Animal Models Of Aging Research Articles

Hormesis as a Pro-Healthy Aging Intervention in Human Beings?

Hormesis is a phenomenon in which adaptive responses to low doses of otherwise harmful factors (also called mild stressors) make cells and organisms more robust. Aging is a complex and poorly understood process. This review explores the positive effects of hormesis on aging in animal models and human cell cultures, and discusses whether it might apply to humans. As an example, repeated mild heat stress confers anti-aging benefits to normal human cells in culture. Calorie restriction and xenohormetic compounds such as resveratrol, in large part via activation of sirtuins, decrease risk of common age-related conditions, such as cancer, cardiovascular disease, type 2 diabetes, and neurological diseases, so lengthening lifespan. Mild stressors and xenohormetic dietary components have diverse molecular targets and affect many pathways. Despite experimental advances in aging research, findings in humans are still quite limited. Moderate-intensity exercise, weight management and healthy diet ameliorate diseases of aging to increase lifespan and this could involve hormesis.

Effect of carvedilol on behavioral, mitochondrial dysfunction, and oxidative damage against d-galactose induced senescence in mice

Growing evidence indicates that oxidative stress and mitochondrial dysfunction plays a critical role in brain aging. Chronic injection of D-galactose can cause gradual deterioration in learning and memory capacity and serve as an animal model of aging. Recently, potential therapeutic effect of carvedilol (CAR) has been reported by virtue of which its antioxidant and mitochondrial permeability transitional property. The present study has been designed to explore the CAR effect against D-galactose-induced behavioral, biochemical, and mitochondrial dysfunction in mice. Systemic administration of D-galactose for 6 weeks significantly impaired behavioral (learning and memory and locomotor activity), biochemical parameters (raised lipid peroxidation, nitrite concentration, depletion of reduced glutathione, and catalase activity), and mitochondrial enzymes (decreased complex I, II and III enzymes levels) as compared to sham group. CAR (2.5 and 5 mg/kg) treatment significantly improved behavioral abnormalities and biochemical and cellular alterations as compared to control. Chronic administration of D-galactose for a period of 6 week results into a significant increase of acetylcholine esterase enzyme level. CAR (2.5 and 5 mg/kg) treatment significantly attenuated the elevated level of acetylcholine esterase of mice. In conclusion, present studies highlight the protective effects of CAR against D-galactose-induced behavioral, biochemical, and mitochondrial dysfunction in mice. The study further provides a hope that CAR could be used in the management of cognitive dysfunction and related symptoms during aging.

Mitochondrial abnormalities drive cell death in Wolfram syndrome 2

Mitochondrial abnormalities drive cell death in Wolfram syndrome 2

Differential impairment of spatial and nonspatial cognition in a mouse model of brain aging

Aims Chronic exposure to d-galactose ( D-Gal), which causes acceleration in aging and simulated symptoms of natural senescence, has been used as a reliable animal model of aging. However, the different influences of D-Gal on spatial and nonspatial cognition are as yet unclear. Main methods In the present study, the object recognition test (ORT), object location test (OLT) and Y-maze test were carried out to assess the cognitive performance of mice after 8 weeks of chronic D-Gal exposure. The expression of oxidative-stress biomarkers in the prefrontal cortex (PFC) and caspase-3 in the hippocampus (HIP) were also determined. Key findings The results of the behavioral tests indicated that after chronic D-Gal exposure, the spatial memory of mice was seriously impaired, whereas nonspatial cognition remained intact. D-Gal exposure also induced more significant changes in malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activities in the HIP than in the PFC. Furthermore, chronic D-Gal exposure triggered more substantial caspase-3 overexpression in the HIP than in the PFC. Significance Together, these findings suggest the impairment of spatial, but not nonspatial, cognitive ability after chronic D-Gal exposure. The differential nature of this impairment might be due to the more substantial reduction of antioxidant enzyme activities and more severe neuronal apoptosis mediated by caspase-3 in the HIP. The present results also indicate that the HIP and HIP-dependent spatial cognition might be more susceptible to oxidative stress during senescence or other pathological processes.

