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1.  Mouse Forepaw Lumbrical Muscles are Resistant to Age-Related Declines in Force Production 
Experimental gerontology  2015;65:42-45.
A progressive loss of skeletal muscle mass and force generating capacity occurs with aging. Mice are commonly used in the study of aging-associated changes in muscle size and strength, with most models of aging demonstrating 15-35% reductions in muscle mass, cross-sectional area (CSA), maximum isometric force production (Po) and specific force (sPo), which is Po/CSA. The lumbrical muscle of the mouse forepaw is exceptionally small, with corresponding short diffusion distances that make it ideal for in vitro pharmacological studies and measurements of contractile properties. However, the aging-associated changes in lumbrical function have not previously been reported. To address this, we tested the hypothesis that compared to adult (12 month old) mice, the forepaw lumbrical muscles of old (30 month old) mice exhibit aging-related declines in size and force production similar to those observed in larger limb muscles. We found that the forepaw lumbricals were composed exclusively of fibers with type II myosin heavy chain isoforms, and that the muscles accumulated connective tissue with aging. There were no differences in the number of fibers per whole-muscle cross-section or in muscle fiber CSA. The whole muscle CSA in old mice was increased by 17%, but the total CSA of all muscle fibers in a whole-muscle cross-section was not different. No difference in Po was observed, and while sPo normalized to total muscle CSA was decreased in old mice by 22%, normalizing Po by the total muscle fiber CSA resulted in no difference in sPo. Combined, these results indicate that forepaw lumbrical muscles from 30 month old mice are largely protected from the aging-associated declines in size and force production that are typically observed in larger limb muscles.
doi:10.1016/j.exger.2015.03.003
PMCID: PMC4397162  PMID: 25762422
lumbrical muscle; contractility; sarcopenia
2.  Effect of age on basal muscle protein synthesis and mTORC1 signaling in a large cohort of young and older men and women 
The rate of muscle loss with aging is higher in men than women. However, women have smaller muscles throughout the adult life. Protein content is a major determinant of skeletal muscle size. This study was designed to determine if age and sex differentially impact basal muscle protein synthesis and mammalian/mechanistic Target Of Rapamycin Complex 1 (mTORC1) signaling. We performed a secondary data analysis on a cohort of 215 healthy, non-obese (BMI <30 kg·m−2) young (18–40 y; 74 men, 52 women) and older (60–87 y; 57 men, 32 women) adults. The database contained information on physical characteristics, basal muscle protein fractional synthetic rate (FSR; n=215; stable isotope methodology) and mTORC1 signaling (n=125, Western blotting). FSR and mTORC1 signaling were measured at rest and after an overnight fast. mTORC1 and S6K1 phosphorylation were higher (P<0.05) in older subjects with no sex differences. However, there were no age or sex differences or interaction for muscle FSR (p>0.05). Body mass index, fat free mass, or body fat were not significant covariates and did not influence the results. We conclude that age and sex do not influence basal muscle protein synthesis. However, basal mTORC1 hyperphosphorylation in the elderly may contribute to insulin resistance and the age-related anabolic resistance of skeletal muscle protein metabolism to nutrition and exercise.
doi:10.1016/j.exger.2015.02.015
PMCID: PMC4397165  PMID: 25735236
Protein metabolism; aging; sarcopenia; stable isotopes; mTOR; gender
3.  EGF Signaling Comes of Age: Promotion of Healthy Aging in C. elegans 
Experimental gerontology  2010;46(2-3):129-134.
More than 400 genes have been noted to modulate C. elegans longevity. Recent studies testing the role of proposed secreted insulin binding proteins unexpectedly revealed a potent role for the EGF signaling pathway in promoting healthy aging and longevity in C. elegans. Activation of EGF receptor LET-23 is associated with increased mean and maximum lifespan, maintained pharyngeal pumping, extended locomotory function, and low lipofuscin and advanced glycation end product accumulation. Conversely, reducing the activity of the EGF pathway is associated with system-wide evidence of progeria. The EGF pathway appears to work in a manner largely independent of the insulin/IGF-like pathway, in that effects are additive with reduction of DAF-2/InsR activity and are not affected by DAF-16/FOXO transcription factor deficiency. Two novel regulators of EGF signaling, called HPA-1 and HPA-2 (for the high performance in old age locomotory phenotypes that their disruption confers), negatively regulate EGF action, possibly by binding and sequestering EGF. Interestingly, whereas HPA-1 appears to control aging of the animal overall, HPA-2 exerts an effect primarily on locomotory aging. As such, HPA-2 is an example of a protein with an effect on healthspan but not lifespan, a gene class that may have been missed in screens focused on longevity endpoint. To date, roles for EGF signaling in adult maintenance (particularly in non-dividing tissues) have not been addressed in other organisms—should EGF signaling exert a conserved impact on healthy aging, testing this hypothesis could hold implications for anti-aging therapies.
doi:10.1016/j.exger.2010.10.010
PMCID: PMC4841623  PMID: 21074601
4.  Effects of aging and levodopa on the laryngeal adductor reflex in rats 
Experimental gerontology  2012;47(12):900-907.
