissue-specificity; Aging rat; Calorie restriction
23.  Multiple pathways to the same end: Mechanisms of myonuclear apoptosis in sarcopenia of aging 
TheScientificWorldJournal  2010;10:340-349.
Sarcopenia, the age-related decline in muscle mass and function, represents a significant health issue due to the high prevalence of frailty and disability associated with this condition. Nevertheless, the cellular mechanisms responsible for the loss of muscle mass in old age are still largely unknown. An altered regulation of myocyte apoptosis has recently emerged as a possible contributor to the pathogenesis of sarcopenia. Studies in animal models have shown that the severity of skeletal muscle apoptosis increases over the course of aging and correlates with the degree of muscle mass and strength decline. Several apoptotic pathways are operative in aged muscles, with the mitochondria- and TNF-α-mediated pathways likely being the most relevant to sarcopenia. However, despite the growing number of studies on the subject, a definite mechanistic link between myocyte apoptosis and age-related muscle atrophy has not yet been established. Furthermore, the evidence on the role played by apoptosis in human sarcopenia is still sparse. Clearly, further research is required to better define the involvement of myocyte apoptosis in the pathogenesis of muscle loss at advanced age. This knowledge will likely help in the design of more effective therapeutic strategies to preserve muscle mass into old age, thus fostering independence of the elderly population and reducing the socioeconomic burden associated with sarcopenia.
doi:10.1100/tsw.2010.27
PMCID: PMC4311890  PMID: 20191247
aging; sarcopenia; myonuclear apoptosis; mitochondria; tumor necrosis factor-alpha (TNF-α); caspases; endonuclease G (EndoG); apoptosis inducing factor (AIF)
24.  EFFECTS OF ACE-INHIBITION ON IGF-1 AND IGFBP-3 CONCENTRATIONS IN OLDER ADULTS WITH HIGH CARDIOVASCULAR RISK PROFILE 
Objectives
The present study evaluates the effects of a 6-month treatment with an ACE-inhibitor (ie, fosinopril) on serum concentrations of total IGF-1 and IGF binding protein (IGFBP)-3 in older adults at high risk for cardiovascular disease.
Design
Data are from the Trial of Angiotensin Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN) study, a double-blind, crossover, randomized, placebo-controlled trial.
Setting
Participants were recruited from the communities of Winston Salem, NC, and Greensboro, NC.
Participants
Subjects ≥55 years old with high cardiovascular disease risk profile.
Intervention
The intervention consisted of 6-month administration of fosinopril vs. placebo.
Measurements
Serum concentrations of total IGF-1 and IGFBP-3 were measured in 100 participants of the TRAIN study at baseline, 6-month and 12-month follow-up visits. Differences in total IGF-1 and IGFBP-3 concentrations were assessed using two-sided paired t-tests.
Results
The mean age of participants (47% women) was 66.5 (standard deviation 7.2) years. Serum concentrations of total IGF-1 were significantly higher after 6-month treatment with fosinopril compared to placebo (203.73 ng/mL vs 194.24 ng/mL; p=0.02): After ACE-inhibitor intervention, significantly higher serum IGFBP-3 concentrations compared to controls (4308.81 ng/mL vs 4086.93 ng/mL; p=0.03) were also reported.
Conclusions
A six-month treatment with fosinopril increases systemic levels of total IGF-1 and IGFBP-3 in older adults with high cardiovascular risk profile. This may represent a potential biological explanation to the beneficial effects of ACE-inhibition on stroke, ischemic heart disease and insulin resistance.
PMCID: PMC4311891  PMID: 20617288
Angiotensin Converting Enzyme inhibitor; Insulin like growth factor 1; Insulin like growth factor binding protein 3; older adults

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