X-Message-Number: 31068
Date: Sat, 20 Sep 2008 21:42:44 -0700 (PDT)
Subject: Naked mole rats - secret of their longevity I


    [Much has been made of the peroxidation resistant cell membranes of mole 
    rats. However mole rats also show high levels of oxidative damage, and it is
    extremely doubtful that a lack of free radicals has anything to do with 
    their longevity. Indeed, increasing free radical generation in Sod2+/-

mice has been proven NOT to accelerate their aging. I conclude that the free 
radical theory of aging is no longer a viable theory of aging. The only reason 
apparent to me for why the free radical theory of aging is still discussed at 
all, I attribute to an institutional lemming effect. If enough

people say wrong is right, then there will always be followers who agree, and 
similarly jump off the cliff.

    Fortunately there does exist a plausible explanation for mole rat longevity.
    Declines in chaperon mediated autophagy (CMA) are known to underlay aging 
    of mouse tissue, and changes in membrane lipids drive this decline. I have a
    strong suspicion that the different membrane composition of mole rat

cells blocks CMA declines, and that this maintained CMA may partly account for 
mole rat longevity. Russians talk about a process called mitoptosis, which 
forces mutated mitochondria to self destruct, as a possible longevity assurance 
mechanism. As near as I can tell, mitoptosis may be driven
primarily by CMA.

    Aging in mouse tissue has been reversed by NFkappaB blockade. I speculate 
    that this effect may be mediated by restoration of CMA. NFkappaB is known to
    increase with aging in humans. Could some NFkappaB inhibitors significantly
    boost human longevity? If I were a billionare funding radical human

life extension related research, I would direct some funds to further 
investigate safe CMA boosters, safe mitoptosis boosters, and safe NFkappaB 

J Comp Physiol [B]. 2008 May;178(4):439-45. Epub 2008 Jan 8.

Negligible senescence in the longest living rodent, the naked mole-rat: insights
from a successfully aging species.

    Buffenstein R. Department of Physiology and The Sam and Ann Barshop 
    Institute for Longevity and Aging Studies, University of Texas Health 
    Science Center at San Antonio, San Antonio, TX 78245, USA.

    Aging refers to a gradual deterioration in function that, over time, leads 
    to increased mortality risk, and declining fertility. This pervasive process
    occurs in almost all organisms, although some long-lived trees and cold 
    water inhabitants reportedly show insignificant aging. Negligible

senescence is characterized by attenuated age-related change in reproductive and
physiological functions, as well as no observable age-related gradual increase 
in mortality rate. It was questioned whether the longest living rodent, the 
naked mole-rat, met these three strict criteria. Naked mole-rats

live in captivity for more than 28.3 years, approximately 9 times longer than 
similar-sized mice. They maintain body composition from 2 to 24 years, and show 
only slight age-related changes in all physiological and morphological 
characteristics studied to date. Surprisingly breeding females show no

decline in fertility even when well into their third decade of life. Moreover, 
these animals have never been observed to develop any spontaneous neoplasm. As 
such they do not show the typical age-associated acceleration in mortality risk 
that characterizes every other known mammalian species and may

therefore be the first reported mammal showing negligible senescence over the 
majority of their long lifespan. Clearly physiological and biochemical processes
in this species have evolved to dramatically extend healthy lifespan. The 
challenge that lies ahead is to understand what these mechanisms
PMID: 18180931

Nat Med. 2008 Aug 10. [Epub ahead of print] Restoration of chaperone-mediated 
autophagy in aging liver improves cellular maintenance and hepatic function.

    Zhang C, Cuervo AM. Department of Developmental and Molecular Biology and 
    Department of Anatomy and Structural Biology, Marion Bessin Liver Research 
    Center and Institute for Aging Research, 1300 Morris Park Avenue, Albert 
    Einstein College of Medicine, Bronx, New York 10461, USA.