Animal Models of Human Cognitive Aging

European Journal of NeurologyVolume 16, Issue 5 p. e108-e108 Animal Models of Human Cognitive Aging K. A. Jellinger, K. A. Jellinger Vienna, AustriaSearch for more papers by this author K. A. Jellinger, K. A. Jellinger Vienna, AustriaSearch for more papers by this author First published: 15 April 2009 https://doi.org/10.1111/j.1468-1331.2009.02593.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume16, Issue5May 2009Pages e108-e108 RelatedInformation

The In Vivo Human Patellar Tendon Mechanical And Collagen-cross-link Properties In Old And Young Men

Aging affects muscle mass and strength, which affects ADL performance, but it remains unknown if the tendon properties also deteriorate with aging. Cross-linking (x-link) of collagen molecules provides structural integrity to the fibrils in tendons, and it is known to change with age in animal models, but has never been examined in humans. PURPOSE: To examine the mechanical properties of the patellar tendon, in vivo, and x-link properties in elderly (OM) and young males (YM). METHODS: Seven OM (67±1yrs, 86±4 kg) and 11 YM (27±1yrs, 81±2 kg) with the same activity level (YM 5±2 hrs/wk, OM 6±1 hrs/wk) were included. MRI was used to assess the tendon structural properties.Patellar tendon mechanical properties were assessed using simultaneous force and ultrasonography samplings. Tendon biopsies were obtained and analyzed for x-link content: Collagen concentration (Coll), Hydroxylysyl-pyridinoline (HP), Lysyl-pyrodinoline (LP), Pentosidine (Pent). Results are reported as Mean±SEM. Collagen and Crosslinks propertiesTABLERESULTS: Tendon structural properties did not differ between OM and YM. Similarly, the tendon mechanical properties did not differ between OM and YM. Significantly different from YM. p<0.05. **p<0.01 CONCLUSION: These data show that the structural and mechanical properties of the human patellar tendon, in vivo, do not differ in OM and YM. At the same time, these are the first data on humans that show an age-related difference in tendon x-link properties to our knowledge. OM displayed lower collagen content, but greater pentosidine x-links compared to YM. This age related increase in pentosidine x-link may serve to maintain the mechanical properties with aging.

Immune and behavioral consequences of microglial reactivity in the aged brain

Bidirectional communication between the immune system and the brain is essential for mounting the appropriate immunological, physiological, and behavioral responses to immune activation. Aging, however, may impair this important bi-directional interaction. In support of this notion, peripheral infection in the elderly is associated with an increased frequency of behavioral and cognitive complications. Recent findings in animal models of aging and neurodegenerative disease indicate that microglia, innate immune cells of the brain, become primed or reactive. Understanding age- and disease-associated alterations in microglia is important because glia (microglia and astrocytes) play an integral role in propagating inflammatory signals that are initiated in the periphery. In this capacity, brain glia produce inflammatory cytokines that target neuronal substrates and elicit a sickness-behavior syndrome that is normally beneficial to the host organism. Increased reactivity of microglia sets the stage for an exaggerated neuroinflammatory cytokine response following activation of the peripheral innate immune system, which may underlie subsequent long-lasting behavioral and cognitive deficits. In support of this premise, recent findings indicate that stimulation of the peripheral immune system in aged rodents causes exaggerated neuroinflammation that is paralleled by cognitive impairment, prolonged sickness, and depressive-like complications. Therefore, the purpose of this review is to discuss the new evidence that age-associated priming of microglia could play a pathophysiological role in exaggerated behavioral and cognitive sequelae to peripheral infection.

