X-Message-Number: 31068
Date: Sat, 20 Sep 2008 21:42:44 -0700 (PDT)
From:
Subject: Naked mole rats - secret of their longevity I
**Speculation**
[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
inhibitors.]
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
are.
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
revealed.
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,
multimeric
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
effort
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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