Age-Related Changes in Brain Metabolism and Vulnerability to Anoxia

Roberts, Eugene; Chih, Ching Ping; Rosenthal, Myron

doi:10.1007/978-1-4615-5865-1_10

Cited by 17 publications

(10 citation statements)

References 21 publications

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“…Mortality rate lower increased Popa-Wagner et al, 1998;Lindner et al, 2003;Rosen et al, 2005;Zhang et al, 2005 Infarct size similar similar Popa-Wagner et al, 1998;Lindner et al, 2003;Li et al, 2005 Neuronal degeneration delayed early, increased Popa-Wagner et al, 2006;Hoane et al, 2004 Apoptosis delayed early, increased Popa-Wagner et al, 2006;He et al, 2006 Inflammation delayed precipitous Badan et al, 2003;Iadecola & Alexander, 2001 Scar formation delayed precipitous Badan et al, 2003 Functional recovery rapid delayed, incomplete Badan et al, 2003 DNA damage delayed increased Li et al, 2005 Oxidative stress; Protein damage delayed increased Li et al, 2005;Roberts et al, 1997 Heat shock protein increased decreased Li et al, 2005 Neurogenesis increased increased Darsalia et al, 2005 CAP23/growth-promoting increased increased, delayed Li & Carmichael, 2006 MAP1B, MAP2/growth-associated increased increased, delayed Popa-Wagner et al, 1999;Badan et al, 2004 MAG mRNA/axonal growth inhibitory decreased increased Li & Carmichael, 2006 Ephrin-A5/axonal growth inhibitory increased increased Li & Carmichael, 2006 Nogo mRNA/axonal growth inhibitory increased decreased Li & Carmichael, 2006 Cytotoxic APP fragments delayed precipitous Popa-Wagner et al, 1998;Badan et al, 2004 …”

Section: Referencesmentioning

confidence: 93%

“…Markedly increased activity of activated microglia/monocytes has been reported recently for intracerebral hemorrhage-induced brain injury in senescence-accelerated prone mice (Lee et al, 2006). Activated macrophages generate free radicals, the production of which is augmented in aged subjects following cerebral ischemia (Roberts et al, 1997;Floyd & Hensley, 2000). A related consideration is that the vulnerability of brain tissue to traumatic injury (Hoane et al, 2004), and to DNA damage and oxidative stress in particular, also increases with age (Floyd & Hensley, 2002;Aliev et al, 2002;Li et al, 2005).…”

Section: Brain Macrophages Are Activated Early Following Stroke In Agmentioning

confidence: 94%

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The Response of the Aged Brain to Stroke: Too Much, Too Soon?

Popa‐Wagner

Carmichael²,

Kokaia³

et al. 2007

CNR

124

101

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Old age is associated with an enhanced susceptibility to stroke and poor recovery from brain injury, but the cellular processes underlying these phenomena are only recently coming to light. Potential mechanisms include changes in brain plasticity-promoting factors, unregulated expression of neurotoxic factors, or differences in the generation of scar tissue that impedes the formation of new axons and blood vessels in the infarcted region. Behaviorally, aged rats are more severely impaired by stroke than are young rats, and they also show diminished functional recovery. Infarct volume does not differ significantly in young and aged animals, but critical differences are apparent in the cytological response to stroke, most notably an age-related acceleration of the establishment of the glial scar. The early infarct in older rats is associated with a premature accumulation of BrdU-positive microglia and astrocytes, persistence of activated oligodendrocytes, a high incidence of neuronal degeneration, and accelerated apoptosis. Regeneration-associated mechanisms in the rat brain are active throughout life, albeit at lower levels in the aged animals. However; after stroke in aged rats, neuroepithelial marker-positive cells emanating largely from capillaries did not make a significant contribution to neurogenesis in the infarcted cortex of aged animals. Furthermore, the expression of plasticity-associated proteins, such as MAP1B, was delayed in aged rats. Tissue recovery was further delayed by the upregulation of Nogo, ephrin-A5 and MAG, which exert a powerful negative effect on axonal sprouting in the aged peri-infarct cortex, and by an age-related increase in the amount of the neurotoxic C-terminal fragment of the beta-amyloid precursor protein (betaAPP) at 2 wks post-stroke. Our findings indicate that the aged brain has the capability to mount a cytoproliferative response to injury, but the timing of the cellular and genetic response to cerebral insult is dysregulated in aged animals, thereby further compromising functional recovery. Elucidating the molecular basis of this phenomenon in the aging brain could yield novel approaches to neurorestoration following stroke or head injury in the elderly.

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Section: Referencesmentioning

confidence: 93%

Section: Brain Macrophages Are Activated Early Following Stroke In Agmentioning

confidence: 94%

The Response of the Aged Brain to Stroke: Too Much, Too Soon?

Popa‐Wagner

Carmichael²,

Kokaia³

et al. 2007

CNR

124

101

View full text Add to dashboard Cite

show abstract

“…Further evidence linking alterations in mtDNA with progressive age-dependent tissue dysfunction can be found in individuals with mitochondrial genetic diseases and mice with deletion mutation of mtDNA, which display a phenotype that resembles premature aging, including kidney dysfunction (8,9). Hypoxia is the cause of age-associated mitochondrial dysfunction (10) and is involved in age-dependent tissue damage affecting the brain (11), heart (12), and kidney (13). Furthermore, hypoxia modulates various cellular processes, such as apoptosis, cell cycle, autophagy, and glucose metabolism (14,15).…”

Section: Introductionmentioning

confidence: 99%

Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney

Kume¹,

Uzu²,

Horiike³

et al. 2010

J. Clin. Invest.

574

490

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Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged Sirt1 +/-mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age-and hypoxia-related tissue damage. IntroductionIncreasing age causes progressive postmaturational deterioration of tissues and organs, leading to impairment of tissue functioning, increased vulnerability to challenges, and death. The kidney is a typical target organ of age-associated tissue damage, and the increased incidence of chronic kidney disease (CKD) in the elderly is a health problem worldwide (1-3). However, there is little or no information on the mechanisms underlying age-associated kidney damage. Thus, studies designed to determine such molecular mechanisms could help formulate interventions that delay the onset and/or progression of CKD in elderly patients.Among the several proposed theories on the pathogenesis of ageassociated tissue damage, the mitochondrial ROS theory provides the basic mechanism of age-associated tissue dysfunction (4, 5): that age-dependent alteration in mitochondrial DNA (mtDNA) plays a fundamental role in the age-associated increase in ROS and subsequent tissue damage (6, 7). Further evidence linking alterations in mtDNA with progressive age-dependent tissue dysfunction can be found in individuals with mitochondrial genetic diseases and mice with deletion mutation of mtDNA, which display a phenotype that resembles premature aging, including kidney dysfunction (8,9). Hypoxia is the cause of age-associated mitochondrial dysfunction (10) and is involved in age-dependent tissue damage affecting the brain (11), heart (12), and kidney (13). Furthermore, hypoxia modulates various cellular processes, such as apoptosis, cell cycle, autophagy, and glucose me...

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“…Roberts and colleagues (Roberts et al 1994, 1997; Roberts 1995, 2000) investigated the effects of aging on the mechanism of body energy regulation and thereby determined the causes of unexplained weight loss in older persons. They found that aging may be associated with a significant impairment in the ability to control food intake following overeating or undereating.…”

Section: Introductionmentioning

confidence: 99%