Call for Papers: Aging Versus Disease

Along-lasting and extensive literature has conceptualized the aging process as a universal and unavoidable process of physiological decline that is associated with increased global vulnerability to diseases and death. On the contrary, diseases occur in some individuals and not in others, are connected with specifi c exogenous risk factors and pathophysiological mechanisms, and may not increase the risk for death. These characteristics make diseases preventable ( 1 ). As a consequence of this view, efforts to understand aging have emphasized the need to distinguish aging from disease. Indeed, the need to study aging separate from diseases was a fundamental premise of the fi rst large-scale study of aging, the Baltimore Longitudinal Study on Aging ( 2 ), which required all participants to undergo a careful physical examination to exclude diseases as possible causes of the observed age-related changes. Beyond theoretical models, chronic diseases accumulate with aging, and together, aging and diseases show mutual interactions in causing deterioration in health, physical and cognitive function, and premature death. Thus, it remains unclear as to whether we can truly distinguish the secondary effects of disease from those of aging per se. In animal models of aging, researchers have begun to characterize aging processes by manipulating diet and genes to change life span ( 3 ), although the effect of modifying these genes on disease susceptibility has not been fully explored. Intermediate phenotypes to longevity have also been examined using measures of physical function. Motility in worms ( 4 ) and gait speed in humans ( 5 ) are perhaps the strongest predictors of mortality even in individuals who are genetically identical. Thus, mobility can be considered to be a proxy phenotype for aging, a sort of universal parameter that can be used to relate the rate of aging across multiple species. Although the pathology of worms has not been studied in depth, it is unlikely that worms suffer from the extreme heterogeneous patterns of disease that contribute to the loss of mobility in humans. Hence, understanding what aspects of mobility loss in humans are due to universal aging processes independent of disease represents a true challenge.

The Anti-Inflammatory Effect of Kaempferol in Aged Kidney Tissues: The Involvement of Nuclear Factor-κB via Nuclear Factor-Inducing Kinase/IκB Kinase and Mitogen-Activated Protein Kinase Pathways

Kaempferol, one of the phytoestrogens, is found in berries and Brassica and Allium species and is known to have antioxidative and anti-inflammatory properties. In the present study, we examined the molecular mechanisms underlying the anti-inflammation effect of kaempferol in an aged animal model. To examine the effect of kaempferol in aged Sprague-Dawley rats, kaempferol was fed at 2 or 4 mg/kg/day for 10 days. The data show that kaempferol exhibited the ability to maintain redox balance. Kaempferol suppressed nuclear factor-kappaB (NF-kappaB) activation and expression of its target genes cyclooxygenase-2, inducible nitric oxide synthase, monocyte chemoattractant protein-1, and regulated upon activation, and normal T-cell expressed and secreted in aged rat kidney and in tert-butylhydroperoxide-induced YPEN-1 cells. Furthermore, kaempferol suppressed the increase of the pro-inflammatory NF-kappaB cascade through modulation of nuclear factor-inducing kinase (NIK)/IkappaB kinase (IKK) and mitogen-activated protein kinases (MAPKs) in aged rat kidney. Based on these results, we concluded that anti-oxidative kaempferol suppressed the activation of inflammatory NF-kappaB transcription factor through NIK/IKK and MAPKs in aged rat kidney.

Differential effects of chronic overload‐induced muscle hypertrophy on mTOR and MAPK signaling pathways in adult and aged rats

