Table 1 A summary of studies on the molecular and cellular pathways contributing to brain aging
From: Molecular and cellular pathways contributing to brain aging
Authors | Goals of Study | Study Subjects | Findings remarks |
|---|---|---|---|
Coviello-McLaughlin and Prowse [150] | Determining relationship between telomere length and ageing | Mus spretus mice | Individual tissues had Independent regulation of telomerase activity and telomere lengths; Genetical control of telomere lengths; Gender differences in mean terminal restriction fragment length |
Ain et al. [158] | Assessing telomere length and telomerase activity in non‐replicative and replicative neural brain populations | C57BL/6 mice | A cell cycle‐dependent and ‐independent manner in telomers lengths; No induction of telomerase activity and nuclear TERT protein by aging; Rela subunit of NF‐κB did not influence telomerase activity or telomere length; telomere instability was a failure to induce or relocate telomerase |
Puhlmann et al. [160] | Assessing relationship between changes in leukocyte telomere length with structural plasticity (cortical thickness) of the brain and influence of mental training on telomere length | Healthy adults | Mental training intervention did not affect leukocyte telomere length; Association between short-term change in leukocyte telomere length and concomitant change in plasticity of the left precuneus extending to the posterior cingulate cortex |
Gampawar et al. [159] | Investigating association between leukocyte telomere length with brain aging characteristics | Elderly individuals | Longer leukocyte telomere length was significantly associated with larger brain parenchymal fraction, larger white matter hyperintensities load and score; Leukocyte telomere length was associated with cognitive domain of attention/speed; Longer leukocyte telomere length protected the global brain volume and contributed to better cognitive functions, especially in the attention/speed domain in the elderly individuals |
Yan et al. [225] | Assess whether Growth hormone (GH)/insulin-like growth factor-1 (IGF-1)-deficiency influences the outcome of cerebral ischemia induced by endothelin-1 with or without early-life growth hormone (GH) treatment | GH/IGF-1 deficient dw/dw rats | GH/IGF-1 deficiency did not affect infarct size but significantly attenuates brain edema and astrocytic infiltration compared with controls; GH-treatment reversed the cerebral ischemia deleterious effects |
Pirger et al. [226] | Assessing effects of pituitary adenylate cyclase activating polypeptide (PACAP38) homolog on age-related complications | Aged Lymnaea | Exogenous PACAP38 promoted memory formation; Endogenous PACAP38 levels were low in the brain; Insulin-like growth factor-1 promoted memory formation |
Rodríguez‐Muela et al. [396] | Investigating relationships between different lysosomal proteolytic systems in the retina during normal aging | Atg5flox/flox; nestin-Cre mice (a mouse model with downregulation of macroautophagy in neuronal precursors) | Increased chaperone mediated autophagy; reduced macroautophagic activity in the retina with age; Increased chaperone mediated autophagy in retinal neurodegeneration |
De Biase et al. [397] | Assessing expression of autophagy markers and Amyloid precursor protein (APP) in aging | Old (aged 11–20 years) and young (aged 1–5 years) bovines’ brains | Impaired autophagy in aged bovine and not in the young animals; increased intraneuronal APP deposition with age |
Park et al. [68] | Investigating involvement of superoxide-producing enzyme NADPH oxidase in aged-induced altered neurovascular regulation | C57BL/6 mice | Nox2 subunit of NADPH oxidase was a main producer of neurovascular oxidative stress and induced deleterious cerebrovascular effects with aging |
Ulmann et al. [73] | Assessing the composition of fatty acids in brain and hippocampus in cognitive deficits | Aged and young Wistar rats | Decreased arachidonic acid concentration in aged rats; Significant phosphatidylserine and phosphatidylinositol classes in aged rats |
Guebel and Torres [408] | Assessing the effects of sexual dimorphism on normal aging | Elderly-healthy individuals | Older women: Diminished expression of LC3, HDAC6, and PINK1; Older men: declined macroautophagic activity evidenced by increased expression of Bcl-2 (inhibitor of Beclin 1); Activation of mitophagy triggered by PARKIN evidenced by increased BAG-2 expression which inhibits PINK1 degradation |
Head et al. [80] | Investigating the link between oxidative damage, aging and b-amyloid (Ab) | Canines brains | Increased lipid peroxidation; Increased oxidative damage of proteins (carbonyl formation); Age-dependent decline in GS activity and in the level of glutathione in the prefrontal cortex |
Çakatay et al. [82] | Investigating the relation of oxidative protein damage parameters with oxidative stress in brain | Young, adult, and old Wistar rats | Protein carbonyl formation (oxidative protein damage parameter) was a marker of brain aging; Protein oxidation was related with lipid peroxidation in brain aging |
Aksenova et al. [83] | Assessing aging and diet restriction’s effects on the brain | Male and female brown Norway rats | Diet restriction alleviated age-associated level of oxidative stress and reduced protein damage |
Nicolle et al. [85] | Assessing protein and nucleic acid oxidative damage in the hippocampus in aging and impaired spatial learning | Long-Evans rats | Oxidative stress in aged hippocampal neurons evidenced by elevated heme oxygenase-1, elevated 8-hydroxy-2P-deoxyguanosine (an oxidative nucleic acid adducts); damaged mitochondrial DNA; Intensified oxidative stress in the learning-impaired rats |
Paul et al. [87] | Investigating the roles of SOD2 in aging and associated pathologies | Sod2 mutants Drosophila | SOD2 protected against mitochondrial oxidative damage, neurodegeneration, age-related defects in behavior and early-onset mortality; SOD2 mutation resulted in mitochondrial aconitase activity, accelerated senescence of olfactory behavior, precocious neurodegeneration, DNA strand breakage in neurons, shortened life span, and increased age-dependent mortality |