Dopaminergic neurotransmission plays an essential role in sensorimotor function, and declines with age. Previously, we found the laryngeal adductor reflex (LAR) was increased in excitation by a dopamine receptor antagonist. If this airway-protective reflex is similarly affected by aging, it will interfere with volitional control in older adults. The current study tested whether the LAR was affected by aging, and whether such deficits were reversed by levodopa administration in aging rats. We recorded thyroarytenoid (TA) muscle activity at rest and during elicitation of LAR responses by stimulation of the internal branch of the superior laryngeal nerve (iSLN) in 6-, 18- and 30-month-old rats under alpha-chloralose anesthesia. Using paired stimuli at different inter-stimulus intervals (ISIs), LAR central conditioning, resting muscle activity, and reflex latency and amplitudes were quantified. Numbers of dopaminergic neurons in the substantia nigra pars compacta (SNpc) were measured using tyrosine hydroxylase staining. We found: (1) increased resting TA muscle activity and LAR amplitude occurred with fewer dopaminergic neurons in the SNpc in 18- and 30-month-old rats; (2) decreases in LAR latency and increases in amplitude correlated with reduced numbers of dopaminergic neurons in the SNpc; (3) test responses were greater at 1000 ms ISI in 18-month-old rats compared with 6-month-old rats; and (4) levodopa administration further increased response latency but did not alter muscle activity, response amplitude, or central conditioning. In conclusion, increases in laryngeal muscle activity levels and re-flex amplitudes accompanied age reductions in dopaminergic neurons but were not reversed with levodopa administration.
doi:10.1016/j.exger.2012.07.008
PMCID: PMC4819337  PMID: 22824541
Aging; Laryngeal adductor reflex; Dopaminergic neurons; Levodopa; Rat
5.  Regrowth after skeletal muscle atrophy is impaired in aged rats, despite similar responses in signaling pathways 
Experimental gerontology  2015;64:17-32.
Skeletal muscle regrowth after atrophy is impaired in the aged and in this study we hypothesized that this can be explained by a blunted response of signaling pathways and cellular processes during reloading after hind limb suspension in muscles from old rats. Male Brown Norway Fisher 344 rats at 6 (young) and 32 (old) months of age were subjected to normal ambulatory conditions (amb), hind limb suspension for 14 days (HS), and HS followed by reloading through normal ambulation for 14 days (RE); soleus muscles were used for analysis of intracellular signaling pathways and cellular processes. Soleus muscle regrowth was blunted in old compared to young rats which coincided with a recovery of serum IGF-1 and IGFBP-3 levels in young but not old. However, the response to reloading for p-Akt, p-p70s6k and p-GSK3β protein abundance was similar between muscles from young and old rats, even though main effects for age indicate an increase in activation of this protein synthesis pathway in the aged. Similarly, MAFbx mRNA levels in soleus muscle from old rats recovered to the same extent as in the young, while Murf-1 was unchanged. mRNA abundance of autophagy markers Atg5 and Atg7 showed an identical response in muscle from old compared to young rats, but beclin did not. Autophagic flux was not changed at either age at the measured time point. Apoptosis was elevated in soleus muscle from old rats particularly with HS, but recovered in HSRE and these changes were not associated with differences in caspase-3, -8 or-9 activity in any group. Protein abundance of apoptosis repressor with caspase-recruitment domain (ARC), cytosolic EndoG, as well as cytosolic and nuclear apoptosis inducing factor (AIF) were lower in muscle from old rats, and there was no age-related difference in the response to atrophy or regrowth. Soleus muscles from old rats had a higher number of ED2 positive macrophages in all groups and these decreased with HS, but recovered in HSRE in the old, while no changes were observed in the young. Pro-inflammatory cytokines in serum did not show a differential response with age to different loading conditions. Results indicate that at the measured time point the impaired skeletal muscle regrowth after atrophy in aged animals is not associated with a general lack of responsiveness to changes in loading conditions.
doi:10.1016/j.exger.2015.02.007
PMCID: PMC4359098  PMID: 25681639
protein synthesis; hind limb suspension; protein degradation; autophagy; apoptosis; inflammation
6.  Effects of Low Dose FGF-2 and BMP-2 on Healing of Calvarial Defects in Old Mice 
Experimental gerontology  2015;64:62-69.
There is an age-associated reduction in the bone healing activity of bone morphogenetic protein -2 (BMP-2) that is currently addressed by administering higher doses of BMP-2 in elderly patients. The unwanted medical complications from high dose BMP-2 motivated this investigation to determine whether the addition of a low dose of fibroblast growth factor 2 (FGF-2) could enhance the ability of a lower dose of BMP-2 to heal calvarial bone defects in old mice (18-20 months old). FGF-2 (5 ng) and BMP-2 (2 μg) were administered by a controlled release two-phase biomaterial scaffold placed into the bone defect. FGF-2 released more rapidly and completely in vitro than BMP-2 (40% vs 2%). In vivo, both BMP-2 and FGF-2+BMP-2 groups formed more new bone in calvarial defects than scaffold alone (p <0.001) or FGF-2 only groups (p < 0.01). The overall total volume of new bone was not statistically increased by the addition of FGF-2 to BMP-2 as measured by microCT, but the pattern of bone deposition was different. In old mice, but not young, there was enhanced bony fill in the central bone defect area when the BMP-2 was supplemented with FGF-2. Histological analysis of the center of the defect revealed an increased bone volume (%BV/TV (p = 0.004)) from the addition of FGF-2. These studies suggest that combining a low dose of FGF-2 with a low dose of BMP-2 has the potential to increase bone healing in old mice relative to BMP-2 alone.
doi:10.1016/j.exger.2015.02.006
PMCID: PMC4388203  PMID: 25681640
7.  The effects of testosterone and insulin-like growth factor 1 on motor system form and function 
Experimental gerontology  2015;64:81-86.