We examined activation of the mammalian target of rapamycin (mTOR) and mitogen‐activated protein kinase (MAPK) signaling pathways in adult (Y; 6 mo old; n = 16) and aged (O; 30 mo old; n = 16) male rats (Fischer 344 x Brown Norway) subjected to chronic overload‐induced muscle hypertrophy of the plantaris (PLA) and soleus (SOL) muscles. Animals underwent either 4 weeks of bilateral surgical ablation (SA) of two‐thirds of the gastrocnemius muscle or sham surgery (CON). Animals were subjected to SA to promote compensatory hypertrophy in the PLA and SOL muscles. Muscle weights of the Y CON (434 ± 39 mg; mean ± SD; p &lt; 0.05) and Y SA (506 ± 56 mg) rats were significantly heavier than the O CON (353 ± 18 mg) and O SA (402 ± 41 mg) rats. There was a significant interaction between group and age for phosphorylated mTOR. Phosphorylated mTOR was higher in the Y SA group (4129 ± 674 A.U.; mean ± SE; p &lt; 0.05) than in the Y CON (1582 ± 674), O SA (2063 ± 630) and O CON (2667 ± 728) groups. The ratio of phosphorylated to total mTOR was significantly higher in both SA groups than in their respective controls (0.107 ± 0.105 A.U. vs. ‐0.297 ± 0.112; p &lt; 0.05). We also observed a significant effect of age on total p44 MAPK. It was higher in the O (17969 ± 1242; p &lt; 0.05) than the Y (13342 ± 1242) rats. These data indicate mTOR signaling is attenuated in an aging animal model of chronic overload‐induced muscle hypertrophy. Supported by USDA 58‐1950‐7‐707, NIA AG‐25270 and DK007651.

Brain-Derived Neurotrophic Factor Reverses Memory Loss and Cognitive Impairment in Animal Models of Aging and Alzheimer Disease

Brain-Derived Neurotrophic Factor Reverses Memory Loss and Cognitive Impairment in Animal Models of Aging and Alzheimer Disease

Women’s cognitive health special edition

Women’s cognitive health special edition

Depression-like behavior of aged male and female mice is ameliorated with administration of testosterone or its metabolites

There may be a role of age-related decline in androgen production and/or its metabolism for late-onset depression disorders of men and women. Thus, the anti-depressant-like effects of testosterone (T) and its metabolites are of interest. Given that these androgens have disparate mechanisms of action, it is important to begin to characterize and compare their effects in an aged animal model. We hypothesized that there would be sex differences in depression behavior of aged mice and that androgens would reduce depression-like behaviors in the forced swim test. To investigate this, male and female mice (~ 24 months old) were subcutaneously administered T, or one of its 5α-reduced metabolites (dihydrotesterone-DHT, 5α-androstane,17β-diol-3α-diol), or aromatized metabolite (estradiol — E 2), or oil vehicle. Mice were administered androgens (1 mg/kg) 1 h before being tested in the forced swim test, an animal model of depression. We found that males spent more time immobile, and less time swimming, than females. Administration of T, DHT, or 3α-diol similarly reduced time spent immobile, and increased time spent struggling, of male and female mice. E 2, compared to vehicle administration, decreased time spent immobile of males and females, but increased time spent swimming of females and time spent struggling of male mice. Together, these data suggest that T and its 5α-reduced and aromatized metabolites have anti-depressant-like effects in aged male and female mice.

Impaired Endothelial Nitric Oxide Bioavailability: A Common Link Between Aging, Hypertension, and Atherogenesis?

Endothelial-derived nitric oxide (NO) is responsible for maintaining continuous vasodilator tone and for regulating local perfusion and systemic blood pressure. It also has significant antiproliferative effects on vascular smooth muscle and platelet anti-aggregatory effects. Impaired endothelial-dependent (NO mediated) vasorelaxation is observed in most animal and human models of healthy aging. It also occurs in age-associated conditions such as atherosclerosis and hypertension. Such "endotheliopathy" increases vascular risk in older adults. Studies have indicated that pharmacotherapeutic intervention with angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methyl-glutaryl coenzyme-A reductase inhibitors may improve NO-mediated vasomotor function. This review, evaluates the association between impaired endothelial NO bioavailability, accelerated vascular aging, and the age-associated conditions hypertension and atherogenesis. This is important, because pharmacotherapy aimed at improving endothelial NO bioavailability could modify age-related vascular disease and transform age into a potentially modifiable vascular risk factor, at least in a subpopulation of older adults.