Lee et al.. [115] | Investigating effects of mild inhibition of mitochondrial respiration on extension of lifespan | Caenorhabditis elegans | Inhibition of mitochondrial respiration increased hypoxia-inducible factor HIF-1 (a transcription factor that activates genes responsible for promoting survival during hypoxia) activity in by elevating the level of reactive oxygen species in Caenorhabditis elegans |
Ghosh et al. [134] | Assessing relation between oxidative redox shift with macromolecular damage in Alzheimer’s disease (AD) | 3xTg-AD mouse model | Precedent of cognitive deficits in AD was a more oxidized redox state and a lower antioxidant GSH defense which both were dissociated from neuronal changes by ROS damage |
Jaskelioff, Muller et al. [153] | Assessing whether reactivation of endogenous telomerase activity halts or reverses the degeneration in adult mice with severe telomere dysfunction | Mice with knock-in allele encoding a 4-hydroxytamoxifen (4-OHT)-inducible telomerase reverse transcriptase-Estrogen Receptor (TERT-ER) | Homozygous TERT-ER mice displayed short dysfunctional telomeres and sustain increased DNA damage signaling and classical degenerative phenotypes upon successive generational mating and advancing age; somatic telomerase reactivation reversed neurodegeneration with restoration of proliferating Sox2+ neural progenitors, DCX+ newborn neurons, and Olig2+ oligodendrocyte populations; telomerase-dependent neurogenesis alleviated hyposmia and recovered innate olfactory avoidance responses |
Molofsky et al. [156] | Assessing whether genes associated with senescence functionally contribute to physiological declines in progenitor activity | Mice | Age-associated decline in progenitor proliferation in the subventricular zone and neurogenesis in the olfactory bulb which was partly related to p16INK4a (which encodes a cyclin-dependent kinase inhibitor linked to senescence); Age-declined multipotent progenitor frequency and self-renewal potential in forebrain |
Bake et al. [224] | Investigating mechanisms underlying IGF-1’s neuroprotective actions un a post-stroke IGF-1 treatment animal model | Middle-aged female rats | IGF-1 downregulated disease-related miRNA in PI3K-Akt signaling, cell adhesion/ECM receptor pathways and T-and B-cell signaling; attenuated reduced phospho-Akt, reduced blood brain barrier permeability, and suppressed IL-6, IL-10 and TNF-a; suppressed IL-6 and reduced infarct volume by 39% |
Cohen et al. [232] | Investigating relation between Insulin/IGF signaling pathway (IIS) and Alzheimer’s disease | AD model mice | Reduced IGF signaling was associated with protection from the Alzheimer's-like disease symptoms including reduced behavioral impairment, neuroinflammation, neuronal and synaptic loss; reduced IGF signaling caused sequestration of soluble Aβ oligomers into dense aggregates of lower toxicity |
Demontis and Perrimon [383] | Investigating muscle functional decline in systemic aging | Drosophila | Progressive accumulation of protein aggregates in muscle aging was associate with impaired muscle function; FOXO and 4E-BP signaling delayed muscle functional decay, extended the lifespan, delayed age-related accumulation of protein aggregates outside muscle tissues via decreasing feeding behavior and the release of Insulin from producing cells |
Zhang et al. [400] | Investigating the roles of 4-hydroxynonenal (HNE) in autophagy—lysosome pathway | Rat primary cortical neurons | HNE (lipid peroxidation product) affected autophagy through lysosome inhibition which resulted in accumulation of damaged and dysfunctional proteins and organelles and consequent neuronal death |
Hara et al. [394] | Investigating the role of autophagy in neurodegeneration | Atg5 deficient mice | loss of autophagy caused accumulation of cytoplasmic inclusion bodies in neurons and resulted in progressive deficits in motor function and neurodegeneration even in the absence of any disease associated mutant proteins |
Komatsu et al. [393] | Investigating roles of autophagy in neurons | Atg7 deficient mice | Impaired autophagy leaded to polyubiquitinated proteins accumulation in neurons as inclusion bodies, which increased in size and number with ageing; Impaired autophagy caused abnormal limb-clasping reflexes, reduced coordinated movement, death within 28 weeks of birth, and massive neuronal loss in the cerebral and cerebellar cortices |
Fernández et al. [391] | Assessing effects of increased autophagy on mammalian lifespan | Mice with F121A (Becn1F121A/F121A) mutation in beclin 1 + mice deficient in Klotho3 | Disrupted beclin 1/Bcl-2 complex disruption increased autophagy in F121A mutated mice; increased autophagy increased lifespan of F121A mutated mice and diminished age-related renal and cardiac pathological changes and spontaneous tumorigenesis; mice deficient in Klotho3 (an anti-aging protein) had increased beclin 1/Bcl-2 interaction, decreased autophagy, premature lethality and infertility which were attenuated by the beclin 1 F121A mutation |
Chang et al. [389] | Assessing autophagic activity throughout life course | wild-type + long-lived daf-2/insulin/IGF-1 mutants + glp-1/Notch mutants Caenorhabditis elegans | age-related decline in autophagic activity in the intestine, body-wall muscle, pharynx, and neurons of wild-type animals; daf-2 and glp-1 long-lived mutants had regulated autophagy in distinct spatiotemporal-specific manners |
Simonsen et al. [385] | Assessing the effects of increased autophagic gene expression in an aging nervous system | Drosophila | Enhanced Atg8a expression in older fly brains extended lifespan by 56% and promoted resistance to oxidative stress and the accumulation of ubiquitinated and oxidized proteins |