In this perspective article, we review the effects of selected anabolic hormones on the motoric system and speculate on the role these hormones may have on influencing muscle and physical function via their impact on the nervous system. Both muscle strength and anabolic hormone levels decline around middle age into old age over a similar time period, and several animal and human studies indicate that exogenously increasing anabolic hormones (e.g., testosterone and insulin-like growth factor-1 (IGF-1)) in aged subjects is positively associated with improved muscle strength. While most studies in humans have focused on the effects of anabolic hormones on muscle growth, few have considered the impact these hormones have on the motoric system. However, data from animals demonstrate that administering either testosterone or IGF-1 to cells of the central and peripheral motor system can increase cell excitability, attenuate atrophic changes, and improve regenerative capacity of motor neurons. While these studies do not directly indicate that changes in anabolic hormones contribute to reduced human performance in the elderly (e.g., muscle weakness and physical limitations), they do suggest that additional research is warranted along these lines.
doi:10.1016/j.exger.2015.02.005
PMCID: PMC4748732  PMID: 25681641
Testosterone; Insulin-like growth factor 1; Aging; Muscle strength; Motor system
8.  Adipose – derived stromal vascular fraction cells isolated from old animals exhibit reduced capacity to support the formation of microvascular networks 
Experimental gerontology  2015;63:18-26.
Adipose-derived regenerative and stem cells, defined collectively as the stromal vascular fraction (SVF), support the formation of neovascular networks at the site of implantation. The effect of advancing age on SVF cell population effectiveness toward stimulated neovascularization was evaluated.
Methods
SVF was enzymatically isolated from adipose of young (ySVF, 4 mo) or old (oSVF, 24 mo) Fisher-344 rats, combined with type I collagen and polymerized. Encapsulated SVF was implanted subcutaneously into young Rag1 mice for two or four weeks. Angiogenic function of age-dependent SVF was also extensively evaluated in vitro using standard assays.
Results
In vitro studies indicated no difference in angiogenic function between ySVF and oSVF (viability, proliferation, migration, and tube-formation). At two weeks post-implantation, there was no age-related difference in percent apoptosis in explanted constructs. By four weeks post-implantation, oSVF implants displayed 36% less total vessels/mm2, 43% less perfused vessels/mm2, and exhibited greater percent apoptosis compared to ySVF (n≥12). Blocking Thrombospondin-1 (Thbs-1), a protein found to be highly expressed in oSVF but not ySVF, increased the percent of perfused vascular volume and vessel diameters in oSVF constructs after two weeks compared to oSVF implants treated with control antibody.
Conclusions
Advancing donor age reduces the potential of adipose-derived SVF to derive a mature microcirculation, but does not hinder initial angiogenesis. However, modulation of Thbs-1 may improve this outcome. This data suggests that greater pruning, dysfunctional structural adaptation and/or poor maturation with initiation of blood flow may occur in oSVF.
doi:10.1016/j.exger.2015.01.044
PMCID: PMC4346434  PMID: 25617825
angiogenesis; aging; ischemia; apoptosis; thrombospondin-1; vascular remodeling; inosculation; maturation
9.  Higher Levels of Adiponectin in Vascular Endothelial Cells are Associated with Greater Brachial Artery Flow-mediated Dilation in Older Adults 
Adiponectin, an adipocyte-derived protein, exerts anti-atherosclerotic effects on the vascular endothelium. Recently adiponectin protein has been reported in murine vascular endothelial cells, however, whether adiponectin is present in human vascular endothelial cells remains unexplored. We sought to examine 1) adiponectin protein in vascular endothelial cells collected from older adults free of overt cardiovascular disease; 2) the relation between endothelial cell adiponectin and in vivo vascular endothelial function; and 3) the relation between endothelial cell adiponectin, circulating (plasma) adiponectin and related factors. We measured vascular endothelial function (brachial artery flow-mediated dilation using ultrasonography), vascular endothelial cell adiponectin (biopsy coupled with quantitative immunofluorescence) and circulating adiponectin (Mercodia, ELISA) in older, sedentary, non-smoking, men and women (55 – 79 years). We found that higher endothelial cell adiponectin was related with greater flow-mediated dilation (r=0.43, P<0.05) and greater flow-mediated dilation normalized for shear stress (r=0.56, P<0.01), but was not related with vascular smooth muscle responsiveness to nitric oxide (r=0.04, P=0.9). Vascular endothelial cell adiponectin was not related with circulating adiponectin (r=−0.14, P=0.6). Endothelial cell and circulating adiponectin were differentially associated with adiposity, metabolic and other factors, but both were inversely associated with renal function (r=0.44 to 0.62, P ≤ 0.04). In conclusion, higher endothelial cell adiponectin levels are associated with higher vascular endothelial function, independent of circulating adiponectin levels in older adults.
doi:10.1016/j.exger.2014.12.018
PMCID: PMC4346491  PMID: 25572013
vascular endothelial function; ultrasound; aging; renal function
10.  Effect of in vivo loading on bone composition varies with animal age 
Experimental gerontology  2015;63:48-58.
