X-Message-Number: 31069
Date: Sat, 20 Sep 2008 21:44:24 -0700 (PDT)
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Subject: Naked mole rats - secret of their longevity II

J Gerontol A Biol Sci Med Sci. 2008 Mar;63(3):232-41.

Fibroblasts from naked mole-rats are resistant to multiple forms of cell injury,
but sensitive to peroxide, ultraviolet light, and endoplasmic reticulum stress.

    Salmon AB, Sadighi Akha AA, Buffenstein R, Miller RA. Cellular and Molecular
    Biology Graduate Program, University of Michigan, Ann Arbor, MI, USA.

    Fibroblasts from long-lived mutant mice are resistant to many forms of 
    lethal injury as well as to the metabolic effects of rotenone and 
    low-glucose medium. Here we evaluated fibroblasts from young adult naked 
    mole-rats (NMR; Heterocephalus glaber), a rodent species in which maximal 
    longevity

exceeds 28 years. Compared to mouse cells, NMR cells were resistant to cadmium, 
methyl methanesulfonate, paraquat, heat, and low-glucose medium, consistent with
the idea that cellular resistance to stress may contribute to disease 
resistance and longevity. Surprisingly, NMR cells were more sensitive

than mouse cells to H(2)O(2), ultraviolet (UV) light, and rotenone. NMR cells, 
like cells from Snell dwarf mice, were more sensitive to tunicamycin and 
thapsigargin, which interfere with the function of the endoplasmic reticulum (ER
stress). The sensitivity of both Snell dwarf and NMR cells to ER

stress suggests that alterations in the unfolded protein response might modulate
cell survival and aging rate.
PMID: 18375872

Rejuvenation Res. 2007 Dec;10(4):543-60.

Theoretical paper: exploring overlooked natural mitochondria-rejuvenative 
intervention: the puzzle of bowhead whales and naked mole rats.

    Prokopov AF. Physician for Integrative Medicine, Heugasse 2, Heidelberg, 
    Germany.

    There is an imperative need for exploring and implementing 
    mitochondria-rejuvenative interventions that can bridge the current gap 
    toward the step-by step realization of strategies for engineered negligible 
    senescence (SENS) agenda. Recently discovered in mammals, natural mechanism 
    mitoptosis-a

selective "suicide" of mutated mitochondria-can facilitate continuous 
purification of mitochondrial pool in an organism from the most reactive oxygen 
species (ROS)-producing mitochondria. Mitoptosis, which is considered to be the 
first stage of ROS-induced apoptosis, underlies follicular atresia (a

"quality control" mechanism in female germline cells that eliminates most 
germinal follicles in female embryos). Mitoptosis can be also activated in adult
postmitotic somatic cells by evolutionary conserved phenotypic adaptations to 
intermittent oxygen restriction (IOR) and synergistically acting

intermittent caloric restriction (ICR). IOR and ICR are common in mammals and 
seem to underlie extraordinary longevity and augmented cancer resistance in 
bowhead whales (Balena mysticetus) and naked mole rats (Heterocephalus glaber). 
Furthermore, in mammals IOR can facilitate continuous stromal stem

cells-de-pendent tissue repair. A comparative analysis of IOR and ICR mechanisms
in both mammals, in conjunction with the experience of decades of biomedical 
and clinical research on emerging preventative, therapeutic, and rehabilitative 
modality-the intermittent hypoxic training/therapy

(IHT)-indicates that the notable clinical efficiency of IHT is based on the 
universal adaptational mechanisms that are common in mammals. Further 
exploration of natural mitochondria-preserving and -rejuvenating strategies can 
help refinement of IOR- and ICR-based synergistic protocols, having value
in clinical human rejuvenation.
PMID: 18072884

Biochim Biophys Acta. 2008 Jul-Aug;1777(7-8):817-25. Epub 2008 Apr 8.

Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis): 
formation of mitoptotic bodies and extrusion of mitochondrial material from the 
cell.

    Lyamzaev KG, Nepryakhina OK, Saprunova VB, Bakeeva LE, Pletjushkina OY, 
    Chernyak BV, Skulachev VP. A.N. Belozersky Institute of Physico-Chemical 
    Biology, Moscow State University Moscow 119992, Russia.

    Energy catastrophe, when mitochondria hydrolyze glycolytic ATP instead of 
    producing respiratory ATP, has been modeled. In highly glycolyzing HeLa 
    cells, 30-50% of the population survived after inhibition of respiration and
    uncoupling of oxidative phosphorylation for 2-4 days. The survival was

accompanied by selective elimination of mitochondria. This type of mitoptosis 
includes (i) fission of mitochondrial filaments, (ii) clustering of the 
resulting roundish mitochondria in the perinuclear area, (iii) occlusion of 
mitochondrial clusters by a membrane (formation of a "mitoptotic body"),

(iv) decomposition of mitochondria inside this body to small membrane vesicles, 
(v) protrusion of the body from the cell, and (vi) disruption of the body 
boundary membrane. Autophagy was not involved in this mitoptotic program. 
Increased production of reactive oxygen species (ROS) was necessary for

execution of the program, since antioxidants prevent mitoptosis and kill the 
cells treated with the mitochondrial poisons as if a ROS-linked mitoptosis 
serves for protection of the cells under conditions of severe mitochondrial 
stress. It is suggested that exocytosis of mitoptotic bodies may be
involved in maturation of reticulocytes and lens fiber cells.
PMID: 18433711

Exp Gerontol. 2007 Nov;42(11):1053-62.