Use of cereal fiber to facilitate adherence to a human caloric restriction program

Caloric restriction (CR) attenuates biological aging in animal models but there is little information on the feasibility and efficacy of CR regimens in humans. We examined the effects of consuming an insoluble cereal fiber supplement on ability to sustain CR over 1 year in healthy overweight adults. In 34 healthy overweight women and men (BMI 25-30 kg/m2, age 20-42 yr), a 30% CR regimen meeting national recommendations for dietary fiber was provided for 24 weeks, and for an additional 24 weeks subjects were counseled to prepare the same regimen at home. During 5-10 weeks of CR, subjects were randomized to consume an extra 20 g/day of dietary fiber from a high fiber cereal (+F) or to not consume additional fiber (-F). After this time, all subjects were encouraged to consume the extra fiber. Outcomes included adherence to the provided and self-prepared CR regimens (energy intake determined using doubly labeled water), changes in body weight, and self-reported satisfaction with the amount of consumed food. During 5-10 weeks of CR when all food was provided, both +F and -F groups were highly adherent to the CR regimen and there was no significant difference between groups in energy intake (p=0.51), weight change (p=0.96), or satisfaction with amount of provided food (p=0.08). During self-prepared CR from 25 to 48 weeks, mean adherence was lower than during the food-provided phase and there was a significant association between fiber intake and % CR (r=0.69, p<0.001), decreased BMI (r=- 0.38, p=0.04) and satisfaction with the amount of consumed food (r=0.59, p=0.002). A high fiber cereal intake may facilitate CR in humans self-selecting their own food; longer-term intervention studies are needed to confirm these findings.

Effect of Aging on Brain-Derived Neurotrophic Factor, proBDNF, and Their Receptors in the Hippocampus of Lou/C Rats

The interest in understanding healthy aging has prompted scientist to look for animal models presenting this feature. Lou/C rats, an inbred strain of Wistar origin, is an animal model of successful aging with a longer lifespan and preserved memory capacities than most laboratory rat strains. In an attempt to shed light on this remarkable aging feature, we investigated the hippocampal patterns (mRNA and proteins) of some protective and plasticity-related molecules, i.e., brain-derived neurotrophic factor (BDNF), its precursor proBDNF, and its receptors (i.e., TrkB.FL, TrkB.T1, TrkB.T2, and p75). Using different experimental approaches, we compared these characteristics in young and aged Lou/C versus matched Wistar rats (the most appropriate controls). Data showed that young and aged Lou/C rats had higher amounts of BDNF and proBDNF content than Wistar rats. In contrast, proBDNF content was reduced in aged Lou/C rats and increased in aged Wistar rats. With aging, Lou/C rats showed a weaker decrease in TrkB.FL receptors than Wistar rats and no changes in TrkB.T1 receptors, which, contrarily, were increased in aged Wistar rats. Overall, these observations could account for the preserved cognitive performances and memory-dependent mechanisms, such as the unaltered long-term potentiation (LTP), throughout the lifespan recently reported in the Lou/C strain. Data suggest that boosting the expression or activity of these endogenous protective systems may be a promising alternative for combating some age-related cognitive declines. Therefore, Lou/C rats represent an interesting model of healthy aging for studying plasticity-related processes that evolve from youthfulness to aging.

Sarcopenia Accelerates at Advanced Ages in Fisher 344xBrown Norway Rats

Although the age-dependent loss of muscle mass and strength, sarcopenia, is an inevitable process, its onset and progression are not well established. Here we defined the onset and the progression of sarcopenia in a healthy aging animal model, Fisher 344xBrown Norway rats. Vastus lateralis, rectus femoris, and vastus medialis muscles (three of the quadriceps muscles) were analyzed at 5 months of age and at 3-month intervals between 12 and 39 months of age. We found an age-dependent decline in muscle mass and fiber number and an increase in fiber atrophy and nonmuscle tissue. Significant changes of fiber number and muscle mass were not observed until very late in life (30-33 months) and were concurrent, whereas fiber cross-sectional area (CSA) gradually declined from maximum CSA (24 months). Sarcopenic declines identified between 30 and 36 months did not continue to 39 months, possibly due to the increased proportion of type I fibers.