Loading can increase bone mass and size and this response is reduced with aging. It is unclear, however how loading affects bone mineral and matrix properties. Fourier Transform Infrared Imaging and high resolution synchrotron scanning small angle X-ray scattering were used to study how bone’s microscale and nanoscale compositional properties were altered in the tibial midshaft of young, adult, and elderly female C57Bl/6J mice after two weeks of controlled in vivo compressive loading in comparison to physiological loading. The effect of controlled loading on bone composition varied with animal age, since it predominantly influenced the bone composition of elderly mice. Interestingly, controlled loading led to enhanced collagen maturity in elderly mice. In addition, although the rate of bone formation was increased by controlled loading based on histomorphometry, the newly formed tissue had similar material quality to new bone tissue formed during physiological loading. Similar to previous studies, our data showed that bone composition was animal and tissue age dependent during physiological loading. The findings that the new tissue formed in response to controlled loading and physiological loading had similar bone composition and that controlled loading enhanced bone composition in elderly mice further supports the use of physical activity as a noninvasive treatment to enhance bone quality as well as maintain bone mass in individuals suffering from age-related bone loss.
doi:10.1016/j.exger.2015.01.048
PMCID: PMC4352172  PMID: 25639943
Bone adaptation; Tibial Compression; Aging; Bone quality; synchrotron sSAXS; FTIRI
11.  Improved Knee Extensor Strength with Resistance Training Associates with Muscle Specific miRNAs in Older Adults 
Experimental gerontology  2015;62:7-13.
Regular exercise, particularly resistance training (RT), is the only therapy known to consistently improve muscle strength and quality (force per unit of mass) in older persons, but there is considerable variability in responsiveness to training. Identifying sensitive diagnostic biomarkers of responsiveness to RT may inform the design of a more efficient exercise regimen to improve muscle strength in older adults. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression. We quantified six muscle specific miRNAs (miR-1, -133a, -133b, -206, -208b and -499) in both muscle tissue and blood plasma, and their relationship with knee extensor strength in seven older (age = 70.5 ± 2.5 years) adults before and after 5 months of RT. MiRNAs differentially responded to RT; muscle miR-133b decreased, while all plasma miRNAs tended to increase. Percent changes in knee extensor strength with RT showed strong positive correlations with percent changes in muscle miR-133a, -133b, -206 and with percent changes in plasma and plasma/muscle miR-499 ratio. Baseline level of plasma or plasma/muscle miR-499 ratio further predicts muscle response to RT, while changes in muscle miR-133a, -133b, -206 may correlate with muscle TNNT1gene alternative splicing in response to RT. Our results indicate that RT alters muscle specific miRNAs in muscle and plasma, and that these changes account for some of the variation in strength responses to RT in older adults.
doi:10.1016/j.exger.2014.12.014
PMCID: PMC4314447  PMID: 25560803
microRNA; skeletal muscle; aging; resistance training
12.  Skeletal muscle mitochondrial DNA deletions are not increased in CuZn-superoxide dismutase deficient mice 
Experimental gerontology  2014;0:15-19.
Mitochondrial DNA (mtDNA) deletion mutations are proposed contributors to aging-related muscle fiber loss and atrophy, but evidence of a causal role for these mutations in muscle aging is lacking. Elucidating the etiology of in vivo mtDNA deletion mutations will help to better understand and test the possible roles of these mutations in aging. The implication of mtDNA mutations in aging is based on the susceptibility of mtDNA to oxidative damage by reactive oxygen species (ROS) due to residing in mitochondria, the primary source of endogenous ROS. Cells possess many pathways for neutralizing ROSs, including a variety of superoxide dismutases (SOD). Mice lacking CuZnSOD (Sod1−/− mice) have high levels of oxidative damage in many tissues including skeletal muscle and are a model for testing the role of oxidative damage in the formation of mtDNA deletion mutations. The increased DNA oxidative damage in Sod1−/− mice is associated with increased mtDNA deletion mutations in a variety of tissues, but skeletal muscle mtDNA mutations have not been reported. We hypothesized that a life-long absence of mouse muscle CuZnSOD would increase mtDNA deletion mutation frequency and focal accumulation of these mutations in aging mouse skeletal muscle. Focal accumulations of mtDNA deletion mutations were detected by histochemical staining for cytochrome c oxidase (cytOX) activity and detection of cytOX-negative fibers, a marker of focal mtDNA mutation accumulation, within approximately 20,000 muscle fibers through a distance of 1000 microns. Total DNA was extracted from intervening unstained sections and mtDNA deletion mutation frequency was measured by droplet digital PCR. Droplet digital PCR quantification of mtDNA deletion mutations showed no difference in mtDNA deletion mutation frequency in Sod1−/− mouse muscle compared to wild-type mice and we observed no significant increase in the number of cytOX-negative muscle fibers, in Sod1−/− mice compared to wild-type mice. These data demonstrate that not all changes in cellular oxidative stress are linked to mtDNA deletion mutations and shift the focus to other etiologies for these mutations that need to be clarified to better test their possible role in aging.
