scholarly journals Lipid membranes from naked mole-rat brain lipids are cholesterol-rich, highly phase-separated, and sensitive to amyloid-induced damage

2020 ◽  
Author(s):  
DANIEL FRANKEL ◽  
Ewan St John Smith ◽  
Kenneth Rankin ◽  
Nicolas Cenac ◽  
Matthew Davies ◽  
...  
Keyword(s):  
Rat Brain ◽  
Amyloid Beta ◽  
Lipid Membranes ◽  
Phase Behaviour ◽  
Brain Lipid ◽  
Brain Lipids ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
High Concentrations

Naked mole-rats are extraordinarily long-lived rodents that do not develop age-related neurodegenerative diseases. Remarkably, they do not accumulate amyloid plaques, even though their brains contain high concentrations of amyloid beta peptide, even from a young age Therefore, these animals offer an opportunity to investigate mechanisms of resistance against the neurotoxicity of amyloid beta aggregation. Working in this direction, here we examine the composition, phase behaviour, and amyloid beta interactions of naked mole-rat brain lipids. Relative to mouse, naked mole-rat brain lipids are rich in cholesterol and contain sphingomyelin in lower amounts and of shorter chain lengths. Proteins associated with metabolism of ceramides, sphingomyelin and ceramide receptor activity were also found to be decreased in naked mole-rat brain lysates. Correspondingly, we find that naked mole-rat brain lipid membranes exhibit a high degree of phase separation, with the liquid ordered phase occupying up to 80% of the supported lipid bilayer. These observations are consistent with the membrane pacemaker hypothesis of ageing, according to which long-living species have lipid membranes particularly resistant to oxidative damage. However, we found that exposure to amyloid beta disrupts the naked mole-rat brain lipid membranes while those formed from mouse brain lipids exhibit small, well-defined footprints, whereby the amyloid beta penetrates deeply into the lipid membranes. These results suggest that in naked mole-rats the lipid composition of cell membranes may offer neuroprotection through resistance to oxidative processes rather than through mechanical effects.

scholarly journals Cholesterol-rich naked mole-rat brain lipid membranes are susceptible to amyloid beta-induced damage in vitro

Aging ◽  
2020 ◽  
Vol 12 (21) ◽  
pp. 22266-22290
Author(s):  
Daniel Frankel ◽  
Matthew Davies ◽  
Bharat Bhushan ◽  
Yavuz Kulaberoglu ◽  
Paulina Urriola-Munoz ◽  
...  
Keyword(s):  
Rat Brain ◽  
Amyloid Beta ◽  
Lipid Membranes ◽  
Brain Lipid ◽  
Mole Rat ◽  
Naked Mole Rat

Na+/K+-ATPase activity is regionally regulated by acute hypoxia in naked mole-rat brain

2021 ◽  
Vol 764 ◽  
pp. 136244
Author(s):  
Elie Farhat ◽  
Maiah E.M. Devereaux ◽  
Hang Cheng ◽  
Jean-Michel Weber ◽  
Matthew E. Pamenter
Keyword(s):  
Atpase Activity ◽  
Rat Brain ◽  
Acute Hypoxia ◽  
Mole Rat ◽  
Naked Mole Rat

scholarly journals How the naked mole-rat resists senescence: a constraints-based theory

2021 ◽  
Author(s):  
Felipe A. Veloso
Keyword(s):  
House Mouse ◽  
House Mice ◽  
Nucleosome Core Particle ◽  
Chromatin Dynamics ◽  
Nucleosome Core ◽  
Differentiated Cells ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Histone Modifying Enzymes

