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.

scholarly journals And the beat goes on: maintained cardiovascular function during aging in the longest-lived rodent, the naked mole-rat

2014 ◽  
Vol 307 (3) ◽  
pp. H284-H291 ◽  
Author(s):  
Kelly M. Grimes ◽  
Anilkumar K. Reddy ◽  
Merry L. Lindsey ◽  
Rochelle Buffenstein
Keyword(s):  
Cardiovascular Function ◽  
Left Ventricular ◽  
Lv Function ◽  
Cross Sectional ◽  
Arterial Stiffening ◽  
Functional Changes ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Negligible Senescence

The naked mole-rat (NMR) is the longest-lived rodent known, with a maximum lifespan potential (MLSP) of >31 years. Despite such extreme longevity, these animals display attenuation of many age-associated diseases and functional changes until the last quartile of their MLSP. We questioned if such abilities would extend to cardiovascular function and structure in this species. To test this, we assessed cardiac functional reserve, ventricular morphology, and arterial stiffening in NMRs ranging from 2 to 24 years of age. Dobutamine echocardiography (3 μg/g ip) revealed no age-associated changes in left ventricular (LV) function either at baseline or with exercise-like stress. Baseline and dobutamine-induced LV pressure parameters also did not change. Thus the NMR, unlike other mammals, maintains cardiac reserve with age. NMRs showed no cardiac hypertrophy, evidenced by no increase in cardiomyocyte cross-sectional area or LV dimensions with age. Age-associated arterial stiffening does not occur since there are no changes in aortic blood pressures or pulse-wave velocity. Only LV interstitial collagen deposition increased 2.5-fold from young to old NMRs ( P < 0.01). However, its effect on LV diastolic function is likely minor since NMRs experience attenuated age-related increases in diastolic dysfunction in comparison with other species. Overall, these findings conform to the negligible senescence phenotype, as NMRs largely stave off cardiovascular changes for at least 75% of their MLSP. This suggests that using a comparative strategy to find factors that change with age in other mammals but not NMRs could provide novel targets to slow or prevent cardiovascular aging in humans.

scholarly journals The hematopoietic landscape at single-cell resolution reveals unexpected stem cell features in naked mole-rats

2019 ◽  
Author(s):  
Stephan Emmrich ◽  
Marco Mariotti ◽  
Masaki Takasugi ◽  
Maggie E. Straight ◽  
Alexandre Trapp ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
Single Cell ◽  
Cell Biology ◽  
List Type ◽  
Hematopoietic Stem ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat

SUMMARYNaked mole-rats are the longest-lived rodents endowed with resistance to cancer and age-related diseases, yet their stem cell characteristics remain enigmatic. We profiled the naked mole-rat hematopoietic system down to single-cell resolution, and identified several unique features likely contributing to longevity. In adult naked mole-rats red blood cells are formed in spleen and marrow, a neotenic feature beneficial for hypoxic environments and to prevent anemia. Platelet numbers are lower compared to short-lived mice, which may preclude age-related platelet increase and thrombosis. T cells mature in thymus and lymph nodes, providing a supply of T cells after age-related thymus involution. The pool of quiescent stem cells is higher than in mice, and HSCs overexpress an oxidative phosphorylation signature, revealing a new paradigm of stem cell metabolism to benefit longevity and oppose oncogenesis. Our work provides a platform to study immunology and stem cell biology in an animal model of healthy aging.HIGHLIGHTSFlow cytometry labelling panel to purify viable naked mole-rat HSPCsThe spleen as the major site of erythropoiesis in the naked mole-ratNaked mole-rats show extrathymic T-cell development under homeostatic conditionsNaked mole-rat hematopoietic stem cells (HSCs) have high OXPHOS activity

scholarly journals Age-related changes in the proteostasis network in the brain of the naked mole-rat: Implications promoting healthy longevity

2015 ◽  
Vol 1852 (10) ◽  
pp. 2213-2224 ◽  
Author(s):  
Judy C. Triplett ◽  
Antonella Tramutola ◽  
Aaron Swomley ◽  
Jessime Kirk ◽  
Kelly Grimes ◽  
...  
Keyword(s):  
Healthy Longevity ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
The Brain ◽  
Age Related Changes

scholarly journals Aggresome-Like Formation Promotes Resistance to Proteotoxicity in Cells from Long-Lived Species

2020 ◽  
Vol 75 (8) ◽  
pp. 1439-1447 ◽  
Author(s):  
Bharath Sunchu ◽  
Ruben T Riordan ◽  
Zhen Yu ◽  
Ido Almog ◽  
Jovita Dimas-Munoz ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Protein Aggregates ◽  
Protective Mechanism ◽  
Disease Etiology ◽  
Related Disease ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Rapid Accumulation ◽  
Ubiquitin Proteasome