doi:10.1016/j.exger.2014.11.012
PMCID: PMC4289650  PMID: 25449857
Mitochondria; mutation; oxidative damage
13.  Attention enhancing effects of methylphenidate are age-dependent 
The psychostimulant methylphenidate (MPH, Ritalin®) is used to treat a variety of cognitive disorders. MPH is also popular among healthy individuals, including the elderly, for its ability to focus attention and improve concentration, but these effects have not been shown to be comparable between aged and adult subjects. Thus, we tested whether MPH would improve performance in sustained attention in both adult and aged rats. In addition, we tested the impact of visual distraction on performance in this task and the ability of MPH to mitigate the effects of distraction. Adult (6–12 months) and aged (18–22 months) male Sprague-Dawley rats were given oral MPH, and their cognitive and motor abilities were tested. Results suggest that while MPH improves task performance in adults; there is no improvement in the aged animals. These outcomes suggest that use of MPH for cognitive enhancement in elderly individuals may be ineffective.
doi:10.1016/j.exger.2014.11.006
PMCID: PMC4289654  PMID: 25449855
aging; attention; methylphenidate; monoamine; psychostimulant; rat
14.  Ethanol-induced differential gene expression and acetyl-CoA metabolism in a longevity model of the nematode Caenorhabditis elegans 
Experimental gerontology  2014;0:20-30.
Previous studies have shown that exposing adults of the soil-dwelling nematode Caenorhabditis elegans to concentrations of ethanol in the range of 100 – 400 mM results in slowed locomotion, decreased fertility, and reduced longevity. On the contrary, lower concentrations of ethanol (0.86 – 68 mM) have been shown to cause a two- to three-fold increase in the life span of animals in the stress resistant L1 larval stage in the absence of a food source. However, little is known about how gene and protein expression is altered by low concentrations of ethanol and the mechanism for the increased longevity. Therefore, we used biochemical assays and next generation mRNA sequencing to identify genes and biological pathways altered by ethanol. RNA-seq analysis of L1 larvae incubated in the presence of 17 mM ethanol resulted in the significant differential expression of 649 genes, 274 of which were downregulated and 375 were upregulated. Many of the genes significantly altered were associated with the conversion of ethanol and triglycerides to acetyl-CoA and glucose, suggesting that ethanol is serving as an energy source in the increased longevity of the L1 larvae as well as a signal for fat utilization. We also asked if L1 larvae could sense ethanol and respond by directed movement. Although we found that L1 larvae can chemotax to benzaldehyde, we observed little or no chemotaxis to ethanol. Understanding how low concentrations of ethanol increase the lifespan of L1 larvae may provide insight into not only the longevity pathways in C. elegans, but also in those of higher organisms.
doi:10.1016/j.exger.2014.11.010
PMCID: PMC4289658  PMID: 25449858
aging; ethanol; fatty acid metabolism; Caenorhabditis elegans; L1 larvae
15.  Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging-related susceptibility to lung fibrosis 
Experimental gerontology  2014;61:62-75.
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder with unknown cause and no effective treatment. The incidence of and mortality from IPF increase with age, suggesting that advanced age is a major risk factor for IPF. The mechanism underlying the increased susceptibility of the elderly to IPF, however, is unknown. In this study, we show for the first time that the protein level of plasminogen activator inhibitor 1 (PAI-1), a protease inhibitor which plays an essential role in the control of fibrinolysis, was significantly increased with age in mouse lung homogenate and lung fibroblasts. Upon bleomycin challenge, old mice experienced augmented PAI-1 induction and lung fibrosis as compared to young mice. Most interestingly, we show that fewer (myo)fibroblasts underwent apoptosis and more (myo)fibroblasts with increased level of PAI-1 accumulated in the lung of old than in young mice after bleomycin challenge. In vitro studies further demonstrate that fibroblasts isolated from lungs of old mice were resistant to H2O2 and tumor necrosis factor alpha-induced apoptosis and had augmented fibrotic responses to TGF-β1, compared to fibroblasts isolated from young mice. Inhibition of PAI-1 activity with a PAI-1 inhibitor, on the other hand, eliminated the aging-related apoptosis resistance and TGF-β1 sensitivity in isolated fibroblasts. Moreover, we show that knocking down PAI-1 in human lung fibroblasts with PAI-1 siRNA significantly increased their sensitivity to apoptosis and inhibited their responses to TGF-β1. Together, the results suggest that increased PAI-1 expression may underlie the aging-related sensitivity to lung fibrosis in part by protecting fibroblasts from apoptosis.
doi:10.1016/j.exger.2014.11.018
PMCID: PMC4384687  PMID: 25451236
Aging; Plasminogen activator inhibitor 1; Idiopathic Pulmonary Fibrosis; Fibroblast apoptosis
16.  Higher Baseline Serum Uric Acid is Associated with Poorer Cognition but Not Rates of Cognitive Decline in Women 
Experimental gerontology  2014;60:136-139.