Here, I present a theory describing how the stabilization of constraints imposed on chromatin dynamics by the naked mole-rat's histone H1.0 protein—which in terminally differentiated cells constrains the accessibility of the nucleosome core particle for histone-modifying enzymes and chromatin remodeling factors—explains its resistance to both senescence and cancer. Further, this theory predicts that a mutant house mouse displaying such stabilization will be similarly resistant to both senescence and cancer. A proof-of-concept computational analysis is presented and two predictions for the direct testing of the theory are provided. These experiments comprise, as test subjects, mutant naked mole-rats synthesizing a house mouse (Mus musculus)-like histone H1.0, and mutant house mice synthesizing a naked mole-rat-like histone H1.0. The predictions are that the constraints on chromatin dynamics embodied by the respective mutant histone H1.0 proteins will negate the otherwise significant resistance to both senescence and cancer of the naked mole-rats and, conversely, confer such resistance to the house mice. A verification of these predictions will imply that constraints on chromatin dynamics embodied by naked mole-rat-like histone H1.0 proteins may confer significant resistance to both senescence and age-related cancer to otherwise senescence-prone and/or cancer-susceptible multicellular species, including humans.

scholarly journals Telomeres and Longevity: A Cause or an Effect?

2019 ◽  
Vol 20 (13) ◽  
pp. 3233 ◽  
Author(s):  
Huda Adwan Shekhidem ◽  
Lital Sharvit ◽  
Eva Leman ◽  
Irena Manov ◽  
Asael Roichman ◽  
...  
Keyword(s):  
Telomere Length ◽  
Ongoing Debate ◽  
Telomere Attrition ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Extreme Longevity ◽  
Linear Chromosomes ◽  
Biological State

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a “biological thermometer” that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

Abstract 316: Enhanced Cardiac Proteasome Function in the Naked Mole-rat, the Longest-lived Rodent

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
David A Kramer ◽  
Kelly M Grimes ◽  
Rochelle Buffenstein
Keyword(s):  
Qualitative Difference ◽  
Physiological Role ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Mouse Heart ◽  
Atp Levels ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Heart Disorders

The ubiquitin-proteasome system (UPS) is responsible for the recycling of misfolded proteins. Dysfunction of the UPS has been implicated in the pathophysiology of multiple heart disorders, including heart failure and reperfusion injury, but the basic science of cardiac UPS function remains unclear. An attractive mode of inquiry into the cardiac proteasome is the long-lived naked mole rat (NMR), which maintains intact cardiac reserve and diastolic function exceptionally late into its lifespan; equivalent to a 90 year old human with a 30 year old’s heart. In this study, we investigated whether the long-lived and healthful NMR had upregulated aspects of UPS function in comparison to the short-lived well-characterized mouse. NMR hearts have more than twofold (p<0.001) greater proteasome-mediated chymotrypsin-like activity than mouse hearts. NMR hearts also have significantly greater levels of proteasome subunits than mice, including α7 and Rpt5, suggesting that the greater numbers of proteasomes could contribute to the high chymotrypsin-like activity, alternatively, the naked mole-rat heart may also have more immunoproteasomes which are more efficient. The UPS is energy-dependent, with its activity significantly influenced by available ATP. Interestingly, basal ATP levels were 40 to 50 fold higher in NMR hearts than in those of mice. This is consistent with the much larger pools of mitochondria observed in the NMR heart than in the mouse heart. Considering that both high and low ATP levels are associated with a decline in proteasome activity, we next asked whether the remarkably high basal ATP levels of the NMR heart caused a qualitative difference in UPS function between NMRs and mice. Levels of ubiquitinated protein were significantly lower in the NMR heart than in the mouse heart, suggesting that the NMR cardiac UPS system is more effective at destroying ubiquitin-tagged damaged proteins than that of the mouse, and that the NMR heart’s elevated ATP levels may play a physiological role in maintaining this enhanced UPS functionality. Overall these data suggest a high basal level of proteasome activity in the NMR heart that may be of paramount importance in this animal’s ability to withstand and/or prevent age-related cardiovascular functional declines.

Extreme hypoxia tolerance of naked mole-rat brain

Neuroreport ◽  
2009 ◽  
Vol 20 (18) ◽  
pp. 1634-1637 ◽  
Author(s):  
John Larson ◽  
Thomas J. Park
Keyword(s):  
Rat Brain ◽  
Hypoxia Tolerance ◽  
Mole Rat ◽  
Naked Mole Rat
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