Mild stress-induced stimulation of heat-shock protein synthesis and improved functional ability of human fibroblasts undergoing aging in vitro

Fonager, Jannik; Beedholm, Rasmus; Clark, Brian F. C.; Rattan, Suresh I. S.

doi:10.1016/s0531-5565(02)00128-6

Cited by 103 publications

(79 citation statements)

References 16 publications

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“…We hypothesized that eHsp70 administration protects normal function of neurons during aging. Similarly, overexpression of HSPs in aging cells in culture or in the intact brain has a protective effect (28,29).…”

Section: Significancementioning

confidence: 99%

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

Бобкова

Евгеньев

Гарбуз

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups. Behavioral assessment after 5 and 9 mo of chronic eHsp70 administration demonstrated improved learning and memory in old mice. Likewise, the investigation of locomotor and exploratory activities after eHsp70 treatment demonstrated a significant therapeutic effect of this chaperone. Measurements of synaptophysin show that eHsp70 treatment in old mice resulted in larger synaptophysin-immunopositive areas and higher neuron density compared with control animals. Furthermore, eHsp70 treatment decreased accumulation of lipofuscin, an aging-related marker, in the brain and enhanced proteasome activity. The potential of eHsp70 intranasal treatment to protect synaptic machinery in old animals offers a unique pharmacological approach for various neurodegenerative disorders associated with human aging.

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Section: Significancementioning

confidence: 99%

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

Бобкова

Евгеньев

Гарбуз

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…For the proteasome assay, the cytosol was used at a concentration of 100 g of protein/ml and the purified human erythrocyte 20 S proteasome at a concentration of 2 g of protein/ml. The hydrolytic activity for the chymotrypsin-like, trypsinlike, and caspase-like hydrolytic activities were determined as described previously (37). The coefficient of variation for the proteasome assay ranged from 0.8 to 6.3% in six independent experiments with the mean being 3%.…”

Section: ␣-Synuclein Inhibits the 20 S Proteasomementioning

confidence: 99%

Proteasomal Inhibition by α-Synuclein Filaments and Oligomers

Lindersson

Beedholm

Højrup

et al. 2004

Journal of Biological Chemistry

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366

310

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A unifying feature of many neurodegenerative disorders is the accumulation of polyubiquitinated protein inclusions in dystrophic neurons, e.g. containing ␣-synuclein, which is suggestive of an insufficient proteasomal activity. We demonstrate that ␣-synuclein and 20 S proteasome components co-localize in Lewy bodies and show that subunits from 20 S proteasome particles, in contrast to subunits of the 19 S regulatory complex, bind efficiently to aggregated filamentous but not monomeric ␣-synuclein. Proteasome binding to insoluble ␣-synuclein filaments and soluble ␣-synuclein oligomers results in marked inhibition of its chymotrypsin-like hydrolytic activity through a non-competitive mechanism that is mimicked by model amyloid-A␤ peptide aggregates. Endogenous ligands of aggregated ␣-synuclein like heat shock protein 70 and glyceraldehyde-6-phosphate dehydrogenase bind filaments and inhibit their anti-proteasomal activity. The inhibitory effect of amyloid aggregates may thus be amenable to modulation by endogenous chaperones and possibly accessible for therapeutic intervention.

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“…HSP70 is hyperactivated in presence of noxious stimuli, such as heat, oxygen stress and infection, in order to protect cells from apoptosis [14] via inhibition of caspase-3 [87]. In vitro study on human fibroblasts undergoing ageing shows that the increment of HSP70 expression is associated with improved functional and survival ability of the cells in terms of increased proteasome activities, increased ability to decompose H 2 O 2 , reduced lipofuscin accumulation and enhanced resistance to ethanol, H 2 O 2 and UV radiation [49]. An overexpression of HSP70 contributes to extend longevity in non-mammalian organism [2,159].…”

Section: Zinc-hsp70 Gene Interactionmentioning

confidence: 99%

Zinc–gene interaction related to inflammatory/immune response in ageing

Mocchegiani

Malavolta

2008

Genes Nutr

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The pivotal role played by zinc-gene interaction in affecting some relevant cytokines (IL-6 and TNF-a) and heat shock proteins (HSP70-2) in ageing, successful ageing (nonagenarians) and the most common age-related diseases, such as atherosclerosis and infections, is now recognized. The polymorphisms of genes codifying proteins related to the inflammation are predictive on one hand in longevity, on the other hand they are associated with atherosclerosis or severe infections. Since the health lifespan has a strong genetic component, which in turn also affected by nutritional factors like zinc, the association of these polymorphisms with innate immune response, zinc ion bioavailability and Metallothioneins (MT) homeostasis is an useful tool to unravel the role played by zinc-gene interactions in longevity, especially due to the inability of MT in zinc release in ageing and chronic inflammation. In ageing, this last fact leads to depressed innate immune response for host defence. In contrast, in very old age the inflammation is lower with subsequent more zinc ion bioavailability, less MT gene expression and satisfactory innate immunity. Therefore, the zinc-gene (IL-6, TNF-a, Hsp70-2) interactions, via MT homeostasis, are crucial to achieve successful ageing. Human genes and longevityAgeing is a universal phenomenon that affects nearly all of animal species. According to Helfand and Rogina [69], ageing can be characterized as: (1) an inevitable consequence of being a multicellular organism; (2) associated with a random, passive decline in function; (3) leading to a global loss of homeostasis over time and (4) mortality increasing with ageing. Evolutionary studies on ageing have drawn the attention on the importance of the genetic mechanisms involved in somatic maintenance and repair that secure longevity [82]. Evidence from model organisms has indicated that subtle variation in the genes can dramatically influence lifespan. However, findings on potential candidate genetic mechanisms determining ageing and lifespan in model organisms are far to explain variations in human populations because phenotypes are critically dependent on the setting in which genes are expressed, while laboratory conditions and modern environments are markedly dissimilar [86]. Genetic analysis of human ageing is mainly approached by searching the genetic basis of susceptibility to major geriatric disorders or the allelic contributions to exceptionally long life span. It is just thanks to these last studies in centenarians populations that several candidate longevity genes or pathways including PON1 [19,130], IGF1/insulin pathway [84,120], elements of lipid metabolism [12], stress response [34] and inflammatory response have been identified [53].Genes related to inflammation and stress response, in particular the pro-inflammatory cytokines IL-1, IL-6, TNFalpha, the anti-inflammatory cytokine IL-10, the HSP70 chaperones and the regulators of trace elements homeostasis, metallothioneins (MT), seem particularly relevant taking into accoun...

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Mild stress-induced stimulation of heat-shock protein synthesis and improved functional ability of human fibroblasts undergoing aging in vitro

Cited by 103 publications

References 16 publications

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

Proteasomal Inhibition by α-Synuclein Filaments and Oligomers

Zinc–gene interaction related to inflammatory/immune response in ageing

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