Serum uric acid is a powerful antioxidant that may have neuroprotective properties. While some studies have found that greater serum uric acid is associated with better cognition in older adults, it is also associated with numerous vascular risk factors that increase risk for dementia. Women may also be particularly vulnerable to the vascular effects of elevated uric acid. We previously found that mildly elevated serum uric acid is a biomarker of cognitive dysfunction in older adults, and that this likely is mediated by cerebral ischemic burden. Here we examine both cross-sectional and longitudinal associations between serum uric acid, and declines in cognition and functioning in 423 cognitively healthy community-dwelling older women in the Women’s Health and Aging Study (WHAS II). We hypothesized that higher serum uric acid would be associated with poorer concurrent functioning and greater declines over 9 years. In linear regression analyses, higher baseline serum uric acid was associated with poorer working memory, with a trend towards slower manual speed and dexterity before and after adjusting for baseline serum uric acid, demographic and health/cardiovascular variables. However, there were no associations for global cognitive functioning, learning/memory, sequencing, verbal fluency, or visuoconstruction. Mixed effects models also revealed no association with subsequent cognitive declines. Future research should examine changes in serum uric acid at earlier periods in the lifespan and their relationships with later cognitive declines.
doi:10.1016/j.exger.2014.10.013
PMCID: PMC4272197  PMID: 25446978
Serum uric acid; cognitive function; cognitive aging; aging; cerebrovascular disease; neuropsychology
17.  Extension of Drosophila lifespan by cinnamon through a sex-specific dependence on the insulin receptor substrate chico 
Experimental gerontology  2014;60:220-230.
Cinnamon is a spice commonly used worldwide to flavor desserts, fruits, cereals, breads, and meats. Numerous health benefits have been attributed to its consumption, including the recent suggestion that it may decrease blood glucose levels in people with diabetes. Insulin signaling is an integral pathway regulating the lifespan of laboratory organisms, such as worms, flies, and mice. We posited that if cinnamon truly improved the clinical signs of diabetes in people that it would also act on insulin signaling in laboratory organisms and increase lifespan. We found that cinnamon did extend lifespan in the fruit fly, Drosophila melanogaster. However, it had no effect on the expression levels of the 3 aging-related Drosophila insulin-like peptides nor did it alter sugar, fat, or soluble protein levels, as would be predicted. In addition, cinnamon exhibited no protective effects in males against oxidative challenges. However, in females it did confer a protective effect against paraquat, but sensitized them to iron. Cinnamon provided no protective effect against desiccation and starvation in females, but sensitized males to both. Interestingly, cinnamon protected both sexes against cold, sensitized both to heat, and elevated HSP70 expression levels. We also found that cinnamon required the insulin receptor substrate to extend lifespan in males, but not females. We conclude that cinnamon does not extend lifespan by improving stress tolerance in general, though it does act, at least in part, through insulin signaling.
doi:10.1016/j.exger.2014.09.019
PMCID: PMC4309393  PMID: 25456850
cinnamon; botanical extract; insulin signaling; lifespan; aging; Drosophila
18.  Asynchrony of senescence among phenotypic traits in a wild mammal population 
Experimental Gerontology  2015;71:56-68.
The degree to which changes in lifespan are coupled to changes in senescence in different physiological systems and phenotypic traits is a central question in biogerontology. It is underpinned by deeper biological questions about whether or not senescence is a synchronised process, or whether levels of synchrony depend on species or environmental context. Understanding how natural selection shapes patterns of synchrony in senescence across physiological systems and phenotypic traits demands the longitudinal study of many phenotypes under natural conditions. Here, we examine the patterns of age-related variation in late adulthood in a wild population of Soay sheep (Ovis aries) that have been the subject of individual-based monitoring for thirty years. We examined twenty different phenotypic traits in both males and females, encompassing vital rates (survival and fecundity), maternal reproductive performance (offspring birth weight, birth date and survival), male rutting behaviour, home range measures, parasite burdens, and body mass. We initially quantified age-related variation in each trait having controlled for annual variation in the environment, among-individual variation and selective disappearance effects. We then standardised our age-specific trait means and tested whether age trajectories could be meaningfully grouped according to sex or the type of trait. Whilst most traits showed age-related declines in later life, we found striking levels of asynchrony both within and between the sexes. Of particular note, female fecundity and reproductive performance declined with age, but male annual reproductive success did not. We also discovered that whilst home range size and quality decline with age in females, home range size increases with age in males. Our findings highlight the complexity of phenotypic ageing under natural conditions and, along with emerging data from other wild populations and laboratory models, suggest that the long-standing hypothesis within evolutionary biology that fitness-related traits should senesce in a synchronous manner is seriously flawed.