    Chaperone-mediated autophagy (CMA), a selective mechanism for degradation of
    cytosolic proteins in lysosomes, contributes to the removal of altered 
    proteins as part of the cellular quality-control systems. We have previously
    found that CMA activity declines in aged organisms and have proposed

that this failure in cellular clearance could contribute to the accumulation of 
altered proteins, the abnormal cellular homeostasis and, eventually, the 
functional loss characteristic of aged organisms. To determine whether these 
negative features of aging can be prevented by maintaining efficient

autophagic activity until late in life, in this work we have corrected the CMA 
defect in aged rodents. We have generated a double transgenic mouse model in 
which the amount of the lysosomal receptor for CMA, previously shown to decrease
in abundance with age, can be modulated. We have analyzed in

this model the consequences of preventing the age-dependent decrease in receptor
abundance in aged rodents at the cellular and organ levels. We show here that 
CMA activity is maintained until advanced ages if the decrease in the receptor 
abundance is prevented and that preservation of autophagic

activity is associated with lower intracellular accumulation of damaged 
proteins, better ability to handle protein damage and improved organ function.
PMID: 18690243

Autophagy. 2007 Jul-Aug;3(4):387-9. Epub 2007 Jul 9.
Comment on:
    EMBO J. 2006 Sep 6;25(17):3921-33.
    J Cell Sci. 2007 Mar 1;120(Pt 5):782-91.

Chaperone-mediated autophagy and aging: a novel regulatory role of lipids 

    Kaushik S, Kiffin R, Cuervo AM. Department of Anatomy and Structural 
    Biology, Marion Bessin Liver ResearchCenter, Institute for Aging Research, 
    Albert Einstein College of Medicine, Bronx, New York 10461, USA.

    A wide pool of cytosolic proteins is selectively degraded in lysosomes by 
    chaperonemediated autophagy (CMA). Binding of these proteins to a receptor 
    at the lysosomal membrane is the limiting step in CMA. Levels of this 
    receptor are tightly regulated through changes in its degradation, 

organization and dynamic distribution between the lysosomal membrane and lumen. 
We have now reported that subcompartmentalization of the receptor in discrete 
lipid microdomains at the lysosomal membrane regulates its engagement in each of
these processes-degradation, multimerization and membrane

retrieval. Changes in the lipid composition of the membrane thus affect the 
dynamics of the receptor and, consequently, CMA activity. As an example of CMA 
dysfunction resulting from perturbation of the lipid composition of the 
lysosomal membrane, we discuss here a second study in which we analyzed

the changes in the dynamics of the receptor during aging. CMA activity decreases
with age primarily due to a decrease in the levels of the CMA receptor at the 
lysosomal membrane. Now we have found that age-related alterations in the lipid 
composition of the discrete microdomains at the lysosomal

membrane are behind the reduced lysosomal levels of the receptor and, 
consequently, the declined CMA activity that occurs during aging.
PMID: 17438364

Cell Cycle. 2008 Mar;7(5):556-9. Epub 2007 Dec 26.
Reversal of aging by NFkappaB blockade.

    Adler AS, Kawahara TL, Segal E, Chang HY. Program in Epithelial Biology and 
    Cancer Biology Program, Stanford University School of Medicine, Stanford, 
    California 94305, USA.

    Genetic studies in model organisms such as yeast, worms, flies, and mice 
    leading to lifespan extension suggest that longevity is subject to 
    regulation. In addition, various system-wide interventions in old animals 
    can reverse features of aging. To better understand these processes, much 

has been put into the study of aging on a molecular level. In particular, 
genome-wide microarray analysis of differently aged individual organisms or 
tissues has been used to track the global expression changes that occur during 
normal aging. Although these studies consistently implicate specific

pathways in aging processes, there is little conservation between the individual
genes that change. To circumvent this problem, we have recently developed a 
novel computational approach to discover transcription factors that may be 
responsible for driving global expression changes with age. We

identified the transcription factor NFkappaB as a candidate activator of 
aging-related transcriptional changes in multiple human and mouse tissues. 
Genetic blockade of NFkappaB in the skin of chronologically aged mice reversed 
the global gene expression program and tissue characteristics to those of

young mice, demonstrating for the first time that disruption of a single gene is
sufficient to reverse features of aging, at least for the short-term.
PMID: 18256548

Aging Cell. 2008 Sep 8. [Epub ahead of print] Aging is Associated with Greater 
Nuclear NFkappaB, Reduced IkappaBalpha and Increased Expression of 
Proinflammatory Cytokines in Vascular Endothelial Cells of Healthy Humans.