Strategies for improving cognition with aging: insights from a longitudinal study of antioxidant and behavioral enrichment in canines

Studies in humans suggest that lifestyle factors can have a beneficial impact on the risk for developing cognitive decline and dementia with age. There is growing evidence that maintaining a physically and intellectually active lifestyle can positively impact cognitive ability in older individuals. Dietary factors, such as the intake of antioxidants, may also prevent age-related cognitive decline. However, studies in humans are challenging; many variables cannot be controlled, making it difficult for researchers to determine the exact types and quantities of enrichment and dietary factors necessary for positive effects on cognition. Studies in animal models of human aging allow researchers to precisely control such variables, and can be used to assess the mechanisms and molecular pathways underlying any positive effects. Here we review the results of an intervention study using a canine model of human aging. The study was unique in that it compared the effects of dietary antioxidant supplementation alone and in combination with behavioral enrichment. We found that both interventions lead to improvements in cognitive ability in aged dogs; however, combining the treatments preserved cognition to a greater extent than either treatment alone. Overall, the results suggest that antioxidant supplementation and behavioral enrichment target separate yet complementary molecular pathways to improve cognition, and support the idea that combinations of treatments to improve cognition and slow brain aging will produce greater benefits than single interventions.

Aberrant Insulin Receptor Signaling and Amino Acid Homeostasis as a Major Cause of Oxidative Stress in Aging

The mechanisms leading to the increase in free radical-derived oxidative stress in "normal aging" remains obscure. Here we present our perspective on studies from different fields that reveal a previously unnoticed vicious cycle of oxidative stress. The plasma cysteine concentrations during starvation in the night and early morning hours (the postabsorptive state) decreases with age. This decrease is associated with a decrease in tissue concentrations of the cysteine derivative and quantitatively important antioxidant glutathione. The decrease in cysteine reflects changes in the autophagic protein catabolism that normally ensures free amino acid homeostasis during starvation. Autophagy is negatively regulated by the insulin receptor signaling cascade that is enhanced by oxidative stress in the absence of insulin. This synopsis of seemingly unrelated processes reveals a novel mechanism of progressive oxidative stress in which decreasing antioxidant concentrations and increasing basal (postabsorptive) insulin receptor signaling activity compromise not only the autophagic protein catabolism but also the activity of FOXO transcription factors (i.e., two functions that were found to have an impact on lifespan in several animal models of aging). In addition, the aging-related decrease in glutathione levels is likely to facilitate certain "secondary" disease-related mechanisms of oxidative stress. Studies on cysteine supplementation show therapeutic promise.

Impairments of astrocytes are involved in the d-galactose-induced brain aging

Astrocyte dysfunction is implicated in course of various age-related neurodegenerative diseases. Chronic injection of d-galactose can cause a progressive deterioration in learning and memory capacity and serve as an animal model of aging. To investigate the involvement of astrocytes in this model, oxidative stress biomarkers, biochemical and pathological changes of astrocytes were examined in the hippocampus of the rats with six weeks of d-galactose injection. d-galactose-injected rats displayed impaired antioxidant systems, an increase in nitric oxide levels, and a decrease in reduced glutathione levels. Consistently, western blotting and immunostaining of glial fibrillary acidic protein showed extensive activation of astrocytes. Double-immunofluorescent staining further showed activated astrocytes highly expressed inducible nitric oxide synthase. Electron microscopy demonstrated the degeneration of astrocytes, especially in the aggregated area of synapse and brain microvessels. These findings indicate that impairments of astrocytes are involved in oxidative stress-induced brain aging by chronic injection of d-galactose.