Highlights
•Striking asynchrony in senescence patterns across 20 phenotypic traits•Unexpected differences in reproductive senescence between sexes•First evidence for senescence in ranging behaviour in wild mammal•Challenges evolutionary hypothesis of synchrony of senescence
doi:10.1016/j.exger.2015.08.003
PMCID: PMC4661475  PMID: 26277618
Ageing; Home range; Natural selection; Ovis aries; Sexual selection; Soay sheep
19.  Do Hassles Mediate between Life Events and Mortality in Older Men? Longitudinal Findings from the VA Normative Aging Study 
Experimental gerontology  2014;59:74-80.
We investigated whether hassles mediated the effect of life events on mortality in a sample of 1,293 men (Mage = 65.58, SD = 7.01), participants in the VA Normative Aging Study. We utilized measures of stressful life event (SLE) and hassles from 1989 to 2004, and men were followed for mortality until 2010. For life events and hassles, previous research identified three and four patterns of change over time, respectively, generally indicating low, moderate, and high trajectories, with one moderate, non-linear pattern for hassles (shallow U curve). Controlling for demographics and health behaviors, we found that those with moderate SLE trajectories (38%) more likely to die than those with low SLE trajectories, HR = 1.42, 95% CI [1.16, 3.45]. Including the hassles classes showed that those with the moderate non-linear hassles trajectory were 63% more likely to die than those with low hassles trajectory, HR = 1.63, 95% CI [1.19, 2.23],, while those with consistently high hassles trajectory were over 3 times more likely to die, HR = 3.30, 95% CI [1.58, 6.89]. However, the HR for moderate SLE trajectory decreased only slightly to 1.38, 95% CI [1.13, 1.68], suggesting that the two types of stress have largely independent effects on mortality. Research is needed to determine the physiological and behavioral pathways through which SLE and hassles differentially affect mortality.
doi:10.1016/j.exger.2014.06.019
PMCID: PMC4253863  PMID: 24995936
Stressful life events; hassles; mortality; trajectories; aging
20.  A theoretical model of the evolution of actuarial senescence under environmental stress 
Experimental Gerontology  2015;71:80-88.
Free-living organisms are exposed to a wide range of stressors, all of which can disrupt components of stress-related and detoxification physiology. The subsequent accumulation of somatic damage is widely believed to play a major role in the evolution of senescence. Organisms have evolved sophisticated physiological regulatory mechanisms to maintain homeostasis in response to environmental perturbations, but these systems are likely to be constrained in their ability to optimise robustness to multiple stressors due to functional correlations among related traits. While evolutionary change can accelerate due to human ecological impacts, it remains to be understood how exposure to multiple environmental stressors could affect senescence rates and subsequently population dynamics and fitness. We used a theoretical evolutionary framework to quantify the potential consequences for the evolution of actuarial senescence in response to exposure to simultaneous physiological stressors – one versus multiple and additive versus synergistic – in a hypothetical population of avian “urban adapters”. In a model in which multiple stressors have additive effects on physiology, species may retain greater capacity to recover, or respond adaptively, to environmental challenges. However, in the presence of high synergy, physiological dysregulation suddenly occurs, leading to a rapid increase in age-dependent mortality and subsequent population collapse. Our results suggest that, if the synergistic model is correct, population crashes in environmentally-stressed species could happen quickly and with little warning, as physiological thresholds of stress resistance are overcome.
Highlights
•Environmental stressors challenge physiological systems linked to senescence.•Various scenarios of stress exposure were simulated on a hypothetical “urban adapter”.•Actuarial senescence increased rapidly in synergistic models of stress.•Wild populations may be at greater risk of collapse than demography alone suggests.•An explicit model of how stressors affect physiology underlying ageing is required.
doi:10.1016/j.exger.2015.08.009
PMCID: PMC4710637  PMID: 26335620
Ageing; Senescence; Urban; Birds; Environmental stress; Evolutionary model
21.  Accelerating Aging Research: How Can We Measure the Rate of Biologic Aging? 
Experimental gerontology  2015;64:78-80.
Claims of accelerated or premature aging are frequently made. However, the lack of standard criteria for measuring speed of aging makes such claims highly questionable. Because of fundamental gaps in our current understanding of the biological mechanisms of aging, the development of specific phenotypes that are due to aging is difficult and such phenotypes can only be derived by observational data. However, a clinical phenotype of aging exists that is experienced by all living individuals and is pervasive across multiple physiologic systems. Characterizing this phenotype can serve as a basis for measuring the speed of aging, and can facilitate a better understanding of the aging process and its interaction with chronic diseases.
doi:10.1016/j.exger.2015.02.009
PMCID: PMC4612579  PMID: 25683017
accelerated aging; aging phenotype; gerosciences; age-associated diseases
22.  Mitochondrial Quality Control and Age-Associated Arterial Stiffening 
Experimental gerontology  2014;0:78-82.