    Donato AJ, Black AD, Jablonski KL, Gano LB, Seals DR. Department of 
    Integrative Physiology University of Colorado Boulder, Colorado, 80309, USA.
    The vascular endothelium may develop a pro-inflammatory profile with aging, 
    but evidence is limited in humans. Expression of inflammatory proteins was 
    determined in vascular endothelial cells (EC) obtained from peripheral veins
    of 24 young (23+/-1 years, mean+/-SE) and 36 older (63+/-1) healthy

men and women using quantitative immunofluorescence. The older subjects had 
lower vascular endothelium-dependent dilation (forearm blood flow responses to 
acetylcholine, P<0.05), and higher plasma concentrations of C-reactive protein, 
interleukin-6 (IL-6) and oxidized low-density lipoprotein (all

P<0.05), but not tumor necrosis factor-alpha (TNF-alpha). Total (O: 0.52+/-0.04 
vs Y: 0.33+/-0.05 NFkappaB /HUVEC intensity P<0.05) and nuclear (O: 0.59+/-0.04 
vs Y: 0.41+/-0.04) expression of nuclear factor kappa B p65 (NFkappaB), a 
proinflammatory gene transcription factor, was greater in EC from

the older subjects (P<0.05). EC expression of the inhibitor (of nuclear 
translocation) of NFkappaB (IkappaBalpha) was lower in the older subjects (O: 
0.16+/-0.02 vs Y: 0.24+/-0.03; P<0.05), whereas IkappaB kinase was not 
different. EC expression of the proinflammatory proteins IL-6 (O: 0.42+/-0.06

vs Y: 0.29+/-0.03, P<0.05), TNF-alpha (O: 0.52+/-0.06 vs Y: 0.33+/-0.05, P<0.05)
and monocyte chemoattractant protein 1 (MCP-1) (O: 0.59+/-0.06 vs Y: 
0.38+/-0.02, P<0.05) was greater in the older subjects, whereas cyclooxygenase 2
and the receptor for advanced glycation endproducts did not differ.

These findings indicate that impaired function with aging in healthy adults is 
associated with the development of a proinflammatory phenotype in the vascular 
endothelium that could be caused in part by reduced IkappaB-mediated activation 
of NFkappaB.
PMID: 18782346

[Free radicals do not accelerate aging in mice.]

Physiol Genomics. 2003 Dec 16;16(1):29-37.

Life-long reduction in MnSOD activity results in increased DNA damage and higher
incidence of cancer but does not accelerate aging.

    Van Remmen H, Ikeno Y, Hamilton M, Pahlavani M, Wolf N, Thorpe SR, Alderson 
    NL, Baynes JW, Epstein CJ, Huang TT, Nelson J, Strong R, Richardson A. 
    Department of Cellular and Structural Biology at the University of Texas 
    Health Science Center at San Antonio, San Antonio 78229-3900, USA.

    Mice heterozygous for the Sod2 gene (Sod2+/- mice) have been used to study 
    the phenotype of life-long reduced Mn-superoxide dismutase (MnSOD) activity.
    The Sod2+/- mice have reduced MnSOD activity (50%) in all tissues 
    throughout life. The Sod2+/- mice have increased oxidative damage as

demonstrated by significantly elevated levels of 8-oxo-2-deoxyguanosine (8oxodG)
in nuclear DNA in all tissues of Sod2+/- mice studied. The levels of 8oxodG in 
nuclear DNA increased with age in all tissues of Sod2+/- and wild-type (WT) 
mice, and at 26 mo of age, the levels of 8oxodG in nuclear DNA

were significantly higher (from 15% in heart to over 60% in liver) in the 
Sod2+/- mice compared with WT mice. The level of 8oxodG was also higher in 
mitochondrial DNA isolated from liver and brain in Sod2+/- mice compared with WT
mice. The increased oxidative damage to DNA in the Sod2+/- mice is

associated with a 100% increase in tumor incidence (the number of mice with 
tumors) in old Sod2+/- mice compared with the old WT mice. However, the life 
spans (mean and maximum survival) of the Sod2+/- and WT mice were identical. In 
addition, biomarkers of aging, such as cataract formation, immune

response, and formation of glycoxidation products carboxymethyl lysine and 
pentosidine in skin collagen changed with age to the same extent in both WT and 
Sod2+/- mice. Thus life-long reduction of MnSOD activity leads to increased 
levels of oxidative damage to DNA and increased cancer incidence but
does not appear to affect aging.
PMID: 14679299

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