Membrane phospholipid composition may contribute to exceptional longevity of the
naked mole-rat (Heterocephalus glaber): a comparative study using shotgun 
lipidomics.

    Mitchell TW, Buffenstein R, Hulbert AJ. Metabolic Research Centre, 
    University of Wollongong, NSW, Australia.

    Phospholipids containing highly polyunsaturated fatty acids are particularly
    prone to peroxidation and membrane composition may therefore influence 
    longevity. Phospholipid molecules, in particular those containing 
    docosahexaenoic acid (DHA), from the skeletal muscle, heart, liver and liver
    
mitochondria were identified and quantified using mass-spectrometry shotgun 
lipidomics in two similar-sized rodents that show an approximately 9-fold 
difference in maximum lifespan. The naked mole rat is the longest-living rodent 
known with a maximum lifespan of >28 years. Total phospholipid

distribution is similar in tissues of both species; DHA is only found in 
phosphatidylcholines (PC), phosphatidylethanolamines (PE) and 
phosphatidylserines (PS), and DHA is relatively more concentrated in PE than PC.
Naked mole-rats have fewer molecular species of both PC and PE than do mice.

DHA-containing phospholipids represent 27-57% of all phospholipids in mice but 
only 2-6% in naked mole-rats. Furthermore, while mice have small amounts of 
di-polyunsaturated PC and PE, these are lacking in naked mole-rats. Vinyl 
ether-linked phospholipids (plasmalogens) are higher in naked mole-rat

tissues than in mice. The lower level of DHA-containing phospholipids suggests a
lower susceptibility to peroxidative damage in membranes of naked mole-rats 
compared to mice. Whereas the high level of plasmalogens might enhance membrane 
antioxidant protection in naked mole-rats compared to mice.

Both characteristics possibly contribute to the exceptional longevity of naked 
mole-rats and may indicate a special role for peroxisomes in this extended 
longevity.
PMID: 18029129

Am J Physiol Heart Circ Physiol. 2007 Aug;293(2):H919-27. Epub 2007 Apr 27.
Vascular aging in the longest-living rodent, the naked mole rat.

    Csiszar A, Labinskyy N, Orosz Z, Xiangmin Z, Buffenstein R, Ungvari Z. 
    Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.
    
    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: approximately 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 (O(2)(*-)) and H(2)O(2) 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 ( approximately 250-300%) in 
arteries of 2-yr-old rats. In contrast, vessels from 12-yr-old NMRs exhibited 
only a approximately 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.
PMID: 17468332


[The free radical theory of aging is refuted in the case of mole rat longevity.]

Aging Cell. 2006 Dec;5(6):525-32.

Disparate patterns of age-related changes in lipid peroxidation in long-lived 
naked mole-rats and shorter-lived mice.

    Andziak B, Buffenstein R. Department of Biology, The City College of the 
    City University of New York, New York, NY 10031, USA.

    A key tenet of the oxidative stress theory of aging is that levels of 
    accrued oxidative damage increase with age. Differences in damage generation
    and accumulation therefore may underlie the natural variation in species 
    longevity. We compared age-related profiles of whole-organism lipid

peroxidation (urinary isoprostanes) and liver lipid damage (malondialdehyde) in 
long living naked mole-rats [maximum lifespan (MLS) > 28.3 years] and 
shorter-living CB6F1 hybrid mice (MLS approximately 3.5 years). In addition, we 
compared age-associated changes in liver non-heme iron to assess how

intracellular conditions, which may modulate oxidative processes, are affected 
by aging. Surprisingly, even at a young age, concentrations of both markers of 
lipid peroxidation, as well as of iron, were at least twofold (P < 0.005) 
greater in naked mole tats than in mice. This refutes the hypothesis

that prolonged naked mole-rat longevity is due to superior protection against 
oxidative stress. The age-related profiles of all three parameters were 
distinctly species specific. Rates of lipid damage generation in mice were 
maintained throughout adulthood, while accrued damage in old animals was

twice that of young mice. In naked mole-rats, urinary isoprostane excretion 
declined by half with age (P < 0.001), despite increases in tissue iron (P < 
0.05). Contrary to the predictions of the oxidative stress theory, lipid damage 
levels did not change with age in mole-rats. These data suggest

that the patterns of age-related changes in levels of markers of oxidative 
stress are species specific, and that the pronounced longevity of naked 
mole-rats is independent of oxidative stress parameters.
PMID: 17129214

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