Stiffening of large elastic arteries with age increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. We investigated the role of mitochondrial quality control (QC, i.e., mitophagy and biogenesis) in arterial stiffening with aging. In C57BL6 mice, aging was associated with impaired aortic expression of mitochondrial QC mediators, greater activation of the mitochondrial redox/stress sensor p66shc, elevated superoxide production and increased arterial stiffness—as indicated by ~20% higher aortic pulse wave velocity (aPWV). In old mice, supplementation with trehalose, a nutraceutical reported to enhance mitophagy, normalized mitochondrial QC markers, p66shc activation and superoxide production, and reduced aPWV and aortic collagen I (a structural protein that confers stiffness). In vitro experiments indicated that mitochondrial QC processes were enhanced in aorta from old trehalose-treated mice, and in aortic rings studied ex vivo, both aging and treatment with the mitochondrial stressor rotenone were associated with increases in p66shc activation and intrinsic mechanical stiffness, whereas co-incubation with trehalose prevented these effects. Taken together, these findings suggest that mitochondrial stress/dysfunction as a result of impaired mitochondrial QC contributes to large elastic artery stiffening with age. Enhancing mitochondrial QC with agents such as trehalose may be a novel strategy for reducing age-associated arterial stiffness and CVD.
doi:10.1016/j.exger.2014.07.008
PMCID: PMC4252265  PMID: 25034910
Collagen; mitophagy; mitochondrial biogenesis
23.  GROWTH HORMONE ABOLISHES BENEFICIAL EFFECTS OF CALORIE RESTRICTION IN LONG-LIVED AMES DWARF MICE 
Experimental gerontology  2014;0:219-229.
Disruption of the growth hormone (GH) axis promotes longevity and delays aging. In contrast, GH over-expression may lead to accelerated aging and shorter life. Calorie restriction (CR) improves insulin sensitivity and may extend lifespan. Long-lived Ames dwarf (df/df) mice have additional extension of longevity when subjected to 30% CR. The aim of the study was to assess effects of CR or GH replacement therapy separately and as a combined (CR+GH) treatment in GH-deficient df/df and normal mice, on selected metabolic parameters (e.g., insulin, glucose, cholesterol), insulin signaling components (e.g., insulin receptor [IR] β-subunit, phosphorylated form of IR [IR pY1158], protein kinase C ζ/λ [p-PKCζ/λ] and mTOR [p-mTOR]), transcription factor p-CREB, and components of the mitogen-activated protein kinases (MAPK) signaling (p-ERK1/2, p-p38), responsible for cell proliferation, differentiation and survival. CR decreased plasma levels of insulin, glucose, cholesterol and leptin, and increased hepatic IR β-subunit and IR pY1158 levels as well as IR, IRS-1 and GLUT-2 gene expression compared to ad libitum feeding, showing a significant beneficial diet intervention effect. Moreover, hepatic protein levels of p-PKCζ/λ, p-mTOR and p-p38 decreased, and p-CREB increased in CR mice. On the contrary, GH increased levels of glucose, cholesterol and leptin in plasma, and p-mTOR or p-p38 in livers, and decreased plasma adiponectin and hepatic IR β-subunit compared to saline treatment. There were no GH effects on adiponectin in N mice. Moreover, GH replacement therapy did not affect IR, IRS-1 and GLUT-2 gene expression. GH treatment abolishes the beneficial effects of CR; it may suggest an important role of GH–IGF1 axis in mediating the CR action. Suppressed somatotrophic signaling seems to predominate over GH replacement therapy in the context of the examined parameters and signaling pathways.
doi:10.1016/j.exger.2014.08.010
PMCID: PMC4252511  PMID: 25152388
Growth hormone; calorie restriction; Ames dwarf mice; metabolism; transcription factors; MAPK signaling
24.  Losartan Improves Measures of Activity, Inflammation, and Oxidative Stress in Older Mice 
Experimental gerontology  2014;0:174-178.
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 gender-matched 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, 2) further identify mechanisms that influence this improvement, and 3) provide additional rationale for translating these findings into older adults.
doi:10.1016/j.exger.2014.07.017
PMCID: PMC4252828  PMID: 25077714
frailty; sarcopenia; oxidative stress; renin-angiotensin system; angiotensin II receptor blocker; inflammation
25.  Coenzyme Q10 and α-tocopherol reversed age-associated functional impairments in mice 
Experimental gerontology  2014;0:208-218.
The purpose of this study was to determine if intake of the antioxidants coenzyme Q10 (CoQ10) or α-tocopherol (Toc), either alone or in combination, could ameliorate cognitive and psychomotor impairments of aged mice, as well as reduce oxidative burden in tissues. For a period of 10 weeks, male C57BL/6J mice (3 or 18 months) were fed either a control diet, or one of three diets supplemented with Toc, CoQ10 or their combination, and were tested for cognitive and psychomotor function. Old mice on the Toc or Toc/CoQ10 diets showed improved coordinated running performance. Mice on the diet containing Toc/CoQ10 demonstrated improved performance in the discriminated avoidance task. CoQ10 and Toc alone also resulted in improved performance, albeit to a lesser degree. Protein damage was decreased especially when the mice received Toc + CoQ10 combination. Overall, these results suggest that, Toc and CoQ supplementation can ameliorate age-related impairment and reduce protein oxidation. Moreover, concurrent supplementation of CoQ10 and Toc may be more effective than either antioxidant alone.
doi:10.1016/j.exger.2014.08.007
PMCID: PMC4252864  PMID: 25149567
Behavior; antioxidants and mitochondria

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