Abstract The capacity of cells to maintain proteostasis declines with age, causing rapid accumulation of damaged proteins and protein aggregates, which plays an important role in age-related disease etiology. While our group and others have identified that proteostasis is enhanced in long-lived species, there are no data on whether this leads to better resistance to proteotoxicity. We compared the sensitivity of cells from long- (naked mole rat [NMR]) and short- (Mouse) lived species to proteotoxicity, by measuring the survival of fibroblasts under polyglutamine (polyQ) toxicity, a well-established model of protein aggregation. Additionally, to evaluate the contribution of proteostatic mechanisms to proteotoxicity resistance, we down-regulated a key protein of each mechanism (autophagy—ATG5; ubiquitin-proteasome—PSMD14; and chaperones—HSP27) in NMR fibroblasts. Furthermore, we analyzed the formation and subcellular localization of inclusions in long- and short-lived species. Here, we show that fibroblasts from long-lived species are more resistant to proteotoxicity than their short-lived counterparts. Surprisingly, this does not occur because the NMR cells have less polyQ82 protein aggregates, but rather they have an enhanced capacity to handle misfolded proteins and form protective perinuclear and aggresome-like inclusions. All three proteostatic mechanisms contribute to this resistance to polyQ toxicity but autophagy has the greatest effect. Overall, our data suggest that the resistance to proteotoxicity observed in long-lived species is not due to a lower level of protein aggregates but rather to enhanced handling of the protein aggregates through the formation of aggresome-like inclusions, a well-recognized protective mechanism against proteotoxicty.

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 Comparative study of protein aggregation propensity and mutation tolerance between naked mole-rat and mouse

2021 ◽  
Author(s):  
Savandara Besse ◽  
Raphaël Poujol ◽  
Julie G. Hussin
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Therapeutic Interventions ◽  
Model Organisms ◽  
Protein Homeostasis ◽  
Aggregation Propensity ◽  
Age Related ◽  
Mole Rat ◽  
Significant Difference ◽  
Naked Mole Rat

The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. However, long-lived species may provide insights into successful strategies of healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes in comparison to mice. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, and specifically their protein homeostasis. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat involved the inflammasome complex, and in nucleic acid binding. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared to the rest of the proteins. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.

Vascular aging in the longest-living rodent, the naked mole rat

2007 ◽  
Vol 293 (2) ◽  
pp. H919-H927 ◽  
Author(s):  
Anna Csiszar ◽  
Nazar Labinskyy ◽  
Zsuzsanna Orosz ◽  
Zhao Xiangmin ◽  
Rochelle Buffenstein ◽  
...  
Keyword(s):  
Cell Death ◽  
Vascular Function ◽  
Successful Aging ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
No Donor ◽  
Age Related ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Age Range

The naked mole rat (NMR; Heterocephalus glaber) is the longest-living rodent known [maximum lifespan potential (MLSP): >28 yr] and is a unique model of successful aging showing attenuated declines in most physiological function. This study addresses age-related changes in endothelial function and production of reactive oxygen species in NMR arteries and vessels of shorter-living Fischer 344 rats (MLSP: ∼3 yr). Rats exhibit a significant age-dependent decline in acetylcholine-induced responses in carotid arteries over a 2-yr age range. In contrast, over a 10-yr age range nitric oxide (NO)-mediated relaxation responses to acetylcholine and to the NO donor S-nitrosopencillamine (SNAP) were unaltered in NMRs. Cellular superoxide anion (O2•−) and H2O2 production significantly increased with age in rat arteries, whereas they did not change substantially with age in NMR vessels. Indicators of apoptotic cell death (DNA fragmentation rate, caspase 3/7 activity) were significantly enhanced (∼250–300%) in arteries of 2-yr-old rats. In contrast, vessels from 12-yr-old NMRs exhibited only a ∼50% increase in apoptotic cell death. In the hearts of NMRs (2 to 26 yr old), expression of endothelial NO synthase, antioxidant enzymes (Cu,Zn-SOD, Mn-SOD, catalase, and glutathione peroxidase), the NAD(P)H oxidase subunit gp91 phox, and mitochondrial proteins (COX-IV, ATP synthase, and porin, an indicator of mitochondrial mass) did not change significantly with age. Thus long-living NMRs can maintain a youthful vascular function and cellular oxidant-antioxidant phenotype relatively longer and are better protected against aging-induced oxidative stress than shorter-living rats.

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